Bridget M. Kuehn

JAMA. 2010;304(3):261-263. doi:10.1001/jama.2010.963

When patients with HIV infection also are addicted to opioids, treating both disorders simultaneously may help improve outcomes and reduce the spread of HIV or other infections transmitted through needle sharing or risky sexual behaviors associated with injection drug use. But accessing such integrated care has sometimes been a challenge for such patients, who generally had to seek care for opioid abuse at addiction treatment centers and primary HIV care elsewhere. This could be logistically difficult and often led to delays in receiving care.

Now, however, buprenorphine prescribing by HIV clinicians is offering patients the option of receiving treatment for both opioid addiction and HIV infection, an approach that a growing body evidence indicates benefits individual patients and public health.

Figure 05072FA
There are currently about 19 000 US physicians certified to prescribe buprenorphine, but experts urge more physicians, particularly those in HIV primary care, to become certified to meet the demand for opioid addiction treatment.

Since 2002, buprenorphine, a partial opioid agonist, has been available in the United States as an office-based treatment for opioid dependence. Physicians who wish to prescribe the drug may under go a training program and become certified through the Substance Abuse and Mental Health Services Administration (SAMHSA) to prescribe buprenorphine (http://buprenorphine.samhsa.gov/). Methadone, a full opioid agonist, remains available through highly regulated, specialized treatment programs.

„Buprenorphine has definitely expanded access [to addiction care],“ said Amina Chaudhry, MD, MPH, an HIV clinician in Baltimore who prescribes buprenorphine. Chaudhry, who is also a medical officer at SAMHSA’s Center for Substance Abuse Treatment in Rockville, Md, explained that even in cities like Baltimore, where there may be specialty addiction programs nearby, the demand for such care often exceeds the available slots. And rural areas may have no specialty addiction programs at all within a reasonable distance.

IMPROVED OUTCOMES


Studies have suggested that patients with HIV infection and untreated opioid addiction often receive HIV treatment later in the course of their illness, may be less adherent to their antiretroviral therapy regimen, and may engage in behaviors such as unprotected sex or injection drug use that put themselves and others at risk of new infections. But treating patients for both HIV and drug use can improve such outcomes. Although much of this research has focused on the effects of methadone, emerging evidence suggests that buprenorphine has similar benefits and may have a few advantages over methadone treatment for patients with HIV.

A recent randomized trial found that office-based care can improve addiction-related outcomes for patients with HIV and opioid addiction and may lead to faster treatment for addiction (Lucas GM et al. Ann Intern Med. 2010;152[11]:704-711). Gregory M. Lucas, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, and colleagues randomized 93 patients at a Baltimore HIV clinic to receive buprenorphine therapy at the clinic or to receive a referral to specialty addiction treatment elsewhere. Patients randomized to clinic-based opioid agonist treatment with buprenorphine entered addiction treatment much more quickly (84% had initiated such care at 2 weeks compared with 11% in the referral group). During the 12-month trial, participation in opioid addiction treatment was significantly greater in the clinic-based care group (74% participated in such treatment vs only 41% in the referral group). Patients receiving buprenorphine in the clinic also had significantly fewer urine test results that were positive for opioids or cocaine and visited their HIV primary care clinicians more frequently.

However, the researchers did not find differences in HIV-treatment participation or HIV treatment effects between the clinic-based vs referral groups. The authors concluded that the improvements in addiction treatment may have been driven by streamlined access to care because patients referred to outside specialty addiction care may have experienced a delay in treatment initiation. The small sample size may have precluded identifying clinically significant differences in HIV treatment outcomes, they also noted.

The study was part of the Health Resources and Services Administration’s (HRSA’s) Buprenorphine in HIV Primary Care National Evaluation and Support Center (BHIVES; http://www.bhives.org). An analysis of pooled data from 10 sites participating in the HRSA program is under way.

David A. Fiellin, MD, associate professor of medicine at Yale School of Medicine and co-investigator on BHIVES, noted that the program is also probing which approaches to primary care delivery work best in HIV clinics. So far, he and his colleagues have demonstrated in a pilot study that an approach that uses a nurse or other staff member to help coordinate buprenorphine care by overseeing such tasks as urine testing, drug counseling, and medication monitoring can help to reduce drug use among HIV patients, has good retention rates, improves patient function, and promotes patient satisfaction (Sullivan LE et al. Clin Infect Dis. 2006;43[suppl 4]:S184-S190).

Previous studies had suggested that physicians‘ concerns about adherence to antiretroviral treatment by injection drug users with HIV played a role in the likelihood that such patients would be offered highly active antiretroviral therapy or at least experience a delay in receiving such treatment. But results of a French study suggest that integrated treatment of HIV and opioid addiction could allay such concerns. The study found that retention in opioid substitution therapy, either buprenorphine or methadone, is associated with improved virologic outcomes in patients treated with highly active antiretroviral therapy and who had opioid use disorders (Roux P et al. Clin Infect Dis. 2009;49[9]:1433-1440). The study included 53 patients receiving buprenorphine, 28 receiving methadone, and 32 who were not receiving opioid substitution therapy. The median duration of opioid substitution treatment was 25 months.

„Having one-stop shopping for patients means one less barrier to accessing care,“ Chaudhry said.

Buprenorphine also appears to have fewer interactions with antiretroviral drugs than methadone. Elinore F. McCance-Katz, MD, PhD, professor of psychiatry at the University of California, San Francisco, and her colleagues published an article reviewing drug interactions involving methadone and buprenorphine and other medications, including antiretroviral therapies (McCance-Katz EF et al. Am J Addict. 2009;19[1]:4-16). Two HIV medications in particular, efavirenz and nevirapine, have been documented to trigger opiate withdrawal in patients taking methadone but not in patients taking buprenorphine, despite observations of reduced levels of both methadone and buprenorphine when these antiretrovirals were given to patients receiving these opioid therapies, noted McCance-Katz in an interview. A possible reason for the observed differences may be that methadone is metabolized to an inactive substance while buprenorphine is metabolized to norbuprenorphine, which also has opioid effects and may protect patients from experiencing opiate withdrawal, McCance-Katz said.

„It’s very difficult to effectively treat patients [with HIV] if they are in withdrawal,“ she said. „They simply don’t comply with antiretroviral therapy if they are in withdrawal.“

Elevated concentrations of buprenorphine have been documented in patients with opioid dependence and HIV taking atazanavir; such elevated levels were associated with cognitive impairment in a few HIV patients in one case study, while another study in non–HIV-infected patients found only increased drowsiness (Bruce RD and Altice FL. AIDS. 2006;20[5]:783-784 and McCance-Katz EF et al. Drug Alcohol Depend. 2007;91[2-3]:269-278). Such elevations of methadone concentrations have not been documented with atazanavir.

„In general, buprenorphine has fewer interactions with HIV medications, but neither drug has been looked at extensively with many other medications,“ she said, adding that many patients with HIV may be taking a number of medications in addition to antiretroviral drugs.

Integrating buprenorphine treatment into the HIV care setting has another potential advantage: it may be easier for clinicians to spot interactions between addiction and HIV therapies when patients receive buprenorphine treatment at their primary HIV clinic, McCance-Katz said. For example, if a patient receives methadone at one clinic and antiretroviral therapy at another, there may be limited communication between clinicians at the 2 sites and adverse events may not be identified.


CLINICIAN ACCEPTANCE


About 19 000 US physicians are certified to prescribe buprenorphine and about 640 000 patients are receiving the prescriptions compared with about 4500 certified prescribers and a little more than 100 000 patients in 2005, according to Nicholas Reuter, MPH, senior public health analyst at SAMHSA. But access to buprenorphine therapy in the HIV primary care setting in the United States may be limited. Reuter noted that psychiatrists and physicians specializing in addiction treatment were early adopters of office-based buprenorphine prescribing. Today, 31% of the prescribers are classified as general or family practitioners, 21% as psychiatrists, 15% as internal medicine specialists, and the remaining third are other specialists who are not HIV clinicians, according to Reuter. (SAMHSA doesn’t track the number of HIV/AIDS specialists who are certified to prescribe buprenorphine.)

A survey of about 500 HIV clinicians (49.7% response rate) who attended International AIDS Society conferences in the United States in 2006 found that only 85 (17%) worked in offices that prescribe buprenorphine. Of the 323 physicians who responded, only 67 (21%) were certified to prescribe the drug, and only 19 (6%) had ever done so (Kunins HV et al. Fam Med. 2009;41[10]:722-728). Additionally, when presented with a vignette of an opioid-addicted patient with HIV, only 16% of the respondents endorsed primary care buprenorphine treatment as the best option for the patient compared with 49% who endorsed buprenorphine treatment in a substance abuse treatment program and 31% who endorsed methadone treatment in a specialty program.

Fiellin noted that other BHIVES efforts have found that clinicians may feel they do not have adequate training and resources to provide addiction treatment but are interested in receiving additional training. The clinics that have implemented primary care buprenorphine care as part of BHIVES have received technical support during implementation, and over time their satisfaction with and sophistication at providing buprenorphine care have improved, he noted.

Another program offering resources to buprenorphine-prescribing physicians is SAMHSA’s Physician Clinical Support System (PCSS), which is directed by Fiellin and includes McCance-Katz as among the clinical experts who work with the program. PCSS helps match new buprenorphine prescribers to more experienced mentors who work in similar settings, including HIV primary care. The program also has drafted a guidance document for buprenorphine prescribing to patients with HIV (http://www.pcssbuprenorphine.org/pcss/documents2/PCSS_OpioidTherapiesHIVDrugInteractions_022808.pdf).

SAMHSA is also working with primary care physicians at federally qualified health centers who may be treating many HIV-infected patients. Reuter explained that the agency would like these centers to offer both buprenorphine and methadone, although the latter would require a center to be licensed as an opioid treatment clinic. He noted that SAMHSA’s goal is to make sure there are as many physicians as possible qualified to provide care to opioid-dependent patients, who may require long-term or recurrent care. For example, the average duration of methadone treatment is 6.8 years. „Our concern is that as long as patients remain engaged in treatment they do very well,“ he said. „A number of patients discontinue and the relapse rate is very high.“

Chaudhry emphasized that primary care buprenorphine treatment is not necessarily a replacement for specialty addiction treatment with methadone or buprenorphine. For example, she noted that some patients may prefer to keep their addiction treatment separate from their HIV care.

„The more treatment choices that providers have to offer the better,“ she said.

A Role for Buprenorphine in Prevention?Between 2004 and 2007, of the 152 917 US individuals in 34 states diagnosed with new HIV infections, 13% of them (n = 19 687) were injection drug users, according to the US Centers for Disease Control and Prevention (MMWR Morb Mortal Wkly Rep. 2009;58[46]:1291-1295). For those who are already infected with HIV, buprenorphine treatment may reduce the likelihood they will spread the infection to others through needle sharing or unprotected sexual activity. And for opioid-dependant individuals who are not already HIV-infected, primary care buprenorphine treatment may reduce risky behaviors that put them at risk of HIV infection, according to a recent study.

Lynn E. Sullivan, MD, and colleagues from the Yale University School of Medicine in New Haven, Conn, compared drug-related and sex-related risk behaviors in 166 buprenorphine-treated individuals at baseline, 12 weeks, and 24 weeks (Sullivan LE et al. J Subst Abuse Treat. 2008;35[1]:87-92). Reports of intravenous drug use among the individuals declined over time, from 37% at baseline to 12% at 12 weeks, to 7% at 24 weeks. The researchers also found a decline in reports of sex while the patient or their partner was high between baseline (64%) and 12 weeks (13%), although such reports increased to 15% a 24 weeks, and inconsistent condom use with a regular partner remained unchanged.

Such benefits may be particularly important in regions of the world where HIV transmission is driven primarily by injection drug use. In Eastern Europe and Central Asia, for example, the Joint United Nations Programme on HIV/AIDS estimates that more than 80% of all HIV infections are caused by contaminated injection equipment (http://www.unaids.org/en/PolicyAndPractice/KeyPopulations/InjectDrugUsers/).

The HIV Prevention Trials Network, an international clinical trials network funded by the National Institute of Allergy and Infectious Diseases, currently has a phase 3 randomized trial under way in China and Thailand to assess whether buprenorphine in combination with naloxone (to reduce the abuse potential) decreases drug use and HIV-related risk behaviors (http://www.hptn.org/research_studies/HPTN058.asp). The trial, which is enrolling about 1500 HIV-uninfected injection drug users, will randomize individuals to receive either buprenorphine plus naloxone for 1 year or detoxification with buprenorphine plus naloxone for up to 18 days (with a second detoxification if necessary). Both groups will also receive counseling for HIV risk reduction. The study will assess cumulative HIV incidence and death and frequency of drug use and drug-related and HIV-related risk behaviors in the 2 groups.—B.M.K.