Background: While previous research has provided evidence of the diagnostic accuracy of the GeneXpert MTB/ RIF (GeneXpert), further information is needed about implementation in the real-world. This study evaluated the impact of the introduction of GeneXpert testing in a tertiary medical center according to the testing algorithm proposed by the National TB Control Program (NTP) guidelines.Methods: All adult medical inpatient persons with presumptive TB admitted between November 2013 and March 2014 were eligible for GeneXpert sputum testing and followed to TB treatment initiation status.Results: We identified 932 persons with presumptive TB, of which 307 (32.9%) were GeneXpert tested. Those tested had an average age of 40 years, 49.2% (151) were male, 34.5% (106) were HIV positive, and 84.1% (249) presented with a cough. Of those GeneXpert tested, 28/307 (9.1%) tested positive, a 55.5% increase in detection compared to smear microscopy. However, the majority (44/72, 61%) of TB diagnoses were made by other modalities and not confirmed microbiologically. Of the 58 patients recommended to start treatment and discharged from the hospital, only 23 (40%) were documented to have started treatment at regional directly observed treatment, short course (DOTS) centers.Conclusions: GeneXpert contributed minimally to overall TB diagnosis and the cascade of care due to implementation challenges of sputum collection, empiric treatment, and weak linkage to care between inpatient and outpatient settings.

Background Pediatric tuberculous meningitis (TBM) commonly causes death or disability. . In adults, high-dose rifampicin may reduce mortality. Fluoroquinolones’ role remains unclear. There have been no antimicrobial treatment trials for pediatric TBM. Methods TBM-KIDS (NCT02958709) was a Phase II open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (a) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, Arm 1); (b) high-dose rifampicin and levofloxacin (R30HZL, Arm 2); or (c) standard-dose rifampicin and ethambutol (R15HZE, Arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL). Results Of 2487 children pre-screened, 79 were screened, and 37 enrolled. Median age was 72 months. 49%, 43%, and 8% had Stage I, II, and III disease. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in Arms 1, 2, and 3, with one death (Arm 1) and six early treatment discontinuations (4 in Arm 1, 1 each in Arms 2 and 3). By Week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in Arm 1 than Arm 3 in fine motor, receptive language, and expressive language domains (p<0.01). Conclusions In a pediatric TBM trial, functional outcomes were excellent overall. The trend towards higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial.

Background The urine lipoarabinomannan (LAM) antigen test is a TB diagnostic test with highest sensitivity in individuals with advanced HIV. Its role in TB diagnostic algorithms for HIV positive outpatients remains unclear. Methods ACTG A5274 trial demonstrated that empiric TB therapy did not improve 24-week survival compared to isoniazid preventive therapy (IPT) in TB screen negative HIV positive adults initiating ART with CD4 counts <50 cells/µL. Retrospective LAM testing was performed on stored urine obtained at baseline. We determined the proportion of LAM-positive participants and conducted modified intent-to-treat analysis excluding LAM-positive participants to determine the effect on 24-week survival, TB incidence and time to TB using Kaplan-Meier method. Results A5274 enrolled 850 participants, 53% were male and median CD4 count was 18 cells/µL (IQR: 9, 32). Of the 850, 566 (67%) had LAM testing (283 per arm); 28 (5%) were positive [21 (7%); 7 (2%) in empiric and IPT arms, respectively]. Of those LAM-positive, 1 participant in each arm died and 5 of 21 and 0 of 7 in empiric and IPT arms, respectively, developed TB. After excluding these 28 cases, there were 19 and 21 deaths in empiric and IPT arms, respectively (p=0.88). TB incidence remained higher (4.6% vs. 2%, p=0.04) and time to TB remained faster in the empiric arm (p=0.04). Conclusions Among outpatients with advanced HIV who screened negative for TB by clinical symptoms, microscopy and Xpert testing, LAM testing identified an additional 5% of individuals with TB. . Positive LAM results did not change mortality or TB incidence.

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