Awal Khan

Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial.

BACKGROUND Rifapentine has a long half-life in serum, which suggests a possible treatment once a week for tuberculosis. We aimed to compare rifapentine and isoniazid once a week with rifampicin and isoniazid twice a week. METHODS We did a randomised, multicentre, open-label trial in the USA and Canada of HIV-negative people with drug-susceptible pulmonary tuberculosis who had completed 2 months of a 6-month treatment regimen. We randomly allocated patients directly observed treatment with either 600 mg rifapentine plus 900 mg isoniazid once a week or 600 mg rifampicin plus 900 mg isoniazid twice a week. Primary outcome was failure/relapse. Analysis was by intention to treat. FINDINGS 1004 patients were enrolled (502 per treatment group). 928 successfully completed treatment, and 803 completed the 2-year 4-month study. Crude rates of failure/relapse were 46/502 (9.2%) in those on rifapentine once a week, and 28/502 (5.6%) in those given rifampicin twice a week (relative risk 1.64, 95% CI 1.04-2.58, p=0.04). By proportional hazards regression, five characteristics were independently associated with increased risk of failure/relapse: sputum culture positive at 2 months (hazard ratio 2.8, 95% CI 1.7-4.6); cavitation on chest radiography (3.0, 1.6-5.9); being underweight (3.0, 1.8-4.9); bilateral pulmonary involvement (1.8, 1.0-3.1); and being a non-Hispanic white person (1.8, 1.1-3.0). Adjustment for imbalances in 2-month culture and cavitation diminished the association of treatment group with outcome (1.34; 0.83-2.18; p=0.23). Of participants without cavitation, rates of failure/relapse were 6/210 (2.9%) in the once a week group and 6/241 (2.5%) in the twice a week group (relative risk 1.15; 95% CI 0.38-3.50; p=0.81). Rates of adverse events and death were similar in the two treatment groups. INTERPRETATION Rifapentine once a week is safe and effective for treatment of pulmonary tuberculosis in HIV-negative people without cavitation on chest radiography. Clinical, radiographic, and microbiological data help to identify patients with tuberculosis who are at increased risk of failure or relapse when treated with either regimen.

Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid

BACKGROUND 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. METHODS 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. FINDINGS 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. INTERPRETATION 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.

Evaluation of the Drug Interaction between Rifabutin and Efavirenz in Patients with HIV Infection and Tuberculosis

BACKGROUND Because of drug-drug interactions mediated by hepatic cytochrome P450, tuberculosis treatment guidelines recommend an increase in rifabutin from 300 mg to 450 or 600 mg when combined with efavirenz-based antiretroviral therapy. To assess this recommendation, rifabutin and efavirenz pharmacokinetic parameters were investigated. METHODS Plasma concentrations of rifabutin were determined as a baseline control in 15 patients with tuberculosis and human immunodeficiency virus (HIV) infection who were treated with rifabutin 300 mg and isoniazid 15 mg/kg (up to 900 mg) twice weekly. Rifabutin, isoniazid, and efavirenz concentrations were determined after a median of 21 days (interquartile range, 20-34 days) of daily efavirenz-based antiretroviral therapy with twice-weekly rifabutin 600 mg and isoniazid 15 mg/kg. RESULTS The mean rifabutin area under the concentration-time curve (AUC(0-24)) increased 20% from the baseline value (geometric mean, 5.0 vs. 4.2 microg.h/mL; ratio of geometric means, 1.2 [90% confidence interval, 1.0-1.4]). Also, the mean efavirenz AUC(0-24) in the 15 patients taking concomitant rifabutin 600 mg twice-weekly was 10% higher than that in 35 historical subjects with HIV infection who were not taking rifabutin. Efavirenz-based antiretroviral therapy was effective; HIV load decreased 2.6 log copies/mL, and the median CD4+ T cell count increased from 141 to 240 cells/mm3 after a median of 21 days of efavirenz-based antiretroviral therapy. No statistically significant differences in isoniazid pharmacokinetic parameters were found. CONCLUSIONS The rifabutin dose increase from 300 mg to 600 mg was adequate to compensate for the efavirenz drug interaction in most patients, and no drug interaction with isoniazid was detected. Efavirenz therapy administered at a standard 600-mg dose achieved adequate plasma concentrations in patients receiving intermittent rifabutin and isoniazid therapy, was generally well tolerated, and demonstrated potent antiretroviral activity.

Clinical Evaluation of the Nelfinavir‐Rifabutin Interaction in Patients with Tuberculosis and Human Immunodeficiency Virus Infection

Study Objective. To characterize the bidirectional interaction between twice‐daily nelfinavir and twice‐weekly rifabutin and isoniazid in patients with tuberculosis and human immunodeficiency virus (HIV) infection.

Factors Associated With Noncompletion of Latent Tuberculosis Infection Treatment: Experience From the PREVENT TB Trial in the United States and Canada.

BACKGROUND Overall rates of noncompletion of treatment (NCT) for latent tuberculosis infection (LTBI) in the PREVENT TB trial were 18% for 3 months of directly observed once-weekly rifapentine (maximum dose, 900 mg) plus isoniazid (maximum dose, 900 mg) (3HP-DOT) and 31% for 9 months of daily self-administered isoniazid (maximum dose, 300 mg; 9H-SAT). NCT for LTBI reduces its effectiveness. The study objective was to assess factors associated with NCT for LTBI among adult participants enrolled at US and Canadian sites of the PREVENT TB trial. METHODS This was a post hoc exploratory analysis of the randomized, open-label PREVENT TB trial. Factors were analyzed by univariate and multivariate logistic regression (with enrollment site as a random effect). RESULTS From 6232 participants analyzed, 1406 (22.6%) did not complete LTBI treatment (317 NCT attributed to an adverse event [NCT-AE] and 1089 NCT attributed to reasons other than an adverse event [NCT-O]). The proportion of NCT-AE was similar with both regimens (3HP-DOT = 6.4% vs 9H-SAT = 5.9%; P = .23); NCT-O was higher among participants enrolled in 9H-SAT (9H-SAT = 24.5% vs 3HP-DOT = 12.7%; P = .02). Among those in the NCT-AE group, being non-Hispanic and receiving 3HP-DOT, having cirrhosis and receiving 9H-SAT, alcohol consumption among men, and use of concomitant medication were associated with NCT-AE. Among those in the NCT-O group, receiving 9H-SAT, missing ≥1 early visit, men receiving 9H-SAT, men with a history of incarceration, alcohol abuse, use ever of intravenous drugs, younger age receiving 9H-SAT, and smoking were associated with NCT-O. CONCLUSIONS Factors associated with NCT, such as missing a clinic visit early during treatment, might help identify persons for whom tailored interventions could improve completion of LTBI treatment. CLINICAL TRIALS REGISTRATION NCT00023452.

Tuberculosis Elimination Efforts in the United States in the Era of Insurance Expansion and the Affordable Care Act

The Patient Protection and Affordable Care Act can enhance ongoing efforts to control tuberculosis (TB) in the United States by bringing millions of currently uninsured Americans into the health-care system. However, much of the legislative and financial framework that provides essential public health services necessary for effective TB control is outside the scope of the law. We identified three key issues that will still need to be addressed after full implementation of the Affordable Care Act: (1) essential TB-related public health functions will still be needed and will remain the responsibility of federal, state, and local health departments; (2) testing and treatment for latent TB infection (LTBI) is not covered explicitly as a recommended preventive service without cost sharing or copayment; and (3) remaining uninsured populations will disproportionately include groups at high risk for TB. To improve and continue TB control efforts, it is important that all populations at risk be tested and treated for LTBI and TB; that testing and treatment services be accessible and affordable; that essential federal, state, and local public health functions be maintained; that private-sector medical/public health linkages for diagnosis and treatment be developed; and that health-care providers be trained in conducting appropriate LTBI and TB clinical care.

Effect of Improving the Quality of Radiographic Interpretation on the Ability to Predict Pulmonary Tuberculosis Relapse

RATIONALE AND OBJECTIVES Chest radiographic findings are important for diagnosis and management of tuberculosis. The reliability of these findings is therefore of interest. We sought to describe interobserver reliability of chest radiographic findings in pulmonary tuberculosis, and to understand how the reliability of these findings might affect the utility of radiographic findings in predicting tuberculosis relapse. MATERIALS AND METHODS Three blinded readers independently reviewed chest radiographs from a randomly selected group of 10% of HIV-seronegative subjects participating in a tuberculosis treatment trial. The three readers then arrived at a fourth, consensus radiographic interpretation. RESULTS A total of 241 films obtained from 99 patients were reviewed. Agreement among the independent readers was very good for the findings of bilateral disease (kappa = 0.71-0.86 among readers) and cavitation (kappa = 0.66-0.73). The original interpretation was reasonably sensitive and specific (compared to the consensus interpretation) for bilateral disease, but the sensitivity for cavity decreased from 81% for the 2-month film to 47% at end of treatment (P = 0.013). Substituting the consensus interpretation for the original interpretation increased the odds ratio for the association between cavitation on early chest radiograph and subsequent tuberculosis relapse from 4.97 to 8.97. CONCLUSION Radiographic findings were reasonably reliable between independent reviewers and the original interpretations. The original investigators, who knew the patients clinical course, were less likely to identify cavitation on the end of treatment chest radiograph. Improving the reliability of these findings could improve the utility of chest radiographs for predicting tuberculosis relapse.

Comparison of different treatments for isoniazid-resistant tuberculosis: an individual patient data meta-analysis

BACKGROUND Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ. METHODS Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study. Studies were identified from two relevant systematic reviews, an updated search of one of the systematic reviews (for papers published between April 1, 2015, and Feb 10, 2016), and personal communications. Individual patient data were obtained from authors of eligible studies. The individual patient data meta-analysis was performed with propensity score matched logistic regression to estimate adjusted odds ratios (aOR) and risk differences of treatment success (cure or treatment completion), death during treatment, and acquired rifampicin resistance. Outcomes were measured across different treatment regimens to assess the effects of: different durations of REZ (≤6 months vs >6 months); addition of a fluoroquinolone to REZ (fluoroquinolone plus 6 months or more of REZ vs 6 months or more of REZ); and addition of streptomycin to REZ (streptomycin plus 6 months of rifampicin and ethambutol and 1-3 months of pyrazinamide vs 6 months or more of REZ). The overall quality of the evidence was assessed using GRADE methodology. FINDINGS Individual patient data were requested for 57 cohort studies and 17 randomised trials including 8089 patients with INH-R tuberculosis. We received 33 datasets with 6424 patients, of which 3923 patients in 23 studies received regimens related to the study objectives. Compared with a daily regimen of 6 months of (H)REZ (REZ with or without isoniazid), extending the duration to 8-9 months had similar outcomes; as such, 6 months or more of (H)REZ was used for subsequent comparisons. Addition of a fluoroquinolone to 6 months or more of (H)REZ was associated with significantly greater treatment success (aOR 2·8, 95% CI 1·1-7·3), but no significant effect on mortality (aOR 0·7, 0·4-1·1) or acquired rifampicin resistance (aOR 0·1, 0·0-1·2). Compared with 6 months or more of (H)REZ, the standardised retreatment regimen (2 months of streptomycin, 3 months of pyrazinamide, and 8 months of isoniazid, rifampicin, and ethambutol) was associated with significantly worse treatment success (aOR 0·4, 0·2-0·7). The quality of the evidence was very low for all outcomes and treatment regimens assessed, owing to the observational nature of most of the data, the diverse settings, and the imprecision of estimates. INTERPRETATION In patients with INH-R tuberculosis, compared with treatment with at least 6 months of daily REZ, addition of a fluoroquinolone was associated with better treatment success, whereas addition of streptomycin was associated with less treatment success; however, the quality of the evidence was very low. These results support the conduct of randomised trials to identify the optimum regimen for this important and common form of drug-resistant tuberculosis. FUNDING World Health Organization and Canadian Institutes of Health Research.

Screening for Latent Tuberculosis Infection Among HIV-Infected Medicaid Enrollees

Objectives: In the United States, universal screening for latent tuberculosis (TB) infection among people with HIV is recommended, but the percentage receiving screening is unknown. This study assessed screening for latent TB infection among people with HIV enrolled in Medicaid during 2006-2010. Methods: We used nationwide fee-for-service Medicaid records to identify people with HIV, measure screening for latent TB infection, and examine associated demographic, social, and clinical factors. We used logistic regression analysis to calculate odds ratios (ORs) and 95% confidence intervals (CIs). We created 2 multivariate models to prevent collinearity between variables for length of HIV infection. Results: Of 152 831 people with HIV, 26 239 (17.2%) were screened for latent TB infection. The factor most strongly associated with screening was TB exposure or suspected TB (OR = 3.78; 95% CI, 3.27-4.37). Significant demographic characteristics associated with screening included being African American (OR = 1.28; 95% CI, 1.24-1.32) or ≤20 years of age (OR = 1.35; 95% CI, 1.28-1.42). Significant clinical and social factors associated with screening included poor housing conditions, low body mass index, chemotherapy treatment, and use of certain substances (ORs ranged from 1.24 [95% CI, 1.20-1.27] to 1.47 [95% CI, 1.22-1.76]). The screening rate for latent TB infection was higher among people with newly diagnosed HIV infection than among those with established infection (OR = 1.37; 95% CI, 1.32-1.41) and among people with a longer established HIV infection than among those with shorter HIV infection (OR = 1.24; 95% CI, 1.23-1.26 for each additional year). Conclusion: Screening for latent TB infection among fee-for-service Medicaid beneficiaries with HIV was suboptimal, despite the presence of demographic, social, or clinical characteristics that should have increased the likelihood of screening. The lack of certain data in Medicaid may have resulted in an underestimation of screening.