Milloy, Michael-John S.a,b; Marshall, Brandon D.L.b,c; Kerr, Thomasb,d; Buxton, Janea,e; Rhodes, Timf; Montaner, Juliob,d; Wood, Evanb,d
HAART has resulted in steep declines in HIV-related morbidity and mortality . With appropriate levels of adherence to prescribed therapies, engagement in HAART has been shown to reliably suppress plasma HIV-RNA, delay disease progression and dramatically improve survival [2,3].
Unfortunately, the full clinical benefits of HAART have not been seen among all HIV-seropositive groups. Uptake of HAART is lower among individuals who use drugs [4,5]; compared with individuals in other risk categories, they exhibit higher rates of suboptimal treatment outcomes [1,6,7]. For example, in a multicenter study of individuals beginning HAART, IDUs experienced mortality rates approximately five times higher than individuals infected through sexual contact . A large multicenter study including over 7500 seroconverters from Europe, Australia and Canada found worsening disparities in progression rates between illicit drug users and members of other exposure groups in the HAART era, suggesting inferior treatment uptake and adherence patterns . As IDU can benefit from HAART at similar rates as non-IDU given adequate compliance to therapeutic regimens , investigations of suboptimal outcomes have largely focused on individual-level barriers and facilitators of HAART access and adherence [11–14], including psychological comorbidities and drug use patterns. Although proximate (i.e. behavioral and drug-related) patterns of exposure to HAART have been shown to be strongly associated with HIV disease outcomes , the relationships between external exposures and disease progression among drug users are unclear.
In recent years, efforts to model and address the negative sequelae of illicit drug use, including accidental overdose death, soft tissue damage and infection with blood-borne pathogens, have expanded beyond proximate causes to include contextual determinants [15–17]. Specifically, the risk environment conceptual framework describes how the interactions between social, political, economic and physical determinants at the macro-environment and micro-environmental levels facilitate or constrain individual behaviors and structure the risk of drug-related harms [15,16]. In line with previous works [15,16], we have chosen to define social-level and structural-level exposures as those external to individuals that interact with individual-level characteristics and behaviors to determine HIV-related vulnerabilities. Although high-profile reviews have recently applied the risk environment framework to HIV transmission patterns , we are unaware of the framework being applied to an examination of factors associated with HIV disease progression. In light of this, and recent high-profile calls for analyses of HIV treatment outcomes among drug users that include broader social-level and structural-level exposures [11,18], we sought to conduct a systematic review explicitly informed by the risk environment framework of the scientific literature on HIV disease progression among illicit drug users.
We used an a priori-defined search strategy based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . We searched the EBM, EMBASE, MEDLINE, PubMed and Science Citation Index electronic databases to identify relevant studies published in peer-reviewed journals between 1 January 1996 and 1 November 2010. Articles were selected for further review if they had at least one match in each of three sets of keywords or search terms: illicit drug use (i.e. ‘heroin’, ‘crack’, ‘amphetamines’, ‘cocaine’, ‘injection drug user’, ‘illicit drug user’); disease progression (i.e. ‘viral suppression’, ‘viral load’, ‘CD4’, ‘death’); and HIV/AIDS. When possible, filters were used to exclude case reports, case series, reviews and other noneligible study types. Only studies among humans were included. We also reviewed the citation lists of included studies for eligible studies.
Inclusion and exclusion criteria
Studies were included if they were conducted among HIV-seropositive individuals who were current or former illicit drug users or contained eligible analyses among strata of current or former drug users. Eligible study endpoints were change or difference in CD4 cell count or percentage; change or difference in plasma HIV-1 RNA viral load (PVL); incidence or prevalence of AIDS, as defined by the US Centers for Disease Control and Prevention diagnostic guidelines; and death, including all-cause, pre-AIDS, HIV-related and infectious disease-related mortality. To be included, studies had to include analyses of factors associated with these outcomes of interest, with significance assessed through appropriate statistical tests or the estimation of effect measures and confidence intervals. Studies were ineligible if they were written in a language other than English or were not published in a peer-reviewed journal.
One author (M.-J.S.M.) conducted the database search and entered study abstracts matching the keywords and criteria into a search database. After removing duplicates, studies clearly not meeting the criteria were excluded from further review. Full-text versions of all remaining potentially eligible articles were retrieved and independently reviewed by two authors (M.-J.S.M. and B.D.M.). Each author marked each remaining study ‘included’ or ‘excluded’; any discrepancies were discussed by the authors until a consensus was reached.
Four thousand one hundred and twenty-two records matched all search criteria and were retrieved from electronic databases; 10 articles were identified following manual searching of reference lists. Following removal of duplicate records, 2668 studies remained eligible for review. After screening citation data and abstracts, the full-text version of 182 reports (6.8%) were assessed by both M.-J.S.M. and B.D.M. Of these, 56 (2.1%) are included in this report [20–77]. Figure 1 presents the results of the acquisition, screening and selection process.
Table 1[20–77] presents details of the included studies stratified by endpoint, setting and sample type. Of the 56 articles, 16 (29%) included an analysis of factors associated with time to AIDS diagnosis among HIV-seropositive drug users. Death was an outcome of interest in 23 (41%) studies. Changes or differences in CD4 cell count was an endpoint in 16 (29%) studies. In 15 (27%) studies, changes or differences in PVL were an endpoint. All but one study (in Thailand ) was conducted among HIV-seropositive drug users in western settings. The plurality (27, 48%) occurred in the United States or Canada; 21 (38%) in western Europe countries; and seven (13.8%) in multinational settings. The mean study sample size was 363 individuals [interquartile range (IQR): 125–524] and the median follow-up time was 44 months (IQR: 30–61). Twenty-one studies (38%), all from North America, recruited participants from community settings; of the remainder, 14 (25%) recruited individuals from hospital settings; 12 (21%) from drug treatment settings; two (4%) used population-based data; and seven (13%) employed analytic samples constituted using multiple recruitment strategies. Table 2 presents details of each included study.
Progression to AIDS
Table 2-b Summary of...Image Tools
Table 2-c Summary of...Image Tools
Table 2-d Summary of...Image Tools
The associations identified in this review, stratified by clinical endpoint and the risk environment framework, are presented in Table 3[20–77]. Sixteen studies compared rates of disease progression among IDUs by modeling the time to a diagnosis of AIDS. In the period preceding the widespread availability of HAART among drug-using populations, several studies [39,57,62,63,67] used samples of individuals with well estimated HIV seroconversion dates to assess factors possibly associated with the natural history of HIV infection. Studies confirmed the well established prognostic value of host immunologic [32,36,49,63,73–75] and virologic characteristics [32,73] observed in other risk categories. In the pre-HAART era, no study found strong evidence of an effect of illicit drug use on clinical progression [58,75]. For example, in a multicenter study of IDUs in Italy and the United States , participants in Baltimore, Maryland, who were mostly polydrug injectors, and participants in Italy, who were mostly cocaine injectors, did not exhibit different rates of AIDS, as might be expected if drug use accelerated disease progression. In addition, neither age at first injection nor length of injection career was associated with time to AIDS in a pooled analysis of all participants . Although no study could be found assessing the direct effect of access and adherence to HAART on time to AIDS among IDUs, studies using calendar time as a proxy measure of the general availability of HAART provide weak evidence of the benefit of HAART on progression to AIDS [57,69–71].
Survival of HIV-seropositive IDU was investigated in 23 studies, in which 11 (20%) [20,22,26,27,37,48,53,57,67,68,70] modeled all-cause mortality, six (11%) [24,34,39,59,62,72] modeled HIV-related or AIDS-related mortality, two (4%) [58,73] modeled infectious disease-related mortality and three (5%) [63,64,71] modeled time to pre-AIDS mortality. Unsurprisingly, both HIV-related and all-cause mortality rates were high in studies of untreated IDU populations, approximating 50 per 1000 person-years [24,27,42,53,59,62,63,72,73]. Studies among HAART-naive samples [20,24,26,27,37,39,53,58,59,62–64,67,68,73] found little evidence of unique clinical or biological correlates of survival among IDUs. As with analyses of time to AIDS, studies of the relationship between patterns of illicit drug use and HIV-related death were contradictory. In two studies of community-recruited IDUs in Baltimore [34,72], cocaine use was associated with lower rates of death; drug use was not associated with survival in other analyses [42,53]. More recently, studies conducted in the wake of HAART uptake among IDUs [34,42,52,57,70–72] have confirmed its beneficial impact on survival. Although based on self-reported data on exposure to medication, individuals treated with HAART had sharply reduced relative hazards of death compared with antiretroviral-naive participants in a study of 665 community-recruited IDUs followed from 1988 to 2002 . In contrast to the well described relationships between endogenous factors and survival, few associations with social-level or structural-level factors were observed. In an early study of the relationship between HIV treatment and opioid substitution therapy, engagement in methadone maintenance therapy at baseline was predictive of survival among IDUs in Germany . Lack of legal income at baseline was the strongest predictor of shortened survival in a small study among Parisian IDUs after adjustment for age, CD4 cell count, p24 antigenemia, age and baseline drug use .
Immunologic status as measured by changes or differences in counts of circulating CD4 cells was a focus of 16 studies. Only weak evidence was found for a relationship between illicit drug use patterns and immunologic progression [43,45,47,61,65]. Only one study identified an association between immunosuppression and social-level or structural-level factors . In the study by Mehta et al. of HAART initiators in Baltimore, individuals reporting recent incarceration had significantly lower adjusted odds of CD4 cell count improvements.
Differences or changes in PVL were assessed in fifteen studies. In studies of drug-using individuals on HAART [21,31,41,55,66], drug use was not a major predictor of elevated viral loads or treatment failure in four of five studies [31,41,55,66]. Conversely, access to substitution therapy was strongly associated with optimal virologic response in studies of community-recruited drug users in France  and Canada . Five studies [29,44,47,50,76] observed virologic trajectories following the initiation of HAART. Notably, in three [44,47,50] of four studies assessing them [44,47,50,76], drug use patterns were not associated with lower relative hazards of suppression. A number of social and structural factors emerged as determinants of PVL [40,41,44,56,66]. Two studies by Knowlton et al.[40,41] identified microsocial factors, such as social support and the quality of communication with medical caregivers, as positively associated with PVL suppression. In Vancouver, Canada, Palepu et al. found that being incarcerated in the 6 months prior to follow-up was a barrier to virologic suppression among drug users in a setting of universal access to HIV care. Similarly, in a multicenter study in the United States , individuals reporting stable housing environments had over three times higher odds of suppression after adjustment for a range of individuals and interpersonal factors.
Consistent with existing critiques of the scientific literature on HIV among drug users [11,18], the major finding of this review is that few studies of disease progression among illicit drug users included measures of exposures at the social and structural levels. Although a strong majority of these studies confirmed endogenous host and viral characteristics associated with the natural history of HIV infection as well as treatment outcomes, only a minority of studies identified associations between physical, social, political or economic factors and disease progression. In this group, the studies by Knowlton et al.[40,41] are a notable example. In their study of individual-level, social-level and structural-level exposures on the likelihood of viral suppression among drug users on HAART , high social support, good communication with healthcare providers and stable housing were independent predictors of suppression. In two studies, incarceration was associated with poorer immunologic  and virologic  response following HAART initiation. This result stands in contrast to many prison-based trials of antiretroviral therapy (ART) delivery, which has produced high levels of adherence to treatment [78,79]. However, the inferior responses to ART identified in this review likely stem from treatment interruptions caused by movement between correctional and community environments [80,81].
Notably, many of the social and structural risk factors for disease progression in this review – specifically incarceration [47,56], poor housing status  and lack of legal income  – have been identified as important determinants of vulnerability to HIV infection in past descriptions of the risk environment framework [16,17]. Thus, future analyses of HIV treatment outcomes might consider using this conceptual framework to model the disease progression process in drug users. More specifically, the evidence gathered in this review suggests that broader social and structural forces produce HIV disease outcomes through the mechanisms of access and adherence to ART and related evidence-based treatments for individuals who use illicit drugs. Thus, future research could be informed by the risk environment framework to investigate the setting-specific social and structural determinants of treatment access and adherence.
This review found only weak evidence of a direct relationship between illicit drug use and disease progression. It is noteworthy that all studies reporting this association among groups of ART-treated participants did not include robust measures of patient adherence. Our finding stands in sharp contrast to numerous laboratory studies that have found important associations between illicit drugs and relevant virologic or immunologic functioning [82–86]. For example, exposure to morphine has been shown to upregulate HIV replication in vitro; cocaine use has been shown to impair immunologic performance in both murine and human models [84,85]. However, these molecular-level effects were not clearly reproduced in studies of untreated humans in this review. In groups of drug users surveyed before the widespread use of HAART, illicit drug use was associated with disease progression in some [28,43,75] but not other [27,43,45,58] studies. In addition, it is possible that the effect of illicit drug use is overestimated if confounding by factors common to both drug use and HAART adherence is not considered. For example, although Weber et al. estimated that crack cocaine users had a faster time to AIDS diagnosis, their multivariate model did not include information on exposures likely to be associated with crack cocaine use and HIV-related morbidity, such as poorer access to healthcare, unstable housing or nutritional deficiencies. Among HAART-treated groups of drug users, the effect of illicit drugs on disease progression is thought to be mediated through lower levels of adherence to therapy. Although many studies are limited by poor or incomparable measures of drug use , stronger support for this hypothesis was found in this review [21,24,55,76]. For example, frequent heroin use was univariately associated with lower odds of viral suppression in the study by Palepu et al. in 2006 of HIV-seropositive drug users in Vancouver; in a multivariate model including ART adherence, this association was not statistically significant, suggesting a mediating relationship. Nevertheless, it should be remembered that these studies largely fail to include any measurement of social or structural factors that might account for some of the effect of illicit drug use on nonadherence, such as higher levels of incarceration, poor housing status and physical and psychological comorbidities. Among these studies, only Baum et al. reported an independent effect for crack cocaine use on both CD4 cell decline and PVL after accounting for exposure to ART. In their short-term longitudinal study of 222 active illicit drug users in Miami, Florida, ongoing crack cocaine use was marginally associated with a faster rate of progression to CD4 cell count less than 200 cells/μl in a multivariate model including baseline CD4+ cell count and HAART exposure but no measure of social or structural vulnerability . However, it is unlikely their self-reported measure of HAART use adequately captured exposure to treatment as it did not predict PVL suppression in a univariate analysis. Also of note is a recent analysis using data from a long-running community-recruited cohort of HIV-seropositive IDUs that failed to find a relationship between patterns of ongoing illicit drug use and viral suppression following HAART initiation .
The two main findings of this review – the strong focus, to date, on individual-level factors and the moderate and likely mediated associations between patterns of illicit drug use and disease progression – should be considered in light of the urgent need for interventions to improve HIV treatment outcomes among drug users. Although the medical management of HIV-seropositive drug users in the clinical setting can be complex , clinical trials have proven directly administered ART twinned with opioid substitution therapy is effective at improving treatment outcomes [88–93]. This review suggests that the emerging evidence of relationships between exogenous factors and disease progression might provide useful new targets for clinical and community-based interventions, for example, among drug users at risk of incarceration or homelessness, to support required levels of adherence among marginalized, drug-using individuals.
Limitations common to many of these studies should be mentioned in order to contextualize the findings. Most notably, although the most recent estimates suggest that close to 100 countries in the Americas, Europe, Africa and Asia are home to HIV-seropositive illicit drug users , these studies only drew from seropositive groups in a small minority of countries in western Europe, the United States and Canada. Notably, the only study including non-western HIV-seropositive illicit drug users identified a novel host genotype associated with swifter CD4+ cell decline among untreated drug users. Although this review has focused on social-level and structural-level factors, the presence of immunologic polymorphisms among drug users has not been well evaluated. More generally, the patterns of disease progression among HIV-seropositive drug users in the countries with the largest ongoing HIV outbreaks outside sub-Saharan Africa  – Russia, China, Ukraine, Vietnam and Malaysia – have not been evaluated. A future study could investigate if this deficit is a result of our reliance on English-language studies or reflects a gap in the scientific literature. A further limitation is the dependence on samples of drug users drawn from treatment settings (25, 45%).
To conclude, this review of disease progression among illicit drug users found that most studies concentrated on individual-level host and viral characteristics. Although few considered the broader physical, social, political and economic determinants of disease production or treatment outcomes, some studies did identify important associations with factors including incarceration, housing status and engagement in opioid substitution therapies. Although many studies focused on the effect of drug use patterns, weak and contradictory evidence was observed to support the hypothesis that drug use is directly related to disease progression. In light of this review, future research and interventions should consider the risk environment framework when seeking to reduce HIV-related morbidity and mortality among drug users.
The authors thank Deborah Graham, Tricia Collingham, Caitlin Johnston, Steve Kain 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 (CIHR) (MOP-79297, RAA-79918). M.-J.S.M. and T.K. are supported by the Michael Smith Foundation for Health Research and CIHR.
J.M. has received grants from Abbott, Biolytical, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare. The author is also supported by the Ministry of Health Services and the Ministry of Healthy Living and Sport, from the Province of British Columbia; through a Knowledge Translation Award from the Canadian Institutes of Health Research (CIHR); and through an Avant-Garde Award (1DP1DA026182–01) from the National Institute of Drug Abuse, at the US National Institutes of Health. The author has also received support from the International AIDS Society, United Nations AIDS Program, World Health Organization, National Institute on Drug Abuse, National Institutes of Health Research-Office of AIDS Research, National Institute of Allergy and Infectious Diseases, the United States President's Emergency Plan for AIDS Relief (PEPFAR), Bill and Melinda Gates Foundation, French National Agency for Research on AIDS and Viral Hepatitis (ANRS) and Public Health Agency of Canada. The author has academic partnerships with the University of British Columbia, Simon Fraser University, Providence Healthcare and Vancouver Coastal Health.
Conflicts of interest
There are no conflicts of interest.
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