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Drug use continues to be a major factor fueling the global epidemic of HIV infection. This paper provides an updated review of the research literature assessing the ability of drug treatment programs to reduce HIV transmission among injection and non-injection drug users. Most data come from opiate dependence treatments and continue to provide strong support for the effectiveness of medication assisted treatments in reducing the frequency of drug use, risk behaviors, and infections. This finding has remained consistent over time and across diverse cultural settings. Data on the ability of medications other than methadone (buprenorphine/naloxone and naltrexone) have emerged in recent years and shown promise as effective prevention interventions and in providing more treatment options to communities most heavily affected by drug use and HIV infection. Still, only a few treatment interventions for stimulant use have shown efficacy in reducing HIV risk. The literature of the past 10 years provides strong support for the importance of drug treatment programs in improving access and adherence to antiretroviral treatment and suggests that drug users in substance abuse treatment are significantly more likely to achieve sustained viral suppression making viral transmission less likely. While important challenges remain in maximizing its impact, the scientific literature provides strong evidence for the efficacy of drug treatment as an HIV prevention strategy.
In 1981 an outbreak of “community acquired” pnuemocystis carinii was reported among 15 young men —7 were drug abusers, 6 were men who had sex with other men(MSM), and 2 were both drug users and MSM. 1 This was among the very first published reports of cases that would later be classified as Acquired Immunodeficiency Syndrome (AIDS). It was a time of great concern among the medical community, those known to be at risk, and increasingly among the general public. Although there was clear evidence of the connection between substance use and HIV, little research at the time had focused on drug users who were not in treatment, their injection and sexual practices, and more broadly, the public health impact of drug use. Researchers and clinicians working with drug users did not typically ask questions about sexual behaviors or practices that could transmit blood borne pathogens. While much attention was focused on the relationship between crime and heroin use, there was little support for drug treatment programs and little attention was paid to the link between drug use and public health. Researchers, treatment professionals, and public health agencies were unprepared to respond to the growing epidemic among drug users and their sexual partners. 2
Current estimates suggest that the global AIDS epidemic has stabilized with over 33,000,000 people living with HIV and approximately equal numbers of new infections and deaths. 3,4 While significant regional variations exist, outside of Sub Saharan Africa, approximately 10% of all new infection are attributed to injection drug use. According to UNAIDS, injection drug use is responsible more than 80% of all HIV infections in Eastern Europe and Central Asia. Injection drug use has initiated HIV epidemics in countries in the Middle East and North Africa and is currently driving the epidemic in Indonesia, Vietnam, and Malaysia. 5
There is increasing recognition of the role of non injection substance use in fueling the HIV epidemic globally. Not only has the sexual transmission of HIV been among IDUs and their sexual partners who do not inject drugs, research focused on heterosexuals, alcohol and drug use is consistently found to be a predictor of HIV risk behavior and new infection. 6-8 Among MSM substance use is not only more common when compared to the general population, but also recognized as a significant risk factor in explaining both HIV risk behaviors and infections. 9 In cross sectional studies of MSM, 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. 10,11 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.12,13 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.
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 14–19. 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. 17,20–22 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.23–26
Consistent with the observed reductions in opiate use, available data suggests that methadone patients participate in 40 to 60 percent fewer instances of opiate injection and needle sharing events. This association has been reported in cross-sectional, prospective and retrospective designs 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.20,21,25,27–30 Findings have also been reported showing significantly lower rates of injection among patients who remain in treatment when compared to patients who leave treatment.22,31
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. 32 HIV prevalence rates have also been correlated with length of time in treatment. In both prospective and retrospective studies, a reduced incidence of new HIV infections has been found to be significantly associated with participation in and duration of methadone treatment.19,22,26,33,34
Thus, data from studies conducted in the United States, Australia, Europe, and more recently Asia, with few exceptions, have found strong associations between participation in methadone treatment and reductions in the frequency of opiate use, fewer injections and injection related HIV risk behaviors, and lower rates of HIV prevalence and incidence. Although no randomized controlled trials have yet been conducted (due primarily to ethical concerns about the random assignment of individuals to no treatment or other treatments that do not include methadone modalities), the consistency of findings from observational and case controlled studies cited here provide a preponderance of evidence suggesting that sustained treatment with methadone is strongly associated with protection from HIV infection 18,35–40.
These finding have provided support for the expanded use of methadone maintenance as an HIV prevention intervention. Its introduction as an HIV prevention intervention is most notable in Asia where the dual epidemics of HIV and drug abuse began in the 1990’s.41 The enormous investment by China in the establishment of a national methadone treatment system is a clear example of this “data-based” policy response. Prior to 2004, methadone treatment was limited to a few private clinics and primarily used as a medication for detoxification. Currently, there are over 700 clinics treating more than 160,000 patients. The MMT system in China has become the largest single drug treatment system in the world and data is now emerging on treatment efficacy and impact on HIV risk and transmission.42
While the data on the impact of methadone treatment is impressive, methadone treatment alone can be expected to have a limited effect on the global epidemic since not all individuals at risk from their drug use are opiate users. In addition, not all opiate users are appropriate for, or have access to, methadone treatment and as mentioned earlier the majority of drug related infections are likely associated with non-injection drug use and sexual transmission. The data however are impressive in their consistency over time and across cultural settings, and provide what might be considered a “proof of concept” --effective drug treatments reduce drug use, risk behavior and HIV transmission.
The approval in 2002 of buprenorphine and the combination of buprenorphine-naloxone (Suboxone), represent the most significant developments in the treatment of opiate dependence in many years. Buprenorphine, a relatively safe and effective partial agonist, significantly expands the treatment options for opiate dependent individuals, particularly in the U.S. because primary care providers can use it outside the highly regulated methadone system. 43,44 Reports on the HIV prevention impact of buprenorphine have begun to appear. They show significant reductions in risk behaviors using both office based and clinic based treatment strategies among adults and adolescents and are quite consistent with those of methadone maintenance treatment.43,45–48 While the public health impact of buprenorphine and it combination with 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.49,50 In a randomized double blind trial among heroin injectors in Malaysia, those assigned to buprenorphine not only reduced risk behaviors significantly, but remained in treatment longer that those assign to naltrexone or placebo.51
Naltrexone, an opiate antagonist that has been available for over 25 year as a daily treatment for opiate dependence, has had very limited impact because patient acceptability has been poor in the U.S> and most Western Countries. Given its historically limited role in treating opiate dependence, few studies have examined its potential as an HIV prevention intervention. However, there are many locations (including large areas of the United States) where agonist treatments are not available due to local or national policy or physician availability and where naltrexone could provide a viable alternative treatment strategy. The most significant of these is the Russian Federation where agonist treatments for opiate dependence are illegal. Russia (and many states of the former Soviet Union) has also experienced a severe HIV epidemic among opiate injectors. These circumstances provided an opportunity to examine the impact of naltrexone on drug use and related risk behaviors. The largest study to date to 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 (50mgs./day) and fluoxetine; naltrexone and fluoxetine placebo; fluoxetine and naltrexone placebo; or double placebo. 52 Although there were no significant effects of fluoxitine, both groups receiving naltrexone showed significant reduction in opiate (heroin) use and HIV risk behavior and were retained in treatment for significantly longer periods than those groups receiving naltrexone placebo.
Research on the role of drug treatment as HIV prevention has focused on the impact of treatment participation on reductions in drug use, injections and the sharing of syringes, rinse water, and cotton. However, for drug users who are already infected, a critical prevention intervention is provision of and adherence to HIV treatment as there is growing consensus on the prevention impact associated with participation in antiretroviral treatment and sustained virologic response. 53–55 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. 56 Despite the personal and public health benefits of antiretroviral treatment, drug use has frequently been associated with poorer access to antiretroviral treatment and poorer adherence among those who receive it.57,58 These data have led to research on the role of drug treatment in providing access to HIV treatment and issues related to adherence. In a 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. 59 The data also demonstrate higher rates of adherence to HIV treatment among those in methadone treatment. 60,61
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.62 In this study patients who continued to inject regardless of their treatment participation showed poorer outcomes. For patients who were in methadone or buprenorphine maintenance 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 study was the first to document the fact that drug treatment participation alone is not sufficient to explain adherence. Importantly, this cohort also produced data showing that retention in medication assisted treatment was linked to long term virologic suppression. 63 These data are consistent with earlier reports of poorer adherence among patients that continue substance use and improved adherence among those in drug treatment. 64
Risky sexual behaviors have frequently been found to co-occur with both injection and non-injection drug use, particularly with cocaine and other stimulant use.65–67 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.67 It has been rare to find evidence that participation in drug treatment alone leads to significant reductions in sexual risk however several studies have reported positive findings with sexual risk reduction interventions when they are delivered within drug treatment programs, using the drug treatment program as a platform for intervention delivery. Both individual and group strategies have been investigated as have gender specific and gender mixed strategies. 68–70 While positive results have been reported, findings have been less consistent than those linking drug treatment to reductions injection related risks.71,72 It seems clear that sexual risk reduction is a more challenging behavioral target than reduction in drug risk behaviors due in part to the absence of effective medication assisted treatments for stimulant use.
HIV testing has become a primary public health strategy in efforts to reduce transmission and an essential component of the “seek, test, and treat” approach to the identify persons who are infected, get them into treatment, and reduce the pread of HIV with the ultimate goal of eradication.73,74 Since both non-injection and injection drug users are at elevated risk of HIV infection, drug treatment programs would seem to be on the “front lines” of efforts to identify individuals infected but unaware of their status. Despite this opportunity, recent studies have documented that only a minority of drug treatment programs actually provide HIV testing to their clients. 75,76
Since the relationship between drug use and AIDS was first identified, drug users have been the target of a broad range of interventions designed to prevent HIV transmission, but none have received as much scientific attention as substance abuse treatment. The data reviewed here provide strong and consistent evidence that effective treatments for drug abuse and dependence reduce the frequency of use, risk behaviors, and infections. While these findings were observed during the first 15 years of the epidemic primarily from countries with existing drug treatment systems, more recent data are able to provide evidence of these same impacts, particularly in countries with more recently established treatment programs and systems. 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. We believe that the primary mechanism underlying this relationship is the ability of medication assisted treatments for opiate dependence to address the biological and behavioral components of abuse and dependence and thereby stop or reduce injections.
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 for those who stay in treatment. This is particularly important considering the need for multiple treatment options in communities affected by HIV and other blood borne and sexually transmitted infections.
Given the importance of effective antiretroviral treatment as an HIV prevention intervention, the recent literature significantly expands the role of effective substance abuse treatments as HIV prevention. Through participation in effective treatments, drug users have improved access to antiretroviral treatment, improved adherence to those treatments, and improved chances of sustained reductions in viral load. These studies have also provided clear evidence that current use of substances, not past diagnoses or individual characteristics, is the critical factor in adherence.
Despite the growth of the literature and continued positive findings on drug treatment as HIV prevention many important issues require additional research attention. Among these is the need for data to more clearly define the role of counseling in medication assisted treatments. While findings that drug treatment reduces risk 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 will undoubtedly help many dependent individuals avoid withdrawal, risk behaviors and other negative consequences associated with dependence, it is not clear that this strategy is a very effective treatment for addiction.
Within treatment programs themselves, there remains much to be done to maximize their HIV prevention potential. The fact that HIV testing is performed in only a minority of treatment programs is a serious concern and in direct conflict with global prevention initiatives. The potential of directly observed treatment and contingency management strategies as a tool for improved adherence to HIV medications among methadone patients provide important direction for future research and program development.60,77,78
Given the fact that only a small portion of drug users ever enter formal treatment, research is also needed to develop and evaluate strategies for embedding effective drug treatments in non-traditional settings where risk behaviors are common and HIV infection is prevalent. Enormous opportunities exist for the delivery of health promoting drug treatment messages outside of drug treatment programs. Schools, work environments, emergency rooms, homeless programs, and primary health care settings are all viable locations for “low intensity” drug treatment interventions and could significantly expand access to drug treatment.
HIV prevention research should be more closely linked to medication development efforts. New, long acting formulations of existing medications (naltrexone and buprenorphine) offer opportunities for significant advances in HIV prevention efforts. As new medications for stimulant abuse move through safety and efficacy trials, measures of risk behavior need to be included. Vaccines for drug abuse are also in early stages of development and prevention research needs to be present. By testing the efficacy of these new products and strategies early in their development, their indication for use as prevention interventions may be accelerated.
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 literature is quite clear that medication assisted treatments are effective HIV prevention strategies. Unfortunately, comparably effective medication assisted treatments for cocaine and other stimulant use 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 remains a high priority.
Clearly, drug treatment programs play a critical role in controlling the spread of HIV and improving its treatment in many communities around the world. Still, the great majority of drug users do not have access to effective substance abuse treatments--even in countries considered to be more highly developed. 79 The data reviewed in this paper can help to promote policies designed to increase access to drug treatment. 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 preparation of this manuscript was supported in part by the following grants: P60-DA-005186-22, Center for Research on Improving the Treatment of Drug Abuse; U10-DA013043-07, Delaware Valley Node of the Clinical Trials Network (CTN); U01-AI-048014, Penn Prevention Clinical Trials Unit (PPCTU); RO1-DA-026344-01A1
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.
George E. Woody, University of Pennsylvania/Treatment Research Institute, 600 Public Ledger Building, 150 South Independence Mall (W), Philadelphia, PA 19106, P: 215-399-0980 X112, F: 267-886-1160.
Charles P. O’Brien, University of Pennsylvania/Treatment Research Center, 3900 Chestnut Street, Philadelphia, PA 19104, P: 215-222-3200 X132, F: 215-386-6770.