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Methadone maintenance therapy decreases the rate of antiretroviral therapy discontinuation among HIV-positive… Reddon, Hudson; Milloy, M-J; Simo, Annick; Montaner, Julio; Wood, Evan; Kerr, Thomas Apr 1, 2014

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Methadone Maintenance Therapy Decreases the Rate ofAntiretroviral Therapy Discontinuation Among HIV-Positive IllicitDrug UsersH. Reddon1, M.-J. Milloy1,2, A. Simo1, J. Montaner1,3, E. Wood1,3, and T. Kerr1,31Urban Health Research Initiative, British Columbia Centre for Excellence in HIV/AIDS, St. Paul’sHospital, University of British Columbia, 608-1081 Burrard Street, Vancouver, BC, V6Z 1Y6,Canada2Faculty of Medicine, University of British Columbia, Vancouver, BC, V6Z 1Y6, Canada3Division of AIDS, Department of Medicine, University of British Columbia, Vancouver, BC, V6Z1Y6, CanadaAbstractWe sought to examine whether methadone maintenance therapy (MMT) decreased rates ofantiretroviral therapy (ART) discontinuation and was associated with plasma HIV RNA responsesamong a cohort of illicit drug users. Cumulative ART discontinuation rates were estimated usingKaplan–Meier methods and factors independently associated with ART discontinuation wereidentified using Cox proportional hazards regression. Engagement in MMT was negatively andindependently associated with ART discontinuation [Adjusted Relative Hazard = 0.67 (95 % CI0.54–0.83); p < 0.001]. Among participants receiving ART and MMT, 81.6 % of plasma HIV-1RNA assessments were <500 copies/mL, while 65.81 % of HIV-1 RNA assessments among thoseprescribed ART without MMT were <500 copies/mL (p < 0.001). These results demonstrate thatengagement in MMT conferred a protective benefit against ART discontinuation and wasassociated with a significant increase in plasma HIV RNA suppression among HIV-infectedopioid-dependent drug users.KeywordsHIV; Drug use; Antiretroviral therapy; Methadone; DiscontinuationINTRODUCTIONSince the mid-1990s, the advent of antiretroviral therapy (ART) has led to substantialreductions in morbidity and mortality among illicit drug users living with HIV/AIDS [1, 2].Treatment effectiveness relies, however, upon high and sustained levels of medicationadherence, which can present challenges for patients [3, 4]. Many treatment regimens arecomplex, with varying dosing protocols, dietary restrictions and potential adverse sideCorresponding author: Thomas Kerr, British Columbia Centre for Excellence in HIV/AIDS, 608-1081 Burrard Street, Vancouver,BC V6Z 1Y6, Canada, Tel: (604) 806-9142, uhri-tk@cfenet.ubc.ca.NIH Public AccessAuthor ManuscriptAIDS Behav. Author manuscript; available in PMC 2015 April 01.Published in final edited form as:AIDS Behav. 2014 April ; 18(4): 740–746. doi:10.1007/s10461-013-0584-z.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptThe final publication is available at Springer via http://dx.doi.org/10.1007/s10461-013-0584-z.effects [5]. While some recent treatments have alleviated these issues by decreasing pillburden, sustained adherence is required for durable viral suppression, as well as theprevention of antiretroviral resistance and disease progression [6–8].Despite the documented benefits of ART, several previous studies have demonstrated thatHIV-infected drug users face barriers to healthcare and optimal treatment outcomes as aresult of social instability related to illicit drug addiction, as well as the pervasive stigmaexperienced by this population [9–13]. ART use may be complicated due to the highprevalence of homelessness, incarceration, and untreated psychiatric illness among peoplewho use illicit drugs [13–15]. As such, drug users are known to have lower uptake of ARTcompared to other HIV-positive individuals and are more likely to die without ever havingreceived treatment [16]. In addition to challenges related to ART access, drug users also facebarriers that preclude adherence to HIV treatment. These barriers have been observed evenin those settings where HIV care is delivered free of charge and where drug users do notface financial barriers to treatment. In Vancouver, Canada, where ART is provided free ofcharge, up to 50 % of drug users discontinue ART prematurely, and among those drug userswho remain engaged in treatment, 60 % have suboptimal levels of adherence [17–19].Accordingly, disparities in HIV-related mortality have been observed due to problems withaccess to ART and/or poor retention in HIV-related treatment among illicit drug users [20].Several recent studies have indicated improved access and adherence to treatment amongdrug users when ART is delivered in conjunction with methadone maintenance therapy(MMT) [21–23]. However, we know of no prospective studies examining the effect ofengagement in MMT on the risk of discontinuation of ART. Given the ongoing problem ofART discontinuation and the associated clinical sequelae potentiated by ARTdiscontinuation, we undertook the present study to evaluate the impact of MMT use on ARTdiscontinuation among a cohort of HIV-positive drug users in a setting of universal access toHIV care and treatment.METHODSStudy ParticipantsThe data for this investigation were collected through a prospective cohort of HIV-positiveillicit drug users, which has been described in detail previously [23]. Briefly, the AIDS CareCohort to evaluate Exposure to Survival Services (ACCESS) is an open prospective cohortof HIV-seropositive illicit drug users in Vancouver, Canada. The cohort was populatedthrough snowball sampling and extensive street outreach methods in the city’s DowntownEastside, the local epicenter of injection drug use and drug-related HIV infection [24].Individuals are eligible for ACCESS if they are aged ≥18 years, are HIV seropositive, have ahistory of illicit drug use and provide written informed consent. Participants answer astandardized interviewer-administered questionnaire and provide blood samples for diseasemonitoring at baseline and at every 6-month follow-up visit. The questionnaire elicitsdetailed demographic data, as well as information pertaining to drug use patterns and relatedexposures, and blood sampling provides a prospective clinical profile, including plasmaHIV-1 RNA viral load and CD4+ cell counts for every participant. All participants provideinformed consent and are remunerated $20 (CAD) for each study visit and, whenReddon et al. Page 2AIDS Behav. Author manuscript; available in PMC 2015 April 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptappropriate, are referred to additional healthcare services, including addiction treatment.Ethical approval is provided annually by the University of British Columbia/ProvidenceHealth Care Research Ethics Board.HIV/AIDS Drug Treatment ProgramIn our setting, antiretroviral therapy and HIV clinical monitoring are available free of cost toall HIV-infected residents of British Columbia. Participants can fill their initial 4-weekprescription and subsequent 3-to 4-month prescriptions for ART at any pharmacy in theprovince. Furthermore, there is a province-wide centralized antiretroviral dispensationprogram and a HIV/AIDS laboratory, which enables a complete prospective profile of allpatient CD4 cell count determinations, plasma HIV-1 RNA levels (as measured by AmplicorMonitor assay, Roche Molecular Systems, Mississauga, Canada), and antiretroviral therapyuse among cohort participants. This consists of the specific antiretroviral agents prescribed,as well as a previously validated measure of patient adherence derived from prescriptionrefill compliance [14, 25]. In addition to antiretroviral therapy, methadone is provided freeof charge under the provincial healthcare program and offered primarily throughpharmacies, doctor offices, and clinics. Within BC and throughout Canada, standardpharmacotherapy for opioid dependence involves oral solution methadone, a long lastingsynthetic opioid agonist that is prescribed by licensed physicians, while pharmacists witnessdaily ingestion [26]. Given that sustained adherence to methadone has been shown todecrease the risk of relapse and mortality, a treatment philosophy emphasizing indefinitemaintenance of MMT has become widely accepted in Canadian settings [27]. Similar toantiretrovirals, the centralized provincial drug dispensation database permits analysis ofdosing patterns among all patients [26]. The universal healthcare system enables theexamination of HIV-related outcomes in a setting where financial barriers to health care andHIV treatment are largely eliminated.Outcome VariablesFor the current analysis, individuals were eligible if they reported being on ART at the timeof recruitment or if they subsequently initiated ART during the study period. Since we wereinterested in the effect of MMT, individuals also had to be on MMT at baseline or opioid-using at baseline or during follow-up. In previous studies involving drug users in our setting,adherence to ART has been defined as the number of days ART was dispensed over thenumber of days an individual was eligible for ART. Non-adherence refers to less than 95 %adherence to ART during this period. In the present study, we looked at discontinuation ofART, which is defined as a ≥90 day period without receiving any antiretrovirals [17]. If apatient died within 3 months of treatment discontinuation, they were censored out of theanalysis at the date of death and defined as a non-event. Since we were interested in theimpact of MMT, the primary independent variable of interest was MMT in the past 6months. Any self-report of MMT treatment (a single dose to 100 % adherence) in the last 6months was classified as MMT participation. The reference category for this variable was noreport of enrollment in MMT in the past 6 months. Within Cox regression analyses,individuals could move from being on MMT in one 6 month period and then off in the next6 month period. This method allowed for the identification of factors associated with theoutcome over the entire study period adjusted by multiple observations for each individual.Reddon et al. Page 3AIDS Behav. Author manuscript; available in PMC 2015 April 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptAs each individual could report MMT use or not during different study visits, the analysesidentified factors correlated with periods of MMT use both within and between individuals.Statistical AnalysesAs a first step, cumulative ART discontinuation rates, stratified by MMT enrolment, wereestimated using Kaplan–Meier methods. Survival curves were compared using the log-ranktest. We then generated bivariate Cox regression analyses to identify predictors of ARTdiscontinuation. We were aware that confounding may have persisted if the rate ofdiscontinuation differed between participants enrolled in ART at varying stages of diseaseprogression, or among those who engaged in higher risk behaviors or who were potentiallyat higher risk of ART discontinuation as a result of other individual-level differences.Therefore, we considered secondary explanatory variables that may be related to methadoneengagement or antiretroviral treatment patterns. These included age (per year older); gender(female vs. male); Aboriginal ancestry (yes vs. no); engagement in MMT (yes vs. no);homelessness (yes vs. no); binge drug use (yes vs. no); sex work involvement (yes vs. no); atleast daily heroin injection (yes vs. less) and at least daily cocaine injection (yes vs. less).All drug-related and behavioral variables refer to behaviors in the past 6 months, and weretime-updated based on data from the semi-annual follow-up visits. Further, all behavioralvariables were lagged in our analyses in order to protect against reverse causality.Specifically, we employed measures of our time-updated independent variables of interest inour model from interviews that occurred prior to ART discontinuation. We also consideredthe following clinical variables: baseline CD4 cell count (cells/µL, per 100-cell increase),baseline plasma HIV-1 RNA (log10/µL, per log10 increase), date of initiating MMT (peryears later) and physician experience. In line with a previous analysis in this setting, anHIV-experienced physician was defined as one who had previously enrolled six or moreindividuals into the HIV treatment registry at the time the participant initiated treatment [7].Inclusion of this variable is warranted given that physician experience with HIV-infectedpatients is associated with improved survival [28]. Since participants were continuouslyenrolled in the treatment program during the study period, a physician could become‘experienced’ over time. However, the experience level assigned to each participant wasdetermined based on their physician’s HIV-related experience at the time of the participant’sfirst interview.To account for possible confounding, we constructed a multivariate Cox regression modelusing a priori-defined modelling strategy proposed by Maldonado and Greenland [29]. As afirst step, we fit a model that included the primary explanatory variable and all secondaryexplanatory variables. In a manual stepwise manner, we removed one secondary variable ata time to construct reduced models. The value of the coefficient for the primary explanatoryin the full model was compared to each of the reduced models. We removed the secondaryexplanatory that corresponded to the smallest relative change. This process was continueduntil the maximum change from the full model exceeded 5 %. The objective of thisprocedure is to retain secondary covariates with a greater relative influence on therelationship between the outcome and the explanatory variable of interest in the final model.Several studies have successfully used this technique to estimate the relationship between anoutcome of interest and a selected explanatory variable [29–31].Reddon et al. Page 4AIDS Behav. Author manuscript; available in PMC 2015 April 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptAs a sub-analysis, we conducted an attributable risks analysis to examine the incidence ofART discontinuation for those on and off MMT and we compared the proportion of HIV-1RNA observations <500 copies/mL for those on and off MMT. All statistical analyses wereperformed using SAS software version 9.2 (SAS, Cary, NC, USA). All tests of significancewere two-sided, with a p value of less than 0.05 indicating that an association wasstatistically significant.RESULTSBetween May 1996 and April 2008, we recruited 574 HIV-positive illicit drug users, ofwhom 408 (71.0 %) were ART-exposed at baseline or initiated treatment during follow-upand were included in this study. Of these, 164 (40.2 %) were women and 150 (36.8 %)individuals reported Aboriginal ancestry. The median age of participants at baseline was 39years (Interquartile range: 33–45) and those engaged in MMT were similar to those notengaged in MMT with respect to gender (p = 0.080) and Aboriginal ancestry (p = 0.202).Participants contributed 940 observations over the study period, and 526 ARTdiscontinuations were observed among 257 (63 %) participants for a cumulative incidenceof 70.6 % (95 % CI 65.8–75.3 %). Among those engaged in ART, the average duration ofenrolment was 15.34 months (IQR 3.70–19.73). There were 91 deaths for an incidence rateestimate of 17 per 100 person years (95 % CI 13.81–21.03).Figure 1 shows the Kaplan–Meier estimates of the cumulative therapy discontinuation ratefor the overall cohort stratified by engagement in MMT. As shown here, the cumulativeincidence rate was significantly elevated among those not engaged in MMT (log-rank p <0.001). By 24 months after ART initiation, the cumulative incidence rate of ARTdiscontinuation was 42.62 per 100 person-years (95 % CI 33.10–52.14) among thoseengaged in MMT and 71.42 per 100 person-years (95 % CI 59.42–83.43) for those notengaged in MMT. Additionally, the proportion of participants on MMT to never discontinuetheir ART was 53 % compared to 67 % among those not on MMT.Table 1 shows the crude and adjusted relative hazards (RH) of treatment discontinuation. Asindicated here, in bivariate analyses, homelessness (RH = 1.72, 95 % CI 1.26–2.35; p <0.001), binge drug use (RH = 1.34, 95 % CI 1.03–1.74; p = 0.031), sex work involvement(RH = 1.51, 95 % CI 1.10–2.07; p = 0.011), daily heroin injection (RH = 2.00, 95 % CI1.48–2.70; p < 0.001), daily cocaine injection (RH = 1.69, 95 % CI 1.29–2.22; p < 0.001)and a higher viral load (RH = 1.18, 95 % CI 1.11–1.24; p < 0.001) were associated withshorter time to ART discontinuation. Conversely, participation in MMT (RH = 0.60, 95 %CI 0.43–0.72; p < 0.001) date of therapy initiation (RH = 0.89, 95 % CI 0.85–0.92; p <0.001) and age (RH = 0.95, 95 % CI 0.94–0.97; p < 0.001) were negatively associated withART discontinuation in bivariate analyses. The multivariate analysis is also shown in Table1 and reveals that engagement in MMT (RH = 0.58, 95 % CI 0.44–0.76; p < 0.001) wasindependently and negatively associated with ART discontinuation after adjustment for yearof initiation, CD4+ cell count, viral load and gender. The attributable risk analyses revealedthat non-use of MMT increased the incidence rate of ART discontinuation by 28.80 casesper 100 person-years.Reddon et al. Page 5AIDS Behav. Author manuscript; available in PMC 2015 April 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptIn a sub-analysis, among 1076 viral load assessments of 198 participants receiving ART andMMT, 878 (81.6 %) of plasma HIV-1 RNA assessments were <500 copies/mL compared to718 (65.81 %) of 1091 plasma HIV-1 RNA assessments <500 copies/mL among thoseprescribed ART without MMT (p < 0.001).DISCUSSIONIn the present analyses, we observed a high rate of ART discontinuation among HIV-positive drug users. However, participants engaged in MMT had significantly lower rates ofART discontinuation compared to those not engaged in MMT. MMT enrollment remainedindependently and negatively associated with treatment discontinuation in multivariateanalyses that adjusted for a range of potential confounders. These findings translated intohigher rates of plasma HIV RNA undetectability among those patients prescribed MMT.Although MMT has previously been shown to enhance access and adherence to ART, to ourknowledge this is the first study to report a positive effect of MMT in preventing ARTdiscontinuation and subsequent plasma HIV RNA responses. These findings areencouraging given that antiretroviral non-adherence has been associated with elevatedmortality [7, 32]. While the mechanisms that explain the association between MMT andART discontinuation are likely to be multifaceted, it seems likely that MMT is having adirect effect in terms of reducing discontinuation of ART in this setting [21]. First, beingenrolled in MMT allows more regular contact with the health care system and relatedprograms including the co-administration of ARVs with daily dispensed MMT [33]. Second,the stabilizing effect of MMT may facilitate supportive counseling and other interventions toaddress barriers to adherence, such as co-occurring mental illness and other psychosocialconcerns [34]. Third, enrollment in MMT may provide opportunities for monitoring andadjustment of ART [21]. Fourth, engagement in MMT has been shown to reduce the risk ofincarceration, which has been shown to be strongly associated with prematurediscontinuation of ART, as well as non-adherence [35, 36]. Prior analyses of treatmentinterventions that address the common psychological and medical co-morbidities of drug usehighlight the need for multifaceted and interdisciplinary treatment delivery systems to HIV-infected drug users [37]. Given that MMT may provide a means of enhancing uptake andadherence to ART while reducing rates of discontinuation, concurrent delivery of MMT andantiretrovirals should be an essential component of prospective treatment interventions tooptimize health outcomes among drug users who are eligible for this therapy. Given therelationship between MMT and higher rates of plasma HIV RNA undetectability, thesefindings have implications for the recently identified role of ART as a HIV preventionstrategy [38].The beneficial effect of MMT for HIV-positive opioid users observed in this study alsohighlights unaddressed HIV-related treatment challenges faced by illicit stimulant users [39,40]. Although this study examined the impact of cocaine use, recent reports have shown thatparticipants using other stimulants are likely to have sub-optimal levels of adherence, and agrowing proportion of HIV infections are attributable to stimulants [41, 42]. This issue is ofparticular concern since no analogous substitution therapy is available to stimulant users.Given the success of MMT as a treatment for opioid dependence [43], and its role inReddon et al. Page 6AIDS Behav. Author manuscript; available in PMC 2015 April 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptimproving adherence to ART, the search for effective addiction treatments for stimulantusers is an urgent priority, as is removing other barriers to optimal HIV treatment outcomes.The present study has limitations. First, like most other cohort studies involving high-riskdrug users, ACCESS is not a random sample. Therefore, our study findings may notgeneralize well to the larger population of HIV-positive drug users in Vancouver. Second,we relied on self-reported measures, which may have introduced response biases into ourresults, such as socially desirable reporting. Although the reliability of self-reporting drugrelated behaviours has been validated previously [44], socially desirable reporting of high-risk and stigmatized behaviors and problems with recall remain concerns [45, 46]. However,we note that engagement in ART was measured based on prescription refill compliancerather than self-report. Third, ART was co-administered with MMT in some cases whileother patients received each medication from separate facilities. It is possible that the co-administration of these treatments could impact ART discontinuation and confound theresults. Additional analyses that measure the proportion of patients who receive thesetreatments in conjunction would provide insight into this matter. Fourth, the data regardinglength of enrolment in MMT was not available but this did not prevent us from assessing theimpact of current MMT enrolment on ART discontinuation, which was the primaryobjective of the analysis. Lastly, since this is an observational study the results presentedmust be interpreted with caution. For instance, the negative association between MMT andART discontinuation may have resulted from unmeasured differences between those whoused MMT and those who did not, rather than the effect of MMT itself. Yet, as priorinvestigations have indicated, there is reason to suggest that this relationship is causal: [1]the study was conducted in a setting where MMT is often dispensed daily with antiretroviraldrugs as a means of improving adherence; [2] dispensing MMT facilitates routine contactwith the health care system; and [3] the accessibility of MMT decreases the time and moneynecessary to procure other opioids, which allows more time for individuals to focus onpersonal health [21, 43].In summary, we found that engagement in MMT confers a protective benefit against ARTdiscontinuation among HIV-infected opioid-dependent drug users and that these resultstranslated into higher rates of plasma HIV RNA undetectability. These results underscorethe importance of providing MMT to opioid-dependent HIV-infected drug users as astrategy to address sub-optimal HIV treatment outcomes. Concurrent delivery of MMT andART should be a fundamental component of efforts to reduce HIV-related morbidity andmortality among opioid-dependent drug users.AcknowledgmentsThe authors thank the study participants for their contribution to the research, as well as current and pastresearchers and staff. We would specifically like to thank Deborah Graham, Tricia Collingham, Caitlin Johnston,and Steve Kain for their research and administrative assistance. The study was supported by the US NationalInstitutes of Health (R01DA021525) and the Canadian Institutes of Health Research (MOP-79297, RAA-79918).Thomas Kerr and M.-J. Milloy are supported by the Michael Smith Foundation for Health Research. M.-J. Milloy isalso supported by the Canadian Institutes of Health Research. This research was undertaken, in part, thanks tofunding from the Canada Research Chairs program through a Tier 1 Canada Research Chair in Inner City Medicinewhich supports Dr. Evan Wood.Reddon et al. Page 7AIDS Behav. 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Author manuscript; available in PMC 2015 April 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptFig. 1.Time to antiretroviral therapy (ART) discontinuation among a prospective cohort of HIV-infected illicit drug users, stratified by baseline enrollment in methadone maintenancetherapy (MMT) Time from recruitment (months)Reddon et al. Page 11AIDS Behav. Author manuscript; available in PMC 2015 April 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptReddon et al. Page 12Table 1Bivariate and multivariate Cox proportional hazard analyses of antiretroviral discontinuation among illicitdrug users (n = 408)CharacteristicUnadjusted relative hazard(RH)Adjusted relative hazard(RH)RH (95 % CI) p-value RH (95 % CI) p-valueAge (per years older) 0.95 (0.94–0.97) <0.001Gender (female vs. male) 1.25 (0.97–1.60) 0.080 1.43 (1.11–1.85) 0.006Aboriginal ancestry (yes vs. no) 1.18 (0.92–1.52) 0.202Homelessnessa (yes vs. no) 1.72 (1.26–2.35) <0.001Binge drug usea (yes vs. no) 1.34 (1.03–1.74) 0.031Sex trade involvementa (yes vs. no) 1.51 (1.10–2.07) 0.011Daily heroin injectiona (yes vs. less) 2.00 (1.48–2.70) <0.001Daily cocaine injectiona (yes vs. less) 1.69 (1.29–2.22) <0.001Physician experience (yes vs. no) 1.06 (0.78–1.46) 0.704CD4 cell count (cells/µL) (per 100 cells increase) 1.04 (0.99–1.10) 0.128 1.08 (1.03–1.15) <0.001Viral load (cells/mL) (per log10 increase) 1.18 (1.11–1.24) <0.001 1.42 (1.07–1.22) <0.001Methadone usea (yes vs. no) 0.60 (0.43–0.72) <0.001 0.58 (0.44–0.76) <0.001Date of therapy initiation (per years later) 0.89 (0.85–0.92) <0.001 0.94 (0.90–0.98) 0.004aBehaviours refer to activities in the 6 months prior to the interview, and variables are time updatedAIDS Behav. Author manuscript; available in PMC 2015 April 01.

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