Original article Ongoing drug use and outcomes from highly active antiretroviral therapy among injection drug users in a Canadian setting

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1 Antiviral Therapy : (doi: /IMP1614) Original article Ongoing drug use and outcomes from highly active antiretroviral therapy among injection drug users in a Canadian setting Andrea Krüsi 1, M-J Milloy 1, Thomas Kerr 1,2, Ruth Zhang 1, Silvia Guillemi 1, Robert Hogg 1, Julio Montaner 1,2, Evan Wood 1,2 * 1 British Columbia Centre for Excellence in HIV/AIDS, St Paul s Hospital, Vancouver, BC, Canada 2 Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada *Corresponding author uhri-ew@cfenet.ubc.ca Background: The effect of ongoing illicit drug use on HIV treatment remains controversial, especially in countries where access to HIV treatment for active injection drug users (IDUs) is limited because of presumed nonadherence. We sought to investigate the influence of drug use patterns on adherence to antiretroviral therapy and virological suppression among IDUs. Methods: Using generalized estimating equation logistic regression, we explored the effect of abstinence versus ongoing drug use on adherence and virological suppression using data from a community-recruited cohort of IDUs in Vancouver (BC, Canada). Results: A total of 381 HIV-positive IDUs were included in this analysis, among whom the median follow-up time was 30 months. In a multivariate model, no relationship was found between abstinence (reference) and active injection (adjusted odds ratio [AOR] 0.88, 95% confidence interval [CI] ) and non-injection (AOR 0.97, 95% CI ) drug use with adherence. In sub analyses, ongoing injection drug use was associated with a lower odds of virological suppression in comparison to abstinence (AOR 0.74, 95% CI ; P=0.026) and both active IDUs and active non-idus had lower odds of virological suppression compared with abstinent participants when longer periods of virological suppression were considered. Conclusions: Given the absence of a strong relationship between abstinence and ongoing drug use and adherence among HIV-positive IDUs, programmes that restrict antiretrovirals to abstinent individuals should be reexamined. The lower rates of virological suppression associated with ongoing drug use nevertheless highlight the importance of comprehensive systems of care and addiction treatment for active drug users. Introduction The past two decades have given rise to remarkable advances in HIV/AIDS treatment and care. The advent of highly active antiretroviral therapy (HAART) has contributed significantly to reductions in morbidity and mortality for individuals living with HIV/AIDS [1 4]. However, HIV-positive injection drug users (IDUs) have benefited less than other HIV-positive individuals from these advances [5,6]. In addition to poorer access to antiretroviral therapy, studies have indicated that, once therapy is initiated, IDUs commonly have lower rates of adherence [7 11] and lower rates of virological suppression than non-idus [11,12]. This might result in a high degree of reluctance by physicians to prescribe antiretroviral therapy to IDUs [13]. Despite a broad literature on adherence to antiretroviral therapy, few studies have examined the effect of ongoing drug use on adherence and HIV disease progression among IDUs. Active drug use has been associated with reduced adherence to antiretroviral therapy [14,15] and poorer virological response [12,14,16,17], whereas other work has found no association between active drug use and virological suppression [18]. Importantly, opioid substitution treatment has been repeatedly associated with increased adherence [15,19,20] and virological suppression [15,17], particularly among IDUs who no longer inject illicit drugs. To date, the effect of ongoing illicit drug use on HIV treatment outcomes is still controversial, especially in countries where access to HIV treatment for active 2010 International Medical Press (print) (online) 789

2 A Krüsi et al. IDUs is restricted because of presumed non- adherence. Therefore, we sought to investigate the influence of drug use patterns on adherence to antiretroviral therapy and virological suppression among a community-recruited cohort of IDUs. Methods Data for these analyses were collected through a prospective cohort study of HIV-positive IDUs, which has been described in detail previously [19,21]. In brief, the present study is a sister cohort to the Vancouver Injecting Drug User Study (VIDUS), created to study issues related to access to HIV/AIDS care among IDUs. Beginning in May 1996, participants were recruited through self-referral and street outreach from Vancouver s Downtown Eastside, the local epicentre of drug-related transmission of HIV. At baseline and semi-annually, all HIV-positive participants provide blood samples and complete an interviewer-administered questionnaire. The questionnaire elicits demographic data as well as information about participants drug use, including information about type of drug, frequency of drug use, involvement in drug treatment and periods of abstinence. All participants provide informed consent and are remunerated $20 CDN for each study visit. The study is unique in that the province of British Columbia has a centralized HIV treatment registry that allows for the linking of participant survey data to the British Columbia Drug Treatment Program to obtain all laboratory measures and measures of pharmacy refill antiretroviral therapy adherence. Ethical approval has been provided annually by the Providence Health Care/ University of British Columbia Research Ethics Board. Participants were eligible for the present analysis if they had initiated antiretroviral therapy before the baseline interview or during follow-up. The primary outcome was adherence to antiretroviral therapy as measured by pharmacy refill. Adherence was calculated as the ratio of days of medical follow-up for a 6-month period for which medication was dispensed prior to each completed questionnaire. We have previously shown this measure of adherence to reliably predict both virological suppression [7,22,23] and mortality [11,24]. As in previous studies, adherence was dichotomized as 95% versus <95% [7,22,25]. Although different thresholds for adherence have been described [26,27], we elected to use a cutoff of 95% because this has been most strongly associated with virological suppression in past analyses using prescription refill compliance [22]. We also conducted a sensitivity analysis where we dichotomized adherence as 80% versus <80% [26,27]. The secondary outcome measure sought to explore the long-term pattern of HIV type-1 (HIV-1) RNA suppression, defined as achieving HIV-1 RNA suppression of <500 copies/ml at least once during the 6-month period prior to each follow-up visit. We used this definition because IDUs are known to commonly discontinue then reinitiate antiretroviral therapy, and because 500 copies/ml was the lower limit of detection for the viral load assay during the study period [28]. However, we also conducted a subanalysis where suppression was defined as two consecutive measures <500 copies/ml. Additionally, we conducted a second subanalysis where we used Cox regression to evaluate the time to plasma HIV-1 RNA suppression <500 copies/ml. For this subanalysis, we included all antiretroviral-therapy-naive individuals with baseline CD4 + T-cell and HIV-1 RNA data who returned for a minimum of one follow-up visit after antiretroviral therapy initiation. Baseline was the antiretroviral therapy initiation date. The primary explanatory variable in both analyses was self-reported drug use in the past 6 months. Drug use was considered using a three-level variable where abstinence constituted the reference category and was compared to the influence of any injection drug use (heroin, cocaine or methamphetamine injecting) and non-injection drug use (crack or crystal methamphetamine smoking) during the previous 6 months. The injection drug use category could include polysubstance users who also used crack or smoked crystal methamphetamine. We also explored the effects of participation in methadone maintenance therapy (MMT) in the past 6 months, gender, Aboriginal ancestry, homelessness, baseline CD4 + T-cell count and baseline HIV-1 viral load. The relationship between possible predictors of adherence to HAART and virological suppression, including the three-level drug use variable, was assessed using a logit model based on generalized estimating equations (GEE) [29]. This approach is commonly used when a repeated measure of a binary dependent variable is obtained in longitudinal studies, and it has been used successfully in previous cohort studies involving IDUs [30,31]. Because the objective of this study was to determine whether drug use versus abstinence, independent of established sociodemographic and individual-level factors, was associated with adherence and virological suppression, we fit a series of confounding models based on the approach described by Rothman and Greenland [32] and Maldonado and Greenland [33]. For both models, we selected explanatory variables with a hypothesized relationship between drug use patterns and the relevant outcome of interest. We conducted initial bivariate screenings of each explanatory variable by the outcomes and included those with a conservative P-value of 0.2 in further analyses. Next, we created full models, including the drug use measure International Medical Press

3 Ongoing drug use and outcomes from HAART Table 1. Sociodemographic, behavioural and clinical characteristics of study participants at the baseline interview stratified by adherence to antiretroviral therapy Characteristic Adherence <95%, n (%) ab Adherence 95%, n (%) ac OR 95% CI P-value Age, years 35.3 ( ) d 37.2 ( ) d 1.41 ( ) Gender Male 94 (53.7) 130 (63.1) 1.00 Female 81 (46.3) 76 (36.9) 0.68 ( ) Ethnicity Non-Aboriginal 105 (60.0) 132 (64.1) 1.00 Aboriginal 70 (40.0) 74 (35.9) 0.84 ( ) Drug use pattern a Abstinent 16 (9.1) 14 (6.8) 1.00 Non-injection only 9 (5.1) 19 (9.2) 2.41 ( ) Injection 150 (85.7) 173 (83.9) 1.31 ( ) MMT No 119 (68.0) 105 (51.0) 1.00 Yes 56 (32.0) 101 (49.0) 2.04 ( ) <0.001 CD4 + T-cell count, per 100 cells 280 ( ) d ( ) d 1.04 ( ) Plasma viral load, copies/ml 42,400 (12, ,010) d 16,000 (125 66,430) d 0.61 ( ) <0.001 Total n=381 HIV-seropositive injection drug users. a Refers to six-month period prior to the baseline interview. b n=175 (45.9%). c n=206 (54.0%). d Values are median (interquartile range). CI, confidence interval; MMT, methadone maintenance therapy; OR, odds ratio. and all secondary explanatory variables, and proceeded with an a priori manual stepwise approach to arrive at the final sets of explanatory variables for each outcome. Starting with the full model, we removed secondary explanatory variables one at a time, noting the relative change in the coefficients for the drug use variable. Variables that did not alter the relative change in these coefficients by >5% were removed in a sequential fashion. As the primary explanatory variable of interest in both models was a categorical variable with three levels, variables were considered confounders if their removal altered either of coefficients by >5%. This technique has been used successfully by several authors [33 35]. To account for the well-established effects of age and clinical values, those variables were forced into the full models and were not subjected to the stepwise procedure. All statistical analyses were performed using SAS software version 9.1 (SAS, Cary, NC, USA). All P-values were two-sided. Results In total, 381 participants were seen for follow-up between July 1996 and December 2007, including 157 (41.2%) women and 144 (37.8%) individuals who selfidentified as being of Aboriginal ancestry. The median age at baseline was 37 years. Table 1 shows sociodemographic, behavioural and clinical characteristics of study participants at the baseline interview stratified by adherence to antiretroviral therapy. The median follow-up time was 30 months with an interquartile range (IQR) of 6 78 months. Overall, the participants contributed to 2,489 observations during the follow-up period. Among the 2,489 observation points, 2,072 (83.2%) had at least one measure of plasma HIV-1 RNA viral load. Of the periods with at least one measure, the median number of observations was 2 (IQR 1 3). For all observation periods, the median number of viral load determinations was 2 (IQR 1 2). During the 6-month period before the baseline interview, 341 (89.1%) participants were on antiretroviral therapy. Of these 341 participants, 135 (39.6%) were <95% adherent to antiretroviral therapy and 210 (61.6%) had not achieved virological suppression <500 copies/ml in the 6 months prior to the baseline interview. Over the study period, 3,110 prescriptions were recorded in the dispensary database. Of the 1,761 (56.6%) prescriptions for boosted protease inhibitors, the largest proportion in the early period ( ) were for indinavir (272, 42.3%) and, in the later period ( ), lopinavir (191, 17.1%) was the most frequently prescribed protease inhibitor. Of the 656 prescriptions for non-nucleoside reverse transcriptase inhibitors (NNRTIs) over the study period, the largest proportion in the early period were for nevaripine (303, 85.1%) and, in the late period, efavirenz (161, 53.7%) was the most frequently prescribed NNRTI. Antiretroviral therapy adherence In the primary analysis, which examined factors associated with antiretroviral therapy adherence, age, being on MMT and CD4 + T-cell count per 100 cells were significantly positively associated in univariate analyses. Antiviral Therapy

4 A Krüsi et al. Female gender, homelessness and plasma HIV-1 viral load were significantly negatively associated with antiretroviral therapy adherence. In the multivariate GEE analysis shown in Table 2, factors that were independently associated with antiretroviral therapy adherence included age (per 10 years increase; adjusted odds ratio [AOR] 1.65, 95% CI ; P<0.001), being on MMT (AOR 1.52, 95% CI ; P<0.001) and if the original antiretroviral therapy regimen contained an NNRTI (AOR 1.59, 95% CI ; P=0.012). We did not observe a significant difference in the likelihood of adherence for individuals reporting any non-injection drug use (AOR 0.97, 95% CI ; P=0.872) or any injection drug use (AOR 0.88, 95% CI ; P=0.375) compared to individuals reporting abstinence from illicit drug use. The sensitivity analysis, preformed using 80% as a cutoff point for adherence, confirmed the same pattern of results. We did not observe a significant difference in the likelihood of adherence for individuals reporting any non-injection drug use (AOR 0.87, 95% CI ; P=0.410) or any injection drug use (AOR 0.78, 95% CI ; P=0.065) compared with individuals reporting abstinence from illicit drug use. HIV-1 RNA suppression In univariate analyses, age, being on MMT, CD4 + T-cell count per 100 cells and antiretroviral therapy adherence were positively and significantly associated with virological suppression among drug users. In the multivariate GEE analysis shown in Table 3, factors that were independently associated with virological suppression included age (per 10 years increase; AOR 1.47, 95% CI ; P<0.001), being on MMT (AOR 1.64, 95% CI ; P<0.001), CD4 + T-cell count per 100 cells (AOR 1.13, 95% CI ; P<0.001), and if the original antiretroviral therapy regimen contained an NNRTI (AOR 1.57, 95% CI ; P=0.019). Virological suppression was independently associated with any injection drug use in the past 6 months (AOR 0.74, 95% CI ; P=0.026) but not with non-injection drug use only (AOR 0.89, 95% CI ; P=0.477) when compared to abstinence from any illicit drug use. In an exploratory analysis, we found that individuals who engaged in injection drug use compared to individuals who engaged in non-injection drug use only had fewer measures of viral load per interval. Assuming that periods without viral load measures corresponded with unsuppressed viral loads, we conducted subanalyses to determine the robustness of our results. When we excluded all observations without viral load measures the pattern of results remained consistent: the likelihood of virological suppression was independently associated with any injection drug use in the past 6 months (AOR 0.69, 95% CI ; P=0.010) but not with non-injection drug use only (AOR 0.85, 95% Table 2. Univariate and multivariate GEE analyses of factors associated with 95% HAART adherence among drug users Characteristic OR 95% CI P-value AOR a 95% CI P-value Drug use pattern b Abstinence Non-injection 1.01 ( ) ( ) Injection 0.95 ( ) ( ) MMT, yes versus no 1.48 ( ) < ( ) <0.001 a The multivariate model was adjusted for age and initial antiretroviral therapy regimen (each variable remained P<0.05 in the multivariate model). b Refers to the 6-month period prior to the interview. AOR, adjusted odds ratio; CI, confidence interval; GEE, generalized estimating equation; HAART, highly active antiretroviral therapy; MMT, methadone maintenance therapy; OR, odds ratio. Table 3. Univariate and multivariate GEE analyses of factors associated with HIV RNA suppression among drug users Characteristic OR 95% CI P-value AOR a 95% CI P-value Drug use pattern b Abstinence Non-injection 0.91 ( ) ( ) Injection 0.82 c ( ) c ( ) MMT, yes versus no 1.62 ( ) < ( ) <0.001 CD4 + T-cell count, 1.15 ( ) < ( ) <0.001 per 100 cells a The multivariate model was adjusted for age and initial antiretroviral therapy regimen (each variable remained P<0.05 in the multivariate model). b Refers to the 6-month period prior to the interview. c Methadone maintenance therapy (MMT) is the covariate that led to the shift in the point estimate for injection drug use from 0.82 to 0.74; therefore, MMT might constitute a potential confounder. AOR, adjusted odds ratio; CI, confidence interval; GEE, generalized estimating equation; OR, odds ratio International Medical Press

5 Ongoing drug use and outcomes from HAART CI ; P=0.354) when compared to abstinence. Additionally, we conducted a subanalysis where we included all observations but adjusted for the number of viral load measures in each follow-up period, which we dichotomized by the median number of observations per period (that is, >2 versus 2). Again, the same pattern of results emerged. Virological suppression was independently associated with any injection drug use in the past 6 months (AOR 0.76, 95% CI ; P=0.043) but not with non-injection drug use only (AOR 0.81, 95% CI ; P=0.241) when compared to abstinence from any illicit drug use. However, in a further subanalysis that defined HIV-1 RNA suppression as two consecutive measures <500 copies/ml, we found that non-injection drug use (AOR 0.75, 95% CI ; P=0.034) and injection drug use (AOR 0.71, 95% CI ; P=0.003) were both associated with reduced HIV-1 RNA suppression in comparison to abstinence. We also conducted a sensitivity analysis to better understand the relationship between patterns of drug use and time to virological suppression among the 337 antiretroviral-therapy-naive individuals who initiated antiretroviral therapy during follow-up. Here, our outcome of interest was time to plasma viral load <500 copies/ml after the initiation of antiretroviral therapy. In a multivariate Cox proportional hazards model adjusted for age, gender, homelessness, initial antiretroviral therapy regimen, CD4 + T-cell count at baseline, HIV-1 RNA level at baseline and antiretroviral therapy adherence, neither measure of drug use compared to abstinence was a significant predictor of time to virological suppression (for any non-injection drug use, adjusted hazard ratio 1.10, 95% CI ; P=0.740 and for any injection drug use adjusted hazard ratio 0.70, 95% CI ; P=0.082). When we explored the distribution of the explanatory variables, Box Tidwell transformation tests showed that simple linear terms were sufficient for age and CD4 + T-cell count in all models. Discussion Consistent with previous work reporting suboptimal levels of adherence to antiretroviral therapy and reduced virological suppression among IDUs [36], in the present study we observed that during the 6 month period prior to the baseline interview, 135 (39.6%) participants were <95% adherent to antiretroviral therapy and 210 (61.6%) had not achieved virological suppression since HAART initiation. Also, consistent with previous findings [15,17,20,37,38], being engaged in MMT was independently associated with antiretroviral adherence and virological suppression. Notably, we did not observe an association between ongoing drug use and adherence among this community-recruited, long-term cohort of individuals with a history of injection drug use. However, ongoing drug use was associated with lower odds of virological suppression in most analyses. Our findings regarding the lack of a strong relationship between ongoing drug use and antiretroviral therapy adherence are inconsistent with previous work identifying active drug use as being negatively associated with antiretroviral therapy adherence [14 16,39]. This discrepancy might be explained, in part, by differences in the length of time under observation as well as by differences in the measurement of adherence across studies. To date, a limited number of studies have examined the effect of ongoing drug use longitudinally and the studies that have employed a longitudinal design have, by and large, employed self-reported measures of antiretroviral therapy adherence [15 17]. Other studies finding a negative effect of illicit drug use on adherence have predominantly used electronic medication event monitoring systems (MEMS) to assess adherence [14,39]. MEMS is a measure found to be more sensitive than self report [40] and correlated with pharmacy refill data [41,42]; however, the MEMS studies of illicit drug use and adherence almost exclusively utilized short follow-up times. In the present study, we assessed pharmacy refill adherence and drug use behaviour over a median follow-up time of 30 months and, as such, our findings contribute a better understanding of the relationship between ongoing drug use on patterns of antiretroviral therapy adherence over the long term and further highlight that cessation of drug use is not a necessary condition among community recruited IDUs to benefit from antiretroviral therapy in our setting. Our multivariate model examining rates of virological suppression revealed that active IDUs, but not active non-idus, had lower odds of virological suppression in comparison to abstinent participants. The finding that active drug users, compared to abstinent participants, have lower odds of virological suppression suggests that virological suppression among this group might be determined by factors beyond antiretroviral therapy adherence, such as food insecurity [43] and increased risks of opportunistic infections [6,44]. However, the finding that MMT remained associated with virological suppression might indicate that MMT constituted a proxy measure for adherence, reduced risk of opportunistic infections and better care for comorbidities, which are all factors that can influence viral suppression [6,44]. Importantly, in a subanalysis examining stable virological suppression, both active non-idus and active IDUs had lower odds of virological suppression in comparison with abstinent participants. This finding is consistent with previous work, which has identified ongoing drug use as negatively affecting the Antiviral Therapy

6 A Krüsi et al. stability of virological suppression among drug users taking antiretroviral therapy [12,14,16,45,46]. In light of the finding that adherence levels between ongoing and abstinent drug users were comparable, programmes that restrict the provision of antiretroviral therapy to individuals who are abstinent from drug use need to be urgently re-examined and should move toward more inclusive treatment strategies [47]. It has been consistently demonstrated that health care providers are poor judges of patients adherence [48 50] and fears regarding increased levels of antiretroviral resistance among IDUs have been unfounded [51]. Our findings further highlight that physicians should not indefinitely withhold antiretroviral therapy from patients based on continued drug use and point to the importance of providing comprehensive and accessible HIV care and support to individuals who continue to use illicit drugs [52]. This study has several limitations. Our sample was not randomly selected and, therefore, might have been comprised of individuals who, in comparison to the larger pool of treatment eligible HIV-positive individuals with a history of injection drug use, were deemed to be potentially more adherent by treating physicians [21]. As such, our sample might not be fully representative of the larger population of treatment-eligible HIV-positive individuals with a history of injection drug use in our setting. Although pharmacy-refill-measured adherence has been identified to be a valid predictor of virological suppression and mortality among HIV infected patients [11,22,24,25], it does not allow direct assessment of whether patients indeed ingested the dispensed medication as prescribed and might have resulted in an overestimation of antiretroviral therapy adherence among our sample. Furthermore, in this analysis, we did not assess the effect of different substances, such as opiates and stimulants, on antiretroviral therapy adherence and virological suppression. Future research on the longitudinal effects of opiates and stimulants would allow for important insights into potentially differential effects of these substances on antiretroviral therapy adherence and virological suppression. Additionally, because of socially desirable reporting, IDUs in our study might have underreported current drug use [53], which could have resulted in a possible underestimation of the influence of ongoing drug use on adherence and virological suppression. A final limitation is that we do not know if HIV treatment outcome affects differential over- or under-reporting of ongoing drug use. Future studies will be required to evaluate this possible explanation for our findings. In summary, in this study we did not observe a relationship between ongoing drug use and antiretroviral therapy adherence among individuals with a history of injection drug use. Ongoing drug use was nevertheless associated with lower odds of stable virological suppression compared to abstinent participants. Our findings suggest that programmes that restrict the provision of antiretroviral therapy to individuals who are abstinent from drug use should be re-examined and further point to the importance of comprehensive systems of HIV care including the provision of evidence-based addiction treatment for individuals who continue to actively use drugs. Acknowledgements The authors thank the study participants for their contribution to the research, as well as current and past researchers and staff. We would specifically like to thank Deborah Graham, Tricia Collingham, Caitlin Johnston, Steve Kain, Benita Yip and Calvin Lai for their research and administrative assistance. The study was supported by the US National Institutes of Health (R01DA021525) and the Canadian Institutes of Health Research (MOP and RAA-79918). TK is supported by the Michael Smith Foundation for Health Research and the Canadian Institutes of Health Research. Disclosure statement RH has received honorariums, travel grants to attend conferences and research grants from pharmaceutical companies working in the field of HIV and AIDS. JM has received grants from, served as an ad hoc advisor to, or spoke at various events sponsored by Abbott Laboratories, Argos Therapeutics, Bioject, Inc., Boehringer Ingelheim, Bristol Myers Squibb, Gilead Sciences, GlaxoSmithKline, F Hoffmann La Roche, Janssen- Ortho, Merck Frosst, Panacos, Pfizer, Schering Plough, Serono, Inc., TheraTechnologies, Tibotec (Johnson & Johnson) and Trimeris. All other authors declare no competing interests. References 1. Hammer SM, Squires KE, Hughes MD, et al. 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