An explosive outbreak of HIV infection among injecting drug users (IDU) during the mid-1990s, has brought international attention to the city of Vancouver [1–3]. The situation has been particularly perplexing due to the presence of legal needle-exchange programs (NEP), access to methadone maintenance treatment, and a range of social programs . Although compelling evidence supports the role of these initiatives in reducing HIV transmission, debate around the efficacy of NEP has been fueled by Vancouver's HIV epidemic [5–9].
The choice of drugs and the patterns in which they are used may help explain the wide variability in HIV incidence and prevalence reported among different drug using populations [10–12]. HIV research and prevention efforts among IDU have focused primarily on communities with a predominance of heroin injectors [13–15]. Injecting cocaine use has been associated with a higher risk of HIV infection among participants attending a methadone clinic in Italy  and poly-drug users in San Francisco . The inhalation of crack cocaine has also been identified as a drug that contributes to enhanced sexual transmission of HIV among drug using groups [18,19]. In Vancouver, however, the use of multiple injected and non-injected drugs is prevalent, with cocaine being the predominant injection drug used in the community.
This study was designed to identify factors associated with HIV infection in this community and to determine how patterns of drug use influence risk of HIV infection over time. In addition, we evaluated if a dose-dependent relationship exists with regards to HIV seroconversion and the frequency of injecting cocaine and heroin.
Materials and methods
Study population and data collection
The Vancouver Injection Drug Users Study (VIDUS) is a prospective open cohort that commenced enrollment in May 1996. Recruitment is conducted through posters in the community, referrals from community organizations and word-of-mouth from other participants. For study entry, individuals must have injected drugs within the past month and be at least 14 years old. All subjects provide written informed consent. The St. Paul's Hospital Ethics Committee for Human Experimentation approved this study.
At enrollment, and at 6-monthly follow-up visits, a trained interviewer administers a detailed semi- structured questionnaire. Revised questionnaires are introduced in June and December each year. Information regarding demographics, patterns of injecting and non-injecting drug use, needle exchange utilization, the sharing of syringes, health care access, sexual practices, and participation in drug treatment programs are collected. Pre- and post-test HIV counseling is conducted and blood is drawn for HIV and Hepatitis C virus testing at each visit, if the tests remain negative. HIV tests that are reactive by enzyme-linked immunosorbent assay are confirmed by Western blot. Participants receive an honorarium of CDN $20 for each visit and those requesting medical or social support services are referred to the appropriate clinic or agency.
We identified 109 HIV seroconversions among VIDUS participants during a 4-year follow-up period. All seroconverters had a documented negative HIV test at the time of enrollment and a subsequent positive HIV test during a follow-up visit. The information recorded at the last available follow-up questionnaire prior to seroconversion (i.e., the last visit with an HIV-negative sample) was used for the analysis. The effect of social variables (housing, incarceration, payment for sex, current sex partners) and drug use variables (cocaine use, heroin use, methadone treatment, borrowing needles) on HIV seroconversion were analyzed by the Kaplan–Meier method. Statistical significance was determined by the log-rank test. Cox proportional-hazards models were used for the multivariate analysis. Variables that were entered into the model included those that met statistical significance at the 0.05 level in the bivariate analysis along with characteristics that were considered to be important based on prior knowledge.
A Kaplan–Meier analysis of the time to HIV seroconversion was performed according to drug use frequency as a dichotomous variable. Frequent users were defined as those who used a given drug once per week or more. Infrequent users were defined as all others, including those that did not report using the drug. Heroin and cocaine responses thus yielded four groups based on the frequency of each drug used at enrollment. The four groups were frequent cocaine/frequent heroin, frequent cocaine/infrequent heroin, infrequent cocaine/frequent heroin, and infrequent cocaine/infrequent heroin.
The intensity of drug use for each drug (heroin and cocaine) was further stratified into four mutually exclusive categories based on the average number of injections reported during the 6 months prior to HIV seroconversion. The baseline group consisted of those who injected less often than once per month. Level one included those who injected at least once per month but not more than once per week, level two included those who injected at least twice per week but not more than three times per day, and level three included those who injected at least four times per day. A similar analysis was performed for both cocaine and heroin using Cox proportional hazards models to determine the hazards ratio for each level of drug use.
The total number of participants enrolled in the VIDUS cohort at the time of this analysis was 1434. Of these, 308 (22%) were HIV seropositive at the time of enrollment and were not considered in the analysis. There were an additional 186 (17%) who did not return for any follow-up visits and could not be assessed for HIV seroconversion. Among these 186 participants, frequent (more than weekly) injection cocaine use was reported by 67 (36%) compared with 395 (42%) who returned for follow-up (P = 0.13).
The 940 HIV negative participants included in the analysis had a mean length of follow-up of 31.3 months. The demographic and behavioral characteristics at enrollment stratified by HIV seroconversion are shown in Table 1. In this bivariate analysis, HIV seroconversion was more likely to occur among cocaine injectors [odds ratio (OR), 2.56; 95% confidence interval (CI), 1.69–3.86], Aboriginal participants (OR, 2.20; 95% CI, 1.46–3.31), and those with unstable housing (OR, 1.63; 95% CI, 1.07–2.49).
Table 2 shows an analysis of risk factors in the 6 months prior to HIV seroconversion. In the bivariate analysis, factors positively associated with HIV seroconversion included: injecting cocaine at least weekly, borrowing used needles, incarceration, unstable housing (i.e., hotels, hostels, and no fixed address), methadone maintenance treatment, more than 20 lifetime sex partners, and receiving payment for sex. In the multivariate analysis injecting cocaine remained the strongest predictor of HIV seroconversion [adjusted hazards ratio (AHR), 3.72; 95% CI, 2.44–5.67]. Incarceration (AHR, 2.74; 95% CI, 1.81–4.15), unstable housing (AHR, 2.36; 95% CI, 1.57–3.54), methadone maintenance treatment (MMT; AHR, 1.98; 95% CI, 1.05–3.73) and Aboriginal ethnicity (AHR, 1.78; 95% CI, 1.19–2.69), also remained significantly associated with HIV seroconversion in the multivariate model adjusted for the other demographic and drug use variables. The weekly use of crack cocaine was inversely associated with HIV seroincidence (AHR, 0.47; 95% CI, 0.30–0.75). Frequent heroin use was not associated with HIV seroconversion.
The risk of HIV seroconversion was directly associated with the intensity of injection cocaine use as shown in Fig. 1a. In these dose–response associations, the intensity of drug use was adjusted for age, sex, ethnicity, needle borrowing, incarceration, unstable housing, methadone maintenance therapy, lifetime sex partners and receiving payment for sex. Compared to those who injected cocaine less often than once per month, HIV seroconversion was significantly higher in those who injected once per month to once per week [hazards ratio (HR), 2.12; 95% CI, 0.99–4.65], higher still in those who injected more often than once per week to three times per day (HR, 3.25; 95% CI, 1.62–6.57), and highest for those who injected more often than three times per day (HR, 7.56; 95% CI, 3.75–15.27). The test for trend was highly significant (P < 0.001). A similar analysis for injection heroin was conducted and there was no association with injection intensity and HIV seroconversion (Fig. 1b).
The time to HIV seroconversion among the four combinations of heroin and cocaine use are shown in Fig. 2. Those who reported frequent cocaine injections at baseline had a significantly higher rate of HIV seroconversion when compared to infrequent cocaine injectors. On the other hand, heroin had no independent effect. Cumulative HIV infections approached 25% among the frequent cocaine users irrespective of heroin use.
Among IDU, the choice of drug and the patterns of drug use are extremely variable. This has important implications for the risk of HIV and Hepatitis C virus infections and the delivery of harm reducing interventions. In this study, among a poly-drug using population, frequent injecting cocaine use in the preceding 6 months was the strongest predictor of HIV seroconversion in a multivariable analysis. Further, the rate of HIV infection was directly related to the intensity of injection cocaine use in a dose-dependent fashion, whereas no such relationship was found with heroin. Finally, the rate of HIV seroconversion was associated with injection cocaine use at study enrollment, with 25% of frequent cocaine injectors becoming HIV positive over a mean follow-up of 31 months, irrespective of heroin use.
For many IDU cocaine use is characterized by bursts of high intensity use or ‘drug runs’ that profoundly influence risk . Although we did not measure drug ‘binges’ directly it can be hypothesized that in the midst of multiple consecutive cocaine injections, the consistent use of clean needles is compromised. This is due to several factors. First, the psychological and physical condition of the individual during a cocaine ‘binge’ is significantly impaired due to the compulsion to obtain more drug and due to long periods of inadequate sleep and nutrition . Second, there are the practical considerations of planning, obtaining and transporting sufficient sterile syringes to carry one through such a binge . Participants reporting multiple injections of cocaine over short periods of time are common, in contrast to those individuals who consistently use heroin and generally require two to four daily injections to avoid withdrawal symptoms. The consistent daily use of heroin lends itself far more than cocaine to regular injection practices, including a more predictable source of drugs and a more orderly preparation of injection paraphernalia. These observations may help to explain the very strong dose-response for HIV seroconversion among cocaine users and the lack of this association for heroin users. We have recently found that difficulty accessing sterile syringes is the primary risk factor for syringe sharing in Vancouver , and this observation, combined with the role of cocaine injection identified in the present study, may help to explain why an HIV epidemic has been observed in Vancouver despite the NEP.
Incarceration within the last 6 months was associated with HIV seroconversion. Preventing the transmission of HIV among the prison population is a major public health challenge. Although it is not possible from this analysis to determine whether any of the HIV infections actually occurred while in jail, this is potentially a very high-risk situation. Recent studies have shown that drug injection occurs while in prison and that prevention messages and harm reduction services are inadequate [24,25]. Further, the drug using activities immediately following release from incarceration may be chaotic with increased risk of HIV infection due to uncertain drug supply and reduced access to clean syringes.
The use of crack cocaine in the previous 6 months was inversely related to HIV seroconversion. This may be explained by the substitution of inhalation crack cocaine by some IDU who wish to avoid needles. The fact that the parenteral transmission of HIV is eliminated with crack cocaine may explain this observation. However, in some populations there is compelling evidence that sexual transmission of HIV is elevated among crack cocaine users [19,26]. We have recently shown that sexual risk taking is high among the Vancouver cohort and the impact of crack cocaine on HIV transmission requires further study .
In this study MMT was associated with HIV seroconversion. As the data collection focused on the events in the preceding 6 months, it is possible that some of the participants were started on MMT after receiving their positive HIV test result from another source. This would show up in the analysis of having been on MMT during the follow-up visit when HIV incidence was observed. Some individuals may also have been started on MMT when they reported accelerated drug use and were considered to be a particularly high risk for HIV infection. It is also possible that some individuals taking MMT may indeed be at higher risk of HIV infection due to increased injection cocaine use. Although overall injecting drug use may be reduced when MMT is initiated, there are reports of increased cocaine use [17,28].
The pattern of drug use at the time of enrollment was predictive of subsequent HIV seroconversion. We observed that among HIV negative participants who were frequently using cocaine at study enrollment, the subsequent risk of seroconversion approached 25%. The cut-offs used for ‘frequent’ cocaine use was quite conservative and probably under-estimated the risk for the most intensive cocaine users.
This study has a number of limitations that are inherent to large observational cohort studies. The recruitment of the cohort was not performed randomly, and therefore it may not be possible to generalize our findings to the larger drug using community. Although the follow-up rate was 83%, the loss to follow-up may have introduced bias into the results. The use of cocaine (more than once per week), however, between those who returned for follow-up and those participants who did not was similar. In addition, the presence of unmeasured confounding in observational studies may influence the strength of associations found with HIV seroconversion. However, a range of pre-determined demographic and behavioral variables were chosen to minimize potential confounding. The actual timing of the seroconversion event was estimated based on the mid-point between the last negative and first positive HIV test. This may have influenced some of the associations as the measured behavior may have actually come after the seroconversion event. The study of illicit drug use and behaviors is problematic due to socially desirable responses, especially as the study progresses and the participants become known to the staff. Although there is some published evidence to suggest that drug users do provide reliable and valid responses in other studies, it is likely that risk would be under-reported if a bias existed [29,30].
Interventions currently available for cocaine dependency are woefully inadequate. The development of both pharmacologic and behavioral interventions must be a high priority. The promotion of MMT as the major intervention strategy for injecting drug use may not be appropriate for the most vulnerable drug using individuals. Success in reducing the incidence of HIV infection among injecting drug users will only be realized by providing relevant interventions in a timely fashion. The catastrophic outbreak of HIV infection in Vancouver during the mid-1990s cannot be attributed to any single event or environmental factor. However, cocaine use in this population has clearly had a major influence on HIV transmission and has contributed in a large part to the epidemic. The upper two curves of Fig. 2 depict the likely incidence experience in the absence of significant cocaine injection. Although injection cocaine use is not unique to this community, access to a relatively inexpensive drug, a highly concentrated number of cocaine users, and the lack of a comprehensive prevention response, have contributed to an excessive number of new HIV infections. Lessons learned from this experience have implications for other communities in North America and internationally where cocaine use is on the increase [31,32].
Sponsorship: Supported by the British Columbia Ministry of Health, Health Canada (National AIDS Research Scientist award to M.T.S.) and the National Institutes of Health Grant ROI DA11591-01.
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