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Social and structural barriers to effective antiretroviral therapy for HIV infection among injection… Milloy, Michael-John Sheridan 2011

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SOCIAL AND STRUCTURAL BARRIERS TO EFFECTIVE ANTIRETROVIRAL THERAPY FOR HIV INFECTION AMONG INJECTION DRUG USERS  by Michael-John Sheridan Milloy  M.Sc., The University of British Columbia, 2008 B.Sc. (Hons), Trent University, 2006 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  Doctor of Philosophy in THE FACULTY OF GRADUATE STUDIES (Health Care and Epidemiology)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  October 2011  © Michael-John Sheridan Milloy, 2011  ABSTRACT  Background: Despite the development of antiretroviral therapy (ART), injection drug users (IDU) continue to have high levels of HIV-related morbidity and mortality. This thesis sought to apply the risk environment conceptual framework on patterns of HIV treatment outcomes by: Systematically reviewing the epidemiologic literature on HIV disease progression among illicit drug users; examining the incidence of viral rebound among IDU on ART; evaluating the role of homelessness on the suppression of plasma HIV RNA viral load; and assessing the role of incarceration on the likelihood of non-adherence to ART. Methods:  HIV-seropositive  IDU  participating  in  an  ongoing  prospective  observational cohort completed biannual interviewer-administered questionnaires. This data was confidentially linked to comprehensive records on HIV treatment and related clinical outcomes held by a clinical monitoring laboratory and antiretroviral dispensary. A variety of longitudinal analytic techniques were used to estimate the independent relationships between selected social- and structural-level exposures and the outcomes of interest while controlling for relevant sociodemographic, clinical and behavioural factors. Results: The systematic review found that only a minority of studies included social- and structural-level measures in analyses of disease progression and treatment outcomes. Longitudinal analysis of viral rebound found that incarceration and sex trade involvement were significantly associated with higher rates. Among individuals initiating ART, homelessness was a significant structural barrier to  ii  suppression. Among individuals prescribed ART, we observed a dose-dependent relationship between non-adherence and the number of incarceration episodes. Conclusions: In this setting of free and universal access to HIV care and ART, suboptimal treatment outcomes were common among IDU. Consistent with an application of the HIV risk environment, a number of prevalent social- and structural-level exposures were associated with higher risks of non-adherence to treatment and poorer treatment outcomes, including homelessness, sex trade involvement and incarceration. Interventions to reduce elevated levels of preventable HIV-related morbidity and mortality among IDU should consider the role played by modifiable aspects of the HIV risk environment.  iii  PREFACE  This statement certifies that the work presented in this thesis was conceived, conducted, written and disseminated by M-J S Milloy (M-JSM). All research described in this dissertation was conducted under the University of British Columbia/Providence Health Care Research Ethics Board approval (certificate H0550233.) The co-authors of the manuscripts, including Dr. Evan Wood (EW), Dr. Jane Buxton (JB), Dr. Thomas Kerr (TK), Dr. Brandon Marshall (BDLM), Dr. Julio Montaner (JM), Dr. Silvia Guillemi (SG), Dr. Robert Hogg (RH), Ms. Surita Parashar (SP), Ms. Andrea Krusi (AK), Dr. David Bangsberg (DB) and Dr. Tim Rhodes (TR) made contributions only as is commensurate with supervisory committee, collegial or co-investigator duties. The principal investigator of the ACCESS study, from which the cohort-based empiric analyses were derived (EW), had access to all of the data and as corresponding author takes full responsibility for the integrity of the results and the accuracy of the statistical analyses. With substantive input from cosupervisors EW and JB, M-JSM designed the studies and wrote the research protocol. With guidance and input from EW, TK, JB, DB, TR and BDLM, M-JSM performed the research and conducted all statistical analyses described in Chapters 2, 3, 4 and 5. M-JSM designed and led the systematic review presented in Chapter 2 and, in collaboration with BDLM, conducted the search strategy and selected eligible studies for final inclusion. BDLM, EW, TK, JB and TR reviewed the material presented in Chapter 2 and approved the final version of the manuscript for submission. EW, JB, RH, SG, JM and AK contributed intellectual content to the material in Chapter 3 and approved the final version of the manuscript for  iv  submission. EW, JB, TK, RH, SG, JM, DB, TR and SP provided scientific input and approved the final version of the manuscript presented in Chapter 4. EW, JB, TK, RH, SG, JM and TR provided scientific input and approved the final version of the manuscript presented in Chapter 5. All manuscripts contained in this thesis were prepared, written and edited by M-JSM. Final drafts of the manuscripts were prepared following the inclusion of material based on comments from all co-authors listed above, the journal editors and external peer reviewers. The following publication arose from work presented in Chapter 5 of this dissertation: 1. Milloy M-JS, Kerr T, Buxton J, Rhodes T, Guillemi S, Hogg R, Montaner J, Wood E. Dose-response effect of incarceration events on non-adherence to HIV antiretroviral therapy among injection drug users. Journal of infectious diseases, 2011. 203: 1215-1221. The analysis presented in Chapter 4 is currently in press: 2. Milloy M-J, Kerr T, Bangsberg D, Buxton J, Parashar S, Guillemi S, Montaner J, Wood E. Homelessness as a structural barrier to effective antiretroviral therapy among HIV-seropositive illicit drug users in a Canadian setting. AIDS Patient Care and STDs, In press. The analyses presented in Chapters 2 and 3 are under review: 3. Milloy M-J, Marshall B, Kerr T, Buxton J, Rhodes T, Montaner J, Wood E. Exogenous factors associated with HIV disease progression among illicit drug users: A systematic review. Under review. 4. Milloy M-J, Kerr T, Buxton J, Rhodes T, Krusi A, Guillemi S, Hogg R, Montaner J, Wood E. Social and environmental predictors of plasma HIV RNA rebound among injection drug users treated with antiretroviral therapy. Under review. v  TABLE OF CONTENTS  Abstract.................................................................................................................................... ii	
   Preface..................................................................................................................................... iv	
   Table of Contents .................................................................................................................. vi	
   List of Tables .......................................................................................................................... ix	
   List of Figures ......................................................................................................................... x	
   Acknowledgements .............................................................................................................. xi	
   Dedication ............................................................................................................................ xiii	
   Chapter 1: Background, rationale, objectives.................................................................... 1	
   1.1	
   The HIV/AIDS pandemic among illicit drug users ............................................ 1	
   1.2	
   Treatment for HIV infection among illicit drug users ......................................... 2	
   1.3	
   Research objectives ................................................................................................... 3	
   1.4	
   Study setting .............................................................................................................. 5	
   1.5	
   Risk environment conceptual framework ............................................................. 5	
   1.6	
   Study objectives and hypotheses ............................................................................ 6	
   1.7	
   Study design and methods ...................................................................................... 9	
   1.8	
   Summary .................................................................................................................. 10	
   Chapter 2: Social and structural factors associated with HIV disease progression among illicit drug users: A systematic review ................................................................ 12	
   2.1	
   Introduction ............................................................................................................. 12	
   2.2	
   Methods .................................................................................................................... 13	
   2.2.1	
   Search strategy.................................................................................................. 13	
   2.2.2	
   Inclusion and exclusion criteria ..................................................................... 14	
    vi  2.2.3	
   Search protocol ................................................................................................. 14	
   2.3	
   Results ....................................................................................................................... 15	
   2.4	
   Discussion ................................................................................................................ 20	
   Chapter 3: Social and environmental predictors of HIV RNA viral rebound among injection drug users treated with antiretroviral therapy................................................ 29	
   3.1	
   Introduction ............................................................................................................. 29	
   3.2	
   Methods .................................................................................................................... 30	
   3.3	
   Results ....................................................................................................................... 33	
   3.4	
   Discussion ................................................................................................................ 35	
   Chapter 4: Homelessness as a structural barrier to effective antiretroviral therapy among HIV-seropositive injection drug users in a Canadian setting .......................... 42	
   4.1	
   Introduction ............................................................................................................. 42	
   4.2	
   Methods .................................................................................................................... 43	
   4.3	
   Results ....................................................................................................................... 46	
   4.4	
   Discussion ................................................................................................................ 48	
   Chapter 5: Dose-response effect of incarceration events on non-adherence to HIV antiretroviral therapy among injection drug users ......................................................... 55	
   5.1	
   Introduction ............................................................................................................. 55	
   5.2	
   Methods .................................................................................................................... 56	
   5.3	
   Results ....................................................................................................................... 59	
   5.4	
   Discussion ................................................................................................................ 61	
   Chapter 6: Discussion, future research, conclusions ..................................................... 69	
   6.1	
   Summary of findings .............................................................................................. 69	
   6.2	
   Study strengths and contributions ....................................................................... 72	
   6.3	
   Study limitations ..................................................................................................... 74	
   vii  6.4	
   Recommendations................................................................................................... 75	
   6.5	
   Future research ........................................................................................................ 77	
   6.6	
   Conclusions .............................................................................................................. 79	
   References ............................................................................................................................. 81	
    viii  LIST OF TABLES  Table 1. Descriptive summary of included studies on HIV disease progression among illicit drug users ...................................................................................................... 26	
   Table 2. Factors associated with HIV disease progression among illicit drug users . 27	
   Table 3. Baseline characteristics of 277 HIV-seropositive IDU on ART with durably suppressed HIV RNA levels............................................................................................... 39	
   Table 4. Unadjusted estimates of the behavioural, social and structural factors associated with viral rebound among 277 IDU on ART with suppressed viral loads at baseline .............................................................................................................................. 40	
   Table 5. Adjusted estimates of the behavioural, social and structural factors associated with viral rebound among 277 IDU on ART with suppressed viral loads at baseline .............................................................................................................................. 41	
   Table 6. Baseline characteristics of 240 IDU initiating ART stratified by HIV RNA plasma viral load suppression over follow-up ................................................................ 52	
   Table 7. Univariate and multivariate analyses of factors associated with time to PVL suppression among 240 IDU initiating ART .................................................................... 53	
   Table 8. Selected sociodemographic, behavioural and clinical characteristics at baseline among 490 ART-exposed IDU ............................................................................ 66	
   Table 9. Univariate and multivariate linear mixed-effects analyses of primary and secondary explanatory variables and non-adherence to ART among 490 IDU.......... 67	
    ix  LIST OF FIGURES  Figure 1. Flowchart of study acquisition, screening and selection process ................. 25	
   Figure 2. Mediation effects for ART adherence on the relationship between homelessness and PVL suppression among 240 HIV-infected IDU............................. 54	
   Figure 3. Median number of incarceration events per follow-up interview among 490 ART-exposed IDU ................................................................................................................ 65	
   Figure 4. Adjusted odds ratios for non-adherence to ART by number of incarceration episodes among 490 IDU .................................................................................................... 68	
    x  ACKNOWLEDGEMENTS  The research contained in this dissertation would not have been possible without the contributions made by the participants in the Aids Care Cohort to evaluate Exposure to Survival Services (ACCESS) study. I offer them my sincere thanks and hope that this research might serve to help lower the barriers they face to fully benefitting from life-saving treatment for HIV infection. In addition, I offer my sincere thanks to all the ACCESS interviewers, field staff, study nurses and staff at the BC Centre for Excellence in HIV/AIDS for their efforts, especially Caitlin Johnston, Deborah Graham, Tricia Collingham and Leslie Rae, as well as the ACCESS co-investigators and my co-authors, including Drs. Robert Hogg and Silvia Guillemi, Andrea Krusi and Surita Parashar. Funding to support my doctoral activities was generously provided by the Canadian Institutes for Health Research through a Banting and Best Canada Graduate Scholarship. I thank CIHR for their support, as well as the University of British Columbia, which provided four years of tuition support. In addition, I thank the BC Centre for Excellence in HIV/AIDS for providing salary support during my graduate studies. I benefitted greatly from the support, advice and encouragement of many colleagues and fellow graduate students at UBC and the Centre for Excellence. Drs. Will Small and Kora DeBeck provided much support and encouragement during my graduate studies. I particularly want to thank Dr. Brandon Marshall for his invaluable contributions to my graduate studies and research accomplishments. I look forward to continuing an intellectual partnership.  xi  I am deeply grateful to Drs. Julio Montaner and Tim Rhodes for the time and effort they contributed to my doctoral programme as members of my supervisory committee, especially in light of their important clinical, professional and academic commitments. I also offer my sincere thanks and gratitude to my co-supervisor Jane Buxton for her timely advice, very helpful guidance and unwavering support. Dr. Thomas Kerr has been involved with my graduate studies since the beginning of my Master’s and his support of my development to become an independent research scientist through his mentorship has been invaluable. In a similar fashion, I doubt I will ever be able to adequately thank Dr. Evan Wood for the support, encouragement and guidance he has offered as my other co-supervisor. This research would not have been possible without the unwavering support of my family. First, I am deeply grateful to my brother Jeremy for his support and friendship during my time in Vancouver as well as my sisters Bridget and Clare. I want to offer my deepest thanks to Gurmeet and Jagdish Aujla, who through their love and example have reinforced the value of dedication to education. My father John not only provided needed encouragement and advice during my undergraduate and graduate-level studies but also provided an invaluable example of rigorous intellectual activity in service to society. I offer him, Laura and my mother Julia Catherine my deepest thanks for everything they have done for me, Teena and Lakshmi Julia Seva. Finally but most importantly, whatever success I enjoy has come as a direct result of the love and friendship of Jagraj Teena Aujla.  xii  DEDICATION  To Jagraj Teena Aujla; for everything.  xiii  CHAPTER 1: BACKGROUND, RATIONALE, OBJECTIVES  1.1  The HIV/AIDS pandemic among illicit drug users In the three decades since its first detection amidst a cluster of atypical  pneumonia cases among previously healthy homosexual men in Los Angeles (1), the disease that would become known as acquired immune deficiency syndrome (AIDS) has emerged as a global pandemic and public health emergency. According to the most recent estimates from Joint United Nations Programme on HIV/AIDS (UNAIDS), 1.8 million adults and children died of AIDS-related causes in 2009, adding to a global toll of approximately 25 million deaths since the beginning of the pandemic (2). The human immunodeficiency virus (HIV), the aetiologic agent of AIDS, was identified in 1983 by researchers at laboratories in France and the United States (3, 4). A novel retrovirus, the pathogen targets cells of the human immune system, including CD4+ T-lymphocyte cells, to integrate proviral DNA into the host genome using the reverse transcriptase enzyme. Transmission of HIV between individuals is dependent on the exchange of HIV-contaminated blood or other bodily fluid, typically through sexual contact, childbirth and breastfeeding, or the use of unsterile medical equipment, including syringes. In the last two decades, the HIV/AIDS pandemic outside sub-Saharan Africa has shifted from being driven largely by sexual contacts to one in which an increasing proportion of new cases are the result of the use of contaminated injection equipment associated with illicit drug use (5). In Asia, Europe and the Americas, more than one-quarter of new cases of HIV are among individuals who use injection drugs (IDU); in countries such as Russia, which has one of the world’s fastest-  1  growing HIV epidemics, eight in ten new infections are among IDU (5). Explosive outbreaks among IDU have been driven by efficient viral transmission through shared injecting equipment (6), tightly interrelated social networks (7) and poor access to preventative healthcare (8). Outbreaks of HIV infection among IDU have been documented in many settings, including Bangkok, Thailand (9); New York City, New York (10) and Edinburgh, Scotland (11), and have been a starting condition of numerous generalized epidemics. As a result, HIV infection has been reported in 120 (81%) of the 148 countries with individuals who use injection drugs (12); the prevalence of HIV infection among drug users approaches 50% in nine countries (12). Of approximately 15 million people estimated to use injection drugs worldwide, three million (20%) are estimated to be HIV-seropositive (12).  1.2  Treatment for HIV infection among IDU In the absence of a preventative vaccine or effective cure, pharmacotherapies to  treat HIV infection have focused on impeding aspects of viral function. For example, zidovudine (AZT), the first medication approved for HIV infection, is a nucleoside analog reverse transcriptase inhibitor (NRTI), which targets the viral enzyme that copies viral nucleic acid into the host genome (13). Since 1997, clinical guidelines have recommended the use of three complementary antiretroviral agents, an approach termed highly-active antiretroviral therapy (HAART). Given adequate adherence, HAART has been shown to reliably suppress levels of HIV-1 RNA virus circulating in the plasma, forestall disease progression, allow the reconstitution of immune functioning, and further survival (14-16). Despite the dramatic improvements in survival and functioning seen at both the individual and population levels following the introduction of HAART (17-19), 2  not all seropositive groups have seen the full benefits of treatment. Studies indicate IDU are less likely to initiate appropriate treatment (20, 21) and more likely to die without receiving therapy, even in areas with no financial barriers to care (22). Those who do initiate treatment are less likely to achieve optimal levels of adherence (23, 24) and more likely to discontinue treatment inappropriately (25, 26). As a result of these sub-optimal treatment patterns, HIV-seropositive IDU experience highly elevated levels of HIV-related morbidity and mortality compared to individuals in other risk categories (17-19). For example, in a collaborative analysis of data from 15 prospective cohorts in nine industrialized countries, drug-using individuals initiating therapy were the least likely to achieve suppression of plasma viral loads and suffered the highest AIDS-related mortality rates compared to other transmission risk groups (19).  1.3  Research objectives Spurred by these persistent deficits in HIV treatment outcomes, research from  clinical settings has identified a number of factors that complicate the medical management of HIV disease among IDU, including physical and psychological comorbidities (27, 28); interactions between illicit drugs, viral function and immunologic processes (29, 30); and the effects of ongoing drug use (31, 32). Studies among IDU have found that psychological problems and characteristics, including lower treatment self-efficacy (25), anxiety (33) and depression (34) present substantial barriers to adherence to HAART. Further, the unstable and chaotic lifestyles of many IDU can be incompatible with the approach to care of many healthcare providers (35).  3  Although clinical trials of interventions that target these factors have demonstrated improvements in clinical outcomes (36-38), substantial deficiencies remain in the understanding of HIV pathogenesis among drug users in the era of HAART. First, many analyses are derived from short-term or cross-sectional studies of HIV-seropositive drug users. Small samples sizes, and studies recruited only from clinical rather than community settings, limit the generalizability of findings. In some studies, access and adherence to HAART is assessed through self-report, an approach that can be prone to recall and social desirability biases (39, 40). Second, existing studies may have incompletely modeled all factors associated with HIV treatment outcomes and disease progression in IDU by not considering a full range of relevant social-, structural- and environmental-level exposures. In recent years, efforts to model the negative impacts of illicit drug use, including HIV infection and overdose-related mortality, have identified important effects for contextual determinants (41-43). For example, exposure to correctional facilities has been independently associated with an increased risk of HIV infection (44) as well as post-release overdose death (45). Although several reviews of HIV transmission patterns have employed conceptual frameworks integrating social-, structural- and environmental-level exposures (46, 47), and several researchers have recently called for broader investigations of treatment outcomes among drug users (48, 49), their utility and relevance in studies of HIV-related pathogenesis has not been rigorously investigated. Thus, given the urgent need to lower rates of HIVrelated morbidity and mortality among IDU, the objective of this dissertation is to identify social- and structural-level factors associated with disease progression and ART treatment outcomes among IDU.  4  1.4  Study setting Beginning in the mid-1990s, the Downtown Eastside (DTES) area in  Vancouver, British Columbia, experienced an explosive outbreak of HIV infection among IDU and their sexual partners (50, 51), driven by a confluence of factors including a shift in drug consumption patterns towards cocaine injection (52); used needle sharing in local correctional facilities (53); and restrictive sterile needle distribution policies (54). The incidence of new infections in an ongoing observational cohort was estimated to be 18.6 per 100 person years at its peak, resulting in an increase in prevalence from under 2% to more than 25% (55). In British Columbia, all HIV-related care, including antiretroviral medications, has been available free of charge through the province’s universal healthcare system since 1986 (56). Starting in 1992, all HIV-related care has been delivered centrally through the British Columbia Centre for Excellence in HIV/AIDS (BCCfE) Drug Treatment Programme (DTP), including antiretroviral dispensation and clinical monitoring, such as CD4+ cell count and plasma HIV RNA viral load determinations (57, 58). Beginning in 1996 with the advent of HAART, active drug users were not automatically excluded from therapy (55, 59). Between 1996 and 2008, over 8100 individuals received antiretroviral therapy through the DTP (60) with approximately 4300 receiving therapy consistent with IAS-2006 guidelines as of January, 2010 (61).  1.5  Risk environment conceptual framework This dissertation will employ the risk environment framework to conceptualize  the possible relationships between individual-, social- and structural-level variables of interest and clinical outcomes from ART. First articulated in analyses of 5  vulnerability for HIV infection among drug users (62), and later expanded to encompass other forms of drug-related harms (63), the risk environment framework describes the interplay between individual behaviours and the physical, social, economic and environmental contexts of health. In contrast to some epidemiologic models that seek to identify individual-focused proximate factors for disease states, the risk environment framework posits that forces external to individuals, for example stigma against drug use (64), laws prohibiting distribution of sterile injection equipment (65) and drug trafficking patterns (66) combine with endogenous factors to determine the likelihood of infection. Despite a number of calls for studies of the broader contexts of treatment delivery among drug users, especially the social and structural level determinants of ART access and adherence (48, 49, 67), the risk environment framework has not been applied to ART outcomes among IDU. However, some preliminary works have suggested the utility of including structural-level exposures in studies of treatment outcomes among drug users (68-71). In a study of 1161 HIV-seropositive drug users at four sites in the United States, stable housing was one of the strongest predictors of successful treatment, after adjustment for a variety of individual and interpersonal factors (68). Thus, the primary objective of this dissertation will be to employ the risk environment framework to study factors associated with treatment outcomes from ART among IDU.  1.6  Study objectives and hypotheses This research project aims to address the abovementioned gaps and limitations  in the existing scientific evidence on HIV treatment outcomes and disease progression among drug users by analyzing data from a long-running prospective 6  cohort of HIV-seropositive IDU, which as part of this thesis, was linked to comprehensive clinical and antiretroviral records in a setting of universal access to care. By employing the risk environment framework, the empirical studies herein aim to validate its utility in modeling HIV disease progression as well as identify relevant factors associated with ART treatment outcomes among HIV seropositive IDU. Specifically, the four study objectives are: 1. To systematically review the epidemiologic literature on HIV disease progression and, informed by the risk environment conceptual framework, identify social- and structural level factors associated with the development of AIDS; death; changes or differences in CD4+ cell count; and changes or differences in plasma viral loads. Chapter 2 provides the results of this systematic review examining disease progression among HIV-seropositive drug users. By characterizing the factors associated with the four outcomes of interest into the risk environment framework, specific objectives and hypotheses were generated for analyses in Chapters 3 to 5. 2. To examine the incidence and identify determinants of viral rebound among HIV-seropositive IDU prescribed antiretroviral therapy. Viral rebound, defined as periods of elevated plasma viral load following initial treatment success, is an important clinical event, associated with a greater risk of resistance to ART and subsequent treatment failure (72). Although previous studies have found that use of illicit drugs and/or alcohol to be associated with a higher risk of viral rebound among individuals on ART (73, 74), the role of social- and structural-level factors in viral rebound among IDU has not been well studied. This study will test the hypothesis that elements of the risk environment for drug users are independently associated with time to viral 7  rebound among individuals with durably suppressed plasma viral loads following ART initiation. 3. To evaluate the role of homelessness on the suppression of plasma HIV RNA viral load among IDU initiating ART. Although housing status has been consistently identified as an important determinant of the health of HIVpositive individuals (75), the role of homelessness on plasma viral load suppression following ART initiation among IDU has not been systematically evaluated in settings with universal access to HIV care. Further, the relationships between housing, adherence and HIV treatment outcomes have not been fully evaluated. This study will test the hypothesis that homelessness poses a significant structural barrier to plasma viral load suppression following ART initiation, and that this association is mediated by lower adherence among homeless individuals. 4. To assess the effect of incarceration on non-adherence to treatment among IDU. A number of clinical trials (76, 77) have confirmed the effectiveness of directly-administered antiretroviral therapy among incarcerated individuals; for many members of vulnerable populations, correctional facilities are one of the few opportunities to access regular medical care. However, other shortterm studies have associated incarceration with a heightened risk of discontinuation of treatment or failure to suppress plasma viral HIV RNA (25, 69). This analysis will test the hypothesis that a greater cumulative burden of incarceration is associated with higher odds of non-adherence to ART.  8  1.7  Study design and methods The quantitative empirical analyses presented in this dissertation (i.e., chapters  3, 4 and 5) are informed by data derived from an ongoing study of HIV-seropositive IDU in Vancouver, Canada. To avoid duplication in the following chapters, elements of the methodology common to all chapters are described here. Beginning in 1996, the AIDS Care Cohort to Evaluate access to Survival Services (ACCESS) is an observational prospective cohort populated using snowball sampling and extensive street outreach (55, 78). Individuals are eligible for inclusion in the study if they are 18 years of age or older; have used injection drugs in the previous month and can provide written informed consent. At recruitment and every six months thereafter, individuals respond to an extensive intervieweradministered questionnaire and undergo a medical examination by a study nurse. During the interview, participants provide confidential answers to questions on socio-demographic characteristics, drug-using and sexual experiences and related exposures. In the medical examination, the individuals provide blood samples for serologic, immunologic and virologic testing. Individuals are compensated $20 for each study visit. The University of British Columbia/Providence Healthcare Research Ethics Board has approved the Drug Treatment Programme at the British Columbia Centre for Excellence in HIV/AIDS, the ACCESS study, as well as this doctoral research. Data gathered during the interview and examination process is augmented with comprehensive information on exposure to HIV care and treatment outcomes from the Drug Treatment Programme (DTP) at the British Columbia Centre for Excellence in HIV/AIDS (BCCfE). As described above, the BCCfE is the provincial body responsible for providing HIV care, including centralized dispensation of 9  antiretroviral medications and plasma viral load determinations, for all seropositive individuals in the province (56). For each participant, the DTP provides a complete prospective clinical profile of CD4+ cell count, plasma viral load, exposure to specific antiretroviral agents and emergence of viral resistance to medications (44, 55). Although the derivation of analytic samples and specific variables of interest are described in each chapter, a number of common definitions are presented here. Among individuals who have initiated ART, adherence to prescribed therapy is modeled using a validated measure of pharmacy refill based on a confidential linkage to DTP records for each individual. In each six month period prior to the follow-up interview, adherence is defined as the number of days for which ART was dispensed over the number of days for which an individual was eligible for therapy. The resulting proportion is dichotomized at less than 95% versus equal to or greater than 95% based on a literature defined cut-off (79). The clinical utility of this measure has been demonstrated and shown to reliably predict viral suppression (52, 80, 81) and survival (78, 82). In each six-month period, CD4+ cell counts are the median of all observations in that period or, if none, the most recent CD4+ cell count; CD4+ cell counts are expressed per 100 cells. Similarly, plasma viral load in the previous six months is the median of all observations in that period or, if none, the most recent value.  1.8  Summary In summary, this dissertation is divided into six chapters. This chapter  provided a broad overview of the HIV/AIDS pandemic among individuals who use illicit drugs, relevant issues in the medical management and treatment of HIV10  seropositive IDU, and an overview of this dissertation’s objectives, hypotheses and methods. The second chapter presents the results of a systematic review of the scientific literature on HIV disease progression among drug users, focusing on social- and structural-level factors associated with mortality, the development of AIDS or changes or differences in CD4+ cell count or plasma viral load. Chapters 3 to 5 present quantitative epidemiologic analyses of hypotheses developed in chapter 1. Specifically, chapter 3 examines the incidence and determinants of viral rebound among IDU on ART; chapter 4 formally tests the hypothesis that homelessness is a structural barrier to plasma viral load suppression among IDU beginning ART; chapter 5 evaluates the effect of the cumulative burden of incarceration on the likelihood of non-adherence to prescribed therapy. All of these analyses are explicitly informed by the risk environment framework, which has modeled vulnerability to HIV infection and other drug-related harms but has not been formally applied to studies of HIV disease progression and ART treatment outcomes. Chapter 6, the concluding chapter, summarizes the key findings of this research project, offers thoughts on their implications for clinical care and public policy, as well as limitations and recommendations for future research.  11  CHAPTER 2: SOCIAL AND STRUCTURAL FACTORS ASSOCIATED WITH HIV DISEASE PROGRESSION AMONG ILLICIT DRUG USERS: A SYSTEMATIC REVIEW  2.1  Introduction The clinical benefits of highly-active antiretroviral therapy (HAART) have not  been observed equally among all HIV-seropositive groups. Compared to individuals in other risk categories, individuals who use illicit drugs exhibit higher rates of suboptimal treatment outcomes (19, 83, 84). For example, in a multi-centre study of individuals beginning HAART, individuals who use injection drugs (IDU) experienced mortality rates approximately five times higher than individuals infected through sexual contact (19). As IDU can benefit from HAART at similar rates as non-IDU given adequate compliance to therapeutic regimens (85), investigations of sub-optimal outcomes have largely focused on individual-level barriers and facilitators of HAART access and adherence (49, 67), including psychological co-morbidities and drug use patterns. We are unaware of any systematic review of factors associated with HIV disease progression among individuals who use illicit drugs. In recent years, efforts to model and address the negative sequelae of illicit drug use, including accidental overdose death, soft tissue damage and infection with blood-borne pathogens, have expanded beyond proximate causes to include contextual determinants (41, 46, 47). Specifically, the risk environment conceptual framework describes the interactions between social, political, economic and environmental determinants to facilitate or constrain individual behaviours and 12  structure the risk of drug-related harms (41, 47). While high-profile reviews have recently applied this framework to HIV transmission patterns (46), we are unaware of the framework being applied to an examination of factors associated with HIV disease progression. In light of this and recent calls for analyses of HIV treatment outcomes among drug users that include broader social- and structural-level exposures (48, 49), we sought to conduct a systematic review explicitly informed by the risk environment framework of the scientific literature on HIV disease progression and treatment outcomes among illicit drug users.  2.2 2.2.1  Methods Search strategy We used an a priori-defined search strategy based on the Preferred Reporting  Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (86). We searched the EBM, EMBASE, MEDLINE, PubMed and Science Citation Index electronic databases to identify relevant studies published in peer-reviewed journals between 1 January 1996 and 1 November 2010. Articles were selected for further review if they had at least one match in each of three sets of keywords or search terms: Illicit drug use (i.e., “heroin”, “crack”, “amphetamines”, “cocaine”, “injection drug user”); disease progression (i.e., “viral suppression”, “viral load”, “cd4”, “death”); and HIV/AIDS. When possible, filters were used to exclude case reports, case series, reviews and other non-eligible study types. Only studies among human subjects were included. We included further studies identified during the course of the search through reviews of citation lists.  13  2.2.2  Inclusion and exclusion criteria Studies were included if they were conducted among HIV-seropositive  individuals who were current or former illicit drug users. Eligible study endpoints included the following measures of HIV disease progression: Change or difference in CD4 cell count or percentage; change or difference in plasma HIV-1 RNA viral load (PVL); incidence or prevalence of AIDS, as defined by US Centres for Disease Control diagnostic guidelines; and death, including all-cause, pre-AIDS, HIV-related and infectious disease-related mortality. To be included, studies had to include analyses of factors associated with these outcomes of interest, with significance assessed through appropriate statistical tests or the estimation of effect measures and confidence intervals. Studies were ineligible if they were evaluations or trials of interventions, were written in a language other than English, or were not published in a peer-reviewed journal. 2.2.3  Search protocol One author (M-JSM) conducted the database search and entered studies  matching the keywords and criteria into a search database. After removing duplicates, studies not meeting the criteria were excluded from further review. Full text versions of all remaining articles were retrieved and independently reviewed by two authors (M-JSM and BDM). Each marked each remaining study “included” or “excluded”; any discrepancies were addressed by both authors until a consensus was reached.  14  2.3  Results Four thousand one hundred twenty-two records matched all search criteria  and were retrieved from electronic databases; 10 articles were identified following manual searching of reference lists. Following removal of duplicate records, 2668 studies remained eligible for review. After screening citation data and abstracts, the full-text version of 182 reports (6.8%) were assessed by both M-JSM and BDM. Of these, 56 (2.1%) are included in this report (68-71, 87-140). Figure 1 presents the results of the acquisition, screening and selection process. Table 1 presents details of the included studies stratified by endpoint, setting and sample type. Of the 56 articles, 16 (29%) included an analysis of factors associated with time to AIDS diagnosis among HIV-seropositive drug users. Death was an outcome of interest in 23 (41%) studies. Changes or differences in CD4 cell count was an endpoint in 16 (29%) studies. In 15 (27%) studies, changes or differences in PVL was an endpoint. All but one study (in Thailand (116)) was conducted among HIV-seropositive drug users in Western settings. The plurality (27, 48%) occurred in the United States or Canada; 21 (38%) in Western Europe; and 7 (13.8%) in multi-national settings. The mean study sample size was 363 individuals (inter-quartile range [IQR]: 125 – 524) and the median follow-up time was 44 months (IQR: 30 – 61). Twenty-one studies (38%), all from North America, recruited participants from community settings; of the remainder, 14 (25%) recruited individuals from hospital settings; 12 (21%) from drug treatment settings; two (4%) used population-based data; and seven (13%) employed analytic samples constituted using multiple recruitment strategies. The associations identified in this review, stratified by clinical endpoint and the risk environment framework, are presented in Table 2. Sixteen studies compared 15  rates of disease progression among IDU by modeling the time to a diagnosis of AIDS. In the period preceding the widespread availability of HAART among drugusing populations, several studies (106, 121, 126, 127, 130) used samples of individuals with well-estimated HIV seroconversion dates to assess factors possibly associated with the natural history of HIV infection. In these analyses, no significant differences in clinical progression were observed in individuals with HTLV-II coinfection (106), HCV co-infection (132), or carrying the CCR5-!32 or CCR2b-64I alleles (130). At the same time, other studies confirmed the well-established prognostic value of immunologic (99, 103, 114, 127, 136-138) and virologic characteristics (99, 136) observed in other risk categories. In a 1998 study, Vlahov et al. used clinical data from a large community-recruited study of mainly AfricanAmerican IDU in Baltimore to demonstrate the predictive utility of baseline PVL and CD4 cell count on time to AIDS (136). In this era, findings on the influence of illicit drug use on clinical progression were equivocal (122, 138). In a group of opiate users drawn from a drug treatment programme in the United States, individuals self-reporting use of crack cocaine exhibited faster progression to AIDS in a multivariate model adjusted for age, gender, HIV monotherapy use and CD4 cell count (138). However, this relationship was not apparent in a multi-centre study of IDU in Italy and the United States. Participants in Baltimore, mostly poly-drug injectors, and participants in Italy, mostly cocaine injectors, did not exhibit different rates of AIDS, as would be expected if drug use accelerated disease progression. In addition, neither age at first injection nor length of injection career was associated with time to AIDS in a pooled analysis of all participants (122). In studies among HAART-treated individuals, drug use has a limited effect on patterns of AIDS development (121, 132-134). Although no study could be found assessing the direct 16  effect of access and adherence to HAART on time to AIDS among IDU, studies using calendar time as a proxy for the general availability of HAART provide weak evidence of the benefit of HAART on clinical progression (121, 132-134). Survival of HIV-seropositive IDU was investigated in 23 studies, in which 11 (20%) (87, 89, 93, 94, 104, 113, 118, 121, 130, 131, 133) modeled all-cause mortality, 6 (11%) (91, 101, 106, 123, 126, 135) modeled HIV- or AIDS-related mortality, 2 (4%) (122, 136) modeled infectious disease-related mortality and 3 (5%) (127, 128, 134) modeled time to pre-AIDS mortality. Unsurprisingly, both HIV-related and all-cause mortality rates were high in studies of untreated IDU populations, approximating 50 per 1000 person-years (91, 94, 107, 118, 123, 126, 127, 135, 136). Studies among HAART-naïve samples (87, 91, 93, 94, 104, 106, 118, 122, 123, 126-128, 130, 131, 136) found little evidence of unique clinical or biological correlates of survival among IDU. Conversely, baseline immunologic factors including IgG and IgA levels (118) and CD4 cell counts (94, 104, 107, 118, 127, 128, 131, 135) were strongly associated with time-to-death. As with analyses of time to AIDS, studies of the relationship between patterns of illicit drug use and HIV-related death were contradictory. In two studies of community-recruited injection drug users in Baltimore (101, 135), cocaine use was associated with lower rates of death; drug use was not associated with survival in other analyses (107, 118). More recently, studies conducted in the wake of HAART uptake among IDU (101, 107, 117, 121, 133-135) have confirmed its beneficial impact on survival. Although based on self-reported data on exposure to medication, individuals treated with HAART had sharply reduced relative hazards of death compared to antiretroviral-naïve participants in a study of 665 communityrecruited IDU followed from 1988 to 2002 (135). In contrast to the well-described relationships between endogenous factors and survival, few associations with 17  exogenous factors were observed. In an early study of the relationship between HIV treatment and opioid substitution therapy, engagement in MMT at baseline was predictive of survival among IDU in Germany (104). Lack of legal income at baseline was the strongest predictor of shortened survival in a small study among Parisian IDU after adjustment for age, CD4 cell count, p24 antigenemia, age and baseline drug use (123). Immunologic status as measured by changes or differences in counts of circulating CD4 cells was a focus of 16 studies. Only weak evidence was found for a relationship between illicit drug use patterns and immunologic progression (108, 110, 112, 125, 129). In two small studies conducted before the general availability of HAART, more intense drug use patterns were associated with declines in CD4 cell count (125, 129). However, in two larger studies using community-recruited groups of drug users (108, 110), evidence was contradictory. Modeling changes in CD4 cell count over the study period, Lyles et al. observed only length of drug using career was associated with the outcome and not changes in frequency or type of drug use (110). In a study of seroconverters, several measures of more intense drug use were associated with steeper declines in CD4 cell count following infection, however most differences became non-significant six months past baseline (108). Following the introduction of HAART to drug users, a study following HAART initiation found individuals reporting recent injection drug use had lower odds of an immunologic response to therapy in a multivariate model that included self-reported adherence (112). In the only other study found of immunologic response to HAART, active drug use was not associated with immunologic progression (92). However, in adjusted analyses, both non-adherence to HAART and clinical depression were predictive of poorer treatment outcomes (92). Only one study identified an 18  association between immunosuppression and aspects of the risk environment (112). In Mehta et al.’s study of HAART initiators in Baltimore, individuals reporting recent incarceration had significantly lower adjusted odds of CD4 cell count improvements (112). Differences or changes in plasma viral load were assessed in fifteen studies. In one study involving ART-naïve drug users, no relationship between current drug use and PVL was seen in participants with less than 10 years of drug use (96). PVL among participants with longer drug using careers was marginally elevated (96). In studies of drug-using individuals on HAART (70, 71, 88, 98, 120), drug use was not a major predictor of elevated viral loads or treatment failure in four of five studies (70, 71, 98, 120). For example, in a multivariate model that included self-reported adherence to HAART, neither drug injection, binge drinking, alcohol abuse, nor heroin use were associated with viral outcomes; cocaine was marginally significant (p = 0.04) (71). Conversely, access to substitution therapy was strongly associated with optimal virologic response in studies of community-recruited drug users in France (71) and Canada (120). Five studies (96, 109, 112, 115, 139) observed virologic trajectories following the initiation of HAART. Notably, in three (109, 112, 115) of four studies assessing them (109, 112, 115, 139), drug use patterns were not associated with lower relative hazards of suppression. In a study using a validated pharmacy-refill measure of adherence in a setting of free HIV care, illicit drug use was not associated with likelihood of PVL suppression or time to suppression following ART initiation in multivariate analyses (109). Conversely, Zaccarelli et al.’s 2002 study of 80 IDU drawn from an HIV outpatient clinic found that active injection drug use was independently associated with virologic failure following initiation of HAART (139). In addition, a number of endogenous factors emerged as 19  determinants of PVL (68-71, 109). Two studies by Knowlton et al. identified microsocial factors, such as social support and the quality of communication with medical care-givers, as positively associated with PVL suppression (68, 70). In Vancouver, Palepu et al. found that being incarcerated in the six months prior to follow-up was a barrier to virologic suppression among drug users in a setting of universal access to HIV care (119). Similarly, in a multi-centre study in the United States (68), individuals reporting stable housing environments had over three times higher odds of suppression after adjustment for a range of individuals and interpersonal factors.  2.4  Discussion Consistent with existing critiques of the scientific literature on HIV among  drug users (48, 49), the major finding of this review is that few studies of disease progression among illicit drug users included measures of exogenous exposures. While a strong majority of these studies confirmed endogenous host and viral characteristics associated with the natural history of HIV infection as well as treatment outcomes, only a minority of studies identified associations between physical, social, political or economic factors and disease progression. In this group, Knowlton et al.’s studies (68, 70) are a notable example. In their study of individual-, social- and structural-level exposures on the likelihood of viral suppression among drug users on HAART,(68) high social support, good communication with healthcare providers and stable housing were independent predictors of suppression. In two studies, incarceration was associated with poorer immunologic (112) and virologic (69) response following HAART initiation. This result stands in contrast to many prison-based trials of ART delivery, which have produced high 20  levels of adherence to treatment (76, 141). However, the inferior responses to ART identified in this review likely stem from treatment interruptions caused by movement between correctional and community environments (142, 143). Notably, many of the exogenous risk factors for disease progression in this review — specifically incarceration (69, 112), poor housing status (68) and lack of legal income (123) — have been identified as important determinants of vulnerability to HIV infection in past descriptions of the risk environment framework (46, 47). Thus, future analyses of HIV treatment outcomes might consider using this conceptual framework to model the disease progression process in drug users. This review found only weak evidence of a direct relationship between illicit drug use and disease progression and it is noteworthy that all studies reporting this association among groups of ART-treated participants did not include robust measures of patient adherence. Our finding stands in sharp contrast to numerous laboratory studies that have found important associations between illicit drugs and relevant virologic or immunologic functioning (144-148). For example, exposure to morphine has been shown to up-regulate HIV replication in vitro (145); cocaine use has been shown to impair immunologic performance in both murine and human subjects (146, 147). However, these molecular-level effects were not clearly reproduced in studies of untreated human subjects in this review. In groups of drug users surveyed before the widespread use of HAART, illicit drug use was associated with disease progression in some (95, 108, 110, 138) but not other (94, 108, 110, 122) studies. Further, residual confounding was not excluded in several studies that linked drug use with disease progression. For example, while Weber et al. estimated that crack cocaine users had a faster time to AIDS diagnosis, their multivariate model did not include information on exposures likely to be associated with crack 21  cocaine use and HIV-related morbidity, such as poorer access to healthcare, unstable housing or nutritional deficiencies. Among HAART-treated groups of drug users, the effect of illicit drugs on disease progression is thought to be mediated through lower levels of adherence to therapy. Although many studies are limited by poor or incomparable measures of drug use (90), stronger support for this hypothesis was found in this review (88, 91, 120, 139). For example, frequent heroin use was univariately associated with lower odds of viral suppression in Palepu et al.’s 2006 study (120) of HIV-seropositive drug users in Vancouver; in a multivariate model including ART adherence, this association was not statistically significant, suggesting a mediating relationship. Nevertheless, it should be remembered that these studies largely fail to include any measurement of exogenous factors which might account for some of the effect of illicit drug use on non-adherence, such as higher levels of incarceration, poor housing status and physical and psychological co-morbidities. Among these studies, only Baum et al. (90) reported an independent effect for crack cocaine use on both CD4 cell decline and PVL after accounting for exposure to ART. In their short-term longitudinal study of 222 active illicit drug users in Miami, Florida, ongoing crack cocaine use was marginally associated with a faster rate of progression to CD4 < 200 cells in a multivariate model including baseline CD4 cell count and HAART exposure but no measure of social or structural vulnerability (90). However, it is unlikely their self-reported measure of HAART use adequately captured exposure to treatment as it did not predict PVL suppression in a univariate analysis. Also of note is a recent analysis using data from a longrunning community-recruited cohort of HIV-seropositive IDU which failed to find a relationship between patterns of ongoing drug use and viral suppression (109).  22  The two main findings of this review — the strong focus, to date, on individual-level factors and the moderate and likely mediated associations between patterns of illicit drug use and disease progression — should be considered in light of the urgent need for interventions to improve HIV treatment outcomes among drug users. While the medical management of HIV-seropositive drug users in the clinical setting can be complex, clinical trials have proven directly administered antiretroviral therapy (DAART) twinned with opioid substitution therapy is effective at improving treatment outcomes (36-38, 149, 150). This review suggests that the emerging evidence of relationships between exogenous factors and disease progression might provide useful new targets for clinical and community-based interventions, for example among drug users at risk of incarceration or homelessness, to support required levels of adherence among marginalized, drugusing individuals. Limitations common to many of these studies should be mentioned in order to contextualize the findings. Most notably, although the most recent estimates suggest that close to one hundred countries in the Americas, Europe, Africa and Asia are home to HIV-seropositive illicit drug users (151), these studies only drew from seropositive groups in a small minority of countries in western Europe, the United States and Canada. Notably, the only study including non-Western HIV-seropositive illicit drug users identified a novel host genotype associated with swifter CD4 cell decline among untreated drug users. While this review has focused on exogenous factors, the presence of immunologic polymorphisms among drug users has not been well evaluated. More generally, the patterns of disease progression among HIV-seropositive drug users in the countries with the largest ongoing HIV outbreaks outside sub-Saharan Africa (48) — Russia, China, Ukraine, Vietnam and 23  Malaysia — have not been evaluated. A further limitation is the dependence on samples of drug users drawn from treatment settings. Although over one-third (22, 37.9%) recruited individuals using community-based techniques, almost all of these studies were conducted by the ALIVE prospective cohort in Baltimore, Maryland. To conclude, this review of disease progression among illicit drug users found that most studies concentrated on individual-level host and viral characteristics. Although few considered the broader physical, social, political and economic determinants of disease production or treatment outcomes, some studies did identify important associations with factors including incarceration, housing status and engagement in opioid substitution therapies. Although many studies focused on the effect of drug use patterns, weak and contradictory evidence was observed to support the hypothesis that drug use is directly related to disease progression. In light of this review, future research and interventions should consider the risk environment framework when seeking to reduce HIV-related morbidity and mortality among drug users.  24  54 Records from EBM 1643 Records from EMBASE 1369 Records from MEDLINE 276 Records from PUBMED 770 Records from SCI 4122 Records from databases 10 Records from citation lists 2668 Records after de-duplication 2496 records excluded after screening Title and Abstract  182 Full-text articles fully reviewed 126 records excluded after screening full text  56 studies included  Figure 1. Flowchart of study acquisition, screening and selection process  25  Table 1. Descriptive summary of included studies on HIV disease progression among illicit drug users AIDS 16 (100%) (99, 102, 103, 106, 114, 121, 122, 126, 127, 130, 132-134, 136-138)  Mortality 23 (100%) (87, 91, 93, 94, 101, 104, 106, 107, 113, 117, 118, 121123, 126-128, 130, 131, 133-136)  CD4 16 (100%) (90, 92, 93, 97, 100, 105, 108, 110, 112, 116, 125, 126, 129, 130, 132, 140)  PVL 15 (100%) (68-71, 88, 95, 96, 98, 109, 112, 115, 119, 120, 124, 139)  All 56 (100%) (68-71, 87140)  6 (38%) (99, 103, 106, 136-138)  9 (39%) (91, 94, 101, 106, 107, 118, 131, 135, 136)  6 (38%) (90, 97, 100, 110, 112, 140)  9 (60%) (68, 70, 88, 98, 109, 112, 119, 120)  Europe  4 (25%) (102, 114, 126, 130)  10 (43%) (87, 89, 93, 104, 113, 117, 123, 126, 127, 130)  6 (38%) (92, 93, 105, 125, 126, 130)  6 (40%) (71, 95, 96, 115, 124, 139)  Asia Multi-centre  0 (0%) 6 (38%) (121, 122, 127, 132-134)  0 (0%) 5 (22%) (121, 122, 127, 133, 134)  1 (6%) (116) 2 (13%) (108, 132)  0 (0%) 0 (0%)  27 (48%) (68-70, 88, 90, 91, 94, 97-101, 103, 106, 107, 109, 110, 112, 118-120, 131, 135-138, 140) 21 (38%) (71, 87, 89, 92, 93, 95, 96, 102, 104, 105, 113-115, 117, 123-126, 128, 130, 139) 1 (2%) (116) 7 (13%) (108, 121, 122, 127, 132-134)  4 (25%) (99, 103, 106, 136)  7 (30%) (91, 101, 106, 118, 131, 135, 136)  6 (38%) (90, 97, 108, 110, 112, 140)  7 (47%) (68, 70, 98, 109, 112, 119, 120)  Clinical/Treatment  4 (25%) (114, 130, 137, 138)  10 (43%) (87, 89, 93, 94, 104, 107, 113, 123, 128, 130)  7 (44%) (92, 93, 100, 105, 116, 125, 130)  7 (47%) (71, 88, 95, 96, 115, 124, 139)  Other  8 (50%) (102, 121, 122, 126, 127, 132134) 600 (504 – 761) 61 (48 – 84)  7 (30%) (117, 121, 122, 126, 127, 133, 134)  2 (13%) (126, 132)  1 (7%) (119)  487 (126 – 686) 56 (41 – 81)  238 (128 – 259) 45 (30 – 57)  189 (106 – 246) 12 (12 – 24)  All  Setting North America  Sample Community  Sample size, mean (IQR) Follow-up months, median (IQR)  21 (38%) (68, 70, 90, 91, 97-99, 101, 103, 106, 108-110, 112, 118-120, 131, 135, 136, 140) 25 (45%) (71, 87-89, 92-96, 100, 104, 105, 107, 113-116, 123125, 128, 130, 137139) 10 (18%) (102, 117, 119, 121, 122, 126, 127, 132-134) 363 (125 – 524) 44 (30 – 61)  26  Table 2. Factors associated with HIV disease progression among illicit drug users EXOGENOUS Macro Physical  Micro  AIDS  Mortality  Study site (106, 126, 127, 133), study year (102, 133, 137)  HAART era (101, 135), study year (121, 133), study site (106, 126, 133)  Social Political Economic Physical  CD4  PVL  Incarceration (112)  Housing (68), incarceration (69) Social support (68, 70), patient-provider communication (68) MMT (71, 109), Retention in OST (71)  CES-D score (92), HCV genotype (132), Syringe borrowing (108), Active injection drug use (112, 125), Injection heroin use (108), Injection drug use duration (108), Illicit drug use duration (110), illicit drug use (129) HAART non-adherence (92)  Alcohol use (69), cocaine use (88), crack use (98), illicit drug use (139), injection drug use (95)  PVL (140)  PVL (69, 119, 124, 139)  Social  Political  MMT (104)  Economic  Lack of legal income (123)  ENDOGENOUS Co-morbidities  Crack use (138), psychological distress (103)  Pharmacotherapies  HIV-related morbidity Virologic characteristics  Anemia (135), cocaine use (135), selenium deficiency (91, 131), withdrawal symptoms (113), STD (101), recent hospitalization (101, 135), serum thiol(111)  HAART use (101, 107, 135), ART use(104), PCP prophylaxis,( 101)  Thrush (103, 114), symptoms (138) PVL (99, 136)  HIV  Thrush (135), AIDS diagnosis (101, 111) PVL (113, 136)  ART regimen (69, 119, 124), HAART adherence (69, 71, 115, 120, 124, 139), time since ART initiation (69, 88, 119, 120) AIDS diagnosis (115)  27  Table 2. Factors associated with HIV disease progression among illicit drug users (continued) AIDS  Mortality  CD4  PVL  ENDOGENOUS sTNFR-II level (87) Genetic characteristics Host characteristics  HLA genotype (93) Age (114, 137), age at seroconversion (126), time since seroconversion (126), gender (121)  Age (104, 113), BMI (131), gender (104, 121), time since seroconversion (123, 127), age at seroconversion(123)  HHE haplotype (116), HLA haplotype (93) Age (95, 112, 120), race (70), gender (88)  28  CHAPTER 3: SOCIAL AND ENVIRONMENTAL PREDICTORS OF HIV RNA VIRAL REBOUND AMONG INJECTION DRUG USERS TREATED WITH ANTIRETROVIRAL THERAPY  3.1  Introduction The primary clinical goal of ART is to inhibit viral replication and suppress  plasma viral load (PVL) to undetectable levels (152). Longitudinal analyses of clinic-based studies have revealed that while a substantial proportion of individuals are able to achieve viral suppression with ART (72, 153), at least one in ten patients will experience at least one episode of viral rebound (72). Clinical factors associated with a greater risk of rebound include shorter duration of viral suppression (154, 155); ART regimen composition (72); and non-adherence to ART (74, 156). Ongoing illicit drug use represents an added challenge in the medical management of HIV infection (31). Previous studies have identified active alcohol and illicit drug use as risk factors for failure to achieve viral suppression (73, 84, 119, 157) and avoid viral rebound (35, 74). However, the determinants of viral rebound among IDU on ART have not been completely investigated. In particular, consideration of the broader social and environmental factors that have been shown to determine vulnerability to HIV infection (46, 47, 158) have not been well evaluated as possible determinants of viral outcomes. Thus, given the urgent need to improve treatment access and delivery for HIV-seropositive IDU, we conducted the following study with the primary objective of identifying social and environmental risk factors for viral rebound among IDU on ART.  29  3.2  Methods These analyses used data from the AIDS Care Cohort to Evaluate access to  Survival Services (ACCESS) cohort, described in detail in section 1.7. In this study, we included all individuals who were exposed to ART at baseline or who initiated ART over the study period; had at least one observation of CD4 cell count and PVL within 12 months of recruitment; and at least two consecutive measurements indicating suppression of PVL during the study period. Because the sensitivity of the viral load assays changed over the study period, we defined suppression as any measurement below 500 copies/mm3 before April 1, 1999 and any measurement below 50 copies/mm3 after April 1, 1999. For all individuals included in these analyses, time zero was defined as the date of the first interview following the second measurement indicating suppression. The primary outcome of interest was confirmed viral rebound, defined as the date of the second of two consecutive measurements of PVL above 1000 copies/mL, consistent with a previous study from our setting (79). Local treatment guidelines recommend that PVL be assessed at ART initiation, four weeks after starting treatment, and every three months thereafter. In this study, measures of PVL, CD4 cell count and other clinical indicators could be ordered by the participant’s physician as well as study physicians. Consistent with previous studies identifying clinical risk factors for viral rebound (74, 154, 159), we considered the following explanatory variables: PVL at ART initiation (per log10 increase); presence of a protease inhibitor in the first ART regimen (yes vs. no); experience of participant’s HIV physician (< 6 patients 30  enrolled BCCfE treatment registry vs. ≥ 6 patients); CD4 cell count (per 100 cells); the time since ART initiation (per year increase); and adherence to ART (>95% vs. ≤95%). The presence of a PI, PVL at ART initiation and HIV physician experience were assessed at baseline and were time-invariant variables; the remaining were time-updated exposures and referred to the six month period prior to each participant’s interview. CD4+ cell counts and ART adherence were ascertained using the methods described in section 1.7. Sociodemographic characteristics assessed at baseline and included as timeinvariant variables were the participant’s age, gender (female vs. male), whether the participant reported Aboriginal ancestry (yes vs. no) and educational attainment (< high school diploma vs. ≥ high school diploma). Patterns of illicit drug use were assessed longitudinally and included as time-updated variables. Consistent with a previous study on illicit drug use and viral suppression from our setting (109), we characterized illicit drug use in the last six months as a three-level variable with abstinence as the reference level vs. any illicit drug use (excluding cannibinoids) vs. any injection drug use. We also included recent binge drug use, defined as any period of more intense drug use than typical in the previous six months (yes vs. no). As there is a growing interest in the role played by the contextual determinants of HIV vulnerability (46, 49), our choice of explanatory variables was informed by the risk environment framework (41, 42). This framework is increasingly used to understand the social, environmental and structural level forces that contribute to the risk of infection with HIV (46). Specifically, we included these time-updated variables: living in unstable housing, defined as being homeless, living in a single-room occupancy hotel room, homeless shelter 31  or transitional housing (yes vs. no); participating in the sex trade, defined as any sexual acts in exchange for money, drugs or other goods or favors (yes vs. no); engagement in methadone maintenance therapy (yes vs. no); and recent incarceration. Exposure to correctional environments was assessed using a threelevel variable with a reference level of no incarceration overnight or longer in any facility vs. any incarceration overnight or longer in pre-trial detention vs. any incarceration overnight or longer in a provincial prison or federal penitentiary. With the exception of engagement in MMT, which referred to current status, all other time-updated characteristics referred to the six-month period prior to the follow-up interview. To model the relationship between these explanatory variables and the time to viral rebound, we constructed a series of univariate and multivariate proportional hazards frailty models including a recurrent events framework. Frailty models are a class of survival statistical techniques that consider the effect of time-updated covariates as well as each individual’s unobservable deviation from the baseline hazard function, consistent with each individual’s inherent risk of viral rebound. Because each individual could experience multiple periods of viral suppression and viral failure, we included a recurrent events framework. All individuals were coded at risk for the outcome from the first time of suppression to the first rebound, if applicable; from then on, their observations were censored until the individual had two consecutive PVL observations indicating suppression at which time they were considered at risk for another failure event. This cycle was continued until the end of all available observations. As a first step, we considered the relationship between all explanatory variables and the risk of rebound by estimating the hazard ratio (HR) with 95% 32  confidence intervals (95% CI) and associated p-value using univariate frailty models. Next, we constructed a multivariate model including all variables with pvalues less than 0.05 in univariate analyses except for adherence to prescribed ART. In a secondary analysis, we fit the same multivariate model, adding the covariate for ART adherence.  3.3  Results Between May 1996 and November 2008, 762 individuals were recruited into  the study. Of these, 538 (70.6%) were ART-exposed, 274 (36.0%) prior to study recruitment and 264 (34.6%) following recruitment. Two hundred seventy-seven individuals (36.3%) had at least two consecutive PVL observations indicating suppression and complete clinical profiles and were included in these analyses. Over the study period, the 277 participants contributed 995 person-years of follow-up with a median follow-up time of 32 months (IQR: 6 – 64) per participant. One hundred twenty-five participants (45.1%) experienced at least one instance of viral rebound over follow-up, equal to a crude incidence of 12.6% (95% CI: 10.5-15.0). The baseline characteristics of the participants, stratified by viral rebound over the study period, are presented in Table 3. Of note, participants who were younger, with less time elapsed on treatment and lower CD4 cell counts at the time of HAART initiation had a greater likelihood of failure. The unadjusted estimates of the effect of the explanatory variables on the time to rebound are presented in Table 4. Younger individuals (HR = 0.98 [95% CI: 0.97 – 0.99]) and individuals reporting sex-trade participation (HR = 1.45 [95% CI: 1.15 – 1.84]) both faced elevated risks of viral rebound. Engagement in 33  methadone maintenance therapy (HR = 0.75 [95% CI: 0.64 – 0.89]) was protective against treatment failure. Although exposure to pre-trial detention facilities was not associated with rebound, incarceration overnight or longer in a provincial prison or federal penitentiary (HR = 1.86 [95% CI: 1.37 – 2.52]) conferred a significant risk of failure. Interestingly, various patterns of illicit drug use, including any use, any injection drug use, and any binge drug use, were not associated with a greater risk of rebound. The adjusted estimates of factors associated with time to treatment failure are presented in Table 5. In Model 1, the multivariate model including all variables significant in univariate analyses, sex trade participation (Adjusted Hazard Ratio [AHR] = 1.40 [95% CI: 1.08 – 1.82]) and incarcerations in a prison or penitentiary (AHR = 1.83 [95% CI: 1.33 – 2.52]) were each independently associated with treatment failure. Engagement in methadone maintenance therapy (AHR = 0.79 [95% CI: 0.66 – 0.94]) was negatively associated with viral rebound. This model was also adjusted for age and clinical predictors of viral rebound significant in univariate analyses, specifically CD4 cell count, treatment duration and the presence of a PI in the initial ART regimen. However, in the model including ART adherence (Model 2), neither age, sex trade participation nor methadone maintenance therapy remained independently associated with viral rebound. The association with provincial or federal incarceration remained, although the effect was substantially attenuated. The significant clinical correlates of rebound remained when adherence was included in the model.  34  3.4  Discussion In this study, the first to our knowledge to investigate social and  environmental determinants of viral rebound among IDU on ART, loss of virologic control following suppression was common, with almost half of participants (45.1%) experiencing at least one episode of treatment failure over follow-up. While this rate of rebound is consistent with previous studies (35, 74), we found patterns of illicit drug use were not significant predictors of rebound. Instead, exogenous factors, including recent incarceration and participation in the sex trade emerged as independent risk factors for rebound while engagement in methadone maintenance therapy was protective. Providing validity to the model, established clinical determinants of viral rebound, specifically CD4 cell count and the length of treatment were also associated in multivariate models. Comparison of the two multivariate models indicates the associations between several exposures and treatment failure are largely driven by poorer adherence to ART within those strata. When adherence to ART is added to the multivariate model (Model 2), several associations in Model 1, specifically age, participation in the sex trade and engagement in MMT, are rendered nonsignificant. This is consistent with previous studies that found adherence to ART was typically lower among younger individuals (160) and those in the sex trade (161) while engagement in MMT was associated with better adherence (162). Interestingly, although the strength of the effect of recent incarceration in a prison or penitentiary also declined, it remained significantly associated with rebound. This highlights the critical need to improve adherence in criminal justice settings (25). Thus, our study supports the provision of increased and improved support  35  for ART adherence among these younger drug users, those in the sex trade and the recently incarcerated, to reduce the risk of viral rebound. In this study, we used the risk environment framework to analyse HIV disease progression among IDU. In the past, the risk environment framework has informed studies of the factors that shape the risk of HIV acquisition (43, 163, 164). Specifically, the framework describes the interplay between exogenous forces, including micro- and macro-level political, social, economic and physical effects, and endogenous characteristics, including host and viral attributes, on the production of vulnerability to HIV infection (46). In the current study, we observed that exposures previously linked with a higher risk of HIV infection were independently associated with higher rates of viral rebound, specifically incarceration (44) and participation in the sex trade (165). As with HIV infection (165), engagement in MMT was protective. Certainly, the causal pathways between these exposures and HIV infection differ from these exposures to treatment non-adherence and viral rebound. However, this study illustrates how the vulnerability produced by the social and structural context of healthcare can contribute to HIV treatment outcomes and disease progression. Thus, the risk environment framework may be a useful model to identify factors contributing to the elevated levels of HIV-related morbidity and mortality among drug users and inform evidence-based interventions in clinical practice, community settings and at the population level. Consistent with previous studies from our setting describing how imprisonment complicates adherence (142, 166) and inhibits suppression (167), incarceration in a prison or penitentiary, but not in pre-trial detention, emerged as the strongest non-clinical predictor of viral rebound. Although health services 36  are typically more rudimentary in local pre-trial facilities and lack the means to care for chronic conditions, the typically short duration of exposure likely minimizes the clinical consequences of any missed doses. Our finding of a deleterious effect of longer-term imprisonment on viral loads contradicts previous prison-based studies of ART delivery in which prisoners achieved viral suppression (76, 77). Our study underlines the challenges incarceration and transition between correctional and non-correctional environments pose to IDU on ART (168). Substantial effort has been devoted to the development of prognostic tools to identify individuals on ART at heightened risk of viral failure using routinely collected data (74, 169). Our results, specifically the lack of an association with patterns of illicit drug use and the strong link with incarceration, participation in the sex trade and engagement in methadone maintenance therapy, suggest that these screens could be improved by the inclusion of these and other measures of vulnerability. Further, the finding that abstinent individuals did not significantly differ from active drug users in the likelihood of viral rebound builds on our previous report that ongoing drug use did not prevent viral suppression (109). These studies are evidence against the blanket refusal to provide medically necessary ART to IDU, as is common in many jurisdictions (48). As in all observational studies, our study has several limitations. First, the study sample was not selected at random and our findings should not be generalized to other groups of IDU on ART. However, our use of snowball sampling and other community recruitment methods hopefully minimized the bias resulting from the selection procedures. Similarly, as with all observational studies, the relationships between the explanatory variables and the outcome of 37  interest may be under the influence of unobserved confounding. We have sought to address this bias with multivariate adjustment of the covariate estimates and the selection of a broad set of possible confounders. We also recognize that many of our measures were self-reported and thus may be affected by social desirability bias. However the key variables emerging as significant in these analyses (sex trade involvement, recent incarceration and engagement in methadone maintenance therapy) were not likely to be differentially reported by individuals with greater or lesser likelihood of experiencing viral rebound.  Finally, for  historical reasons, we were forced to use a cut-off for PVL suppression of 500 copies/mm3. Although we cannot know with certainty, we know of no reason why our results would differ had a cut-off of < 50 copies have been possible with our data. To conclude, we assessed the patterns and predictors of viral rebound among community-recruited drug users on ART with suppressed PVL. Consistent with previous studies finding that exposure to characteristics of the risk environment framework were associated with vulnerability to HIV infection, we found that individuals engaged in the sex trade or recently incarcerated in a prison or penitentiary were at higher risk of viral rebound. Concurrently, active drug use was not associated with viral rebound. Our findings not only demonstrate the utility of the risk environment framework in analyzing patterns of HIV disease progression but also suggest that efforts to HIV-seropositive IDU in effective treatment should include consideration of the social, environmental and structural contexts of treatment delivery.  38  Table 3. Baseline characteristics of 277 HIV-seropositive IDU on ART with durably suppressed HIV RNA levels  Characteristic Age Median (IQR) Gender Male Female Aboriginal ancestry No Yes Years since ART Median (IQR) HIV RNA load 3 (log10) Median (IQR) 3 CD4 cell (per 100) Median (IQR) 3 PI in first regimen No Yes 3 HIV MD experience ≥ 6 patients < 6 patients  No viral rebound over follow-up 152 (54.9%)  ≥ 1 viral rebound over follow-up 125 (45.1%)  OR  95% CI  44.1 (38.7 – 49.6)  38.4 (32.7 – 44.1)  0.98  0.97 – 0.99  < 0.001  96 (63.2) 56 (36.8)  67 (53.6) 58 (46.4)  1.00 1.48  0.92 – 2.40  0.108  89 (58.6) 63 (41.4)  73 (58.4) 52 (41.6)  1.00 1.01  0.62 – 1.62  0.978  2.8 (0.0 – 5.9)  2.6 (0.9 – 4.3)  0.98  0.96 – 0.99  < 0.001  4.8 (4.5 – 5.2)  4.9 (4.4 – 5.3)  1.06  0.98 – 1.14  0.162  2.0 (1.2 – 2.8)  2.9 (1.5 – 4.2)  1.06  1.04 – 1.09  < 0.001  98 (64.4) 54 (35.6)  84 (67.2) 41 (32.8)  1.00 0.89  0.54 – 1.46  0.634  127 (83.6) 25 (16.4)  98 (78.4) 27 (21.6)  1.00 1.40  0.76 – 2.56  0.274  1  2  p-value  1. Odds Ratio; 2. 95% Confidence Interval; 3. Observed at initiation of HAART  39  Table 4. Unadjusted estimates of the behavioural, social and structural factors associated with viral rebound among 277 IDU on ART with suppressed viral loads at baseline Characteristic 2 Age Per year older 2 Gender Female vs. male 2 Aboriginal ancestry Yes vs. no 2 Education < HS dip vs. ≥ HS dip 3 Illicit drug use None vs. any None vs. injection 3 Binge drug use Yes vs. no 3 Unstable housing Yes vs. no 3 Sextrade participation Yes vs. no 3 Methadone maintenance Yes vs. no 3 Incarceration None vs. pre-trial detent None vs. prison or pen 3 CD4 cell count Per 100 cells 2 HIV MD experience < 6 patients vs. ≥ 6 3 Time since initiation Per year 2 PI in first regimen Yes vs. no 2 pVL at ART initiation Per log10 increase ART adherence >95% vs. ≤95%  1  HR  95% CI  p-value  0.98  0.97 – 0.99  < 0.001  1.11  0.94 – 1.31  0.201  0.89  0.75 – 1.05  0.171  1.04  0.88 – 1.24  0.651  0.93 0.99  0.15 – 5.74 0.14 – 6.85  0.591 0.910  1.23  0.99 – 1.52  0.060  0.90  0.76 – 1.06  0.211  1.45  1.15 – 1.84  0.002  0.75  0.64 – 0.89  < 0.001  1.07 1.86  0.72 – 1.61 1.37 – 2.52  0.726 < 0.001  0.88  0.84 – 0.92  < 0.001  1.03  0.83 – 1.28  0.812  0.89  0.85 – 0.93  < 0.001  1.32  1.11 – 1.56  0.001  0.97  0.88 – 1.08  0.574  0.16  0.12 – 0.21  < 0.001  1. Hazard Ratio; 2. Time invariant, measured at baseline; 3. Time updated, refers to six-month period prior to follow-up interview  40  Table 5. Adjusted estimates of the behavioural, social and structural factors associated with viral rebound among 277 IDU on ART with suppressed viral loads at baseline Characteristic Age Per year older Sextrade participation Yes vs. no Methadone maintenance Yes vs. no Incarceration None vs. pre-trial detent None vs. prison or pen CD4 cell count Per 100 cells Time since initiation Per year PI in first regimen Yes vs. no ART adherence >95% vs. ≤95%  AHR  Model 1 95% CI  p-value  AHR  Model 2 95% CI  p-value  0.98  0.97 – 1.00  0.006  1.00  0.99 – 1.02  0.602  1.40  1.08 – 1.82  0.014  1.23  0.95 – 1.60  0.120  0.79  0.66 – 0.94  0.024  0.98  0.82 – 1.16  0.803  1.09 1.83  0.71 – 1.67 1.33 – 2.52  0.846 0.003  1.14 1.45  0.74 – 1.75 1.05 – 2.01  0.563 0.025  0.88  0.84 – 0.92  < 0.001  0.92  0.87 – 0.96  < 0.001  0.90  0.85 – 0.95  < 0.001  0.91  0.87 – 0.97  < 0.001  1.22  1.01 – 1.46  0.131  1.06  0.88 – 1.28  0.538  0.16  0.12 – 0.21  < 0.001  1  1  1. Adjusted Hazard Ratio  41  CHAPTER 4: HOMELESSNESS  AS  A  STRUCTURAL  BARRIER  TO  EFFECTIVE ANTIRETROVIRAL THERAPY AMONG HIV-SEROPOSITIVE INJECTION DRUG USERS IN A CANADIAN SETTING  4.1  Introduction Studies among HIV-seropositive individuals who inject drugs (IDU) have  identified how ongoing illicit drug use and other behavioural factors pose substantial barriers to effective antiretroviral therapy (ART)  (161, 170). In  comparison, however, the contribution of social and structural factors to treatment outcomes have yet to be well described (49). Homelessness, as well as living in poor or unstable housing conditions, has long been recognized as an important component of vulnerability for infection with HIV (171-173). In addition to poorer access to preventative healthcare (75), individuals who are homeless also suffer from high levels of mental illness (174), illicit drug use (175), incarceration (176), and violence (177), as well as seroprevalence of HIV many times higher than among comparable non-homeless populations (171, 178). For example, in a study involving over 1200 homeless and marginally-housed adults in San Francisco, California, 187 (15.4%) tested seropositive for HIV; the population had high levels of incarceration (22%), sex trade involvement (33%) and unprotected sex (44%) (178). While studies have illuminated the links between housing and the health of individuals who are infected with HIV (75, 179-181), a number of important issues remain to be addressed. Most notably, while homelessness is a common experience for individuals who use drugs and an important determinant of their  42  health (158), we are unaware of any prospective analysis that has considered the independent effect of homelessness within the course of HIV treatment and disease progression among IDU. While numerous studies have identified suboptimal ART adherence among homeless individuals (182-184), including a recent study from our setting (185), existing evidence has usually been derived from short-term studies, often cross-sectional, involving participants recruited from treatment settings. A further issue is that, up to now, studies have been conducted in settings where access to ART and/or medical care is neither free of charge or universal. Thus, in the current study, we sought to test the hypothesis that homelessness is a significant structural barrier to effective HIV treatment acting through lower levels of ART adherence using data from a long-running prospective cohort of community-recruited IDU in a setting of universal access to HIV treatment and care.  4.2  Methods Data for these analyses was ascertained from the AIDS Care Cohort to  Evaluate access to Survival Services (ACCESS), as described in section 1.7. In this study, we included all participants who were naïve to ART at recruitment and initiated treatment during the study period. As well, to be included in these analyses, at least one observation of both CD4 cell count and PVL had to be completed within 12 months of ART initiation. The outcome of interest was suppression of PVL, or the date of the first of two consecutive observations < 500 copies per mm3. The primary explanatory variable of interest was reporting homelessness, defined as living on the street with no fixed address, at any time in the six-month period proceeding the follow-up interview. 43  To estimate the relationship between homelessness and PVL response, we also considered secondary explanatory variables we hypothesised may confound this relationship. These included demographic and socioeconomic characteristics such as age; gender (female vs. male); Aboriginal ancestry (yes vs. no); educational attainment (< high school diploma vs. ≥ high school diploma); and legitimate employment in the previous six months (yes vs. no). We used a threelevel variable to describe illicit drug use: No illicit drug use (reference) vs. any illicit drug use vs. any injection drug use. We also considered any involvement in the sex trade in the previous six months (yes vs. no); and any incarceration overnight or longer in the previous six months (yes vs. no). Clinical variables included were the HIV experience of the prescribing physician (as before (52), less than six patients at initiation vs. six patients or greater); the year of ART initiation; HIV RNA viral load at baseline (per log10); CD4 cell count (per 100 cells/µl). Clinical variables and ART dispensation information was ascertained as described in section 1.7. As a first step, we examined the cohort characteristics at baseline, stratified by the number of suppression events over the study period (≥ 1 vs. 0). To test for significant differences, we calculated Pearson’s χ2 statistic; in instances where at least one cell contained a count of five or less, Fisher’s Exact test statistic was calculated. Next, we used Cox Proportional Hazards regression of the time to viral suppression to estimate unadjusted Relative Hazards (RH) for the effect of homelessness and all secondary explanatory variables on time to viral load suppression. Homelessness, all behavioural variables and CD4+ cell count, were all considered as time-updated measures.  44  To estimate the independent effect of homelessness on time to viral suppression, we constructed a multivariate model using an adaptation of a method described previously by Greenland and colleagues (186, 187). To start, we fit a full model including all explanatory variables, noting the value of the coefficient associated with homelessness. Using a manual stepwise approach, we then constructed reduced models, each with one secondary explanatory variable removed from the full set of secondary explanatory variables. Comparing the value of the coefficient for the primary explanatory variable in the full model and each of the reduced models, we removed the secondary variable corresponding to the smallest relative change in the coefficient for homelessness. We continued this iterative process until the maximum change of the value for homelessness from the full model exceeded 5%. The intent of this model building strategy is to retain secondary variables in the final multivariate model with greater relative influence on the relationship between homelessness and time to viral suppression. This technique has been used successfully by several authors to estimate the independent relationship between an outcome of interest and a selected explanatory variable (186, 188, 189). To test whether the relationship between homelessness and PVL suppression was mediated by differences in ART adherence, we performed a mediation analysis as defined by Baron and Kenny (190). Their technique involves fitting four regression models and observing a covariate of interest and associated p-value in each. These regressions correspond to four paths describing the relationships between the three variables of interest: path a, the effect of homelessness on ART adherence; path b, the effect of ART adherence on viral suppression; path c, the effect of homelessness on viral suppression; and path c’, 45  the effect of homelessness on viral suppression adjusted for the effect of ART adherence. Each path was also adjusted with the set of secondary covariates identified in the procedure described above to build the multivariate model. Plasma HIV-1 RNA was measured using the Roche Amplicor Monitor assay (Roche Molecular Systems, Mississauga, Canada). All statistical analyses were completed using R v2.10.1 (R Foundation, Vienna, Austria).  4.3  Results Between May, 1996 and October, 2009, 762 HIV-seropositive IDU were  recruited into the study. Of these, 488 (64.0%) were ART-naïve at recruitment; 240 (31.5%) initiated ART over follow-up and had complete interview and clinical monitoring data within 12 months of recruitment. This group, which included 112 (46.7%) women and 111 (46.2%) individuals reporting Aboriginal ancestry, was retained for the analysis of time to HIV RNA suppression. Over the study period, the participants contributed 1755 person-years of follow-up, with a median follow-up time per participant of 46.5 months (IQR: 5.9 - 87.1). Over the study period, 136 participants achieved at least one episode of viral suppression for an incidence density of 56.7 (95% Confidence Interval [CI]: 46.9 — 66.0) per 100 person-years. The baseline characteristics of the sample, stratified by HIV RNA viral load suppression over follow-up, are presented in Table 6. For participants, homelessness was common during the study period. At baseline, 41 (17.1%) individuals reported at least one instance of homelessness in the previous six month period. In the 2354 interviews over the study period, 248 (10.5%) contained a report of homelessness. Of 240 participants included in this 46  analysis, 101 (42.1%) experienced at least one episode of homelessness since initiating ART. Table 7 presents the unadjusted Relative Hazards (RH) of time to viral suppression by all primary and explanatory factors. As shown, homelessness was inversely and significantly associated with time to suppression (RH = 0.56, 95% CI: 0.40-0.78; p-value < 0.001) as was incarceration in the previous six months (RH = 0.65, 95% CI: 0.49-0.86, p-value = 0.003). In the multivariate model, also shown in Table 7, homelessness was independently associated with a lower likelihood of achieving viral suppression following the initiation of treatment (Adjusted Hazard Ratio [AHR] = 0.60, 95% CI: 0.43 – 0.84, p-value = 0.003) after adjustment for age, recent incarceration, the year of ART initiation and baseline PVL. The results of the mediation analysis are detailed in Figure 2. As described above, homelessness was independently and inversely associated with PVL suppression (path c, β = -0.51, p = 0.003). Homelessness was also independently associated with HAART adherence (path a, β = -0.68, p-value < 0.001); HAART adherence was also an independent predictor of a greater likelihood of PVL suppression (path b, β = 1.50, p-value < 0.001). Finally, when we considered the relationship between homelessness and PVL in the presence of HAART adherence (path c’), there was no longer an association (β = -0.28, p-value = 0.105).  47  4.4  Discussion In this study, the first to our knowledge to prospectively evaluate the effects  of homelessness on HIV treatment outcomes among individuals who use injection drugs, we observed that failure to achieve plasma viral load suppression after initiating ART was common. In almost half (104, 43.3%) of the participants we did not observe two consecutive plasma viral load measures indicating suppression following initiation of ART. In a multivariate model, homelessness was independently associated with a lower rate of suppression (AHR = 0.56, 95% CI: 0.41 - 0.80). In an analysis of the relationship between homelessness, ART adherence and PVL suppression, we found that the effect of homelessness on viral suppression was mediated by lower levels of adherence among homeless individuals. This is consistent with a recent analysis using data from this prospective cohort by Palepu et al (185). In a multivariate model adjusted for possible confounders including high-intensity heroin injection, homelessness was independently associated with lower odds of achieving at least 95% adherence in the previous six month period (Adjusted Odds Ratio = 0.65, 95% CI: 0.36 – 0.60.) The current study not only extends this work by identifying an effect of homelessness on treatment success but also identifies a possible pathway through which exogenous exposures present barriers to optimal treatment response among IDU. Our finding of sub-optimal ART adherence linked to homelessness echoes previous studies comparing homeless to housed individuals on ART (191-194). In their study of 113 current and former IDU recruited from a methadone clinic, Berg et al. found that lacking permanent and stable housing was significantly associated with worse ART adherence (191). Unfortunately, this study and others 48  were conducted in areas without universal access to ART and did not include the nature of access to ART as an explanatory covariate. Thus, it is possible these analyses were unable to distinguish the effect of homelessness on adherence independent of the confounding influence of financial need. For example, a recent study of 125 HIV-seropositive homeless and marginally-housed individuals in San Francisco found that individuals on Medicare Part D — a governmentsupported drug insurance plan that covers only a limited proportion of the cost of antiretrovirals — had six times higher odds of ART interruptions over the study period (195). Most individuals on Part D who discontinued cited drug cost as their primary barrier (195). By conducting our study in an area of universal access to HIV care, we have identified an effect of homelessness on treatment outcomes independent of financial constraints. We believe several environmental aspects of homelessness, such as lacking a space to safely store medication, may account for some of this effect, as might the need for homeless individuals to prioritize immediate survival over the secondary demands of medication adherence (196, 197). Our results do not contradict previous authors (196, 198) who have observed that homeless individuals, given adequate adherence, can benefit from ART at levels similar to non-homeless individuals. Our findings support the development of measures to improve adherence among homeless individuals. Considering the complex barriers to adherence that homeless individuals experience, there is a need to develop and expand comprehensive adherence support programs that cater to the specific needs of this population. A range of programs and services has emerged to fill this need for marginalized seropositive groups (199-201) and they have been shown to increase adherence, retention and viral load suppression (38, 202). 49  The finding of an independent effect of the housing environment on the success of ART for IDU has a number of implications for both the health of HIV seropositive individuals as well as efforts to control the ongoing pandemic. First, it bears out the observations from other settings that providing housing can be an important structural intervention to support the health of vulnerable HIVseropositive individuals. An ethnographic survey of women living with HIV/AIDS in four US cities (197) as well as Aidala et al.’s study (179) from New York state revealed how individuals who possess stable housing are better able to concentrate on meeting the demands of treatment. However, results from a recent randomized clinical trial (203) of providing housing to homeless and marginally housed individuals with HIV suggests this strategy might have limited effect directly reducing elevated levels of HIV-related morbidity and mortality. Although Wolitski et al. noted significant gains in health care utilization, mental and physical health in the treatment group, no differences were observed in CD4+ cell count, the proportion of individuals with undetectable viral load or opportunistic infections, or adherence to ART (203). Similarly, in a large study of survival among individuals in the San Francisco AIDS Registry, while homelessness at baseline was a significant risk factor for death, a greater risk was faced by individuals with no health insurance as compared to individuals with private or public support (204). Thus, in settings without universal access to ART, provision of housing might have limited benefit on treatment outcomes. Finally, with increasing recognition of the important role both individual- and community-level viral loads play in HIV transmission dynamics (205-207), housing interventions effective at improving adherence and treatment outcomes  50  might contribute to lowered incidence of HIV infection among vulnerable populations in our setting and others (208). Our study has some limitations. First, although the cohort was recruited through community outreach, it was not randomly recruited and thus might not be representative of HIV-seropositive IDU in this setting or others. Second, numerous studies have identified mental illness as a predictor of HIV treatment adherence and outcomes (209). Although we were unable to include a consistent measure of mental health throughout the study period, we believe that our findings are not overly affected by this residual confounding, given the prevalence of homelessness among participants. To conclude, we analyzed patterns of homelessness and response to ART using data from a long-running community-recruited prospective cohort of HIVseropositive IDU in a setting of free and universal access to HIV care. We observed that both homelessness and failure to achieve at least one instance of plasma viral load suppression was common this sample. In a multivariate model, homelessness was independently associated with lower rates of viral load suppression, although this relationship was not observed when HAART adherence was considered simultaneously. Thus, our findings support the provision of enhanced services to support ART adherence among IDU initiating treatment as an intervention to overcome this structural barrier to effective ART and reduce elevated levels of HIV-related morbidity and mortality.  51  Table 6. Baseline characteristics of 240 IDU initiating ART stratified by HIV RNA plasma viral load suppression over follow-up Characteristic Homelessness No Yes Age  > 0 viral suppression 136 (56.7)  Odds Ratio  95% Confidence Interval  p-value  87 (83.7) 17 (16.3)  112 (82.4) 24 (17.6)  1.00 1.10  0.55 – 2.17  0.791  35.8 (28.2 – 43.3)  37.2 (31.2 – 43.1)  1.01  1.00 – 1.01  0.083  53 (51.0) 51 (49.0)  75 (55.1) 61 (44.9)  1.00 0.85  0.51 – 1.41  0.520  57 (54.8) 47 (45.2)  72 (52.9) 64 (47.1)  1.00 1.08  0.65 – 1.80  0.774  62 (59.6) 42 (40.4)  84 (61.8) 52 (38.2)  1.00 0.91  0.54 – 1.54  0.735  102 (98.1) 2 (1.9)  127 (93.3) 9 (6.6)  1.00 3.61  0.76 – 17.10  0.085  9 (8.7) 11 (10.6) 84 (80.8)  12 (8.8) 15 (11.0) 109 (80.1)  1.00 1.02 0.97  0.32 – 3.27 0.39 – 2.42  0.970 0.953  83 (79.8) 21 (20.2)  116 (85.3) 20 (14.7)  1.00 0.68  0.35 – 1.34  0.263  75 (72.1) 29 (27.9)  111 (81.6) 25 (18.4)  1.00 0.58  0.32 – 1.07  0.081  87 (83.7) 17 (16.3)  117 (86.0) 19 (14.0)  1.00 0.83  0.41 – 1.69  0.610  1998 (1995 – 2001)  1999 (1997 – 2001)  1.00  0.98 – 1.01  0.662  4.7 (4.3 – 5.1)  3.6 (2.6 – 4.6)  0.83  0.79 – 0.87  < 0.001  2.7 (1.5 – 3.9)  2.6 (1.7 – 3.5)  1.01  0.98 – 1.04  0.709  1  Median (IQR) Gender Male Female Aboriginal ancestry No Yes 1 Education ≥ High school dipl < High school dipl 1 Employment No Yes 1 Illicit drug use None Any illicit drug use Any injection drug 1 Sextrade participation No Yes 1 Incarceration No Yes HIV MD experience ≥ 6 patients < 6 patients Year of ART initiation Median (IQR) Plasma HIV-1 RNA Median (IQR) CD4 cell count Median (IQR) 1.  No viral suppression 104 (43.3)  Refers to the six-month period prior to the baseline interview  52  Table 7. Univariate and multivariate analyses of factors associated with time to PVL suppression among 240 IDU initiating ART Characteristic 4 Homelessness No Yes Age Per 10 years older Gender Male Female Aboriginal ancestry No Yes 4 Education ≥ High school dip < High school dip 4 Employment No Yes 4 Illicit drug use None Any illicit use Any injection use 4 Sextrade participation No Yes 4 Incarceration No Yes 5 HIV MD experience ≥ 6 patients < 6 patients 5 Year of ART initiation Per year increase 5 Baseline PVL Per log10 increase 4 CD4 cell count Per 100 cells  1  HR  95% CI  1.00 0.56  2  3  2  p-value  AHR  95% CI  p-value  0.40 – 0.78  < 0.001  1.00 0.60  0.43 – 0.84  0.003  1.03  1.02 – 1.04  < 0.001  1.02  1.01 – 1.03  < 0.001  1.00 0.98  0.84 – 1.15  0.827  1.00 0.99  0.85 – 1.16  0.894  1.00 0.89  0.76 – 1.05  0.170  1.00 0.90  0.68 – 1.19  0.458  1.00 0.91 0.94  0.70 – 1.19 0.77 – 1.16  0.502 0.586  1.00 0.77  0.58 – 1.04  0.090  1.00 0.65  0.49 – 0.86  0.003  1.00 0.84  0.63 – 1.13  0.248  1.00 0.96  0.76 – 1.21  0.720  1.11  1.07 – 1.15  < 0.001  1.07  1.03 – 1.11  < 0.001  0.68  0.63 – 0.72  < 0.001  0.72  0.67 – 0.77  < 0.001  1.08  1.05 – 1.12  < 0.001  1. Hazard Ratio 2. 95% Confidence Interval 3. Adjusted Hazard Ratio 4. Refers to the six month period prior to the interview 5. Measured at baseline  53  ART adherence (>95% vs. 95%)  path a:  Homelessness (Yes vs. no)  = -0.68, p < 0.001  path b:  = 1.50, p < 0.001  path c:  = -0.51, p = 0.003  path c':  = -0.28, p = 0.105  PVL suppression  Figure 2. Mediation effects for ART adherence on the relationship between homelessness and PVL suppression among 240 HIV-infected IDU Coefficient estimates adjusted for age, PVL at baseline, incarceration in the previous six months and year of ART initiation  54  CHAPTER 5: DOSE-RESPONSE EFFECT OF INCARCERATION EVENTS ON NON-ADHERENCE  TO  HIV  ANTIRETROVIRAL  THERAPY  AMONG  INJECTION DRUG USERS  5.1  Introduction In the era of highly-active antiretroviral therapy (HAART), a primary  determinant of survival is adherence to prescribed therapy. High levels of adherence are required to guarantee durable clinical benefits, such as suppression of HIV RNA plasma viral load and reconstitution of immunologic function (56). IDU are known to commonly have lower levels of adherence (210); several behavioural factors have been identified as barriers to adherence to ART, including higher intensity drug use (170), concern over side effects (161) and lower adherence self-efficacy (211). Although social- and structural-level exposures are increasingly appreciated as important determinants of many forms of drug-related harm (42, 47), most studies of HIV treatment adherence and disease progression have focused on individual-level factors (49). Imprisonment is a common experience for IDU (212, 213). In recent years, some optimism has been expressed that correctional facilities can serve as important sites for detecting infections and initiating treatment (214, 215). In the United States, where approximately 10% of all HIV-seropositive individuals are thought to cycle through a correctional setting every year (216), jails and prisons are the de facto primary site for HIV care for people who lack access to community-based treatment (143). Thus, the quality of prison-based care and the effect of imprisonment on HIV disease is of central importance to the health of  55  the most vulnerable HIV-seropositive groups, such as the poor, illicit drug users, and ethnic minorities. Although impressive clinical gains have been observed among HIV-infected prisoners engaged in treatment in some state-run prison systems (214), the general effect of incarceration on HIV outcomes among IDU remains equivocal, with some studies identifying a heightened risk of ART discontinuation associated with incarceration (25) and failure to suppress viral load (69). We are unaware of any studies of community recruited IDU that have considered the effects of the typical patterns of incarceration on adherence to ART over the long term. Thus, in this study, we aimed to estimate the effect of the cumulative burden of incarceration, measured longitudinally, on ART nonadherence using data from a long-running prospective cohort of IDU in a Canadian setting.  5.2  Methods Data for these analyses was accessed from the AIDS Care Cohort to evaluate  Exposure to Survival Services (ACCESS), described in section 1.7. In this study, we included all participants who were ART-exposed at recruitment or who initiated ART during the study period. The outcome of interest was non-adherence to antiretroviral therapy. ART patterns were ascertained using the confidential linkage to comprehensive dispensation records described in section 1.7. We defined non-adherence to ART as any level less than 95% adherence in the previous six months. Although therapy for individuals in this study was not directly observed, we have previously demonstrated the clinical validity of this pharmacy refill data and shown it reliably predicts virologic suppression (80, 81, 85) and survival (78, 82). Of note is the fact that in 56  the province of British Columbia all ART delivered to correctional and noncorrectional environments is dispensed through the British Columbia Centre for Excellence in HIV/AIDS. Thus, our outcome measure is complete and includes both community- and prison-based adherence patterns. The primary explanatory variable was the burden of incarceration during the study period. This was measured by assessing the number of times individuals had been held overnight or longer in youth detention, local jails, provincial prisons or federal penitentiaries during each six month period prior to each semi-annual follow-up visit. For these analyses, this repeated measure was converted into a cumulative sum of incarceration events up to the current interview, updated at each interview period.  To aid in interpretation, we  converted this variable into a categorical factor with four levels: Zero incarceration events; 1 - 2 incarceration events; 3 - 5 incarceration events; more than five incarceration events. To best estimate the relationship between the burden of incarceration and non-adherence, we also considered secondary explanatory variables we hypothesised might confound this relationship. These included demographic and socioeconomic characteristics such as age (per year older); gender (female vs. male); aboriginal ancestry (yes vs. no); educational attainment (< high school diploma vs. ≥ high school diploma); formal employment (yes vs. no) and homelessness (yes vs. no). All variables except gender and aboriginal ancestry were time-updated; formal employment referred to having salaried or temporary work at any time in the previous six months. Information on aboriginal ancestry was included as possible confounder due to previous work identifying elevated HIV incidence (67), lower levels of ART uptake among aboriginal IDU (217) and 57  overrepresentation of aboriginal individuals in Canadian correctional facilities (218). The variable used was dichotomized from an open-ended question asked during the baseline interview about the individual’s ethnic group or family background. Any response of “First Nations”, “Métis”, “Aboriginal” or “Inuit” was coded as aboriginal ancestry. Consistent with Canadian government research guidelines (219), representatives of local aboriginal groups are involved in the ongoing work of the ACCESS cohort through a community advisory board. Homelessness referred to living on the street or having no fixed address at the time of the interview. In addition, we included the individual-level behavioural variables: injection cocaine use (≥ daily vs. < daily); injection heroin use (≥ daily vs. < daily); inhalation methamphetamine use (≥ daily vs. < daily); inhalation crack cocaine use (≥ daily vs. < daily.) We also included self-reported public drug use (yes vs. no) and participation in the sex trade, defined as any exchange of money, drugs or other goods for sex (yes vs. no). These variables were timeupdated, referred to the six month period prior to the interview and were consistent with previous analyses (220). Clinical variables included were the CD4+ cell count (per 100 cells/mm3) and HIV-1 RNA plasma viral load (per log10.) For both measures, we used the mean of all available observations in the previous six months; if none were available, we used the most recent observation. Plasma HIV-1 RNA was measured using the Roche Amplicor Monitor assay (Roche Molecular Systems, Mississauga, Canada). We also included the time since ART initiation, measured in months. As a first step, we examined the frequency and distribution of incarceration and non-adherence longitudinally as well as selected explanatory variables at baseline. We estimated univariate statistics for the relationships between non58  adherence and all explanatory variables over the study period using generalized linear mixed-effects modeling. This form of regression modeling was used to account for the correlation between covariates gathered over time from the same individual and estimate the independent effect of incarceration on the likelihood of non-adherence within each individual. To account for possible confounding and calculate the best effect estimate, we constructed a multivariate model using an a priori defined modeling strategy suggested by Greenland and colleagues (186, 187). First, we fit a full model including the primary explanatory and all secondary explanatory variables. Using a manual stepwise approach, we constructed reduced models, each with one variable removed from the full set of secondary explanatory variables. Comparing the value of the coefficient for the primary explanatory in the full model and each of the reduced models, we removed the secondary explanatory corresponding to the smallest relative change. We continued this process until the maximum change from the full model exceeded 5%. This technique has been used successfully by several authors to estimate the independent relationship between an outcome of interest and a selected explanatory variable (186, 188, 189) by retaining secondary covariates with greater relative influence on the relationship between the outcome and the primary explanatory variable.  5.3  Results Between May, 1996 and September, 2009, 490 ART-exposed individuals  were recruited and included in these analyses, of whom 201 (41.0%) were female and 192 (39.2%) reported aboriginal ancestry. The median follow-up duration was 28.8 months (Inter-quartile range [IQR]: 0.0 - 64.0) contributing to 2220 59  person-years of follow-up. Select sociodemographic and clinical characteristics at baseline are presented in Table 8, stratified by the number of incarceration events during the study period (zero vs. ≥ 1). Compared to participants with no incarceration episodes over the study period, incarcerated individuals were more likely to be younger and not possess a high school diploma at baseline. Figure 3 presents the mean number of incarceration events per participant by interview. More than half (271, 55.3%) of participants were incarcerated during the study period giving a crude incarceration rate of 52.5 per 100 personyears (95% Confidence Interval: 49.6 - 55.7). Among those, the median number of incarceration episodes was 3 (IQR = 1 - 6). In total, there were 1,156 incarceration episodes, of which 6 (0.5%) were in youth detention facilities; 621 (53.7%) in local jails; 511 (41.2%) in provincial prisons; and 18 (1.6%) in federal penitentiaries. Over the entire study period, the median level of adherence to ART was 61.0% (IQR = 11.0 - 100.0). Of the 3731 follow-up periods, 1345 (36.0%) were characterized by less than 95% adherence to prescribed ART. Table 10 presents the univariate estimates of the likelihood of nonadherence for each primary and secondary explanatory variable over the study period. The cumulative burden of incarceration, measured longitudinally, was a strong predictor of non-adherence to ART. Compared to individuals with no history of incarceration, participants with one or two incarceration events had almost double the odds of non-adherence at each follow-up period (Odds Ratio [OR] = 1.91, 95% CI: 1.35 - 2.72). The odds increased to 2.85 (95% CI: 1.87 - 4.33) for individuals with three to five previous incarceration episodes and to 3.59 (95% CI: 2.12 - 6.09) for individuals with more than five incarceration events. This relationship persisted in the multivariate model after adjustment for possible 60  confounders including female gender, frequent cocaine use, engagement in methadone maintenance therapy, the number of months since ART initiation and HIV RNA plasma viral load. As presented in Figure 4, individuals with a burden of one to two incarceration events were 1.49 times more likely to be non-adherent in the previous six months (95% CI: 1.03 - 2.05); a burden of three to five incarceration events was independently associated with 2.48 times greater odds of non-adherence (95% CI: 1.62 - 3.65); individuals with five or more incarceration events were 3.11 (95% CI: 1.85 - 4.95) times more likely to be non-adherent in comparison with individuals free of incarceration episodes, after adjustment for socio-demographic,  behavioural  and  clinical  confounders.  As  newer  antiretroviral regimes, including longer-acting protease inhibitors and nonnucleoside reverse transcriptase inhibitors, have shifted the relationship between incomplete adherence and disease progression (221), we repeated our model building protocol using <85% adherence in the past six months as the outcome of interest. The results again showed a dose-response effect of incarceration on nonadherence.  5.4  Discussion In this study, we observed a dose-dependent association between the  cumulative burden of incarceration and ART non-adherence. Since these findings are from a long-running observational cohort linked to complete ART dispensation records in a setting of universal access to free HIV care, these results are not under the influence of the confounding effect of financial ability or biased by the limitations of self-reported adherence (39). Further, unlike prison-based studies, our analysis considers the effect of incarceration within the course of HIV 61  disease among community-recruited IDU and clearly indicates that increasing number of cycles of imprisonment, release and reincarceration is associated with poorer ART adherence in this population of IDU. As with all observational studies, the exposure of interest in these analyses was not randomly assigned and, thus, we cannot unequivocally conclude that a causal relationship between imprisonment and non-adherence exists. The possibility remains that the behaviours that led to arrest, such as illicit drug use, were a contributing cause of non-adherence. However, three major lines of evidence support the potential for a causal relationship between the burden of incarceration and patterns of adherence. First, our estimates for the effect of the burden of incarceration were derived from a multivariate model which also adjusted for gender, intensive drug use and engagement in methadone maintenance therapy, all previously associated with both access or adherence to ART (109, 162, 222). Further, the multivariate model was constructed to isolate the independent effect of incarceration on non-adherence by retaining and adjusting for  explanatory variables with greater relative influence on that  association. Second, support for a causal effect for incarceration on nonadherence can also be found in previous studies which have reported that incarceration has been associated with a greater risk of discontinuation and failure to achieve viral suppression among IDU (25, 69, 167). Similarly, prior studies have demonstrated that only a small minority of newly-released prisoners typically manage to avoid HIV treatment interruptions (143) and any in-prison treatment gains appear short-lived (77, 223). Finally, multiple prison-associated barriers to adherence were identified in an ethnographic investigation into inprison HIV treatment in this setting (142), including a lack of medical care in 62  short-term holding cells, the desire of participants to conceal HIV-serostatus from other inmates and the lack of continuity of care between community-based and in-prison providers. Given the tight link between non-adherence and HIV disease progression, our findings have direct relevance to public health efforts to reduce AIDS-related morbidity and mortality as well as continued viral transmission. Although our results do not entirely discount a role for correctional facilities in identification of HIV infections and initiation of treatment, they show an association between incarceration episodes and ART non-adherence and, thus, an increased risk of HIV disease progression. To be sure, some small interventions have shown promise in improving HIV treatment outcomes during and after incarceration, especially when paired with substance abuse treatment (36). In addition to programmes seeking to minimize the adverse effects of incarceration on HIV treatment, future research might also investigate how social- and structural-level reforms, such as diverting non-violent drug users from correctional settings, might improve HIV treatment outcomes. This study has some limitations which should be noted. Although the cohort was recruited using street outreach and snowball sampling, no registries of HIV-seropositive individuals exist and random sampling is not possible. Thus, our results might not be representative of HIV-seropositive IDU in this settings or others. Also, several measures, including incarceration, were self-reported by participants and may have been under the influence of social desirability bias. However, we believe it is unlikely that this bias differentially effected the data by adherence level. In addition, the independent association between the primary explanatory variable and the outcome of interest may be the result of unobserved 63  confounding rather than a causal association. However, as detailed above, evidence exists for a causal relationship between incarceration and poorer adherence patterns; a trial randomizing imprisonment for HIV-seropositive IDU in ART is ethically impossible. Finally, adherence is only a marker for plasma HIV RNA suppression and future studies should seek to examine the impact of incarceration experiences on viral load levels. To conclude, we used data gathered from almost 15 years of follow-up of a community-recruited sample of HIV-seropositive IDU and, using comprehensive antiretroviral dispensation records, observed a dose-dependent association between increasing burden of incarceration and ART non-adherence. Given the importance of correctional facilities in shaping the health of vulnerable HIVpositive individuals, our findings should spur efforts to reform the delivery of inprison HIV care and ease transitions to non-correctional environments.  64  8 6 4 0  2  Events  1  5  10  Interview  FIGURE 1. Mean number of incarceration (solid line), ± 1 among Figure 3. Median number of incarceration eventsevents per follow-up interview standard deviation (dotted lines), among all participants by 490 ART-exposed IDU interview in ACCESS (n = 490 antiretroviral therapy-exposed Legend: Solid line: Median number of incarceration episodes; dotted line: ± 1 standard injection drug users) deviation  65  Table 8. Selected sociodemographic, behavioural and clinical characteristics at baseline among 490 ART-exposed IDU  Characteristic Age Median (IQR) Gender Male Female Aboriginal ancestry No Yes Educational attainment < High school diploma ≥ High school diploma Current MMT No Yes CD4+ cell count 3 Per 100 cells/mm HIV-1 RNA viral load Per log10 increase  Burden of incarceration during study Zero events ≥ 1 events 219 (44.7%) 271 (55.3%)  OR  95% CI  43.5 (37.7 - 49.3)  35.6 (30.0 - 41.2)  0.90  0.88 - 0.92  128 (58.4) 91 (41.6)  161 (59.4) 110 (40.6)  1.00 0.96  0.67 - 1.38  136 (62.1) 83 (37.9)  162 (59.8) 109 (40.2)  1.00 1.10  0.77 - 1.59  116 (54.2) 98 (45.8)  170 (63.7) 97 (36.3)  1.00 0.68  0.47 - 0.97  125 (57.3) 93 (42.7)  164 (60.5) 107 (39.5)  1.00 0.88  0.61 - 1.26  2.8 (1.5 - 4.1)  2.8 (1.7 - 3.9)  1.01  0.93 - 1.10  4.3 (3.2 - 5.3)  4.5 (3.9 - 5.1)  1.44  1.17 - 1.77  1  2  1. Odds Ratio; 2. 95% Confidence Interval  66  Table 9. Univariate and multivariate linear mixed-effects analyses of primary and secondary explanatory variables and non-adherence to ART among 490 IDU CHARACTERISTIC 4 Incarceration events 0 1-2 3-5 >5 Gender Male Female Aboriginal ancestry No Yes 5 Homeless No Yes Educational attainment < High school diploma ≥ High school diploma 5 Formal employment No Yes 5 Cocaine use, injection < Daily ≥ Daily 5 Heroin use, injection < Daily ≥ Daily 5 Methamphetamine use, inhalation < Daily ≥ Daily 5 Crack cocaine use, inhalation < Daily ≥ Daily Methadone maintenance therapy No Yes 5 Sex-trade participation No Yes 5 Public drug use No Yes CD4 cell count 3 Per 100 cells/mm HIV-1 RNA plasma viral load Per log10 unit increase Time since ART initiation Per month  1  OR  95% CI  1.00 1.91 2.85 3.59  2  3  2  AOR  95% CI  1.35 — 2.72 1.87 — 4.33 2.12 — 6.09  1.00 1.49 2.48 3.11  1.06 — 2.12 1.66 — 3.71 1.93 — 5.03  1.00 1.57  1.07 — 2.32  1.00 2.11  1.50 — 2.97  1.00 1.01  0.68 — 1.51  1.00 1.51  0.97 — 2.35  1.00 1.17  0.90 — 1.51  1.00 0.73  0.48 — 1.11  1.00 1.54  1.21 — 1.97  1.00 1.23  0.94 — 1.62  1.00 2.38  1.80 — 3.16  1.00 2.64  0.75 — 9.28  1.00 1.40  1.09 — 1.79  1.00 0.41  0.32 — 0.54  1.00 0.47  0.36 — 0.62  1.00 1.73  1.21 — 2.47  1.00 1.25  0.91 — 1.72  0.72  0.67 — 0.77  5.41  4.74 — 6.17  5.41  4.73 — 6.20  1.00  1.00 — 1.01  1.01  1.00 —1.01  1. Odds Ratio 2. 95% Confidence Interval 3. Adjusted Odds Ratio 4. Cumulative number of incarceration events, timeupdated. 5. Refers to six month period prior to interview  67  6.00  Adjusted Odds Ratio  5.00  4.00 3.11  3.00 2.48  2.00 1.49  1.00  1-2  3-5  >5  Number of incarceration episodes  FigureFIGURE 4. Adjusted odds ratios non-adherence to ART by number 2. Adjusted OddsforRatios and 95% Confidence Intervalsof incarceration episodes among 490 IDU for antiretroviral therapy (ART) non-adherence by number of Multivariate model adjusted for: gender, daily injection use, number of months incarceration episodes during study among 490cocaine ART-exposed since ART initiation, methadone maintenance therapy, and HIV-1 RNA plasma viral load ACCESS participants. (Multivariate model adjusted for: gender,  daily injection cocaine use, time since ART initiation, methadone maintenance therapy, and HIV-1 RNA plasma viral load)  68  CHAPTER 6: DISCUSSION, FUTURE RESEARCH, CONCLUSIONS  6.1  Summary of findings The objective of this thesis was to assess the contribution of social- and  structural-level exposures on HIV disease progression and various indicators of HIV treatment success (e.g. adherence, plasma HIV RNA suppression). Chapter 2 summarizes the findings of a systematic review of the scientific literature on HIV disease progression among groups of illicit drug users. After assessing over 2,500 studies, this review identified 56 studies in the peer-reviewed literature conducted among well-defined groups of illicit drug users that analyzed at least one of four major endpoints: a diagnosis of AIDS; death; changes or difference in CD4+ cell counts; or changes or differences in plasma HIV RNA. Employing the risk environment conceptual framework, statistically significant associations identified in these studies were categorized into factors exogenous to individuals — specifically, macro- and micro-level physical, social, political and economic forces — or endogenous to individuals — specifically, co-morbidities, pharmacotherapies, HIV-related morbidity, or virologic, immunologic, genetic or host characteristics. The major finding of the review was that few studies of HIV disease progression in the pre-HAART or HAART era contained meaningful consideration of the social- and structural-factors that have previously been found to determine vulnerability to HIV infection and other drug-related harms. While many studies confirmed the endogenous host and viral characteristics associated with disease progression in other groups, only a minority of studies included information on the physical, social, political or economic contexts of  69  HIV disease and treatment of individuals who use illicit drugs. Second, only weak evidence was found for a direct relationship between the use of illicit drugs and the outcomes of interest. Despite findings from laboratory studies that described interactions between illicit drugs and viral or immunologic functioning (144-148), this pattern was not clearly reproduced in studies of HAART-untreated subjects. In studies of individuals engaged in HAART, stronger support was found for the hypothesis that disease progression was mediated by lower levels of adherence among active drug users, notwithstanding widespread weaknesses in measures of both drug use and adherence. Finally, among exogenous factors, exposure to correctional facilities was associated with lower odds of plasma viral load suppression following treatment initiation (69) and poorer early immunologic response to therapy (112). The risk environment conceptual framework guided the hypotheses and analytic strategies undertaken in the empirical studies in chapters 3, 4 and 5. Chapter 3, a survival analysis of the time to viral rebound among IDU on ART with suppressed plasma viral loads, evaluated the effects of a broad variety of individual-, social- and structural-level exposures. The major finding of Chapter 3 was that illicit drug use patterns were not significant predictors of plasma HIV RNA rebound. However, a number of exogenous aspects of the risk environment framework, including incarceration and involvement in the sex trade, were independently associated with viral rebound in a multivariate model not adjusted for adherence to therapy. Methadone maintenance therapy was protective for rebound. In a second multivariate model adjusted for adherence, neither sex trade involvement nor methadone maintenance therapy were  70  associated with rebound, suggesting these factors operate through their impact upon adherence to ART. The hypothesis that distal structural-level effects are mediated through adherence to treatment was explicitly tested in Chapter 4, an analysis of time to plasma viral load suppression among IDU beginning ART. In this study, the primary explanatory variable of interest was homelessness, defined as any instance of living on the streets or with no fixed address in the six month period prior to the follow-up interview. Using a mediation protocol outlined by Baron and Kenny (190), homelessness was found to be a significant structural-level barrier to successful plasma HIV RNA suppression among IDU. This is the first study to prospectively assess the effect of homelessness on HIV treatment outcomes in a setting of universal access to care. Although previous studies comparing homeless to housed individuals found lower levels of adherence associated with poorer housing (191-193), these were conducted in settings without universal access to healthcare. Thus, the confounding effect of financial need could not be excluded in earlier investigations. As our study was conducted in an area with universal access to ART, our findings suggest that the social and environmental aspects of homelessness pose unique obstacles to achieving necessary levels of adherence to treatment that are independent of financial concerns and mediated by lower levels of adherence. The final empirical analysis sought to estimate the effect of the cumulative burden of incarceration on the likelihood of non-adherence to ART. In a longitudinal multivariate model adjusted for a variety of individual, drug-using and clinical factors, increasing numbers of incarceration events over the study period were independently associated with a greater likelihood of non-adherence 71  to ART in a dose-dependent fashion. This study demonstrates the important effect of incarceration, a prevalent structural- and environmental-level exposure among drug users, on one of the most critical determinants of HIV treatment success (79). Although it does not entirely discredit the idea that correctional facilities could serve as important sites for the detection of HIV infections and initiation of treatment among members of vulnerable populations including drug users (214, 215, 224), this study identifies the role that repeated incarceration events likely play in hindering adherence to ART.  6.2  Study strengths and contributions This dissertation makes a number of significant contributions to the  scientific literatures on HIV treatment and illicit drug use. Preeminently, the four studies in this dissertation demonstrate the validity of the risk environment as a conceptual framework for understanding and responding to the production of positive or negative HIV treatment outcomes as well as HIV-related morbidity and mortality among drug users. Although a select few previous studies have explicitly included social- and structural-level exposures in models of HIV treatment access, adherence and outcomes (49, 68, 70), this dissertation contributes to the scientific literature by extending the risk environment framework into the study of HIV treatment outcomes and disease pathogenesis. It accomplishes this using a number of complementary methods. Chapter 2, a systematic review of HIV disease progression among illicit drug users, establishes that the majority of past studies focused on endogenous factors, specifically the role of individual-level co-morbidities, pharmacotherapies and viral, immunologic, genetic and other host characteristics. However, exogenous 72  factors previously linked to vulnerability to HIV infection have been found to be associated with various measures of HIV disease progression and treatment outcomes. Chapter 3, an analysis of risk factors for viral rebound, demonstrated the applicability of the risk environment framework. Specifically, by restricting the analytic sample to individuals who had successfully initiated ART and had suppressed plasma HIV viral loads, the analysis was better able to identify the effect of social- and structural- level exposures. Chapter 4, a study of the effect of homelessness on treatment success, confirmed the hypothesis that lower adherence is a possible causal pathway for social- and structural-level exposures on disease outcomes. Thus, the studies of this dissertation contribute to the establishment of the risk environment conceptual framework as a useful analytic tool for modeling and developing responses to HIV treatment challenges among HIV-seropositive illicit drug users. Second, the quantitative studies in this dissertation are notable for their use of a rigorous and comprehensive dataset that was prepared through a process led by the candidate. The integration of comprehensive antiretroviral dispensation information, complete prospective clinical profiles including CD4+ cell counts and plasma viral loads with information on individual-, social- and structurallevel exposures, produced a dataset with unique discriminatory power for modeling HIV treatment outcomes among drug users. Given the universal nocost access to all HIV care including antiretroviral medications in this setting, the resulting analyses are largely free of the confounding influence of financial ability. Further, the quantitative analyses in this dissertation are distinguished by being from a long-running cohort of community-recruited individuals both engaged and not engaged in HIV treatment. Although no claims to 73  generalizability to other settings are made, these analyses stand in contrast to many others which have used short-term, often cross-sectional datasets from clinic-recruited samples of drug users. Most importantly, the analyses in this dissertation strongly support the improved and enhanced provision of antiretroviral therapy and related care to IDU. In some jurisdictions, indications of drug use remain prima facie reasons for refusal to provide access to life-saving care (48). In many more settings, coverage of antiretroviral therapy and other evidence-based medical interventions for individuals who use illicit drugs remains sub-optimal (12, 46, 151). Using robust data sources, these analyses describe important social- and structural-level barriers to optimal HIV care and, in so doing, may help address these concerns.  6.3  Study limitations While each study presents limitations specific to each analysis and that  have been described in the individual chapters, those common to all studies are briefly presented here. First, as with all studies in which individuals are not randomly assigned to specific exposures, the possible influence of confounding variables on the outcomes of interest cannot be excluded. However, a number of approaches were used in an attempt to minimize the effect of unobserved or residual confounding. All studies used multivariate models to estimate the independent effect of explanatory variables on the outcome of interest while adjusting for potential confounders. The analyses in chapter 4 and 5 used a multivariate model building procedure explicitly constructed to systematically include or exclude secondary explanatory variables based on their effect on the primary association of interest. Second, several variables of interest were 74  measured through self-report by study participants, an approach that could introduce a variety of biases, including recall bias and socially-desirable reporting. However, a number of techniques were used by the study interviewers to minimize the likelihood of bias, including schedules and cue cards to improve recall and asking questions involving sensitive matters later in the interview process, in order to build trust and rapport with participants. It is also noteworthy that a number of studies have demonstrated that self-reports from drug users are reliable (225-227) Finally, as comprehensive lists of HIVseropositive individuals or individuals who use illicit drugs in Vancouver are not available, random methods cannot be used to generate a representative sample. The ACCESS study uses a variety of community-based techniques, including word-of-mouth and snowball sampling, to recruit individuals. However, this cohort is not necessarily representative of the populations of interest and these findings should not automatically be generalized to analogous groups in other settings.  6.4  Recommendations Specific recommendations resulting from each analysis are contained in  chapters 3, 4 and 5. The recommendations for public health- or policy-based interventions presented below arise from a consideration of the studies as a whole. The findings presented herein clearly support the provision of expanded and improved interventions to support ART adherence among HIV-seropositive individuals who use injection drugs. Although the analyses in chapters 3 and 4 identified important associations between specific social- and structural-level 75  exposures on ART outcomes, their effects are largely driven by poorer adherence levels within those strata, as indicated by the mediation analysis of homelessness, adherence and plasma viral load suppression in chapter 4. Similarly, in chapter 3, individuals who had successfully suppressed plasma viral loads following the initiation of ART suffered higher rates of plasma HIV RNA rebound linked to sub-optimal levels of adherence. To date, public health-based interventions demonstrated to improve adherence among individuals engaged on ART have focused on contingency management (228), direct administration of medication (229, 230) and engagement in substitution therapy (229, 230). The findings presented here support earlier calls to expand interventions to target social- and structural-level barriers to treatment access and adherence (49, 67). Second, the findings in this dissertation on the HIV treatment-related effects of incarceration, including a link between incarceration and a greater risk of viral rebound (chapter 4) and non-adherence to prescribed ART (chapter 5), provide more evidence of the deleterious effect of illicit drug criminalization on the health of drug users (44, 45, 231). In this case, the analyses in this dissertation highlight the elevated risk of ART interruptions within prison settings (142) and during transitions between penal and non-penal settings (143). These findings are particularly disturbing in light of the interrelated epidemics of HIV infection, substance use and mental illness among prison populations (232). Fortunately, a number of programmes have been developed to address prison-associated barriers to HIV care and optimize ART outcomes in this group (233, 234). In light of findings that in-prison ART treatment benefits are quickly eroded once individuals are released from custody (77, 223), efforts to transition individuals to HIV care in community settings have been established (234). For example, a small 76  study of HIV-infected and opioid-dependent prisoners transitioned using buprenorphine saw no significant immunologic or virologic changes 12 weeks post-release (168). In this setting, findings from this dissertation indicate there is a need to address prison-related barriers to HIV care among incarcerated drug users, including enhancing linkages with community-based healthcare providers. In addition, recent years have seen increasing concern over the individual and societal costs of incarcerating non-violent individuals convicted of illicit drug offenses (235, 236), especially in light of the lack of evidence for its effectiveness on rates of illicit drug use (237, 238). In response, a number of calls have been made for thorough reform of government policy on illicit drug use, promoting greater use of evidence-based measures (239, 240). The findings in this dissertation illustrate how the societal reliance on criminal justice sanctions as a response to illicit drug use complicates programmes to improve the health of individuals who use injection drugs. Thus, efforts to improve HIV treatment outcomes among IDU should directly address incarceration (241); conversely, societal responses to illicit drug use should be reformed to prioritize the use of evidence-based public health-based interventions that can help sustain IDU on treatment rather than contributing to treatment interruptions.  6.5  Future research The studies presented herein suggest important new directions for  understanding and responding to sub-optimal HIV treatment outcomes and HIV disease progression among IDU. First, the use of comprehensive data on antiretroviral treatment, clinical outcomes and individual-, social- and structurallevel exposures points to the importance of conducting research using long77  running and community-recruited groups of illicit drug users. As identified in the systematic review conducted in chapter 2, the majority of studies of HIV disease progression among drug users rely on short-term studies, often among HIV-seropositive drug users recruited from clinical settings. Similarly, the analysis of the cumulative burden of incarceration on the risk of non-adherence presented in chapter 5 illustrates the importance of assessing the effects of factors that may develop over the course of HIV treatment. Thus, future research using data from this study should consider the longitudinal patterns of important determinants, such as multiple episodes of engagement in methadone maintenance therapy (242), on treatment access and adherence. The overarching concern of this dissertation has been the employment of the risk environment framework to model HIV treatment outcomes among IDU. The findings of this dissertation support its use as a tool to conceptualize the effect of various social and structural level exposures on HIV treatment and disease progression. Although prospective work should continue to articulate the risk environment for HIV treatment outcomes and disease progression among IDU, future research might also investigate how specific aspects of that environment could be modified to optimize treatment outcomes (48). For example, a recent systematic review and modeling exercise estimated the number of future HIV infections in specific epidemic settings given a variety of relevant clinical and structural parameters (46). Hence, a future analysis might use findings from this dissertation on the incidence of incarceration, mean adherence levels among incarcerated and non-incarcerated IDU, and the incidence of viral rebound among incarcerated IDU to parameterize a mathematical model on the HIV treatment benefits of diverting non-violent HIV-positive IDU from secure 78  custody. Beyond this, a randomized trial could examine the effect on HIV treatment of incarceration versus community-based diversion programs for nonviolent drug offenders (e.g. drug courts).  6.6  Conclusions In the three decades since the initial detection of what would become  known as AIDS, the development of effective pharmacotherapies has resulted in dramatic improvements in survival and functioning for HIV-seropositive individuals. Despite the availability of ART, HIV-related morbidity and mortality remains highly elevated among HIV-seropositive individuals who use illicit drugs. Although a wealth of previous studies have identified a number of proximate behavioural and clinical factors associated with poor ART access and adherence and sub-optimal treatment outcomes, the analyses comprising this doctoral dissertation describe the important effects of social- and structural-level exposures. Specifically, the risk environment framework, previously used to model vulnerability to HIV infection and other drug-related harms, can serve as a useful conceptual model for the study of HIV treatment outcomes and HIV disease pathogenesis among IDU. Various important elements of the framework, including incarceration, homelessness and involvement in the sex trade, were associated with poorer treatment outcomes through lower adherence to ART. As a result, policy and health-related interventions should support improved adherence patterns among this vulnerable population by investigating the impact of targeting relevant social- and structural-level barriers to care. 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