BackgroundThe World Health Organization recommends universal drug susceptibility testing for Mycobacterium tuberculosis complex to guide treatment decisions and improve outcomes. We assessed whether DNA sequencing can accurately predict antibiotic susceptibility profiles for first-line anti-tuberculosis drugs. MethodsWhole-genome sequences and associated phenotypes to isoniazid, rifampicin, ethambutol and pyrazinamide were obtained for isolates from 16 countries across six continents. For each isolate, mutations associated with drug-resistance and drug-susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These were predicted to be pan-susceptible if predicted susceptible to isoniazid and to other drugs, or contained mutations of unknown association in genes affecting these other drugs. We simulated how negative predictive value changed with drug-resistance prevalence.Results10,209 isolates were analysed. The greatest proportion of phenotypes were predicted for rifampicin (9,660/10,130; (95.4%)) and the lowest for ethambutol (8,794/9,794; (89.8%)). Isoniazid, rifampicin, ethambutol and pyrazinamide resistance was correctly predicted with 97.1%, 97.5% 94.6% and 91.3% sensitivity, and susceptibility with 99.0%, 98.8%, 93.6% and 96.8% specificity, respectively. 5,250 (89.5%) drug profiles were correctly predicted for 5,865/7,516 (78.0%) isolates with complete phenotypic profiles. Among these, 3,952/4,037 (97.9%) predictions of pan-susceptibility were correct. The negative predictive value for 97.5% of simulated drug profiles exceeded 95% where the prevalence of drug-resistance was below 47.0%. ConclusionsPhenotypic testing for first-line drugs can be phased down in favour of DNA sequencing to guide anti- tuberculosis drug therapy.

IntroductionThis study explores factors associated with virological detectability, and viral re-suppression after enhanced adherence counselling, in adults and children on antiretroviral therapy (ART) in Swaziland.MethodsThis descriptive study used laboratory data from 7/5/2012 to 30/9/2013, which were linked with the national ART database to provide information on time on ART and CD4 count; information on enhanced adherence counselling was obtained from file review in health facilities. Multivariable logistic regression was used to explore the relationship between viral load, gender, age, time on ART, CD4 count and receiving (or not receiving) enhanced adherence counselling.ResultsFrom 12,063 patients undergoing routine viral load monitoring, 1941 (16%) had detectable viral loads. Children were more likely to have detectable viral loads (AOR 2.6, 95%CI 1.5–4.5), as were adolescents (AOR 3.2, 95%CI 2.2–4.8), patients with last CD4<350 cells/µl (AOR 2.2, 95%CI 1.7–2.9) or WHO Stage 3/4 disease (AOR 1.3, 95%CI 1.1–1.6), and patients on ART for longer (AOR 1.1, 95%CI 1.1–1.2). At retesting, 450 (54% of those tested) showed viral re-suppression. Children were less likely to re-suppress (AOR 0.2, 95%CI 0.1–0.7), as were adolescents (AOR 0.3, 95%CI 0.2–0.8), those with initial viral load> 1000 copies/ml (AOR 0.3, 95%CI 0.1–0.7), and those with last CD4<350 cells/µl (AOR 0.4, 95%CI 0.2–0.7). Receiving (or not receiving) enhanced adherence counselling was not associated with likelihood of re-suppression.ConclusionsChildren, adolescents and those with advanced disease were most likely to have high viral loads and least likely to achieve viral suppression at retesting; receiving adherence counselling was not associated with higher likelihood of viral suppression. Although the level of viral resistance was not quantified, this study suggests the need for ART treatment support that addresses the adherence problems of younger people; and to define the elements of optimal enhanced adherence support for patients of all ages with detectable viral loads.

A year of genomic surveillance reveals how the SARS-CoV-2 pandemic unfolded in Africa

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Background To better understand transmission dynamics, we characterized Plasmodium falciparum genetic diversity in Eswatini, where transmission is low and sustained by importation. Methods Twenty-six P. falciparum microsatellites were genotyped in 66% of confirmed cases (2014–2016; N = 582). Population and within-host diversity were used to characterize differences between imported and locally acquired infections. Logistic regression was used to assess the added value of diversity metrics to classify imported and local infections beyond epidemiology data alone. Results Parasite population in Eswatini was highly diverse (expected heterozygosity [HE] = 0.75) and complex: 67% polyclonal infections, mean multiplicity of infection (MOI) 2.2, and mean within-host infection fixation index (FWS) 0.84. Imported cases had comparable diversity to local cases but exhibited higher MOI (2.4 vs 2.0; P = .004) and lower mean FWS (0.82 vs 0.85; P = .03). Addition of MOI and FWS to multivariate analyses did not increase discrimination between imported and local infections. Conclusions In contrast to the common perception that P. falciparum diversity declines with decreasing transmission intensity, Eswatini isolates exhibited high parasite diversity consistent with high rates of malaria importation and limited local transmission. Estimates of malaria transmission intensity from genetic data need to consider the effect of importation, especially as countries near elimination.