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A Trial of Integrated Buprenorphine/Naloxone and HIV Clinical Care

  1. Lynn E. Sullivan1,
  2. Declan Barry2,
  3. Brent A. Moore2,
  4. Marek C. Chawarski2,
  5. Jeanette M. Tetrault1,
  6. Michael V. Pantalon2,
  7. Patrick G. O'Connor1,
  8. Richard S. Schottenfeld2, and
  9. David A. Fiellin1
  1. 1 Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
  2. 2 Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
  1. Reprints or correspondence: Dr. Lynn E. Sullivan, Yale University School of Medicine, 333 Cedar St., PO Box 208025, New Haven, CT 06520-8025 (lynn.sullivan{at}yale.edu).
 
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Abstract

Background Untreated opioid dependence adversely affects the care of human immunodeficiency virus (HIV)-positive patients. Buprenorphine, a partial opioid agonist, is available for maintenance treatment of opioid dependence in HIV specialty settings. We investigated the feasibility and efficacy of integrating buprenorphine, along with 2 levels of counseling, into HIV clinical care.

Methods HIV-positive, opioid-dependent patients were enrolled in a 12-week pilot study and randomized to receive daily buprenorphine/naloxone treatment along with either brief physician management or physician management combined with nurse-administered drug counseling and adherence management. Primary outcomes included treatment retention; illicit drug use, assessed by urine toxicology test and self-report; CD4 lymphocyte counts; and log10 HIV type 1 (HIV-1) RNA levels.

Results Of the 16 patients who received at least 1 dose of buprenorphine, 13 (81%) completed 12 weeks of treatment. The proportion of opioid-positive weekly urine test results decreased from 100% at baseline to 32% (month 1), 20% (month 2), and 16% (month 3). Only 4 patients reported any opioid use (in the prior 7 days) during the 12-week study. CD4 lymphocyte counts remained stable over the course of the study. The mean log10 HIV-1 RNA level (± standard deviation) declined significantly, from 3.66 ± 1.06 log10 HIV-1 RNA copies/mL at baseline to 3.0 ± 0.57 log10 HIV-1 RNA copies/mL at month 3 (P < .05). No significant differences based on counseling intervention were detected. All 13 patients who completed the study continued to receive treatment in an extension phase of at least 0–15 months' duration.

Conclusions We conclude that it is feasible to integrate buprenorphine into HIV clinical care for the treatment of opioid dependence. Patients experienced good treatment retention and reductions in their opioid use. HIV biological markers remained stable or improved during buprenorphine/naloxone treatment.

Injection drug use directly and indirectly accounted for more than one-third (36%) of AIDS cases in the United States and 22% of the 43,000 new AIDS cases reported in 2003 [1]. Many patients with HIV infection and opioid dependence do not receive treatment for one or both conditions or receive care in 2 distinct locations, an opioid treatment program and an HIV specialty setting. The separation of medical care increases burdens on patients for whom adherence to HAART and opioid agonist therapies is necessary to ensure improved health outcomes. Regimens for the treatment of HIV infection have become increasingly complicated; thus, patient adherence to these regimens is particularly challenging, especially for opioid-dependent individuals. Opioid-dependent HIV-positive patients are less likely than non-opioid-dependent HIV-positive patients to receive HAART and, when prescribed it, are less likely to adhere [2–6].

One approach to increasing adherence to HAART is to provide HIV treatment within opioid-dependence treatment programs. Several studies evaluating this practice in treatment programs providing methadone indicate that this approach is associated with increased adherence to HIV treatment protocols and may decrease viral replication, reduce illicit opioid use, and decrease HIV transmission [7–9]. An alternative approach, evaluated in the present study, is to provide opioid agonist maintenance treatment as part of the services offered in an HIV specialty treatment clinic. This approach is facilitated by the recent approval of buprenorphine, a partial μ-opioid agonist that is effective for the treatment of opioid dependence and can be prescribed by office-based physicians [10, 11] who have undergone the required training and certification [12]. The provision of buprenorphine by physicians for opioid agonist maintenance treatment outside of opioid treatment programs introduces the possibility of providing an integrated office-based treatment model for patients with opioid dependence and HIV infection. Although data on the use of buprenorphine among HIV-positive patients are limited, an evaluation of a cohort in France revealed that there was no adverse short-term impact of buprenorphine on HIV biological markers in patients receiving HIV medications and that, compared with active injection drug users, patients receiving buprenorphine had a significantly higher level of adherence to their HIV treatment regimens [13].

Counseling services are an integral part of the treatment of opioid dependence and HIV infection, but strategies for providing counseling and the optimal intensity of counseling for patients receiving integrated office-based treatment have not been systematically evaluated. Prior research demonstrates that treatment outcomes are improved when patients receiving opioid agonist maintenance treatment receive additional counseling for opioid dependence [14, 15] and HIV infection [7]. The purpose of the present pilot study was to determine the feasibility and efficacy of providing buprenorphine maintenance treatment, in conjunction with 2 levels of psychosocial support, to patients in an HIV clinical care setting.

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Patients and Methods

Patients

HIV-positive individuals seeking opioid agonist maintenance treatment were recruited for this 12-week clinical trial. Potential subjects were identified from among those receiving care at one of the HIV specialty clinics in New Haven County, Connecticut. Neighboring substance abuse treatment programs also served as sources of referral and recruitment. In addition, flyers and advertisements were used for recruitment purposes. To reach patients not currently engaged in HIV care, a sampling approach termed “respondent-driven sampling” was employed [16]. One of the goals of this approach is to gain more access to hidden populations of drug abusers who would not ordinarily seek routine medical care. In using respondent-driven sampling, we attempted to engage current study participants as active recruiters by way of the provision of incentives.

HIV-positive individuals were eligible for inclusion in the study if they met the criteria for opioid dependence as outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [17] and had opioid-positive urine toxicology test results during intake. Patients were excluded if they met criteria for current alcohol, cocaine, benzodiazepine, or sedative dependence; were suicidal or homicidal; or had acute medical or psychiatric conditions. Women had to agree to use adequate contraception and to receive monthly pregnancy monitoring throughout the study.

Treatment setting

The study was conducted in the Nathan Smith Clinic, the HIV primary care clinic of Yale-New Haven Hospital. The Nathan Smith Clinic is an urban HIV clinic serving ∼850 HIV-positive patients. Sixty percent to 70% of these patients have a lifetime history of heroin and/or cocaine use, although levels of current use are lower. The clinical staff includes attending and fellow-level HIV physicians, a mid-level HIV provider, social work and nursing staff, and physicians providing on-site hepatitis C treatment and psychiatric services. Study patients received their medications and underwent counseling and research assessments on site at the Nathan Smith Clinic.

Dosing of buprenorphine

Buprenorphine was provided as buprenorphine/naloxone (4 : 1) in a sublingual tablet form. Patients received 8 mg (buprenorphine component) on day 1, 12 mg on day 2, and 16 mg thereafter. The dosing protocol allowed for 2 dose upgrades (to 20 mg and 24 mg). The dose of buprenorphine/naloxone was increased when urine toxicology results continued to be positive for opioids or when patient discomfort resulted from withdrawal or opioid craving. All patients received a 2-week buprenorphine/naloxone stabilization regimen, during which time they attended the clinic 3 times per week, received an observed dose of buprenorphine/naloxone, and took home a 1-day or 2-day supply of medication. During the 10-week maintenance period, patients came to the clinic once weekly to take their buprenorphine/naloxone under direct observation and were given a 6-day supply for take-home administration. After completion of the maintenance period, patients were offered the option to undergo a 2-week buprenorphine/naloxone tapering and withdrawal protocol or to continue in a compassionate-use extension phase (see below) of the protocol.

Psychosocial support

All patients received physician management (PM), which is a brief (15 min/session), manual-guided, medically focused treatment. PM has been adapted from the Standard Medical Management manual (D. A. Fiellin, M. V. Pantalon, L. Gordon, R. S. Schottenfeld, and P. G. O'Connor, unpublished manual) used in our previous study of primary care maintenance treatment [18]. PM was provided by a study physician, who was certified in addiction medicine and experienced in HIV care, at each patient's biweekly visit. In PM, the physician reviewed and monitored the patient's drug use, symptoms, and progress. Half of the patients received PM plus manual-guided drug counseling (DC) (duration, 30 min) along with adherence management (AM) (duration, 15 min). DC is manual-guided advice and counseling that follows the general outline for PM but provides additional information and the opportunity to review 12 addiction-specific topic areas (e.g., triggers, relationships, and craving) that are not systematically covered in PM [19]. AM was adapted from a medication management strategy employed by Sorensen et al. [20] for opioid-dependent patients receiving methadone; AM uses 9 strategies designed to increase HAART adherence among opioid-dependent patients receiving opioid agonist maintenance treatment. DC/AM was provided on a weekly basis by trained and supervised nursing staff. Weekly review of the nurse counseling issues with the supervising physician and a doctorate-level clinical psychologist was provided. Adherence to the PM and DC/AM manuals and competence/performance of the nurse counselors were assessed throughout the study during weekly supervision and through ratings of audiotapes of sessions with subjects.

Treatment assignment

Patients were randomly assigned to 1 of the 2 counseling strategies, by use of a randomization procedure that included gender and achievement of abstinence during the 2 weeks of the stabilization phase [21].

Treatment outcomes

Primary outcome measures included retention in buprenorphine/naloxone treatment; illicit drug (opioids and cocaine) use, assessed by urine toxicology test and self-report; CD4 lymphocyte count; and log10 HIV-1 RNA level. Urine toxicology testing for opioids included assays for morphine metabolites, oxycodone, and methadone. For 1 patient with end-stage renal disease who was receiving peritoneal dialysis and was unable to reliably submit urine samples, we substituted self-report data when no urine toxicology data was available. Secondary outcomes included adherence to buprenorphine/naloxone and HAART medications, as measured by Medication Event Monitoring System caps (APREX) that contain a microcomputer chip that records the date and time each time that the pill bottle is opened; liver function test results; HIV transmission risk behaviors, as determined by the AIDS/HIV Risk Inventory [22]; health status, as measured by the Medical Outcomes Study 36-item Short Form Health Survey [23]; and patient satisfaction. The AIDS/HIV Risk Inventory is a validated, structured interview that assesses high-risk drug and sexual behaviors in opioid-dependent patients and investigates both the frequency and recency of these high-risk behaviors. Patient satisfaction was measured by use of standard questionnaires modified for the purposes of this study, using items with a 5-point Likert scale [24]. Measurements at study completion are reported.

Extension phase

Patients who were clinically stable throughout the 12-week study without evidence of ongoing illicit drug use were offered compassionate-use extension of the protocol and the opportunity to continue to receive their treatment with buprenorphine/naloxone in the Nathan Smith Clinic. These patients continued to receive buprenorphine/naloxone dispensed at 2-week intervals, with monthly physician evaluations and substance abuse counseling provided as needed to prevent relapse.

Statistical analysis

We conducted an analysis of baseline characteristics, including descriptive statistics for all patients who received at least 1 dose of buprenorphine/naloxone. Outcomes were compared, using the χ2 test and Fisher's exact test for dichotomous variables and the t test for continuous measures, for all patients who completed the 2-week induction and stabilization period.

Treatment retention was evaluated using the Kaplan-Meier product limit method and the generalized Wilcoxon test. Mixed models were used to conduct repeated-measures analysis with fixed and random effects on the primary outcome measures. We determined the proportion of urine specimens positive for opioids for each month that the participant was in treatment. Urine toxicology test results were considered to be positive for opioids if the specimen was positive for morphine metabolites, methadone, or oxycodone. Cutoff levels were 300 ng/mL for opioids and 1000 ng/mL for methadone and oxycodone. Missing specimens were not counted as positive. All analyses used 2-tailed tests of significance and were performed using SPSS software, version 12.0 (SPSS). P < .05 was considered to be statistically significant.

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Results

Patient flow

Twenty-seven patients demonstrated interest in receiving integrated buprenorphine/naloxone treatment and HIV clinical care over a 16-month period. Of these, 16 (59%) completed the baseline evaluation and received an initial dose of buprenorphine/naloxone, and 11 patients completed the baseline evaluation but did not receive an initial dose of buprenorphine/naloxone because they either chose to continue to receive methadone treatment or did not maintain contact with the research team.

Demographic and clinical characteristics

The demographic and clinical characteristics of the 16 patients who received at least 1 dose of buprenorphine/naloxone are shown in table 1.

View this table:
Table 1

Baseline demographic and clinical characteristics of HIV-positive opioid-dependent patients receiving buprenorphine/naloxone in an HIV clinic.

Retention in treatment

Of the 16 patients who received a dose of buprenorphine/naloxone, 13 (81%) completed the 12-week study, and 3 (19%) discontinued treatment after receiving the first dose of medication.

Illicit drug use

In general, the proportion of opioid-positive urine toxicology test results decreased over time for the 13 patients (figure 1). All patients had a documented opioid-positive urine toxicology test result at baseline. The proportion of urine toxicology test results positive for opioids decreased, from 32% at month 1, to 20% at month 2, to 16% at month 3 (P = .36). Only 4 patients reported any opioid use (in the prior 7 days) during the 12-week study. Of these 4 patients, 3 reported 2 days of opioid use during this time frame, and 1 reported 1 day of opioid use.

Figure 1
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Figure 1

Opioid urine toxicology test results for opioid-dependent HIV-positive patients receiving buprenorphine/naloxone in an HIV clinic.

Twenty-one percent of patients had a cocaine-positive urine toxicology test result at baseline. The proportion of cocaine-positive urine toxicology test results was relatively stable throughout the 12-week study, with 33% positive at month 1, 34% positive at month 2, and 33% positive at month 3 (P = .36). The percentage of days of self-reported cocaine use for each participant was stable during the study: 19% at baseline, 5% at month 1, 9% at month 2, and 7% at month 3 (P = .40).

HIV biological markers

Figure 2 shows the CD4 lymphocyte counts of the 13 patients who completed the 12-week study. The mean CD4 lymphocyte count (±SD) was 414 ± 344 cells/µL at baseline and 385 ± 255 cells/µL at month 3 (P = .56). At baseline, 6 (46%) of the 13 patients met criteria for AIDS, with a CD4 lymphocyte count of <200 cells/µL (range, 123–186 cells/µL). The mean log10 HIV-1 RNA level of 3.0 ± 0.57 log10 HIV-1 RNA copies/mL at month 3 was significantly lower than the mean baseline level of 3.66 ± 1.06 log10 HIV-1 RNA copies/mL (P < .05) (figure 3).

Figure 2
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Figure 2

CD4 lymphocyte counts for opioid-dependent HIV-positive patients (patients 1–13) receiving buprenorphine/naloxone in an HIV clinic

Figure 3
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Figure 3

Log10 HIV-1 RNA levels in opioid-dependent HIV-positive patients (patients 1–13) receiving buprenorphine/naloxone in an HIV clinic

Adherence to treatment

The overall mean adherence to buprenorphine/naloxone treatment was 91%, and there was significant improvement in adherence over time (P = .03). The overall mean adherence to HAART was 68%. Time had no effect on adherence to HAART.

Liver enzyme tests

There were no significant changes in alanine aminotransferase or aspartate aminotransferase levels during the course of study. The mean alanine aminotransferase level (±SD) was 39.8 ± 18.1 U/L at baseline and 43.0 ± 29.4 U/L at month 3 (P = .71); the mean aspartate aminotransferase levels (±SD) were 36.5 ± 16.0 and 39.2 ± 23.4 U/L, respectively (P = .56).

HIV-transmission risk behaviors

Although overall HIV transmission risk behavior, as assessed by the AIDS/HIV Risk Inventory, was lower at the end of treatment, with a mean score (±SD) of 69.9 ± 63.4, compared with the mean baseline score (±SD) of 95.6 ± 63.5, the difference was not statistically significant (P = .31). The subscale scores examining sex-related HIV transmission risk behaviors also did not differ statistically over the course of treatment (P = .84). However, there was a decrease (P = .06) in the mean AIDS/HIV Risk Inventory drug use-related subscale score, from a baseline mean (±SD) of 24.8 ± 28.6 to an end-of-treatment mean (±SD) of 8.5 ± 10.5.

Health status

There were no significant changes in the mean total Medical Outcomes Study 36-item Short Form Health Survey scores from the baseline value (±SD) of 105.0 ± 18.2 to the end-of-treatment value (±SD) of 109.5 ± 23.3 (P = .60).

Patient satisfaction

Of the 13 patients completing the study, 12 (92%) completed a patient satisfaction questionnaire at week 12. Eight (67%) of the 12 patients reported that they were “somewhat satisfied” or “very satisfied” with the treatment overall. All of the patients stated that the quality of care that they received at the HIV clinic was either “very good” or “excellent.” Ten (83%) of the 12 patients felt that the physician and nursing staff “completely understood” or “understood a lot” about their substance abuse problem, and all of the patients thought that the physician and nursing staff were knowledgeable about treating this problem. In addition, 100% of respondents felt that the services helped them deal more effectively with their drug problem, and 6 (67%) of the 9 patients who were receiving HIV medications reported that receiving buprenorphine treatment helped them in taking their HIV medications.

Psychosocial counseling interventions

There were no differences in treatment retention by counseling group, because all participants randomized to the 2 counseling interventions were retained in treatment. There were no significant group or group-by-time effects on illicit drug use based on the 2 counseling interventions (P ⩾ 0.14, for all comparisons).

Extension phase

On completion of the 12-week trial, patients entered the extension phase serially, with observed retention in treatment up to 15 months. All 13 patients who completed the 12-week trial continued treatment in the extension phase. Eleven (85%) of 13 patients completed an additional 3 months of follow-up, for a cumulative treatment time of 6 months. Nine patients were followed for an additional 6 months (cumulative period, 9 months), 6 (67%) of whom remained in treatment. Of the 10 patients with 3 months of follow-up, 5 (50%) had at least 1 opioid-positive urine toxicology test result during that follow-up. The patient receiving peritoneal dialysis was unable to provide urine samples during the 3-month follow-up, although he reported no illicit drug use. At the 3-month follow-up point, the mean CD4 lymphocyte count remained stable, and the mean log10 HIV-1 RNA level continued to decline (figures 2 and 3). During the extension phase, 2 patients with significant comorbid conditions (progressive multifocal leukoencephalopathy and end-stage renal disease) died of conditions that were neither drug related nor treatment related (1 after a total of 7 months of treatment, and 1 after a total of 8 months of treatment).

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Discussion

To our knowledge, this study represents the first reported clinical trial of buprenorphine/naloxone in HIV-positive patients in the United States. The results demonstrate that a significant portion of interested patients carry through to receive a first dose of buprenorphine/naloxone. We found that, of the patients who received a first dose, the majority were retained in treatment for ⩾3 months and that these patients demonstrated a decrease in their illicit opioid use, as well as stable or improved HIV biological markers. Over the 3-month period, patients demonstrated good buprenorphine/naloxone adherence, moderate HAART adherence, decreased levels of HIV transmission risk behaviors, good health status, and high levels of satisfaction. The lack of significant changes in serum transaminase levels over time is notable, given that buprenorphine is a thebaine derivative and, as such, may lead to hepatotoxic effects, especially in patients with hepatitis C [25–28]. In the present study, 10 (77%) of the 13 patients who completed the 12-week study had antibodies to hepatitis C virus. We believe that this study demonstrates that it is feasible to provide integrated buprenorphine/naloxone and HIV clinical care. The study also indicates that it is possible to integrate minimum and more-enhanced counseling services for patients receiving integrated care. Although a determination of which type or intensity of counseling is most efficacious is important to clinicians, researchers, and administrators, a larger clinical trial, currently under way, will be required to answer this question.

Our results provide empirical data to support the theoretical discussion regarding integrated buprenorphine and HIV care. As such, we provide information that complements the results of the MANIF 2000 cohort study, which used buprenorphine rather than buprenorphine/naloxone. This earlier work demonstrated adequate CD4 lymphocyte and viral load responses and increased adherence among HIV-positive patients receiving buprenorphine [13, 29, 30]. In contrast, the present study is unique, in that it is entirely made up of patients who were actively using opioids before treatment admission. The 2 deaths seen in the extension phase reflect the underlying trajectory for HIV-positive patients with significant morbidity and the mortality associated with opioid dependence [31].

A growing literature has outlined potential and clinically significant medication interactions between methadone and HAART medications, especially the protease inhibitor class [32]. Limited research is available regarding potential and clinically significant medication interactions between buprenorphine and HAART medications [33, 34]. The limited series of patients in the present study experienced no episodes of opioid withdrawal secondary to HAART medication, and there were no reports of HAART failure due to medication interactions with buprenorphine. Finally, the present study demonstrates similar, if not improved, treatment retention, compared with studies of buprenorphine that have focused exclusively on HIV-negative patients [11, 14, 35, 36].

The implications of this study are limited to similar patient populations. Although not all patients who expressed initial interest in treatment elected to enter the trial, the baseline demographic and clinical characteristics of those patients who expressed an interest in treatment but did not go on to receive a first dose of buprenorphine/naloxone did not differ from those of patients who did receive buprenorphine/naloxone, and so the lack of participation of such patients in the study is not likely to have had a significant impact on the final results. To assess the feasibility of this new treatment paradigm, we excluded patients who had untreated alcohol dependence or severe untreated mental illness. Future studies should address the appropriate level of services needed to treat, in office-based settings, patients with these other comorbidities. We strove to model routine clinical care by developing a team that included a physician and nurse team; however, our team included physicians with expertise in HIV infection and buprenorphine/naloxone treatment and nurses experienced in the provision of buprenorphine/naloxone and psychosocial counseling. This model, akin to the models of on-site psychiatric or hepatitis C treatment teams, requires that providers receive a relatively short period of initial training followed by continuing education and supervision regarding opioid dependence treatment. Finally, this pilot study was not adequately sized to detect a difference between the 2 counseling arms, but it was able to demonstrate a successful reduction in illicit opioid use and a significant reduction in HIV-1 RNA levels.

These results have implications for clinical care, education, policy, and research. Our findings suggest that patients with HIV infection and opioid dependence are able to benefit from an integrated model of treatment for their dual conditions. HIV providers should be made aware of these results and encouraged to receive the requisite training and support to implement these services in their practices. Training in the treatment of opioid dependence occurs on a regular and ongoing basis, and specialized training and support services have been developed to assist HIV care providers [37–]. The results of this early demonstration mirror the experience of a number of HIV care providers who have incorporated buprenorphine/naloxone into their practices nationally. Given this early success and the uniform demonstration of the cost-effectiveness of opioid agonist treatment, funding bodies should consider full coverage for the necessary services.

Further work is needed to optimize patient outcomes with regard to their HIV infection and addictive disorders. Given the constraints of time and staffing in HIV clinical care sites, further investigation, currently ongoing, will help to inform these decisions in the future [40]. Despite the need for continuing research, however, HIV care clinicians should strongly consider adding these services to their practice, to allow their eligible patients to benefit from this new treatment paradigm.

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Acknowledgments

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Financial support

National Institute on Drug Abuse (Physician Scientist Award K12 DA00167-11 to L.E.S.; grants K24 DA000445-03 and R01 DA009803-07 to R.S.S.; and grant K23 DA15144 to M.V.P.). L.E.S. is a Robert Wood Johnson Foundation Physician Faculty Scholar, and D.A.F. was a Robert Wood Johnson Foundation Generalist Physician Faculty Scholar.

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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.

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Potential conflicts of interest

M.V.P. was a consultant for Bristol-Myers Squibb during the conduct of this study. All other authors: no conflicts.

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  1. Clin Infect Dis. (2006) 43 (Supplement 4): S184-S190. doi: 10.1086/508182
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