Faculty Bibliography

BACKGROUND: It is critical for providers caring for HIV-positive methadone recipients to have accurate information on pharmacologic interactions between methadone and antiretroviral therapy. If providers do not have these data, symptoms of narcotic withdrawal or excess due to medication interactions may be mismanaged, and antiretroviral regimens may be suboptimal in efficacy or associated with increased side effects and toxicities. This review was undertaken to clarify what is known about interactions between pharmacotherapies of opiate dependence and HIV-related medications, to suggest clinically useful approaches to these issues, and to outline areas which need further study. METHOD: A search for relevant published papers and abstracts presented at scientific meetings was conducted using electronic databases. These documents were obtained and reviewed, and additional publications referenced in them were also reviewed. RESULTS: Pharmacokinetic interactions between methadone and zidovudine, didanosine, stavudine, abacavir, nevirapine, efavirenz and nelfinavir have been documented. The mechanisms, clinical implications and management of these interactions are reviewed. CONCLUSIONS: Interactions between methadone and some HIV-related medications are known to occur, yet their characteristics cannot reliably be predicted based on current understanding of metabolic enzyme induction and inhibition, or through in vitro studies. Only carefully designed and conducted pharmacologic studies involving human subjects can help us define the nature of the interactions between methadone (and other pharmacotherapies for opiate dependence) and specific HIV-related medications. Clinicians must be aware of known interactions and be alert to the possibility that interactions which are still undocumented may be present among their patients

AIDS: The second installment in a two-part series on Methadone and antiretroviral medications is presented. The use of methadone and potential drug interactions between Methadone and anti-HIV medications are reviewed. Several studies about drug interactions, other substance-abuse therapies and opiates, and the future direction of antiretroviral and opiate interaction studies are discussed. Physicians are advised to consider the potential effects of Methadone on HIV-related medications when designing a treatment regimen. EDAT- 2001/05/22 10:00 MHDA- 2001/05/22 10:01 P

AIDS: The interactions of Methadone with NRTIs and NNRTIs are presented in the first of a two-part article. Methadone is an effective treatment for heroin addiction; however, insufficient information is available on its interactions with HAART. Methadone is metabolized by the cytochrome P450 system, and NRTIs do not appear to be inducers or inhibitors of the cytochrome P450 system. Pharmacokinetics between Methadone and AZT have been studied in detail, and AZT appears to have no effect on plasma Methadone levels. However, NNRTIs do share metabolic pathways with Methadone, indicating that important interactions between Methadone and these drugs are possible, but formal study is still needed. A table of current information is presented on NRTI and NNRTI interactions with Methadone. EDAT- 2001/05/22 10:00 MHDA- 2001/05/22 10:01 P

OBJECTIVE: To define the effectiveness of chemoprophylaxis, outside of a clinical trial setting, in preventing tuberculosis among tuberculin-reactive and anergic HIV-infected drug users at high risk of developing active tuberculosis. DESIGN: An observational cohort study. SETTING: Methadone maintenance treatment program with on-site primary care. PARTICIPANTS: Current or former drug users enrolled in methadone treatment. INTERVENTIONS: Annual skin testing for tuberculosis infection and anergy was performed, and eligible patients were offered daily isoniazid for 12 months and followed prospectively. MAIN OUTCOME MEASURE: The development of active tuberculosis. RESULTS: A total of 155 persons commenced chemoprophylaxis. Among tuberculin reactors, tuberculosis rates were 0.51 and 2.07/100 person-years in those completing 12 months versus those not taking prophylaxis [rate ratio 0.25, 95% confidence interval (CI) 0.06-1.01]. Among anergic individuals, comparable rates were 0 and 1.44/100 person-years. Lower tuberculosis rates among completers were not attributable to differences in immune status between the treated and untreated groups. CONCLUSION: The completion of isoniazid chemoprophylaxis was associated with a marked reduction in tuberculosis risk among tuberculin reactors and anergic persons in this high-risk population. These data support aggressive efforts to provide a complete course of preventative therapy to HIV-infected tuberculin reactors, and lend weight to the findings of others that isoniazid can reduce the rate of tuberculosis in high-risk anergic HIV-infected persons

This study was done to determine whether there were any differences in subjective symptoms of opiate withdrawal or methadone pharmacodynamics among patients as they were switched between three different oral formulations of methadone. Patients enrolled in a three-way double-blind crossover trial of three methadone formulations. Subjective symptoms and pharmacodynamic measures were assessed throughout the study period. Eighteen patients were enrolled the study. No statistically significant differences in any of the pharmacodynamic parameters studied were found among the three methadone preparations. There was no significant difference among preparations in the rate and extent of rise and fall in plasma methadone levels during a 24-hour intensive sampling period. Subjective symptoms also did not correlate with methadone formulation. Intolerance to changes in methadone formulation, often observed clinically, do not appear to have a pharmacodynamic basis. Our findings support the notion that such change intolerance reflects factors other than the pharmacologic properties of the different formulations of methadone

BACKGROUND: Nucleoside analogue reverse transcriptase inhibitors are a critical component of antiretroviral therapy in HIV-infected persons. Several of these medications cause painful, dose-limiting peripheral neuropathy (PN), which may develop earlier and more intensely in persons with preexisting neuropathy. The prevalence of baseline peripheral neuropathy in injection drug users (IDUs), one of the largest populations of HIV-infected persons, has not been described, yet has important implications for the selection of antiretroviral therapy. METHODS: The authors performed a cross-sectional study of PN in 212 HIV-seronegative and HIV-seropositive IDUs using detailed neurologic histories, physical examinations, quantitative electrophysiologic study, and quantitative sensory testing. Data were used to assign patients to one of four positive categories of PN or one of two negative categories. RESULTS: PN was present in 24.5% of HIV-seronegative IDUs, three to four times the reported frequency for HIV-seronegative persons in the general or male homosexual population. PN was present in 32.1% of HIV-seropositive patients. PN was axonal in nature and associated with increased age and alcohol use. PN was asymptomatic in 81% of HIV-seronegative and 71% of HIV-seropositive patients with PN. CONCLUSIONS: There is a high prevalence of PN in HIV-seronegative IDUs. Although these PNs do not seem to predispose HIV-seropositive IDUs to HIV-related PN, they may increase the likelihood of iatrogenic neuropathy. Intravenous drug users may need more diligent monitoring when administered nucleoside analogues than patients in risk groups with lower endemic rates of PN

SETTING: Self-assessment of tuberculin test results, if accurate, could enhance tuberculosis screening efforts by reducing the need for follow-up visits for skin test reading. We investigated tuberculin test self-assessment in a longitudinal study of tuberculosis infection among drug users. OBJECTIVE: To determine the accuracy of tuberculin reaction self-assessment by drug users at high risk for tuberculosis infection. DESIGN: Two readings were compared of the same skin test, performed 48-72 hours after placement: 1) self-assessment using a simple yes-no approach to induration, versus 2) trained examiner reading. Self-assessments were performed immediately prior to trained examiner readings. RESULTS: Participants were 137 human immunodeficiency virus (HIV) seropositive and 344 HIV-seronegative current and former drug users. Ten per cent (35/344) of reactions read by participants as 'flat' were read by trained examiners as > or =5 mm (54% of which were > or =10 mm). Twenty-three per cent (19/82) of reactions read by trained examiners as > or =10 mm and 32% (35/110) of reactions read by trained examiners as being > or =5 mm were self-read by participants as 'flat'. Sensitivity (0.68) and specificity (0.83) of self-read tuberculin reactions were sub-optimal. Inter-reader reliability was poorer between participants and trained examiners than between trained examiners. CONCLUSION: Self-assessments of tuberculin skin test responses by drug users with or at risk for HIV infection are not reliable

OBJECTIVE: To compare HIV disease progression and mortality in a cohort of female and male drug users. DESIGN: A prospective cohort study of 222 HIV-seropositive women and 302 HIV-seropositive men who attended a hospital-affiliated methadone maintenance program with on-site primary care. METHODS: Regression slopes of CD4+ cell decline were compared using the two sample t-test, and the distribution of AIDS-defining illnesses evaluated by Mantel-Haenszel chi2 test. Time to AIDS-defining clinical conditions and death were compared using the Kaplan-Meier log-rank test. Multivariate estimates of progression to clinical AIDS or death, for all participants, stratified by sex, were derived from Cox proportional hazards models. RESULTS: Ninety-five persons (43 women and 52 men) developed AIDS-defining conditions. Analyses of the rates of CD4+ cell decline, the distribution of first AIDS-defining illnesses, and the time to clinical AIDS did not differ by sex. In the multivariate model, sex was not associated with an AIDS outcome, whereas crack-cocaine use [hazards ratio (HR), 1.815; 95% confidence interval (CI), 1.151-2.863], CD4+ cell count (100 x 10(6)/l; HR, 0.589; 95% CI, 0.511-0.679), and two or more HIV-related symptoms (HR, 1.702; 95% CI, 1.125-2.576) were associated. Mortality rates (8.71 per 100 person-years in women and 9.85 per 100 person-years in men) were similar, using univariate or multivariate methods. CONCLUSIONS: There was little difference in clinical outcomes or mortality between HIV-seropositive female and male drug users with access to primary care. However, crack-cocaine use was independently associated with progression to clinical AIDS

OBJECTIVE: To determine whether active tuberculosis alters the rate of progression of HIV infection in dually infected patients. METHODS: HIV-seropositive patients at two Bronx, New York hospitals with tuberculosis confirmed by culture from July 1992 to February 1995, who survived the initial hospitalization for tuberculosis, were matched on gender, age, CD4+ percentage, and calendar time with HIV-seropositive patients without tuberculosis participating in a study of the natural history of HIV infection. Patients received follow-up observation prospectively until May 23, 1995 to determine survival rates and development of AIDS-defining opportunistic infections (OIs). RESULTS: 70 patients had tuberculosis; 120 did not. Mean CD4+ percentages were 12.4% and 12.5%, respectively. At study entry, 27% of those with tuberculosis had prior AIDS-defining OIs other than tuberculosis, compared with 10% of those without tuberculosis (p = .004). In multivariate survival analysis, controlling for CD4+ level, tuberculosis was not an independent predictor of increased other causes of AIDS-related mortality. However, in a logistic regression model, independent predictors of subsequent OIs included tuberculosis (hazard ratio, 4.1; 95% confidence intervals [CI], 1.9, 8.7), CD4+ count <100/mm3 (hazard ratio, 2.4; 95% CI, 1.1, 5.0) and prior OIs (hazard ration, 3.3; 95% CI, 1.3, 8.3). CONCLUSIONS: Tuberculosis was not an independent predictor of increased non-tuberculosis-related mortality in HIV-seropositive patients but was associated with increased risk of development of OIs