Since the mid-1990s, there have been major advances in the medical management of HIV disease . In particular, antiretroviral therapies have been shown to suppress plasma HIV RNA to undetectable levels, and in turn substantial reductions in HIV-related morbidity and mortality have been documented among persons receiving antiretroviral therapy [2,3]. Despite these survival benefits, the clinical management of HIV disease presents major challenges. High levels of adherence are required to durably suppress the plasma HIV RNA , and incomplete adherence has been associated with virological failure and the rapid emergence of antiretroviral resistance .
During the past two decades, the HIV epidemic has transitioned from primarily a sexually driven epidemic to one in which syringe sharing among illicit injection drug users (IDUs) contributes to a significant proportion of new infections . The Joint United Nations Program on HIV/AIDS (UNAIDS) estimates that one-third of new HIV infections outside sub-Saharan Africa are attributable to injection drug use . In North America, injection drug use accounts for approximately one in four cases of HIV , and in some areas where HIV is spreading most rapidly, such as Eastern Europe and Central Asia, more than 80% of all HIV cases occur among IDUs . In turn, as the HIV epidemic has matured among this population, large and growing numbers of HIV-infected injection drug users are in need of highly active antiretroviral therapy (HAART) [8–10]. Frequently, HIV-positive IDUs first come to the attention of the healthcare system as a result of harms related to the use of injection drugs (e.g., endocarditis, cellulitis, drug overdose, etc.) and are therefore identified early, while other cases are identified at late stages of HIV disease and subsequent to the development of life-threatening opportunistic infections.
At present, the provision of optimal care to HIV-infected IDUs is a major challenge . In addition to the instability resulting from compulsive drug-seeking behaviours , challenges also stem from the fact that IDUs often exhibit several characteristics, such as homelessness and psychiatric illness, which severely complicate the challenges of HAART delivery described above [13–16]. Despite the complexity and increasing frequency of this clinical scenario, there has until now been no contemporary evidence-based review of best practices for the treatment of HIV among IDUs, and existing barriers to HAART and potential solutions have remained poorly understood. We, therefore, conducted the following narrative review to summarize the latest evidence regarding barriers and facilitators to HAART among IDUs and to describe the best evidence for the optimal treatment of HIV infection among this population.
Search strategy and selection criteria
For the present review, published studies were extracted from nine academic databases (EMBASE, Cochrane CENTRAL, MEDLINE (via PubMed), AIDSLINE, AMED, CINAHL, TOXNET, Psych-info, and Web of Science), with no language or date specified in the search criteria. Key words used in the initial search included HIV, AIDS, intravenous, injection, illicit, drug, antiretroviral, and treatment, and additional studies were found by examining references from relevant articles. In addition, abstracts presented at relevant international HIV and infectious disease meetings during the past 2 years were reviewed (extraction was from each database's inception up to 1 November 2007).
Access to treatment
Myriad concerns have been identified with respect to the management of HIV infection among IDUs. A primary issue is access to HIV treatment, and a range of studies from various international settings have demonstrated that, even in settings where HAART is widely available, injection drug users have lower uptake of antiretroviral therapy than other HIV-infected populations [8–10,17–19].
Although there is geographical variability with IDUs presenting early for HIV treatment, several studies have shown that IDUs commonly present for HAART late in the course of HIV disease and often after AIDS-defining illnesses have developed. This is of particular concern, since research has consistently shown that initiation of HAART during later-stage HIV infection presages a worse survival outcome . In addition, among IDUs not on antiretroviral therapy, both gender and ethnicity have been associated with differential access to antiretrovirals; as demonstrated in Fig. 1, female IDUs and IDUs from ethnic minorities may be particularly affected by issues of access to HIV/AIDS care [8,9,21–23]. Studies have also shown that, because of these concerns, HIV-infected IDUs are more likely to die without ever having received HAART, even in settings where antiretroviral therapy and other medical care is available free of charge .
Several factors have been shown to explain poor access to HAART among IDUs. A review of the literature demonstrates that these factors can generally be grouped into socio-structural, individual-level, and provider-based concerns (Table 1). Socio-structural concerns have primarily been explored with respect to HIV prevention among this population [25–29]. These studies have consistently shown how national illicit drug strategies which predominantly employ criminal sanctions and create social marginalization of IDUs have served to create a ‘hidden population’ that is extremely difficult to reach with HIV care and prevention services such as HIV testing and needle exchange programmes [25–29]. More recently, studies have elucidated how these same socio-structural influences may also create barriers to HIV treatment among IDUs: public policies that seek to reduce the prevalence of drug use by stigmatizing this behaviour may create a social stigma in the social and medical systems, which in turn may create tension with care providers [30–34].
Alternatively, individual-level concerns are issues inherent in injection drug users themselves. A primary individual-level issue which has been identified is the common perception among IDUs that the side effects of HAART will be intolerable [35–37]. Similarly, low self-efficacy, or doubt about one's ability to adhere to HAART, has also been identified as a common barrier to initiating HAART among this population [37,38]. Other individual-level issues include psychiatric illness, addiction-related instability, limited social support, and homelessness—all of which create barriers to readiness for the daily rigours of HIV treatment [12,15,16,39–44].
Finally, provider-based factors are those barriers to treatment that arise through physician reluctance rather than unwillingness on the part of the IDU patient [37,44–46]. A host of studies have demonstrated that physicians may be reluctant to prescribe HAART to IDUs even when patients express an interest, because of the perception that IDUs may be less likely to adhere to HAART [37,47–49]. Other physician concerns include the belief that IDUs may be more likely to develop and transmit antiretroviral-resistant HIV , and the belief that the potential for HIV risk behaviour may be increased after the initiation of HAART . These issues obviously overlap with the issues of stigma raised above.
Adherence to treatment
In addition to poorer access to HAART, studies have consistently shown that, once therapy is initiated, IDUs commonly have lower rates of adherence to HAART than non-IDUs [4,11,13,39,52]. Furthermore, compounding the problem of lower adherence is the fact that IDUs are also significantly more likely to discontinue HAART outright after it has been started .
A range of barriers to HAART adherence has been identified. These again can generally be grouped into socio-structural, individual, and provider-based concerns (Table 1), and essentially operate through the same mechanisms as barriers to accessing therapy [34,53]. Socio-structural factors that are specifically relevant to adherence and antiretroviral discontinuation include incarceration, which is frequent among IDUs in most settings and has been associated with worse virological suppression . Individual barriers to adherence include the instability caused by higher-intensity illicit drug use (which creates difficulties making appointments, etc.)  and lower adherence self-efficacy. An additional individual-level concern, which has been reviewed in detail elsewhere , is the common co-morbidity of hepatitis C infection, which can increase side effects and limit tolerability of HAART . Finally, provider-based issues, which have been identified as inhibiting HAART use after it has been initiated, include lack of understanding of social issues facing IDUs and geographic distance between providers and IDUs' residence [37,58].
The lower rates of access and adherence to HAART have generally translated into inferior clinical outcomes among HAART-treated IDUs. For instance, IDUs have been shown often to have lower rates of virological suppression [52,59], although, as shown in Fig. 2, this observation can be entirely explained by incomplete adherence among this population . Blunted CD4 cell count responses to HAART among IDUs have similarly been reported , although this also appears to be mediated through lower adherence . Finally, these concerns, as well as competing causes of death due to illicit drug overdoses and co-infections such as hepatitis C, have translated into overall elevated mortality among IDUs. Recently, a collaboration among 13 international observational HIV treatment databases demonstrated that a history of injection drug use was associated with a 2.4-fold higher likelihood of mortality , an observation that has been demonstrated in individual settings [62,63].
Addressing challenges to highly active antiretroviral therapy delivery to injection drug users
Together, in comparison to non-IDUs, the picture of reduced access and adherence and subsequent inferior virological response and elevated mortality [64,65] paints a grim picture of the current status of HIV infection among injection drug users . While challenges certainly exist, it is important to stress that, despite the above concerns, the advent of HAART has nevertheless been associated with dramatic reductions in HIV-related mortality among IDUs [3,63,66,67]. Although the majority of studies are observational in nature, there is increasing evidence that the above-described barriers to access and adherence to HAART can be readily modified using well characterized evidence-based interventions.
Not surprisingly, these strategies have generally targeted the previously described socio-structural, individual, and provider-based barriers to access and adherence (Table 2). For instance, strategies aimed at addressing socio-structural barriers include outreach programmes that help to identify HIV-infected IDUs and refer them to appropriate HIV prevention and care [68–70]. These programmes may be particularly important for case finding, since accessing HIV testing has been associated with uptake of HAART [71,72] and obviously testing and counselling of IDUs unaware of their HIV status serve a secondary public health benefit . Similarly, meeting IDUs on their own terms is important, and this may be most effectively accomplished when HIV testing and treatment services incorporate low-threshold HIV prevention services (also known as harm reduction services), such as needle exchange. Harm reduction services are low-threshold in that they do not require abstinence from illicit drug use. Several reports have demonstrated the value of incorporating HIV testing and treatment into low-threshold services for illicit drug users [71,74,75].
Strategies to address individual-based concerns largely overlap with provider-based strategies that are discussed in detail below. In brief, these strategies include efforts to improve health insurance coverage and free access to medical care [8,18,76,77]. Similarly, HAART self-efficacy and willingness to initiate HAART have been shown to increase through improved relationships with HIV-experienced physicians [53,77–80]. Finally, improvements in stability from addiction treatment and housing support may help to address physician reluctance to prescribe HAART .
In terms of provider-related strategies, several clinic characteristics have been associated with improved uptake and adherence to HAART. Specifically, HAART delivery models which tend to be highly flexible, comprehensive, and interdisciplinary have been particularly helpful in this setting . Several key features of such programmes include on-site pharmacists, HIV specialist nurses, drop-in services, less geographic distance between home and HIV services, and services which offer case management strategies [14,81–87]. An additional key strategy is the linking of the provision of addiction treatment with antiretroviral therapy. Methadone maintenance therapy has been most widely investigated and has been associated with both improved uptake and adherence to HAART [88–91]. More recently, buprenorophine has shown similar potential . This may be of particular importance, given the known contribution of ongoing drug use on reduced access and lower adherence to HAART, and the evidence that patients infected with HIV through injection drug use, but who stop using illicit drugs, may have similar adherence to other risk groups . An additional clinical consideration when initiating antiretrovirals is the co-administration of HAART with opioid substitution therapy such as methadone. Since methadone is metabolized by the cytochrome p-450 (CYP450) enzymes, and since antiretroviral drugs can act as inhibitors or inducers of this process, some antiretrovirals may lead to opioid withdrawal among persons on methadone due to reduced methadone effect . Conversely, opioids may inhibit or induce metabolism of components of a HAART regimen, since many antiretrovirals are largely metabolized by enzymes of the CYP450 pathway . The optimal strategies for the co-administration of methadone and antiretrovirals have been reviewed elsewhere, and a knowledge of these patterns is required for successful co-administration of these agents .
In addition, directly administered therapy programmes, which provide daily supervision of antiretroviral therapy, have also been associated with improved adherence [94–97]. While prison environments have traditionally been associated with risk of HIV transmission and worse HIV care [54,98], it has also been observed that prisons with well resourced HIV care systems can create an environment where HIV care is facilitated . Finally, management of co-morbid psychiatric conditions has been associated with better HIV treatment outcomes [15,16].
In terms of provider-specific strategies, it has been demonstrated that more experienced physicians may be more likely to prescribe HAART to IDUs and to promote higher levels of adherence among their patients [77,80,100]. In light of this evidence, it must be noted that increasing physician education in the area of evidence-based HIV and substance abuse treatment has significant potential to improve evidence-based HIV care in this population [77,80,100]. One major concern is the discordance between physician perceptions and empirical evidence regarding potential harms of HAART use in marginalized populations [46,48,49,101]. For instance, although IDUs are known to have lower levels of adherence, studies have repeatedly demonstrated that many IDUs can manage high adherence to antiretroviral therapy (Fig. 2). Accordingly, ethical analyses have specifically concluded that physicians should not indefinitely withhold HAART from patients on the basis of the presumption that they will be nonadherent, and this argument is strengthened by the studies [41,102,103] that have consistently demonstrated that providers are poor judges of patients' adherence. With respect to the common concern of providers regarding potential for increased rates of antiretroviral resistance among IDUs and potential for community transmission of antiretroviral resistance, this concern is not supported by evidence. On the contrary, monitoring studies have not shown elevated rates of antiretroviral resistance among the newly HIV-infected IDU population [104–107]. Similarly, the studies, which have evaluated HIV risk behaviour among HAART-treated IDUs, have been generally inconsistent, and it is likely that any rise in HIV risk behaviour among this population may be less than the rise in HIV risk behaviour seen in other populations, such as gay men . Finally, as shown in Fig. 3, data from one of the few studies to compare rates of antiretroviral resistance between IDUs and other populations demonstrated similar rates of antiretroviral resistance to all classes of antiretrovirals between IDUs and non-IDUs. The paradoxical finding of overall lower adherence but similar resistance rates may be attributed to the fact that high but incomplete rates of adherence to HAART (i.e., 80–90%) are required to rapidly select and maintain antiretroviral-resistant mutations in plasma [108–110].
A limitation of many of the above studies is that they are based on observational data. Nevertheless, there are several commonalities observed across international settings, as well as several differences which likely reflect differing policies. For instance, in comparison to no HIV treatment, the survival benefits of HAART in IDUs have been observed across settings [3,63,66,67], but IDUs have also regularly been shown to have inferior clinical outcomes to HAART in comparison to non-IDUs [3,62,63]. This observation is likely explained by universal concerns that are more common among all IDU populations, including compulsive drug-seeking behaviour and psychiatric illness, as well as higher rates of homelessness and social stigma [15,46,111]. Not surprisingly, the beneficial effects of certain interventions, such as methadone maintenance therapy [18,88], are only observed in settings where methadone is in common use, and the limited availability of methadone in particular regions in Eastern Europe and south-east Asia is of particular concern . Finally, it is key to distinguish opiate (e.g., heroin)-dependent drug users from those who are using stimulant-based compounds such as cocaine and methamphetamine. Unlike heroin, which has a long half-life and so is generally injected only every few hours at most, the short half-life of certain stimulants such as cocaine allows for thirty or more injections per day . Stimulant addiction is also noteworthy in that there exists no gold standard substitution therapy in widespread use, as there is with heroin addiction. Both behavioural and pharmacologic strategies for the stabilization of HIV-infected stimulant users remain urgently needed.
HIV treatment poses particular challenges for clinicians faced with the large and growing number of infections occurring among IDUs, since this population commonly exhibits several co-morbidities and social issues that complicate the delivery of HAART [6,7]. These concerns are often exacerbated by illicit drug policies that entrench stigma and marginalization among IDUs [30–34] and have resulted in lower access and adherence to HAART and inferior clinical outcomes among this population [8–10,17–19]. Specifically, worse clinical outcomes among IDUs are explained by a range of barriers to HAART access and adherence that fall broadly into the categories of socio-structural, individual-level, and provider-based barriers. It is critical that these issues be addressed, given the known cost-effectiveness of HAART and the fact that engaging injection drug users in medical care may have significant potential to avert new infections [114,115].
Finally, it must be stressed that major antiretroviral-associated survival gains have been observed among this population [3,63], and the preponderance of evidence demonstrates that several under-utilized interventions and novel HAART delivery modalities have significantly addressed the barriers to access and adherence. These interventions and modalities include strategies that directly address known barriers to HAART by closing the gap between IDUs and the public health and medical systems [8,18,44,68–72,74–77]. The outcome of HIV-infected IDUs in the era of HAART is strictly dependent on the scaling-up and rigorous evaluation of these strategies. To this end, significant physician education is also urgently required to improve awareness of evidence-based care delivery and to address discordance between perceptions about IDUs' inferior responses to HAART and observed clinical outcomes.
We thank Deborah Graham, Peter Vann and Kelly Hsu for their administrative assistance. Particular thanks goes to Daniel Werb for his assistance with the literature review. This work was also supported by grants from the US National Institutes of Health, the Canadian Institutes of Health Research, and the Canadian Foundation for AIDS Research. T.K. is supported by a Canadian Institutes of Health Research New Investigator Award and a Michael Smith Foundation for Health Research Scholar Award. M.W.T. is supported by a Michael Smith Foundation for Health Research Senior Scholar Award.
There are no conflicts of interest for E.W. and T.K. M.W.T. reports having served on advisory boards of Abbott, GlaxoSmithKline, Boehringer Ingelheim, and Bristol-Meyers Squibb, and has received research support from Merck Frosst Canada. J.S.G.M. has received educational grants from, served as an ad hoc adviser to or spoken at various events sponsored by Abbott Laboratories, Agouron Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals Inc., Borean Pharma AS, Bristol–Myers Squibb, DuPont Pharma, Gilead Sciences, GlaxoSmithKline, Hoffmann–La Roche, Immune Response Corporation, Incyte, Janssen–Ortho Inc., Kucera Pharmaceutical Company, Merck Frosst Laboratories, Pfizer Canada Inc., Sanofi Pasteur, Shire Biochem Inc., Tibotec Pharmaceuticals Ltd. and Trimeris Inc.
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