IntroductionThere is lack of information on the proportion of new smear—positive pulmonary tuberculosis (PTB) patients treated with a 6-month thrice-weekly regimen under Revised National Tuberculosis Control Programme (RNTCP) who develop recurrent TB after successful treatment outcome.ObjectiveTo estimate TB recurrence among newly diagnosed PTB patients who have successfully completed treatment and to document endogenous reactivation or re-infection. Risk factors for unfavourable outcomes to treatment and TB recurrence were determined.MethodologyAdult (aged ≥ 18 yrs) new smear positive PTB patients initiated on treatment under RNTCP were enrolled from sites in Tamil Nadu, Karnataka, Delhi, Maharashtra, Madhya Pradesh and Kerala. Those declared “treatment success” at the end of treatment were followed up with 2 sputum examinations each at 3, 6 and 12 months after treatment completion. MIRU-VNTR genotyping was done to identify endogenous re-activation or exogenous re-infection at TB recurrence. TB recurrence was expressed as rate per 100 person-years (with 95% confidence interval [95%CI]). Regression models were used to identify the risk factors for unfavourable response to treatment and TB recurrence.ResultsOf the1577 new smear positive PTB patients enrolled, 1565 were analysed. The overall cure rate was 77% (1207/1565) and treatment success was 77% (1210 /1565). The cure rate varied from 65% to 86%. There were 158 of 1210 patients who had TB recurrence after treatment success. The pooled TB recurrence estimate was 10.9% [95%CI: 0.2–21.6] and TB recurrence rate per 100 person–years was 12.7 [95% CI: 0.4–25]. TB recurrence per 100 person–years varied from 5.4 to 30.5. Endogenous reactivation was observed in 56 (93%) of 60 patients for whom genotyping was done. Male gender was associated with TB recurrence.ConclusionA substantial proportion of new smear positive PTB patients successfully treated with 6 –month thrice-weekly regimen have TB recurrence under program settings.

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The current vaccine against tuberculosis (TB), Mycobacterium bovis BCG, fails to protect against the most prevalent disease form, pulmonary TB in adults. It is generally assumed that active TB occurs because of a weakening of the immune system, which keeps Mycobacterium tuberculosis in check as long as it is fully competent. M. tuberculosis does not induce the optimum protection because the pathogen is not eradicated, and it has now been shown that exogenous reinfection does occur, suggesting that natural immunity is insufficient (26) and fails to control the pathogen in the long run. Hence, other mycobacterial strains which share cross-reactive antigens (Ags) with M. tuberculosis have also been considered as alternatives to M. bovis for vaccine use. One strain, "Mycobacterium w," had been evaluated for its immunomodulatory properties in leprosy. M. w is a nonpathogenic, cultivable mycobacterium (18) which has been found to improve immunity to leprosy (30). A vaccine against leprosy based on M. w is approved for human use, where it has resulted in clinical improvement, accelerated bacterial clearance, and increased immune responses to Mycobacterium leprae Ags (13,21,25). M. w shares Ags not only with M. leprae but also with M. tuberculosis (29), and initial studies have shown that vaccination with killed M. w induces protection against TB in animal models (22, 23) and also resulted in early sputum conversion in TB patients (17). Recently it has been suggested that M. w be referred to as Mycobacterium indicus pranii to avoid confusion with M. tuberculosis-W (Beijing strain) (24). It is generally known that live bacteria impart greater protection than killed bacteria. It may be that persistence of live bacteria in the host for some time results in a robust memory response (12). Another important factor is that secretory proteins which are absent in the killed bacterial vaccines have been shown to play an important role in protection. In this study, we analyzed the M. tuberculosis-specific immune response induced in mice immunized with live or killed M. w and compared it with the BCG-induced immune response and also compared the protective efficacies of the two mycobacteria.As the lung is the primary target organ of this disease, immunization potential by the aerogenic route was also studied. Inhalation of aerosols provides a noninvasive delivery system that physically targets the lung as the desired site of the pharmacological effect. This route of immunization has emerged a very attractive route of vaccine delivery, inducing both local and systemic immunity (7, 10).

IntroductionShorter duration of treatment for the management of drug-susceptible pulmonary tuberculosis (TB) would be a significant improvement in the care of patients suffering from the disease. Besides newer drugs and regimens, other modalities like host-directed therapy are also being suggested to reach this goal. This study’s objective is to assess the efficacy and safety of metformin-containing anti-TB treatment (ATT) regimen in comparison to the standard 6-month ATT regimen in the treatment of patients with newly diagnosed sputum smear-positive drug-sensitive pulmonary TB.Methods and analysisWe are conducting a multicentric, randomised open-label controlled clinical trial to achieve the study objective. The intervention group will receive isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) along with 1000 mg of daily metformin (Met) for the first 2 months while the control group will receive only HRZE. After 2 months, both the groups will receive HRE daily for 4 months. The primary endpoint is time to sputum culture conversion. Secondary endpoints will include time to detection of Mycobacterium tuberculosis in sputum, pharmacokinetics and pharmacogenomics of study drugs, drug–drug interactions, safety and tolerability of the various combinations and measurement of autophagy and immune responses in the study participants.Ethics and disseminationThe ethics committee of the participating institutes have approved the study. Results from this trial will contribute to evidence towards constructing a shorter, effective and safe regimen for patients with TB. The results will be shared widely with the National Programme managers, policymakers and stakeholders through open access publications, dissemination meetings, conference abstracts and policy briefs. This is expected to provide a new standard of care for drug-sensitive patients with pulmonary TB who will not only reduce the number of clinic visits and lost to follow-up of patients from treatment but also reduce the burden on the healthcare system.Trial registration numberCTRI/2018/01/011176; Pre-results.

Although the occurrence of tuberculous meningitis (TBM) in children is relatively rare, but it is associated with higher rates of mortality and severe morbidity. The peak incidence of TBM occurs in younger children who are less than five years of age, and most children present with late-stage disease. Confirmation of diagnosis is often difficult, and other infectious causes such as bacterial, viral and fungal causes must be ruled out. Bacteriological confirmation of diagnosis is ideal but is often difficult because of its paucibacillary nature as well as decreased sensitivity and specificity of diagnostic tests. Early diagnosis and management of the disease, though difficult, is essential to avoid death or neurologic disability. Hence, a high degree of suspicion and a combined battery of tests including clinical, bacteriological and neuroimaging help in diagnosis of TBM. Children diagnosed with TBM should be managed with antituberculosis therapy (ATT) and steroids. There are studies reporting low concentrations of ATT, especially of rifampicin and ethambutol in cerebrospinal fluid (CSF), and very young children are at higher risk of low ATT drug concentrations. Further studies are needed to identify appropriate regimens with adequate dosing of ATT for the management of paediatric TBM to improve treatment outcomes. This review describes the clinical presentation, investigations, management and outcome of TBM in children and also discusses various studies conducted among children with TBM.