The Potential Role of Buprenorphine in the Treatment of Opioid ...

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SUPPLEMENT ARTICLE

The Potential Role of Buprenorphine in the Treatment of Opioid Dependence in HIVInfected Individuals and in HIV Infection Prevention Frederick L. Altice,1 Lynn E. Sullivan,2 Duncan Smith-Rohrberg,1 Sanjay Basu,1 Sharon Stancliff,3 and Lois Eldred4 1

AIDS Program, Section of Infectious Diseases, and 2Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; 3Harm Reduction Coalition, New York, New York; and 4HIV/AIDS Bureau, Health Resources Services Administration, Department of Health and Human Services, Washington, DC

Untreated opioid dependence is a major obstacle to the successful treatment and prevention of human immunodeficiency virus (HIV) infection. In this review, we examine the interwoven epidemics of HIV infection and opioid dependence and the emerging role of buprenorphine in improving HIV treatment outcomes among infected individuals, as well as its role in primary and secondary prevention. This article addresses some of the emerging issues about integrating buprenorphine treatment into HIV clinical care settings and the various strategies that must be considered. Specifically, it addresses the role of buprenorphine in improving HIV treatment outcomes through engagement in care, access to antiretroviral therapy and preventive therapies for opportunistic infections, and the potential benefits of and pitfalls in integrating buprenorphine into HIV clinical care settings. We discuss the key research questions regarding buprenorphine in the area of improving HIV treatment outcomes and prevention, including a review of published studies of buprenorphine and antiretroviral treatment and currently ongoing studies, and provide insight into and models for integrating buprenorphine into HIV clinical care settings. Dialogue among practitioners and policy makers in the HIV care and substance abuse communities will facilitate an effective expansion of buprenorphine and ensure that these beneficial outcomes are achieved. OVERVIEW OF HIV INFECTION AND OPIOID DEPENDENCE IN THE UNITED STATES Since the early 1980s, the epidemics of HIV infection and opioid dependence have been intertwined, especially in the inner cities of the United States [1]. Today, 1.5 million–2.4 million Americans are opioid dependent, with as many as 898,000 of those individuals being heroin dependent; many have or are at risk for HIV infection [2–5]. Although many opioids can be taken orally or intranasally or can be smoked, injectable opioids (especially heroin) have figured most promi-

Reprints or correspondence: Dr. Frederick L. Altice, Yale University AIDS Program, 135 College St., Ste. 323, New Haven, CT 06510 ([email protected] or [email protected]). Clinical Infectious Diseases 2006; 43:S178–83  2006 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2006/4312S4-0003$15.00

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nently in the HIV infection epidemic. Injection drug users (IDUs) and their partners and children currently account for 36% of the cumulative number of AIDS cases in the United States. HIV transmission associated with injection drug use continues to take an exacting toll, accounting for ∼10,000 of the 40,000 new HIV infections each year [6, 7]. The transmission of drugresistant strains is alarming as well [8]. Although HIV care clinicians have been somewhat effective in counseling patients about reducing HIV risk behaviors [9] and adhering to HAART [10], the most effective treatment strategy for the management of opioid dependence—methadone maintenance treatment (MMT)—has been largely unavailable to HIV care clinicians. Despite 140 years of empirical research demonstrating the efficacy and cost-effectiveness of methadone in treating opioid dependence and in secondarily reducing crime, overdoses, HIV infection, and viral hepatitis [11, 12], US Drug Enforcement Agency regu-

lations have largely excluded HIV care and other generalist clinicians from prescribing the medication. Because of these regulatory issues, combined with inadequate funding and treatment availability and the stigma associated with MMT, only 15%–20% of opioid-dependent patients in the United States are receiving MMT [13, 14]. The introduction of the partial opioid agonist buprenorphine has broadened the number of agonist-based methods available to treat opioid dependence and offers the HIV care clinician an opportunity to address opioid dependence in some patients. Empirical evidence collected over 20 years has provided strong support for buprenorphine as an effective treatment for opioid dependence, typically equivalent to methadone, except in certain patients requiring higher doses of methadone (160–100 mg) [15–19]. The unique pharmacologic properties and regulatory status of buprenorphine, reviewed elsewhere in this supplement, enable the medication to be prescribed by general practitioners. For the first time, opioid agonist therapy is available outside of specially licensed clinics in the United States, thereby potentially expanding access to opioid treatment. In the present article, we describe the role of buprenorphine as an opioid agonist therapy for use among HIV-infected patients and discuss its additional role in HIV infection prevention. Empirical research determining the optimal strategies for delivering this care is limited at this point; however, potential models for the integration of buprenorphine maintenance treatment (BMT) have recently been described [20]. Where available, the empirical literature on BMT is presented, with the gaps filled in by the extensive experience gleaned from MMT. THE EXPANDING ROLE OF THE HIV CARE CLINICIAN BMT, similar to the management of other comorbid conditions, will continue to expand the expertise of the HIV care clinician and create new and unique challenges. In the early part of the HIV/AIDS epidemic, the HIV care clinician primarily diagnosed and treated opportunistic infections and AIDS-related malignancies. Over time, the role of the HIV care clinician has evolved into one involving a more comprehensive and holistic approach to care, including prescribing prophylaxis for opportunistic infections and HAART, managing short- and long-term adverse consequences of HAART, and diagnosing and treating comorbid conditions, such as some forms of hyperlipidemia, mental illness, and hepatitis C virus infection. Moreover, because patients are living significantly longer, some HIV care clinicians now address the myriad consequences of aging. It is in this setting of the expanded role of the primary HIV care clinician that the availability of buprenorphine treatment provides opportunities and challenges in the management of the HIV-infected patient. Although many HIV care clinicians have learned the chal-

lenges of providing care to the substance-abusing patient population, before BMT, medical options had not been available to physicians other than specialists in addiction medicine. Fortunately, BMT allows clinicians who are not addiction specialists to become adept at managing patients with HIV infection comprehensively. BMT is a concrete pharmacological option that HIV primary care physicians may provide for their patients with comorbid opioid dependence, not unlike the use of selective serotonin reuptake inhibitors for patients with depression or oral hypoglycemics for patients with diabetes. Despite the need and willingness on the part of HIV care clinicians to offer their clients comprehensive services, integrating buprenorphine into HIV clinical care presents many challenges. Not surprisingly, many physicians feel unskilled and uncomfortable in managing patients with substance abuse disorders [21, 22]. Physicians receive little training in managing patients with such disorders [23–25] and may not understand that drug dependence is a medical illness rather than a behavioral problem. For example, a sample of the attitudes of 495 HIV-treating physicians showed that the doctors were less willing to appropriately prescribe HAART to IDUs [26]. On the other hand, physicians in drug treatment programs may have different philosophies than HIV care clinicians, regarding how to address active substance abuse. Oftentimes, the primary goal of treatment for drug dependence has been complete abstinence from drugs, whereas HIV care clinicians may be more willing to embrace a harm-reduction approach, by accepting a reduction in substance abuse as a means toward creating stability and improving adherence to HAART rather than imposing the contracts and restrictions that are part of many substance abuse programs. For their part, HIV care clinicians often have little training in therapies for substance abuse [27]. These conflicts, therefore, need to be addressed if the whole patient, rather than a sum of disparate diagnoses, is to be treated [28]. Hence, clinics in HIV care settings will need to determine the model of care to provide BMT in their clinic on the basis of a number of organizational issues [20]. IMPACT OF BUPRENORPHINE ON HIV CARE For patients already infected with HIV, active opioid use decreases both access and adherence to HAART, as well as other health-promoting treatments and behaviors [29–34]. Active substance abuse can lead to early discontinuation of HAART once prescribed [35] and can contribute to such destabilizing conditions as homelessness and mental illness, both of which have a negative impact on adherence to treatment [36]. The long-standing experience with MMT provides some evidence of the benefits that can be conferred to the HIV-infected patient, in addition to reduction in illicit opioid use. The stability provided by reductions in illicit substance abuse improves

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general HIV medical care [37–40], including prophylaxis against opportunistic infections [41–43], preventive vaccinations [44], and treatment of HIV infection [41, 45, 46] and concomitant hepatitis C virus infection [47, 48]. Although not yet demonstrated empirically, it is hoped that BMT will achieve similar positive health outcomes. Data from France, where buprenorphine has been available since 1996, support but do not definitively demonstrate a similar effect for BMT. In one study that included 32 of 164 HIV-infected patients who were receiving BMT, although numbers were too low to reach significance, patients not receiving BMT were 5 times more likely to be nonadherent to HAART than were patients receiving BMT [49]. One of the barriers to effective implementation of buprenorphine in the HIV clinical care setting will be overcoming negative attitudes toward substance abuse. Such punitive and pejorative attitudes have been shown to adversely affect patient recruitment, retention, and outcomes among substance abusers in research studies [26, 50, 51]. Indeed, several studies have demonstrated that (1) substance abusers are less likely to be offered antiretroviral therapy [52–56], as discussed above, and (2) among those for whom HAART is initiated, high levels of adherence are less likely. In a survey of New York State primary care and HIV specialty clinics, HIV specialty clinics were more likely to be willing to prescribe either buprenorphine or methadone than were primary care clinics. Willingness to prescribe buprenorphine in these settings was positively associated with the degree of continuing medical education among providers, a lack of concern about buprenorphine diversion and abuse, and the immediate availability by telephone of someone experienced in substance abuse management [57]. Hence, successful intervention in the HIV care setting will require continued medical education, at specialty conferences, about the management of opioid dependence; successful demonstration of effective buprenorphine provision in HIV clinical care settings; and the development of effective relationships with staff experienced in working with patients with drug dependence. POTENTIAL IMPACT OF BUPRENORPHINE ON PRIMARY AND SECONDARY HIV INFECTION PREVENTION In addition to its impact on HIV clinical care, it is hoped that buprenorphine will have a beneficial role in both the primary and the secondary prevention of HIV infection. Currently, the data on the potential of buprenorphine to reduce both the drugassociated and the non–drug-associated risk for HIV infection are quite limited. Extensive experience with methadone in HIV infection prevention, however, suggests that this will be the case. Probably the biggest impact that opioid agonist therapy has on HIV transmission is among opioid-dependent patients who S180 • CID 2006:43 (Suppl 4) • Altice et al.

engage in injection drug use. In various studies, rates between 287 and 11000 injections/year have been reported among IDUs not engaged in treatment, with ∼20%–51% of these injections involving the sharing of needles. Numerous studies have shown that MMT reduces injection drug use, often resulting in as high as a 70% reduction. Of the injection events that do occur, the proportion that involves shared needles also decreases by ∼70% [45, 58–62]. So, for example, an untreated IDU who might inject 300 times/year and share needles 20% of those times (60 shared injections) would benefit greatly from BMT. Such an individual would reduce their annual number of injections to 90 and their number of shared injection events to 18. Many such individuals, however, would become completely abstinent, which would result in no HIV transmission resulting from injection. Thus, BMT has the potential to markedly reduce HIV transmission. Interestingly, this reduction may cross over to nonopioid injection drug use; in one cross-sectional survey of IDUs, methadone was associated with the fairly typical 50%– 65% reduction in overall injection drug use, as well as with a 33%–50% reduction in injection of cocaine and a 40% reduction in injection of “speedballs” [63]. The impact of these reductions in injection-related risk behaviors was shown in a prospective, longitudinal study of IDUs who were HIV negative at baseline. At 18 months of followup, 3.2% of IDUs receiving MMT had seroconverted, versus 22% of those who were untreated. Although this was not a randomized controlled trial, it is compelling evidence for the effectiveness of opioid agonist treatment for primary HIV infection prevention among opioid-dependent patients [64, 65]. An additional mechanism for both primary and secondary HIV infection prevention is through reduction in sexual risk. Sexual risk behaviors, which account for ∼10% of ongoing IDU-associated HIV transmission in the United States, may be less influenced by agonist therapy. Sexual risk behaviors may also be adversely affected by ongoing substance abuse. Rates of condom use among opioid-dependent patients are typically low, and, even in studies showing a positive impact among patients receiving MMT, the effect tends not to be that large. In one cross-sectional survey, the adjusted average response from patients receiving MMT was that they used condoms “sometimes, at least 25% of the time,” versus “rarely, a few times” in the group not receiving treatment [66]. A metaanalysis of 8 studies assessing the impact of MMT on sexual risk behaviors showed a moderate effect size (r) of 0.2. One practical interpretation of this effect size is the following. If the median rate of condom use is ∼20% in the typical untreated opioid-dependent population (i.e., 50% of patients use condoms at least 20% of the time), then ∼60% of the patients receiving MMT would use condoms at least 20% of the time. Hence, it is unlikely that BMT would directly reduce sexual HIV risk behaviors; however, it provides a potentially effective

site to integrate evidence-based risk-reduction counseling, as has been demonstrated with MMT [67–69]. Although few data on buprenorphine are available, one randomized controlled trial comparing methadone and buprenorphine among 405 patients showed equivalence on multiple measures, including self-reported opioid use and injection risk behaviors [70]. In a randomized controlled trial evaluating the effect of different doses for BMT, sexual risk behaviors were noted to have been reduced, compared with behaviors noted at baseline, in all dosage groups [71]. Opioid maintenance therapy also promotes greater engagement in health care, as was discussed in the previous section. This can allow for greater opportunities for clinical teams to promote behavioral change through brief, targeted secondary prevention interventions. Such interventions have had a demonstrable impact on behavior [9, 72], although the extent to which opioid agonist therapy enhances this is less clear. Ensuring that busy providers make this a priority is no easy task, however, and will require adequate funding for provider education and research into effective and cost-effective approaches. The impact of prevention interventions by health care staff can be magnified by engaging substance abusers in their local communities. Contrary to popular perception, active IDUs are able to deliver prevention messages, such as messages regarding safe injection practices [73, 74]. Patients whose conditions stabilized while receiving buprenorphine should also be capable of participating in such outreach activities, and they can play a major role in promoting HIV infection prevention and testing and in recruiting other IDUs into BMT. RESEARCH AGENDA: EVALUATING THE IMPACT The implementation of buprenorphine, as the first medication to be approved under the Drug Addiction Treatment Act of 2000 [75], will serve as a testing ground for future therapies for substance abuse. The quality of the design of buprenorphine interventions and the collection and analysis of the data will play a major role in shaping public policy for these future therapies. The development of models for integrating buprenorphine into HIV clinical care settings has recently been reviewed. Although it is clear that many challenges can be expected, additional expertise in the area of addiction medicine is urgently needed in the HIV clinical care setting, whether it is provided through general education to all providers within the setting or through provision of on-site addiction specialists. The location of the setting (e.g., urban, rural, or private practice) and the availability and expertise of staff and resources will ultimately dictate how services are organized and delivered [20]. As part of the future empirical evaluation, Ryan White’s Special Programs of National Significance grants have funded 10 sites within the United States to examine the effectiveness of buprenorphine induction and maintenance therapy integration into

HIV clinical care. These funded sites will serve as demonstration projects through which primary data will be extracted for clinical practice and long-term policy planning. Unrelated projects that are in the early stages of implementation are described by Sullivan et al. [76] elsewhere in this supplement. Although some MMT programs have successfully integrated HIV care, there are numerous barriers to such integration, related to licensing, reimbursement, and privacy requirements. With buprenorphine, both drug treatment and HIV care can, in some cases, be provided in a single clinical setting. This may augment all the attendant health benefits of opioid agonist therapy. Another issue will be the determination of the impact of buprenorphine on patients with more-complicated conditions, including multiple comorbid medical and social problems. Many of the studies demonstrating the effectiveness of either BMT or MMT in treating opioid dependence have been conducted primarily among individuals without other comorbid conditions, such as severe mental illness and hepatitis C virus infection [4, 77]. It will be important to evaluate the condition of these patients while they are receiving BMT and how to optimize care. Although, in many cases, randomized controlled trials may not be feasible or even desirable, longitudinal cohort studies and operations research can address many of the key questions facing these patients who have multiple severe comorbidities. As these programs evolve, it will be important to assess the cost-effectiveness of BMT, specifically in the HIV-infected patient population. Even by conservative measures, buprenorphine is a cost-effective intervention for the general population of opioiddependent patients [78, 79]. A full determination of its costeffectiveness requires assessment of its public health impact and not only of its beneficial effects on individual patients. Such effects will need to be measured in terms of their impact on substance abuse treatment outcomes and on HIV treatment outcomes, including quality of life. It should also be noted that buprenorphine is not a replacement for methadone but, rather, an additional pharmacological tool for the treatment of opioid dependence. One study demonstrated higher retention with methadone than with BMT [80]. Methadone is also likely to be the preferred treatment for opioid dependence in patients with chronic pain syndromes. Several pilot projects have found that methadone can be successfully prescribed in the community setting [38]. Success with buprenorphine will ultimately lead to the development of further innovative strategies in the HIV care setting. CONCLUSIONS Data on the role of buprenorphine in improving outcomes among HIV-infected patients with opioid dependence, as well as on its role in HIV infection prevention, are currently emerging. As buprenorphine becomes more widely accessible across a number of different health care settings, BMT can meet the Integrating Buprenorphine and HIV Care • CID 2006:43 (Suppl 4) • S181

goals of treating opioid dependence, enhancing the treatment and prevention of HIV infection, and providing models for the future of physician-prescribed pharmacological therapies for the treatment of substance abuse.

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Acknowledgments Financial support. National Institute on Drug Abuse (grant K24 DA017072 to F.L.A. and Physician Scientist Award [grant K12 DA00167] to L.E.S.); Department of Health and Human Services Health Resources and Services Administration (grant H97HA03800 to F.L.A.); Substance Abuse and Mental Health Services Administration (grant H79 TI 15767 to F.L.A.); National Institutes of Health (Medical Scientist Training Program Grants at the Yale University School of Medicine to D.S.-R. and S.B.). L.E.S. is a Robert Wood Johnson Physician Faculty Scholar. Supplement sponsorship. This article was published as part of a supplement entitled “Buprenorphine and HIV Primary Care: New Opportunities for Integrated Treatment,” sponsored by the National Institute on Drug Abuse, National Institutes of Health, Public Health Service, US Department of Health and Human Services. Potential conflicts of interest. All authors: no conflicts.

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