Valerie A. Gruber

Methadone, Buprenorphine, and Street Drug Interactions with Antiretroviral Medications

While street drugs appear unlikely to alter the metabolism of antiretroviral (ARV) medications, several ARVs may induce or inhibit metabolism of various street drugs. However, research on these interactions is limited. Case reports have documented life-threatening overdoses of ecstasy and gamma-hydroxybutyrate after starting ritonavir, an ARV that inhibits several metabolic enzymes. For opioid addiction, methadone or buprenorphine are the treatments of choice. Because a number of ARVs decrease or increase methadone levels, patients should be monitored for methadone withdrawal or toxicity when they start or stop ARVs. Most ARVs do not cause buprenorphine withdrawal or toxicity, even if they alter buprenorphine levels, with rare exceptions to date including atazanavir/ritonavir associated with significant increases in buprenorphine and adverse events related to sedation and mental status changes in some cases. There are newer medications yet to be studied with methadone or buprenorphine. Further, there are many frequently used medications in treatment of complications of HIV disease that have not been studied. There is need for continuing research to define these drug interactions and their clinical significance.

A randomized trial of 6-month methadone maintenance with standard or minimal counseling versus 21-day methadone detoxification.

BACKGROUND Important questions remain regarding the necessary duration and intensity for methadone treatment to be effective. METHODS As part of a clinical trial of tuberculosis chemoprophylaxis [Batki, S.L., Gruber, V.A., Bradley, J.M., Bradley, M., Delucchi, K., 2002. A controlled trial of methadone treatment combined with directly observed isoniazid for tuberculosis prevention in injection drug users. Drug Alcohol Depend. 66 283-293. doi:10.1016/S0376-8716(01)00208-3], patients with opioid dependence were recruited from an outpatient 21-day methadone detoxification program and were randomly assigned to one of three treatment conditions: (1) continuation in 21-day methadone detoxification; (2) transfer to 6-month methadone maintenance with only minimal counseling; or (3) transfer to 6-month methadone maintenance with standard twice monthly counseling and as-needed social work and psychiatric services. Both the 6-month maintenance treatments were followed by 1.5 months of detoxification. Urine drug tests and self-report measures were collected at baseline, months 1-6, and month 8.5. RESULTS Compared to 21-day methadone detoxification, 6-month methadone maintenance with either minimal or standard counseling resulted in fewer opiate positive urine tests and days of self-reported heroin and alcohol use. There was no change in cocaine use or other outcome measures. The increased counseling available in the standard counseling condition did not appear to reduce heroin use further than the minimal counseling condition, in contrast to the effect found for more structured counseling in long-term methadone maintenance (McLellan et al., 1993). CONCLUSIONS Six months of methadone maintenance, even with minimal counseling, reduces heroin and alcohol use more than 21-day methadone detoxification.

A controlled trial of methadone treatment combined with directly observed isoniazid for tuberculosis prevention in injection drug users.

Substance abuse is associated with high risk for tuberculosis (TB) and poor adherence to medication regimens. This study compared completion rates for isoniazid (INH) preventive therapy for injection drug users (IDUs) randomly assigned to methadone treatment combined with directly observed preventive treatment (DOPT) versus those assigned to routine TB clinic referral without methadone treatment. One hundred and eleven opioid-dependent patients with latent TB were assigned to one of three 6-month treatment conditions: standard methadone treatment including substance abuse counseling combined with daily INH DOPT (n=37); minimal methadone treatment without counseling, also combined with daily INH DOPT (n=35); or routine care referral to TB clinic for monthly INH supplies without DOPT and without methadone treatment (n=39). INH completion rates were 77.1% for minimal methadone and 59.5% for standard methadone, as compared with only 13.5% for routine care (P<0.0001). Mean duration of INH treatment retention was 5.7, 5.0 and 1.6 months, respectively (P<0.0001). TB incidence at 4-year follow-up was 0 of 54 subjects who completed preventive therapy versus 2 of 57 who failed to complete. One of these two had been assigned to routine care, and the other to minimal methadone. In conclusion, INH retention time and completion rates were significantly improved by methadone treatment combined with observed INH, whether or not substance abuse counseling was provided. The results of this study indicate that methadone treatment offers clear public health benefits when it is used to deliver preventive medical services.

Gender differences among HIV-positive methadone maintenance patients enrolled in a medication adherence trial

Abstract This study examined baseline gender differences among HIV-positive methadone maintenance outpatients currently prescribed antiretroviral medications. Participants were enrolled in a larger clinical trial, which included a 4-week observation period using electronic monitors to track medication adherence. Contrary to previous literature, no significant differences were detected between men (n = 42) and women (n = 36) on medication adherence or depression. Both groups showed remarkably poor adherence during baseline (M = 56% of doses taken on time), high overall prevalence of depression (47%) and illicit cocaine use (47%). Women reported significantly more medication side effects (M = 21.4 vs. 14.9), higher severity of ASI psychiatric problems (M = 0.50 vs. 0.40), and lower SF-36 health-related quality of life in physical (M = 42.1 vs. 63.3) and emotional functioning (M = 26.9 vs. 58.9) than men. Women tested positive for opioids at higher rates than men (53% vs. 29%, respectively), whereas men were more likely to be positive for benzodiazepines than women (26% vs. 6%, respectively). Findings suggest that gender differences between male and female methadone maintenance patients have relevance to treatment providers. Extensive assessment, specialized medical care and mental health services may be warranted in the treatment of HIV-positive female drug abusers.

Interactions Between Buprenorphine and the Protease Inhibitors Darunavir-Ritonavir and Fosamprenavir-Ritonavir

BACKGROUND This study examined drug interactions between buprenorphine, a partial opioid agonist used for opioid dependence treatment and pain management, and the protease inhibitors (PIs) darunavir-ritonavir and fosamprenavir-ritonavir. METHODS The pharmacokinetics of buprenorphine and its metabolites and symptoms of opioid withdrawal or excess were compared in opioid-dependent, buprenorphine-naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (11 for darunavir-ritonavir and 10 for fosamprenavir-ritonavir) before and after 15 days of PI administration. PI pharmacokinetics and adverse effects were compared between the buprenorphine-maintained participants and an equal number of sex-, age-, race-, and weight-matched, healthy, non-opioid-dependent volunteers who received darunavir-ritonavir or fosamprenavir-ritonavir but not buprenorphine. RESULTS There were no significant changes in buprenorphine or PI plasma levels and no significant changes in medication adverse effects or opioid withdrawal. Increased concentrations of the inactive metabolite buprenorphine-3-glucuronide suggested that darunavir-ritonavir and fosamprenavir-ritonavir induced glucuronidation of buprenorphine. CONCLUSIONS Dose adjustments are not likely to be necessary when buprenorphine and darunavir-ritonavir or fosamprenavir-ritonavir are coadministered for the treatment of opioid dependence and HIV disease.

Untreated HIV infection is associated with higher blood alcohol levels

Background:Alcohol abuse has been associated with HIV/AIDS progression, but the effects of HIV infection and treatment on alcohol exposure have not been explored to date. This pilot study examines the relationship of untreated HIV infection to blood alcohol concentrations (BAC) relative to BAC after initiation of antiretroviral therapy (ART). Methods:Fifteen volunteers with untreated HIV/AIDS participated in 2 sets of alcohol or alcohol placebo administration studies before and after initiation of ART. Oral alcohol (1 g/kg) or alcohol placebo was administered, participants were followed for pharmacokinetics, subjective responses, and cognitive effects over 8 hours. After initial alcohol studies, the ART regimen selected by participant clinicians was instituted. Observed ART dosing took place for at least 2 weeks. Participants then returned for a second set of alcohol/placebo administration studies while on ART. Results:Participants had significantly higher BAC (P < 0.001) before ART than after ART administration. Alcohol area under the curve was significantly higher in untreated HIV disease (P = 0.011) with significantly higher Cmax (P = 0.015) and Cmin (P = 0.05). The elimination rate was not different between pre-ART and post-ART conditions. Despite declines in BAC after ART initiation, no differences in subjective responses were observed with alcohol administration. Conclusions:Untreated HIV infection is associated with risk for higher BAC than that observed after ART. These findings indicate that patients with untreated HIV disease who ingest alcohol are at greater risk for alcohol associated adverse events and toxicities and underscores the need for simultaneous treatment of alcohol use disorders and HIV in patients with co-occurring conditions.

Interactions between alcohol and the antiretroviral medications ritonavir or efavirenz.

Objective:Alcohol abuse occurs frequently in those with human immunodeficiency virus (HIV) infection. Alcohol has been linked to poor response to HIV treatment and more rapid progression of HIV. One possible contributor to such observations is drug interactions between alcohol and antiretroviral (ARV) medications. This study examined drug interactions between antiretroviral therapies (ARTs) containing either efavirenz or ritonavir with alcohol. Methods:Human immunodeficiency virus–infected individuals not currently receiving ARTs participated in a randomized, double-blind, placebo-controlled study in which alcohol (or placebo) was administered and followed by blood sampling for pharmacokinetics, subjective, cardiovascular, and neuropsychological responses obtained at predetermined times. Antiretroviral therapy was then initiated and alcohol (or placebo) sessions were repeated after at least 2 weeks of observed ART. Results:Blood alcohol concentrations (BAC) were lower after ART in a pattern consistent with decreased bioavailability. No effect of alcohol on ritonavir or efavirenz pharmacokinetics was observed. A pharmacodynamic interaction between alcohol and efavirenz was observed as evidenced by no change in intoxication or drowsiness before and after efavirenz ART despite lower BAC. Conclusions:These results show the effectiveness of implementing ART and its role in diminution of BAC, which could be associated with decreased risk of physiological toxicities related to alcohol consumption relative to those with untreated HIV infection. A potential pharmacodynamic interaction between alcohol and efavirenz was observed as demonstrated by a lack of decline in ratings of intoxication and drowsiness despite decreased BAC. Alcohol consumption did not alter the pharmacokinetics of ritonavir or efavirenz.

Directly administered antiretroviral therapy: Pilot study of a structural intervention in methadone maintenance

Devising interventions to provide integrated treatment for addiction and medical problems is an urgent issue. This study piloted a structural intervention, Directly Administered Antiretroviral Therapy (DAART), to assist methadone-maintenance patients in HIV medication adherence. Twenty-four participants received: (1) antiretroviral medications at the methadone clinic daily before receiving their methadone; (2) take-home antiretroviral medication for days they were not scheduled to attend the methadone clinic, and (3) brief adherence counseling to address adherence barriers. DAART lasted 24 weeks, with a planned step-down to twice-weekly administration in weeks 25-36, followed by self-administration in weeks 37-48. Retention rates at weeks 24, 36, and 48 were 83, 92, and 75% respectively. DAART was associated with improvement in the proportion of participants achieving viral suppression as well as with high medication adherence rates (clinic-verified; 85% and self-reported 97%) during the active intervention phase. DAART was effective as an intervention but did not promote transition to self-administration. This study demonstrates that DAART is adaptable and simple enough to be implemented into methadone treatment programs interested in providing HIV adherence services.

HAART Adherence Strategies for Methadone Clients Who Are HIV-Positive A Treatment Manual for Implementing Contingency Management and Medication Coaching

Research demonstrates that injection drug users with HIV and/or AIDS have difficulty adhering to complex regimens of HIV medications. Because of the risk of increased viral resistance associated with irregular medication adherence, there is considerable clinical need to assist clients who abuse substances in taking their antiretroviral medications on time and as directed. This article outlines intervention strategies to improve medication adherence among clients who are in methadone maintenance. In this treatment manual, the authors delineate contingency management procedures, including voucher incentives and a fishbowl lottery prize system. They also describe intervention elements and adherence tools for medication coaching. The purpose of this manual is to describe the intervention procedures for clinicians and to serve as a resource for drug abuse treatment programs that serve clients who are HIV-positive.

Direct Experience with a Cancer Self-Exam: Effects on Cognitions and Behavior

We tested and expanded Fazios hypothesis that direct experience enhances attitude-behavior consistency (Fazio & Zanna, 1981) to identify effects of experience on the relation of behavior to subjective norm and intention. We also monitored the endurance of the experience effect over time. In order to manipulate experience, we instructed male college students in the United States to perform the testicle self-exam (TSE) a prescribed number of times during an initial week. We compared attitude, subjective norm, intention, and self-reported behavior across experience condition and three postmanipulation times. Direct experience increased later reported TSE behavior and tended to increase attitude and intention. It also enhanced consistency of attitude, subjective norm, and intention with early reported behavior as well as intention with later reported behavior.