Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults.

BACKGROUND: A 9-month regimen of isoniazid can prevent active tuberculosis in persons with latent tuberculosis infection. However, the regimen has been associated with poor adherence rates and with toxic effects. METHODS: In an open-label trial conducted in nine countries, we randomly assigned adults with latent tuberculosis infection to receive treatment with a 4-month regimen of rifampin or a 9-month regimen of isoniazid for the prevention of confirmed active tuberculosis within 28 months after randomization. Noninferiority and potential superiority were assessed. Secondary outcomes included clinically diagnosed active tuberculosis, adverse events of grades 3 to 5, and completion of the treatment regimen. Outcomes were adjudicated by independent review panels. RESULTS: Among the 3443 patients in the rifampin group, confirmed active tuberculosis developed in 4 and clinically diagnosed active tuberculosis developed in 4 during 7732 person-years of follow-up, as compared with 4 and 5 patients, respectively, among 3416 patients in the isoniazid group during 7652 person-years of follow-up. The rate differences (rifampin minus isoniazid) were less than 0.01 cases per 100 person-years (95% confidence interval [CI], -0.14 to 0.16) for confirmed active tuberculosis and less than 0.01 cases per 100 person-years (95% CI, -0.23 to 0.22) for confirmed or clinically diagnosed tuberculosis. The upper boundaries of the 95% confidence interval for the rate differences of the confirmed cases and for the confirmed or clinically diagnosed cases of tuberculosis were less than the prespecified noninferiority margin of 0.75 percentage points in cumulative incidence; the rifampin regimen was not superior to the isoniazid regimen. The difference in the treatment-completion rates was 15.1 percentage points (95% CI, 12.7 to 17.4). The rate differences for adverse events of grade 3 to 5 occurring within 146 days (120% of the 4-month planned duration of the rifampin regimen) were -1.1 percentage points (95% CI, -1.9 to -0.4) for all events and -1.2 percentage points (95% CI, -1.7 to -0.7) for hepatotoxic events. CONCLUSIONS: The 4-month regimen of rifampin was not inferior to the 9-month regimen of isoniazid for the prevention of active tuberculosis and was associated with a higher rate of treatment completion and better safety. (Funded by the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council; ClinicalTrials.gov number, NCT00931736 .).

Successful Treatment of Multiple Multidrug Resistant Intracranial Tuberculomata.

A 21-year-old Bangladesh-born man presented with a month history of evolving neurological symptoms in the context of a six-month history of fever, night sweats, and axillary lymphadenopathy. He was subsequently diagnosed with multiple multidrug resistant intracranial tuberculomata and was successfully treated over two years. Intracranial multidrug resistant tuberculosis has a high mortality and successful treatment is rarely reported. Management is complex and requires consideration of the penetration and likely effect of antituberculous agents within the central nervous system. We discuss the role of various antituberculous agents, the duration of therapy, the utility of corticosteroids, the value of intrathecal and systemic therapy, and the need for rapid diagnosis.

HIV testing rates and co-infection among patients with tuberculosis in south-eastern Sydney, 2008-2013.

OBJECTIVE: To evaluate the rate of HIV and tuberculosis co-infection and changes in HIV testing practices for patients with tuberculosis managed in South Eastern Sydney Local Health District (SESLHD), New South Wales, Australia. DESIGN, PARTICIPANTS AND SETTING: A retrospective review of tuberculosis notification data from four public tuberculosis treatment clinics in SESLHD (population, >800,000), 2008-2013. Data were extracted from the NSW Notifiable Conditions Information Management System. INTERVENTION: Published evidence regarding clinical management of HIV and tuberculosis co-infection and feedback of HIV testing rates was provided to senior clinicians managing tuberculosis in SESLHD between 2008 and 2012. MAIN OUTCOME MEASURES: Proportion of patients with tuberculosis with HIV infection status ascertained and proportion with HIV co-infection. RESULTS: Of 506 people with notified tuberculosis treated in SESLHD during the study period, 369 had their HIV status ascertained (72.9%), of whom 20 were HIV co-infected (5.4%). Eleven of these cases were new HIV diagnoses. Seven people offered an HIV test declined the offer. The rates of HIV co-infection varied between clinics (1.5%-9.7%; P=0.02) as did the rate of HIV status ascertainment (61.5%-85.4%; P<0.001). The rate of HIV status ascertainment increased between 2008 and 2013 (52.9%-87.1%; P<0.001). CONCLUSIONS: The rate of HIV co-infection among people treated for tuberculosis in south-eastern Sydney is of clinical importance. Rates of HIV testing in this population have increased, but further gains are desirable. It is unclear if the intervention influenced the increase in HIV testing rates.

Editor's choice: Implications of isoniazid resistance in Mycobacterium bovis Bacillus Calmette-Guérin used for immunotherapy in bladder cancer.

We report a case of sepsis from Mycobacterium bovis Bacillus Calmette-Guérin (BCG) with low-level isoniazid resistance following intravesical treatment for bladder cancer. Isoniazid resistance in BCG has therapeutic implications when it causes infections after intravesical instillation. For these circumstances, we propose some modifications to existing treatment guidelines for BCG infection.

A polymorphism in the P2X7 gene increases susceptibility to extrapulmonary tuberculosis.

RATIONALE: Genetic variation influences susceptibility to clinical tuberculosis (TB). Activation of the P2X(7) receptor on human macrophages induces killing of mycobacteria. We have identified polymorphisms in the P2X(7) gene that markedly reduce this killing. OBJECTIVE: To determine if polymorphisms in P2X7 are associated with increased risk of TB, the prevalence of four polymorphisms was assessed in individuals from Southeast Asia, where the majority of patients with TB in our study originate. The association of these polymorphisms with clinical TB was subsequently investigated in two separate case-control cohorts and the function of P2X(7) was assessed in subjects from one cohort. METHODS: Genotyping of P2X7 polymorphisms was performed from subjects in a nested case-control study of a longitudinal refugee cohort and a separate case-control study. The functional capacity of P2X(7) was investigated by measuring ATP-mediated mycobacterial killing and apoptosis. RESULTS: Only the 1513A-C polymorphism was present in Southeast Asians and the allele was associated with reduced killing of Mycobacterium tuberculosis. The 1513C allele was strongly associated with extrapulmonary, but not pulmonary, TB in the first (odds ratio, 3.8; 95% confidence interval, 1.6-9.0) and second cohorts (odds ratio, 3.7; 95% confidence interval, 1.7-8.0). ATP-mediated killing of mycobacteria was ablated in macrophages from subjects homozygous for the 1513C allele and significantly impaired in macrophages from heterozygous subjects. There was strong correlation between the degree of mycobacterial killing and ATP-induced apoptosis. CONCLUSIONS: The 1513C allele increases susceptibility to extrapulmonary TB, and this defect is associated with the reduction in the capacity of macrophages to kill M. tuberculosis.