rifapentine and AIDS-Related-Opportunistic-Infections

Nine months of daily isoniazid is efficacious in treating latent M. tuberculosis infection, but completion rates are low, limiting treatment effectiveness. In 2011, three important studies were published involving novel regimens for the treatment of latent M. tuberculosis infection. At least 36 months of isoniazid was more effective than 6 months of isoniazid in one study, but not in another-both of which were conducted among tuberculin skin test positive HIV-infected adults living in high tuberculosis incidence settings. Three months of once-weekly isoniazid plus rifapentine or twice-weekly isoniazid plus rifampin (both given under direct observation) resulted in tuberculosis rates similar to those seen with 6 months of isoniazid among HIV-infected persons in high tuberculosis incidence settings. Three months of once-weekly, directly-observed isoniazid plus rifapentine was at least as effective as 9 months of daily isoniazid among predominantly HIV-uninfected persons living in low and medium tuberculosis incidence countries. The 3-month once-weekly isoniazid plus rifapentine regimen demonstrates promise for treatment of latent M. tuberculosis infection in HIV-infected persons.

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Rifampin; Time Factors; Treatment Outcome; Tuberculin Test; Tuberculosis, Multidrug-Resistant

Tuberculosis is the leading killer of patients with human immunodeficiency virus (HIV) infection. Preventive therapy is effective, but current regimens are limited by poor implementation and low completion rates.. We conducted a randomized, open-label, phase 3 noninferiority trial comparing the efficacy and safety of a 1-month regimen of daily rifapentine plus isoniazid (1-month group) with 9 months of isoniazid alone (9-month group) in HIV-infected patients who were living in areas of high tuberculosis prevalence or who had evidence of latent tuberculosis infection. The primary end point was the first diagnosis of tuberculosis or death from tuberculosis or an unknown cause. Noninferiority would be shown if the upper limit of the 95% confidence interval for the between-group difference in the number of events per 100 person-years was less than 1.25.. A total of 3000 patients were enrolled and followed for a median of 3.3 years. Of these patients, 54% were women; the median CD4+ count was 470 cells per cubic millimeter, and half the patients were receiving antiretroviral therapy. The primary end point was reported in 32 of 1488 patients (2%) in the 1-month group and in 33 of 1498 (2%) in the 9-month group, for an incidence rate of 0.65 per 100 person-years and 0.67 per 100 person-years, respectively (rate difference in the 1-month group, -0.02 per 100 person-years; upper limit of the 95% confidence interval, 0.30). Serious adverse events occurred in 6% of the patients in the 1-month group and in 7% of those in the 9-month group (P = 0.07). The percentage of treatment completion was significantly higher in the 1-month group than in the 9-month group (97% vs. 90%, P<0.001).. A 1-month regimen of rifapentine plus isoniazid was noninferior to 9 months of isoniazid alone for preventing tuberculosis in HIV-infected patients. The percentage of patients who completed treatment was significantly higher in the 1-month group. (Funded by the National Institute of Allergy and Infectious Diseases; BRIEF TB/A5279 ClinicalTrials.gov number, NCT01404312.).

Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Medication Adherence; Rifampin; Tuberculosis

Treatment of latent tuberculosis in patients infected with the human immunodeficiency virus (HIV) is efficacious, but few patients around the world receive such treatment. We evaluated three new regimens for latent tuberculosis that may be more potent and durable than standard isoniazid treatment.. We randomly assigned South African adults with HIV infection and a positive tuberculin skin test who were not taking antiretroviral therapy to receive rifapentine (900 mg) plus isoniazid (900 mg) weekly for 12 weeks, rifampin (600 mg) plus isoniazid (900 mg) twice weekly for 12 weeks, isoniazid (300 mg) daily for up to 6 years (continuous isoniazid), or isoniazid (300 mg) daily for 6 months (control group). The primary end point was tuberculosis-free survival.. The 1148 patients had a median age of 30 years and a median CD4 cell count of 484 per cubic millimeter. Incidence rates of active tuberculosis or death were 3.1 per 100 person-years in the rifapentine-isoniazid group, 2.9 per 100 person-years in the rifampin-isoniazid group, and 2.7 per 100 person-years in the continuous-isoniazid group, as compared with 3.6 per 100 person-years in the control group (P>0.05 for all comparisons). Serious adverse reactions were more common in the continuous-isoniazid group (18.4 per 100 person-years) than in the other treatment groups (8.7 to 15.4 per 100 person-years). Two of 58 isolates of Mycobacterium tuberculosis (3.4%) were found to have multidrug resistance.. On the basis of the expected rates of tuberculosis in this population of HIV-infected adults, all secondary prophylactic regimens were effective. Neither a 3-month course of intermittent rifapentine or rifampin with isoniazid nor continuous isoniazid was superior to 6 months of isoniazid. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00057122.).

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-Retroviral Agents; Antitubercular Agents; Cause of Death; Drug Administration Schedule; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Isoniazid; Kaplan-Meier Estimate; Male; Mycobacterium tuberculosis; Patient Compliance; Proportional Hazards Models; Rifampin; Risk; Tuberculosis; Tuberculosis, Multidrug-Resistant

Rifapentine is undergoing development for the treatment of pulmonary tuberculosis. This study was conducted to characterize the single-dose pharmacokinetics of rifapentine and its 25-desacetyl metabolite and to assess the effect of food on the rate and extent of absorption in participants infected with human immunodeficiency virus (HIV). Twelve men and four women, mean age, 38.6 +/- 6.9 years, received a single 600-mg oral dose of rifapentine in an open-label, randomized two-way, complete crossover study. Each volunteer received rifapentine following a high-fat breakfast or during a fasting period. Serial blood samples were collected for 72 h and both rifapentine and its metabolite were assayed by a validated high-performance liquid chromatography method. Pharmacokinetics of rifapentine and 25-desacetylrifapentine were determined by noncompartmental methods. Mean (+/- the standard deviation) maximum concentrations of rifapentine in serum and areas under the curve from time zero to infinity following a high-fat breakfast were 14.09 +/- 2.81 and 373.63 +/- 78.19 micrograms/ml, respectively, and following a fasting period they were 9.42 +/- 2.67 and 256.10 +/- 86.39 micrograms. h/ml, respectively. Pharmacokinetic data from a previously published healthy volunteer study were used for comparison. Administration of rifapentine with a high-fat breakfast resulted in a 51% increase in rifapentine bioavailability, an effect also observed in healthy volunteers. Although food increased the exposure of these patients to rifapentine, the infrequent dosing schedule for the treatment of tuberculosis (e.g., once- or twice-weekly dosing) would be unlikely to lead to accumulation. Additionally, autoinduction has been previously studied and has not been demonstrated with this compound, unlike with rifabutin and rifampin. Rifapentine was well tolerated by HIV-infected study participants. The results of our study suggest that no dosage adjustments may be required for rifapentine in HIV-infected patients (Centers for Disease Control and Prevention classification A1, A2, B1, or B2) undergoing treatment for tuberculosis.

Topics: Administration, Oral; Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Cross-Over Studies; Female; Food; HIV Seropositivity; HIV-1; Humans; Male; Middle Aged; Mycobacterium Infections; Rifampin; Tuberculosis

Rifapentine is a cyclopentyl-substituted rifamycin whose serum half-life is five times that of rifampin. The US Public Health Service Study 22 compared a once-weekly regimen of isoniazid and rifapentine with twice weekly isoniazid and rifampin in the continuation phase (the last 4 months) of treatment for pulmonary tuberculosis in HIV-seropositive and HIV-seronegative patients. This report concerns only the HIV-seropositive part of the trial, which has ended. The HIV-seronegative part will stop follow-up in 2001.. Adults with culture-positive, drug-susceptible pulmonary tuberculosis who completed 2 months of four-drug (isoniazid, rifampin, pyrazinamide, ethambutol) treatment (induction phase) were randomly assigned 900 mg isoniazid and 600 mg rifapentine once weekly, or 900 mg isoniazid and 600 mg rifampin twice weekly. All therapy was directly observed. Statistical analysis used univariate, Kaplan-Meier, and logistic and proportional hazards regression methods.. 71 HIV-seropositive patients were enrolled: 61 completed therapy and were assessed for relapse. Five of 30 patients in the once-weekly isoniazid/rifapentine group relapsed, compared with three of 31 patients in the twice-weekly isoniazid/rifampin group (log rank chi2=0.69, p=0.41). However, four of five relapses in the once-weekly isoniazid/rifapentine group had monoresistance to rifamycin, compared with none of three in the rifampin group (p=0.05). Patients who relapsed with rifamycin monoresistance were younger (median age 29 vs 41 years), had lower baseline CD4 cell counts (median 16 vs 144 microL), and were more likely to have extrapulmonary involvement (75% vs 18%, p=0.03) and concomitant therapy with antifungal agents (75% vs 9%, p=0.006). No rifamycin monoresistant relapse has occurred among 1004 HIV-seronegative patients enrolled to date.. Relapse with rifamycin monoresistant tuberculosis occurred among HIV-seropositive tuberculosis patients treated with a once-weekly isoniazid/rifapentine continuation-phase regimen. Until more effective regimens have been identified and assessed in clinical trials, HIV-seropositive people with tuberculosis should not be treated with a once-weekly isoniazid/rifapentine regimen.

Topics: Adult; AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Recurrence; Rifampin; Time Factors; Tuberculosis, Pulmonary

Studies have shown clarithromycin (Biaxin) and rifabutin to be effective against Mycobacterium avium complex (MAC), and to improve survivability. Abbott Laboratories is seeking approval from the Food and Drug Administration (FDA) for clarithromycin use in preventing MAC. Marion Merrell Dow, the manufacturer of rifabutin, is planning a prophylaxis trial with a close cousin of the drug, rifapentine. Rifapentine has a long half-life, and has the potential to lengthen intermittent treatment for tuberculosis. It is believed that this long half-life may mean it can maintain a higher blood level and thereby maintain better effectiveness than rifabutin against fast-growing MAC organisms.

Topics: AIDS-Related Opportunistic Infections; Animals; Antitubercular Agents; CD4 Lymphocyte Count; Clarithromycin; Half-Life; Humans; Mycobacterium avium-intracellulare Infection; Placebos; Randomized Controlled Trials as Topic; Rifabutin; Rifampin

Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Infant; Infant, Newborn; Isoniazid; Rifampin; Tuberculosis

Topics: AIDS-Related Opportunistic Infections; Anti-Infective Agents; Antitubercular Agents; Clinical Trials as Topic; Drug Approval; Drug Industry; Fluoroquinolones; Humans; Mycobacterium avium-intracellulare Infection; Rifampin; Technology, Pharmaceutical; Tuberculosis, Multidrug-Resistant; United States