BACKGROUND: Globally, over one-third of pulmonary tuberculosis (TB) disease diagnoses are made based on clinical criteria after a negative bacteriological test result. There is limited information on the factors that determine clinicians' decisions to initiate TB treatment when initial bacteriological test results are negative. METHODS AND FINDINGS: We performed a systematic review and individual patient data meta-analysis using studies conducted between January 2010 and December 2022 (PROSPERO: CRD42022287613). We included trials or cohort studies that enrolled individuals evaluated for TB in routine settings. In these studies, participants were evaluated based on clinical examination and routinely used diagnostics and were followed for ≥1 week after the initial test result. We used hierarchical Bayesian logistic regression to identify factors associated with treatment initiation following a negative result on an initial bacteriological test (e.g., sputum smear microscopy (SSM), Xpert MTB/RIF). Multiple factors were positively associated with treatment initiation: male sex [adjusted odds ratio (aOR) 1.61 (1.31, 1.95)], history of prior TB [aOR 1.36 (1.06, 1.73)], reported cough [aOR 4.62 (3.42, 6.27)], reported night sweats [aOR 1.50 (1.21, 1.90)], and having HIV infection but not on ART [aOR 1.68 (1.23, 2.32)]. Treatment initiation was substantially less likely for individuals testing negative with Xpert [aOR 0.77 (0.62, 0.96)] compared to smear microscopy and declined in more recent years. We were not able assess why clinicians made treatment decisions, as these data were not available. CONCLUSIONS: Multiple factors influenced decisions to initiate TB treatment despite negative test results. Clinicians were substantially less likely to treat in the absence of a positive test result when using more sensitive, PCR-based diagnostics.

OBJECTIVE: Thirty-six months of isoniazid preventive therapy (36IPT) was superior to 6 months of IPT (6IPT) in preventing tuberculosis (TB) among HIV-infected adults in Botswana. We assessed the posttrial durability of this benefit. DESIGN: A 36-month double-blind placebo controlled trial (1 : 1 randomization) with recruitment between November 2004 and July 2006 and observation until June 2011. METHODS: One thousand, nine hundred and ninety-five participants were followed in eight public health clinics. Twenty-four percent had a tuberculin skin test ≥5 mm (TST-positive). A minimum CD4 lymphocyte count was not required for enrolment. Antiretroviral therapy (ART) was provided in accordance with Botswana guidelines; 72% of participants retained by June 2011 had initiated ART. Multivariable analysis using Cox regression analysis included treatment arm, TST status, ART as a time-dependent variable and CD4 cell count at baseline and updated at 36 months. RESULTS: In the posttrial period, 2.13 and 2.14 per 100 person-years accumulated, whereas 0.93 and 1.13% TB incidence rates were observed in the 36IPT and 6IPT arms, respectively (P = 0.52). The crude hazard ratio of TB during the trial and posttrial was 0.57 [95% confidence intervals (CI) 0.33, 0.99] and 0.82 (95% CI 0.46, 1.49), and when restricted to TST-positive participants was 0.26 (95% CI 0.08, 0.80) and 0.40 (95% CI 0.15, 1.08), respectively. Multivariable analysis showed that ART use was associated with reduced death (adjusted hazard ratio 0.36, 95% CI 0.17-0.75) but not TB (0.92, 95% CI 0.55-1.53) in the posttrial period. CONCLUSION: The benefit of 36IPT for TB prevention declined posttrial in this cohort. Adjunctive measures are warranted to prevent TB among HIV-infected persons receiving long-term ART in TB-endemic settings.

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 muL. 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.

BACKGROUND: Isoniazid preventive therapy (IPT) prevents tuberculosis (TB) in people living with HIV (human immunodeficiency virus, PLWH). Symptom screening without chest radiographs (CXRs) was established as the strategy for excluding TB disease among PLWH seeking IPT in Botswana's 2001 pilot project. This strategy was evaluated in 2004-2006 among candidates screened for an IPT clinical trial. METHODS: PLWH referred from clinics and HIV testing centers were screened for TB symptoms. All asymptomatic candidates received CXRs; those with abnormal CXRs were investigated further. RESULTS: Among 2732 asymptomatic candidates screened, 302 (11%) had abnormal CXRs potentially compatible with TB; TB disease was diagnosed in 43 of these 302 (14%), or 43 (1.6%) of the 2732 asymptomatic candidates. While not associated with CD4 lymphocyte counts < 200 cells/mm(3), TB was associated with a positive tuberculin skin test (relative risk 2.1, 95%CI 1.1-4.0). IPT was initiated in 113 (62%) of 182 asymptomatic PLWH with abnormal CXRs; 8/113 (7%) subsequently developed TB, and 7/8 (88%) successfully completed anti-tuberculosis treatment. CONCLUSIONS: The prevalences of abnormal CXRs and TB were respectively 2.6- and 8.9-fold higher among asymptomatic PLWH screened for the trial than in the pilot. A cost-effectiveness analysis is needed to determine whether the benefits of symptom screening alone are offset by the risk of inducing INH resistance by excluding CXRs during screening.

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 ≥5 mm in 24% of those enrolled and 31% had CD4 lymphocyte counts <200 cells/mm. 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.