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Expansion of HAART Coverage Is Associated with Sustained Decreases in HIV/AIDS Morbidity, Mortality and… Montaner, Julio; Das Lima, Viviane; Harrigan, Paul Richard; Lourenco, Lillian; Yip, Benita; Nosyk, Bohdan; Wood, Evan; Kerr, Thomas; Shannon, Kate; Moore, David; Hogg, Robert S.; Barrios, Rolando; Gilbert, Mark; Krajden, Mel; Gustafson, Reka; Daly, Patricia; Kendall, Perry R. W. (Perry Robert William), 1943- Feb 12, 2014

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Expansion of HAART Coverage Is Associated withSustained Decreases in HIV/AIDS Morbidity, Mortalityand HIV Transmission: The ‘‘HIV Treatment asPrevention’’ Experience in a Canadian SettingJulio S.G. Montaner1,2*, Viviane D. Lima1,2, P. Richard Harrigan1,2, Lillian Lourenc¸o1, Benita Yip1,Bohdan Nosyk1,3, Evan Wood1,2, Thomas Kerr1,2, Kate Shannon1,2, David Moore1,2, Robert S. Hogg1,3,Rolando Barrios1,5, Mark Gilbert4, Mel Krajden4, Reka Gustafson5, Patricia Daly5, Perry Kendall61 BC Centre for Excellence in HIV/AIDS, Providence Health Care, Vancouver, British Columbia, Canada, 2Division of AIDS, Department of Medicine, University of BritishColumbia, Vancouver, British Columbia, Canada, 3 Faculty of Health Sciences, Simon Fraser University, Vancouver, British Columbia, Canada, 4 BC Centre for DiseaseControl, Vancouver, British Columbia, Canada, 5 Vancouver Coastal Health Authority, Vancouver, British Columbia, Canada, 6Ministry of Health, Province of BritishColumbia, Victoria, British Columbia, CanadaAbstractBackground: There has been renewed call for the global expansion of highly active antiretroviral therapy (HAART) under theframework of HIV treatment as prevention (TasP). However, population-level sustainability of this strategy has not beencharacterized.Methods: We used population-level longitudinal data from province-wide registries including plasma viral load, CD4 count,drug resistance, HAART use, HIV diagnoses, AIDS incidence, and HIV-related mortality. We fitted two Poisson regressionmodels over the study period, to relate estimated HIV incidence and the number of individuals on HAART and thepercentage of virologically suppressed individuals.Results: HAART coverage, median pre-HAART CD4 count, and HAART adherence increased over time and were associatedwith increasing virological suppression and decreasing drug resistance. AIDS incidence decreased from 6.9 to 1.4 per100,000 population (80% decrease, p = 0.0330) and HIV-related mortality decreased from 6.5 to 1.3 per 100,000 population(80% decrease, p = 0.0115). New HIV diagnoses declined from 702 to 238 cases (66% decrease; p = 0.0004) with aconsequent estimated decline in HIV incident cases from 632 to 368 cases per year (42% decrease; p = 0.0003). Finally, ourmodels suggested that for each increase of 100 individuals on HAART, the estimated HIV incidence decreased 1.2% and forevery 1% increase in the number of individuals suppressed on HAART, the estimated HIV incidence also decreased by 1%.Conclusions: Our results show that HAART expansion between 1996 and 2012 in BC was associated with a sustained andprofound population-level decrease in morbidity, mortality and HIV transmission. Our findings support the long-termeffectiveness and sustainability of HIV treatment as prevention within an adequately resourced environment with nofinancial barriers to diagnosis, medical care or antiretroviral drugs. The 2013 Consolidated World Health OrganizationAntiretroviral Therapy Guidelines offer a unique opportunity to further evaluate TasP in other settings, particularly withingeneralized epidemics, and resource-limited setting, as advocated by UNAIDS.Citation: Montaner JSG, Lima VD, Harrigan PR, Lourenc¸o L, Yip B, et al. (2014) Expansion of HAART Coverage Is Associated with Sustained Decreases in HIV/AIDSMorbidity, Mortality and HIV Transmission: The ‘‘HIV Treatment as Prevention’’ Experience in a Canadian Setting. PLoS ONE 9(2): e87872. doi:10.1371/journal.pone.0087872Editor: Nicolas Sluis-Cremer, University of Pittsburgh, United States of AmericaReceived November 5, 2013; Accepted December 30, 2013; Published February 12, 2014Copyright:  2014 Montaner et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Funding: The work here described [Treatment as Prevention in BC initiative (PI: JM)] has been financially supported by the British Columbia Ministry of Health, aswell as an Avant-Garde Award (No. 1DP1DA026182) and grant 1R01DA036307-01 from the National Institute of Drug Abuse (NIDA), at the US National Institutes ofHealth (NIH). In addition, JM was funded through a Knowledge Translation Award from the Canadian Institutes of Health Research (CIHR). VDL is supported by aScholar Award from the Michael Smith Foundation for Health Research and a New Investigator Award from CIHR, and by a NIDA award (R03DA033851) and CIHRaward (MOP-125948). TK was supported in part by a NIDA award (R01DA028532) and a CIHR award (MOP–102742). EW is supported by a Tier 1 Canada ResearchChair in Inner City Medicine. Additional limited unrestricted funding was provided by Abbvie, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences,Janssen, Merck and ViiV Healthcare. None of the funders played any role in study design, data collection and analysis, decision to publish, preparation or review ofthe manuscript.Competing Interests: This study received limited unrestricted funding from Abbvie, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen,Merck and ViiV Healthcare. The funding provided by the commercial sources has been directed to the institution and not to the investigators. There are nopatents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data andmaterials.* E-mail: jmontaner@cfenet.ubc.caPLOS ONE | www.plosone.org 1 February 2014 | Volume 9 | Issue 2 | e87872IntroductionAfter 30 years, controlling the HIV epidemic remains anextraordinary challenge. This is despite the availability of anumber of proven prevention tools, including harm-reductionstrategies and emerging biomedical interventions. [1–7] Recently,increasing attention has been focused on the potential role that theexpansion of HIV treatment may offer to curb progression toAIDS and premature death among HIV infected individuals andsecondarily reduce HIV transmission, commonly referred to asHIV treatment as prevention or TasP. [8–11] In brief, HIV-1RNA concentration (hereafter referred to as viral load) is a keydeterminant of the level of risk associated with sexual, vertical andneedle sharing-related HIV transmission. [12–21] Appropriate useof HAART suppresses HIV replication on a sustained basis,leading typically to undetectable, viral load in plasma and haltingdisease progression to AIDS and premature death.11 In addition,as viral load rapidly declines in plasma and subsequently in otherbiological fluids (including semen, vaginal fluids and rectalmucosa), the likelihood of HIV transmission per exposure eventis markedly reduced. [12–21] The concept of scaling up highlyactive antiretroviral therapy (HAART), commonly referred to asTasP, has gained substantial momentum, as its efficacy andeffectiveness have become increasingly apparent. [8,9,22–24]However, the real-world population-level effectiveness andsustainability of this strategy remains to be adequately character-ized.British Columbia (BC), Canada, provides a unique environmentto address this issue within a concentrated HIV epidemic.HAART eligibility in BC has remained consistent with the IAS-USA guidelines since 1996 to the present. [11,25] BC is anadequately resourced environment with a publically funded healthcare system, that fully subsidizes access to medical services,centralized laboratory monitoring and access to HAART with noco-payments or deductibles. In addition, a single agency, the BCCentre for Excellence in HIV/AIDS (BC-CfE), is responsible forthe centralized distribution of all antiretrovirals and monitoring ofkey HIV-related outcomes in BC. Additionally, the availability ofunique personal health numbers for all BC-residents provideunique opportunities to evaluate the impact of this strategythroughout the province using anonymized data linkages betweenadministrative datasets.We therefore conducted a longitudinal ecological study toevaluate the population-level effectiveness and sustainability ofHAART expansion in BC. Specifically, we sought to characterizethe association between HAART coverage, and the proportion ofindividuals virologically suppressed with the number of new AIDSdiagnoses, and all-cause mortality among HIV-infected BCresidents, as well as the number of new HIV diagnoses andestimated HIV incident cases between 1996 and 2012.MethodsAggregate- and individual-level data on the key study variableswere collected from a number of sources, including the BC-CfELaboratory and Drug Treatment Registries, the BC Centre forDisease Control (BCCDC), the BC Ministry of Health (BC MoH)population-level health resource utilization files, and the PublicHealth Agency of Canada (PHAC).HIV Incidence and PrevalenceWe also obtained HIV prevalence estimates for BC from 1996to 2011, independently generated by the Public Health Agency ofCanada (PHAC) [26] using previously published methods. [27]The method is a modified back-projection method to estimateHIV incidence and prevalence. Unlike the back-projectionmethods used the literature, this new method does not requirelinking HIV and AIDS diagnostic registries. It is based on linkingthe estimated parametric distribution between the time to HIVtesting and time since HIV infection. These distributions wereadjusted for testing practices over time (e.g. HIV testing trends),reporting delays, multiple reporting of cases, AIDS cases reporting(adjusting for the effect of HAART), survival time before and afterHAART was introduced, and birth cohort effects. [28,29] Data for2012 are not yet available, and therefore, we extrapolated theavailable data to obtain preliminary estimates for these twoindicators for the year 2012.New HIV Diagnoses and AIDS Morbidity and MortalityThe BCCDC collates all BC HIV surveillance data and housesHIV testing data from the provincial public health referencelaboratory, which accounts for approximately 90% of all HIVscreening and all confirmatory testing in BC. Of note, HIVinfection became provincially reportable in 2003.30 Data regard-ing new HIV diagnoses were extracted from annual and monthlyBCCDC HIV/AIDS Update and Reportable Diseases reportsfrom 1996 to 2012. [30] The AIDS case-reports were allocatedaccording to the year when a client was diagnosed with the firstAIDS defining illness.HIV Treatment and MonitoringHIV/AIDS care is fully publically funded by the health caresystem in BC. This includes publically funded access to medicalservices, virological and laboratory monitoring and HAART (withno co-payments or deductibles). HAART use in BC is driven bythe BC-CfE HIV treatment guidelines, [31] which have remainedconsistent with those of the International AIDS Society-USA (IAS-USA) since 1996. [11,25].Clinical, treatment and laboratory data were obtained from theBC-CfE, which has a centralized system capturing all antiretro-viral distribution, all plasma viral load testing, and all resistancetesting, as well as baseline CD4 count for 96% of all patientsstarting antiretroviral therapy in BC. Specifically, HAARTcoverage, CD4 cell counts, viral load, treatment adherence (asmeasured by validated prescription refill compliance), [32] andgenotypic drug resistance were obtained from the BC-CfEdatabases. For HAART coverage, we obtained the yearly numberof individuals on HAART in BC. Viral Load data were adjustedfor changes in viral load assay sensitivity over time, as previouslydescribed. [33] For the purpose of these analyses, we recorded thehighest viral load for every individual per year. To accommodateirregular frequency of measurements or missing values, the highestyearly value was carried forward until a new measurement wasavailable. Individuals were censored if they moved out of theprovince or died.Population-level adherence to antiretroviral therapy was assess-ed by prescription refill compliance for each year as previouslydescribed. [32] In brief, this was estimated by dividing the numberof months of medications dispensed by the number of months offollow-up during each calendar year. Resistance testing wasperformed on stored viral load samples collected immediatelybefore starting HAART and upon virological rebound thereafter.Samples were assigned to 1 of 4 resistance categories on the basisof a modified International AIDS Society-USA table, as previouslydescribed. [34] In brief, samples were considered to be resistant ifthey displayed one or more major resistance mutations in any ofthe following 4 categories: I) lamivudine, or emtracitabine; II)other nucleoside reverse transcriptase inhibitors; III) proteaseTasP Experience in CanadaPLOS ONE | www.plosone.org 2 February 2014 | Volume 9 | Issue 2 | e87872inhibitors; and IV) non-nucleoside reverse-transcriptase inhibitors.Then, the data were classified into the following categories: I)individuals with no evidence of HIV resistance or with wild typeHIV only II) those who were never genotyped, and individualsdemonstrating HIV resistance to III) one, IV) two or V) threeantiretroviral drug classes, respectively. Those who were nevergenotyped include individuals with viral load samples ,250copies/mL, which were not tested given that sequence analysis isnot reliable in this setting. Antiretroviral resistance data aredisplayed by calendar year, and include all individuals who haveever enrolled on the BC-CfE program - whether or not they everused antiretrovirals, from January 1996 to December 2012.All-Cause Mortality among HIV-Positive IndividualsHIV-related mortality data were obtained from BC VitalStatistics for all HIV-positive individuals regardless of whether ornot they had or not ever accessed antiretroviral therapy between1996 and 2011. [35] Data for 2012 were not yet available. TheHIV-related diagnoses were based on the 10th revision of theInternational Statistical Classification of Diseases and RelatedHealth Problems (ICD-10) codes B20 to B24. [36].Population DataPopulation estimates were obtained for the years 1996–2011 tocalculate mortality and AIDS rates. These estimates were obtainedthrough Statistics Canada through BCStats. [37] Data for 2012were not yet available.Statistical AnalysisTo be consistent throughout the text, we included the year 2012for all variables. However, since the estimates of the Public HealthAgency of Canada were complete until 2011, we used apolynomial function of degree three to extrapolate the data. Thispolynomial function provided the best fit for the incidence andprevalence data from 1996 to 2011, and we therefore usedestimated values of these two indicators for 2012.We modeled trends using generalized additive models, whichaccounts for the non-linear temporal trends in these longitudinaldata. [38,39] We fitted different Poisson regressions, [40] withcorrection for over dispersion in the data, for each of the followingoutcomes: estimated HIV incidence rate, HIV-related mortalityrate and the rate of AIDS cases. The primary explanatoryvariables of interest were the number of individuals actively onHAART and the percentage of individuals with the highest yearlyviral load lower than 500 copies/mL. Note that for the rates, thesize of the BC population was used as an offset in the models.These models were performed using the statistical package SAS(version 9.3). All p values reported were two-sided, andsignificance was set at the 5% level.Ethics ApprovalThe BC-CFE received approval for this study from theUniversity of British Columbia ethics review committee at the StPaul’s Hospital, Providence Health Care site (P05–123). The studycomplies with the BC’s Freedom of Information and Protection ofPrivacy Act. The study was conducted primarily using anon-ymized laboratory and administrative databases, and thereforeinformed consent was not required. Incidence data wereaugmented with data collected through prospective researchcohort studies, which include written informed consent by studyparticipants and separate IRB approval.Role of the Funding SourceThe sponsors had no role in the design, data collection, dataanalysis, data interpretation, or writing of the report. Thecorresponding author had full access to all data in the study andhad final responsibility to submit for publication.ResultsFrom January 1st 1996 to December 31st 2012, the estimatedHIV prevalence in BC increased from 7,900 to 11,972 cases (52%;p-value ,0.0001), and the number of individuals actively onHAART increased from 837 to 6772 (709%; p-value ,0.0001).Based on these figures, we estimated that HAART coverageincreased from 11% to 57% (p-value 0.0004) during this period.HIV Disease ProgressionAs shown in Figure 1, the trend in the number of HIV-relateddeaths from 1996 to 2011, with 253 individuals dying in 1996 andonly 59 individuals dying in 2011. Using the overall BC populationas a denominator, the HIV-related mortality rate decreased from6.5 to 1.3 per 100,000 of the BC population during 1996–2011(80% decrease, p-value 0.0115). Figure 1 also shows that the AIDSrates decreased from 6.9 to 1.4 per 100,000 population over thestudy period (80% decrease, p-value 0.0330).As shown in Figure 2, the overall median baseline or pre-therapy CD4 cell count increased from 270 cells/mL (25–75thpercentile 130–390) in 1996 to 380 cells/mL (25–75th percentile235–550) in 2012 (41% increase; p-value ,0.0001). The medianpre-therapy CD4 cell count among individuals with a history ofinjection drug use (IDU) was 350 cells/mL (25–75th percentile180–500) in 2012.As shown in Figure 3, HAART adherence levels for individualswho ever started therapy in BC increased over time. While only37% of individuals had adherence levels $95% in 1996, thisincreased to 71% for individuals (p-value 0.0032) by 2012.Table 1 shows the estimated aggregate viral load levels at thepopulation-level over time. Using a 500 copies/mL cut-off, weestimated that the proportion of individuals virologically sup-pressed increased from 8% in 1996 to 74% in 2012 (p-value ,0.0001). The analysis was repeated using a 50 copies/mL cut-off;however, this was restricted to the period of 1999–2012, as themore sensitive test was not available prior to 1999. Using a 50copies/mL cut-off, the proportion of individuals suppressedincreased from 6% to 59% (p-value ,0.0001).As shown in Figure 4, emergent antiretroviral drug resistanceamong individuals with unsuppressed viral load (includingindividuals on or off therapy) decreased from 1996 to 2012 inBC. Since 1996, the number of individuals never genotypeddecreased markedly from 64% in 1996 to 10% in 2012 (p-value ,0.0001). At the same time, the prevalence of individuals with wildtype virus (i.e.: no drug resistance) increased from 15% in 1996 to69% in 2012 (p-value ,0.0001).HIV New DiagnosesAs shown in Figure 5, there was a steady decline in the numberof HIV new diagnoses from 702 to 238 cases (266%; p-value0.0004) and for estimated reduction of HIV incident cases from632 to 368 cases per year (242%; p-value 0.0003) between 1996and 2012. New HIV diagnoses decreased by 92% (p-value 0.0013)among individuals with a history of injection drug use, and by 22%(p-value 0.0046) among MSM. Further, when the size of the MSMpopulation was factored in, based on US CDC estimates, the ratesof HIV new diagnoses was found to have declined from 4.43 per1000 in 1996 to 3.21 per 1000 in 2004 to 1.81 per 1000 in 2012.TasP Experience in CanadaPLOS ONE | www.plosone.org 3 February 2014 | Volume 9 | Issue 2 | e87872All confirmed HIV positive tests have been documented since1989, however HIV became reportable in 2003 in BC withsystematic follow-up of positive test results from that time forward.Therefore reports prior to 2003 are biased because duplicatepositive tests were not consistently removed. All longer-term trendsin Figure 5 after 2003 are statistically significant. Therefore it isunlikely that over-counting cases prior to 2003 substantiallyimpacted the overall conclusions of the paper.Statistical ModelsNext, we developed two statistical models with the outcomebeing the estimated HIV incidence rate and the explanatoryvariables being the number of individuals actively on HAART andthe percentage of individuals suppressed on HAART (using a 500copies/mL cut-off to allow a consistent definition of suppressionover time). The model showed that for each 100 individualsactively on HAART the estimated incidence rate decreased by1.2% (estimated rate ratio 0.9879; 95% CI 0.9868; 0.9891) and foreach 1% increase in the number of individuals suppressed onHAART, the HIV incidence decreased by 1% (estimated rateratio 0.9900; 95% CI 0.9887; 0.9912).For the model with HIV-related mortality rate as the outcomeand the explanatory variables being the number of individualsactively on HAART and the percentage of individuals suppressedon HAART (using a 500 copies/mL cut-off), we observed that foreach 100 individuals actively on HAART the estimated mortalityrate decreased by 2.51% (estimated rate ratio 0.9749; 95% CI0.9703; 0.9795) and for each 1% increase in the number ofindividuals suppressed on HAART, the mortality rate decreasedby 2.06% (estimated rate ratio 0.9794; 95% CI 0.9754; 0.9834).For the model with the outcome being the AIDS rate and theexplanatory variables being the number of individuals actively onHAART and the percentage of individuals suppressed on HAART(using a 500 copies/mL cut-off), we observed that for each 100individuals actively on HAART the estimated AIDS ratedecreased by 2.48% (estimated rate ratio 0.9752; 95% CI0.9679; 0.9826) and for each 1% increase in the number ofindividuals suppressed on HAART, the AIDS rate decreased by1.95% (estimated rate ratio 0.9805; 95% CI 0.9737; 0.9874).DiscussionOur results demonstrate that between 1996 and 2012, theexpansion of HAART coverage in BC was strongly andstatistically significantly associated with population level decreasesin incident AIDS diagnoses and all cause mortality among HIVinfected individuals. In addition, the expansion of HAARTcoverage in BC was strongly and statistically significantlyassociated with decreased HIV new diagnoses and estimatedHIV incidence. Overall, we estimated that for every 1% increasein the number of individuals suppressed on HAART, the HIV/Figure 1. Number and rate of AIDS and death (HIV-related) cases by calendar year, 1996–2011. AIDS: data for AIDS defining illnessreported by the BC Centre for Disease Control, based on the first AIDS-defining illness reported for each person. Denominator for rates was BCpopulation counts based on Statistics Canada estimates during 1996–2011.doi:10.1371/journal.pone.0087872.g001TasP Experience in CanadaPLOS ONE | www.plosone.org 4 February 2014 | Volume 9 | Issue 2 | e87872AIDS morbidity and mortality decreased by 2%, and HIVincidence rate decreased by 1%.As expected, we documented a shift towards earlier initiation ofHAART during the study period, as demonstrated by a steadyincrease in the median pre-HAART CD4 cell count. In contrast toearlier predictions based on mathematical models, [41–45] ourresults showed that overall level of adherence to HAARTimproved, with a consequent increase in the proportion ofindividuals virologically suppressed and a decrease in theprevalence of antiretroviral drug resistance during the studyperiod. [10,24,46].Figure 2. Distribution of baseline CD4 cell count by year of therapy initiation, 1996–2012. Calendar year (horizontal axis) refers to theyear when antiretroviral therapy was first started.doi:10.1371/journal.pone.0087872.g002Figure 3. Distribution of individuals’ adherence to antiretrovirals by calendar year, 1996–2012.doi:10.1371/journal.pone.0087872.g003TasP Experience in CanadaPLOS ONE | www.plosone.org 5 February 2014 | Volume 9 | Issue 2 | e87872Table 1. Distribution of the highest plasma viral load from HIV infected individuals by calendar year, 1996–2012.Year NPatients with ,500copies/ml (%)Median HIV-1 RNA plasmaconcentration (copies permL; Q1–Q3)Patients with ,50copies/mL (%)Median HIV-1 RNA plasmaconcentration (copies permL; Q1–Q3)1996 2924 224 (8%) 35500 (6800–100010) NA (2) NA (2)1997 4180 585 (14%) 24000 (3200–100010) NA (2) NA (2)1998 4879 1292 (26%) 13000 (499–92000) NA (2) NA (2)1999 5443 1755 (32%) 9470 (499–84200) 307 (6%) 9470 (359–84200)2000 5931 2052 (35%) 9400 (499–85000) 1387 (23%) 9400 (88–85000)2001 6461 2386 (37%) 7700 (499–80200) 1693 (26%) 7700 (49–80200)2002 6985 2670 (38%) 10200 (499–97000) 1939 (28%) 10200 (49–97000)2003 7437 2902 (39%) 8960 (499–86200) 2185 (29%) 8960 (49–86200)2004 7906 3340 (42%) 5035 (499–71200) 2577 (33%) 5035 (49–71200)2005 8277 3775 (46%) 2230 (499–61600) 3014 (36%) 2230 (49–61600)2006 8552 4195 (49%) 699.5 (499–52350) 3431 (40%) 699.5 (49–52350)2007 8868 4621 (52%) 499 (499–45350) 3803 (43%) 359 (49–45350)2008 9343 5324 (57%) 499 (499–26800) 4033 (43%) 136 (49–26800)2009 9963 6227 (63%) 499 (499–14400) 4992 (50%) 49 (49–14400)2010 10548 7060 (67%) 499 (499–8514) 5600 (53%) 49 (49–8514)2011 11191 7918 (71%) 499 (499–2770) 6237 (56%) 49 (49–2770)2012 11805 8747 (74%) 499 (499–755) 7007 (59%) 49 (49–755)Includes all individuals ever having a plasma viral load test done regardless of whether they received antiretroviral therapy.doi:10.1371/journal.pone.0087872.t001Figure 4. Distribution of HIV drug resistance among individuals with unsuppressed viral load by calendar year, 1996–2012.doi:10.1371/journal.pone.0087872.g004TasP Experience in CanadaPLOS ONE | www.plosone.org 6 February 2014 | Volume 9 | Issue 2 | e87872Of note, the changes in HIV/AIDS morbidity, mortality andtransmission, took place against a background of persistently highrates of genital chlamydia and genital gonorrhea, infectioussyphilis. A declining trend in the rate of hepatitis C new caseswas seen during the study period and the ecological nature of ourpopulation-based study, preclude us from excluding a liberal biasin this regard. In this context, it should be noted that progressivedrug policies adopted in BC, including low threshold drugtreatment facilities, wide availability of needle and syringeprograms, extensive opioid substitution therapy program, andthe first supervised injection site in North America, have beenshown to act as both facilitators of the expansion of HAARTcoverage among injection drug users and could have also affectedHIV and HCV transmission dynamics.Our results support the long-term population-level effectivenessand sustainability of the treatment as prevention strategy, as itrelates to its impact on HIV/AIDS morbidity and mortality, aswell as HIV new diagnoses, within a resource rich environmentwith a fully subsidized health care system. It is important toemphasize that the declining trends in new HIV diagnosed in BCare unique in Canada. [47] This is despite the fact that Canadaenjoys a health care system, which is a publically funded anduniversally accessible. However, BC is the only jurisdiction inCanada where HIV/AIDS services, including medical services,centralized laboratory monitoring and HAART are fully subsi-dized, with no co-payments or deductibles. BC has alsodifferentiated itself within Canada for the establishment of acentralized unit devoted to implementing, monitoring, andevaluating HIV/AIDS programs in the province.It is reassuring to note that evidence in support of a population-based impact of treatment on the prevention of HIV transmissioncontinues to emerge from diverse global settings. Such effects havebeen described in Taiwan, [22] and more recently in Vancouver,[9,21,33] Baltimore, [48] San Francisco, [23] China, [49,50] andKwazulu-Natal. [46] It is important to mention that themagnitude of the impact of the expansion of HAART coverageon HIV transmission derived from our models is entirelyconsistent with the effect noted from the experience in Kwazulu-Natal. [46] Further monitoring of the population-level impact ofHAART roll out efforts will help to validate the predictions ofrecent [51,52] and further characterize the field impact of TasP indiverse epidemiological situations and settings. [53] Undoubtedly,this will be greatly facilitated by the recent release of the 2013World Health Organization (WHO) Consolidated Global HIVARV Treatment Guidelines. [54,55] In brief, the 2013 WHOGuidelines recommend that HAART eligibility be expanded to allHIV infected individuals regardless of symptoms if they have aCD4 cell count of less than 500/mm3, or regardless of CD4 countlevel if there is TB co-infection, or liver disease due to hepatitis Bvirus co-infection, or for individuals at very high risk for HIVtransmission, such as sero-discordant couples and pregnant HIVinfected women, who are encouraged to start HAART duringpregnancy and continue lifelong therapy thereafter, and forchildren infected with HIV under the age of 5 years old who arealso advised to continue lifelong therapy. The 2013 WHOGuidelines are expected to expand HAART eligibility to at least80% of those infected with HIV worldwide. As such, they trulyopen the door for the global implementation of HIV TasP. Ourdata suggest that this may indeed be a game changer in the fightagainst HIV/AIDS, as it would be expected to dramatically curbmorbidity and premature mortality, as well as HIV transmissionglobally, with impressive economic impact. Indeed, we haveFigure 5. Selected HIV epidemic indicators for British Columbia by calendar year, 1996–2012.doi:10.1371/journal.pone.0087872.g005TasP Experience in CanadaPLOS ONE | www.plosone.org 7 February 2014 | Volume 9 | Issue 2 | e87872previously used mathematical modeling to project that expansionof HAART coverage, or TasP, has a favorable cost-benefit ratiowhen morbidity and mortality benefits are considered, and isbecomes cost-averting when the HIV transmission benefit isadded. [56] This has been independently confirmed by themodeling work of Granich et al [57] and, more recently byWalensky et al. [58].As in any study of this nature, changing patterns of riskbehaviours could have influenced our results. However, back-ground incidence rates of sexually transmitted illnesses and bloodborne diseases can serve as adequate surrogates for riskbehaviours. In this context, it is important to note that the ratesof infectious syphilis, gonorrhea, and chlamydia in BC haveremained alarmingly high during the study period. Indeed,infectious syphilis is currently rising at a very high rate in BC,particularly within MSM. Specifically, over the study period inBC, infectious syphilis rate increased from 0.5 to 7.7 (1446%, p-value ,0.0001), genital chlamydia rate increased from 106 to 256(141%, p-value ,0.0001), and genital gonorrhea rate increasedfrom 14 to 30 (119%, p-value,0.0001). Indeed, a recent report bythe BCCDC, [59] confirms alarmingly high and increasing rates ofsyphilis among MSM in BC. While there are limitations toecological comparison (e.g., with the majority of Chlamydiainfections likely occurring among younger adults due to hetero-sexual sex, and HIV positive MSM being over-represented amongsyphilis cases), against this background, the decrease in HIV newdiagnoses reported here is even more striking.In BC, over the study period, the hepatitis C rate (per 100,000population) decreased from 172 to 36 (279%, p-value ,0.0001).As we discussed above, the latter is a reflection of the efficacy ofBC’s progressive drug policies, which in turn facilitated engage-ment on HAART, and as such had a beneficial effect on theexpansion of HAART in our setting. This is significant givenpersistent reluctance to offer HAART to the IDU population insome settings, often attributed to concerns regarding potential forincomplete adherence leading to HIV drug resistance and thethreat of spreading primary HIV drug resistance to the populationat large, [60] which may in turn compromise the effectiveness ofthe TasP, as recently suggested. [43] Also, we should acknowledgethat there has been some reluctance to embrace TasP within IDUcommunities as they have (rightly so, in some settings) advancedthe argument that TasP could compete for resources against othervaluable evidence based initiatives, particularly harm reduction,and that TasP may be used as a pretext to promote coercivetesting and treatment initiatives. These are sad realities that needto be overcome if the full benefit of TasP is to be globally realized.Further, given that IDU continue to drive new infections in severalsettings contending with growing HIV epidemics, [61] such asRussia, and given that IDU have high potential to promote moregeneralized epidemics of HIV infection, [61] the data presentedherein suggest that there is an urgent need to ensure that TasPinitiatives are extended to IDU on a global scale without coercionand with continued promotion of other evidence based interven-tions, including harm reduction.Our report is derived from a population based ecological studywithin the province of BC, in Canada. As a result, we cannot drawa causal link between increased HAART coverage and declines inHIV/AIDS morbidity, mortality, and HIV transmission. Withregard to clinical outcomes, we cannot find an alternativeexplanation or confounder that may explain the associationbetween HAART coverage expansion and declining HIV/AIDSmorbidity and mortality uncovered by our models. With regard totransmission, we needed to account for changes in risk behavioursas a potential confounder, as discussed above. As described above,the high and increasing rates of STIs during the study periodsuggest that high prevalence of risky sexual behaviours over thestudy period. In contrast, the declining trends in HCV diagnosessuggest that high-risk injection practices were on the declineduring the study period. These findings suggest that there may bea conservative bias in our estimates for sexual transmission, and aliberal bias for injection based transmission. Further work will beneeded to derive more precise estimates of the degree of protectionthat HAART offers in each setting, and the relative contribution ofspecific risk factor modification strategies. However, we arereassured by the similarity of our overall estimates for the impactof the expansion of HAART coverage on HIV transmissionbetween the present study and a recently reported populationbased study from Kwazulu-Natal, in South Africa. [46] Addition-ally, our findings are entirely consistent with those of HPTN 052,[10] a recently reported randomized clinical trial that demon-strated that immediate ART decreased sexual HIV transmissionby 96.3% among sero-discordant heterosexual couples.In conclusion, our results show that HAART expansion in BCbetween 1996 and 2012 was strongly and statistically significantlyassociated with sustained population-level decreases in HIV/AIDSrelated morbidity and mortality, as well as concomitant decreasesin new HIV diagnoses, and estimated HIV incidence. Expansionof HAART coverage was also associated with increased adherencerates, increased rates of viral suppression, and decreased rates ofHIV resistance. Overall, our model suggests that for every 1%increase in the number of individuals suppressed on HAART, theestimated HIV incidence also decreased by 1%. Our resultssupport the real world and long-term effectiveness and sustain-ability of the HIV treatment as prevention strategy, within aresource rich environment with a fully subsidized health caresystem. The 2013 Consolidated World Health OrganizationAntiretroviral Therapy Guidelines offer a unique opportunity tofurther evaluate this issue in other settings, particularly withingeneralized epidemics, and resource-limited setting, within thecontext of much needed programmatic HAART expansioninitiatives, as advocated by UNAIDS.AcknowledgmentsThe authors would like to acknowledge Kelly Hsu for her assistance in thedevelopment and management of the project and the manuscript, Irene L.Day, RN, BN, MBA and Katherine Heath, PhD for assisting in thecoordination of the project and Chris Archibald, MD for facilitating accessto PHAC data.Author ContributionsConceived and designed the experiments: JSGM. Performed theexperiments: JSGM VDL PRH LL BY BN EW TK KS DM RSH RBMG MK PD PK. Analyzed the data: JSGM VDL LL. Wrote the paper:JSGM VDL. Developed the first draft of the manuscript: JSGM VDL.Coordinated all edits thereafter, and contributed to the literature search ofthis manuscript: JSGM. Contributed to accessing and analyzing the dataand approving the final version of the manuscript: VDL. Contributed tothe preparation of document and collection of resistance data: PRH.Provided input on the scientific content of the manuscript: LL. Processeddata, prepared datasets for analyses and edited the manuscript: BY.Reviewed and provided input on the scientific content of the manuscript:PRH LL BY BN EW TK KS DM RSH RB MK. Contributed to theinterpretation of the incidence data and provided input on the scientificcontent of the manuscript: MG PD RG PK.TasP Experience in CanadaPLOS ONE | www.plosone.org 8 February 2014 | Volume 9 | Issue 2 | e87872References1. Lagakos S, Gable A (2008) Challenges to HIV prevention-seeking effectivemeasures in the absence of a vaccine. N Engl J Med 358: 1543–1545.2. Vermund SH, Allen KL, Karim QA (2009) HIV-prevention science at acrossroads: advances in reducing sexual risk. Curr Opin HIV AIDS 4: 266–273.3. 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