The benefits of antiretroviral therapy (ART) for the management of HIV disease have been well established, with substantial improvements in HIV-related morbidity and mortality having been documented among individuals receiving antiretroviral agents [1,2]. As such, in many areas of the world, HIV infection is increasingly being viewed as a chronic and manageable illness . Despite these advances, there is growing evidence that a high proportion of the ongoing AIDS mortality in the developed world is the result of poor access to therapy among disadvantaged or marginalized populations, such as illicit injection drug users (IDU), and strategies to improve the uptake of ART are in urgent need of investigation [4–6].
Previous studies have demonstrated that methadone maintenance therapy (MMT) for the treatment of opiate addiction has been consistently associated with improved adherence to ART among IDU [7–9]. However, to our knowledge, the impact of accessing MMT on the subsequent uptake of ART has not been well demonstrated in settings in which MMT and HIV/AIDS care are available free of charge. We therefore conducted the present study to examine whether accessing MMT was associated with subsequently initiating ART among antiretroviral-naive IDU.
The Barriers to Antiretroviral Therapy (BART) cohort is a prospective study of HIV-infected IDU who have been recruited through self-referral and street outreach from Vancouver's downtown eastside since May 1996, and has been described in detail previously . Briefly, at baseline participants provide a venous blood sample and complete an interviewer-administered questionnaire. Follow-up interviews are conducted semi-annually thereafter, and participants are provided a nominal stipend at each study visit. Ethical approval has been provided annually by the University of British Columbia's Research Ethics Board. The BART cohort is somewhat unique because it does not rely on the self-reported use of ART because endpoints related to the use of ART can be accurately ascertained through a confidential record linkage with the province's centralized HIV/AIDS monitoring and treatment registry, which includes all patients receiving ART in the province [4,10].
The primary endpoint of interest in the present analysis was the time to the first use of antiretroviral agents. To be eligible for the present study, participants had to be HIV infected at the time of the baseline visit and to have never been on ART at the time of the baseline visit. In order to ascertain the impact of receiving methadone on the uptake of ART, we stratified patients into those who reported being on methadone at baseline. The time to the initiation of ART among those participants who were on methadone or not at baseline was examined using Kaplan–Meier analyses.
In addition, Cox regression was used to model the time to the first use of antiretroviral agents. We considered age, sex, ethnic background (white versus other), use of MMT, daily heroin injection, and daily cocaine injection as potential explanatory variables of the time to the first use of antiretroviral agents. Variable definitions were consistent with previous analyses [4,10], and behavioral variables, including the use of MMT, were treated as time updated covariates. As previously, we also adjusted for the time to the receipt of the study HIV test results, which is encouraged by study staff, but optional to study participants to comply with ethical requirements . The multivariate model was fit using an a priori defined model-building approach in which we adjusted for all variables that were statistically significant at the P < 0.05 level in the bivariate analyses, as well as the use of heroin in the preceding 6 months because we were aware that recent use of heroin would be required to be eligible for methadone. All statistical analyses were performed using SPSS 12.0. All P-values are two sided.
Between May 1996 and May 2003, 312 HIV-infected individuals were enrolled into the BART cohort, of whom 234 (75.0%) had never been on ART at baseline and were therefore eligible for the present study. Overall, 147 individuals (62.8%) initiated ART before the end of the study period. Statistical comparisons of these groups demonstrated that age (P = 0.545), sex (P = 0.848), ethnic background (P = 0.595), daily cocaine injection (P = 0.318), and daily heroin injection (P = 0.907) were not significantly different between those who were and those who were not on MMT at baseline.
The Kaplan–Meier analysis of the time to the first use of antiretroviral agents stratified by whether participants were on MMT at baseline is shown in Fig. 1. As shown here, at 24 months after enrolment into the cohort, the rate of ART use was 69.7% among those on MMT at baseline and was 44.4% among those not on MMT at baseline (log-rank P = 0.001).
In a Cox model that adjusted for the time to receiving HIV test results (P = 0.025), and the use of heroin in the previous 6 months (P = 0.344), being currently on methadone was associated with a significantly elevated rate of initiating antiretroviral agent use (relative hazard 2.10; 95% confidence interval 1.28–3.46; P = 0.003).
In the present study, we examined a cohort of antiretroviral-naive HIV-infected IDU, and observed that the use of methadone both at baseline and when considered as a time-updated covariate, was associated with initiating ART at a significantly elevated rate. Whereas the use of MMT has been demonstrated to improve adherence to and retention on an ART regimen in previous studies [7–9], the present study indicates that MMT may also be effective at improving the uptake of ART among IDU.
The use of MMT among opiate addicts has been shown to improve health and social functioning by reducing withdrawal symptoms to illicit opiates [7,11,12]. Our findings are probably explained by the fact that those receiving MMT were more likely to achieve the level of social stabilization that may be required to access ART. Although the present study has limitations that are inherent in all observational studies, it is noteworthy that it would be unethical to assign drug users randomly to the receipt or non-receipt of MMT, and we should note that the two groups were statistically similar in terms of sociodemographic and drug use characteristics.
In sum, the receipt of MMT was associated with elevated rates of ART uptake among antiretroviral-naive HIV-infected IDU. These data demonstrate that ongoing HIV/AIDS mortality rates that are attributable to a low uptake of antiretroviral agents among IDU may be amenable to improvement through the provision of MMT to HIV-infected opiate IDU .
The authors would particularly like to thank the VIDUS participants for their willingness to participate in the study. They also thank Drs Kevin Craib, Richard Harrigan, and Cari Miller, for their research assistance, and Bonnie Devlin, John Charette, Caitlin Johnston, Vanessa Volkommer, Steve Kain, Nancy Laliberte, Jennifer Adachi, Kathy Churchill, Sue Currie, Cody Callon, and Peter Vann for their administrative assistance.
Sponsorship: The study was further supported by the US National Institutes of Health (R01 DA011591-04A1) and CIHR grant (MOP-67262).
1. Hammer SM, Katzenstein DA, Hughes MD, Gundacker H, Schooley RT, Haubrich RH, et al
. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimetre. AIDS Clinical Trials Group Study 175 Study Team. N Engl J Med 1996; 335:1081–1090.
2. Hogg RS, Yip B, Chan KJ, Wood E, Craib KJ, O'Shaughnessy MV, Montaner JS. Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug therapy. JAMA 2001; 286:2568–2577.
3. Ledergerber B, Egger M, Opravil M, Telenti A, Hirschel B, Battegay M, et al
. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study. Lancet 1999; 353:863–868.
4. Wood E, Hogg RS, Bonner S, Kerr T, Li K, Palepu A, et al
. Staging for antiretroviral therapy among HIV-infected drug users. JAMA 2004; 292:1175–1177.
5. Wood E, Montaner JS, Bangsberg DR, Tyndall MW, Strathdee SA, O'Shaughnessy MV, Hogg RS. Extending access to HIV antiretrviral therapy to marginalized populations in the developed world. AIDS 2003; 17:2419–2427.
6. Wood E, Montaner JS, Schechter MT, Tyndall MW, O'Shaughnessy MV, Hogg RS. Prevalence and correlates of untreated HIV-1 infection in the era of modern antiretroviral therapy. J Infect Dis 2003; 188:1164–1170.
7. Kerr T, Wodak A, Elliot R, Montaner JS, Wood E. Opiod substitution therapy and HIV/AIDS treatment and prevention. Lancet 2004; 364:1918–1919.
8. Sambamoorthi U, Warner LA, Crystal S, Walkup J. Drug abuse, methadone treatment, and health services use among injection drug users with AIDS. Drug Alcohol Depend 2000; 60:77–89.
9. Yeni PG, Hammer SM, Hirsch MS, Saag MS, Schechter M, Carpenter CC, et al
. Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society – USA Panel. JAMA 2004; 292:251–265.
10. Strathdee SA, Palepu A, Cornelisse PG, Yip B, O'Shaughnessy MV, Montaner JS, et al
. Barriers to use of free antiretroviral therapy in injection drug users. JAMA 1998; 280:547–549.
11. Stein MD, Urdaneta ME, Clarke J, Maksad J, Sobota M, Hanna L, Markson LE. Use of antiretroviral therapies by HIV-infected persons receiving methadone maintenance. J Addict Dis 2000; 19:85–94.
12. Sorensen JL, Mascovich A, Wall TL, DePhilippis D, Batki SL, Chesney M. Medication adherence strategies for drug abusers with HIV/AIDS. AIDS Care 1998; 10:297–312.