Robert Douglas Bruce

Developing a Directly Administered Antiretroviral Therapy Intervention for HIV-Infected Drug Users: Implications for Program Replication

Directly administered antiretroviral therapy (DAART) is one approach to improving adherence to among human immunodeficiency virus (HIV)-infected drug users. We evaluated the essential features of a community-based DAART intervention in a randomized, controlled trial of DAART versus self-administered therapy. Of the initial 72 subjects, 78% were racial minorities, and 32% were women. Social and medical comorbidities among subjects included homelessness (35% of subjects), lack of interpersonal support (86%), major depression (57%), and alcoholism (36%). At baseline, the median CD4+ cell count was 403 cells/mL and the median HIV-1 RNA load was 146,333 copies/mL (log10 5.31 copies/mL). During the prior 6 months, 33% of subjects had missed a medical appointment, and 47% had visited an emergency department. Although most subjects (67%) preferred to take their own medications, 76% would accept DAART if it were made compulsory. A methadone clinic was the DAART venue acceptable to the fewest subjects (36%), and a mobile syringe-exchange program was acceptable to the most subjects (83%). Adherence was higher for supervised than for unsupervised medication administration (P<.0001), a finding that supports use of daily supervision of once-daily regimens. Moreover, DAART should incorporate enhanced elements such as convenience, flexibility, confidentiality, cues and reminders, responsive pharmacy and medical services, and specialized training for staff.

Adherence to hepatitis B virus vaccination at syringe exchange sites.

Injection drug users (IDUs) are at high risk for hepatitis B virus (HBV); however, they often do not receive preventive vaccination. ‘IDUs who use mobile health care services linked to a syring exchange program in New Haven were routinely screened for HBV, hepatitis C virus, and syphilis. Individuals without prior exposure to HBV were offered three-part vaccination series. Of the 212 IDUs screened for HBV infection, 134 (63%) were eligible (negative for HBV surface and core antibodies) for vaccination and 10 (4.7%) had evidence of chronic HBV infection. Compared to those with previous exposure to HBV, vaccine-eligible patients were significantly more likely to be younger and use heroin and less likely to be black, homeless, daily injectors, and cocaine users. Of the 134 vaccine-eligible subjects, 103 (77%) and 89 (66%) completed two and three vaccinations, respectively. Correlates of completing all three vaccinations included older age (OR=1.06, 95% CI=1.04–1.07). injecting daily (OR=2.12,95% CI=1.36–6.73), and being homeless (OR=1.98,95% CI=1.14–12.27). These results suggest that IDUs remain at high risk for acquiring HBV infection. Programs that link health care to a syringe exchange program are effective ways to provide preventive health care services to IDUs, particularly HBV vaccination. Trust engendered by and mutual respect afforded by such programs result in repeated encounters by active IDUs over time.

Clinical Outcomes of Hepatitis C Treatment in a Prison Setting: Feasibility and Effectiveness for Challenging Treatment Populations

BACKGROUND More than one-third of people in the United States with hepatic C virus (HCV) infection pass through the correctional system annually. Data are lacking on outcomes of treatment with pegylated interferon plus ribavirin (PEG-RBV) in correctional settings. METHODS During 2002-2006, we analyzed patients in the Connecticut Department of Correction who received PEG-RBV. We assessed the rates of sustained virological response, hospitalization, and use of medications to treat psychiatric disorders and anemia. RESULTS Of 138 treatment-naive patients referred for treatment, 68 (49%) were approved. Overall, sustained virological response occurred in 47.1% of patients (for HCV genotype 1, 43.1%; for HCV genotypes 2 and 3, 58.8%). Only 9 patients (13%) discontinued treatment because of adverse effects. Multiple regression analysis revealed that not achieving a sustained virological response was correlated with HCV genotype 1 infection plus cirrhosis (adjusted odds ratio, 12.9; 95% confidence interval, 1.1-148) and baseline major depression (adjusted odds ratio, 3.4; 95% confidence interval, 1.01-11.6), but not with HIV infection, a baseline HCV RNA level >or=400,000 IU/mL, or black race. Compared with baseline, the rate of prescription of a new mood stabilizer (2.2 vs. 0.8 prescriptions per person-year) or an opioid (1.8 vs. 0.5 prescriptions per person-year) was higher during treatment, whereas there was no change in the rate of prescription of benzodiazepines and antipsychotic medications. CONCLUSIONS These results support the feasibility and clinical effectiveness of PEG-RBV for the treatment of chronic HCV infection in correctional facilities.

Persistence of Virological Benefits Following Directly Administered Antiretroviral Therapy Among Drug Users: Results From a Randomized Controlled Trial

Background:Although directly administered antiretroviral therapy (DAART) has demonstrated impressive biological benefits compared with self-administered therapy (SAT) among drug users, the persistence of DAART after transition to SAT has not been examined. Methods:We conducted a community-based, prospective, randomized controlled trial of 6 months of DAART compared with SAT. The primary outcome was the proportion of subjects who achieved virological success at 6 months postintervention, defined as either a 1.0 log10 reduction from baseline or HIV-1 RNA <400 copies per milliliter. Secondary outcomes included the change from baseline in HIV-1 RNA and CD4 lymphocyte count. Results:Of the 53 subjects in the SAT arm and 88 subjects in the DAART arm, 52 and 82, respectively, provided blood samples at 6 months postintervention. The DAART (n = 88) and SAT (n = 53) arms did not differ on virological success (DAART 58.0% vs. SAT 56.6%, P = 0.64), mean reduction in log10 HIV-1 RNA (−0.79 vs. −0.31 log10 copies/mL, P = 0.53), or mean change in CD4 lymphocyte count (+60.2 vs. −15.4 cells/mL, P = 0.12). In the multivariate analysis, only high levels of social support significantly predicted virological success. Conclusions:This analysis, from the first randomized controlled trial of DAART among active drug users, failed to show the persistence of the DAART intervention at improving virological outcomes. Additional strategies are needed to ensure the on-treatment benefits persist following the cessation of DAART.

Pharmacokinetic drug interactions and adverse consequences between psychotropic medications and pharmacotherapy for the treatment of opioid dependence

Background: Psychiatric comorbidities among opioid-dependent patients are common. Many medications used to treat both conditions are metabolized through complimentary cytochrome P450 isoenzymes. When medication-assisted treatment for opioid dependence is concurrently used with psychotropic medications, problematic pharmacokinetic drug interactions may occur. Methods: We reviewed relevant English language articles identified through the MedLine, Scopus, and Embase databases from 1950 to December 2009 using the specific generic names of medications and keywords such as pharmacokinetics and drug interactions with buprenorphine, methadone, and naltrexone. Selected references from these articles were reviewed. Additionally, a review was conducted of abstracts and conference proceedings from national and international meetings from 1990 to 2009. A total of 60 studies were identified and reviewed. Results: Clinical case series and carefully controlled pharmacokinetic interaction studies have been conducted between methadone, buprenorphine, or naltrexone and some psychoactive medications. Important pharmacokinetic drug interactions have been demonstrated within each class of medications affecting either methadone and buprenorphine or psychoactive drugs. Few studies, however, have been conducted with naltrexone. Conclusions: Several interactions between methadone, buprenorphine, or naltrexone and psychoactive medications are described and may have important clinical consequences. To optimize care, clinicians must be alerted to these interactions.

Case Series on the Safe Use of Buprenorphine/Naloxone in Individuals with Acute Hepatitis C Infection and Abnormal Hepatic Liver Transaminases

Background: Hepatitis C virus (HCV) is the most prevalent chronic viral illness in the United States. Many individuals with virus HCV are opioid dependent requiring treatment with opiate substitution treatment such as buprenorphine. Previous reports in the literature have suggested hepatotoxicity with buprenorphine tempering initial enthusiasm of the safety of buprenorphine in HCV-infected patients. Methods: As part of an ongoing SAMHSA-funded grant to expand opiate substitution therapy with buprenorphine, all opioid-dependent patients seeking treatment with buprenorphine undergo a laboratory evaluation including transaminases (AST/ALT) as well as laboratory evaluation for acute and chronic hepatitis. Results: Of the 121 patients screened for entry into buprenorphine treatment, 4 patients had evidence of acute HCV infection. Conclusions: Despite markedly elevated transaminases in the setting of acute hepatitis C infection, these patients tolerated buprenorphine treatment with improvement in their transaminases during the course of buprenorphine treatment.

Testing an optimized community-based HIV risk reduction and antiretroviral adherence intervention for HIV-infected injection drug users

The authors conducted a preliminary study of the 4-session Holistic Health for HIV (3H+), which was adapted from a 12-session evidence-based risk reduction and antiretroviral adherence intervention. Improvements were found in the behavioral skills required to properly adhere to HIV medication regimens. Enhancements were found in all measured aspects of sex-risk reduction outcomes, including HIV knowledge, motivation to reduce sex-risk behavior, behavioral skills related to engaging in reduced sexual risk, and reduced risk behavior. Improvements in drug use outcomes included enhancements in risk reduction skills as well as reduced heroin and cocaine use. Intervention effects also showed durability from post-intervention to the follow-up assessment point. Females responded particularly well in terms of improvements in risk reduction skills and risk behavior. This study suggests that an evidence-based behavioral intervention may be successfully adapted for use in community-based clinical settings where HIV-infected drug users can be more efficiently reached.

The pharmacokinetic and pharmacodynamic interactions between buprenorphine/naloxone and elvitegravir/cobicistat in subjects receiving chronic buprenorphine/naloxone treatment.

Background: Interactions between HIV and opioid-dependence therapies are known to occur. We sought to determine if such interactions occurred between buprenorphine/naloxone and elvitegravir boosted with cobicistat. Methods: We performed a within-subject open-labeled pharmacokinetic and pharmacodynamic study in 17 HIV-seronegative subjects stabilized on at least 2 weeks of buprenorphine/naloxone therapy. Subjects underwent baseline and steady state evaluation of the effect of elvitegravir 150 mg once daily boosted with 150 mg once daily of cobicistat (EVG/COBI) on buprenorphine/naloxone parameters. Safety was monitored throughout the study. Results: Compared with baseline values, buprenorphine mean AUCtau (69.0 versus 95.6 hr*ng/mL) and mean Cmax (8.4 versus 9.3 ng/mL) increased significantly in the presence of EVG/COBI. Compared with baseline values, norbuprenorphine mean AUCtau (103.4 versus 163.4 hr*ng/mL) and mean Cmax (6.9 versus 9 ng/mL) also increased significantly after achieving steady state EVG/COBI. Naloxone mean AUCtau (0.57 versus 0.45 hr*ng/mL) and mean Cmax (0.25 versus 0.16 ng/mL) decreased after the addition of EVG/COBI. The AUCtau, Cmax and Ctau of EVG and cobicistat did not significantly differ from historical controls. Opioid withdrawal or overdose was not observed among subjects in this study. Conclusion: The addition of EVG/COBI to stabilized patients receiving buprenorphine/naloxone modestly increased buprenorphine and norbuprenorphine levels without affecting the opioid pharmacodynamics.

Pharmacokinetic interactions between buprenorphine/naloxone and once-daily lopinavir/ritonavir

Background:This study was conducted to examine the pharmacokinetic interactions between buprenorphine/naloxone (BUP/NLX) and lopinavir/ritonavir (LPV/r) in HIV-seronegative subjects chronically maintained on BUP/NLX. Methods:This study was an open labeled pharmacokinetic study in twelve HIV-seronegative subjects stabilized on at least 3 weeks of BUP/NLX therapy. Subjects sequentially underwent baseline and steady-state pharmacokinetic evaluation of once-daily LPV/r (800/200 mg). Results:Compared to baseline values, BUP AUC0-24h (46.8 vs. 46.2 ng*hr/mL) and Cmax (6.54 vs. 5.88 ng/mL) did not differ significantly after achieving steady-state LPV/r. Similar analyses of norBUP, the primary metabolite of BUP, demonstrated no significant difference in norBUP AUC0-24 hours (73.7 vs. 52.7 ng·h/mL); however, Cmax (5.29 vs. 3.11 ng/mL) levels were statistically different (P < 0.05) after LPV/r administration. Naloxone concentrations were similarly unchanged for AUC0-24 hours (0.421 vs. 0.374 ng·hr/mL) and Cmax (0.186 vs. 0.186 ng/mL). Using standardized measures, no objective opioid withdrawal was observed. The AUC0-24 hours and Cmin of LPV in this study did not significantly differ from historical controls (159.6 vs. 171.3 μg·hr/mL) and (2.3 vs. 1.3 μg/mL). Conclusions:The addition of LPV/r to stabilized patients receiving BUP/NLX did not affect buprenorphine pharmacokinetics but did increase the clearance of norbuprenorphine. Pharmacodynamic responses indicate that the altered norbuprenorphine clearance did not lead to opioid withdrawal. Buprenorphine/naloxone and LPV/r can be safely coadministered without need for dosage modification.

Implementation and Operational Research: Linkage to Care Among Methadone Clients Living With HIV in Dar es Salaam, Tanzania.

Background: The first methadone maintenance treatment clinic in Tanzania was launched in February 2011 to address an emerging HIV epidemic among people who inject drugs. We conducted a retrospective cohort study to understand factors associated with linkage to HIV care and explore how a methadone maintenance treatment clinic can serve as a platform for integrated HIV care and treatment. Methods: This study used routine programmatic and clinical data on clients enrolled in methadone at Muhimbili National Hospital from February 2011 to January 2013. Multivariable proportional hazards regression model was used to examine time to initial CD4 count. Results: Final analyses included 148 HIV-positive clients, contributing 31.7 person-years. At 30, 60, and 90 days, the probability of CD4 screening was 40% [95% confidence interval (CI): 32% to 48%], 55% (95% CI: 47% to 63%), and 63% (95% CI: 55% to 71%), respectively. Clients receiving high methadone doses (≥85 mg/d) [adjusted hazard ratio (aHR): 1.68, 95% CI: 1.03 to 2.74] had higher likelihood of CD4 screening than those receiving low doses (<85 mg/d). Clients with primary education or lower (aHR: 1.62, 95% CI: 1.05 to 2.51) and self-reported poor health (aHR: 1.96, 95% CI: 1.09 to 3.51) were also more likely to obtain CD4 counts. Clients with criminal arrest history (aHR: 0.56, 95% CI: 0.37 to 0.85]) were less likely to be linked to care. Among 17 antiretroviral therapy eligible clients (CD4 ⩽ 200), 12 (71%) initiated treatment, of which 7 (41%) initiated within 90 days. Conclusions: Levels of CD4 screening and antiretroviral therapy initiation were similar to Sub-Saharan programs caring primarily for people who do not inject drugs. Adequate methadone dosing is important in retaining clients to maximize HIV treatment benefits and allow for successful linkage to services.