R. Douglas Bruce

Hiv Treatment Outcomes Among Hiv-infected, Opioid-dependent Patients Receiving Buprenorphine/naloxone Treatment within Hiv Clinical Care Settings: Results From a Multisite Study

Background:Having opioid dependence and HIV infection are associated with poor HIV-related treatment outcomes. Methods:HIV-infected, opioid-dependent subjects (N = 295) recruited from 10 clinical sites initiated buprenorphine/naloxone (BUP/NX) and were assessed at baseline and quarterly for 12 months. Primary outcomes included receiving antiretroviral therapy (ART), HIV-1 RNA suppression, and mean changes in CD4 lymphocyte count. Analyses were stratified for the 119 subjects not on ART at baseline. Generalized estimating equations were deployed to examine time-dependent correlates for each outcome. Results:At baseline, subjects on ART (N = 176) were more likely than those not on ART (N = 119) to be older, heterosexual, have lower alcohol addiction severity scores, and lower HIV-1 RNA levels; they were less likely to be homeless and report sexual risk behaviors. Subjects initiating BUP/NX (N = 295) were significantly more likely to initiate or remain on ART and improve CD4 counts over time compared with baseline; however, these improvements were not significantly improved by longer retention on BUP/NX. Retention on BUP/NX for three or more quarters was, however, significantly associated with increased likelihood of initiating ART (β = 1.34 [1.18, 1.53]) and achieve viral suppression (β = 1.25 [1.10, 1.42]) for the 64 of 119 (54%) subjects not on ART at baseline compared with the 55 subjects not retained on BUP/NX. In longitudinal analyses, being on ART was positively associated with increasing time of observation from baseline and higher mental health quality of life scores (β = 1.25 [1.06, 1.46]) and negatively associated with being homo- or bisexual (β = 0.55 [0.35, 0.97]), homeless (β = 0.58 [0.34, 0.98]), and increasing levels of alcohol addiction severity (β = 0.17 [0.03, 0.88]). The strongest correlate of achieving viral suppression was being on ART (β = 10.27 [5.79, 18.23]). Female gender (β = 1.91 [1.07, 3.41]), Hispanic ethnicity (β = 2.82 [1.44, 5.49]), and increased general health quality of life (β = 1.02 [1.00,1.04]) were also independently correlated with viral suppression. Improvements in CD4 lymphocyte count were significantly associated with being on ART and increased over time. Conclusions:Initiating BUP/NX in HIV clinical care settings is feasible and correlated with initiation of ART and improved CD4 lymphocyte counts. Longer retention on BPN/NX was not associated with improved prescription of ART, viral suppression, or CD4 lymphocyte counts for the overall sample in which the majority was already prescribed ART at baseline. Among those retained on BUP/NX, HIV treatment outcomes did not worsen and were sustained. Increasing time on BUP/NX, however, was especially important for improving HIV treatment outcomes for those not on ART at baseline, the group at highest risk for clinical deterioration. Retaining subjects on BUP/NX is an important goal for sustaining HIV treatment outcomes for those on ART and improving them for those who are not. Comorbid substance use disorders (especially alcohol), mental health problems, and quality-of-life indicators independently contributed to HIV treatment outcomes among HIV-infected persons with opioid dependence, suggesting the need for multidisciplinary treatment strategies for this population.

Superiority of Directly Administered Antiretroviral Therapy over Self-Administered Therapy among HIV-Infected Drug Users : A Prospective, Randomized, Controlled Trial

BACKGROUND Directly administered antiretroviral therapy (DAART) is one approach to improve treatment adherence among human immunodeficiency virus (HIV)-infected drug users. METHODS In this randomized, controlled trial (ClinicalTrials.gov identifier, NCT00367172), the biological outcomes of a 6-month community intervention of DAART were compared with those of self-administered therapy among HIV-infected drug users. Patients randomized to receive DAART received supervised therapy 5 days per week from workers in a mobile health care van. The primary outcome, using an intention-to-treat approach, was the proportion of patients achieving either a reduction in HIV-1 RNA level of > or = 1.0 log10 copies/mL or an HIV-1 RNA level < or = 400 copies/mL at 6 months. Secondary outcomes included the mean change from baseline in HIV-1 RNA level and CD4+ T lymphocyte count. RESULTS Of the 141 patients who met the entry criteria, 88 were randomized to receive DAART, and 53 were randomized to receive self-administered therapy; 74 (84%) of 88 of the patients randomized to receive DAART accepted the intervention. Of the 74 patients who initiated DAART, 51 (69%) completed the full 6-month intervention. At the end of 6 months, a significantly greater proportion of the DAART group achieved the primary outcome (70.5% vs. 54.7; P=.02). Additionally, compared with patients receiving self-administered therapy, patients receiving DAART demonstrated a significantly greater mean reduction in HIV-1 RNA level (-1.16 log10 copies/mL vs. -0.29 log10 copies/mL; P=.03) and mean increase in CD4+ T lymphocyte count (+58.8 cells/microL vs. -24.0 cells/microL; P=.002). CONCLUSIONS This randomized, controlled trial was, to our knowledge, the first to demonstrate the effectiveness of DAART at improving 6-month virologic outcomes among drug users. These results suggest that DAART should be more widely available in HIV treatment programs that target drug users who have poor adherence to treatment.

Pharmacokinetic drug interactions between opioid agonist therapy and antiretroviral medications: implications and management for clinical practice.

Background: Opioid dependence and HIV/AIDS are 2 of the most serious yet treatable diseases worldwide. Global access to opioid agonist therapy and HIV treatment is expanding but when concurrently used, problematic pharmacokinetic drug interactions can occur. Methods: We reviewed English, Spanish, French, and Italian language articles from 1966 to 2005 in Medline using the following keywords: HIV, AIDS, HIV therapy, antiretroviral therapy, HAART, drug interactions, methadone, and buprenorphine. Additionally, we reviewed abstracts from national and international meetings and conference proceedings. Selected references from these articles were reviewed as well. Results: Clinical case series and carefully controlled pharmacokinetic interaction studies have been conducted between methadone and most approved antiretroviral therapies. Important pharmacokinetic drug interactions have been demonstrated within each class of agents, affecting either methadone or antiretroviral agents. Few studies, however, have been conducted with buprenorphine. The metabolism of both therapies, description of the known interactions, and clinical implications and management of these interactions are reviewed. Conclusions: Certain interactions between methadone and antiretroviral medications are known and may have important clinical consequences. To optimize care, clinicians must be alert to these interactions and have a basic knowledge regarding their management.

Lack of Reduction in Buprenorphine Injection After Introduction of Co-Formulated Buprenorphine/Naloxone to the Malaysian Market

Background: Diversion of buprenorphine (BPN) has been described in settings where it is legally prescribed and has resulted in increasing concern. To address this concern, co-formulation of buprenorphine/naloxone (BPN/NLX) replaced buprenorphine alone in Malaysia in December 2006. Methods: To assess the significance of BPN/NLX introduction, 41 BPN/NLX injectors in Kuala Lumpur, Malaysia were recruited using a modified snowball recruitment technique. Results: In January 2007, all subjects had previously injected BPN alone. During the transition from injecting BPN alone to co-formulated BPN/NLX, the mean daily BPN injection dose increased from 1.88 mg (range 1.0–4.0 mg) to 2.49 mg/day (p < .001). Overall, 18 (44%) subjects increased their daily amount of injection while 22 (54%) had no change in dose; only one subject reduced the amount of injection. Development of opioid withdrawal symptoms was the primary outcome, however the only symptom that was significantly associated with BPN/NLX dosage was the report of “stomach pains” (p = .01). In logistic regression analysis, the development of opioid withdrawal symptoms was associated with increased benzodiazepine injection and increased syringe sharing. Conclusion and Scientific Significance: These data suggests that the introduction of BPN/NLX did not reduce injection related risk behaviors such as syringe sharing and was associated with increased benzodiazepine use. Evidence-based approaches to treat BPN injection are urgently needed.

Models for Integrating Buprenorphine Therapy into the Primary HIV Care Setting

Opiate dependence among human immunodeficiency virus (HIV)-infected patients has been associated with negative clinical outcomes, yet few affected patients receive appropriate and coordinated treatment for both conditions. The introduction of buprenorphine maintenance therapy into HIV care settings provides an opportunity for providers to integrate treatment for opiate dependence into their practices. Buprenorphine maintenance therapy has been associated with reductions in opiate use, increased social stability, improved adherence to antiretroviral therapy, and lowered rates of injection drug use. We describe the following 4 models for the integration of buprenorphine maintenance therapy into HIV care: (1) a primary care model, in which the highly active antiretroviral therapy-administering clinician also prescribes buprenorphine; (2) a model that relies on an on-site specialist in addiction medicine or psychiatry to prescribe the buprenorphine; (3) a hybrid model, in which an on-site specialist provides the induction (with or without stabilization phases) and the HIV care provider provides the maintenance phase; and (4) a drug treatment model that provides buprenorphine maintenance therapy services with HIV services in the substance abuse clinic setting. The key barriers against effective integration of buprenorphine maintenance therapy and primary HIV services are discussed, and we suggest several mechanisms to overcome such obstacles.

Impact of Enhanced Services on Virologic Outcomes in a Directly Administered Antiretroviral Therapy Trial for HIV-Infected Drug Users

Background:Directly administered antiretroviral therapy (DAART) is a promising intervention for improving HIV outcomes among active drug users, but the elements associated with successful DAART programs remain largely unknown. This study aimed to assess the impact of colocated medical, case management, and referral to substance abuse services (DAART-Plus) among the subjects receiving DAART as part of a larger randomized controlled trial comparing DAART with self-administered therapy. Methods:The health services utilization of 72 subjects receiving DAART was analyzed for its impact on changes in HIV-1 RNA levels at 6 months. The primary outcome was virologic success, defined as achieving an HIV-1 RNA level ≤400 copies/mL or a ≥1.0 log10 reduction in HIV-1 RNA level. A second analysis consisted of linear regression assessing the effect of covariates on log10 HIV-1 RNA reduction from baseline to 6 months. Results:In multivariate analyses, achieving virologic success at 6 months was associated with high medical services utilization [adjusted odds ratio [AOR] = 10.0 (1.4, 73.9); P = 0.02] and with the use of case management services [AOR = 5.8 (1.1, 30.5); P = 0.04]. Both services resulted in a larger reduction in log10 HIV-1 RNA from baseline (difference in slopes: −0.9 and −1.0, respectively; P = 0.02 for both). Referral to off-site substance abuse services treatment did not significantly predict either virologic outcome. Conclusions:Among individuals who receive DAART, the utilization of on-site medical and case management services was independently associated with improved virologic outcomes. These results suggest the potential utility of integrating these services into DAART interventions (DAART-Plus) targeting HIV-infected drug users with problematic adherence.

Pharmacokinetic Interactions between Buprenorphine and Antiretroviral Medications

Buprenorphine is used for the treatment of opioid dependence. As the number of persons receiving buprenorphine treatment and antiretroviral therapy continues to grow, so too does the existence and clinical impact of drug interactions between buprenorphine and medications for treating human immunodeficiency virus (HIV) infection. Awareness that such interactions exist may deter some patients and physicians from initiating potentially lifesaving therapy or lead to complications among patients whose treatment is already under way. Complications include nonadherence to antiretroviral therapy and the development of viral resistance. Illicit drug use is a frequent consequence of adverse drug effects experienced by injection drug users. The occurrence of unrecognized drug interactions can lead to unsuccessful therapy for HIV infection and the treatment of substance dependence. The present review is organized to provide a working background of buprenorphine pharmacology. Review of the current state of knowledge regarding specific interactions between buprenorphine and antiretrovirals is followed by a review of the clinical applicability of these interactions.

Methadone as HIV prevention: High Volume Methadone Sites to decrease HIV incidence rates in resource limited settings

The link between injection drug use and HIV has been extensively described. Despite worldwide prevention efforts, injection drug use continues to be a risk factor for HIV transmission and both HIV and injection drug use continues to spread across the globe. Although methadone has demonstrated multiple health benefits including the reduction in injection drug use and HIV acquisition, the utilisation of methadone in many areas of the world remains one of secondary, rather than primary, HIV prevention. As a result, many who finally begin methadone enter treatment having accumulated medical and mental health problems as a result of delayed treatment. Rapid access to treatment and a more aggressive policy that realizes that methadone can help reduce opioid drug use is necessary if methadone is effectively going to act as primary HIV prevention. To delay access to methadone only increases the probability that the individual will acquire an infectious disease that is more costly to the individual in terms of morbidity and mortality and more costly to society as a whole.

Clinical management of depression and anxiety in Hiv-infected adults

HIV clinical care providers are increasingly confronted by comorbid psychiatric illness among their patients. Prevalence rates of psychiatric disorders among HIVinfected patients approach 50% [1]. These conditions commonly manifest around the time of diagnosis [2], but many patients develop symptoms later in their course of illness [1]. Axis I disorders, including anxiety and depression, are particularly likely to occur at times of stress–—including an illness episode, a psychosocial stressor such as divorce or loss of a loved one, and when facing a new disability. Anxiety and depression are among the most commonly diagnosed psychiatric conditions affecting HIV-infected patients [3,4]. These can complicate the treatment of HIV, presenting numerous diagnostic and interventional challenges for the clinician.

An Intronic Variant in OPRD1 Predicts Treatment Outcome for Opioid Dependence in African-Americans

Although buprenorphine and methadone are both effective treatments for opioid dependence, their efficacy can vary significantly among patients. Genetic differences may explain some of the variability in treatment outcome. Understanding the interactions between genetic background and pharmacotherapy may result in more informed treatment decisions. This study is a pharmacogenetic analysis of the effects of genetic variants in OPRD1, the gene encoding the δ-opioid receptor, on the prevalence of opioid-positive urine tests in African-Americans (n=77) or European-Americans (n=566) undergoing treatment for opioid dependence. Patients were randomly assigned to treatment with either methadone or buprenorphine/naloxone (Suboxone) over a 24-week open-label clinical trial, in which illicit opioid use was measured by weekly urinalysis. In African-Americans, the intronic SNP rs678849 predicted treatment outcome for both medications. Methadone patients with the CC genotype were less likely to have opioid-positive urine tests than those in the combined CT and TT genotypes group (relative risk (RR)=0.52, 95% confidence interval (CI)=0.44–0.60, p=0.001). In the buprenorphine treatment group, however, individuals with the CC genotype were more likely to have positive opioid drug screens than individuals in the combined CT and TT genotypes group (RR=2.17, 95% CI=1.95–2.68, p=0.008). These findings indicate that the genotype at rs678849 predicts African-American patient response to two common treatments for opioid dependence, suggesting that matching patients to treatment type based on the genotype at this locus may improve overall treatment efficacy. This observation requires confirmation in an independent population.