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Research conducted during the first 20 years of the AIDS epidemic provided a solid foundation of data supporting methadone treatment as HIV prevention. Drug users in methadone treatment were consistently found to reduce the frequency of drug use, risk behaviors, and infections. These data have been consistent over time and across cultural settings and have been used to promote the expansion of drug treatment as a prevention intervention. More recently, data has emerged suggesting the prevention potential of medication assisted treatments other than methadone (buprenorphine/naloxone and naltrexone). Still, with a few notable exceptions, global drug treatment coverage for opiate injectors remains remarkably low and only a few treatment interventions for stimulant use have shown efficacy in reducing HIV risk. Importantly, more recent data provides support for the role of drug treatment programs in improving access and adherence to antiretroviral treatment that injection drug users in substance abuse treatment are more likely to achieve sustained viral suppression. While important challenges remain in maximizing its impact, the scientific literature provides strong evidence of the efficacy of drug treatment as an HIV prevention strategy.
The research literature of the past 25 years provides strong evidence that methadone treatment is an effective HIV prevention intervention. Patients in methadone treatment have been found to significantly reduce the frequency of their opiate use.1–3 This finding has been observed when methadone patients have been compared to their community counterparts who are not in treatment and when patients’ opiate use during treatment has been compared to their pre and post-treatment use. 4–7 Further, significantly lower rates of opiate use have been observed when patients with regular methadone program attendance have been compared to those with poor attendance, and when patients receiving minimal ancillary services were compared to those receiving more intensive services.8–11
Although drug use is not eliminated for most patients in treatment, the data suggests that methadone patients participate in approximately 40 to 60 percent fewer instances of opiate injection and needle sharing events. This association has been reported in a variety of non-randomized research approaches comparing methadone patients to heroin users who are not in treatment and in studies focused on measuring changes in cohorts of methadone patients during treatment. 12 Findings have also been reported showing significantly lower rates of injection among patients who remain in treatment when compared to patients who leave treatment.7,13
Perhaps most importantly, from a public health perspective, research has documented strong associations between methadone participation and lower rates of HIV prevalence and incidence. Heroin users who remained in methadone treatment during periods of rapid HIV transmission in their surrounding communities were found to have a dramatically lower prevalence of infection. HIV prevalence rates have also been correlated with length of time in treatment. In both prospective and retrospective studies, the incidence of new HIV infections has been found to be significantly associated with participation in and duration of, methadone treatment .1,2,12
In sum, findings from studies conducted during the first two decades of the AIDS epidemic provide consistent evidence that sustained treatment with methadone is strongly associated with protection from HIV infection. While these data may be considered a “proof of concept” that effective drug treatments are effective prevention interventions, it’s important to note several qualifying issues. First, no randomized controlled trials have yet been completed. This is due primarily to ethical concerns regarding the random assignment of individuals to no treatment or other treatment modalities. Consequently, it is quite possible that selection biases have influenced the findings. Those individuals who enter drug treatment may also be more likely to be concerned with self protection. Second, nearly all of the research has focused on methadone treatment for opiate injectors. While opiate injection has been the primary vector in injection driven epidemics, the early literature does not adequately address non-injection drug use and related treatments. Finally, the majority of studies conducted during the first two decades of the epidemic took place in more highly developed regions of the world.
As we move into the fourth decade of the epidemic it’s important to recognize that drug and alcohol use, abuse, and dependence continue to play an important role in the transmission of new HIV infections. Our best estimates suggest that outside of Sub Saharan Africa, approximately 10% of all new infection are attributed to injection drug use. Reflecting the significant regional variations in attributable risk, according to UNAIDS, injection drug use is responsible more than 80% of all HIV infections in Eastern Europe and Central Asia and is currently driving the epidemic in Indonesia, Vietnam, and Malaysia. 14
As summarized above, the research findings of the first 20 years of the AIDS epidemic provide an evidence base supporting the expanded use of methadone treatment as an HIV prevention intervention for epidemics driven by opiate injection. While these data alone cannot be considered to have changed policy, in every locale where treatment has been expanded, the data have been an important part of the rationale for methadone treatment initiation and scale up. China provides the most dramatic example of this evidence based response.15 Prior to 2004, the use of methadone treatment in China was quite limited with only a few private clinics and used as a medication for detoxification. Currently, there are over 700 clinics and the methadone treatment program in China has become the largest single drug treatment system in the world. Data is now emerging on treatment efficacy and it’s impact on HIV risk. 16 As in other regions of the world, methadone treated heroin addicts in China, reduce their use of heroin, show improvements in social functioning and reduce rates of needle sharing.
In 2002, buprenorphine and the combination of buprenorphine/naloxone were approved for in the US for the treatment of opiate dependence. The addition of naloxone is intended to discourage crushing, disovling and injecting the tablet. Buprenorphine, a partial agonist with strong affinity to the opiate receptor, expands treatment options in several ways for opiate dependent individuals. 17,18 First, the medication can be prescribed by a trained physician in a private practice. Second, buprenorphine has a narrow dose range making stabilization on buprenorphine relatively easy. Most patients are able to be treated safely and comfortably with dosages of approximately 16 mgs. per day.
Reports on the HIV prevention impact of buprenorphine and its naloxone combination have begun to appear in the literature and reported findings are quite consistent with those of methadone treatment. 17,19–21 Studies have reported significant reductions in risk behaviors using both office based and clinic based treatment strategies among adults and adolescents. 19,22 While the public health impact of buprenorphine and buprenorphine-naloxone has been limited by their higher cost per daily dose relative to methadone, cost effectiveness studies have resulted in very favorable comparisons with methadone.23,24
In a randomized double blind trial among heroin injectors in Malaysia, those assigned to the buprenorphine arm not only reduced risk behaviors significantly but remained in treatment significantly longer that those assign to naltrexone or placebo.25
Naltrexone is an opiate antagonist and has been available as a treatment for opiate dependence for over 25 years. However, due primarily to poor patient acceptability it is not widely prescribed and has not been evaluated, until recently, as a treatment intervention for HIV prevention. Naltrexone itself has none of the reinforcing properties of opiate agonists (methadone and buprenorphine) and in its oral form must be taken on a daily basis to maintain its blockade effect–the primary mechanism of action. Also, patients receiving naltrexone must be opiate free in order to avoid precipitated withdrawal on their first dose. Unless highly motivated to remain abstinent, this blockade strategy has not been effective over the long term for many opiate dependent individuals seeking treatment.
In considering this prevention potential, it’s also important to remember that there are many locations (in the United States and elsewhere) where agonist treatments are not available due to provider availability, local or national policy. For example, in Russia agonist treatments for opiate dependence are illegal. This restriction is rooted in a view of agonists as merely sustaining dependence by substituting one drug for another. Despite the fact that Russia (and many of the states of the former Soviet Union) continues to experience a severe HIV epidemic among opiate injectors, data on the efficacy of agonist treatments has not had an impact on policy. These circumstances provided an important opportunity to examine the impact of naltrexone on drug use and related risk behaviors. The largest study to date to assess the prevention potential of naltrexone was conducted in St. Petersburg and involved 280 opiate dependent individuals with an average age of just under 24 years. In this double blind four group trial subjects were randomly assigned to receive naltrexone and fluoxitine or placebo. 26 Both groups receiving naltrexone showed significant reduction in risk behavior and were retained in treatment for significantly longer periods than those groups receiving placebo (fluoxitine had no impact on retention or risk behavior).
Recently, a depot formulation of naltrexone (Vivitrol) was approved for use as a treatment agent in the prevention of relapse to alcohol use for individuals with history of alcohol dependence. This formulation provides long acting (one month) coverage with a single injection thus eliminating the possibility of patient initiated discontinuation of medication during the month following medication administration. A study testing this formulation on a group of injection drug users from St. Petersburg Russia was recently reported. The authors reported that both opiate use and craving for opiates were significantly reduced among those receiving the depot naltrexone compared to those receiving placebo.
During the first two decades of the AIDS epidemic, most research on the role of drug treatment as HIV prevention was focused on the impact of treatment participation on reductions in drug use, injections and the sharing of syringes, rinse water, and cotton. However, for those drug users who are already infected, a critical prevention intervention is the provision of HIV treatment. There is growing body of research that supports the prevention impact of HIV positive individuals participating in antiretroviral treatment and achieving sustained virologic response. 27 Not only are risk behaviors lower among patients in HIV care, but sustained reductions in viral load are achieved by the majority of adherent patients, regardless of mode of initial infection. 28 Despite personal and public health benefits of antiretroviral treatment, drug use has frequently been associated with poorer access to antiretroviral treatment and poorer adherence for those on antiretroviral therapy for those who continue to use alcohol and other drugs.29,30
Recent research provides support for the hypothesis that participation in drug treatment improves access to HIV treatment. In one prospective observational study of 231 HIV infected opiate using injection drug users, participation in methadone treatment was found to be a significant, independent predictor of more rapid entry into antiretroviral treatment. 31 The data also demonstrate higher rates of adherence to HIV treatment among those in methadone treatment. 32,33
In a retrospective analyses of 1558 visits accrued among a cohort of 276 HIV positive drug injectors in France, the relationship between drug use, treatment participation and adherence was more clearly defined.34 In this study those patients who continued to inject regardless of their treatment participation showed poorer outcomes. For patients who were in methadone treatment or buprenorphine treatment and not injecting drugs, adherence did not differ from patients with no history of drug use. However, for those who continued to inject, adherence was two to three times worse, regardless of drug treatment participation. This is the first study to report data showing that drug treatment participation alone is not sufficient to explain adherence. Only those patients who stopped injection showed the benefits of drug treatment on adherence. Importantly, data from this cohort also provided evidence that retention in medication assisted treatment was associated with long term virologic suppression. 35 These findings are quite consistent with a number of findings that have now reported negative impacts on adherence among patients that continue substance use and improved adherence among those in treatment. 36
There is increasing recognition of the major role played by non injection substance use in fueling the HIV epidemic globally. Not does sexual transmission of HIV occur among IDUs and their sexual partners who do not inject drugs, but in research focused on heterosexuals and men who have sex with men alcohol and drug use is consistently associated with risk behavior and new infection. 37–39 Among MSM, substance abuse is more common when compared to the general population, but is widely recognized as a significant risk factor in explaining both HIV risk behaviors and infections in this population. 40 In cross sectional studies, alcohol and stimulant use are associated with HIV risk and prevalence while in prospective studies substance abuse has been found to be a powerful predictor of new infections. Among the 4,295 MSM who participated in Project Explore, the largest intervention trial ever conducted among HIV-negative MSM, drug and alcohol use prior to sex was found to be a stronger predictor of incident infections than unprotected receptive anal intercourse with a partner of unknown HIV status.41,42 Despite widespread awareness of the major role of non-injection substance use in the sexual transmission of HIV, most of the literature on treatment as prevention has focused on injection drug use.
Risky sexual behaviors have frequently been found to co-occur with both injection and non-injection drug use. A number of the studies reviewed here have included variables designed to assess the relationship between participation in treatment and sexual risk reduction. Generally, multi-session psycho-social interventions directed at reducing sexual risk among drug users have not shown greater efficacy than more basic educational approaches.43 In fact it has been rare to find evidence that psychosocial interventions or participation in drug treatment alone lead to significant reductions in sexual risk. Several studies have reported positive findings when sexual risk reduction interventions are delivered within drug treatment programs. These interventions use drug treatment programs as a platform for intervention delivery. Both individual and group strategies have been investigated as have gender specific and gender mixed strategies. 44–46 While positive results have been reported, findings have been less consistent than drug treatment outcomes. It seems clear that sexual risk reduction is a more challenging behavioral target than reduction in drug risk behaviors.
There is now a large and growing body of research demonstrating thepositive relationship between effective treatments for substance abuse and reductions in risky behaviors and HIV infection. The consistency of this relationship over time and across cultural settings is impressive and serves as a reminder that drug abuse and dependence, like other medical conditions, respond in a reliable and predictable manner when treated using evidence based approaches. The strongest evidence for this relationship has been derived from studies of methadone treatment. This data has been used to support the expansion of methadone treatment and the use of other The underlying mechanism of action is assumed to be the ability of medication assisted treatments for opiate dependence to address both the biological and behavioral components of abuse and dependence.
Importantly, there is increasing evidence of the positive effects of medication assisted treatments other than methadone. Studies of buprenorphine/naloxone and naltrexone now appear in the literature and are producing findings consistent with those of methadone treatment. This is particularly important considering the need for treatment multiple options in communities affected by HIV and other blood borne and sexually transmitted infections.
The recent literature significantly expands our understanding of the role of effective substance abuse treatments as HIV prevention by documenting its role in improving access and adherence to antiretroviral treatment. The data is clear and consistent. Through participation in substance abuse treatments, drug users have improved access to antiretroviral treatment, improved adherence to those treatments, and for those who remain in treatment, sustained reductions in viral load. These studies have also provided clear evidence that current use of substances, not past diagnoses is the critical factor in improved adherence. Thus, enrollment in drug treatment alone is not sufficient to achieve the positive effects of treatment. Rather, it’s the reduction in drug use that occurs among patients who are actively participating in their treatment. Thus, the data suggest that periodic screening of drug and alcohol use among individuals in HIV care is warranted.
Although the literature provides continued positive findings on drug treatment as HIV prevention there are limitations to the data. Still there have been no randomized controlled trials and as a consequence it is impossible to attribute risk reduction to the treatment alone. Given the important role of heroin injection in propelling the spread of HIV via injection related risk, most of the published research has involved opiate users and their treatment.
The findings that medication assisted treatments reduce use, risk behaviors, and infection with HIV have been widely promulgated, this has in some instances promoted the mere distribution of agonist medication. While such “low demand” interventions can help dependent individuals avoid withdrawal and reduce risk behaviors, these impacts will only be observed when the medication is available and used. The availability of methadone or buprenorphine without efforts to address the behavioral components of addiction cannot be expected to maximize efficacy and sustained impact.
The literature is quite clear that methadone treatment is an effective HIV prevention strategy and as reported here, early reports indicate that buprenorphine and buprenorphine-naloxone will produce similar protective effects. Unfortunately, comparable medication assisted treatments for cocaine and other stimulants are not currently available. While treatment strategies that do not use medications have shown some evidence of efficacy among high risk stimulant users, the development of a safe and effective treatment medication for stimulant abuse and dependence must remain a high priority.
Drug treatment programs can have an important role in reducing risk of HIV infection and transmission and in improving HIV treatment outcomes in many communities around the world. In order for this impact to be achieved, effective treatments must be available, accessible, and affordable. Currently, the vast majority of drug users do not have access to effective substance abuse treatments--even in countries considered to be more highly developed. 47 While data on the positive impacts of drug treatment may be a necessary condition for the development of policies that expand access, it is definitely not sufficient. The expansion of drug treatment access will continue to be dependent upon the combined efforts of basic research focused on medication development, operational research designed to demonstrate cost effective delivery strategies, and policy makers committed to the health of drug users and the communities in which they live.
Preparation of this manuscript was supported in part by the following grants:
U01-AI-048014, Penn Prevention Clinical Trials Unit (Metzger, PI);
RO1-DA-026344-01A1, (Metzger, PI);
6-P30-AI-45008 (Hoxie, PI)
David S. Metzger, University of Pennsylvania/ HIV/AIDS Prevention Research Division, 3535Market Street, Ste 4000, Philadelphia, PA 19104, P: 215-746-7346, F: 215-746-7377.
Yan Zhang, University of Pennsylvania, HIV/AIDS Prevention Research Division, 3535Market Street, Ste 4000, Philadelphia, PA 19104, P: 215-746-7355, F: 215-746-7377.