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Background. Using hollow-fiber tuberculosis studies, we recently demonstrated that nonadherence is not a significant factor for ADR and that therapy failure only occurs after a large proportion of doses are missed. Computer-aided clinical trial simulations have suggested that isoniazid and rifampin pharmacokinetic variability best explained poor outcomes. We were interested in determining whether isoniazid pharmacokinetic variability was associated with either microbiological failure or ADR in the clinic. Methods. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Prospective, randomized, controlled clinical trials that reported isoniazid acetylation status and microbiological outcomes were selected. The main effects examined were microbiological sputum conversion, ADR, and relapse. Effect size was expressed as pooled risk ratios (RRs) comparing rapid with slow acetylators. Results. Thirteen randomized studies with 1631 rapid acetylators and 1751 slow acetylators met inclusion and exclusion criteria. Rapid acetylators were more likely than slow acetylators to have microbiological failure (RR, 2.0; 95% confidence interval [CI], 1.5-2.7), ADR (RR, 2.0; CI, 1.1-3.4), and relapse (RR, 1.3; CI, .9-2.0). Higher failure rates were encountered even in drug regimens comprising >3 antibiotics. No publication bias or smallstudy effects were observed for the outcomes evaluated. Conclusions. Pharmacokinetic variability to a single drug in the regimen is significantly associated with failure of therapy and ADR in patients. This suggests that individualized dosing for tuberculosis may be more effective than standardized dosing, which is prescribed in directly observed therapy programs.

Treatment of latent tuberculosis infection is an important control measure, especially in patients coinfected with HIV. In this international phase 3 trial, 1 month of isoniazid plus rifapentine was noninferior to the standard 9 months of isoniazid in HIV-infected patients.

In this study, early treatment of HIV infection with antiretroviral therapy decreased traditionally HIV-associated and non–HIV-associated complications (at CD4+ counts <800 cells per cubic millimeter), and early isoniazid prophylaxis prevented active tuberculosis. The recommended CD4+ count threshold for starting antiretroviral therapy (ART) in asymptomatic human immunodeficiency virus (HIV)–infected adults in lower-resource countries was increased from 200 cells per cubic millimeter in 2006 to 500 cells per cubic millimeter in 2013. 1 , 2 This change was supported by the results of two randomized, controlled trials. 3 , 4 Meanwhile, three types of arguments have emerged to support even earlier initiation of ART. First, there is increasing documentation of inflammation in people with uncontrolled viral replication and of non–acquired immunodeficiency syndrome (AIDS)–defining noninfectious diseases as causes of death in HIV-infected persons 5 , 6 (with AIDS-defining diseases identified as . . .

Treatment for tuberculosis, a leading cause of death worldwide, typically involves 6 months of continuous therapy. In this trial, a strategy involving shorter initial treatment was noninferior to standard treatment.

Treatment of latent TB is an important public-health strategy, but 9 months of daily isoniazid (270 doses) poses challenges for compliance. In this study, 3 months of weekly isoniazid plus rifapentine (12 doses) was found to be noninferior to 9 months of isoniazid alone. Tuberculosis results in nearly 2 million deaths annually worldwide. 1 More than 2 billion persons are infected with Mycobacterium tuberculosis, 2 and from this reservoir active tuberculosis will develop in millions of persons in coming decades. Treatment of latent M. tuberculosis infection among the persons at highest risk for progression to active disease is an important strategy for tuberculosis control and elimination. 3 – 6 The current standard regimen for the treatment of latent M. tuberculosis infection is 9 months of daily isoniazid. 3 The efficacy for isoniazid was found to be 69 to 93% in a study that was published in 1982 (before the . . .

In pretreatment isolates of M. tuberculosis with decrements of the minimum inhibitory concentration of isoniazid or rifampin below the standard resistance breakpoint, higher MIC values were associated with a greater risk of relapse than lower MIC values.

Background Monotherapy with the drug isoniazid (INH) was for a long time the main therapeutic regimen used for tuberculosis preventive treatment (TPT). Research is progressing into the use of new therapeutic regimens that provide more complete TPT. The objective was to analyze the completion and safety of TPT with the drug INH in the form of 300 mg tablets. Methods Pragmatic, randomized, non-blinded, multicenter clinical trial conducted in Brazil from January 2019 to December 2022. Subjects over the age of 18 years with an indication for TPT was included and those whose index case of active tuberculosis was in retreatment, multidrug-resistant and extremely resistant, transferred, and people deprived of their liberty was excluded. The intervention was TPT with 1 INH 300 mg tablet and the control group with 3 INH 100 mg tablets. The primary outcome was TPT completion. Pearson's chi-square test was used to analyze the association of TPT completion. The risk of TPT completion was estimated by Poisson regression. The mean treatment effect was calculated. The results were expressed as a risk ratio (RR) with a 95% confidence interval (95%CI). Results A total of 207 individuals were included, 103 (49.7%) in the intervention group. Seventy-two (69.9%) of the individuals who used INH 300 mg completed TPT. The risk ratio for completing TPT was 1.39 times higher in the group that used the INH 300 mg treatment (RR 1.39, 95%CI 1.08 to 1.79). The mean effect of the intervention was 19% (Coefficient 0.19, 95%CI 0.06 to 0.32). There was no significant difference in adverse events between the groups. Conclusion The pragmatic use of INH 300 mg in TPT showed a positive effect on the treatment completion rate and is a safe presentation for use in INH monotherapy regimens. Trial registration The protocol is registered in the Brazilian Registry of Clinical Trials under the code RBR-2wsdt6 in September 2019 10th.

In this report, the timing of isoniazid therapy to prevent tuberculosis in pregnant women with HIV infection was assessed. Intrapartum isoniazid treatment resulted in a higher incidence of adverse pregnancy outcomes than treatment during the postpartum period.

Background Tuberculosis (TB) lymphadenitis is the most common form of extra-pulmonary TB, and the treatment duration is six months. This non-inferiority based randomized clinical trial in South India evaluated the efficacy and safety of a four-month ofloxacin containing regimen in tuberculosis lymphadenitis (TBL) patients. Methods New, adult, HIV-negative, microbiologically and or histopathologically confirmed superficial lymph node TB patients were randomized to either four-month oflaxacin containing test regimen [ofloxacin (O), isoniazid (H), rifampicin (R), pyrazinamide (Z) -2RHZO daily/ 2RHO thrice-weekly] or a six-month thrice-weekly control regimen (2HRZ, ethambutol/4RH). The treatment was directly observed. Clinical progress was monitored monthly during and up to 12 months post-treatment, and thereafter every three months up to 24 months. The primary outcome was determined by response at the end of treatment and TB recurrence during the 24 months post-treatment. Results Of the 302 patients randomized, 298 (98.7%) were eligible for modified intention-to-treat (ITT) analysis and 294 (97%) for per-protocol (PP) analysis. The TB recurrence-free favourable response in the PP analysis was 94.0% (95% CI: 90.1–97.8) and 94.5% (95% CI: 90.8–98.2) in the test and control regimen respectively, while in the ITT analysis, it was 92.7% and 93.2%. The TB recurrence-free favourable response in the test regimen was non-inferior to the control regimen 0.5% (95% CI: -4.8-5.9) in the PP analysis based on the 6% non-inferiority margin. Treatment was modified for drug toxicity in two patients in the test regimen, while one patient had a paradoxical reaction. Conclusion The 4-month ofloxacin containing regimen was found to be non-inferior and as safe as the 6-month thrice-weekly control regimen.

Tuberculosis preventive treatment (TPT) is essential for the end TB Strategy, but shorter and better tolerated regimens are needed to boost its coverage and acceptance. Silicosis patients aged 18 to 65 years received a novel 1H3P3 regimen (400 mg isoniazid and 450 mg rifapentine, thrice-weekly for 4 weeks) under direct observation and were actively followed up for 3 years. The safety and efficacy were compared to the 3-month, once-weekly isoniazid/rifapentine (3HP) group and observation group from our previous trials. A total of 279 eligible participants were enrolled, and 238 participants provided informed consent. All eligible participants had a median age of 56 years (IQR 52-60), 163 (68.5%) participants had a Bacillus Calmette-Guerin vaccine scar, and 74 (31.1%) participants were QuantiFERON-TB Gold In-Tube positive. There were 88 adverse events from 66 (27.7%) participants and only one (0.4%) participant had a Grade 3 adverse event. The completion rate was 92.0% (219/238). Six (2.5%) participants were diagnosed with active TB, five of which were bacterial confirmed cases. The cumulative active TB rate was 1.67 cases per 100 person-years. Compared to the previous study, the 1H3P3 regimen significantly reduced the 3-year cumulative active TB rate than the observation group (HR = 0.26, Log-rank = 0.02) and was comparable with the 3HP group (HR = 0.74, Log-rank = 0.69), while significantly reducing adverse events. The 1H P TPT regimen was both safe and effective among silicosis patients. Further work is necessary to test the regimen in other high-risk populations. ClinicalTrials.gov identifier: NCT06022146 and NCT03900858.