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Background: In accordance with WHO guidelines, people with HIV infection in Botswana receive daily isoniazid preventive therapy against tuberculosis without obtaining a tuberculin skin test, but duration of prophylaxis is restricted to 6 months. We aimed to assess effectiveness of extended isoniazid therapy., Methods: In our randomised, double-blind, placebo-controlled trial we enrolled adults infected with HIV aged 18 years or older at government HIV-care clinics in Botswana. Exclusion criteria included current illness such as cough and an abnormal chest radiograph without antecedent tuberculosis or pneumonia. Eligible individuals were randomly allocated (1:1) to receive 6 months' open-label isoniazid followed by 30 months' masked placebo (control group) or 6 months' open-label isoniazid followed by 30 months' masked isoniazid (continued isoniazid group) on the basis of a computer-generated randomisation list with permuted blocks of ten at each clinic. Antiretroviral therapy was provided if participants had CD4-positive lymphocyte counts of fewer than 200 cells per μL. We used Cox regression analysis and the log-rank test to compare incident tuberculosis in the groups. Cox regression models were used to estimate the effect of antiretroviral therapy. The trial is registered at ClinicalTrials.gov, number NCT00164281., Findings: Between Nov 26, 2004, and July 3, 2009, we recorded 34 (3·4%) cases of incident tuberculosis in 989 participants allocated to the control group and 20 (2·0%) in 1006 allocated to the continued isoniazid group (incidence 1·26% per year vs 0·72%; hazard ratio 0·57, 95% CI 0·33-0·99, p=0·047). Tuberculosis incidence in those individuals receiving placebo escalated approximately 200 days after completion of open-label isoniazid. Participants who were tuberculin skin test positive (ie, ≥5 mm induration) at enrolment received a substantial benefit from continued isoniazid treatment (0·26, 0·09-0·80, p=0·02), whereas participants who were tuberculin skin test-negative received no significant benefit (0·75, 0·38-1·46, p=0·40). By study completion, 946 (47%) of 1995 participants had initiated antiretroviral therapy. Tuberculosis incidence was reduced by 50% in those receiving 360 days of antiretroviral therapy compared with participants receiving no antiretroviral therapy (adjusted hazard ratio 0·50, 95% CI 0·26-0·97). Severe adverse events and death were much the same in the control and continued isoniazid groups., Interpretation: In a tuberculosis-endemic setting, 36 months' isoniazid prophylaxis was more effective for prevention of tuberculosis than was 6-month prophylaxis in individuals with HIV infection, and chiefly benefited those who were tuberculin skin test positive., Funding: US Centers for Disease Control and Prevention and US Agency for International Development., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objectives: To describe reasons for exclusion from isoniazid tuberculosis preventive therapy (IPT) and outcomes of persons living with HIV (PLWH) during 6 months of IPT., Methods: In a clinical trial conducted in government clinics, first screening (screen 1) used National IPT Program guidelines and a second screening (screen 2) was trial specific. Adherence was defined as attending 6 monthly visits., Results: Between 2004 and 2006, at 4018 screening visits, 2934 (73%) PLWH met screen 1 criteria; 1995 (68%) met screen 2 criteria and were enrolled. Major reasons for exclusion were illness (66%) at screen 1 and abnormal chest radiographs (36%) at screen 2. Tuberculin skin tests were > or = 5 mm in 24% of those enrolled and 31% had CD4 lymphocyte counts <200 cells/mm(3). During the 6 months, 8 (0.40%) developed tuberculosis disease, 28 (1.4%) had severe adverse events (19/28 were hepatitis including one death probably isoniazid-associated), 20 others died, and 22% initiated antiretroviral therapy (ART). Although adherence was 86%, being on ART improved adherence: relative risk 1.41 (95% confidence limits 1.04-1.91). In multivariate analysis, ART was associated with a 4.38 greater odds of adherence to IPT., Conclusions: Six months of IPT was relatively safe and well-tolerated by PLWH. Adherence to IPT was significantly better among those receiving ART with IPT.

A sensitive and accurate tuberculosis (TB) serodiagnostic test would aid in the control of TB, but results of current tests are relatively unreliable for persons infected with human immunodeficiency virus (HIV). We evaluated a new prototype immunochromatographic strip test and 5 commercially available serodiagnostic TB tests in a prospective study comprised of 465 consecutively enrolled patients with suspected TB from 2 hospitals in Botswana. Consenting adults underwent HIV testing, >/=2 sputum smears and cultures, and mycobacterial blood culture. Patients were defined as having TB on the basis of any positive smear or culture. Between January and September 2002, 465 of 498 consecutive patients consented to enrollment. A total of 384 patients (83%) were infected with HIV, and 175 (38%) had TB; the mycobacterial blood culture was the sole source of diagnosis for 26 patients (15%) with TB. Among the tests evaluated, the sensitivity was 0%-63%, the specificity was 39%-99%, the positive predictive value was 0%-39%, and the negative predictive value was 63%-65%. We conclude that the serodiagnostic tests evaluated in this study lacked sufficient sensitivity as sole tests for TB in this population.