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Association of patterns of methadone use with antiretroviral therapy discontinuation : a prospective… Bach, Paxton; Wood, Evan; Dong, Huiru; Guillemi, Silvia; Kerr, Thomas; Montaner, Julio; Milloy, M-J Nov 19, 2015

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RESEARCH ARTICLE Open AccessAssociation of patterns of methadone usewith antiretroviral therapy discontinuation:a prospective cohort studyPaxton Bach2, Evan Wood1,2, Huiru Dong1, Silvia Guillemi1, Thomas Kerr1,2, Julio Montaner1,2 and M-J Milloy1,2*AbstractBackground: Methadone maintenance therapy (MMT) is a proven treatment strategy for opioid dependent patients.Although studies have demonstrated that MMT increases contact with the medical system and improves adherence toantiretroviral therapy (ART) in HIV-positive people who inject drugs (PWID), the effect of MMT discontinuation on ARTdiscontinuation has not been well described.Methods: We examined the impact of continuous MMT use, MMT non-use and MMT discontinuation on the time toART discontinuation (defined as 90 days of continuous non-use following previous enrolment) in a community-recruitedprospective cohort of HIV-positive PWID followed between May 1996 and May 2013 in Vancouver, Canada. MultivariateCox proportional hazards regression was used to examine the association between MMT use patterns and time to ARTdiscontinuation while adjusting for socio-demographic confounders.Results: A total of 794 HIV-positive PWID were included during the study period. In an adjusted analysis, in comparisonto those who were continuously on MMT, MMT non-use (Adjusted Hazard Ratio [AHR] = 1.44, 95 % Confidence Interval[CI]: 1.19–1.73) as well as discontinuing MMT (AHR = 1.82, 95 % CI: 1.27–2.60) were both found to be independentlyassociated with time to ART discontinuation.Conclusions: This study reinforces the known benefits of MMT use on ART adherence and demonstrates howdiscontinuation of MMT is independently associated with an increased risk of ART cessation. These data highlightthe importance of retaining PWID on MMT.Keywords: Methadone, Opiate substitution treatment, HIV, Antiretroviral therapy, Highly activeBackgroundPeople who inject drugs (PWID) constitute a populationat exceptionally high-risk for HIV infection, representingapproximately 10 % of all new HIV infections in NorthAmerica annually [1, 2]. In addition to an increased riskof HIV infection, PWID exhibit higher rates of diseaseprogression and higher HIV/AIDS mortality rates as aresult of increased co-morbidities and suboptimal accessto antiretroviral therapy (ART) [3–6]. There is also awell-documented association between ongoing drug useand decreased ART adherence [7, 8], which can lead tothe development of drug resistance [9, 10], disease pro-gression [11, 12], and increased mortality [13]. Whileboth ART initiation and adherence remain issues forPWID, it is encouraging to note that former PWIDachieve comparable treatment outcomes as their non-PWID counterparts [14, 15], and that good results areattainable in PWID should they remain adherent to theirART regimen [16].Methadone maintenance therapy (MMT) is anevidence-based approach to treating opioid dependenceand reducing illicit opioid use [17]. Within BritishColumbia it is widely available through physician’s of-fices, health authorities, and various private services,contributing to the fact that 53.3 % of Vancouver PWIDreported MMT use in 2011 [18]. In addition to its effectson opioid use, MMT is also a useful tool in combatting* Correspondence: uhri-mjsm@cfenet.ubc.ca1British Columbia Centre for Excellence in HIV/AIDS, St. Paul’s Hospital,Vancouver, BC, Canada2Department of Medicine, University of British Columbia, Vancouver, BC,Canada© 2015 Bach et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Bach et al. BMC Infectious Diseases  (2015) 15:537 DOI 10.1186/s12879-015-1255-7the spread of HIV and has been shown to reduce drug-related behaviours associated with a high risk of HIVtransmission [19]. In HIV-positive PWID, MMT in-creases uptake and adherence to ART and improvesoverall treatment outcomes [20, 21]. Enrolment in MMTprograms also decreases the incidence of ART discon-tinuation in this population [22]. Despite these benefitsMMT remains inaccessible in many countries due tolocal drug regulations, and the five countries with thelargest injection-drug driven HIV epidemics provide opi-oid substitution therapy to less than 2 % of their totalpopulations of PWID [21].While MMT has been demonstrated as an effectivetool for improving ART treatment outcomes in HIV-positive PWID, many PWID will decline MMT and ratesof drop out from treatment are high [23]. In this con-text, the impact that MMT discontinuation has on ARTadherence has not been well described. The followingstudy was conducted to test the hypothesis that discon-tinuation of MMT predicts a higher risk of discontinu-ation of ART in a long-running prospective cohort ofHIV-positive PWID in Vancouver, Canada.MethodsThis study was conducted using data from the AIDS CareCohort to Evaluate Access to Survival Services (ACCESS),an ongoing prospective cohort study of HIV-positivePWID [24, 25]. Briefly, recruitment for the cohort occursthrough street outreach in the Downtown Eastside ofVancouver, the regional epicenter for injection drug use.Participants are eligible if they are a minimum of 18 yearsold, are HIV seropositive, and have a history of illicit druguse. At baseline and semi-annually participants provideblood samples for virologic and serologic analysis and re-spond to an interviewer-administered questionnaire elicit-ing data on demographics, drug use patterns, andinteractions with the criminal justice system. In turn, theyare compensated $20 (CAD) per visit and are offered refer-rals to addictions treatment and other health services. Datagathered from the visits is supplemented by informationon HIV treatment received from the local province-widedrug treatment program (DTP) at the British ColumbiaCentre for Excellence in HIV/AIDS (BC-CfE), a centralizedART dispensary and HIV laboratory for the province ofBritish Columbia. These data include complete retrospect-ive and prospective profiles of CD4 counts, plasma HIV-1RNA viral loads (VL), and history of exposure to specificantiretroviral agents. The cohort receives annual ethics ap-proval by the Providence Health Care/University of BritishColumbia Research Ethics Board. All individuals providewritten informed consent upon study recruitment.The study period extended from May 1996 to May 2013.Participants were eligible for inclusion if they were exposedto ART at baseline or had initiated ART during follow-up.For individuals who initiated ART during the study period,the date of ART initiation was considered their baselinedate. Study eligibility required that individuals had a base-line CD4 count and viral load measured within 6 monthsbefore or after their baseline date.The primary outcome of our study was discontinu-ation of ART, defined as 90 days of continuous ARTnon-use following previous enrolment in ART [26]. Dis-continuation was determined through confidential link-age with the pharmacy database of the existingprovince-wide antiretroviral treatment program. The pri-mary explanatory variable was methadone status, andparticipants at each study visit were categorized as eitherMMT non-users, continuous MMT users adherent tomethadone for at least six months, or as prior MMTusers who had discontinued therapy over the previoussix months. This variable was time-varying, as their cat-egory could change if answers to the question “are youin a methadone treatment program right now?” werediscordant between 6-month follow-up periods. Patientsconsistently on MMT were used as the reference cat-egory and participants were grouped based on self-reported data. Potential confounders that were consid-ered included: gender (male vs. female), age (per 10 yearsolder), ethnicity (Caucasian vs. other), homelessnesswithin previous six months (yes vs. no), sex work in-volvement (yes vs. no), at least daily heroin injection (yesvs. no), at least daily cocaine injection (yes vs. no), atleast daily crack cocaine smoking (yes vs. no), at leastdaily alcohol use (yes vs. no), a protease inhibitor in ini-tial ART regimen, baseline CD4 count, baseline VL, andthe number of individuals the participant’s ART-prescribing physician had experience treating at the timethe participant initiated ART (previously demonstratedto affect the rate of VL suppression [27]). All behav-ioural variables refer to activities taking place within theprevious 6 months and all variable definitions were iden-tical to earlier ACCESS reports [24, 25].Initially, we examined the baseline characteristics ofthe analytic sample stratified by methadone use. To testfor significant differences we calculated Pearson’s chi-squared for categorical variables and the Wilcoxon rank-sum test for continuous variables. To estimate thebivariable relationships between each explanatory vari-able and the time to ART discontinuation, we used Coxproportional hazards regression. Extended multivariableCox proportional hazards regression was then applied toexamine whether methadone status was independentlyassociated with time to ART discontinuation, afteradjusting for potential confounders [28]. A confoundingmodel selection approach was used, as previously de-scribed [29]. Briefly, we fit a multivariate model contain-ing all variables found to be significantly associated withART discontinuation in bivariate analyses (at p < 0.10).Bach et al. BMC Infectious Diseases  (2015) 15:537 Page 2 of 7One secondary variable at a time was then removed in astepwise manner to construct reduced models. At eachstep the values of the coefficients for methadone statusin the full model was compared with those in thereduced models. Secondary explanatory variables corre-sponding to the smallest relative change were removedsequentially, and the process was continued until theminimum change from the full model was greater than5 %. As it is an important clinical variable associatedwith eligibility for ART, baseline CD4 count was a prioriretained in the final model despite non-significant re-sults in the bivariate analysis. Finally, we describe themedian HIV viral load for each methadone use categoryusing all available data including baseline and follow-upmeasures.ResultsIn total, 794 HIV-positive PWID were included in thepresent analyses between May 1996 and May 2013,among whom 494 (62.2 %) were male and 451 (56.8 %)self-identified as Caucasian. The median follow-up timewas 44.9 (interquartile range [IQR]: 24.8–78.5) months.The median age of participants at baseline was 41.1(IQR: 34.3–46.6) years old. Table 1 displays additionalsocio-demographic, behavioural, social, and clinical data.When grouped by methadone status at the start time ofthe survival analysis, 449 participants (57 %) were noton MMT, 327 (41 %) were continuously on MMT, and18 (2 %) had discontinued MMT within the last sixmonths. Among 794 participants, 377 experienced atotal of 766 ART discontinuation events (defined as90 days off ART following previous enrolment), for anincidence density of 27.7 (95 % confidence interval [CI]:25.1–30.5) per 100 person-years. Among the 794 partici-pants, 269 (33.9 %) switched their category for MMTuse during follow-up.Table 2 shows results of the bivariate and multivariateCox regression analyses of time to ART discontinuation.In the bivariate analyses, both being continuously offMMT (hazard ratio [HR] = 1.36, 95 % CI: 1.12–1.65) aswell as discontinuing methadone (HR = 3.03, 95 % CI:2.12–4.33) were associated with an increased risk of dis-continuing ART when compared to consistent MMTuse. Additionally risk factors included homelessnesswithin the previous six months (HR = 1.94, 95 % CI:1.57–2.39), sex work involvement (HR = 1.64, 95 % CI:1.28–2.10), at least daily heroin injection (HR = 2.59,95 % CI, 2.09–3.21), at least daily cocaine injection(HR = 2.10, 95 % CI: 1.72–2.58), at least daily crack co-caine smoking (HR = 1.40, 95 % CI: 1.17–1.68), at leastdaily alcohol use (HR = 1.63, 95 % CI: 1.27–2.09), and ahigher baseline VL (per log10 copies/mL; HR = 1.49,95 % CI: 1.40–1.58). Male gender (HR = 0.71, 95 % CI:0.58–0.86), older age (per 10 year increase; HR = 0.49,95 % CI: 0.43–0.55), Caucasian ethnicity (HR = 0.78,95 % CI: 0.64–0.95), and baseline CD4 count (per 100cells/mm3; HR = 0.95, 95 % CI: 0.90–0.99) were nega-tively associated with ART discontinuation.In the multivariate analysis, both being continuouslyoff MMT (adjusted hazard ratio (AHR) = 1.44, 95 % CI:1.19–1.73) and discontinuing MMT (AHR = 1.82, 95 %CI: 1.27–2.60) were each independently associated withan increased risk of discontinuing ART.When we looked at the median plasma HIV viral loadthroughout study period, the median viral load was lessthan 50 (IQR: 35–1005) copies/mL among individualswhere MMT was used continuously and was 1482 (IQR:49–39099) copies/mL among individuals who were onbut discontinued MMT in the prior six months.As a subanalyis, we investigated all possible interactionsbetween engagement in methadone and all other explana-tory variables significant in the final multivariable model.Of these, neither MMT * age (p = 0.085) nor MMT * home-lessness (p = 0.315) were significantly associated with theoutcome. The interaction terms for MMT *≥ daily heroininjection (p = 0.008) and MMT * baseline VL (p = 0.012)were significant. In light of these findings, we fit stratifiedmodels to estimate MMT effects by each level of heroin in-jection. Among individuals < daily heroin injection, not be-ing on MMT was associated with ART discontinuation(AHR= 1.30, 95 % CI: 1.05–1.60) while discontinuingMMT was not associated with ART discontinuation(AHR = 1.45, 95 % CI: 0.90–2.34). Among individualswith ≥ daily heroin injection, both not being onmethadone (AHR = 2.38, 95 % CI: 1.60–3.52) andMMT discontinuation was associated with ART dis-continuation (AHR = 3.05, 95 % CI: 1.80–5.19).DiscussionIn this study we examined the relationship with beingoff of MMT as well as with discontinuing MMT on ARTdiscontinuation. Our analysis revealed that participantsnot engaged in MMT have a higher likelihood of ARTdiscontinuation, and additionally demonstrated the inde-pendent association of MMT discontinuation reducingtime to ART discontinuation. Despite MMT discontinu-ation occurring within only the previous six-monthperiod, it is notable that the median VL of these partici-pants was higher than those who remained on MMT.Multiple behavioural, social, and structural barrierscomplicate the treatment of HIV infection among PWID[21, 30]. In this setting, it is well documented that on-going injection drug use contributes to poor ART adher-ence, and as a result poor health outcomes [7, 8, 13].MMT has been shown to mitigate these outcomes inopioid-dependant PWID by enabling initiation of HIVtreatment and by improving ART adherence [20–22].Our data add further support to the positive effects ofBach et al. BMC Infectious Diseases  (2015) 15:537 Page 3 of 7MMT on optimizing HIV/AIDS treatment outcomes,while providing evidence suggesting that MMT discon-tinuation is independently associated with ART discon-tinuation. This is consistent with studies demonstratingthat other benefits of MMT are improved with extendedduration of methadone treatment including decreasedrelapse into drug use, reduction in illegal activity, and in-creased full-time employment [31, 32]. Interestingly, thenegative consequences of forced discontinuation ofMMT have recently been hypothesized following theRussian occupation of Crimea and a resulting reversal ingovernment policy previously supportive of MMT [33].Our data lends support to the suggestion that such pol-icy changes could have significant negative impacts onHIV/AIDS treatment programs in affected regions.The mechanisms through which remaining on MMTdecreases the discontinuation of ART are likely multifac-torial. MMT provides a stabilizing effect on opioid use,encouraging improved social function, social support,and development of daily routines [34]. These have ademonstrated positive effect on ART adherence [35].Furthermore, MMT necessitates regular contact withTable 1 Baseline demographics of study participants stratified by mmt use (n = 794)Methadone StatusVariable Total (%) (n = 794) Discontinued MMT (%) (n = 18) Current MMT (%) (n = 327) MMT Naive (%) (n = 449)GenderMale 494 (62.2) 9 (50.0) 166 (50.8) 319 (71.1)Female 300 (37.8) 9 (50.0) 161 (49.2) 130 (28.9)Age (years)Median (IQR) 41.1 (34.3–46.6) 37.8 (30.0–42.9) 40.6 (34.2–46.2) 41.6 (34.6–47.2)EthnicityCaucasian 451 (56.8) 12 (66.7) 205 (62.7) 234 (52.1)Other 343 (43.2) 6 (33.3) 122 (37.3) 215 (47.9)HomelessnessaYes 166 (20.9) 2 (11.1) 68 (20.8) 96 (21.4)No 625 (78.8) 16 (88.9) 258 (78.9) 351 (78.2)Sex work involvementaYes 125 (15.7) 3 (16.7) 60 (18.4) 62 (13.8)No 667 (84.0) 15 (83.3) 266 (81.4) 386 (86.0)Daily heroin injectionaYes 131 (16.5) 8 (44.4) 53 (16.2) 70 (15.6)No 662 (83.4) 10 (55.6) 274 (83.8) 378 (84.2)Daily cocaine injectionaYes 148 (18.6) 5 (27.8) 57 (17.4) 86 (19.2)No 640 (80.6) 13 (72.2) 268 (82.0) 359 (80.0)Daily crack cocaine smokingaYes 208 (26.2) 4 (22.2) 104 (31.8) 100 (22.3)No 585 (73.7) 14 (77.8) 222 (67.9) 349 (77.7)Protease inhibitor initial regimenaYes 325 (40.9) 11 (61.1) 143 (43.7) 171 (38.1)No 469 (59.1) 7 (38.9) 184 (56.3) 278 (61.9)CD4 count (cells/mm3)Median (IQR) 300 (190–440) 255 (190–310) 320 (180–470) 295 (190–425)Viral load (log10 copies/mL)Median (IQR) 3.7 (1.7–4.7) 4.5 (4.0–4.8) 3.5 (1.7–4.7) 3.8 (1.7–4.8)Physician HIV experiencebMedian (IQR) 60 (14–161) 133 (34–203) 71 (19–185) 52 (11–139)aRefers to behaviors in the previous six months. b Refers to number of total HIV patients physician has treated prior to initial visit with participant. IQR = inter-quartile range.Percentages may not sum up to 100 % due to missing data and/or rounding errorBach et al. BMC Infectious Diseases  (2015) 15:537 Page 4 of 7the medical system, allowing for the establishment ofpositive patient-provider relationships, providing oppor-tunities for the management of psychiatric co-morbidities and medication side effects, and offeringregular access to counselling and other programs. Theseare all factors understood to improve ART adherence inPWID [35].In response to the beneficial effects of MMT on ARTenrolment and adherence, co-administration has beenstudied in multiple models of directly observed therapy(DOT) or directly administered antiretroviral therapy(DAART) [36, 37]. In our setting, ART is regularly co-administered with MMT, which can be prescribedthrough community physician’s offices and dispensed bycommunity pharmacies for witnessed ingestion. A recentsystematic review identified these programs as successfuladherence interventions for HIV-positive PWID in theshort-term [36], while a second meta-analysis also ob-served a positive effect on virologic, immunologic, andadherence outcomes, particularly when they target indi-viduals with a high risk of non-adherence [37]. Of note,both studies comment on the need for further evaluationof the long-term benefits of these interventions as initialintervention effects appeared to wane following comple-tion of the programs. These results are congruent withour work, demonstrating that short-term interventionsTable 2 Bivariate and multivariate cox proportional hazards analyses of factors associated with art discontinuation among a sampleof injection drug users in vancouver, canada (n = 794)Unadjusted Hazard Ratio (HR) Adjusted Hazard Ratio (AHR)Variable HR 95 % CI p value AHR 95 % CI p valueMMTCurrent MMT 1.00 — — 1.00 — —Not on MMT 1.36 1.12–1.65 0.002 1.44 1.19–1.73 <0.001Discontinued MMT 3.03 2.12–4.33 <0.001 1.82 1.27–2.60 0.001Gender(Male vs. female) 0.71 0.58–0.86 <0.001 — — —Age(Per 10 years older) 0.49 0.43–0.55 <0.001 0.59 0.52–0.66 <0.001Ethnicity(Caucasian vs. other) 0.78 0.64–0.95 0.015 — — —Homelessnessa(Yes vs. no) 1.94 1.57–2.39 <0.001 1.53 1.24–1.87 <0.001Sex work involvementa(Yes vs. no) 1.64 1.28–2.10 <0.001 — — —Daily heroin injectiona(Yes vs. no) 2.59 2.09–3.21 <0.001 1.70 1.39–2.08 <0.001Daily cocaine injectiona(Yes vs. no) 2.10 1.72–2.58 <0.001 — — —Daily crack cocaine smokinga(Yes vs. no) 1.40 1.17–1.68 <0.001 — — —Daily alcohol use(Yes vs. no) 1.63 1.27–2.09 <0.001 — — —Protease inhibitor initial regimena(Yes vs. no) 0.97 0.79–1.19 0.771 — — —Baseline CD4 count(Per 100 cells/mm3) 0.95 0.90–0.99 0.025 1.03 0.98–1.07 0.234Baseline viral load(Per log10 copies/mL) 1.49 1.40–1.58 <0.001 1.39 1.29–1.50 <0.001Physician HIV experienceb(Per # prev. patients) 1.00 1.00–1.00 0.074 — — —aRefers to behaviors in the previous six months. bRefers to number of total HIV patients physician has treated prior to initial visit with participantBach et al. BMC Infectious Diseases  (2015) 15:537 Page 5 of 7are less effective at improving ART adherence over time.Our data is further complemented by the recent obser-vation that act of enrolling in MMT decreases the riskof ART discontinuation [22], suggesting clearly thatlong-term treatment is necessary to maximize the bene-fits of MMT on ART adherence.This study has several limitations, in part due to itsnature as an observational cohort study. While our co-hort is largely representative of the local population ofPWID, the generalizability of our findings to other set-tings is not known. Additionally, much of our data relieson self-reporting of sensitive subjects and there is a pos-sibility of a response bias in our survey results. Third,data on reasons for discontinuation was not available.This information could potentially provide further infor-mation as to which patients are at higher risk, includingthose taking particularly complicated ART regimens orthose experiencing significant side effects, and might bebest explored through a future qualitative study. Fourth,as our study does not include diagnostic screening foropioid dependence, some misclassification bias may havebeen introduced by including individuals not eligible forMMT. We did, however, include various measures ofillicit drug use in this analysis, and our model-buildingprotocol indicated that high-intensity cocaine and crackuse did not substantively affect the relationship betweenMMT engagement and time to ART discontinuation.Finally, as this is an observational study we must ac-knowledge the possibility that the described relationshipbetween MMT and ART discontinuation is not a causalone. Factors with known effects on ART adherence notincluded in our survey include the presence of psychi-atric co-morbidities and treatments and the strength ofsocial supports, which we were unable to incorporateinto our analysis [38]. Despite these limitations, the datasuggesting that MMT plays a positive role in successfullymaintaining patients on ART continues to grow.ConclusionsThis study provides evidence that discontinuing MMT isindependently associated with an increased risk of dis-continuing ART. These data offer further support forMMT as an important component of comprehensiveHIV treatment programs, and highlight the need forevidence-based strategies for retaining PWID on MMT.AbbreviationsART: Antiretroviral therapy; DAART: Directly administered antiretroviral therapy;DOT: Directly observed therapy; DTP: Drug-treatment programs; MMT: Methadonemaintenance therapy; PWID: People who inject drugs; VL: Viral load.Competing interestsDr. Milloy is supported in part by the United States National Institutes ofHealth (R01-DA021525.) This work was supported in part by a Tier 1 CanadaResearch Chair in Inner-City Medicine awarded to Dr. Wood. Dr. Montaner issupported by the British Columbia Ministry of Health and through anAvant-Garde Award (No. 1DP1DA026182) from the National Institute of DrugAbuse (NIDA), at the US National Institutes of Health (NIH). He has also receivedfinancial support from the International AIDS Society, United Nations AIDSProgram, World Health Organization, National Institutes of HealthResearch-Office of AIDS Research, National Institute of Allergy & InfectiousDiseases, The United States President’s Emergency Plan for AIDS Relief (PEPfAR),UNICEF, the University of British Columbia, Simon Fraser University, ProvidenceHealth Care and Vancouver Coastal Health Authority. The other authors declarethey have no competing interests.Authors’ contributionsThe study was conceived by PB and EW and statistical analyses were providedby HD. Results were compiled and interpreted by PB, EW and M-JSM. The initialmanuscript was completed by PB and M-JSM. SG, TK and JM provided data andfeedback on the initial manuscript. 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