Background Symptom-based screening for tuberculosis (TB) is recommended for all people living with HIV (PLHIV) resulting in unnecessary Xpert MTB/RIF testing for the vast majority of individuals living in TB endemic areas and thus, poor implementation of intensified case finding (ICF) and TB preventive therapy. Novel approaches to TB screening are therefore critical in achieving global targets for TB elimination. Methods In a prospective study of PLHIV with CD4+ T-cell count ≤350 cells/uL initiating antiretroviral therapy (ART) from two HIV/AIDS clinics in Uganda, we evaluated the performance of C-reactive protein (CRP) measured using a rapid and inexpensive point-of-care (POC) assay as a screening tool for active pulmonary TB. Findings Of 1177 HIV-infected adults (median CD4+ T-cell count 168 cells/µL) enrolled, 163 (14%) had culture-confirmed TB. POC CRP had 89% (145/163) sensitivity and 72% (731/1014) specificity for culture-confirmed TB. Compared to the WHO symptom screen, POC CRP had lower sensitivity (difference −7% [95% CI: −12 to −2], p=0.002) but substantially higher specificity (difference +58% [95% CI: +61 to +55], p<0.0001). When Xpert MTB/RIF results were used as the reference standard, sensitivity of POC CRP and the WHO symptom screen were similar (94% [79/84] vs. 99% [83/84]; difference −5% [95% CI: −12 to +2], p=0.10). Interpretation The performance characteristics of CRP support its use as a TB screening test for PLHIV with CD4+ T-cell count ≤350 cells/µL initiating ART. HIV/AIDS programs should consider POC CRP-based TB screening to improve the efficiency of ICF and increase uptake of TB preventive therapy. FUNDING National Institutes of Health; Presidential Emergency Plan for AIDS Relief; University of California, San Francisco, Nina Ireland Program for Lung Health

SummaryBackgroundCross-resistance after first-line antiretroviral therapy (ART) failure is expected to impair activity of nucleoside reverse-transcriptase inhibitors (NRTIs) in second-line therapy for patients with HIV, but evidence for the effect of cross-resistance on virological outcomes is limited. We aimed to assess the association between the activity, predicted by resistance testing, of the NRTIs used in second-line therapy and treatment outcomes for patients infected with HIV.MethodsWe did an observational analysis of additional data from a published open-label, randomised trial of second-line ART (EARNEST) in sub-Saharan Africa. 1277 adults or adolescents infected with HIV in whom first-line ART had failed (assessed by WHO criteria with virological confirmation) were randomly assigned to a boosted protease inhibitor (standardised to ritonavir-boosted lopinavir) with two to three NRTIs (clinician-selected, without resistance testing); or with raltegravir; or alone as protease inhibitor monotherapy (discontinued after week 96). We tested genotypic resistance on stored baseline samples in patients in the protease inhibitor and NRTI group and calculated the predicted activity of prescribed second-line NRTIs. We measured viral load in stored samples for all patients obtained every 12–16 weeks. This trial is registered with Controlled-Trials.com (number ISRCTN 37737787) and ClinicalTrials.gov (number NCT00988039).FindingsBaseline genotypes were available in 391 (92%) of 426 patients in the protease inhibitor and NRTI group. 176 (89%) of 198 patients prescribed a protease inhibitor with no predicted-active NRTIs had viral suppression (viral load <400 copies per mL) at week 144, compared with 312 (81%) of 383 patients in the protease inhibitor and raltegravir group at week 144 (p=0·02) and 233 (61%) of 280 patients in the protease inhibitor monotherapy group at week 96 (p<0·0001). Compared with results with no active NRTIs, 95 (85%) of 112 patients with one predicted-active NRTI had viral suppression (p=0·3) and 20 (77%) of 26 patients with two or three active NRTIs had viral suppression (p=0·08). Over all follow-up, greater predicted NRTI activity was associated with worse viral load suppression (global p=0·0004).InterpretationGenotypic resistance testing might not accurately predict NRTI activity in protease inhibitor-based second-line ART. Our results do not support the introduction of routine resistance testing in ART programmes in low-income settings for the purpose of selecting second-line NRTIs.FundingEuropean and Developing Countries Clinical Trials Partnership, UK Medical Research Council, Institito de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, WHO, Merck.

Oral swab analysis (OSA) has been shown to detect Mycobacterium tuberculosis (MTB) DNA in patients with pulmonary tuberculosis (TB). In previous analyses, qPCR testing of swab samples collected from tongue dorsa was up to 93% sensitive relative to sputum GeneXpert, when 2 swabs per patient were tested. The present study modified sample collection methods to increase sample biomass and characterized the viability of bacilli present in tongue swabs. A qPCR targeting conserved bacterial ribosomal rRNA gene (rDNA) sequences was used to quantify bacterial biomass in samples. There was no detectable reduction in total bacterial rDNA signal over the course of 10 rapidly repeated tongue samplings, indicating that swabs collect only a small portion of the biomass available for testing. Copan FLOQSwabs collected ~2-fold more biomass than Puritan PurFlock swabs, the best brand used previously (p = 0.006). FLOQSwabs were therefore evaluated in patients with possible TB in Uganda. A FLOQSwab was collected from each patient upon enrollment (Day 1) and, in a subset of sputum GeneXpert Ultra-positive patients, a second swab was collected on the following day (Day 2). Swabs were tested for MTB DNA by manual IS6110-targeted qPCR. Relative to sputum GeneXpert Ultra, single-swab sensitivity was 88% (44/50) on Day 1 and 94.4% (17/18) on Day 2. Specificity was 79.2% (42/53). Among an expanded sample of Ugandan patients, 62% (87/141) had colony-forming bacilli in their tongue dorsum swab samples. These findings will help guide further development of this promising TB screening method.