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SummaryBackgroundAntiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART.MethodsThe TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene.FindingsWe included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1·50, 95% CI 1·27–1·77 for CD4 cell count <100 cells per μL). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1·48, 95% CI 1·20–1·82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma viral load at virological failure was similar in individuals with and without tenofovir resistance (145 700 copies per mL [SE 12 480] versus 133 900 copies per mL [SE 16 650; p=0·626]).InterpretationWe recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial.FundingThe Wellcome Trust.

SummaryBackgroundThere is concern over increasing prevalence of non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance in people initiating antiretroviral therapy (ART) in low-income and middle-income countries. We assessed the effectiveness and cost-effectiveness of alternative public health responses in countries in sub-Saharan Africa where the prevalence of pretreatment drug resistance to NNRTIs is high.MethodsThe HIV Synthesis Model is an individual-based simulation model of sexual HIV transmission, progression, and the effect of ART in adults, which is based on extensive published data sources and considers specific drugs and resistance mutations. We used this model to generate multiple setting scenarios mimicking those in sub-Saharan Africa and considered the prevalence of pretreatment NNRTI drug resistance in 2017. We then compared effectiveness and cost-effectiveness of alternative policy options. We took a 20 year time horizon, used a cost effectiveness threshold of US$500 per DALY averted, and discounted DALYs and costs at 3% per year.FindingsA transition to use of a dolutegravir as a first-line regimen in all new ART initiators is the option predicted to produce the most health benefits, resulting in a reduction of about 1 death per year per 100 people on ART over the next 20 years in a situation in which more than 10% of ART initiators have NNRTI resistance. The negative effect on population health of postponing the transition to dolutegravir increases substantially with higher prevalence of HIV drug resistance to NNRTI in ART initiators. Because of the reduced risk of resistance acquisition with dolutegravir-based regimens and reduced use of expensive second-line boosted protease inhibitor regimens, this policy option is also predicted to lead to a reduction of overall programme cost.InterpretationA future transition from first-line regimens containing efavirenz to regimens containing dolutegravir formulations in adult ART initiators is predicted to be effective and cost-effective in low-income settings in sub-Saharan Africa at any prevalence of pre-ART NNRTI resistance. The urgency of the transition will depend largely on the country-specific prevalence of NNRTI resistance.FundingBill & Melinda Gates Foundation, World Health Organization.

To describe the clinical features and assess the determinants of severity and in-hospital mortality of patients with coronavirus disease 2019 (COVID-19) from a unique setting in Ethiopia. Methods: Consecutive patients admitted to a COVID-19 isolation and treatment centre were included in this study. The overall clinical spectrum of COVID-19, and factors associated with risk of severe COVID-19 and in-hospital mortality were analysed. Results: Of 2617 quarantined patients, three-quarters (n = 1935, 74%) were asymptomatic and only 114 (4.4%) presented with severe COVID-19. Common characteristics among the 682 symptomatic patients were cough (n = 354, 50.6%), myalgia (n = 212, 31.1%), headache (n = 196, 28.7%), fever (n = 161, 23.6%), dyspnoea (n = 111, 16.3%), anosmia and/or dysgeusia (n = 90, 13.2%), sore throat (n = 87, 12.8%) and chest pain (n = 77, 11.3%). Factors associated with severe COVID-19 were older age [adjusted relative risk (aRR) 1.78, 95% confidence interval (CI) 1.61-1.97; P < 0.0001], diabetes (aRR 2.00, 95% CI 1.20-3.32; P = 0.007), cardiovascular disease (aRR 2.53, 95% CI 1.53-4.17; P < 0.0001), malignancy (aRR 4.57, 95% CI 1.62-12.87; P = 0.004), surgery/trauma (aRR 23.98, 95% CI 10.35-55.57; P < 0.0001) and human immunodeficiency virus infection (aRR 4.24, 95% CI 1.55-11.61; P = 005). Factors associated with risk of in-hospital mortality included older age (aRR 2.37, 95% CI 1.90-2.95; P < 0.001), malignancy (aRR 6.73, 95% CI 1.50-30.16; P = 0.013) and surgery/trauma (aRR 59.52, 95% CI 12.90-274.68; P < 0.0001). Conclusions: A significant proportion of cases of COVID-19 were asymptomatic, and key comorbid conditions increased the risk of severe COVID-19 and in-hospital mortality. These findings could help in the design of appropriate management strategies for patients.