Medicine, Faculty of
Population and Public Health (SPPH), School of
DSpace
UBCV
Nisingizwe, Marie Paul
Doctor of Philosophy - PhD
University of British Columbia
Hepatitis C virus (HCV) affects 58 million people globally and resulted in 290,000 deaths in 2019. While global targets aim to eliminate HCV by 2030, there remains limited knowledge regarding the accessibility and impact of HCV treatment, particularly in resource-limited settings. This dissertation assessed access to HCV testing and treatment in Rwanda and investigated inequities in global access to HCV medicines. I conducted a retrospective cohort study and hierarchical logistic regression to assess factors associated with HCV positivity, treatment dropout, and treatment failure among people who received HCV services during the 2017-19 mass campaign. In addition, I used qualitative methods to investigate patients' perspectives on accessing HCV care during the campaign. Lastly, I used data from 54 countries to describe sales of HCV medicines and conducted an Interrupted Time Series (ITS) analysis to assess the effect of COVID-19 on sales using Autoregressive Integrated Moving Average Model (ARIMA). Among people who attended the campaign, the prevalence of HCV was 2.9%, and 52% of those who tested positive initiated treatment. Sustained Virological Response (SVR) was achieved in 88% of individuals who initiated treatment and returned for assessment. Age, socioeconomic status, and comorbidities were associated with higher HCV positivity and dropout rates. Treatment failure was associated with advanced stage of HCV, and a prior history of HCV. My qualitative study found that patients experienced unavailability of second-line treatment and delays in testing results and treatment initiation. Lastly, globally I found that high-income countries had much higher sales of Direct Acting Antivirals (DAAs) and higher use of newer generations of DAAs. The COVID-19 pandemic led to a decrease of DAA sales of 85% of the countries I studied. This dissertation suggests that future HCV treatment interventions in Rwanda should focus on older individuals and people with comorbidities. In addition, improvements should be sought in the follow-up and timeliness of screening and treatment. Internationally, future policy should prioritize improving access to DAAs in countries with limited resources through pricing policies and licensing agreements. Lastly, elimination strategies may need to be revised given current inequities in access to DAAs and the impact of the COVID-19 pandemic.
INVESTIGATING ACCESS TO HEPATITIS C TESTING AND TREATMENT IN RWANDA AND BEYOND by Marie Paul Nisingizwe MSc., Jomo Kenyatta University of Agriculture and Technology, 2016 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Population and Public Health) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) October 2023 © Marie Paul Nisingizwe, 2023 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Investigating Access to Hepatitis C Testing and Treatment in Rwanda and Beyond submitted by Marie Paul Nisingizwe in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Population and Public Health Examining Committee: Michael R. Law, Professor, Population and Public Health, UBC Supervisor Nick Bansback, Associate Professor, Population and Public Health, UBC Supervisory Committee Member Naveed Z. Janjua, Professor, Population and Public Health, UBC Supervisory Committee Member Jerry Spiegel, Professor, Population and Public Health, UBC University Examiner Mary de Vera, Associate Professor, Pharmaceutical Sciences, UBC University Examiner Additional Supervisory Committee Members: Bethany Hedt-Gauthier, Associate Professor, Global Health and Social Medicine, Harvard Medical School Supervisory Committee Member iii Abstract Hepatitis C virus (HCV) affects 58 million people globally and resulted in 290,000 deaths in 2019. While global targets aim to eliminate HCV by 2030, there remains limited knowledge regarding the accessibility and impact of HCV treatment, particularly in resource-limited settings. This dissertation assessed access to HCV testing and treatment in Rwanda and investigated inequities in global access to HCV medicines. I conducted a retrospective cohort study and hierarchical logistic regression to assess factors associated with HCV positivity, treatment dropout, and treatment failure among people who received HCV services during the 2017-19 mass campaign. In addition, I used qualitative methods to investigate patients' perspectives on accessing HCV care during the campaign. Lastly, I used data from 54 countries to describe sales of HCV medicines and conducted an Interrupted Time Series (ITS) analysis to assess the effect of COVID-19 on sales using Autoregressive Integrated Moving Average Model (ARIMA). Among people who attended the campaign, the prevalence of HCV was 2.9%, and 52% of those who tested positive initiated treatment. Sustained Virological Response (SVR) was achieved in 88% of individuals who initiated treatment and returned for assessment. Age, socioeconomic status, and comorbidities were associated with higher HCV positivity and dropout rates. Treatment failure was associated with advanced stage of HCV, and a prior history of HCV. My qualitative study found that patients experienced unavailability of second-line treatment and delays in testing results and treatment initiation. Lastly, globally I found that high-income countries had much iv higher sales of Direct Acting Antivirals (DAAs) and higher use of newer generations of DAAs. The COVID-19 pandemic led to a decrease of DAA sales of 85% of the countries I studied. This dissertation suggests that future HCV treatment interventions in Rwanda should focus on older individuals and people with comorbidities. In addition, improvements should be sought in the follow-up and timeliness of screening and treatment. Internationally, future policy should prioritize improving access to DAAs in countries with limited resources through pricing policies and licensing agreements. Lastly, elimination strategies may need to be revised given current inequities in access to DAAs and the impact of the COVID-19 pandemic. v Lay Summary Early access to HCV testing and treatment is crucial for therapeutic success. However, very little is known about how people access HCV services and medicines, especially in resource-limited settings. This dissertation investigated access to HCV testing and treatment in Rwanda and internationally. We used patient-level quantitative and qualitative interview data to examine whether patients were successfully diagnosed, treated, and cured in Rwanda during the mass campaign. We also used administrative data to assess global inequities in access to HCV medicines and the impact of COVID-19 on HCV medicines sales globally. We found that only 52% of HCV patients initiated treatment, and HCV was cured 88% of the time. Patients experienced testing and treatment delays and the unavailability of HCV second-line drugs. Globally, HCV drug sales were higher in high-income countries than other income groups, and COVID-19 decreased HCV medicines sales in 85% of study countries and regions. vi Preface This dissertation includes three original research studies conducted at the Center for Health Services and Policy Research at the University of British Columbia (UBC). I was the lead investigator for all the chapters and completed them in consultation with my primary supervisor and thesis committee. I led the identification of research questions, developed the study designs, conducted data analyses, and led the authorship of the chapters. I also prepared all study documents, including ethics approvals and data access requests. Michael Law was my primary supervisor for this dissertation, and he provided direct mentorship and technical support throughout all phases of the work. My thesis committee, including Nick Bansback, Bethany Hedt-Gauthier, and Naveed Janjua, provided feedback on the study design, analysis, and manuscripts. Given the contribution of my thesis committee and other co-authors, I have used “We” instead of “I” in the manuscripts of the three studies (Chapters 2, 3, and 4). Study I (Chapter 2) includes data extracted from patient medical charts. I led the data extraction process and worked with a team of data collectors who supported data extraction activities at different hospitals in Rwanda. Study II (Chapter 3) includes primary qualitative interviews conducted by the Rwanda Biomedical Center (RBC). I received de-identified recorded interviews and field notes for analysis. The qualitative analysis involved an independent review of the transcripts and coding by me and Dr. Germaine Tuyisenge. Chapters 2 and 3 focused on HCV services during the Rwanda mass screening and treatment campaign. These studies were approved by UBC Behavioral Research Ethics Board with certificate numbers H19-02224 and H21-03745. Study III (Chapter 4) did not involve human vii subjects and was granted ethics approval by the institutional review board at the University of Pittsburgh (certificate number STUDY21060160). A version of Chapter 2 was published in the journal Viruses [Nisingizwe MP, Makuza JD, Janjua NZ, Bansback N, Hedt-Gauthier B, Serumondo J, Remera E, Law MR. The Cascade of Care for Hepatitis C Treatment in Rwanda: A Retrospective Cohort Study of the 2017-2019 Mass Screening and Treatment Campaign. Viruses. 2023 Feb 28;15(3):661. doi: 10.3390/v15030661]. I was the lead author of this manuscript and received comments on the manuscript draft from my primary supervisor (Law MR), my thesis committee (Bansback N, Hedt-Gauthier B, Janjua NZ), and collaborators at RBC (Makuza JD, Serumondo J and Remera E). viii Table of Contents Abstract ......................................................................................................................................... iii Lay Summary .................................................................................................................................v Preface ........................................................................................................................................... vi Table of Contents ....................................................................................................................... viii List of Tables .............................................................................................................................. xiv List of Figures ...............................................................................................................................xv List of Abbreviations ................................................................................................................. xvi Acknowledgements .................................................................................................................. xviii Dedication ................................................................................................................................... xix Chapter 1: Introduction ............................................................................................................... 1 1.1 Overview ..................................................................................................................... 1 1.2 Hepatitis C Definition and Transmission .................................................................... 1 1.3 Hepatitis C Natural History ........................................................................................ 2 1.4 HCV Epidemiology .................................................................................................... 4 1.5 HCV Global Genotypes Distribution .......................................................................... 6 1.6 HCV Diagnosis ........................................................................................................... 7 1.6.1 HCV Antibody Screening ............................................................................... 7 1.6.2 HCV Ribonucleic Acid (RNA) Testing (Confirmatory Test) ......................... 8 1.6.3 HCV Simplified Diagnostic Tests .................................................................. 9 1.6.4 HCV Screening and Testing Gaps ................................................................ 10 1.7 HCV Treatment ......................................................................................................... 11 1.7.1 Evolution of HCV Treatment ........................................................................ 11 ix 1.7.2 Direct Acting-Antivirals ............................................................................... 11 1.7.2.1 First Generation of DAAs ............................................................................. 12 1.7.2.2 Second Generation of DAAs ........................................................................ 12 1.7.2.3 Newer Generation of DAAs .......................................................................... 13 1.7.3 Sustained Virologic Response ...................................................................... 15 1.8 Global Access to DAAs ............................................................................................ 17 1.9 HCV Elimination ...................................................................................................... 20 1.9.1 Global Elimination ........................................................................................ 20 1.9.2 Elimination in LMICs ................................................................................... 21 1.10 HCV Cascade of Care ............................................................................................... 22 1.11 Rwanda Health System, HCV Burden, and Elimination Plan .................................. 25 1.11.1 Rwanda Demographics and Geography ........................................................ 25 1.11.2 Overview of the Health System in Rwanda .................................................. 26 1.11.3 HCV Care in Rwanda ................................................................................... 27 1.11.4 HCV Mass Screening and Treatment in Rwanda ......................................... 28 1.11.5 Cascade of Care in the Rwanda Mass Campaign ......................................... 29 1.12 HCV Epidemiology and Evidence in Rwanda .......................................................... 33 1.13 Dissertation Rationale ............................................................................................... 34 1.13.1 Justification of Study I – HCV Cascade of Care in Rwanda ........................ 35 1.13.2 Justification of Study II – Patients’ Healthcare-seeking and Treatment Experience during the HCV Mass Screening and Treatment Campaign in Rwanda ....... 36 1.13.3 Justification of Study III – Global Disparities in Access to DAAs .............. 37 1.14 Dissertation Objectives ............................................................................................. 38 x 1.15 Overview and Conceptual Framework ..................................................................... 39 Chapter 2: The Cascade of Care for Hepatitis C Treatment in Rwanda: A Retrospective Cohort Study of the 2017–2019 Mass Screening and Treatment Campaign ........................ 44 2.1 Synopsis .................................................................................................................... 44 2.2 Background ............................................................................................................... 46 2.3 Methods..................................................................................................................... 48 2.3.1 Study Context ............................................................................................... 48 2.3.2 Study Design ................................................................................................. 49 2.3.3 Study Sites and Population ........................................................................... 49 2.3.4 Data Sources ................................................................................................. 49 2.3.5 Cascade of Care ............................................................................................ 50 2.3.6 Outcome Variables ........................................................................................ 50 2.3.7 Other Variables ............................................................................................. 51 2.3.8 Data Analysis ................................................................................................ 52 2.3.9 Informed Consent and Ethics ........................................................................ 53 2.4 Results ....................................................................................................................... 53 2.4.1 Descriptive Characteristics ........................................................................... 53 2.4.2 Cascade of Care ............................................................................................ 55 2.4.2.1 Anti-HCV Seroprevalence ............................................................................ 56 2.4.2.2 HCV RNA Testing ........................................................................................ 57 2.4.2.3 Dropout at HCV RNA .................................................................................. 59 2.4.2.4 Treatment Success (Achieving SVR) ........................................................... 60 2.4.2.5 Dropout at Final SVR Test ........................................................................... 62 2.5 Discussion ................................................................................................................. 63 xi 2.5.1 Limitations .................................................................................................... 66 2.6 Conclusion ................................................................................................................ 67 Chapter 3: Patients’ Healthcare-seeking and Treatment Experience during the Mass Screening and Treatment of Hepatitis C Virus in Rwanda .................................................... 68 3.1 Synopsis .................................................................................................................... 68 3.2 Background ............................................................................................................... 70 3.3 Methods..................................................................................................................... 72 3.3.1 Study Design ................................................................................................. 72 3.3.2 Study Site and Settings ................................................................................. 72 3.3.3 Participant Recruitment ................................................................................ 73 3.3.4 Data Collection and Management ................................................................. 74 3.3.5 Data Analysis ................................................................................................ 75 3.3.6 Ethics and Informed Consent ........................................................................ 76 3.4 Results ....................................................................................................................... 76 3.4.1 Response to Community-level HCV Screening ........................................... 78 3.4.2 Circumstances and Perceptions Related to Confirmatory Testing ............... 82 3.4.3 Experience of Linkage to Care and Treatment ............................................. 84 3.5 Discussion ................................................................................................................. 90 3.5.1 Strengths and Limitations ............................................................................. 94 3.6 Conclusion ................................................................................................................ 95 Chapter 4: Assessing Global Disparities in Access to Hepatitis C Medicines before and during the First Phase of the COVID-19 Pandemic ................................................................ 96 4.1 Synopsis .................................................................................................................... 96 4.2 Background ............................................................................................................... 98 4.3 Methods..................................................................................................................... 99 xii 4.3.1 Study Design and Period ............................................................................... 99 4.3.2 Data Sources and Study Sites ..................................................................... 100 4.3.3 Outcome ...................................................................................................... 101 4.3.4 Data Analysis .............................................................................................. 101 4.4 Results ..................................................................................................................... 102 4.4.1 Descriptive Statistics and DAA Trends by Income Group and Geographic Location….. .................................................................................................................... 102 4.4.2 Trends in Use of Specific DAAs ................................................................ 104 4.4.3 Effect of COVID-19 on Monthly DAA Sales ............................................. 107 4.5 Discussion ............................................................................................................... 112 4.5.1 Limitations .................................................................................................. 115 4.6 Conclusion .................................................................................................................... 116 Chapter 5: Conclusion .............................................................................................................. 117 5.1 Summary of Chapters and Overview ...................................................................... 117 5.2 Key Findings and Contributions ............................................................................. 117 5.3 Policy Implications and Recommendations ............................................................ 121 5.3.1 Simplification of HCV Screening, Treatment, and Service Delivery ......... 122 5.3.2 Implementing Prevention Strategies ........................................................... 122 5.3.3 Integration of HCV Services into the Health System ................................. 122 5.3.4 Promote Stakeholder Partnerships to Improving Access to DAAs ............ 123 5.4 Strengths and Limitations ....................................................................................... 125 5.4.1 Secondary Data ........................................................................................... 126 5.4.2 Data from Voluntary Mass Screening and Aggregated Data ...................... 127 5.4.3 Qualitative Study Limitations ..................................................................... 128 xiii 5.5 Future Research ...................................................................................................... 128 5.6 Conclusion .............................................................................................................. 130 References ...................................................................................................................................131 Appendices ..................................................................................................................................151 Appendix A Study I Patients’ Characteristics per Treatment Outcome ......................... 151 Appendix B Summary Table of Qualitative Study Findings ............................................ 153 Appendix C Qualitative Study Data Collection Materials ................................................ 155 C.1 Information Sheet for Qualitative Interviews ............................................................. 155 C.2 Consent Form .............................................................................................................. 156 C.3 Data Collection Questionnaire for Qualitative Interviews .......................................... 160 Appendix D Percentage Change in DAAs Unit Sales per 100,000 HCV Cases per Country Comparing March-August 2020 vs Same Period in 2019 .................................. 165 Appendix E List of Countries per World Bank Country Classifications by Income Level and Geographic Location ..................................................................................................... 166 xiv List of Tables Table 1.1: Rwanda 2024 HCV Elimination Targets ..................................................................... 29 Table 2.1: Stages in the HCV Cascade of Care ............................................................................ 51 Table 2.2: Characteristics of Patients Screened and Treated during the Mass Screening Campaign for Hepatitis C Virus in Rwanda (2017–2019) ............................................................................. 54 Table 2.3: Unadjusted and Adjusted Associations between Anti-HCV Seroprevalence and Socio-economic, Demographic, Clinical, and Behavior Factors ............................................................ 57 Table 2.4: Unadjusted and Adjusted Associations between HCV RNA Positivity and Socio-economic, Demographic, Clinical, Behavioral, and Hospital Characteristics Factors ................. 58 Table 2.5: Unadjusted and Adjusted Associations between Dropout at HCV RNA Testing Stage and Socio-economic, Demographic, Clinical, Behavioral, and Hospital Characteristics Factors......................................................................................................................................................... 60 Table 2.6: Adjusted and Unadjusted Relationships between Treatment Failure, Dropout at SVR Assessment Stage, and Socio-economic, Demographic, Clinical, Behavioral, and Hospital Characteristics Factors .................................................................................................................. 61 Table 3.1: Study Participants Characteristics ............................................................................... 77 Table 4.1: Pre-post Comparison of DAA Units Sold per 100,000 HCV Prevalent Cases per Income Group and Geographical Location ................................................................................. 110 Table 4.2: ARIMA Model Findings on the Effect of COVID-19 on Monthly DAA Unit sales per 100,000 HCV Cases .................................................................................................................... 111 xv List of Figures Figure 1.1: Natural History of Hepatitis C Virus ............................................................................ 3 Figure 1.2: Global HCV Distribution in 2015 and 2022 ................................................................ 5 Figure 1.3: Global HCV Treatment Cascade ................................................................................ 24 Figure 1.4: HCV Treatment Cascade in Africa ............................................................................ 24 Figure 1.5: Mass Screening and Testing Process ........................................................................... 32 Figure 1.6: Conceptual Framework for Outcomes Research Studies of Hepatitis C .................... 40 Figure 1.7: Andersen Conceptual Framework for Healthcare Services Utilization ..................... 41 Figure 1.8: Access to Medicine Conceptual Framework from a Health System Perspective ...... 43 Figure 2.1: HCV Cascade of Care in Rwanda for the 2017–2019 Mass Screening and Treatment Campaign Cohort .......................................................................................................................... 56 Figure 4.1: Monthly DAA Unit Sales per 100,000 HCV Prevalent Cases per Country Income Group and Geographic Location ................................................................................................. 103 Figure 4.2: Monthly DAA Unit Sales per 100,000 HCV Prevalent Cases in Latin America, Middle East and Africa, and Countries with High HCV Prevalence .......................................... 104 Figure 4.3: Monthly DAA Unit Sales per 100,000 HCV Prevalent Cases per Drug Type per Country Income Group ............................................................................................................... 106 Figure 4.4: Monthly DAA Unit Sales per 100,000 HCV Prevalent Cases per Drug Type in Countries with Highest HCV Prevalence ................................................................................... 107 Figure 4.5: Percentage Change in DAA Unit Sales per 100,000 HCV Cases per Country in March-August 2020 Compared with Same Period in 2019 ........................................................ 108 Figure 4.6: DAA Units Sold per 100,000 HCV Prevalent Cases per in March-August 2020 vs with Same Period in 2019 ........................................................................................................... 112 xvi List of Abbreviations ACF Autocorrelation Function AIC Akaike Information Criteria AIDS Acquired Immunodeficiency Syndrome ARIMA Autoregressive Integrated Moving Average CBHI Community-Based Health Insurance CDC Center for Disease Control CHWs Community Health Workers CI Confidence Interval DAA Direct Acting Antiviral DBS Dry Blood Spot DRC Democratic Republic of Congo ELISA Enzyme-Linked Immunosorbent Assay GDP Gross Domestic Product HBV Hepatitis B Virus HCC Hepatocellular Carcinoma HCV Hepatitis C Virus HIV Human Immunodeficiency Virus ID Identification Number ITS Interrupted Times series LMICs Low-Middle Income Countries MIDAS Multinational Integrated Data Analysis Database NAT Nucleic Acid Testing NGO Non-Government Organization OR Odds Ratio PACF Partial Autocorrelation Function PCR Polymerase Chain Reaction PegINFa Pegylated Interferon Alpha POC Point-of-Care RAMA Rwandaise d'Assurance Maladie RBC Rwanda Biomedical Center RCT Randomized Control Trial RDT Rapid Diagnostic Tests RNA Ribonucleic Acid RNEC Rwanda National Ethics Committee RSSB Rwanda Social Security Board RWF Rwandan Francs xvii SES Social Economic Status SSA sub-Saharan Africa SVR Sustained Virologic Response TB Tuberculosis UAE United Arab Emirates UBC University of British Columbia UK United Kingdom UMICs Upper-Middle Income Countries UN United Nations US United States USD United States Dollars WHO World Health Organization xviii Acknowledgements I want to express my sincere gratitude and appreciation to those who have supported me throughout this dissertation. First and foremost, I am deeply grateful to my supervisor, (Prof. Michael R. Law), for his exceptional guidance, invaluable insights, and unwavering support. His patience, expertise, and encouragement have shaped the direction and quality of this dissertation. I extend my heartfelt thanks to my thesis committee members, (Dr. Nick Bansback, Dr. Bethany Hedt-Gauthier, and Dr. Naveed Z. Janjua) for their scholarly contributions, constructive feedback, and valuable time. Their insights and critical evaluation have immensely enriched the content and depth of this dissertation. I want to acknowledge Public Scholar Initiative for providing the funding that supported this dissertation. To the School of Population and Public Health staff and faculty, thank you for providing resources, knowledge, and administrative support, which have been crucial in facilitating my research process. I also want to thank RBC and Rwanda Ministry of Health staff for administrative assistance during ethics approval and data access request. Finally, I express my most profound appreciation to my family for their love, understanding, and encouragement throughout my academic pursuits. Special thank you to my mother and late father for teaching me resilience and determination. To my sisters and brothers, thank you for constantly checking on me. xix Dedication To my mother, thank you for your love and sacrifices that made me who I am today. To my husband, Innocent, thank you for your love, encouragement, and support on this journey. To my daughter, Kaella, thank you for teaching me unconditional love. 1 Chapter 1: Introduction 1.1 Overview HCV is a significant global health problem that impacts millions of people worldwide. New highly effective HCV drugs became available in 2014, resulting in an increased global focus on treatment and virus elimination through various measures. This thesis is comprised of three research studies related to HCV testing and treatment in Rwanda, and how it is influenced by the global access to medicines. This dissertation includes (1) an analysis of the cascade of care for HCV in Rwanda; (2) patients’ perspectives on access to HCV testing and treatment in Rwanda; and (3) an analysis of global access to HCV medicines. In this introductory chapter, I first describe the hepatitis C virus, its natural history and transmission. Second, I provide some background on the global epidemiology and treatment options for HCV. Third, I discuss the cascade of care for HCV treatment, including testing, diagnosis, treatment initiation, and completion. Further, I discuss HCV global elimination objectives, current progress, and research gaps. Lastly, I describe the mass testing and treatment campaign for HCV in Rwanda that forms the basis for the first two chapters. Finally, I discuss justification of the three studies, outline my study objectives and the conceptual framework that guide the studies discussed in this dissertation. 1.2 Hepatitis C Definition and Transmission Hepatitis C is a liver disease caused by the bloodborne hepatitis C virus.1 HCV is mainly transmitted through contaminated blood, and in rare cases, through sexual intercourse. The route of HCV transmission varies globally.2 In high-income countries, the leading cause of HCV is injection drug use, while in Low-and-Middle Income Countries (LMICs),3 many people acquire HCV through unsafe medical practices such as unsafe blood transfusion and the use of unsterilized 2 medical equipment.4 Injection drug use is associated with 23%-39% of new HCV infections globally.5 A modelling study showed that new HCV infections could be reduced by 43% by eradicating drug injections in high-income countries.2 Before 1992, HCV was not screened among blood donors, and the risk of post-transfusion hepatitis infection was approximately 30%.6 With advanced screening tests and the use of disposal of medical materials, post-transfusion HCV rates and transmission in healthcare facilities have decreased drastically over the past three decades in high-income countries.7 In LMICs however, unsafe medical practices remain the primary source of HCV transmission.8 For instance, Egypt has one of the highest rates of HCV globally, due to the poor sterilization of medical equipment used during the country’s treatment of schistosomiasis in the 1960s- 1980s.9 In the 1990s-2000s, only 19% of blood was screened for HCV before transfusion in sub-Saharan Africa (SSA) due to the high cost of HCV testing.10 Also, recent studies conducted in Ghana and Cameroon found that healthcare-related injections and transfusion were the main routes of HCV transmission.11,12 Similarly, the available evidence shows that the primary source of transmission in Rwanda was scarification practices, unsafe injection in healthcare settings, and exposure to infected blood during the 1994 Genocide against the Tutsi.13,14 1.3 Hepatitis C Natural History Hepatitis C causes liver inflammation which can lead to acute or chronic hepatitis.15 The incubation period of HCV is between two to six weeks. As shown in Figure 1.1, multiple pathways for disease progression are possible following infection. Most acute infections are asymptomatic with approximately 30% of people clearing the virus naturally within six to 12 months. This 3 process called spontaneous clearance, is defined as clearance of virus without treatment, and is determined through repeated undetected HCV RNA. Spontaneous clearance is more common among women and young people and can also be genetically related.16 Conversely, approximately 70% of acute infections progress to chronic cases, defined as having HCV RNA presence six months post-exposure. While most acute HCV cases are asymptomatic, individuals can transmit the disease. Between 20 and 30% of people with chronic infection develop liver cirrhosis after over 20 years.15 The annual risk of Hepatocellular Carcinoma(HCC) is 1-4% for patients with cirrhosis, while the risk of liver decompensation for patients with cirrhosis is 3-6%.17 If not diagnosed and treated early, HCV can lead to death, with cirrhosis and HCC complications being the leading cause of mortality.18 Despite advances in pharmacotherapies, between 2007 and 2017; the global rate of HCV mortality from cirrhosis and HCC increased by 17.4% and 30.4%, respectively.18 Figure 1.1: Natural History of Hepatitis C Virus Acute Hepatitis CSpontaneous clearance (~30%)Chronic Hepatitis C (~70%)Cirrhosis (20-30%) at 20 yearsDecompasation (3-6% per year)HCC (1-4% per year)Death (3-4% per year) 4 1.4 HCV Epidemiology Chronic hepatitis C affects 58 million people worldwide, more than twice the global estimate of people infected with HIV.19 Globally HCV prevalence amongst the general population is between 0.6% and 1.0%, and the annual number of incident cases is estimated at 1.5 million.1 The highest number of individuals infected with HCV live in the Eastern Mediterranean Region (1.6%) and European Region (1.3%).20 The North and South America have the lowest burden with only 0.5% prevalence. In 2015, Pakistan, China, India, and Egypt were the top four countries with the highest burden of HCV.21 Although Egypt ranked amongst the top four countries, it has experienced a consistent decline in infections in the past several decades, with prevalence dropping from 14.7% in early 2000s to 0.5% by 2020.22 As of 2022 however, Pakistan, India, and China remained the top three countries reporting the highest number of HCV cases, ranging from 6 million cases in India to 10 million in Pakistan.21 Overall, as seen in Figure 1.2 below, countries with higher HCV burden are mostly in LMICs. 5 Figure 1.2: Global HCV Distribution in 2015 and 2022 Historically, HCV has been most prevalent in LMICs. In 2018, the World Health Organization (WHO) reported that 75% of HCV-infected people lived in LMICs.22 Despite declines in the estimated number of HCV-infected people in LMICs from 34.4 million in 2015 to 30.9 million in 2020, the number of infections in low-income countries remained at 4.9 million. While some LMICs have experienced a decrease in HCV infections, eastern SSA experienced a marginal increase from 2.9 million in 2015 to 3.0 million in 2020.21 Prevalence estimates in Africa, however, are controversial, and studies have reported different estimates depending on the available data.9,15 While some research suggests that the prevalence of HCV in Africa is low in comparison to other regions, these findings may simply due to the region's lack of HCV prevalence data.23,24 6 As seen in Figure 1.2, many countries in Africa do not report data on HCV prevalence. Where data are available, the evidence shows a heterogeneous burden at the subnational level and across countries. For example, estimates from Burkina Faso suggest a high HCV seroprevalence of 13.2% in the southwest region, while the national seroprevalence was only 3.2%.25 There are also large discrepancies in HCV prevalence across African countries, with prevalence ranging from 0.9% in Kenya to 13.8% in Cameroon.21 While the WHO reported Africa to account for at least 26% of the HCV global burden, these estimates are likely conservative as they are based on estimates from countries with HCV data.22,23 Additionally, most studies report seroprevalence; there are still gaps in the confirmation of chronic HCV infection estimates due to a lack of well-equipped laboratories in many African countries.10,26 Where these estimates are available, high rates of false-positive HCV antibody tests have been reported.25 Given all of these factors, there is a scarcity of reliable data on chronic HCV in Africa, which limits the implementation and evaluation of elimination strategies.10 1.5 HCV Global Genotypes Distribution HCV genotype is the categorization of HCV strains based on their genetic makeup. There are six main HCV genotypes, and the distribution varies across countries.27 Genotype 1 is the most common globally, accounting for 46.2% of all HCV cases, followed by genotype 3, which accounts for 30.1% of global HCV infections. Genotypes 2,4, and 6 accounts for 22.8% of all cases, while genotype 5 is the rarest genotype and is only responsible for less than 1% of global infections.28 Genotype 4 and 5 are the most common in LMICs, while genotype 1 is the most common in high-income countries.11 For countries with data in SSA, genotype 4 is the most 7 common. 10,28,29 A study conducted in Rwanda found that 83% of HCV cases were of genotype 4.30 1.6 HCV Diagnosis Despite the advancements in testing strategies, a large number of people with HCV remain undiagnosed,31 in large part due to the fact that HCV can be asymptotic for decades. The asymptomatic nature of the virus poses a significant issue, as it results in late and advanced-stage diagnosis in many people.1 HCV is diagnosed in two steps: first through (1) antibody screening, then followed by (2) a confirmatory test. 1.6.1 HCV Antibody Screening The first step in HCV diagnosis involves a screening for HCV antibody (anti-HCV testing) presence using a serological test. HCV antibody screening can be done using a rapid test or enzyme-linked immunosorbent assay (ELISA).32,33 ELISA is the gold standard for HCV antibody detection and has high sensitivity and specificity (>99%).34 However, several challenges are associated with using ELISA, especially in LMICS. First, it is costly, requires laboratory equipment, and can require transporting samples to better-equipped testing sites where capacity is limited.34 As an alternative, in 2016, the WHO approved using the SD BIOLINE™ and OraQuick® HCV rapid tests for HCV antibody screening.26 HCV rapid tests are popular since they are simple, less expensive, and have a shorter turnaround time.26 However, these approaches are associated with higher false positive rates, especially in settings where there are issues of fraudulent test kits being distributed. In such cases, the tests might be counterfeit or substandard and can lead to false diagnoses.35,36 Addressing the issue of falsified tests for HCV in SSA is still a significant challenge due to the diverse healthcare landscapes, varying levels of regulatory capacity, and limited 8 resources in this region. In contrast to other regions, SSA lacks a universal regulatory standards authority for validating diagnostics. Some countries, in collaboration with international organizations, have put in place laws and regulations to reduce the production and distribution of falsified tests. These have included penalties against individuals and organizations involved in these activities and conducting regular inspections and audits of manufacturers, distributors, and health facilities.37 Other public institutions have launched awareness campaigns to educate the public and healthcare providers about the risks of falsified diagnostic tests and the importance of using reliable testing kits.38,39 1.6.2 HCV Ribonucleic Acid (RNA) Testing (Confirmatory Test) If the antibody test is positive, the diagnosis of active HCV is then confirmed using nucleic acid testing (NAT) for HCV RNA.33 This test has sensitivity of around 98% and specificity of 99%.40 It is conducted in a laboratory and includes a polymerase chain reaction (PCR) test used to measure the amount of virus (viral load), in the blood. A person is confirmed positive if the amount of HCV in the blood is at least 20UI/mL. A positive confirmatory test indicates an active HCV infection. In contrast, a negative result may indicate that the virus has been cleared or that the viral load is too low to be detected.1,41 Once a patient is confirmed HCV positive, additional tests are conducted to assess the stage of liver damage using a biopsy or alternative non-invasive tests.1 While the HCV RNA test is the optimal diagnostics for active HCV, they are generally costly, require laboratory infrastructure, and takes several days to return results.34 These challenges can lead to loss-to-follow-up for some patients. Recent developments have led to more simplified testing approaches, such as Dry Blood Spot (DBS), Point-of-Care (POC) testing machine,42 and HCV core antigen test.43 9 1.6.3 HCV Simplified Diagnostic Tests Given the challenges posed by conventional two-step testing, particularly in LMICs,34 the WHO recently approved the use of simplified approaches to HCV diagnosis, including Point-of-Care (POC) testing for HCV RNA assays, the Dry Blood Spot (DBS), and HCV core antigen.32 These approaches have been previously used in HIV and Tuberculosis (TB) testing, and are especially useful in LMICs.42 These diagnostic algorithms are recommended for resource-constrained or remote settings, where the availability of a standard approach is limited, and populations are vulnerable to lost-to-follow-up.44 DBS involves the collection of blood samples from a finger-prick and analyzes the blood using a DBS filter card.45 This method is a decentralized approach of sample collection and allows batch processing. It is simple, non-invasive, requires less training, can be done in any setting.46 However, DBS is not available for routine testing in most places since although it is helpful with sample collection, it does not reduce the cost associated with testing. Another simplified alternative is the POC machine for HCV RNA testing. The POC machine uses GeneXpert® technology that uses molecular diagnostic techniques to detect HCV RNA and can provide results within 60 minutes.31 The POC approach is easy to use, can provide rapid results, has high sensitivity (it can detect HCV RNA as low as 4IU/mL), and has a lower risk of contamination.32 However, this technology is more expensive than other diagnostic tests, requires a specific machine and trained personnel, and has limited capacity (e.g., number of samples at a time). Lastly, the HCV core antigen test is a third approach to detecting active HCV. In a recent systematic review, two testing essays (Abbott-ARCHITECT and Ortho ELISA) had high 10 performance in HCV detection. Abbott-ARCHITECT had 93.4% sensitivity and 98.8% specificity, while Ortho ELISA had 93.2% sensitivity and 99.2% specificity.47 The evidence also shows that HCV core antigen was correlated with HCV RNA above 3000IU/mL.47 This approach might be cost-effective compared to NAT, but it has low sensitivity in individuals with low viral load or those at the early stages of infection.48 These alternative simplified testing approaches all have strengths and limitations; their use should thus be context-dependent. 1.6.4 HCV Screening and Testing Gaps The burdensome cost of HCV screening and testing services poses a significant global health challenge, and leads to low HCV diagnosis rates in the general population.34 These rates are highest in high-income countries, yet in 2020 it was estimated that just 47% of HCV was diagnosed.21 In comparison, of the estimated 30.9 million individuals with HCV in LMICs, only 15% were diagnosed.21 The diagnosis rate is even lower in Africa at an estimated 10%.49 Most studies that report the number of HCV-diagnosed people only take into account antibody test results. As such, there are gaps in HCV RNA testing estimates, which are essential to properly estimate country-specific HCV burden and guide treatment interventions. Unlike other infectious diseases with globally accepted diagnostic approaches, HCV screening and testing guidelines are highly variable. In 2016, the WHO published HCV testing guidelines for LMICs;44 However, these guidelines are implemented differently across countries, and are adjusted to local conditions based on available diagnostics and resources.26 Limited access to screening and testing services in LMICs leads to reduced, delayed, and under-diagnosis of HCV; 25 and demonstrates the need for greater resources, laboratory infrastructure, 11 and trained personnel for HCV RNA testing in many countries. Issues of testing accessibility are further compounded by low awareness and knowledge about HCV, especially in LMICs, which further reduces demand for testing.50 Overall, improving the HCV diagnosis rate will require investment in healthcare infrastructure, awareness campaigns, and affordable access to care. 1.7 HCV Treatment 1.7.1 Evolution of HCV Treatment Pharmaceutical companies have significantly improved access to HCV services globally by developing HCV drugs and facilitating generic licensing agreements. Unlike many other infectious diseases, such as HIV and hepatitis B, chronic HCV is curable through treatment.1 Historically, the standard treatment for HCV included interferon monotherapy or in combination with ribavirin. However, interferon therapy has significant side effects,51 a low cure rate (30%)52 and requires multiple weekly injections.53 In the 1990s, HCV treatment shifted to combining interferon with ribavirin, which increased treatment success rates to between 33% to 41%.54 In 2002 pegylated interferon alpha (PegINFa) was developed, which was more effective but continued to have a lower response rate as a monotherapy (39%) and in combination with ribavirin (54-56%).51 1.7.2 Direct Acting-Antivirals New HCV medications called Direct Acting-Antivirals (DAAs) have been developed and are a class of medications used to treat HCV.51 DAAs are associated with fewer side effects than interferon, and are only taken orally once a day for 8-12 weeks, cure infection in over 95% of cases.55 DAAs were very expensive and when they were first introduced, the total cost of full regimen was around US$84,000.1 Currently, the average cost for a full regimen is approximately 12 US$40,000.56 DAAs have also been evolving over time, leading to different generations discussed here below. 1.7.2.1 First Generation of DAAs The first generation of DAAs included telaprevir and boceprevir and were officially approved for global use in 2011.51 Both drugs were used as alone or in combination with ribavirin or PegINFa. Although the efficacy and effectiveness studies showed improved treatment outcomes (68%-84%)54 compared to the interferon therapy and were cost saving,57 they also had significant side effects and were not effective against all HCV genotypes. As such, these drugs were discontinued and replaced by a second generation that is more tolerated with less adverse events.51 1.7.2.2 Second Generation of DAAs The second generation of DAAs was approved in 2013. These treatments are shorter in duration than most existing treatments at an 8-24 week regimen.51 They are genotype-specific antivirals and are highly effective in patients with HCV genotypes 1, 3 and 4.51 This generation includes a combination treatment of sofosbuvir/ledipasvir and has an efficacy of 94% in non-cirrhotic naïve patients.58 sofosbuvir/ledipasvir is usually used in combination with ribavirin for cirrhotic patients or patients with a prior history of HCV54, and has a treatment success of 86%.51 Sofosbuvir with simeprevir was also introduced as a first-line treatment option for patients with HCV genotype 1 without cirrhosis, and the treatment success rate was approximately 97%.59 The second generation also includes triple therapy (ombitasvir/paritaprevir/ritonavir), including ombitasvir, that blocks a protein responsible for the replication of the HCV in the body. 13 Paritaprevir also inhibits viral replication by blocking the HCV NS3/4A protease's activity, while ritonavir helps boost blood levels.51 The course of treatment is 12 weeks or 24 weeks, depending on the stage of disease, and it is highly effective in patients with genotype 1.54 A study conducted in Turkey using this combination with or without ribavirin showed a response rate of 99% in all patients and 95.5% in compensated cirrhotic patients with genotype 1 and 4 infections.60 The triple combination is sometimes used with Dasabuvir for the treatment of genotype 1, and it has a response rate ranging between 89% and 95%.61 Lastly, Daclatasvir is highly effective in genotype 3 HCV-infected patients. It is the only second-generation option with high efficacy without a ribavirin or interferon combination.51 One efficacy study showed a treatment success rate of 93% in naïve patients and 98% if used with a ribavirin combination or 93% in treatment-experienced patients. The response rate without ribavirin was lower (87%) in treatment-experienced patients.62 Most of these agents are no longer used and are not available on the market especially in high income countries where they were replaced by the newer generation.63 1.7.2.3 Newer Generation of DAAs Between 2016 and 2017, there was a discovery of DAAs that can treat all HCV genotypes. The first pan-genotypic drugs were sofosbuvir/velpatasvir and elisbasivir/grazoprevir, followed by a triple therapy of sofosbuvir/velpatasvir/voxilaprevir and lastly, the newest and most highly effective combination of glecaprevir and pibrentasvir.51 14 The sofosbuvir/velpatasvir combination has a response rate ranging between 98% in genotype 1 and 100% in genotype 4 and 6 in patients with or without cirrhosis.64 A global effectiveness study showed a cure rate of 99% in all patients and 98% in those with compensated cirrhosis.65 sofosbuvir/velpatasvir is also a recommended combination for patients with HIV coinfection 66and renal failure, with a reported treatment success of 95%.67 In 2017, the triple therapy sofosbuvir/velpatasvir/voxilaprevir was also introduced as a second line treatment for people who previously failed other types of DAAs, with a response rate of 90%, and has thus become a salvage therapy for people with HCV.68,69 Based on a recent systematic review, the effectiveness of sofosbuvir/velpatasvir/voxilaprevir is 98%.70 Elisbasivir/grazoprevir is another pan-genotypic combination used as a single tablet to treat HCV.71 In an effectiveness study conducted in Europe, Asia, and Central and North America for treatment-experienced patients, treatment success was achieved in 92.4% without ribavirin and 94.2% with ribavirin for a 12-course treatment. For 16 weeks of treatment, the cure rate was the same without ribavirin and 98.1% with ribavirin.71 This combination is no longer a recommended therapy where other options with high cure rates are available. Lastly, the newest combination(glecaprevir and pribrentasvir) was approved in August 2017 and is also available as a single tablet to be taken three times a day.51 It has high efficacy with a 95% success rate in cirrhotic patients and a 100% success rate for non-cirrhotic patients for all genotypes.72 In a real-world study using glecaprevir/pribrentasvir for HCV treatment, the response rate was achieved in 98% of all patients and 97% in cirrhotic patients.73,74 15 While there is extensive evidence on the efficacy and effectiveness of DAAs for HCV treatment, most of the published literature comes from high-income countries.75 Given the distribution of different HCV genotypes throughout LMICs,28 assessing DAA efficacy and effectiveness in this region is essential. Additionally, the limited evidence that exists in LMICs on DAA efficacy is mainly from Randomized Control Trials (RCTs) that include small sample sizes and are not representative of the general population. For instance, clinical trials conducted in Rwanda assessed the efficacy of ledipasvir/sofosbuvir among 300 patients and found a treatment success of 87%.76 A similar study assessed the efficacy of sofosbuvir/elbasvir/voxilaprevir among only 40 patients who previously failed treatment, and the success rate was observed in 98 % of study participants.77 In both studies however, the sample size was small, and the participants were selected and monitored in hospital settings. It is essential to evaluate DAAs' real-world effectiveness in LMICs since several factors can impact treatment outcomes, including medication adherence, resource constraints and other health systems challenges.25 1.7.3 Sustained Virologic Response The primary goal of HCV treatment is to reduce the burden of the disease, including transmission, morbidity, and mortality.46 In practical terms, this means maximizing the number of patients who have cleared their infection. An HCV patient is considered cleared if they have achieved a sustained virologic response (SVR) 12 weeks or more after completion of DAAs, translating to an undetectable level of HCV RNA in their bloodstream.78 Quantitatively, this means having an HCV RNA level below 20IU/mL HCV.79 As described in the previous section, the introduction of DAAs has improved SVR rate from 30%–60% with interferon-based therapy to more than a 95% cure rate.80 16 While the SVR rates have increased globally following the introduction of DAAs, several challenges to achieving high SVR rates in real world settings persist. While SVR rates vary widely across the globe depending on the stage of the disease and the medicines used, certain patient and health systems-level factors affect SVR outcome. Such factors include: 1. Access to HCV diagnosis and treatment: Access to HCV testing and treatment is crucial for breaking the chain of transmission, which contributes to overall public health security. However, in many LMICs, access to HCV services remains limited, resulting in delayed screening and later-stage diagnosis. Delayed diagnosis coupled with potentially limited DAA options result in reduced SVR rates in many countries. For example, only specific types of DAAs are recommended for cirrhotic patients or previously treated patients who failed to achieve a SVR;81 however, these treatments may not be available, leading to treatment failure or further disease progression.32 2. High burden of other comorbidities:23 Patients with HCV may have other medical conditions, such as diabetes, HIV and hepatitis B infections or liver cirrhosis, that make treatment more complex , thereby reducing the chances of achieving SVR. For example, evidence suggests that 5% of HCV patients with type 2 diabetes are at an increased risk of developing cirrhosis.82 3. Drug resistance: The development of drug resistance is a potential challenge to achieving SVR, particularly for patients who have failed prior treatment regimens. This is particularly true in LMICs where lack of the best first-line treatments leads to people having to be treated more times, leading to higher levels of drug resistance.83 17 4. Adherence to treatment:84 HCV treatment is complex and may require taking multiple medications over several months. Poor adherence to treatment can reduce the chances of achieving SVR. A recent study showed that treatment failure was 48% higher among patients with poor or fair adherence to DAAs.85 All the above-described factors contribute to large variations in SVR rates between countries. A systematic review of the global cascade of HCV care found significant variability in the national rate of SVR achievement among different countries, ranging from 74% in Georgia to 96% in the United States (US). The lowest SVR rates were mainly observed in LMICs, while several high-income countries achieved SVR rates of 90% and above.86 Although there have been improvements in access to DAAs globally, more investigation into treatment outcomes is needed, especially in resource-limited settings where HCV medicine availability and accessibility varies widely.26 Specifically, treatment failure is particularly common in Africa and other low-income countries due to lack of treatment options.10 Therefore, estimating SVR rates at national and subnational levels in LMICs is essential to inform future HCV treatment strategies. 1.8 Global Access to DAAs The availability and accessibility of DAAs is a major global health issue. A systematic review of the HCV cascade of care reported that among 11 countries with population-level HCV data, treatment initiation was less than 30%.86 This is mainly due to the high cost of DAAs, which render them inaccessible for many diagnosed patients.56 The factors contributing to the affordability of DAAs vary across countries and depend on the disease burden, local production capacity, the 18 presence of patent agreements, the availability of generic drugs, public coverage, and national pricing policy.56 In high-income countries, where HCV drugs are more widely available, people can typically access these treatments through public healthcare systems or private insurance where it is available. However, in LMICs, many people cannot afford these drugs, and DAAs are not subsidized through their healthcare systems.56 To address this issue, some governments and international organizations have taken steps to increase access to DAAs. For example, some pharmaceutical companies have offered voluntary licensing agreements to generic drug manufacturers to produce and sell DAAs at lower prices in these countries. As a result, some LMICs can now buy generic DAAs for a full 12 week round for less than US$60.56 A stark contrast to the treatment prices in high-income countries, which can exceed $40,000 for some DAAs.87 Despite these efforts, significant inequities in access to DAAs persist. While many LMICs have access to affordable generic drugs, Upper-Middle-Income Countries (UMICs) and high-income countries do not have access to generic drugs due to patent protection.88 For instance, the generic sofosbuvir and daclatasvir combination in Pakistan is $US25 per full regimen while the originator version costs US$8,787 in China. The lowest cost for full regimen of the newer generation of sofosbuvir/velpatasvir is US$156 in Pakistan, while the originator version is US$1,500 in Brazil and US$19,000 in Lebanon.56 Some high-income and UMICs have negotiated alternative options with manufacturers to improve accessibility, including a lump-sum agreements where countries pay a specific amount for a given period or an annual fixed amount for unlimited supply that meets country-specific demands. While LMICs have access to generic versions of some DAAs, at present 19 this generally only includes first and second generation DAAs. The newer generation, which is highly effective and recommended for patients with a prior history of HCV and cirrhotic patients, is not available in generic form in many LMICs. Therefore, implementing differential pricing strategies only broadens the disparities in global pricing and availability of these medicines.56 Several policies have been implemented to improve global access to DAAs, including voluntary licensing agreements, improved access to generic drugs in LMICs, and lump-sum agreements in high- and middle-income countries; however, it is still unknown how these policies might have affected global DAA accessibility or how access varies across economies or geographic locations. The existing evidence focuses mainly on differences in treatment rates or barriers to accessing DAAs. A study conducted in Ontario, Canada, found that treatment rates ranged from 28 per 100,000 people in the northwestern region of the province to 188 in eastern Ontario. 89 Individuals living in rural areas also have to travel a greater distance to reach a DAA prescribers than people living in urban areas.89 A recent review showed that even at lower prices, some LMICs still face barriers to accessing HCV drugs, including regulatory obstacles, a lack of infrastructure to deliver DAAs, and inadequate funding for healthcare systems.26 Furthermore, a study conducted in seven African countries with licensing and pricing agreements for DAAs, found that the average cost for treatment in most cases was higher than the population's average annual income. There was also a significant disparity in healthcare expenditure amongst the countries, suggesting an increase in the healthcare budget of only 4% in South Africa to as high as 403% in Cameroon for the DAAs to be covered under government health insurance.90 20 Overall, there are significant gaps in the existing research on access to DAAs, and an assessment of how disparities in DAA licensing and price policy affect treatment accessibility across countries is needed to inform future HCV elimination strategies. 1.9 HCV Elimination 1.9.1 Global Elimination In 2016, the World Health Assembly set the ambitious goal of eliminating HCV globally, by 2030.91 In 2017, the WHO published a strategic plan to help guide countries in the eradication of HCV. The recommended strategies included: (1) the continuous collection and analysis of HCV-related data to inform policymakers; (2) increased screening and treatment coverage; (3) maintaining sustainable and scalable financing for testing and treatment; and (4) developing new affordable diagnostics, vaccines, and treatments. The WHO also set targets of an 90% reduction in new HCV infections, diagnosing 90% of estimated cases, treating 80% of diagnosed patients, and a 65% decrease in mortality by 2030.21 While there has been an improvement in access to HCV care, only a handful of countries are on track to achieving the majority of the WHO targets.92 Of the countries where data is available, only 12 (Australia, Denmark, Spain, France, Georgia, Canada, Egypt, Finland, United Kingdom, and Japan) appear to be on track to achieving the targets by 2030.49 Another 21 countries were projected to achieve the targets between 2030 and 2050, while the remaining countries were not expected to achieve the targets even by 2050.92 In addition, there is limited data from many countries to assess progress, including a large number of countries in SSA. With regard to new HCV infection rates specifically, evidence suggests most countries will not meet the designated 21 target.93 According to the Centers for Disease Control (CDC), new HCV infections have been increasing over time in the US, with an estimated 66,700 new cases in 2020, which is more than double the set target for elimination to be achieved in 2030.94 Despite the progress made to eliminate HCV, several factors continue to hinder elimination efforts globally. The greatest challenge is that elimination efforts are not equally distributed. There are major disparities in diagnosis, treatment, and prevention services between countries. There is also a lack of data on HCV burden, treatment uptake, and treatment outcomes that that are necessary to develop effective strategies to eliminate HCV, particularly in SSA.25 Further, the recent COVID-19 pandemic has affected health services utilization95 and disrupted global supply chains.96 A 1-year delay in HCV elimination due to disruption in healthcare services utilization because of the pandemic has resulted in an estimated 44,800 more HCC cases and 72,3000 excess cases of liver-related mortality.97 The reduction in HCV treatment was more frequently recorded in LMICs than in other countries.97 1.9.2 Elimination in LMICs A few LMICs have been selected to implement elimination programs as part of the global elimination plan. These countries were given access to generic drugs through voluntary licensing agreement and were supported in implementing elimination guidelines.25 Seven African countries (Rwanda, Egypt, Ethiopia, Nigeria, Democratic Republic of Congo (DRC), Cameroon, and South Africa) were selected to be part of these licensing agreements.90 A study conducted in these seven countries after the implementation of the new licensing policy showed that in addition to the price reduction of DAAs, there remained a need for a healthcare expenditure increase for these countries 22 to achieve the 2030 targets. The increase in expenditures ranged from 2% in South Africa, to 59% in Rwanda, and to 92% increase in Cameroon.90 The study also found that, even at the reduced price, in some countries individuals still had to pay out of pocket for DAAs, and the cost of a full regimen of treatment was still more than the annual income of people in lowest or highest wealth quintiles.90 Additionally, many LMICs still lack screening and treatment programs at the national level. For example, HCV prevalence in Pakistan was 3.6% in 2015, and remained above 3% in 2022.21,49 Despite the increased availability of generic DAAs, Pakistan still ranked first amongst countries with the highest HCV burden worldwide in 2022, largely due to the lack of a committed national strategy towards HCV elimination.98 Evidence demonstrates that despite policies to improve access to DAAs in LMICs, increasing treatment rates continues to be a challenge in many countries. Of the 769,568 patients treated for HCV globally in 2022, only 7% were from low-income countries, with Africa ranking lowest out of all regions (7%).49 As a result, Egypt is the only African country that is currently on track to achieving the WHO elimination targets.49 1.10 HCV Cascade of Care The cascade of care is a public health concept that outlines the various steps in the care pathway for a specific disease or health condition. It was first used in the follow-up of HIV patients and has been adapted for monitoring other infectious diseases, such as TB and hepatitis C.99 The cascade of care typically describes several stages of care, each of which represents a critical step where individuals with the condition can either progress or drop off the care pathway. The cascade of care is often used to identify gaps or barriers in care delivery for a particular disease and to develop 23 interventions to address these gaps. The cascade helps to monitor patient care pathways, which can ultimately lead to better health outcomes for individuals with the disease and reduce the disease transmission in the general population.100 The WHO defines the HCV cascade of care in nine stages which can be combined into five major components, including: (1) prevention; (2) testing; (3) linkage to care; (4) treatment; and (5) chronic care.100 Despite the definition and description of the cascade of care for HCV, there is limited data on it. Where the data are available, there is still a considerable shortfall in the number of diagnosed and treated patients compared with WHO targets.86 Based on 2023 estimates from the Polaris observatory, of the estimated 65 million people infected globally since 2015, only 20% of them were diagnosed, and 15% were treated.92 Of those treated, however, 86% were estimated to have achieved SVR (see Figure 1.3).92 Global cascade estimates for HCV vary widely worldwide, and many low-income countries do not have available data, especially on treatment numbers or SVR achievement.86 As shown in Figure 1.4, which illustrates the stages of HCV care in Africa, there is a wide disparity in the number of patients infected to those diagnosed and treated. 92 According to 2019 estimates, only 5% of people living with HCV in Africa knew their status, compared to 22% in the Americas, 24% in Europe, and 37% in the Eastern Mediterranean region.21 24 Figure 1.3: Global HCV Treatment Cascade Figure 1.4: HCV Treatment Cascade in Africa A recent global systematic review on the cascade of care reported that only 11 countries had data on the HCV care cascade by the end of 2019.25 All of these countries were high-income, or UMICs, with the exception of Egypt.86 Of 9 countries with HCV cascade of care at the general population level, only four countries had national level care cascade, while the other studies were from small cities or provinces. Egypt was the only African country with a population level cascade in this article, and no SSA countries had available data on the HCV cascade.86 25 With the advent of DAAs and subsequent price reductions in several LMICs, SSA countries have a unique opportunity to eliminate the viral disease.55,101 However, governments must prioritize monitoring patients through the continuum of care to achieve the targets. Overall, several research gaps in the HCV cascade of care in SSA still need to be addressed. Further research on the HCV cascade of care in SSA is required, particularly with regard to identifying at-risk populations, gaps in diagnosis and linkage to care, factors that influence treatment adherence, and the burden of late diagnosis on treatment success. One of the few SSA countries that have started implementing HCV elimination strategies, including patient monitoring, is Rwanda which launched the elimination program in early 2017. 1.11 Rwanda Health System, HCV Burden, and Elimination Plan1 1.11.1 Rwanda Demographics and Geography Rwanda is a landlocked nation in East Africa with a population of 13.5 million people in 2022,102 60% of which is under the age of 25. The population has been steadily increasing over time, with an average annual growth rate of around 2.5%. Life expectancy has similarly been increasing, moving from 64 years in 2012 to 70 years in 2022. 102 Rwanda is one of Africa's most densely populated countries, with a population density of approximately 525 people per square kilometer. The urbanization rate in Rwanda is also increasing, with around 18% of the population living in urban areas.102 Rwanda's economy heavily depends on agriculture, which accounts for around 30% 1 A version of this section has been published in MDPI-The virus journal Nisingizwe MP et al. The Cascade of Care for Hepatitis C Treatment in Rwanda: A Retrospective Cohort Study of the 2017–2019 Mass Screening and Treatment Campaign. Viruses [Internet] 2023;15(3):661. Available from: http://dx.doi.org/10.3390/v1503066 26 of GDP and employs around 60% of the population. The country has five provinces, which are divided into 30 distinct districts.103 1.11.2 Overview of the Health System in Rwanda The health system in Rwanda has experienced significant improvements in recent years.104 The government has committed to providing universal health coverage for all Rwandans since 2005 and has invested heavily in expanding access to primary health care services.105 The majority of the population is covered by the community-based health insurance (CBHI) scheme (also known as Mutuelles de Santé). Under this coverage system, community members pay an annual premium, which varies depending on the household wealth index. This scheme covers 90% of the cost of primary healthcare services, essential medicines,106 and provides coverage for hospital-based services, including surgeries.107 The country also has private health facilities and providers, which are regulated by the Rwanda Ministry of Health (MoH); however, CBHI is only accepted in public health facilities. As a result of CBHI coverage, most of the Rwandan population utilizes public health facilities. The country has a decentralized health system, with health services provided at the national, provincial, district, and community level. Each level provides a minimum package of healthcare services to avoid overlap at different levels and ensure efficient use of resources.108 Public health facilities are organized into three levels. The first level is health centers, which provide primary care, and focus on activities such as consultations, chronic disease management, and maternal and childcare. Additionally, this first level of care also provides preventive and health 27 promotion services. Primary care services also include community health workers (CHWs), who are based in each health center catchment area and can administer treatments for simple illnesses and refer patients to health centers when needed. The second level of care is provided through district or provincial hospitals, which provide all primary care services offered by the health center. The focus at this level is mainly on complicated cases referred from health centers, as these hospitals have more advanced medical equipment and specialists. Administratively, each health center operates under a designated district or provincial hospital based on the catchment area. On average, each hospital receives referrals from 16 to 20 health centers.104,108 Lastly, referral hospitals are the highest level of health facility that provide tertiary care services. This level encompasses all health-related services and is equipped with advanced medical technology and specialists in each domain that may not be available at other levels. While Rwanda has made significant progress in its healthcare system, they are still challenges in the program implementation and in translating policies into effective practices. Some of the key factors contributing to this gap include limited funding, health workforce shortages, healthcare infrastructure gaps such as poorly-equipped laboratories, and the prioritization of short-term gains over long-term sustainability. 1.11.3 HCV Care in Rwanda Rwanda has developed a comprehensive plan to eliminate HCV by 2024, with focus on prevention, testing, treatment, and surveillance.109 In 2011, the Rwanda MoH initiated a viral hepatitis program as part of the country’s effort to reduce the burden of infectious diseases.14 When the program started, there were only 4 HCV specialists nationwide, based in only four referral hospitals. Three 28 of the four referral hospitals were in the capital city of Kigali, which limited the availability of HCV services for the country’s rural population.110 Subsequently, in 2013, the country developed national HCV testing and treatment guidelines.110 An assessment conducted in 2015 found that only 253 of the estimated 55,000 HCV patients had received treatment. Most of these patients in treatment had a late stage HCV, and were either paying for therapy out-of-pocket for therapy or relying on private health insurance to cover treatment cost.111 DAAs were introduced in Rwanda in 2015. However, the cost of a full regimen ($1200) at the time was high relative to average incomes in the country, and many patients had to pay out-of-pocket or rely on insurance to cover the cost of medications. In line with the World Health Assembly’s HCV elimination call and pharmaceutical licensing agreement negotiations, the Government of Rwanda negotiated a price reduction for DAAs. Through these arrangements, the cost of a single HCV treatment was lowered from US$1,200 in 2015 to US$750 in 2017, and eventually decreased to US$60 by 2018. The DAAs that were first introduced in Rwanda included sofosbuvir/ledipasvir and sofosbuvir/daclatasvir.110 1.11.4 HCV Mass Screening and Treatment in Rwanda To maximize the benefit of the price reductions, in 2017 the Rwandan government initiated a mass screening and treatment program across the country, and in 2018 launched a 5-year HCV elimination plan (see Table 1.1).109,110 The campaign initially targeted at individuals aged 15 years and older. To build capacity and support nationwide screening and treatment, the Rwandan MoH trained an additional 110 physicians across the country to treat HCV and prescribe DAAs. Additional nurses and laboratory technicians were also trained to support the campaign 29 implementation. To ensure access to HCV services, at least one screening center was established in each of the thirty districts of Rwanda. Table 1.1: Rwanda 2024 HCV Elimination Targets Indicator Target Number of individuals screened 4,064,919 Number of individuals for confirmatory testing 232,069 Number of individuals treated 112,000 Number of individuals achieving SVR12 110,880 Number of new infections averted 10,638 Number of premature deaths averted 35,000 1.11.5 Cascade of Care in the Rwanda Mass Campaign2 The mass HCV screening and treatment campaign involved three major stages of care: (1) screening; (2) HCV RNA testing; and (3) treatment. Screening At the outset of the campaign, voluntary antibody screening centers were setup in public spaces, such as stadiums and playgrounds, or near popular public areas, such as markets. Each district had at least one screening center, where patients could voluntarily be screened free of charge. Trained nurses collected demographic information and blood samples from attendees, and venous blood samples (5 mL collected in an ethylenediamine tetraacetic acid tube) and laboratory request forms were transported to the nearest of 13 facilities that provided ELISA services.112,113 Murex-ELISA (version 4.0; DiaSorin S.p.A., Italy)114 was used across all testing sites. The samples were stored 2A version of this section has been published in MDPI-The virus journal Nisingizwe MP et al. The Cascade of Care for Hepatitis C Treatment in Rwanda: A Retrospective Cohort Study of the 2017–2019 Mass Screening and Treatment Campaign. Viruses [Internet] 2023;15(3):661. Available from: http://dx.doi.org/10.3390/v1503066 30 at room temperature (20–25 °C) for less than 12 hours without refrigeration and then transported to laboratory facilities using prespecified routes to ensure efficient distribution across testing sites. At the testing sites, samples were tested for the presence of HCV antibody (anti-HCV), hepatitis B (HBsAg), and HIV. Starting in April 2019, capillary blood was drawn to test HCV antibodies using SD Bioline™ rapid diagnostic tests (RDTs) at the screening venues. Finger pricks were conducted for the present patients and immediately tested on site. These tests had near 100% sensitivity and a specificity of 99.4%.115 Although RDTs were pre-approved by WHO for HCV screening, the Rwandan MoH, through the national referral laboratory, also conducted an internal validation to evaluate the performance of these tests before official use in Rwanda. The findings showed 97% sensitivity and 99% specificity (unpublished internal report). Patients who had a positive antibody test were provided with information on RNA viral load testing and were referred to a specialist for HCV RNA testing at their nearest hospital. While the cost of initial screening was subsidized as part of the mass campaign, HCV RNA testing and any subsequent assessments were billed to patients who had to rely on health insurance to cover the costs or pay out-of-pocket. The cost per patient for HCV RNA was US$9 (approximately 10,000 Rwandan francs). From 2019 onward, trained nurses and doctors treated patients with positive HCV RNA tests at the nearest health center. HCV RNA Testing Following referral and sample collection, trained laboratory technicians conducted HCV RNA testing at 9 designated HCV viral load testing sites.110 Blood samples could also be collected at 31 hospitals where viral load testing was unavailable, and the samples were transferred same day to testing sites. Each sample had patient and hospital identification information. The hospital at which the sample was taken called patients to inform them of their results. Patients who did not provide contact information had to return to the hospital at a given date to check their results. Patients who were confirmed HCV RNA positive received counseling and were provided information on the treatment process by an HCV specialist and were then referred for treatment. Figure 1.5 provides a schematic overview of the screening and testing process. 32 Figure 1.5: Mass Screening and Testing Process Treatment All patients who tested positive for HCV RNA test (detectable 15–20 copies/mL) were offered treatment free of out-of-pocket charges.112,113 During the campaign, the HCV treatment available in Rwanda included ledipasvir/sofosbuvir and sofosbuvir/daclatasvir. Both of these DAA combinations were mostly recommended for genotype 1 and 3.116 However, some studies also suggest them for the treatment of genotype 4 which is more common in Rwanda.101 After treatment completion, all patients were asked to return to the hospital for SVR assessment. All patients whose HCV results were undetectable (below 20 copies/mL) within at least 12 weeks after the date of treatment completion were considered cured during the campaign. 33 1.12 HCV Epidemiology and Evidence in Rwanda Some evidence on HCV prevalence in Rwanda has been published; however, to date it has largely limited to high-risk groups such as HIV-infected individuals, older populations, refugees, blood donors and healthcare workers. For example, in 2017, Umutesi et al. estimated HCV prevalence among HIV-positive patients to be approximately 5%,112 while other studies estimated an anti-HCV prevalence of 1.3% in healthcare workers,117 1.6% in blood donors118 and 1.1% in refugees.117 Further, a 2020 study conducted in six Rwandan districts with the highest HCV disease burden reported 6.8% anti-HCV prevalence.13 The mass screening and treatment campaign provided an opportunity to assess anti-HCV prevalence in a larger population. To this end, a study of people who were screened during the first phase of the mass screening campaign found a rate of 8.6%, and viremia rate (proportion of HCV RNA positive individuals out of individuals with positive antibody test) was 56.6%.119 Factors contributing to HCV high-risk population included age, social and economic status, and advanced WHO clinical stage for HIV patients. Age, household contact with anti-HCV, and history of HCV and liver disease were also associated with anti-HCV positivity in refugees.101 There is also prior evidence on treatment outcomes for HCV before the free treatment era in Rwanda, where SVR was achieved in 92% for patients who had treatment outcomes information. One in three patients who initiated treatment were either lost-to-follow up or did not return for SVR assessment.120 Additional studies that assessed treatment outcomes were mainly randomized trials, and the treatment success in these studies ranged between 86% to 98%.30,77,101 A small study that evaluated the time to complete the HCV cascade of care in two rural poorest districts of 34 Rwanda found that 83.4% of individuals for which viral load data was available had chronic HCV, 99% of them initiated treatment, and 94% achieved SVR.121 Lastly, previous qualitative studies conducted in Rwanda before the launch of the HCV campaign and free treatment found that patients encountered financial hardship associated with out-of-pocket payments for HCV testing services and treatment.122,123 Other challenges included the lengthy period of care resulting from geographically separated testing, treatment, and follow-up sites; a lack of access to HCV specialists; misdiagnosis; and lack of HCV knowledge among healthcare providers.123 Despite the extant evidence, there remain significant gaps in knowledge regarding HCV epidemiology and treatment in Rwanda. Namely, we know little about progression through the HCV cascade of care, the factors that contribute to achieving treatment success, dropout before treatment completion, and patients’ perspectives about the mass screening and treatment campaign. 1.13 Dissertation Rationale This dissertation aims to shed light on HCV treatment in Rwanda, and globally. The first paper describes the cascade of care and assesses factors contributing to dropout and treatment outcomes at different stages of the care cascade. The second paper investigates patient perspectives on HCV services access during the Rwanda’s mass screening and treatment campaign. Lastly, we conducted a multinational study to assess global inequities in access to DAAs and the effect of COVID-19 on DAAs utilization globally. 35 1.13.1 Justification of Study I – HCV Cascade of Care in Rwanda While the WHO recommends using the cascade of care to identify gaps or barriers in HCV care delivery and develop interventions to address these gaps, very few countries have data on progression through the cascade of care.100 As previously referenced, in 2019 only 11 countries had data on the HCV care cascade,86 only four of which reported data at a national-level, and only one was an LMIC.86 Despite the high burden of HCV, there is still limited evidence on the national-level cascade of care in SSA.23,24,92 There are several reasons why the cascade of care is limited and may differ in SSA, including limited diagnostic capacity, fragmented healthcare and data systems, and little research. Addressing these challenges is critical to improving our understanding of HCV in SSA and developing effective strategies for preventing and treating the disease. While we have some indication of HCV prevalence among high-risk subgroups in Rwanda, we lack information on the rates within the general population, and on the cascade of care at the national scale. One study that evaluated the cascade of care in two districts of Rwanda was conducted in only two of the poorest districts of Rwanda and used a small sample size. Additionally, over 40% of the patients who initiated treatment did not have SVR12 test results.121 Therefore, although DAA treatments are highly effective in curing HCV, treatment success represents only a small proportion of the study population. Another study that evaluated treatment outcomes of the first cohort of HCV patients that initiated DAAs included only patients who could pay for HCV treatment out of pocket or had access to treatment through public or private health insurance. This group of patients was likely wealthier and was from only four referral hospitals since, initially, HCV treatment was only available in the 36 referral hospitals.14,120 Although this study provided information on treatment outcomes of the first cohort of patients on DAAs in Rwanda, there is still a need to assess the gaps in the treatment of HCV from initial screening to the achievement of SVR during free treatment. Other studies that assessed treatment outcomes were mainly clinical trials conducted in controlled environments with small sample sizes, limiting the generalizability of findings. Overall, very little is known about Rwanda's general population cascade of care and the factors contributing to outcomes at each stage of care. It is also important to assess factors contributing to dropout along the care cascade. 1.13.2 Justification of Study II – Patients’ Healthcare-seeking and Treatment Experience during the HCV Mass Screening and Treatment Campaign in Rwanda Although effective HCV treatments exist, many patients in SSA face significant barriers to accessing them. Qualitative research has the potential to explore these barriers from the patient's perspective, including how cost, lack of awareness, availability of medicines, and cultural beliefs about health and illness affect treatment success. While there is existing evidence on HCV patients’ experience in SSA,124–127 the approach to HCV testing can vary significantly across countries due to differences in healthcare systems, policies, resources, and priorities. For example, the challenges faced by HCV patients in West Africa124 are different from those faced by patients in Southern Africa,128 and policy solutions must reflect those differences. At the country level, understanding the lived experience of HCV patients can help healthcare providers and policymakers develop healthcare policies and interventions tailored to the specific needs of patients in that country. 37 While prior qualitative evidence from Rwanda regarding HCV treatment exists, it was conducted prior to the introduction of the mass screening program when treatment was not yet subsidized.122,123 Research on patients' experience accessing HCV care services after the mass campaign intervention has yet to be conducted. Rwanda is the second country in Africa, after Egypt, to implement an HCV mass screening and treatment campaign;110 therefore, qualitative evidence that evaluates patients’ experience with government-subsidized HCV care will be critical in informing policymakers on how to improve, and scale-up HCV programs in Rwanda, and other countries. 1.13.3 Justification of Study III – Global Disparities in Access to DAAs DAA drugs have revolutionized the treatment of HCV infection, with high cure rates and fewer side effects compared to older therapies.55 However, there are still significant global disparities in access to DAAs due to economic, social, and political factors.56 DAAs, while highly effective, access to these drugs is still limited, particularly in LMICs where healthcare budgets are limited. In Study I and II, we observed significant barriers to access to DAAs and delays in treatment initiation in Rwanda. Given these results, we investigated global access to DAAs to assess whether these limitations are specific to Rwanda or are shared in other resource-limited settings. Prior studies on access to DAAs have mainly focused on efficacy,55,60 treatment uptake, and outcomes.55,69 Therefore, a gap in knowledge exists regarding how access to DAAs differs across countries. Further, it is still unclear how current strategies to increase access to DAAs have affected utilization globally. For example, there is a need to evaluate how the voluntary licensing and bulk 38 purchasing agreements might have improved access to DAAs. 56,90 It is also essential to assess how these policies affect the types of DAAs that are available and being utilized across countries. In the context of the recent COVID-19 pandemic, which has impacted healthcare services globally, it is unclear whether the supply chain of essential commodities, such as HCV medications, has been maintained.96,97,97 While one prior study found a decrease of 43% in DAA utilization during the early stages of the pandemic, it only evaluated trends within higher-income G7 countries.129 In addition, this study also adjusted for the total population instead of HCV cases in each country which does not account for the variance in disease prevalence between countries. Further analysis of the global DAA accessibility is needed considering the number of HCV patients in each country to better understand access disparities across settings, particularly LMICs. 1.14 Dissertation Objectives For countries to achieve the ambitious global HCV elimination targets by the year 20301, research is needed to inform future policy decisions. This dissertation aims to contribute to the global HCV elimination goal by producing necessary evidence on access to HCV testing and treatment in Rwanda and beyond through three interrelated studies. The specific objectives of this dissertation are to: 1. Describe the cascade of care for HCV patients in Rwanda and assess factors contributing to outcomes at each stage of care cascade. 2. Gain an understanding of patients’ experience accessing HCV care services in the era of HCV elimination, and their perspectives on the implementation of the mass campaign in Rwanda. 39 3. Investigate how DAA access varies across country income groups and geographic locations and assess the impact of COVID-19 on DAA sales. 1.15 Overview and Conceptual Framework In this introductory section (Chapter 1), I provided information on what is known about HCV testing and treatment, the gaps in the literature, and how my dissertation contributes to filling these gaps by highlighting study objectives. In Chapter 2 (Study I), I describe the cascade of care for HCV treatment in Rwanda and assess factors contributing to outcome and dropout at different stages of care. Study I is guided by the conceptual framework for HCV outcomes research developed by Sbarigia and colleagues.130 This conceptual framework (Figure 1.6) defines four concepts relevant to Study I : (1) healthcare system structure; (2) patients' characteristics: (3) the process of care; and (4) patients' outcomes. The healthcare system structure is defined as a procedure of delivering care to patients involving health facilities and healthcare providers' characteristics and surveillance systems.130 Patient characteristics refers to demographic, socioeconomic, and clinical information. The process of care includes different factors like pre-treatment assessment, treatment, and treatment monitoring, whereas patient outcomes entail the results of treatment and healthcare utilization. In Study I, I use health facility and patients’ characteristics (healthcare systems, patients characteristics), treatment history, and types of drugs received (the process of care) to assess which patients were more likely to be HCV positive, drop out of care, or achieve SVR (patients’ outcomes). 40 Figure 1.6: Conceptual Framework for Outcomes Research Studies of Hepatitis C Source: Sbarigia U, Denee TR, Turner NG, Wan GJ, Morrison A, Kaufman AS, et al. Conceptual framework for outcomes research studies of hepatitis C: An analytical review. Infect Drug Resist. 2016;9:101–17 Building on the findings from Study I, in Chapter 3 I used a qualitative approach and conducted interviews with patients who participated in the Rwanda mass screening and treatment campaign to understand their experience in care and challenges that they faced while seeking HCV care. This chapter describes facilitators and barriers to care from HCV patients who failed treatment or achieved SVR during the campaign. This study draws on Andersen’s conceptual framework for healthcare services utilization.131 Andersen's conceptual framework for healthcare services utilization is a widely used model that explains the various factors that influence an individual's utilization of healthcare services. The framework identifies three categories of factors that impact healthcare utilization: predisposing factors, enabling factors, and need factors. Predisposing factors refers to individual characteristics that exist prior to the onset of the disease and are believed to influence healthcare utilization. Enabling factors are elements that facilitate or hinder healthcare utilization while need factors are the perceived or actual health needs of an individual that prompt healthcare seeking (Figure 1.7).131 These three concepts guided thematic analysis to identify common themes of HCV healthcare services utilization during the Rwanda mass screening and 41 treatment. While the framework guided our analysis and understanding of healthcare utilization during the Rwandan campaign, it may not have captured complex factors that might affect access to HCV care. These factors could include social pressure, cognitive biases, and patient emotions. However, the qualitative approach used in this study allowed study participants to express their barriers to healthcare and allowed us to assess the potential biases associated with this framework. Figure 1.7: Andersen Conceptual Framework for Healthcare Services Utilization Source: Andersen RM. Revisiting the Behavioral Model and Access to Medical Care: Does it Matter? J Health Soc Behav. 1995 Mar;36(1):1. Finally, in Chapter 4, I conducted a multinational study to investigate utilization of DAAs globally based on country income groups and geographical locations. I also used an interrupted times series to assess the effect of COVID-19 on DAA sales and investigated how the effect varies across countries, country income groups, and geographical locations. This study was based on an adapted conceptual framework on access to medicines from a health system perspective developed by 42 Bigdeli and colleagues.132 This framework is divided into broad categories: the health system, medicines market dynamics, governance and, individual, and household socio-economic and cultural factors. The health system includes all the organizations, institutions, and resources involved in the provision of healthcare services. Within the health system, the availability, accessibility, and affordability of medicines are influenced by factors such as financing mechanisms, procurement and supply chain management, regulatory frameworks, and governance structures. Medicine market dynamics includes all the actors involved in producing, dispensing, and consuming medicines. Factors such as intellectual property rights, market competition, pricing policies can all affect the availability and affordability of medicines. Lastly, access to medicines is also influenced by broader socio-economic and cultural factors, including poverty, education, and cultural beliefs. These factors can impact the demand for medicines, as well as affect an individual's ability to access healthcare services and health outcomes (Figure 1.8).132 In Chapter 4, I described global inequities in access to DAAs. I discussed how these inequities are due to factors defined in the Bigdeli conceptual framework, such as licencing agreements, pricing policies, resource constraints, and overall health system structure. 43 Figure 1.8: Access to Medicine Conceptual Framework from a Health System Perspective Source: Bigdeli M, Jacobs B, Tomson G, Laing R, Ghaffar A, Dujardin B, et al. Access to medicines from a health system perspective. Health Policy Plan. 2013 Oct 1;28(7):692–704. The last chapter (Chapter 5) provides key findings from the three studies, policy implications, and recommendations for future research. 44 Chapter 2: The Cascade of Care for Hepatitis C Treatment in Rwanda: A Retrospective Cohort Study of the 2017–2019 Mass Screening and Treatment Campaign3 2.1 Synopsis Background: Access to HCV testing and treatment is still limited globally. To address this, the Government of Rwanda launched a voluntary mass screening and treatment campaign in 2017. We studied the progression of patients through the cascade of HCV care during this campaign. Methods: We conducted a retrospective cohort study and included all patients screened at 46 hospitals between April 2017 and October 2019. We used hierarchical logistic regression to assess factors associated with HCV positivity, gaps in care, and treatment failure. Results: A total of 860,801 people attended the mass screening during the study period. Some 5.7% tested positive for anti-HCV, and 2.9% were confirmed positive. Of those who were confirmed positive, 52% initiated treatment, and 72% of those initiated treatment, completed treatment and returned for assessment 12 weeks afterward. The cure rate was 88%. HCV positivity was associated with age, socio-economic status, sex, marital status, and HIV coinfection. Treatment failure was associated with cirrhosis, baseline viral load, a prior HCV diagnosis, and a family history of HCV. 3 A version of this chapter has been published in MDPI-The virus journal. Nisingizwe MP, Makuza JD, Janjua NZ, Bansback N, Hedt-Gauthier B, Serumondo J, et al. The Cascade of Care for Hepatitis C Treatment in Rwanda: A Retrospective Cohort Study of the 2017–2019 Mass Screening and Treatment Campaign. Viruses [Internet] 2023;15(3):661. Available from: http://dx.doi.org/10.3390/v15030661 45 Conclusion: Our results suggest that future HCV screening and testing interventions in Rwanda and other similar settings should target high-risk groups. High dropout rates suggest that more effort should be put into patient follow-up to increase adherence to care. 46 2.2 Background HCV is associated with substantial morbidity and mortality worldwide, which is mainly attributable to the sequelae of infection, including liver cirrhosis, liver failure, and HCC.133–136 In 2019, 58 million people globally were living with chronic HCV, and approximately 290,000 people died from the virus.20 Between 55% and 85% of acute infections progress to chronic HCV if not treated early.19 Notably, while deaths from AIDS, malaria, and tuberculosis have declined.137 HCV-related mortality remains high, based on 2021 WHO estimates.20 HCV is also associated with a high economic burden, both with high drug costs and the costs associated with disease progression,136–140. Liver cirrhosis was among the top ten causes of death in low-income countries in 2019.137 The advent of a short course, well tolerated, and highly effective HCV treatment has revolutionized the management of the disease. However, while timely diagnosis and delivery of antiviral therapy can cure and prevent progression to later stages of disease, access to HCV diagnosis and treatment has been limited.139,141–143 In 2019, only 21% of people living with HCV infection globally knew their status, and approximately 62% among those diagnosed had access to treatment.19 Access to HCV diagnosis and treatment is particularly challenging in sub-Saharan Africa (SSA),111 despite the region accounting for 20% of global infections.23 One reason why newer treatments for HCV have had limited use in SSA countries is their high cost and the costs associated with viral testing. However, in recent years, manufacturers have shown a willingness to lower these prices in resource-limited settings.90 For example, in 2017, the government of Rwanda negotiated a price reduction for DAAs that reduced treatment costs in the country from USD1200 in 2015 to USD 60 in 2018.1,144,145 47 In 2016, the World Health Assembly set an ambitious goal of eliminating HCV by 2030. In 2017, the World Health Organization published five strategies to guide countries willing to eliminate HCV as a public health concern.19 These strategies include continuous collection and analysis of HCV-related data to inform policymakers, increasing screening and treatment coverage, sustainable and scalable financing, and developing new affordable diagnostics, vaccines, and treatments. In line with this, the government of Rwanda initiated a mass screening and treatment program across the country and launched a 5-year HCV elimination plan.109,110 While similar programs have been considered elsewhere, there is a lack of evidence regarding the impact of such programs in terms of the progression of patients through the care cascade and outcomes, particularly in SSA. The HCV cascade of care is an approach used to evaluate patient retention throughout the different stages of care that are needed to achieve HCV treatment success.146 Evidence related to the HCV cascade remains limited to high-income countries where medicine accessibility, laboratory equipment, and HCV awareness are high. A recent global systematic review that evaluated estimates on the cascade of care for HCV included mostly high-income countries, and no country in SSA had estimates of their HCV cascade.147 Furthermore, while the number of studies reporting HCV epidemiology has been increasing, there remains limited evidence on the total number of people who initiate treatment and their treatment outcomes in SSA.24,135 SSA is among the regions with the highest burden of HCV and other co-infections, such as HIV; therefore, it is crucial to review the HCV cascade in these settings. Prior studies have estimated the HCV population prevalence in Rwanda to be between 4% and 8%.1,147 One study that assessed the cascade of care in two rural districts of Rwanda found that 83.4% of patients tested for HCV had detectable viral loads. Almost everyone considered for 48 treatment initiated treatment, while 93.7% of patients achieved SVR12.121 Although this study provided information on patients’ journeys in HCV care, the findings cannot be generalized, since the study was conducted in only two of the poorest districts of Rwanda and used a small sample size. Additionally, over 40% of the patients who initiated treatment did not have SVR12 test results. Therefore, although DAA treatments are highly effective in curing HCV, treatment success represents only a small proportion of the study population. Lastly, the study did not assess factors contributing to outcomes and dropouts at each stage of care. Therefore, we studied the progression of patients through the cascade of HCV care in Rwanda’s general population using data from all public hospitals providing HCV care. We also assessed factors contributing to outcomes at each stage of the care cascade and dropouts. 2.3 Methods 2.3.1 Study Context Over the past 20 years, Rwanda has shown progress in improving access to healthcare services across the health sector.104 However, this same progress has not been seen in HCV care: in 2015, less than 1% of the estimated 55,000 HCV patients received drug treatment.111 Before 2015, patients who obtained drug treatment could only do so through four hospitals that had hepatitis C specialists, and it was delivered to only a small group of comparatively wealthier patients.120 To take advantage of the negotiated price reduction, the Rwanda MoH launched the first voluntary mass screening and treatment campaign for HCV. The program first targeted people living with HIV and was subsequently expanded to the prison population and then to the general population. The general population screening was performed in age cohorts, starting with those who were 45 years and above and then everyone who was 15 years and older at the time of the campaign. Testing 49 and treatment were available at one or more public health facilities (health centers or hospitals) in each of Rwanda’s 30 districts. 2.3.2 Study Design We conducted a retrospective cohort study using secondary data to describe the HCV treatment cascade of care and assessed factors associated with outcomes and dropouts at different stages of care. 2.3.3 Study Sites and Population We studied all patients screened at 46 of 47 public hospitals that provided HCV testing and treatment between April 2017 and October 2019. The excluded hospital is a neuropsychiatric hospital that did not provide HCV services. We also excluded patients who had indeterminate screening tests, refugees, those who died during follow-up, and those who received care from private health facilities. Eighty-five percent of Rwanda’s population seeks care at public health facilities,148 and during the mass screening, patients were only referred to public hospitals. 2.3.4 Data Sources We used an electronic database compiled throughout the screening activities by the Rwanda Biomedical Centre (RBC). This database contained patients’ sociodemographic characteristics and other risk factors collected at the screening stage. This database has previously been used in analyses of HCV, HIV, and HBV in Rwanda.112,113,121 We linked this database to additional information on treatment initiation and treatment outcomes extracted from patient charts. Each HCV patient had a record at the hospital that contained demographic characteristics, clinical variables (e.g., treatment and testing results, medical history, and behavior characteristics), and hospital visit dates. We used a unique identification number and demographic characteristics to 50 link data extracted from patients’charts to the electronic database. Data extraction was conducted by two trained nurses in each hospital who were overseen by an HCV nurse mentor. 2.3.5 Cascade of Care The cascade of care for patients in Rwanda consisted of three major stages: Screening, HCV RNA testing, and treatment. More details on these stages are described in Chapter 1. 2.3.6 Outcome Variables Table 2.1 lists the outcomes that we used to describe the cascade of care for patients with HCV. Along with the number and proportion of patients who completed each stage of care, we also estimated the proportion of patients who dropped out at two stages of the cascade: (1) patients with no confirmed diagnosis and (2) patients who did not return for their final check-up 12–24 weeks following treatment completion. We defined treatment failure as having an HCV viral load that was above 20 copies/mL between 12- and 24-weeks post-treatment. 51 Table 2.1: Stages in the HCV Cascade of Care Outcome Numerator Denominator Proportion of patients who were anti-HCV positive Number of patients with a positive HCV antibody test Number of patients screened HCV RNA viremia rate Number of patients who tested HCV RNA positive Number of patients who screened positive for anti-HCV with HCV RNA test conducted Proportion of patients who dropped out of care before HCV RNA viremia testing Number of patients who screened positive for anti-HCV and did not return for an HCV RNA test Number of patients who screened positive for anti-HCV Proportion of patients who initiated treatment Number of patients who initiated treatment with available records in hospital registers Number of patients who were confirmed HCV RNA positive Proportion of patients who achieved SVR (treatment success) Number of patients whose HCV viral load result was below 20 copies/mL within 12–24 weeks post-treatment and returned for SVR test Number of patients who completed treatment with available records and returned for SVR assessment (excluding those who died) Proportion of patients who did not return for SVR tests Number of patients who initiated treatment and did not come back for SVR assessment Number of patients who initiated treatment with available records in the registers (excluding those who died) 2.3.7 Other Variables We included covariates identified in previous studies111,146,149, including the following demographic and socio-economic factors: age, sex, Social Economic Status, health insurance, and marital status. In Rwanda, households are classified into four different Social Economic Status (SES) (known as ubudehe) categories based on their household income and assets, with category 1 being the lowest wealth group and category 4 representing the highest wealth group.150 This variable includes a category called unknown that represents new families that have not yet been classified into any SES category. We also collected clinical and behavioral features, including 52 previous HCV treatment, hepatitis B vaccination status, previous transfusion and surgical history, family history of HCV, comorbidities (hepatitis B, HIV, diabetes, liver diseases, cancer, and renal failure status), and traditional operation practices. For treatment outcomes, we included variables related to the type of drugs a patient received, previous HCV treatment history, baseline viral load, and cirrhosis status (stage of HCV). Lastly, we included hospital-level variables, such as number of staff and hospital type (referral, teaching, provincial, or district). 2.3.8 Data Analysis We started by generating descriptive statistics to estimate the proportion of patients at each stage of care and treatment success, followed by bivariate analysis using chi-square tests and t-tests to assess the association between covariates and outcomes. Following this, we used a hierarchical logistic regression model to assess factors associated with HCV positivity, dropout at different stages of care, and treatment failure while controlling clustering in the data. Continuous variables were centered or standardized for modeling and interpretation purposes. Some covariates had missing values, and we included a missing category for each variable with missing values to enable us to retain all observations in the analysis.151 Our model-building process included three steps. First, we estimated the interclass correlation coefficient using an empty model. Second, we included all patient-level and hospital-level variables that were significant in the bivariate analysis and those that were important based on prior literature. Covariates were included in the model using a forward stepwise selection process using the AIC and the likelihood ratio test. Finally, we tested all interaction terms between 53 variables for significance at α = 0.05 and retained those that were significant. All analyses were conducted using STATA 16.0. 2.3.9 Informed Consent and Ethics At the screening sites, patients were informed about the screening activity and the use of data for research and monitoring purposes. Patients provided verbal consent and signed consent forms. This study was approved by the Rwanda National Ethics Committee (No.028/RNEC/2021, February 28, 2021) and the University of British Columbia (UBC) Behavioral Research Ethics Board (H19-02224, November 8, 2020). 2.4 Results 2.4.1 Descriptive Characteristics The characteristics of our cohort are shown in Table 2.2. Our cohort included 860,801 people who were screened for HCV at 46 different public hospitals. The average age was 42 years old (Standard Deviation (SD): 18), and overall, the participants ages ranged from 15 to 89 years old. Approximately half were in the third category of SES (47.7%), 68.0% were female, and 63.6% were married or in a union. Approximately 18.8% did not have health insurance. In terms of comorbidities, 2.9% were HIV positive, and 3.0% had hepatitis B (HBsAg). In terms of previous medical history, 1.7% had previously been diagnosed with liver disease, and 2.8% had a family history of HCV. 54 Table 2.2: Characteristics of Patients Screened and Treated during the Mass Screening Campaign for Hepatitis C Virus in Rwanda (2017–2019) Total Sample Anti-HCV Positive HCV RNA Testing Variables Total Sample Total (%) Total Number Screened Anti-HCV Positive Anti-HCV Positive (%) Total Number HCV RNA Tested HCV RNA Positive (%) Total Dropouts Dropout (%) Age <44 426,186 59.4 9378 19.4 3324 13.3 686 15.1 44–54 112,264 15.6 6165 12.8 2977 11.9 265 5.8 55–64 100,439 14 9918 20.6 5498 22 340 7.5 64+ 78,493 10.9 22,848 47.3 13,203 52.8 3252 71.6 Sex Female 555,389 68.4 32,159 66.5 16,442 65.7 3259 68.1 Male 256,701 31.6 16,580 33.5 8587 34.3 1528 31.9 SES categories Category 1 104,681 12.2 8077 23.3 4971 19.9 1163 25.5 Category 2 260,537 30.3 12,211 35.2 6854 27.4 1510 33.1 Category 3 or 4 or unknown 495,583 57.6 14,456 41.6 8201 52.7 1888 41.3 Marital status Single 109,552 15.1 1625 4.9 910 4.8 126 4.6 Married or in union 461,231 63.6 21,522 64.9 11,911 63.4 1707 62 Separated/divorced/widowed 153,919 21.2 9927 30.2 5972 31.8 920 33.4 Health insurance No insurance 161,853 18.8 7867 15.9 172 19.3 1045 21.8 Community insurance 657,067 76.3 40,076 81.1 19,517 78 3643 76.1 Private or other government insurance (RAMA/RSSB) 41,881 4.9 1437 3 694 2.8 99 2.1 Diabetes status No 694,243 99 32,956 98 18,681 97.5 2835 98.9 Yes 7353 1 676 2 475 2.5 32 1.1 HTA status No 448,936 97.7 30,204 92.5 17,626 90.2 1845 92.4 Yes 10,653 2.3 2455 7.5 1915 9.8 152 7.6 Renal failure status No 453,150 98.8 30,926 98.1 18,461 98.7 2078 97.9 Yes 5365 1.2 592 1.9 247 1.3 44 2.1 HIV status Negative 680,082 97.1 31,789 94.6 17,719 92.8 2836 98.6 Positive 20,071 2.9 1806 5.4 1371 7.2 40 1.4 HBV result Negative 829,644 97 42,548 97.7 20,278 98.7 4323 97.6 Positive 25,652 3 984 2.3 267 1.3 105 2.4 55 Total Sample Anti-HCV Positive HCV RNA Testing Variables Total Sample Total (%) Total Number Screened Anti-HCV Positive Anti-HCV Positive (%) Total Number HCV RNA Tested HCV RNA Positive (%) Total Dropouts Dropout (%) Family History of viral hepatitis C No 837,090 97.2 32,317 95.4 17,962 96 4709 98.4 Yes 23,711 2.8 1543 4.6 1006 4 78 1.6 Ever been traditionally operated on No 597,913 85.1 26,955 79.3 15,598 80.4 2312 81.7 Yes 104,688 14.9 7020 20.7 3801 19.6 517 18.3 Ever been transfused No 683,769 97.3 32,931 96.9 18,770 96.8 2759 97.5 Yes 18,729 2.7 1047 3.1 617 3.2 70 2.5 Ever been medically operated on No 665,094 94.7 32,108 94.3 18,430 94.7 2674 94.6 Yes 37,518 5.3 1945 5.7 1022 5.3 152 5.4 Ever been diagnosed with liver disease No 399,965 98.3 18,211 97.58 15,000 97.9 895 98.2 Yes 6947 1.7 452 2.42 310 2.1 16 1.8 HBV vaccination Partially or fully vaccinated 53,723 6.24 5245 31.3 4519 32.8 66 1.4 Not vaccinated 807,078 93.76 43,435 68.7 20,512 67.2 4721 98.6 2.4.2 Cascade of Care The overall progression through each stage of the cascade of care is shown in Figure 2.1. Below, we will discuss the results from each individual step in the cascade: 56 Figure 2.1: HCV Cascade of Care in Rwanda for the 2017–2019 Mass Screening and Treatment Campaign Cohort 2.4.2.1 Anti-HCV Seroprevalence As shown in Figure 2.1, a total of 48,680 people, or 5.7%, had a positive anti-HCV test. The odds of being anti-HCV positive increased with age. Other factors associated with being positive included being HIV positive (OR: 1.91, 95% CI: 1.80 to 2.03), having a family history of viral hepatitis (OR: 1.1, 95% CI: 1.04 to 1.18), and having had a traditional operation (OR: 1.31, 95% CI: 1.27 to 1.36). Factors associated with lower positivity rates included being HBV positive (OR: 0.72, 95% CI: 0.67 to 0.77) and being vaccinated for HBV (OR: 0.53, 95% CI: 0.51 to 0.55). More details are provided in Table 2.3. 57 Table 2.3: Unadjusted and Adjusted Associations between Anti-HCV Seroprevalence and Socio-economic, Demographic, Clinical, and Behavior Factors Unadjusted Model Adjusted Model † Variables N OR 95% CI OR 95% CI Age <44 426,186 1 1.00, 1.00 1 1.00, 1.00 44–54 112,264 2.53 2.44, 2.61 2.41 2.33, 2.50 55–64 100,439 4.66 4.52, 4.80 4.45 4.31, 4.60 64+ 78,493 18.1 17.64, 18.61 15.1 14.67, 15.59 Missing 143,419 0.064 0.06, 0.07 0.0093 0.01, 0.01 SES categories Category 1 104,681 1 1.00, 1.00 1 1.00, 1.00 Category 2 260,537 0.66 0.64, 0.68 0.84 0.81, 0.87 Category 3 or 4 or unknown 336,580 0.59 0.58, 0.61 Missing 159,003 1.45 1.40, 1.50 Marital status Single 109,552 1 1.00, 1.00 1 1.00, 1.00 Married or in union 461,231 2.9 2.75, 3.06 1.47 1.39, 1.55 Separated/divorced/widowed 153,919 3.59 3.39, 3.79 1.25 1.18, 1.33 Missing 136,099 6.69 6.33, 7.07 6.5 5.95, 7.11 HIV No 680,082 1 1.00, 1.00 1 1.00, 1.00 Yes 20,071 2.2 2.09, 2.32 1.91 1.80, 2.03 Missing 160,648 1.55 1.51, 1.59 0.91 0.76, 1.08 Family history of viral hepatitis No 677,376 1 1.00, 1.00 1 1.00, 1.00 Yes 23,711 1.27 1.21, 1.35 1.1 1.04, 1.18 Missing 159,714 1.48 1.44, 1.52 1.51 1.20, 1.90 Ever been traditionally operated on No 597,913 1 1.00, 1.00 1 1.00, 1.00 Yes 104,688 1.52 1.48, 1.56 1.31 1.27, 1.36 Missing 158,200 1.55 1.51, 1.59 0.23 0.17, 0.32 † Controlled for sex, diabetes status, transfusion and surgical history, hepatitis B status, and HBV vaccination status. 2.4.2.2 HCV RNA Testing Of those who screened positive, 43,893 (90%) completed an HCV RNA test. Of these individuals, 25,031 (57%) tested positive. This suggests a chronic HCV infection prevalence of 2.9% among individuals who were screened during our study period and 3.2% among those who were HCV 58 RNA tested. The socio-economic and demographic characteristics associated with a positive HCV RNA test included age, SES, marital status, and sex. HIV positivity (OR: 2.51, 95% CI: 2.20 to 2.87) and having hypertension (OR: 2.05, 95% CI: 1.80 to 2.34) were associated with a positive HCV RNA test. Factors associated with lower rates of HCV positivity included being HBV positive, having ever been medically operated upon, and not being vaccinated for HBV (Table 2.4). Table 2.4: Unadjusted and Adjusted Associations between HCV RNA Positivity and Socio-economic, Demographic, Clinical, Behavioral, and Hospital Characteristics Factors Unadjusted Model Adjusted Model † Variables N OR 95% CI OR 95% CI Age <44 8803 1 1.00, 1.00 1 1.00, 1.00 44–54 5991 1.5 1.36, 1.58 1.65 1.51, 1.80 55–64 9744 1.8 1.69, 1.93 1.89 1.75, 2.04 >64 19,164 2.7 2.51, 2.82 2.88 2.67, 3.10 Missing 191 0.2 0.11, 0.25 0.33 0.20, 0.53 Social Economic Status Category 1 7061 1 1.00, 1.00 1 1.00, 1.00 Category 2 10,957 0.7 0.67, 0.77 0.8 0.74, 0.87 Category 3 or 4 or unknown 12,839 0.7 0.66, 0.76 0.78 0.72, 0.85 Missing 13,036 0.3 0.32, 0.36 0.3 0.27, 0.33 Sex Female 28,834 1 1.00, 1.00 1 1.00, 1.00 Male 15,059 1.1 1.04, 1.13 1.34 1.27, 1.42 Marital status Single 1528 1 1.00, 1.00 1 1.00, 1.00 Married or in union 20,191 1.3 1.12, 1.41 0.85 0.75, 0.97 Separated/divorced/widowed 9292 1.5 1.30, 1.66 0.84 0.73, 0.97 Missing 12,882 0.7 0.59, 0.75 1.24 1.04, 1.49 Hepatitis B Ag results Negative 38,922 1 1.00, 1.00 1 1.00, 1.00 Positive 880 0.5 0.39, 0.55 0.53 0.44, 0.65 Missing 4091 15 13.29, 16.60 109.4 95.49, 125.34 HIV No 29,622 1 1.00, 1.00 1 1.00, 1.00 Yes 1789 2 1.80, 2.31 2.51 2.20, 2.87 Missing 12,482 0.4 0.42, 0.46 0.49 0.41, 0.58 59 Unadjusted Model Adjusted Model † Variables N OR 95% CI OR 95% CI Hypertension No 29,048 1 1.00, 1.00 1 1.00, 1.00 Yes 2323 2.3 1.99, 2.54 2.05 1.80, 2.34 Missing 12,522 0.4 0.33, 0.37 0.12 0.11, 0.14 Ever been traditionally operated on No 25,212 1 1.00, 1.00 1 1.00, 1.00 Yes 6623 1 0.90, 1.02 0.9 0.84, 0.97 Missing 12,058 0.4 0.41, 0.46 0.66 0.45, 0.97 Ever been medically operated on 43,893 No 30,066 1 1.00, 1.00 1 1.00, 1.00 Yes 1853 0.7 0.60, 0.74 0.66 0.58, 0.74 Missing 12,755 0.4 0.41, 0.45 1.67 0.98, 2.83 HBV vaccination status Partially or fully vaccinated 5635 1 1.00, 1.00 1 1.00, 1.00 Not vaccinated 38,258 0.3 0.29, 0.34 0.49 0.45, 0.53 † Controlled for transfusion history, family history of viral hepatitis, and diabetes status 2.4.2.3 Dropout at HCV RNA Of the 48,680 individuals who screened anti-HCV positive, 10% (4787) did not return for HCV RNA testing (Figure 2). Table 2.2 shows the descriptive characteristics of those who were lost to follow-up at this stage. Our model found that patients who were 44–54 years old (OR: 0.58, 95% CI: 0.46 to 0.74) and 55–64 years old (OR: 0.4, 95% CI: 0.35 to 0.47) were less likely to drop out compared to those who were younger than 44 years old, while those who were above 64 years old had four-fold higher odds (OR: 4.54, 95% CI: 4.03 to 5.12). Other factors associated with lower dropout rates included being male, being HIV positive, being diabetic, having a family history of viral hepatitis, and being in a higher SES category. Factors related to higher dropout rates included being married or in a union, having community insurance, and not being vaccinated for HBV (Table 2.5). 60 Table 2.5: Unadjusted and Adjusted Associations between Dropout at HCV RNA Testing Stage and Socio-economic, Demographic, Clinical, Behavioral, and Hospital Characteristics Factors Unadjusted Model Adjusted Model † Variables N OR 95% CI OR 95% CI Age <44 8987 1 1.00, 1.00 1 1.00, 1.00 44–54 6250 0.6 0.51, 0.69 0.5 0.42, 0.59 55–64 10,081 0.48 0.42, 0.55 0.4 0.35, 0.47 >64 22,927 2.53 2.31, 2.77 4.54 4.03, 5.12 Missing 435 14.23 10.78, 18.78 491 328.16, 734.68 Social Economic Status Category 1 8224 1 1.00, 1.00 1 1.00, 1.00 Category 2 12,462 0.66 0.60, 0.72 0.77 0.70, 0.86 Category 3 or 4 or unknown 14,747 0.7 0.64, 0.76 0.95 0.86, 1.05 Missing 13,247 0.066 0.06, 0.08 0.011 0.01, 0.01 Sex Female 32,100 1 1.00, 1.00 1 1.00, 1.00 Male 16,580 0.86 0.81, 0.92 0.87 0.80, 0.95 Health insurance No insurance 7867 1 1 1.00, 1.00 Community insurance 39,312 0.71 0.65, 0.76 1.7 1.40, 2.06 Private or other government insurance (RAMA/RSSB) 1501 0.41 0.32, 0.51 1.13 0.82, 1.56 HIV No 32,449 1 1.00, 1.00 1 1.00, 1.00 Yes 1829 0.27 0.19, 0.37 0.37 0.25, 0.54 Missing 14,402 1.34 1.25, 1.43 0.18 0.10, 0.31 Diabetes No 33,611 1 1.00, 1.00 1 1.00, 1.00 Yes 693 0.68 0.47, 0.99 0.57 0.43, 0.76 Missing 14,376 1.43 1.34, 1.54 1.6 1.07, 2.40 Family history of viral hepatitis C No 32,958 1 1.00, 1.00 1 1.00, 1.00 Yes 1583 0.57 0.45, 0.72 0.63 0.41, 0.98 Missing 14,139 1.44 1.35, 1.54 0.28 0.16, 0.50 HBV vaccination status Partially or fully vaccinated 5701 1 1.00, 1.00 1 1.00, 1.00 Not vaccinated for hepatitis B 42,979 6.62 5.15, 8.51 8.77 6.66, 11.54 †Controlled for marital status, hepatitis B status, hypertension status and total number of hospital staff 2.4.2.4 Treatment Success (Achieving SVR) Of the 25,031 people who were HCV RNA positive, 12,940 (52%) initiated treatment, as recorded in hospital registers. Of these, 9332 (72%) completed treatment and returned for SVR assessment. 61 Our data suggested that 0.4% died in hospital before treatment completion, and 27.6% initiated treatment but did not return for their final assessment. The majority (80.4%) of people who died were above 64 years old. Of those who completed treatment and returned for SVR assessment, 8232 (88%) were cured (Figure 2.1). Of those who failed treatment, approximately half were above 64 years old, and 59% were female (Appendix A). As shown in Table 2.6, treatment failure was associated with increased baseline viral load (OR: 1.14, 95% CI: 1.02 to 1.28), having cirrhosis (OR: 1.71, 95% CI: 1.20 to 2.43), having had previous treatment for HCV (OR: 1.9, 95% CI: 1.34 to 2.70), and having a family history of HCV (OR: 1.57, 95% CI: 1.10 to 2.25). Table 2.6: Adjusted and Unadjusted Relationships between Treatment Failure, Dropout at SVR Assessment Stage, and Socio-economic, Demographic, Clinical, Behavioral, and Hospital Characteristics Factors Treatment Failure Dropout at SVR Assessment Stage N Unadjusted model Adjusted model+ Unadjusted model Adjusted model† OR 95% CI OR 95% CI N OR 95% CI OR 95% CI Baseline viral load 9332 1.12 1.04, 1.39 1.14 1.02, 1.28 - - - - - Age <44 1227 1 1.00, 1.00 1 1.00, 1.00 1591 1 1.00, 1.00 1 1.00, 1.00 44–54 1262 1.02 0.79, 1.32 1.34 0.93, 1.91 1571 1.02 0.83, 1.26 1.1 0.88, 1.39 55–64 2343 0.94 0.75, 1.18 1.18 0.86, 1.63 2968 0.96 0.80, 1.15 1.11 0.91, 1.35 64+ 4500 0.94 0.76, 1.15 1.12 0.82, 1.53 6754 1.9 1.63, 2.23 1.42 1.17, 1.72 Sex Female 5654 1 1.00, 1.00 1 1.00, 1.00 7939 1 1.00, 1.00 1 1.00, 1.00 Male 3678 1.01 0.87, 1.16 1.1 0.90, 1.33 4945 0.81 0.73, 0.90 0.76 0.67, 0.85 SES Category 1 1835 1 1.00, 1.00 1 1.00, 1.00 2573 1 1.00, 1.00 1 1.00, 1.00 Category 2 2541 0.97 0.79, 1.18 0.98 0.76, 1.25 3296 0.89 0.77, 1.03 0.96 0.82, 1.14 Category 3 or 4 or unknown 3224 1.15 0.95, 1.40 1.13 0.88, 1.45 5174 0.64 0.56, 0.73 0.73 0.62, 0.84 Missing 1732 1.41 1.12, 1.78 0.61 0.43, 0.86 1841 3.58 3.01, 4.26 2.53 2.08, 3.08 HIV positive No 7795 1 1.00, 1.00 1 1.00, 1.00 11,075 1 1.00, 1.00 1 1.00, 1.00 Yes 922 0.8 0.62, 1.03 1.09 0.81, 1.46 1125 0.31 0.25, 0.38 0.3 0.24, 0.38 Missing 615 5.92 4.73, 7.40 0.77 0.20, 3.01 684 0.07 0.05, 0.13 0.059 0.03, 0.11 62 Treatment Failure Dropout at SVR Assessment Stage N Unadjusted model Adjusted model+ Unadjusted model Adjusted model† OR 95% CI OR 95% CI N OR 95% CI OR 95% CI HBV Ag positive No 8873 1 1.00, 1.00 1 1.00, 1.00 12,291 1 1.00, 1.00 1 1.00, 1.00 Yes 140 1.27 0.79, 2.05 1.11 0.57, 2.18 274 0.86 0.57, 1.31 0.6 0.37, 0.99 Missing 319 2.8 2.00, 3.92 1.48 0.84, 2.63 319 0.73 0.54, 0.99 0.79 0.50, 1.22 Cirrhotic No 8898 1 1.00, 1.00 1 1.00, 1.00 12,440 1 1.00, 1.00 1 1.00, 1.00 Yes 434 1.12 0.81, 1.54 1.71 1.20, 2.43 444 0.06 0.03, 0.13 0.059 0.03, 0.12 Family history of viral hepatitis C No 8220 1 1.00, 1.00 1 1.00, 1.00 11,376 1 1.00, 1.00 1 1.00, 1.00 Yes 437 1.57 1.17, 2.12 1.57 1.10, 2.25 721 0.42 0.30, 0.57 0.14 0.08, 0.24 Missing 675 5.96 4.79, 7.42 3.62 1.07, 12.31 787 0.66 0.53, 0.81 0.18 0.08, 0.39 Ever been medically operated on No 8351 1 1.00, 1.00 - - 1 1.00, 1.00 1 1.00, 1.00 Yes 306 1.34 0.90, 1.97 - - 0.57 0.47, 0.68 0.39 0.27, 0.56 Missing 675 5.8 4.71, 7.29 - - 1.21 0.56, 1.40 1.44 0.89, 2.32 HBV vaccination status Not vaccinated 6985 - - - - 1 1.00, 1.00 1 1.00, 1.00 Partially or fully vaccinated 2347 - - - - 0.11 0.09, 0.13 0.14 0.11, 0.16 † Controlled for marital status, health insurance, hypertension, diabetes, and total number of staff. 2.4.2.5 Dropout at Final SVR Test Of the 3552 individuals who did not complete an SVR assessment, most were above 64 years old (N = 2273, 64%) and female, and the majority did not have comorbidities or a prior history of HCV. More details on descriptive statistics can be found in Appendix A. In our final model (Table 2.6), patients who were more than 64 years old (OR: 1.42, 95% CI: 1.17 to 1.72) were less likely to complete their SVR assessment. In contrast, males and patients with comorbidities, including HIV, HBV, and cirrhosis, were more likely to attend their final checkups. Finally, 63 patients with a family history of viral hepatitis (OR: 0.14, 95% CI: 0.08 to 0.24), those who had ever been medically operated on (OR: 0.39, 95% CI: 0.27 to 0.56), and those who were fully or partially vaccinated (OR: 0.14, 95% CI: 0.11 to 0.16) were more likely to undergo their SVR test. 2.5 Discussion HCV remains a significant source of morbidity and mortality in LMICs. The advent of lower prices for both DAA therapy and HCV testing has increased the opportunities for the treatment of a broader proportion of the population. Our study of the first 2 years of voluntary mass screening for HCV in Rwanda found that a notable proportion of the population was tested, and 2.9% of the total screened population was confirmed chronic HCV-positive. People who attended the screening campaign were, on average, older than the general population152 but had HIV and HBV prevalence that were comparable to the prior general population estimates.153 Of the nearly 13,000 individuals for whom we had records, HCV was cured 88% of the time. However, we also found a significant number of dropouts at each stage of the HCV care cascade, which merits attention in the design of future interventions. Anti-HCV Screening and HCV RNA Testing The observed HCV prevalence and viremia rate is consistent with the existing literature.13,112,153 The likelihood of HCV positivity increased with age and was inversely related to SES. As previously reported in other studies,147,154 HCV increases with age, mainly due to a history of unsafe medical procedures and unsterile injection practices in SSA.111,119,155 Our findings are consistent with prior studies in Rwanda,113,154 Tanzania,156 and Egypt157,158 that showed an association between HCV diagnosis and being economically disadvantaged due to low access to 64 preventive and treatment services. As reported in other studies, we also found that chronic HCV is more common in men than in women.159 HIV positivity and hypertension were associated with the presence of HCV. In our study, 7.2% of HIV patients had a positive HCV RNA test. A recent global meta-analysis reported that the odds of HCV were six-fold higher among HIV-positive patients compared to those who were HIV negative.160 As both infections have common routes of transmission, including needle sharing and contaminated blood products, the high coinfection rate is not surprising.161 In contrast, consistent with prior studies conducted in Rwanda and Morocco,119,162 those with HBV coinfection were less likely to be confirmed HCV positive. Treatment Initiation and Success In our study, only half of all diagnosed patients initiated treatment through a public hospital. HCV treatment initiation is still a significant challenge in SSA due to the limited availability of drugs.90 In Rwanda, healthcare providers have previously reported being out of stock of HCV medicines and testing commodities, which might have led to the low initiation rate observed.122 Similarly, a study conducted in Tanzania among people who injected drugs reported that none of the HCV-diagnosed individuals had initiated treatment.156 Our observed treatment success rate was similar to a prior study on the efficacy of ledipasvir/sofosbuvir, which found that 87% of patients in Rwanda achieved SVR12.101 Patients in both studies were treated with the first generation of DAAs. In two single-arm studies that evaluated the efficacy of the new generation of DAAs (sofosbuvir/velpatasvir and 65 sofosbuvir/velpatasvir/voxilaprevir), treatment success was above 90%.77 The difference in treatment success is mainly due to the use of the newer DAAs, which are known to have higher treatment success rates.77,163 Currently, patients with advanced stages of HCV or previously failed treatment are recommended to use the new generation of DAAs. 77,163 However, the availability of these medicines is still limited in many LMICs,90 which might explain the higher rate of failure in this group. In addition, it is essential to note that although patients are given medication instructions on timing and daily intake, adherence to these instructions and medications is still unknown. Treatment failure can also be associated with non-adherence to treatment. HCV RNA and SVR Testing Dropout Similar to previous studies,24,120,164,165 our study showed significant dropout at the HCV RNA testing and SVR stages. The older group was less likely to undergo HCV RNA and SVR testing, while those in the higher SES categories were more likely to attend. Similarly, Naveed et al.166, in their study describing the cascade of care for British Columbia, Canada, showed that the older generation had higher rates of dropout, while those with comorbidities, such as HIV and cirrhosis, were more likely to be in care. Comorbidities (HIV, HBV, diabetes, hypertension, and cirrhosis) and a family history of viral hepatitis also contributed to patients being more likely to complete HCV RNA and SVR testing. Unlike patients with a single disease, patients with multimorbidity are more likely to seek care,166 likely in part because they are aware of early treatment benefits, are familiar with the health system, and already have established relationships with healthcare providers. Additionally, they are aware that they are at an increased risk of death if not treated.167 Lastly, it should be noted that patients 66 received a complete regimen at once and that patients without a prior medical history are less likely to return for care.168 We also found that those with community insurance were more likely to drop out. It is important to note that although HCV medicines were free during the mass campaign, patients had to pay the costs associated with assessment tests. The HCV RNA test costs USD 9, which is equivalent to approximately 10,000 Rwandan francs.164 Patients who have insurance pay 10–15% of the total cost. However, the country still has approximately 40% of the population living under the poverty line,169 and this cost may be too high in many cases. Additionally, unlike other primary care services provided at the closest health centers, when the HCV mass campaign started, patients who screened positive were referred to hospitals for HCV RNA testing and had to return for a final viral load checkup after treatment completion. The burden associated with travel cost and distance might also have contributed to these gaps in service delivery. There was also low awareness and knowledge of HCV in the general population,170 which could be addressed through continued public education regarding HCV. Recently, the government has decentralized all HCV services to the low level of health facility (health centers),110 which is expected to improve public awareness and testing and treatment uptake. The HCV program has been integrated into the existing healthcare system. Further analysis assessing the impact of this change on the cascade of care and dropout estimates would be helpful. 2.5.1 Limitations Our study has some limitations that are worth noting. First, it is important to note that the mass screening and treatment campaign was voluntary in nature. Therefore, the characteristics of the people who participated may differ from those who did not. While this might limit the 67 generalizability of some findings, particularly the population rate of HCV infection, it would not impact the outcomes of the cascade of care among participants at the later stages. Second, our data were limited to what was available in patient records, which means that some important factors, such as distance to a health facility, use of injectable drugs, and sexual behaviors, could not be included. The patients’ records also only included deaths that took place in the hospital. Thus, patients who died in the community might have been incorrectly misclassified as lost to follow-up. We believe the bias associated with this misclassification would likely be small because of the relatively short follow-up time involved. In addition, the treatment initiation rate could only be calculated for those who had records in hospital registers. However, given the high cost of HCV treatment and the availability of free, publicly financed medicines in Rwanda, we are confident that the number we missed would be small. Finally, we had missing data for many of our variables of interest. However, we used a missing indicator approach in our analysis for each variable to utilize most of the sample in the analysis.151 In addition, both our reported missing indicator and complete case analyses resulted in similar findings. 2.6 Conclusion We found that the mass screening campaign reached many people, especially those with a prior history of viral hepatitis and other comorbidities. Our findings suggest that future HCV screening and testing interventions in Rwanda and other countries should focus on the older population, those with lower SES levels, and individuals with comorbidities. We also observed that the success rate was lower than that of patients treated with the new generation of DAAs, and we recommend further negotiation for the availability of newer combination DAAs, especially for cirrhotic patients and those who previously failed HCV treatment. Finally, efforts should be made to increase adherence to SVR assessment and the completion of all stages of care. 68 Chapter 3: Patients’ Healthcare-seeking and Treatment Experience during the Mass Screening and Treatment of Hepatitis C Virus in Rwanda 3.1 Synopsis Background: Early access to HCV treatment is crucial for long-term therapeutic success. However, this remains challenging, especially in SSA, which accounts for almost 20% of global infections. The introduction of newer and more simplified DAAs for HCV has led to the worldwide implementation of national screening and treatment programs. In this study, we investigated patients' experience accessing HCV care services during the mass screening and treatment of HCV in Rwanda. Methods: We conducted one-on-one semi-structured interviews with 15 patients who were screened and initiated treatment during the campaign. Study participants were from four provinces, and interviews took place at five different hospitals across the country. We transcribed and translated interviews verbatim from Kinyarwanda to English alongside field notes. A thematic approach guided our analysis, and in the findings, we incorporated direct quotes to assist with analytic trustworthiness. Findings: We identified three themes and nine sub-themes related to screening, HCV RNA testing, linkage to care, and treatment. Many patients appreciated the availability of free treatment, communication with healthcare providers, and opportunities for screening for other diseases. Challenges encountered included delays in test results and treatment initiation, lack of privacy and 69 counseling, inadequate follow-up, and the unavailability of alternative treatments for those who failed. Conclusion: This study highlights patients' experience with HCV testing and treatment services during a mass screening and treatment campaign in Rwanda. Although patients faced several challenges, the campaign's contribution to the reduction of HCV was shared by all participants. Future HCV intervention in Rwanda should focus on timely access to HCV services and improvements to patient follow-up. 70 3.2 Background Early access to HCV treatment is crucial for long-term therapeutic success and plays a significant role in reducing HCV-related diseases, mortality, and transmission.149,171 However, it is still globally challenging, especially in SSA, a region that accounts for almost 20% of global infections.23,172 The seroprevalence of HCV in SSA is approximately 3%, with a higher seroprevalence of 12% in high risks groups such as people who inject drugs, HIV-positive patients, or those who have received blood products.173 Although the burden of the disease is high in SSA, the access to HCV treatments and diagnostics is limited due to resource constraints.90 Pharmacological treatments for HCV have evolved rapidly in recent years, most notably in the development of DAAs.55 Previous therapies required the use of costly interferon-based drugs administered at health facilities through multiple injections per week and had a high risk of side effects. High costs combined with cumbersome administration meant that most HCV-infected individuals within SSA did not access treatment. The introduction of DAAs that are administered orally, are generally well-tolerated, and are highly effective has allowed countries to reduce the disease's health and economic impact.90,111 After launch, some DAA patent-holders introduced differential pricing and licensing strategies to improve accessibility to countries with limited resources.90 While in many high-income countries, patients still pay standard prices, many LMICs now pay lower prices for these drugs. Rwanda was among the first seven African countries chosen to implement this new plan.90 Following the price reduction for DAAs, the Government of Rwanda launched a mass screening and treatment of HCV across the country in 2017. In addition, in December 2018, the government 71 launched a 5-year national elimination plan to achieve elimination by 2024.110 Through this campaign, the Rwanda MoH planned to screen 7 million individuals and treat more than 110,000 patients.110,145 To date, more than 7,000,000 people have been screened across the country, and approximately 60,000 with a confirmed diagnosis have been initiated on treatment free of charge. This large-scale screening and treatment program was the first of its kind implemented in SSA.110,174 In order to inform the continued development of treatment in Rwanda and to share lessons with other similar countries, we sought more information on patient experiences with this campaign. Previous qualitative studies of HCV patients conducted in Rwanda before the mass campaign and free treatment era found that patients encountered financial hardship associated with out-of-pocket payments for HCV testing services and treatment.122,123 Other challenges included the lengthy period of care resulting from geographically separated testing, treatment, and follow-up sites; a lack of access to HCV specialists; misdiagnosis; and lack of HCV knowledge among healthcare providers. 123 Patients reported that what encouraged them most to seek care was supportive family members and healthcare providers, the curability of the disease, and less stigma in the community.122,123 Although these studies provided information on HCV patients’ experience in care, the reported views represent patients who sought care before the recent campaign. Therefore, it is crucial to investigate patients’ experience accessing HCV care services in the present campaign. In the current study, we investigated if and how patients’ experiences have changed since free treatment coverage began. Additionally, we sought patients’ perspectives on the implementation of the 72 program and their recommendations to facilitate the successful treatment of HCV in Rwanda. Finally, we also investigated the challenges patients encountered accessing care. 3.3 Methods 3.3.1 Study Design This analysis was part of a larger study on the cascade of care for hepatitis C in Rwanda for the 2017-19 mass screening and treatment campaign cohort. This qualitative study was a primary data analysis of in-depth interviews conducted with HCV patients who were HCV positive and were diagnosed during the HCV campaign. 3.3.2 Study Site and Settings Rwanda is a small country in East-Central Africa with a population of approximately 12 million, of which 80% live in rural areas.176 The country is divided into five provinces: the Northern Province, the Southern Province, the Eastern Province, the Western Province, and Kigali City. Each province has about five to eight districts, except for Kigali City, the capital city, which has three districts. The study was conducted in four provinces, and HCV patients were from five districts: Nyarugenge and Kicukiro in Kigali City (urban), Musanze in the Northern Province (rural), Muhanga in the Southern Province (rural), and Bugesera in the Eastern Province (rural). To increase the diversity of participants' perspectives on campaign implementation across the country, we consulted with the hepatitis program team at the MoH to assess potential district hospitals for inclusion in the study. The study sites were purposively selected considering geographical and economic diversity. We collected data in rural and urban settings to investigate similarities and differences in intervention implementation in the two settings while considering 73 the participants' socioeconomic characteristics. Data collection took place in the following hospitals: Kigali University Teaching Hospital (Teaching hospital in Nyarugenge district); Ruhengeli Hospital (Referral hospital in Musanze district); Masaka Hospital (District hospital in Kicukiro district), Kabgayi Hospital (District hospital in Muhanga district), and Nyamata Hospital (District hospital in Bugesera District). 3.3.3 Participant Recruitment We selected study participants using a purposeful sampling method. In each district, we invited individuals who participated in the mass screening and received HCV care from district hospitals to participate in the study. This sampling method is common in qualitative studies and allows the selection of participants based on pre-determined criteria.177 Since the intent of this study was to obtain the perspectives of patients who achieved SVR and those who failed treatment, purposive sampling allowed to include participants from each of these groups. We interviewed individuals who had participated in the mass screening and followed HCV treatment in the hospitals where their diagnosis was confirmed. We aimed to speak with individuals who had lived in their current district for at least one year to ensure they participated in all stages of the cascade of care in the same area. We recruited participants with the help of the HCV mentor at each hospital. Each hospital has an HCV mentor who oversees contacting patients and reminding them to return for additional tests or pick up drugs. We shared the identification number of participants selected for interview from our quantitative analysis with the mentor at each selected hospital. The mentor used this information to identify contact information from patients' files, and he/she was the one who initially contacted the participants. The mentors then provided written and verbal information about the study to potential participants and explained the 74 study's objective and any benefits associated with participating. Twenty-five potential participants received information, and 20 contacted the interviewer to gain more information about the study and agreed to schedule an interview. Recruitment and data collection was guided by a temporal cut-off, which was the point at which our fieldwork was scheduled to end. We conducted interviews in October 2021. The interviewer, who is Rwandan and fluent in Kinyarwanda (Rwanda’s national language), arranged to meet each participant who had agreed to participate in the study at a location of their choice. This was typically at or near the district hospital where the individuals received HCV treatment. To maintain confidentiality, the HCV mentors were not informed who ultimately participated in the study. We provided participants with Rwf 5,000 [~US$4.50] to incentivize participation and cover transportation costs. 3.3.4 Data Collection and Management We used a semi-structured questionnaire (see Appendix C.3) to guide the in-person interviews and asked questions to elicit views from participants on their experience of HCV mass screening and treatment. We conducted interviews in Kinyarwanda and the questions focused on the following main themes: 1. Access to HCV screening (including guidance on screening and site characteristics); 2. HCV RNA testing (how participants were informed of their tests results, including the location and explanation of their results, the turnaround time of the results, privacy considerations, and the description of the next steps after receiving the results); 75 3. Linkage to care and treatment (wait times to initiate treatment, financial considerations, information on treatment, experience with treatment success and failure, and communication with healthcare providers, and; 4. We gathered information on participants’ experiences living with HCV to gain a thorough understanding of any stigma or support patients might have experienced along the journey of living with the disease. The interviewer started by asking participants for socio-demographic information to help the research team better contextualize the data. Interviews lasted between 45 to 70 min and were audio-recorded with participants’ permission. Body language, as well as field notes, were also captured and incorporated alongside interview transcripts. 3.3.5 Data Analysis Our analysis was guided by a thematic approach.178 In the interest of research team members who were not fluent in Kinyarwanda and for dissemination purposes, interviews were transcribed and then translated verbatim from Kinyarwanda to English alongside the field notes. The analysis consisted of an independent review of transcripts by two research team members (MPN & GT). The two created a coding scheme and coded transcripts in NVIVO™ software according to conceptual and practical topics that formed an understanding of the experiences of individuals who participated in HCV mass screening and treatment. A meeting was then held by the research team to discuss emergent themes and identify potential codes. We reviewed coding extracts to confirm the scope and scale of the emerging themes. Consistent with thematic analysis, the themes were also contrasted against existing knowledge of the topic to identify novel contributions. In findings, we incorporated direct quotes to assist with analytic trustworthiness. We use direct quotes to illustrate the themes better and let participants' voices speak to the data. 76 3.3.6 Ethics and Informed Consent This study was approved by the Rwanda National Ethics Committee (028/RNEC/2021) and the Research Ethics Board of the University of British Columbia (H21-03745). Before beginning data collection, the interviewer read the consent section (Appendix C.2) describing the activity and outcomes of the study to the participant and obtained verbal and written consent from participants before starting the interview. Participants were assured of confidentiality, anonymity, and freedom to withdraw from the study at any time. Participants also received an information sheet (Appendix C.1) containing all details in Kinyarwanda (local language) regarding the study, their role, and their right not to answer any question(s) and to stop the interview at any time. Any information which included identifiable information, such as information extracted from patient records, audio tapes, and transcripts, was encrypted and stored on password-protected computers. In the analysis, we used the de-identified data from each participant. 3.4 Results The study reached the saturation point at 15 interviews with adult patients who were screened between April 2017 and October 2019. All participants had completed all stages of the HCV cascade: anti-HCV screening, HCV RNA confirmatory testing, treatment initiation, treatment completion, and sustained virologic response assessment. Eight were cured by treatment and 7 participants failed treatment. We had intended to include patients who dropped out at different stages of care; however, those who received an invitation refused to participate, and our attempts to contact other patients who dropped out of care were not successful. The participants ranged in age between 27 and 81. Participants had a broad range of marital statuses, including single, married, or widowed. Participants had between one and five children. Most participants lived with 77 their children, in addition to other family members. Table 3.1 has more details on participants characteristics. Table 3.1: Study Participants Characteristics Participant ID Age Highest Education level Sex Marital status Occupation Treatment outcome Comorbidities 1 62 No education Female Married Agriculture Failed Hypertension 2 81 No education Female Widow Agriculture (retired) Failed Hypertension, thrombosis 3 47 High school Male Married Construction Cured None 4 68 Primary school Male Widow Agriculture Cured None 5 49 Primary school Female Widow Social worker Failed Anemia 6 69 High school Female Married Trade Failed None 7 59 High school Female Widow Unemployed Cured Intestinal problems 8 60 No education Female Widow Unemployed Cured HIV 9 62 Primary school Female Widow Farmer Failed HBV, cirrhotic 10 47 High school(S3) Male Married Farmer Failed Liver disease, cirrhotic 11 37 High school(S3) Female Married Farmer Cured None 12 67 No education Female Widow Unemployed Failed Hypertension/HIV 13 60 Primary school Male Married Trade Cured Hypertension 14 61 No education Male Single Security guard Cured None 15 27 No education Male Married Mining Cured None We categorized participants' experiences in the mass screening and treatment campaign into three themes. The first theme—responding to community-level HCV screening, included participants' experiences on their participation in HCV screening: how they got information on mass screening, testing wait times, privacy, and results turnaround time. The second theme—circumstances and perceptions related to confirmatory testing, included information related to the HCV RNA test at the hospital, including wait times and process details. The third theme—experience of linkage to 78 care and treatment, relates to lived experiences after diagnosis and initiation of treatment, including wait times, financial considerations, treatment success or failure, communication with healthcare providers, and psychosocial support system from healthcare providers, friends, and family. Under each theme, we included sub-themes that emerged during our interviews. A summary of the main themes is shown in Appendix B. 3.4.1 Response to Community-level HCV Screening Mass Screening Participation Through the campaign initiatives, individuals had the opportunity to get tested at the closest screening center. Participants' experiences varied depending on their location. Most participants explained that they walked to these places voluntarily to get tested once they learned about the campaign. Others shared that they did not know about the mass screening but realized it was happening when they were passing where it took place and saw crowds of people. For example, one participant said, "I was lucky to have had someone who informed me about the campaign. I fear having an illness at any organ in my abdomen; that is why I was interested in going for screening voluntarily, without having any signs or symptoms.” Although the participant did not know about the campaign, they mentioned that the event was broadly broadcasted and added the following: “I remember when they tested us, there were journalists, and the screening event was among the news headlines that were broadcasted at 12h45pm on television; I spoke with a journalist, and it was at the stadium”. Different news channels were established and information on mass screening was broadly shared through different news outlets. Despite this, however, some people remained unaware of the program. For example, some participants revealed that they learned about the mass screening when 79 they were passing by a site where it was happening, such as markets, stadiums, or health centers as mentioned by one of the participants: “I was going to the health center for my baby’s immunization, and there was a team of health care providers who were carrying HCV screening equipment, and that is how I got tested.” Other participants attended the mass screening because they suspected they had a medical condition: “I had some symptoms – sometimes, I would feel pains here [stomach], and I wanted to scratch there. When I heard about the screening program, I attended to know what might be causing that pain.” Potential Benefit of a New HCV Program Some participants attended mass screening because they had previously failed treatment or could not afford the treatment before the campaign. For example, one participant said, “Well, I thought I could again get medicines; because it was a mass screening opportunity, I just went there like anyone else. Like all other people, I behaved as if I didn’t know anything.” In this case, the participant did not reveal the previous diagnosis and treatment outcome to the healthcare providers at the mass screening, hoping to have a negative result, “because sometimes, I could feel that I had some strength, and I told myself maybe I have already recovered…I just trusted my health because I didn’t have any other option…I went there, and they diagnosed me with it again.” Other participants revealed that the mass screening was an opportunity to be part of the new program and benefit from free treatment since they could not afford HCV medicine in the past. This was emphasized by one participant who said the following: “They charged me around 1.2 million [Rwandan Francs], but I couldn’t afford that! I told them, ‘Okay, whether I am destined to die, I’ll die; and if I’m to recover, I’ll recover. God will do what he wants with my life.” The participant shared how relieved they were after learning about the mass screening: “Then came mass screening, and I attended!” 80 Participants were also informed about the advantage of getting tested, including early diagnosis and free treatment: “I was lucky to have had someone who told me that those who will be tested positive would receive free treatments." As emphasized by this participant, getting tested through mass screening was not convincing enough for people to participate voluntarily in the program. However, knowing that they would get free treatment if they had HCV was reassuring for them to undergo screening. "The screening campaign went well. I wonder why some people fear getting tested when there are free medicines for hepatitis – I used to think like such people, not caring about getting tested. I believe community sensitization is necessary". This suggests that the campaign provided access to services and treatment and improved awareness in the general population about HCV and other diseases. Most participants were happy that they were part of the program and could be tested to know their status. Another participant emphasized the benefits of getting tested and the opportunity of receiving treatment free of charge: Some people have died without knowing their diagnosis… Some people had hepatitis C when they had never known about the illness; their liver had swollen, and they quarried with others, claiming they were the victim of poisoning. My friend, some people died thinking that they had been poisoned! This parent of ours [The President] who thought and found sponsors to come and conduct voluntary screening has removed confusion for many people. In addition to HCV screening, the campaign team tested participants for other health conditions such as HIV, hepatitis B, and hypertension. Participants shared that they appreciated these services 81 because they helped them know their health status even though some never considered getting checked for such health conditions: “Many people are surprised to discover they have other illnesses through screening services. I learned that I have hypertension… I didn’t know…I never thought of getting my blood pressure checked at the hospital because I didn’t have any health-related concerns”. Participants received this well and considered it one of the benefits of participating in the mass screening. Wait Times for Screening and Results Turnaround Alongside this positive aspect, participants also noted some challenges they experienced. In particular, the turnaround time for results was noted as an issue by several respondents. For example, one participant said, “Everything went well except that the results were delayed so much and that we started getting bored of waiting for them – they delayed but, in the end, we got them. It took so long before we got them; it took like six months or seven months.” Here, the participant was referring to how long they waited for the results, without knowing when exactly they would receive them. Another aspect that discouraged people from appreciating the process was wait times during the screening. For example, there were cases of individuals who had to go to screening centers a few times before they got tested due to the long queues and wait times: “There were so many people waiting to get screened, the stadium was full, and some people were told to return home and come back the following day.” 82 3.4.2 Circumstances and Perceptions Related to Confirmatory Testing HCV RNA Test Results Turnaround Delays As part of the campaign, those who got a positive anti-HCV test had to get a confirmatory test (HCV RNA) at a district hospital. Participants shared their experiences learning about their HCV RNA test results and how they were informed of the next treatment steps if they were confirmed HCV positive. The wait time varied between places and ranged between one to three months, depending on the resources and hospital lab capacity to perform viral load tests. One participant mentioned: “The results were available two months after the test. I went to the health center, and they gave me a paper, and I can remember well, on the paper was my viral load, and they said that I should come back to meet with the doctor.” Participants either were given an appointment to return to the health center or district hospital (whichever is the closest) or could call to get the results. Due to the low number of viral load testing sites, there were delays in viral load turnaround time across all hospitals, as shared by another participant in the following: The test was taken in August, and the doctor told me to call back early in September. Later, I called back… sorry I didn’t call… I just went there [to the hospital]. They told me: “Not yet. We even do not have the results for the samples that were taken in June; the results have not yet been returned here”. Then I waited a bit more, but then I had an idea of visiting Legacy Clinic in Kigali. When I arrived there, they said that I must go to Kanombe Hospital, and when I arrived there, they also took the same test. They also told me to wait for the results for a month….Oh my God! When you have been informed of your illness but do not get medications for it, you feel disappointed! 83 A few participants shared their feelings and experiences of waiting for the results and the toll it took on them, as expressed in the following: “I kept coming to get my results, but they would tell me they do not have them yet…I was tired of going there and always being told the same story, let alone transportation fees which were difficult to get.” Most notably, those in rural areas shared that the results took a long time due to the lack of testing sites at the nearest health facilities. Even though most participants experienced delays in getting their results, some of them revealed that the wait times were not unusual since they were familiar with long periods of waiting for lab test results at their respective hospitals: “One month after the screening, they told me that I had a liver problem. The following day, I went to our health center, which referred me to Kabgayi Hospital. I had medical tests when I arrived, and they gave me medicines.” Privacy Concerns during Results Delivery In addition to delays, there were concerns about how patients were informed about the test results, either on the phone or at the hospital, with no proper privacy or counseling. For example, when asked how she was informed of the results, one interviewee said, “Healthcare providers showed me the results on an HCV test kit. It indicated that I was diagnosed with HCV. I was in a hall when they told me, but they used a low voice while talking to me.” In other instances, privacy concerns were also experienced in communities when the participant received information about results, which they got through a phone call as one participant mentioned: “I received a call when I was with my friends where I live, they told me that I tested positive for hepatitis C, and I had to go to the hospital, my friends asked me who called me because I looked concerned after the call.” 84 3.4.3 Experience of Linkage to Care and Treatment Initiation to Treatment and Adjusting Lifestyle Participants shared their experiences with HCV treatment, including those who were cured and those who failed treatment. The experiences were a combination of gratitude, individual circumstances, such as financial constraints, and others related to lifestyles. For example, participants shared how they had to change their diet once they were on treatment: “The healthcare provider advised not to take alcohol, smoke, or take traditional medicine while taking the HCV treatment.” Another mentioned that: They advised me to stop eating fatty meat and too much oil in food. They recommended that I eat little salt in the food.” Some participants made their own adjustments: “I started doing all my best, and I lived on a healthy diet because I had some money at that time, trying to avoid losing weight so people would not realize my problem. This illness is a serious burden.” Participants shared other adjustments they had to make, including those related to smoking: “I used to chew tobacco… I didn’t smoke cigarettes. They told me that the reason I did not recover was that I used smokeless tobacco… so, I decided to give up chewing tobacco.” Others were forced to make work-related changes, especially if it involved heavy physical activity: “I used to be a farmer, but nowadays I cannot go to the land and cultivate; my legs swell and become numb and sore. Besides, I become short of breath, and I cannot walk an uphill path either”. Despite challenges associated with making lifestyle changes, participants were grateful for healthcare providers' explanations of medication. For example, most participants shared that they were told when to take the medicines and were urged to report any issues resulting from taking them. "They told me to choose a comfortable time in the day to take the medicines at the same hour 85 every day. I was told to take a pill from the tall and short capsules daily. I had chosen to take the pills at 9h00." As such, participants were able to stick to a consistent schedule of when to take their medication. Treatment Initiation Delays One of the main issues that was shared among participants was the long wait periods to get initiated on medication, as suggested by one participant who was ultimately cured: “I waited for the drugs for six months. When they become available, they called me on the phone, and they asked me to come and receive my medicines. I met with many other people, everyone had their own appointment; there were many of us, to the extent that when they gave us numbers, we were 80 people and above.” The delay in receiving medication was emphasized by another participant: “I was impatient about receiving the drugs – because, when you are ill, and you do not get medication on time, you become so worried. For me, I had been traumatized by the lack of medicines." The wait times to get drugs was also experienced by those who failed their first course of treatment, as expressed by some participants. Patients who failed the first course of treatment had been promised to get the second line of treatment, and when we conducted interviews, some of them were still waiting for treatment and did not know when it was going to happen as this patient mentioned: Do you know how it feels to wait for medications when you are ill, but you cannot pay for them? Do you know that when you have someone hospitalized, they do not discharge them unless they die? You see, they tested me and said I still have the illness. They said that there is still little of the disease, which the lacking pills would clear out. I have taken so many 86 drugs in vain! I know they cannot care for me alone because the government has many people to look after. So, you can tell the sponsors to see how we can get those medicines. I am still alive, but now and again, I think, If only I could get those pills, I would recover. Maybe I would have recovered had I got those pills! The above quote highlights one of the challenges encountered by those who failed treatment multiple times. Financial Burden Associated with HCV Despite these challenges, patients reported being lucky to get free treatment, especially those who knew how expensive HCV treatment used to be and were financially inaccessible to many. For example, one participant who was also HIV positive said the following: “I used to work in a hospital and knew that HCV treatment was only for rich people…when I got diagnosed with it, I thought I would die shortly … I could not afford the treatment … I am grateful to the government for making sure that everyone can be treated.” Another participant who first diagnosed with HCV before the campaign mentioned: “I was received by a doctor whose name was [name], and he told me to take medicines, sorry he told me that I should take injections, and I failed to pay for them because I did not have money.” The financial constraint was also mentioned by participants in relation to paying fees associated with additional tests and drugs for those who did not respond to treatment multiple times. One participant said: "He told me it happens that medicines do not work, so at a certain point, you start paying for it because there is a limit that we cannot go beyond... you have taken the medicines, 87 and they are worth millions, and they could have cured many people; so, go and try to find money on your account." Some participants could not get laboratory tests because of lack of insurance and testing fees, as mentioned by one participant: "I was told to pay (16,100 RWF) for one laboratory test; otherwise, I would not get it. I went back home the next morning without taking the lab test." In addition to consultation and laboratory fees, transport fees were also a barrier for some patients: "I came from [location], and I paid more than 1,000 francs for round trip transport, plus the money you pay for healthcare services you get here.” As described in this section, the campaign reduced the burden associated with the high cost of drugs. However, there were still financial constraints related to testing and transport costs, as well as the cost of alternative treatment for those who failed DAAs multiple times. Patient Counselling A few patients felt that there was more that could have been done by healthcare providers in terms of explaining the disease, in addition to telling them how to take medication: "What I can add is that I wish they explained to us the illness that we have, and they must tell us why we have those illnesses; they should not just give us medicines and leave us alone." This quote links to participants' experiences with the healthcare system, as shared in different aspects of the program. The following section underlines the experiences with SVR assessment for those who failed and those for whom treatment was successful. Most participants developed a close relationship with their healthcare providers and would call them to ask questions and tell them how their health status was evolving. They also spoke about using this opportunity to ask other healthcare- 88 related questions. Some participants had other infectious diseases, such as HIV. These patients had an existing relationship with the healthcare providers and felt more comfortable seeking healthcare and advice. However, a few participants thought that they did not get the needed support other than being given the medication and being told how to take them: They gave us medicines, and we followed the instructions they gave us. However, they did not call any patients and ask them halfway through about their experience with the medicines. This should have happened, mainly because you may take your medicines an hour later than the usual time. No patient could ask questions like, “I have taken the medicines at a late hour; what should I do?” They gave us the medicines but just abandoned us and waited until we returned to inform them that we had finished them. So, I wish that if they give us medicines for three months, they should call us at the end of one month and a half and ask us “How are things going? Are you okay?” or “Are you taking the medicines properly?” I must teach them to start doing this. You said the medicines are costly, so once they give them to you, they should check on you to know how you use them and your experience. The above quote speaks to how much hope HCV patients we talked to had in the program. However, it was not always responding to everyone’s needs, which they attributed to the insufficient capacity of the healthcare providers to accommodate situations where the patients had to be on treatment for extended periods. 89 Participants shared their experiences related to SVR, and those who were still on treatment after failing the initial cycle expressed their feelings: “They keep telling me that I have not yet recovered… I do not understand why; considering all the medicines I have taken…I never skipped taking pills nor did do anything wrong…I did everything according to the doctor’s instructions…I wonder why I am not recovering!”. Some participants felt judged by healthcare providers who told them that they were not taking medicines properly. As a result, the treatment failed: “He assumed that I did not take medicines properly; whereas I did not do anything opposite his instructions…I am eager to recover…there is nothing that could prevent me from following instructions... I wonder why the treatment failed but cannot find any answer.” In some instances, there was confusion on next steps after failing treatment: After 6 months, I returned to the hospital…When I returned, I told him that the medicines had finished – we had to come with empty capsules to show the healthcare provider that we had used all the medication completely. He told me, “You must spend another 3 months without taking any medicine. Go back home; I will call you to come and have another check-up”. After 3 months, I returned to the hospital, and I had another test to check if the viral load had reduced. The results of those tests delayed, and I waited for them for one or two months. I would often come here out of impatience; every time they looked at my appointment, they found that I had come before the results were available. One day, I came after one month and a half or after two months, and he asked me, “What’s the matter?” and I said, “I am here to get the test results. He asked me for my name, and he looked into the file, and he said, “You no longer have the problem.” 90 The above quote shows participant’s lived experience of wait times for test results for SVR test and lack of proper explanation on the reasons why treatment failed. The feeling of confusion was shared among all participants with failed treatment. 3.5 Discussion In this study, we identified nine themes related to screening, confirmatory testing, linkage to care and treatment. Overall, our findings show that patients had a mixed experience with the campaign, as they both expressed their appreciation and noted several challenges associated with delays in access to healthcare services. Relieve of Financial Burden Associated with Costly Drugs Participants were grateful for the intervention, especially those who could not afford medicines before the campaign. Also, participants shared that the campaign was an opportunity to know their status for other diseases due to the screening services. Before the price reduction policy, most patients could not receive any further services beyond diagnosis.111 The treatment was costly,90 and patients largely had to pay out of pocket. Further, Rwanda had only four HCV specialists who were operating in four referral hospitals. Only the HCV specialists could enroll patients in care and prescribe medicines across the country. Additionally, insurance companies were not fully covering the cost associated with HCV tests and treatment.122 The high price of drugs and the lack of HCV specialists in the country led to many diagnosed patients being untreated.14,111,122 The campaign was an opportunity for previously untreated patients to get free drugs and for undiagnosed people to know their health status. 91 Delays in Testing Results and Treatment Initiation We found that screening services did not necessarily translate into immediate access to HCV care and medicines due to delays in laboratory results turnaround and treatment initiation. HCV diagnosis involves two steps (screening for HCV antibody and HCV RNA testing), which often leads to the loss-to-follow up along the HCV care cascade. HCV RNA testing requires advanced laboratory equipment and trained personnel, which are still limited in many SSA countries.149 Lack of equipment and staff leads to fewer testing sites and delays in testing results turnaround time. A study conducted in Rwanda found that only 45% of study participants with positive HCV RNA results were assessed for treatment initiation within 90 days, while 33% of screened people did not have their HCV viral load returned within 30 days.121 These issues are associated with higher drop-out since patients get tired of waiting for results and stop returning for care.179 Especially patients who are asymptotic and do not see any treatment urgency.180 Patients also reported issues related to delays in treatment initiation after getting all results.181 Serumondo and colleagues, in their study with HCV patients and healthcare providers in Rwanda, found similar results and reported that stock-out of medicines and laboratory commodities and a low number of HCV RNA testing sites were the major factors contributing to delays in test results and treatment initiation.122 Currently, the Government of Rwanda has decentralized HCV services to the health center level, and more testing sites have been created, which is expected to reduce the results' turnaround time.110 Further, the price reduction for drugs combined with voluntary licensing for generic versions of HCV drugs is expected to increase medicines availability in LMICs.90 92 Testing and Transport Cost Burden Although there was a relief of cost associated with HCV drugs, patients still paid testing fees and transportation for those who live far from screening centers and hospitals. The cost of screening in Rwanda is approximately 1 USD, while HCV RNA costs 9 USD, equivalent to 10,000 Rwandan francs (unpublished internal report). Rwanda has universal health coverage, and nearly 90% of the population is covered.107Those covered under this scheme only pay 10% of the total cost. However, the country still has approximately 40% of the population living under the poverty line,182 and this cost is still high for them, and those who are uninsured pay the total cost out-of-pocket. Additionally, some patients have to travel to get testing and treatment services. The previous qualitative studies in Rwanda and elsewhere have reported similar testing and travel cost issues and associated consequences, including lost-to-follow and delays in treatment initiation.122,123,181 Privacy and Counselling As reported in other prior qualitative studies,181,183 our findings show that some patients did not receive counseling after diagnosis or received test results via a phone call or in public locations. Given low awareness about HCV in the Rwandan community,184 the chronic nature of the disease, and the financial burden that comes with treatment, HCV diagnosis might affect patients' mental health.181,183 Additionally, many infectious diseases are associated with high stigma in the community123; therefore, ensuring that results are delivered privately by a counselor or healthcare provider is vital for patients' security and well-being. The mass screening was conducted in Rwanda when many people were waiting to know their status, and other patients had waited for treatment for a while. Therefore, the centers were mostly crowded, and privacy was not always 93 possible. Current task shifting interventions should consider incorporating counseling services and where and how these services should be provided.109 Communication with Healthcare Providers Most patients acknowledged healthcare providers’ explanations on how to take medicines and advice on lifestyle changes. They also appreciated providers who provided detailed information about HCV transmission, and benefit of early diagnosis. However, in some cases, there was a lack of communication on the next steps and follow-up during the treatment period. A similar qualitative study conducted in Cameroon among HCV and HBV patients found that miscommunication about results and treatment follow-up was common. This led to low patient knowledge or misinformation about the disease and increased patients stress.181 A lack of patient follow-up is prevalent in a health system with critical staff shortages.185 For example, HCV nurse mentors and doctors in Rwanda are also in charge of HIV patient follow-up and daily healthcare activities; therefore, they have multiple responsibilities and less time to do adequate follow-up. A qualitative study conducted in Rwanda with HCV healthcare providers reported a heavy workload and inability to have regular check-ups with patients for providers who manage both HIV and HCV patients.122 The task shifting of HCV services to the lowest level of healthcare have been implemented and more personnel have been trained in HCV care as part of the elimination plan.110 We recommend a study assessing how the decentralization policy might have shifted patients ‘perception about HCV follow-up care. 94 Unavailability of Second Line Drugs Our study participants included patients who had failed treatment several times and shared their concerns about the unavailability of second-line options. During the study period, the only DAAs that were available in Rwanda were sofosbuvir/ledipasvir and sofosbuvir/daclatasvir. The course of treatment for DAAs is usually 12 weeks. Patients who fail the first course of therapy are given similar drugs for extended periods (24 weeks). Contrary to high-income countries with more DAA options,90 the prescription is determined based on a fibrosis assessment. This assessment determines the duration of treatment and drug choice. This is not the case in many LMICs due to accessibility issues with different DAAs and the complexity of liver tests. As the country implements new HCV elimination strategies, it will be important to negotiate further price reductions for newer generation of DAAs (sofosbuvir/velpatasvir and glecaprevir/pibrentasvir) which have higher efficacy. This could increase the overall cure rate and allow patients who fail first course of treatment to have alternative options. 3.5.1 Strengths and Limitations This is the first qualitative study to explore patients’ experience with HCV testing and treatment during the 2017-19 mass campaign. We included the perspectives of patients who were cured and those who failed treatment. However, our study did not have the view of those who dropped out of care. Although their experience in care might be different from patients who remained in care, we believe that the current study highlights several challenges encountered by the campaign participants that might have influenced their choice to leave care. Lastly, we did not include healthcare providers’ and policymakers’ perspectives. Therefore, we recommend that future qualitative research explore their views on HCV care during mass screening campaigns. 95 3.6 Conclusion Overall, our study suggests that individuals who have been part of the campaign and underwent treatment appreciated the services they were receiving, but also had several concerns that could be mitigated in future programs. Although patients faced several challenges, the program's contribution to the reduction of HCV was shared by all participants. Future and current HCV elimination interventions should focus on improving access to timely testing results and treatment initiation. Some immediate steps that might help in this regard include integrating HCV services into primary health care, making HCV services accessible to the lowest level of health facilities, and simplifying HCV service delivery. The existing HIV infrastructure can be leveraged and could act as a bridge toward efforts to eliminate HCV in Rwanda. 96 Chapter 4: Assessing Global Disparities in Access to Hepatitis C Medicines before and during the First Phase of the COVID-19 Pandemic 4.1 Synopsis Background: The introduction of DAAs has allowed countries to reduce the health and economic burden of HCV. However, access to DAAs remains expensive and limited in many countries globally due to wide disparities in HCV drug pricing. We assessed how global use of HCV drugs has changed over time and the effect that COVID-19 might have had on DAA utilization. Methods: We assessed longitudinal changes in DAA sales by country income group, geographical region, and drug type. We also conducted an interrupted time series analysis to assess COVID-19 related changes in the trend of DAA units sold globally. Our analysis used DAA sales data from the IQVIA multinational integrated data analysis database (MIDAS) of 52 countries and two regions and HCV prevalence data from Polaris from 2014 to 2020. Our primary outcome was the monthly rate of DAAs sold per 100,000 people living with HCV per country, country income group, and geographic region. We then compared the pre-post change in DAA units by drug type and country income group. We fitted autoregressive moving average (ARIMA) models with a ramp function to assess the impact of COVID-19 on monthly DAA units sold. Results: Across all countries, from August 2014 to August 2020, a monthly average of 44,219 DAA units per 100,000 HCV cases were sold. High-income countries purchased more units than other groups. In terms of geographic location, North America (124,144 per 100,000 HCV cases) and Europe (81,001 per 100,000 HCV cases) had the highest DAA sales over time, the newer 97 generation of combination DAAs were mainly utilized in high-income countries. In contrast, first and second generation DAAs were the predominant types of DAAs sold in LMICs. The pre-post analysis showed a 23% (p<0.001) average decrease in global sales of DAAs during the first phase of COVID-19. The decrease in LMICs (69%, p<0.001) was approximately double that of high-income countries (33%, p<0.001) while UMICs had 34% (p<0.001) increase in DAA sales. The pandemic was associated with an immediate and sustained decrease of 9,263 units per month (95% CI: -14,668; -3,857.46) in high-income countries, a 73.14 (-850.96, 997.24) unit increase in UMICs, and a 742.58(95% CI: -5505.91, 4020.75) unit decrease in LMICs. Conclusion: Our study showed uneven access to DAAs globally, with higher prevalence-adjusted utilization in high-income countries compared to lower income countries. Our study also found that the COVID-19 pandemic has significantly decreased DAA sales in many countries. To counter these trends, additional strategies, such as price reductions, increased competition among manufacturers, and licensing agreements, may help to improve access and utilization of DAAs globally. 98 4.2 Background The introduction of DAAs has dramatically changed the management of HCV infection globally.55 well-tolerated and highly effective treatment, these medicines have provided countries with the ability to reduce the health and economic impact of their HCV burden. However, access to DAAs remains expensive and limited in many countries across the globe.187 In 2019, of the estimated 15 million people diagnosed with HCV globally, only 62% were treated with DAAs.19 If untreated, HCV can lead to many complications including, liver cirrhosis, liver cancer, and death; as such, increasing access to these new therapies remains a priority for many countries, in particular in light of the WHO’s global HCV elimination targets.19 Access to some DAAs has been advanced through price reductions for some medications in LMICs. These patent arrangements have allowed 11 India-based generic manufacturers to develop and sell generic versions of HCV medicines to more than 100 countries.188 Despite these price-reducing strategies, demand for DAAs remains low in many countries as inadequate screening infrastructure means patients go undiagnosed and therefore do not seek treatment.25,93 In countries with established HCV screening and treatment programs, patient demand for DAAs may be limited by other barriers, such as out-of-pocket charges for treatment where health insurance coverage is limited. A complete HCV generic regimen can cost up to US$1,000, which is very expensive in many LMICs.56 In addition, the cost of DAAs remains challenging for many UMICs and high-income countries due to the high cost of drugs and restricted access to the more affordable regimens.56,189 99 In addition to the burdensome cost of DAAs, the COVID-19 pandemic has also affected the utilization of HCV healthcare services. For example, a recent report on the impact of COVID-19 found a 15% decrease in HCV RNA testing in China and the United States (US).190 Similarly, a study that assessed global utilization trends of DAAs during the pandemic observed an average decrease of 43% in their use.129 This study however, only included higher-income G7 countries and adjusted for the total population instead of the number of HCV cases per country, which does not account for variance in disease prevalence between countries. The authors therefore recommended that further analyses address these limitations by including data on lower-income countries, and by adjusting HCV cases per country. Given that we are only seven years away from the 2030 global elimination target and variability in global HCV drug pricing remains an issue, it is essential to assess how global use of HCV drugs has changed over time and how these changes varied across country income groups. This assessment could provide insight into what countries face the most significant financial barriers and inform policymakers where to direct future efforts. In addition, it is important to assess the effect that COVID-19 might have had on DAA utilization to inform future supply chain strategies. Therefore, this study used longitudinal data to describe global DAA sales trends across income groups and geographic locations and assessed the effect of COVID-19 on global utilization patterns of DAAs. 4.3 Methods 4.3.1 Study Design and Period We compared longer-term trends of DAA sales across country income groups, geographic location, and drug type from August 2014 to August 2020. We then conducted an interrupted time 100 series analysis to assess COVID-19 related changes in the level and trend of DAA units sold globally. To compare between regions, we standardized monthly sales per 100,000 people living with HCV between September 2018 and August 2020. This time-period followed the launch of elimination plans in several countries that had negotiated access to DAAs, and as such, we assessed how COVID-19 affected this improvement in DAAs accessibility. Our interruption was March 2020 when COVID-19 was declared as a pandemic by the WHO.191 4.3.2 Data Sources and Study Sites We used DAA sales data from the IQVIA-MIDAS database of 52 countries (Appendix E) and two regions.96,192 The two regions included: (1) Central America (Guatemala, El Salvador, Honduras, Nicaragua, Costa Rica, and Panama); (2) French West Africa (Benin, Burkina Faso, Cameroon, Côte d’Ivoire, Democratic Republic of the Congo, Gabon, Guinea, Mali, Senegal, and Togo). All countries were classified into income groups based on the 2022-23 World Bank country-level classification. The group classification include high-income, upper-middle income, or low-middle income countries.193 We also assessed DAA trends by geographic location including North America, Europe, Asia, and the Middle East and Africa. The IQVIA-MIDAS database contains data on global pharmaceutical product sales which are collected from retail pharmacies and coding centers. For this analysis, we determined DAAs by using Anatomical Therapeutic Chemical code J05AP.194 The database covers, on average, 90% of all country-level pharmaceutical sales and have been validated against external data sources.195 Based on a 2020 global precision index, the IQVIA sales data have high accuracy ranging from 81% in Asia Pacific to 96% in North America.196,197 We also used data from Polaris198 to estimate the number of people living with HCV across countries from 2014 to 2020. The Polaris estimates 101 are gathered from the literature, shared by country HCV experts, or estimated using a disease progression model described in more detail elsewhere.199 The database has been previously used in other studies of HCV.200,201 4.3.3 Outcome Our primary outcome was the monthly rate of DAAs sold per 100,000 people living with HCV per country, country income group, or geographic region. We also estimated the relative changes per 100,000 HCV prevalent cases, which we defined as the difference between DAA units sold in March through August 2020 with the same period in 2019. DAA units were defined as a single capsule/pill (generic and brand name formulations). Table 4.1 provides a detailed list of DAAs available in the IQVIA database and included in the study. 4.3.4 Data Analysis We first plotted monthly DAA units sold per 100,000 HCV prevalent cases of HCV by country income groups and geographical location, from August 2014 to August 2020. We also described monthly DAA sales trends by geographical region and drug type. We then compared the change in DAA units by drug type and income group. Consistent with other literature using this data,129 we fitted ARIMA models with a ramp function to assess the impact of COVID-19 on monthly DAA unit sales sold. ARIMA is a robust statistical approach that is frequently used in the impact assessment of health interventions as it controls for trends, seasonality and autocorrelation in the data.202 102 In our model building process, we differenced the data where necessary to account for existing trends and controlled for autocorrelation. We used autocorrelation and partial autocorrelation coefficients plots (ACF/PACF) and the Ljung-box test to assess correlation in the data and determine model orders. We also compared different potential autocorrelation models using the Akaike information criteria (AIC) and selected the model with lowest AIC. We used residual plots and the Ljung-box test for white noise to assess the goodness of fitted model. The analysis was stratified by country income groups (LMICs, UMICs, and high-income groups). Given the high shifts observed in LMICs due to the implementation of Egypt’s HCV elimination program in 2018203; we conduced sensitivity analyses by excluding Egypt from the income group model and ran a separate ARIMA model to assess the effect of COVID-19. We also ran a separate ARIMA model countries with the highest HCV prevalence in 2020.198 All analyses were conducted in Stata Version 16 204 and R version 4.2.1.205 4.4 Results 4.4.1 Descriptive Statistics and DAA Trends by Income Group and Geographic Location Between August 2014 to August 2020, a monthly average of 44,219 DAAs units per 100,000 HCV cases per month were sold across all countries. As shown in Figure 4.1 and Figure 4.2, high-income countries purchased more units (142,098 per 100,000 HCV cases) than UMIC (17,537 per 100,000 HCV cases) and LMIC groups (15,906 per 100,000 HCV cases) throughout study period. The lowest use groups were French-west Africa and Central America (1,334 per 100,000 HCV cases). The Figure 4.1 also shows that DAA sales varied greatly over time, even within different income groups. The right side of Figure 4.1 also shows that North America had the highest DAA sales over time (124,144 per 100,000 HCV cases) followed by Europe (81,001 per 100,000 HCV cases). 103 In contrast, Africa, and the Middle East (15,783 per 100,000 HCV cases) and Asian regions (28,334 per 100,000 HCV cases) had the lowest sales levels. Figure 4.1: Monthly DAA Unit Sales per 100,000 HCV Prevalent Cases per Country Income Group and Geographic Location Figure 4.2 shows the breakdown of DAA sales in several countries across the region of Latin America, and the Middle East and Africa, as well as three countries with highest HCV prevalence globally. As the Figure demonstrates, the observed shifts in these regions were largely due to increased sales in Brazil in 2017 and Egypt in 2018, respectively. These increases correspond to the launch of mass treatment campaigns in both countries. Despite high HCV burden in China, 104 Pakistan, and India, DAA utilization was found to be low in these countries, particularly in China. Pakistan and India experienced a increased level and trend from mid-2016 onward, and sales began to decline slightly before the pandemic and continued to decrease further during the pandemic. Figure 4.2: Monthly DAA Unit Sales per 100,000 HCV Prevalent Cases in Latin America, Middle East and Africa, and Countries with High HCV Prevalence 4.4.2 Trends in Use of Specific DAAs As shown in Figure 4.3, the newer generation of combination DAAs (e.g. glecaprevir/pibrentasvira) were mainly utilized in high-income countries. In contrast, the second versions (e.g. daclatasvir, sofosbuvir) and one newer generation (sofosbuvir/velpatasvir) remained the most dominant types of DAAs sold in LMICs. While glecaprevir/pibrentasvira and 105 sofosbuvir/velpatasvir are of the same generation, sofosbuvir/velpatasvir is available in generic form, and therefore more accessible and more readily utilized to LMICs, unlike glecaprevir/pibrentasvira which remains under patent protection. As Figure 4.3 illustrates, use of all DAA types decreased in high-income countries while utilization of glecaprevir/pibrentasvira increased from mid-2017 onward. There was a large increase in the use of dasabuvir/ombitasvir/paritaprevir/ritonavir in UMICs in 2017, and a trend increase in daclatasvir sales in LMICs. These trends were similar to changes observed in Brazil and Egypt, suggesting that these countries’ rates were largely responsible for the observed shifts. Figure 4.4 shows utilization of DAA types amongst countries with high HCV burden. Sofosbuvir and daclatasvir (second generation) were the most common drugs used in Pakistan and India, while sofosbuvir/velpatasvir and glecaprevir/pibrentasvira were most predominant in China. Overall, the rate of DAA sales across these three countries was lower than those of high-income countries where HCV prevalence is low. 106 Figure 4.3: Monthly DAA Unit Sales per 100,000 HCV Prevalent Cases per Drug Type per Country Income Group Abbreviations: DOPR:Dasabuvir/Ombitasvir/Paritaprevir/Ritonavir; EG: Elbasvir/Grazoprevir LS: Ledipasvir and Sofosbuvir; GP: Glecaprevir/Pibrentasvir; OPR: Ombitasvir/Paritaprevir and Ritonavir; SV: Sofosbuvir/Velpatasvir; SVV: Sofosbuvir/ Velpatasvir/ Voxilaprevir) 107 Figure 4.4: Monthly DAA Unit Sales per 100,000 HCV Prevalent Cases per Drug Type in Countries with Highest HCV Prevalence 4.4.3 Effect of COVID-19 on Monthly DAA Sales Based on a pre-post analysis, there was an average decrease of 23% (p<0.001) in global sales of DAAs when comparing March-August 2019 to the same period in 2020. The decrease in LMICs (69%, p<0.001) was approximately double that of high-income countries (33%, p<0.001), while UMICs had 34% (p<0.001) increase. As shown in Figure 4.5 and Appendix D, 46 of the 54 countries and regions in our analysis had a decrease when comparing these two timeframes. These decreases varied widely across countries, ranging from a 5% reduction in the Czech Republic to a Abbreviations: EG: Elbasvir/Grazoprevir; LS: Ledipasvir and Sofosbuvir; GP: Glecaprevir/Pibrentasvir; OPR: Ombitasvir/Paritaprevir and Ritonavir; SV: Sofosbuvir/Velpatasvir) 108 93% reduction in Brazil. In contrast, the remaining 8 countries experienced an average increase in DAA sales of 167%, ranging from an 8% increase in Finland to a 459% increase in South Africa. As shown in Table 4.1 and Figure 4.6, there was a significant decrease in sales during the pandemic across all DAA types, with the exception of increases in sofosbuvir/velpatasvir (10%) in high-income countries, ledipasvir/sofosbuvir (93%) and elbasvir/grazoprevir (457%), sofosbuvir/velpatasvir (562%), and ribavirin (32%) in UMICs, and ribavirin(47%) in LMICs. Figure 4.5: Percentage Change in DAA Unit Sales per 100,000 HCV Cases per Country in March-August 2020 Compared with Same Period in 2019 The results of our ARIMA model analyses are shown in Table 4.2. Our models suggest that monthly DAA sales declined in high-income countries and LMICs, while it increased in UMICs. The pandemic was associated with an immediate and sustained decrease of 9,263 units per month (95% CI: -14,668; -3,857.46) in high-income countries, a 73.14 (-850.96, 997.24) unit increase in UMICs, and a 742.58(95% CI: -5505.91, 4020.75) unit decrease in LMICs. Our sensitivity analysis 109 excluding Egypt from the LMICs group still showed a decreasing slope with average decrease of 464.43 units (95% CI: -1676.18, 747.32). Among countries with the highest HCV prevalence, China and Pakistan had a decreasing trend during the pandemic, while India experienced a slight but non-significant increase (see Table 4.2). 110 Table 4.1: Pre-post Comparison of DAA Units Sold per 100,000 HCV Prevalent Cases per Income Group and Geographical Location High-income countries Upper-Middle Income Countries Lower-Middle Income Countries March-August 2019 March-August 2020 % change (p-value) March-August 2019 March-August 2020 %change (p-value) March-August 2019 March-August 2020 %change (p-value) All drugs 78,639 52,577 -33%(p<0.001) 10,726 14,363 34%(p<0.001) 39,288 12,061 -69%(p<0.001) Daclatasvir 44 4 -33%(p<0.001) 791 320 -60%(p<0.001) 17,092 2,483 -85%(p<0.001) Daclatasvir/sofosbuvir 257 67 -74%(p<0.001) Dasabuvir/ombitasvir/paritaprevir/ritonavir 0 0 1,965 1,367 -30%(p<0.001) Elbasvir 67 21 -68%(p<0.001) Elbasvir/grazoprevir 5,245 1,625 -69%(p<0.001) 115 662 475%(p<0.001) 15 0 -99%(p=0.054) Glecaprevir/pibrentasvir 45,270 29,249 -35%(p<0.001) 379 0 100%(P<0.001) Grazoprevir 134 42 -68%(p<0.001) Ledipasvir/sofosbuvir 6,903 2,323 -66%(p<0.001) 156 300 93%(p<0.001) 3,723 647 -83%(p<0.001) Ombitasvir/paritaprevir /ritonavir 1121 994 -11% (P=0.006) 328 4 -99%(p<0.001) 0 0 Ribavirin 5422 2996 -45%(p<0.001) 6,175 8,134 32%(p<0.001) 264 386 47%(p<0.001) Simeprevir 2 0 -100% (0.998) 90 0 -100% 0 0 Sofosbuvir 98 30 -69%(p<0.001) 458 625 37%(p<0.001) 9,167 2,722 -70%(p<0.001) Sofosbuvir/velpatasvir 13163 14520 10%(p<0.001) 268 1,777 562% 8,770 5,742 -35% Sofosbuvir/velpatasvir/voxilaprevir 1171 773 -34%(p<0.001) 0 0 0 0 14 100% 111 Table 4.2: ARIMA Model Findings on the Effect of COVID-19 on Monthly DAA Unit sales per 100,000 HCV Cases Region or Country Coefficient (slope change) 95% CI Goodness of fit p-value Income groups High-income -9263.182 (-14,668.90, 3,857.46) 0.845 Upper-Middle Income Countries 73.1414 (-850.96, 997.24) 0.457 Lower-Middle Income Countries (Excluding Egypt) -464.43 (-1676.18, 747.32) 0.613 Lower-Middle Income Countries -742.58 (-5505.91, 4020.75) 0.825 Countries with highest HCV prevalence Pakistan -273.6112 (-573.92, 26.69) 0.979 India 33.88 (-301.403, 369.18) 0.146 Egypt -2035.451 (-4942.01, 871.11) 0.837 112 Figure 4.6: DAA Units Sold per 100,000 HCV Prevalent Cases per in March-August 2020 vs with Same Period in 2019 4.5 Discussion DAA medications have radically changed the treatment of Hepatitis C treatment landscape. We found that sales of these drugs were greater in high-income countries compared to other regions. In terms of geography, DAA sales were consistently higher in North America and Europe than in other regions. Notably, we observed a large increase in Latin America in 2017 and a trend increase in the Middle East and Africa regions in 2018. Newer generations of DAAs were mostly utilized in high-income countries, while second generation treatments, which are less effective were most common in LMICs. We also observed low sales in countries with high prevalence including China, India, and Pakistan. Our study also found that 85% of 54 countries and regions included in the study experienced a decline in DAA sales during the -200% -100% 0% 100% 200% 300% 400% 500% 600%All drugsBoceprevirDaclatasvirDaclatasvir/ SofosbuvirDasabuvir / Ombitasvir / Paritaprevir / RitonavirElbasvirElbasvir / GrazoprevirGlecaprevir / PibrentasvirGrazoprevirLedipasvir / SofosbuvirOmbitasvir / Paritaprevir / RitonavirRibavirinSimeprevirSofosbuvirSofosbuvir / VelpatasvirSofosbuvir / Velpatasvir / VoxilaprevirLMICs UMCIs High-Income 113 pandemic. Our statistical models suggested that while DAA use increased in UMICs, it decreased in two of the three countries where HCV burden was highest, and in both high-income and LMICs. Following the of the WHO’s HCV elimination guidelines,206 many countries launched HCV prevention and treatment strategies.109,206–208 In 2017, Brazil launched an HCV elimination plan that included the expansion of screening, diagnosis, and treatment services.209,210 For patients with a positive HCV diagnosis, this program also included the provision of treatment free of charge. The level and trends shift observed in Latin America were due to the high sales observed in Brazil, following the countries ambitious elimination efforts.209,210 We observed a similar pattern in the Middle East and Africa region, where an increase in sales was driven by Egypt, a country with some of the highest prevalence rates of HCV globally (5-7% in 2018).200 In May of 2018, after Egypt was selected to be one of the seven African countries to receive a price reduction for DAAs 189, the country launched a mass screening campaign that subsequently increased HCV diagnosis and demand for DAAs.203 Both Brazil and Egypt illustrate how mass campaigns can impact the use of DAAs and lead to lower prevalence of HCV infection. Of note, we found the lowest utilization of DAAs in UMICs. We believe this is likely linked to patents and licensing policies for this set of countries. While many LMICs can purchase generic DAAs under-pricing and licensing policies, UMICs are typically not able to access these lower cost medicines.56 Therefore, DAAs are still expensive in UMICs. As reported by the WHO, UMICs such as China, Colombia, Kazakhstan, Mexico, Russia, and Turkey have not benefited from licensing and price reduction policies.56 The inability for these countries to 114 locally produce or import generic DAAs is likely a major cause of their lower sales volumes compared to HCV prevalence rates. While the global HCV elimination target deadline is only seven years away, our study found that low use of DAAs and the impact of COVID-19 in many countries might hinder progress toward meeting these elimination goals. First, we observed that the lowest DAA accessibility was in Africa and Central America, where many countries with the highest HCV disease burden are located. Poor access to DAAs means that treatment rates will be lowest in areas where demand is greatest. Second, we observed that newer generation DAAs (e.g., glecaprevir/pibrentasvir) were mostly sold in high-income countries, while countries with the highest HCV burden, like India and Pakistan, had no access to them. Studies have reported that many patients in LMICs are diagnosed at an advanced stage of HCV due to low access to screening services.25,211 Lack of access to newer generation DAAs in LMICs is therefore of particular concern, given they have higher cure rates, and are currently recommended for patients with advanced HCV stage. The unavailability of these more efficacious drugs is creating inequities in access and disparities in health outcomes. This is exemplified in Europe, where newer generation DAAs are the only medications recommended in current HCV treatment guidelines.213 The unavailability of newer generations in LMICs is mainly linked to patents and licensing policies. In 2018, the manufacturer of glecaprevir/pibrentasvir agreed to allow 96 manufacturers in LMICs to develop and sell generic versions of their drug. However, this agreement did not extend to countries with high burden, such as India56, a leading manufacturer of generic DAAs for many LMICs, which may be limiting the availability of glecaprevir/pibrentasvir in many countries. 115 Lastly, we observed a significant impact of the COVID-19 pandemic on DAA sales across many countries, with the highest decreases in LMICs. Our findings are similar to other single-country studies that have found decreases in DAA utilization and treatment rates in Canada and the United States.214,215 COVID-19 has affected healthcare globally, and many countries have restructured their health systems and updated their health strategic plan to accommodate the effect of the pandemic.95,190,216 The 2030 HCV elimination targets were set before the pandemic. Based on our findings, the pandemic impeded progress toward these targets in many countries. For example, a recent report showed that only 12 countries were on track to achieve their 2030 targets before the pandemic, most of which were high income countries.217 However, our analysis found that of the 12 countries we included in our analysis, even the high-income ones experienced a significant decrease in DAA sales during the pandemic. The majority of other countries in our analysis were predicted to achieve the targets in 2050 without taking into account the COVID-19 pandemic.218 Our findings show that the 2030 targets may have to be revaluated for many countries considering the reductions in DAA use as a result of COVID-19. 4.5.1 Limitations Our study has some limitations that are worth noting. First, the dataset used in this study was aggregated at the country level, meaning we could not assess any sub-national impacts of COVID-19 on DAA sales. This might be particularly important for countries with decentralized healthcare systems. Second, as we observed in our analysis, there was variability in DAA sales across countries, especially in the regions of Latin America, the Middle East, and Africa. Therefore, the decrease of sales observed during the pandemic may also be due to 116 decreases in disease burden following the launch of HCV elimination strategies in each country. For example, HCV prevalence has drastically reduced in Egypt after the launch of mass screening before the pandemic, which is also observed in our trend analysis.208 The reduction in DAA sales in Brazil could also be due to fewer patients needing treatment, either due to successful elimination strategies or fewer diagnoses due to disruptions in screening services. Lastly, we did not have data on many low-income countries, mainly in the sub-Saharan African and South American regions. Data on DAA access and HCV burden in these regions and other settings remains scarce. We recommend that future studies explore how DAA sales have changed over time in these countries. Additionally, while the IQVIA database coverage is high, it is essential to note that the data coverage in resource-limited settings is lower than that of high-income countries. However, our findings are comparable to what has been previously reported on limited accessibility to DAAs in low-income countries; therefore, the underestimation of sales in these countries due to data completeness might be minimal. 4.6 Conclusion Our study showed uneven access to DAAs globally, with higher prevalence-adjusted sales in high income countries compared to lower income countries. In addition, we found that DAA sales varied widely between countries, most notably in UMICs. Our study also found that following the COVID-19 pandemic, DAA sales in many countries decreased significantly. To counter these trends, additional strategies, such as price reductions and licensing agreements, may help to improve access and utilization of DAAs globally. 117 Chapter 5: Conclusion 5.1 Summary of Chapters and Overview This dissertation investigated access to HCV testing and treatment in both Rwanda and internationally during the era of HCV global elimination campaigns. Chapter 1 introduced the concepts of hepatitis C infection, transmission, screening and treatment, and the cascade of care as a way of assessing HCV care. Chapter 1 also discussed the existing literature on HCV screening and treatment globally, explored the gaps in this literature, and provided the rationale and study objectives for this dissertation. The first two dissertation objectives pertained specifically to HCV research gaps in the Rwandan context, while the third objective pertained to knowledge gaps at the global level. Chapters 2, 3 and 4 introduced the three studies that comprise this dissertation, presented the findings from each study, and provided discussion information on these research areas. In this chapter, I have integrated the results from the three studies and discuss the key findings, policy implications, strengths and limitations, and future research recommendations in this field of study. 5.2 Key Findings and Contributions In Chapter 2, I described the HCV cascade of care and assessed factors contributing to treatment progression in Rwanda. For this study, I used secondary data collected during the HCV mass screening and treatment campaign that started in 2017. This analysis identified the stages of HCV that were most prone to dropout, suggesting that more attention to specific interventions and groups of people should be prioritized in HCV screening and treatment interventions in Rwanda. In addition, Chapter 2 found that chronic HCV was confirmed in 2.9% of the screened population, and the likelihood of HCV positivity increased with age, 118 lower SES, and being HIV positive. These findings provide insight onto where future screening campaigns should focus to identify the largest number of undiagnosed cases in the country. The findings suggest that among patients who initiated treatment following screening, 88% achieved SVR. Treatment failure was associated with late-stage presentation (high baseline HCV viral load, having cirrhosis), previous HCV diagnosis, and family history of HCV. Importantly, I observed high dropout across many stages in the cascade of care, at the HCV RNA test, treatment initiation, and SVR assessment stages. The older age group was more likely to drop out at the HCV RNA and SVR testing stages. In contrast, patients with comorbidities and a family history of HCV were more like to complete all the recommended stages of care. Lastly, this study found that those with community insurance (CBHI) were more likely to drop out than other groups. Overall, this study suggests that older individuals, and those with no prior history of HCV or other comorbidities should be prioritized in patient follow-up interventions. Chapter 3 presented a complementary qualitative study that explored patients' perspectives on accessing HCV care services as part of Rwanda’s mass screening and treatment campaign. I found that although patients were grateful for the opportunity to get tested and treated, they experienced several challenges related to access HCV care. Patients who had been previously diagnosed but could not afford treatment were grateful for the commencement of the free treatment program. Those who did not know their status also appreciated the screening initiative and the additional opportunity to learn their health status on other diseases such as HIV, HBV, and hypertension. Patients also noted several challenges they faced along the care cascade, such as lengthy test results turnaround times, or delays in treatment initiation. Other 119 challenges included the high costs associated with transport and testing, a lack of privacy and counselling, and poor communication during the treatment period. Finally, patients who failed treatment one or more times expressed frustration that they did not have access to alternative types of DAAs. When we conducted interviews, they were still waiting for second line treatments to become available. In Chapter 4, I investigated global disparities in access to DAAs and assessed the effect of COVID-19 on DAA sales across country income groups and geographic regions. This study showed global inequities in DAA sales, with high-income countries having higher use of drugs than low-income countries. I also found that countries with higher HCV disease burden had lower DAA use, while wealthier countries with lower HCV burden had higher DAA utilization and wider access to multiple types of DAAs. I also observed consistently lower access to and use of DAAs in UMICs than in high-income countries. This study also demonstrated a significant shift in DAA utilization following the launch of the WHO’s viral hepatitis elimination guidelines.1 Countries like Egypt and Brazil that implemented mass screening campaigns experienced notable upward shifts in their use of DAA medications. In addition to these disparities in use, this dissertation also established a significant decrease in DAA utilization during the COVID-19 pandemic. Of 54 countries and regions considered in the analysis, 85% experienced a decline in DAA sales after the start of the pandemic. Considered together, the three studies illustrate improvements in access to HCV testing and treatment, both in Rwanda and internationally; however, there remain significant challenges that need to be addressed to achieve the 2030 WHO elimination targets. For example, I observed high dropout rates at different stages of care in Rwanda. The reasons for these rates 120 were explored in Chapter 3, where patients explained important challenges related to delays in receiving testing results. In many LMICs, insufficient laboratory infrastructure leads to delayed results, and likely increases loss to follow-up.25,219 Specifically, in Rwanda, there were only 9 HCV RNA testing sites across the entire country during the mass screening and treatment campaign. As a result, patients’ blood samples had to be transported to the nearest facility with laboratory equipment, which led to delays in results turn-around time and likely increased dropout rates.112 Additionally, HCV testing involves two steps and additional assessments if a patient is confirmed HCV RNA positive. The findings from the qualitative study (Chapter 3) confirm that the observed dropouts might be due to delays experienced by patients along the care cascade. In particular, participants explained how they had to wait for results at each stage of care with little follow-up from healthcare providers or understanding of the next steps. In Chapter 2, we also observed that healthier people were less like to return for their appointment. Given that HCV can be asymptotic for a long period of time,220 these patients are likely more susceptible to drop out due to delays or extended hospital wait times during their prior appointments.221 The quantitative and qualitative work also help explain why those with community insurance were more likely to drop out. Although Rwanda has universal health coverage, which covers 90% of the fees for healthcare services, 102 participants expressed that costs, such as the remaining 10% for treatment fees, as well as transportation fees, were barriers to care. Lastly, in Chapter 2, I found that HCV treatment failure was associated with being at an advanced stage of HCV. In qualitative interviews, I similarly found that the patients who failed 121 treatment were more often those who had a prior history of HCV and could not afford treatment. While the mass screening campaign granted them free treatment, the virus may have advanced to late stages, leading to a higher chance of treatment failure. DAA availability was limited to sofosbuvir/ledipasvir and sofosbuvir/daclatasvir in Rwanda at the time of the HCV elimination campaign, and these earlier DAA combinations have lower response rates in treatment-experienced and cirrhotic patients compared to newer versions of the drugs.62 Treatment-experienced and cirrhotic patients, were not able to access the more efficacious drugs such as sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, and glecaprevir/pibrentasvir.90 As observed in Chapter 4, these newer-generation DAAs were mainly used in high-income countries, with access remaining limited among LMICs and explains why patients reported a lack of treatment options at the time of the mass screening campaign. Although Rwanda benefited from the new pricing and licensing policy since 2017, the country would benefit from more treatment options.122 5.3 Policy Implications and Recommendations The dissertation findings lead to several suggestions for designing HCV interventions, particularly as efforts continue toward disease elimination. These recommendations include the following areas that will be explored below: simplification of services, implementation of prevention intervention, better integration of HCV services into the healthcare system, promoting stakeholder partnerships, and improving access to newer types of DAAs. 122 5.3.1 Simplification of HCV Screening, Treatment, and Service Delivery I found significant gaps along the care cascade in Rwanda that were at least in part attributable to testing and treatment delays. HCV testing remains a complicated procedure that requires advanced laboratory services.31 Rwanda could benefit from simplifying testing services to facilitate the scale-up of subsequent HCV services. In addition to using validated rapid tests, Rwanda could consider using the existing tuberculosis GeneXpert platforms available nationwide for HCV testing. These approaches were successful in HIV testing in Rwanda and could be adopted to increase HCV testing uptake and reduce delays in testing results.222 5.3.2 Implementing Prevention Strategies Simplification of HCV testing should be implemented alongside prevention strategies to avoid reinfection, especially in high-risk groups. In Chapter 2, I observed that age, traditional medical practices, and comorbidities contributed to HCV infection. The reason for the high HCV burden among the older generation is primarily cumulative result of unsafe medical practices they were exposed to in the 1960.223 Increasing education on routes of HCV transmission in the general population and health facility settings could reduce transmission rates. 5.3.3 Integration of HCV Services into the Health System Beyond the mass screening campaign, it is important HCV services are better integrated into the standard health system in Rwanda. For comparison, in the past, HIV services in Rwanda have been shifted into routine care, and found to be safe and effective when providers were adequately trained and given continuous support and mentorship.224,225 However, low numbers 123 of experienced HCV specialists, particularly in resource-limited settings such as Rwanda, may limit the expansion of HCV services into standard care processes. To mitigate this challenge, Rwanda should continue training personnel in HCV care and shift some HCV services to primary care settings when appropriate. During the mass elimination campaign, each hospital in Rwanda had at least one physician or nurse who was trained in HCV screening and treatment. Despite these efforts, treatment wait times remained lengthy and led to high levels of treatment dropout. Training primary care providers in the provision of HCV services should improve patient follow-up times, and patient progression through the cascade of care. Such changes to HCV services could mirror the experience of HIV decentralization in Rwanda, which improved the accessibility of services across the country.226 The integration of HIV services into primary care increased testing rates, early diagnosis, and reduced loss-to-follow-up in the country.227 Given the high rate of co-infection with HIV and HCV,112 the integration of HCV services with HIV services has the potential to reduce HCV infection. Rwanda’s MoH has already begun such an integration, with national guidelines mapping out HCV service packages that should be available at each health facility.14 Recently the country also shifted HCV services from hospital to health center level.110 Future work should assess the impact of this decentralization process on the availability and accessibility of HCV services for patients seeking care. 5.3.4 Promote Stakeholder Partnerships to Improving Access to DAAs The elimination of HCV will require a combination of efforts from public and private stakeholders. This dissertation highlighted gaps in the cascade of care due to the limited 124 availability of medicines and costly testing procedures. To improve access to HCV services, advocacy on cost reduction for HCV testing and treatment is needed. Rwanda’s MoH should continue establishing new partnerships with pharmaceutical and health insurance companies to support the goal of HCV elimination. The government could work with private insurance companies to incorporate HCV services into their health services package. These partnerships could improve access to HCV healthcare, which can enhance patient outcomes. Through these collaborations, Rwanda, and other countries with limited access to newer DAAs could also negotiate further price reductions for the newer generation of DAAs55 for treating cirrhotic and treatment-experienced patients. Increasing access to and the use of DAAs is crucial for achieving global HCV elimination targets. Chapter 4 demonstrated existing inequities in the global use of DAAs, which largely appear to be related to patent and licensing policies, and subsequently the high cost of medications. To achieve universal access to DAAs, the following strategies should be considered: 1. Price negotiation and generic licensing: LMICs and UMICs governments should negotiate with pharmaceutical companies to lower the prices of DAAs, particularly for newer generations. As evidenced in Rwanda and other countries, this can make them more affordable and increase utilization. Additionally, the addition of countries to generic licensing agreements, where possible, could facilitate the production of lower-cost versions of DAAs. 125 2. Implementation of HCV screening and treatment programs: As shown in Rwanda and in other countries, HCV screening programs can dramatically increase the number of people seeking treatment. Since the number of diagnosed people is still unknown in many countries, particularly LMICs, the needed supply of DAAs and power to negotiating price reductions remains limited. Implementing comprehensive screening programs to identify individuals with HCV is essential to assess the demand for DAAs. 3. Collaboration and international support: Collaborative efforts among governments, NGOs, and UN agencies such as the WHO, are vital for improving the accessibility of DAAs, globally. These collaborations can facilitate knowledge sharing, resource allocation, advocacy, and funding to ensure equitable DAA access for all populations. By implementing these strategies, it is possible to enhance access to DAAs for hepatitis C treatment. 5.4 Strengths and Limitations This dissertation used multi-method approach including quantitative and qualitative methods to produce novel evidence on HCV treatment, in Rwanda and globally. Using both methodological approaches gave voice to the patient experience, and highlighted challenges in the cascade of care that would not have been captured by quantitative methods alone. This dissertation also addressed research gaps in access to HCV care in SSA settings where HCV data remains limited. Additionally, global datasets allowed me to highlight inequities and explain some challenges regarding use of HCV medicines in resource-limited settings. I also used a rigorous quasi-experimental design (ITS) to assess the impact of COVID-19 on sales of HCV treatments. Nevertheless, this dissertation also has several limitations that are worth 126 noting, many of which have been described in the respective chapters. Below, I review some of the key limitations related to data and study design. 5.4.1 Secondary Data First, it is worth noting that the two quantitative studies in this dissertation relied on secondary data. The use of existing data comes with challenges, including missing values, and limited variables. In Chapter 2, missing values were present among many variables. However, I used an indicator for missing data with each variable, which allowed me to use most of the data in the analysis and reduced bias due to loss of information. Additionally, in Chapter 2, the analysis was limited to variables in the electronic database or patient charts, and as such, I were unable to include some essential variables identified by the literature in our models. This remains a limitation of our work. However, secondary data represents a source of information that helped to generate evidence in a timely manner as shown in this dissertation. Further, as discussed in Chapter 2, the mortality and treatment initiation proportions were estimated among patients with available records in the public hospital registers. As some patients might have received treatment from pharmacies or private facilities, they might have been misclassified as not completing treatment because their records were not available. However, given that treatment was free of charge in public hospitals, and there were HCV mentors in charge of patient follow-up, it is unlikely that I missed a large number of patients. In addition, I did not have reliable data on deaths that might have happened in the community. As a result, patients who died might have been misclassified as lost to follow-up. The bias 127 associated with this misclassification would likely be minimal because of the relatively short follow-up period of the study. Finally, in Chapter 4, six countries did not have complete information on DAA sales for the pre-intervention period. For analysis purposes, these countries were excluded. however, since this is such a small number, and the excluded countries were from different income groups, I do not believe that selection bias is a major concern. 5.4.2 Data from Voluntary Mass Screening and Aggregated Data In Chapter 2, I used data from a voluntary mass screening. Patients who attended a screening are likely different from those who did not, and therefore limits the generalizability of some of the findings to the wider population. For instance, in study I, I found that the average age of the study population was high relative to the general population, while the estimate of other comorbidities, such as HIV and HBV, were comparable. As a result, it is unclear whether the results regarding the population prevalence of HCV are systematically biased. In Chapter 4, I used country-level data. While this level of analysis was informative and provided a picture of inequities in sales of DAAs, I could not capture sub-national or individual-level variations in DAA use. Also, it is important to note that purchasing DAAs at the country level does not necessarily translate to greater individual-level access. Previous studies have shown a high volume of medicine expiration due to procurement and administrative processes.228 Further, the impact of COVID-19 might have been different at 128 sub-national and local levels; therefore, the findings of Chapter 4 should only be interpreted at the country-level. 5.4.3 Qualitative Study Limitations In addition to the major limitations of my quantitative work, there are limitations in my qualitative findings that merit discussion. As discussed in Chapter 3, the qualitative study was limited to patients who completed HCV treatment. While my initial plan was also to include the perspectives from patients who dropped out of care, we were unable to recruit them into our study. However, I believe that the qualitative findings captured the challenges patients encountered during the mass campaign, and any concerns from those who did not complete care would only be more pronounced. Second, as with all qualitative studies, the analysis required coding and analysis by the research team. This process might lead to researcher bias given subjective judgement and interpretation cannot be entirely avoided. To mitigate this bias, two investigators independently coded the data, and we met regularly to discuss the emerging themes from our work. We also exercised reflexivity, allowing us to recognize our positionality, biases, and assumptions.229 This exercise helped us to make conscious decisions during data analysis and interpretation. 5.5 Future Research Future research in Rwanda and internationally can focus on several key areas to enhance our understanding of HCV epidemiology, the care cascade, and access to HCV treatment. These include the following potential areas for future research: 129 1. Long-term epidemiology of HCV: In Chapter 2, I estimated the SVR rate and assessed factors contributing to treatment outcomes in Rwanda. However, I did not follow patients who failed treatment to assess their outcomes in the long term. Although many HCV treatments have high cure rates, it is important to follow patients and assess their health status in the long term. There is a need for prospective study to understand disease progression among patients who fail treatment. In addition, future studies should assess the long-term outcomes for those who successfully completed treatment in order to understand the durability of HCV treatment outcomes and reinfection rates. Lastly, a significant proportion of patients dropped out of care and future research should investigate treatment pathway of the untreated patients. 2. Impact of changes in HCV care on the cascade of care: As noted above, Rwanda has commenced significant changes to HCV care, including task-shifting, decentralization, and simplification of service delivery. As services are decentralized and offered in lower-level health facilities, it will be important to assess the impact on HCV treatment rates and outcomes. 3. Patient-reported outcomes: While cure rates are essential, patient-reported outcomes such as quality of life, adherence to treatment, and DAA side effects remain important yet unknown measures of treatment success. More research is needed to understand these outcomes. 4. Cost-effectiveness: Although many HCV treatments are highly effective, they are also expensive. Further research is needed to understand the cost-effectiveness of HCV treatments, particularly in resource-limited settings such as Rwanda. Cost-effectiveness studies comparing different screening and treatment options are needed to inform future policy decisions. Further, 130 costing and cost-effectiveness studies exploring innovative approaches for rapid and affordable HCV diagnostics in resource-limited settings would also help to inform future program implementation. This could include evaluating POC tests, DBS, and NAT techniques, and determine their appropriateness in specific settings. 5. Impact of cost reduction strategies: One significant barrier to accessing DAAs is their high cost. Future research could investigate innovative approaches to reduce the production, distribution, and procurement costs of DAAs. This could include exploring generic versions, price negotiation strategies, or alternative funding models to make treatment more affordable and accessible to both individuals and health systems. 5.6 Conclusion This dissertation provided evidence on the impact of mass screening in Rwanda and global access to HCV treatment. Gaps in treatment and the factors associated with these gaps identified in this thesis can guide the future design of HCV services, as they are decentralized to low levels of health care in Rwanda. Globally, these lessons will be important as modern HCV treatments that are necessary for promoting HCV elimination strategies remain out of reach for many LMICs and UMICs. Lastly, this dissertation also showed that COVID-19 impacted the utilization of DAAs, which suggest that revisions to HCV elimination strategies may be needed to reach elimination targets in the aftermath of the pandemic. 131 References 1. WHO | Combating hepatitis B and C to reach elimination by 2030 [Internet]. WHO. [cited 2019 Feb 7]. Available from: http://www.who.int/hepatitis/publications/hep-elimination-by-2030-brief/en/ 2. Trickey A, Fraser H, Lim AG, Peacock A, Colledge S, Walker J, et al. 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Available from: https://medicine.unimelb.edu.au/school-structure/medical-education/research/qualitative-journey/themes/reflexivity 151 Appendices Appendix A Study I Patients’ Characteristics per Treatment Outcome Variables Total sample Cured Failed Death Discontinuation Total Age <44 1,591 13 14.4 0 10.2 12.3 44-54 1,573 13.5 14 3.6 8.7 12.2 55-64 2,977 25.1 24.9 16.1 17.6 23 64+ 6,799 48.4 46.7 80.4 63.5 52.5 Total 12,940 100 100 100 100 100 Sex Female 7,965 60.8 59.3 48.2 64.3 61.6 Male 4,974 39.2 40.7 51.8 35.7 38.4 Total 12,939 100 100 100 100 100 Social Economic Status Category 1 2,587 23.9 26.6 29.2 31 25.8 Category 2 3,305 33.7 32.1 18.8 31.7 33 Category 3 or 4 or unknown 4,124 42.5 41.3 52.1 37.2 41.2 Total 10,016 100 100 100 100 100 Marital status Single 3,780 12.1 25.1 25 70.3 29.2 Married or in union 6,390 61.6 52.3 42.9 20.3 49.4 Separated/divorced/Widow 2,770 26.3 22.6 32.1 9.4 21.4 Total 12,940 100 100 100 100 100 Health Insurance No insurance 2,611 4.7 10.5 16.1 59 20.2 Community insurance 9,942 91.8 86.4 75 39.2 76.8 Private or other government insurance RAMA/RSSB) 387 3.5 3.1 8.9 1.8 3 Total 12,940 100 100 100 100 100 Diabetes status No 9,688 97.3 96.5 84.4 97.9 97.2 Yes 274 2.7 3.5 15.6 2.1 2.8 Total 9,962 100 100 100 100 100 HIV status No 8,970 89.3 90.5 77.3 94.2 90 Yes 1,002 10.7 9.5 22.7 5.8 10 Total 9,972 100 100 100 100 100 Cancer status No 9,827 98.7 99.1 86.7 99.3 98.7 Yes 126 1.3 0.9 13.3 0.7 1.3 Total 9,953 100 100 100 100 100 152 Variables Total sample Cured Failed Death Discontinuation Total Family History of Viral Hepatitis No 9,253 95.1 92.9 95.5 98.3 95.3 Yes 459 4.9 7.1 4.5 1.7 4.7 Total 9,712 100 100 100 100 100 Renal failure status No 12,769 98.2 99 96.4 99.7 98.7 Yes 171 1.8 1 3.6 0.3 1.3 Total 12,940 100 100 100 100 100 HTA status No 11,672 87.5 88.5 76.8 97.3 90.2 Yes 1,268 12.5 11.5 23.2 2.7 9.8 Total 12,940 100 100 100 100 100 HBV result Negative 10,421 98.6 97.6 100 98.5 98.5 Positive 163 1.4 2.4 0 1.5 1.5 Total 10,584 100 100 100 100 100 HCV treatment history No 11,701 88.8 85.1 96.4 99.7 91.6 Yes 1,077 11.2 14.9 3.6 0.3 8.4 Total 12,778 100 100 100 100 100 Treatment regimen Ledipasvir/sofosbuvir 3,452 37.2 22 42.9 3.6 26.7 Sofosbuvir/daclatasvir 4,761 52.7 31.5 17.9 1.8 36.8 Other combination 4,727 10.1 46.5 39.3 94.7 36.5 Total 12,940 100 100 100 100 100 Ever been traditionally operated No 8,009 81.2 78.5 66.7 84.3 81.3 Yes 1,848 18.8 21.5 33.3 15.7 18.7 Total 9,857 100 100 100 100 100 Ever been transfused No 9,584 96.8 96.8 91.1 98.5 97 Yes 297 3.2 3.2 8.9 1.5 3 Total 9,881 100 100 100 100 100 Ever been operated No 9,552 96.5 96 93.3 96.3 96.4 Yes 353 3.5 4 6.7 3.7 3.6 Total 9,905 100 100 100 100 100 Mean baseline Viral load (IU/mL) 12,940 2,092,958 3,712,036 1,030,728 1,948,949 2,155,255 Mean number of hospital staff 12,940 224 214 363 256 232 153 Appendix B Summary Table of Qualitative Study Findings Theme Sub-theme Example Quote Response to community-level HCV screening Mass screening participation Potential benefit of a new HCV program Wait times for screening and results turnaround I was lucky to have had someone who informed me about the campaign. I fear having an illness at any organ in my abdomen; that is why I was interested in going for screening voluntarily, without having any signs or symptoms. Well, I thought I could again get medicines; because it was a mass screening opportunity, I just went there like anyone else. Like all other people, I behaved as if I didn’t know anything. There were so many people waiting to get screened, the stadium was full, and some people were told to return home and come back the following day. Everything went well except that the results were delayed so much and that we started getting bored of waiting for them – they delayed but, in the end, we got them. It took so long before we got them; it took like six months or seven months Circumstances and perceptions related to confirmatory testing HCV RNA test results turnaround delays I kept coming to get my results, but they would tell me they do not have them yet…I was tired of going there and always being told the same story, let alone transportation fees which were difficult to get 154 Theme Sub-theme Example Quote Privacy concerns during results delivery What I can add is that I wish they explained to us the illness that we have, and they must tell us why we have those illnesses; they should not just give us medicines and leave us alone Experience of linkage to care and treatment Initiation to treatment and adjusting lifestyle Treatment initiation delays Financial burden associated with HCV Patient counselling I started doing all my best, and I lived on a healthy diet because I had some money at that time, trying to avoid losing weight so people would not realize my problem. This illness is a serious burden. I was impatient about receiving the drugs – because, when you are ill, and you do not get medication on time, you become so worried. For me, I had been traumatized by the lack of medicines I used to work in a hospital and knew that HCV treatment was only for rich people…when I got diagnosed with it, I thought I would die shortly … I couldn't afford the treatment … I am grateful to the government for making sure that everyone can be treated What I can add is that I wish they explained to us the illness that we have, and they must tell us why we have those illnesses; they should not just give us medicines and leave us alone. 155 Appendix C Qualitative Study Data Collection Materials C.1 Information Sheet for Qualitative Interviews I am _____________________________ and I am a member of the research team investigating the evaluation of mass screening and treatment for the treatment of hepatitis C in Rwanda. I am a part of a project led by the Rwanda Biomedical Center (RBC) in collaboration with the University of British Columbia. We would like to gather information on access to HCV testing and treatment services as well as adherence to care for HCV in Rwanda. You are being invited to participate in one-on-one interviews because of your first-hand experience with HCV treatment in Rwanda. Participation in the interview is completely voluntary. The interview will take approximately 30 to 60 minutes. You will be asked questions about your experience in HCV treatment in Rwanda, the challenges you face, and any suggestions you have for improving the program. You can stop answering questions at any point or decide to end your participation in the study completely. If you do not feel comfortable answering any questions, you can choose to skip them. Depending on the amount of information we are able to collect, the answers you provide may or may not be included in the final report for this project. Risks: Your relationship with the RBC, hospital staff, and your doctor will not be affected by whether or not you decide to participate in the interviews or by your responses. Your decision to participate in this study will be kept confidential and we will not share your decision with any other staff, including your doctor. Care will be taken to provide a private place for the interview, and information collected will be securely stored so that only the research team has 156 access to your responses. Your name and other identifying information will not be given to any individual who is not part of the research team. Benefits: Participation in this study can help to improve HCV testing and treatment in Rwanda but there are no individual benefits for participating in the study. However, you will be compensated 5,000 RWF for each interview you participate in. Please contact the individual listed below if you have any questions or concerns about this study. Rwanda Biomedical Center Serumondo Janvier (RBC), phone: If you have any concerns or complaints about your rights or the conduct of the study, you may contact Rwanda National Ethics Committee Dr. Jean- Baptiste Mazarate (Chair), phone: Dr. David Tumusiime (Secretary), phone: C.2 Consent Form Purpose The purpose of this study is to evaluate the mass screening and treatment for HCV in Rwanda. The study will be describing patients’ trajectory in care, and also assess factors associated with drop-out along the cascade of care. We would also like to understand patients’ perceptions of the HCV care and the challenges encountered throughout the treatment process. This 157 information will be used to help improve the HCV treatment here in Rwanda by promoting best practices and identifying areas of the program that could benefit from further development. What happens if I choose to participate? I understand that this is a research project and participation in this study is completely voluntary. As part of this study, I will be asked to participate in one-on-one interview with a research team member. The interview will take approximately 30 to 60 minutes to complete, and I understand that I will be asked questions related to the Hepatitis C treatment in Rwanda. My answers will be recorded using an audio recording device and sometimes the interviewer may take handwritten notes. Will my answers in this interview be kept confidential? My name and identifying information will not appear in any report. All answers I give during this interview will be kept strictly confidential and will only be used for research purposes. Paper records will be kept on computers protected with a password. My choice to participate will not be shared with anyone and will not affect my daily life and relationship with my health care providers What are the benefits of being involved? The main benefit of my involvement is helping to guide the development of improvements for the Hepatitis C testing and treatment in Rwanda but there is no individual benefit. However, I will be given 5,000 RWF as compensation for my time. 158 What are the risks of being involved? There are no risks associated with participating in the interviews. Only the researchers involved in this study will have access to the information I am providing. No identifying information will be published or shared. I understand that the interview will take 30 to 60 minutes of my time. I also understand that I may feel uneasy as I talk about issues related to the Hepatitis C treatment, but I know that I can skip any questions I do not want to answer and that I can stop the interview at any time. Can I choose not to participate? My participation is entirely voluntary, and I am free to say no. If I say no, my relationship with the Hepatitis C treatment program, the Rwanda Biomedical Center, and the University of British Columbia will not be affected. I may choose to answer some, all, or none of the questions. I may stop the interview at any time for any reason. Who should I contact if I have concerns about this study? If I have any questions or complaints about this study, I may contact Dr. Janvier Serumondo, Telephone:…….., of The Rwanda Biomedical Center. If I have questions about my rights as a research participant or think I have not been treated fairly, I may contact the Rwanda National Ethics Committee: Dr. Jean-Baptiste Mazarate (Chair), Phone: or Dr. David Tumusiime (Secretary), Telephone: Do you want to participate? I agree that all the information which I give you may be used for research purposes by University of British Columbia and Rwanda Biomedical Center. 159 By signing below, I agree to participate in this research study: Signature----------- Participant name ………….. Phone number …… Signature ----------- Data collector name ………….. Phone number …… Witness signature……… (if participant is illiterate) Witness name……………. Phone number…... If I have any questions or complaints about this study, I may contact: Rwanda Biomedical Center Janvier Serumondo, Phone: If I have questions about my rights as a research participant or think I have not been treated fairly, I may contact Rwanda National Ethics Committee: Dr. Jean-Baptiste Mazarate (Chair), Phone: Dr. David Tumusiime (Secretary), Phone: 160 C.3 Data Collection Questionnaire for Qualitative Interviews The following interview questions were adopted from previous studies. Some questions were adjusted, added or removed to fit the context of the current study. Annex 1. Interview guide for patients [Headings and notes in brackets are not to be read aloud to the participant] [Introduce yourself and the project in your own words] [State your name, employer, and the goal of the project] [Explain the purpose of the interview in your own words] [Explain that we would like to get honest feedback on the challenges and successes of HCV care in Rwanda] [Describe the audio recording in your own words] [Explain that we want to make sure we have an accurate account of their experiences and that it is possible that some or all of their responses might not be included in our reports] [Answer any questions from the participant] [Start recording] I. Demographics [Record gender of participant Male Female] First, can you tell me a little bit about yourself? 1. How old are you? 2. What do you do for a living? 3. What is your level of education? 4. What is your profession? 161 5. What district and sector are you from? 6. Are you married? 1. What other problems with your health have you experienced recently besides hepatitis C II. Diagnosis If it’s ok with you, I’d like to get into the specifics of how you were diagnosed with HCV. 2. Can you share how and approximately what date you were tested for HCV? What was it that made you want to be tested? 3. What was your experience during the mass screening? What was the screening site? 4. How did you know your testing results? How long did it take to get the results after the initial screening? 5. After being diagnosed, about how long was it before you started your treatment? 6. After diagnosis, can you describe how you connected with the hepatitis health care provider who led your treatment? 11. How concerned did you feel about your diagnosis? What kinds of questions did you have about HCV after you received your diagnosis? Were you able to find answers to these questions? If so, who answered them for you? III. Care and Treatment I’d like to get a sense of your experiences in receiving treatment for hepatitis C. 12. How often did visit you doctor for hepatitis C? 13. What services do you receive when you visited your doctor? Describe what a typical visit was like. 162 14. Can you tell me about any good experiences with the HCV care you received? 15. Can you tell me about any bad experiences with the HCV care you received? (Possible follow-up: What were the challenges you faced during the HCV care you received; what could have made that experience (even) better?) 16. How were you handling payment for your care if you had to pay? Can you share how much you usually had to pay for your care? 17. Were you able to complete all stages of care? [Ask follow up questions if patient terminated treatment prematurely] - At what point did you discontinue your HCV care? (i.e. at what stage?) - Why did you discontinue your HCV care/treatment? What challenges did you face that made you unable to complete all stages of care? [depending on the stage of care at which the patient dropped-out, follow-up with the following question] [Ask follow up questions if patient did not complete all stages of care] - Why you were not able to do the last blood test/confirmatory test/initiate treatment/? What challenges did you face? [Ask follow up questions if patient completed all stages of care] -How often were you taking the prescribed medicines? What was your experience taking the medicines? Did you have any health problems due to drugs? 19. How satisfied do you feel about the outcome of your HCV treatment? [Ask follow up questions if patient was not cured] 163 20. When you heard your hepatitis C was not cleared; how did you respond? How did it make you feel? What kinds of questions did you have? What concerns did you have? Did your doctor tell you what will be the next steps for the treatment? IV. Living with Hepatitis C 20. What other medical problems do you have besides hepatitis C? 21. Do you know how you contracted or got HCV? Can you share that with us? 22. When you heard you had hepatitis C; how did you respond? How did it make you feel? What kinds of questions did you have? What concerns did you have? 23.Overall, how has having hepatitis C impacted your life? How about on a day to day basis? are there problems/concerns/challenges that you have now that you didn’t have before you knew about the hepatitis C? 24.How does it affect your health, or change things medically? 25.How does it affect other, non-medical parts of your life (like how you relate to others, to your family, things you do/don’t do? 26. How has your daily functioning changed since you got hepatitis C? Is it more limited? In what ways? 27. How has having hepatitis C impacted the lives of your family or friends? Do they know about it? What are their attitudes about it? Have any of them been tested for hepatitis C? Has hepatitis C changed the ways they act with you or you act with them? 164 28. Are there any recommendations you would like to give to the managers of the hepatitis program or health care providers to improve the quality of services delivered? That is the end of the interview. Thank you again for agreeing to participate in this project. [Have the participant sign the receipt book for the 5,000 RWF] 165 Appendix D Percentage Change in DAAs Unit Sales per 100,000 HCV Cases per Country Comparing March-August 2020 vs Same Period in 2019 -200% -100% 0% 100% 200% 300% 400% 500%SOUTH AFRICABELARUSMEXICOCZECH REPUBLICGERMANYAUSTRALIAKOREAMOROCCOFRANCEBOSNIAPUERTO RICOFRENCH WEST AFRICATHAILANDSLOVENIAHUNGARYLITHUANIAPOLANDIRELANDBRAZIL 166 Appendix E List of Countries per World Bank Country Classifications by Income Level and Geographic Location High-income countries UMCIs LMICs Geographic location Austria Belarus Ukraine Europe Belgium Bosnia Egypt Middle East and Africa Czech Republic Bulgaria Morocco Pacific, Eastern and Northern Asia Denmark Russia India Latina America Estonia Turkey Pakistan North America Finland Mexico France Argentina 52 Germany Brazil Hungary China Ireland Kazakhstan Italy Serbia Latvia Thailand Lithuania South Africa Netherlands Norway Poland Portugal Romania Slovakia Slovenia Spain Sweden Switzerland UK Puerto Rico Chile Japan Korea Taiwan New Zealand Australia UAE US Canada
Thesis/Dissertation
eng
Population and Public Health
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Law, Michael R.
Investigating access to hepatitis C testing and treatment in Rwanda and beyond
Text