The evidence summarised above indicates that IDUs benefit significantly from antiretroviral treatment but that mortality remains higher in HIV-positive ART-treated IDUs as compared with non-drug user HAART-treated HIV-positive patients. Several factors contribute to the overall lower impact of HAART on mortality in HIV-positive IDUs, including delayed initiation to treatment, poor adherence to treatment regimen, interruptions in medical care and continuing drug use.
Although financial barriers limiting access to treatment have been removed in most Western countries, delay in treatment initiation among IDUs is still observed: in a national random sample of HIV-positive patients in France, CD4 counts at the time of initiation of HAART were lower in IDUs than in non-IDUs, except for migrants who remain most often diagnosed at advanced stages of HIV infection [Dray-Spira, 2007
]. In Spain, in a multicenter hospital-based cohort, among naive patient followed from 1997 to 2003, IDUs were found less likely to start HAART compared with male homosexuals (HR 0.67 95%IC: 0.57–0.79) (Rodriguez-Artenas, 2006
). Comparing HAART initiation among IDUs with known dates of HIV-seronversion, accross European sites, Van Asten (2005)
found variations in CD4 counts at initiation: in Amsterdam, Innsbruck and Edimburg, HAART started with lower CD4 counts than in Paris, geneva and Glasgow. Late access to treatment may be dependent on patients or on physicians’ attitudes and stereotypes (Ding, 2005
). However poor knowledge of HIV positive IDU regarding HIV treatment was not found associated with their acceptance of HAART (Clarke, 2003
). In the early period of HAART in France, patients with ongoing heroin use were three times less likely to be prescribed ART than former IDUs [Carrieri, 1999
]. Substitution therapy may however decrease or avoid these delays. Thus, among ART-naïve HIV-positive IDUs recruited in the BART cohort in Vancouver (n=234), the uptake of HAART occurred earlier among patients who were on methadone substitution, both at baseline and during follow-up (69.7 % vs. 44.4 % at 24 months) [Wood, 2005
]. In a Cox model adjusting for time since receiving results of the HIV test being on methadone significantly increased the chance of initiating ARV treatment (relative hazard 2.10 95%CI 1.28–3.46). The study concluded that social stabilisation obtained via substitution treatment favours the initiation of HAART.
Adherence is a key issue to prevent failure of HAART, particularly in the early months following initiation of therapy. Evidence from several studies, and reviewed in this volume by Carrieri and Spire (2007), indicate that ongoing injecting drug use, alcohol consumption and cocaine use are associated with non-adherence and adherence failure. In former IDUs who are not on substitution treatment, social vulnerability is the only factor associated with non-adherence. In IDUs on substitution treatment, adherence was found to be significantly higher than in active IDUs and higher (although statistical significance was not reached) to that of former IDUs. Substitution therapy with methadone or buprenorphine often allows the patient to be followed at regular intervals in an integrated network of care involving physicians, pharmacists, and other health care and social workers.
In the MANIF 2000 cohort of HIV infected drug users, poor adherence to ART was positively associated with younger age, alcohol use, negative life events in the last six months and current drug use [Moatti 2000
]. IDUs often exhibit a high prevalence of psychiatric co-morbidities. Among patients with CD4 cell counts above 200/mL at initiation of ART, progression, as defined by the occurrence of AIDS-related death or CD4 counts <200/mL, was found to be correlated with depressive symptoms, independently of adherence. Factors in addition to adherence may contribute to a poorer impact of HAART in IDUs [Bouhnik, 2005
]. In the cross-sectional VESPA survey in France, among a representative sample of 2932 persons living with HIV, almost one in three patients with an history of injecting drug use reported interruptions in medical care for six months or more, whereas this proportion was below 10 % in other groups of ART-treated HIV-positive patients [Dray-Spira, 2007
Evidence on the relationship between continuing drug use, drug treatment and progression of HIV disease are inconsistent, due to the diversity of populations studied and study designs. As mentioned above however, continuing drug use tends to be associated with poorer outcomes.
Among women (n=1148), included in a cohort study during pregnancy and followed up from 1989–1995 to 2001, hard drug use (defined as injecting, cocaïne or heroin) at any time (at baseline or during follow-up) was not found to be associated with changes in CD4 cells count, nor in HIV RNA level, nor with an increased mortality from all causes [Thorpe, 2004
]. Women who used drugs were however more likely to develop non-fatal infections and to reach stage C of HIV disease (1.65 95%IC 1.00–2.72).
In the ALIVE cohort (AIDS Linked to Intravenous Experience), drug use and drug treatment were not identified as independent prognostic factors of survival between 1988 and 2000 [Galai, 2005
]. HIV-related and non-HIV-related deaths from infectious conditions were studied among HIV-positive patients with CD4 cell counts below 500/mL at entry. They were investigated in both the pre-HAART and HAART periods, taking into account treatment with methadone, ongoing use of heroin, cocaine and crack, and heavy alcohol intake. The overall survival of patients improved in the HAART era, but risk factors for progression did no differ between the pre-HAART and HAART periods. Drug use was not found to be a prognostic factor of progression, except for the use of crack, which appeared as “protective” across all CD4 strata. This counter-intuitive finding is interpreted by the authors as dependent on a selection bias: individuals able to use crack might have been less debilitated than others.
The association between methadone maintenance treatment and outcome of HAART has recently been investigated by matching the data of the VIDUS cohort (Vancouver Injection Drug User Study) for the period 1996–2003 with those of the British Columbia treatment monitoring system [Palepu, 2006
]. Among 278 participants on HAART, methadone maintenance treatment was found to be independently associated with enhanced viral suppression (aOR 1,34; 95%CI 1.00–1.79) and greater increases in CD4 cell counts (aOR 1.58; 95%IC 1.26–1.99).
A more recent analysis assessed the impact of active drug use on the course of HIV disease in Baltimore (USA) [Lucas, 2006
]. In this study, HIV positive subjects (1851) were defined as persistent heroin and/or cocaine user, intermittent user, or non-user. For each six month period before intake and during follow-up, active substance use was assessed. Over 36 months, the risk of opportunistic infection was observed to be lower in non-users than in intermittent users, and lower in intermittent users than in persistent users. In intermittent users compared to non-users, the risk of opportunistic infection during six month abstinence periods was similar, while it was higher during active substance use periods (OR 2.2; 95%IC 1.4–2.9) as it was for persistent user (OR 1.9; 95%IC 1.2–2.8). The authors suggested several interpretations for the association of active drug use with HIV progression. The hypothesis of a direct impact of drug use on progression of HIV infection is not consistent across studies. A second hypothesis was the decreased access to effective HIV treatment either from the physicians who could be uncomfortable treating drug users or from the patient’s behavior through poor adherence to treatment, unstable living conditions, poor social support or irregular attendance at medical appointments during periods of active drug use. However, taking account of heavy alcohol use and adherence to treatment did not alter the effect of active drug use on HIV progression. The mechanisms linking current active drug use to lesser benefit from HAART remain unexplained.
Pharmacokinetic interactions between opioid substitution drugs and antiretroviral drugs have been suspected of leading to possible complications in the treatment of opioid-maintained patients [McCance-Katz, 2005
, Bruce, 2006
]. Studies of interactions between methadone and ARV have shown both withdrawal and excess opioid syndromes, depending upon the ARV medication. Despite the increasing use of burpenorphine in drug dependence treatment, studies on its interactions with ARV remain limited. Available data, from in vitro and pharmacological studies and from case reports, require that HIV specialists manage carefully patients with both treatments. However to date, specific guidelines for HAART in opioid-maintained HIV-infected patients have not been considered necessary.