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Summary Background In DISCOVER, a multinational, randomised controlled trial, emtricitabine and tenofovir alafenamide compared with emtricitabine and tenofovir disoproxil fumarate showed non-inferior efficacy for HIV prevention and improved bone mineral density and renal safety biomarkers at week 48. We report outcomes analysed after all participants had completed 96 weeks of follow-up. Methods This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in Europe and North America. Adult cisgender men and transgender women who have sex with men, both with a high risk of acquiring HIV as determined by self-reported sexual behaviour or recent sexually transmitted infections, were randomly assigned (1:1) to receive either emtricitabine and tenofovir alafenamide (200/25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine and tenofovir disoproxil fumarate (200/300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). The primary efficacy outcome was incident HIV infection. Incidence of HIV-1 infection per 100 person-years was assessed when the last participant had completed 96 weeks of follow-up. This trial is registered with ClinicalTrials.gov , number NCT02842086 . Findings Between Sept 13, 2016, and June 30, 2017, 5387 participants were randomly assigned to receive emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693), contributing 10 081 person-years of follow-up. At 96 weeks of follow-up, there were eight HIV infections in participants who had received emtricitabine and tenofovir alafenamide (0·16 infections per 100 person-years [95% CI 0·07–0·31]) and 15 in participants who had received emtricitabine and tenofovir disoproxil fumarate (0·30 infections per 100 person-years [0·17–0·49]). Emtricitabine and tenofovir alafenamide maintained its non-inferiority to emtricitabine and tenofovir disoproxil fumarate for HIV prevention (IRR 0·54 [95% CI 0·23–1·26]). Approximately 78–82% of participants reported taking study medication more than 95% of the time across all study visits. Rates of sexually transmitted infections remained high and similar across groups (21 cases per 100 person-years for rectal gonorrhoea and 28 cases per 100 person-years for rectal chlamydia). Emtricitabine and tenofovir alafenamide continued to show superiority over emtricitabine and tenofovir disoproxil fumarate in all but one of the six prespecified bone mineral density and renal biomarkers. There was more weight gain among participants who had received emtricitabine and tenofovir alafenamide (median weight gain 1·7 kg vs 0·5 kg, p Interpretation Emtricitabine and tenofovir alafenamide is safe and effective for longer-term pre-exposure prophylaxis in cisgender men and transgender women who have sex with men. Funding Gilead Sciences.

Summary Background & aims Nutritional deficiency and inflammation may impact CD4+ T cell recovery during combination antiretroviral therapy (cART), particularly in resource-limited settings where malnutrition is prevalent. The aim of this study was to investigate the relationship of micronutrient and inflammation biomarkers to CD4 recovery after cART initiation. Methods We conducted a secondary analysis of a random sub-cohort sample (n = 270) from a multinational randomized trial of cART regimen efficacy among 1571 cART-naive adults. We measured pre-cART serum levels of micronutrients (Vitamin A, B6, B12, D, total carotenoids, selenium, and iron) and inflammation (C-reactive protein, soluble CD14 (sCD14), IFNγ, TNFα, Interleukin-6, and C-X-C motif chemokine 10 (CXCL10/IP10), EndoCab (IgM)) biomarkers. Biomarker status (i.e. micronutrient deficiency vs. sufficiency and elevated vs. low inflammation) was defined using established cutoffs or quartiles. Mixed-effects linear regression models were used to determine the association of baseline (pre-cART) concentrations of individual biomarkers with CD4 recovery through 96 weeks post-cART initiation. Results In models adjusting for time-dependent viral load and baseline CD4 count, age, sex, body mass index, country, treatment regimen, anemia and hypoalbuminemia status, pre-cART vitamin D deficiency was associated with lower CD4 recovery (−14.9 cells/mm3, 95% CI: −27.9, −1.8) compared to sufficiency. In contrast, baseline selenium deficiency (20.8 cells/mm3, 95% CI: 3.3, 38.3), vitamin A deficiency (35.9 cells/mm3, 95% CI: 17.6, 54.3) and high sCD14 (23.4 cells/mm3, 95% CI: 8.9, 37.8) were associated with higher CD4 recovery compared to sufficient/low inflammation status. Conclusions In summary, baseline vitamin D deficiency was associated with diminished CD4 recovery after cART initiation; impaired CD4 recovery may contribute to the poor clinical outcomes recently observed in individuals with vitamin D deficiency. Vitamin A, selenium and sCD14 were associated with CD4 recovery but future studies are needed to further explore these relationships.

Background: In DISCOVER, a multinational randomized controlled trial, emtricitabine and tenofovir alafenamide compared with emtricitabine and tenofovir disoproxil fumarate demonstrated noninferior efficacy for HIV prevention and improved bone mineral density and renal safety biomarkers at week 48. Here, we report outcomes analysed after all participants had completed 96 weeks of follow up. Methods: Adult cisgender men and transgender women who have sex with men with a high risk of acquiring HIV were randomly assigned (1:1) to either of two study arms. This trial is registered with ClinicalTrials.gov, NCT02842086. Findings: 5,387 participants were randomly assigned to receive emtricitabine and tenofovir alafenamide (n=2,694) or emtricitabine and tenofovir disoproxil fumarate (n=2,693), contributing 10,081 person-years (PY) of follow-up. There were eight HIV infections in emtricitabine and tenofovir alafenamide users (0·16 infections/100 PY [95% CI 0·07–0·31]), and 15 in emtricitabine and tenofovir disoproxil fumarate users (0·30 infections/100 PY [0·17–0·49]). Emtricitabine and tenofovir alafenamide was noninferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the infection rate ratio (IRR) was less than the prespecified noninferiority margin of 1·62 (IRR 0·54 [95% CI 0·23–1·26]). Approximately 78% to 82% of participants reported taking study medication more than 95% of the time across all study visits. Rates of sexually transmitted infections remained high and similar across arms (21 per 100 PYs for rectal gonorrhea and 28 per 100 PY for rectal chlamydia). Emtricitabine and tenofovir alafenamide continued to demonstrate superiority over emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarkers. There was more weight gain among emtricitabine and tenofovir alafenamide users (median weight gain 1·7 kg vs. 0·5 kg, p

thy) and histologic (epithelial erosions, crypt hyperplasia, mononuclear cellular infiltrate) lesions were inversely associated with changes in composition of the intestinal microbiota of IL-10-/mice at all time points. Conclusions: Changes in the relative densities and spatial distribution of dominant bacterial groups occur and precede the development of colitis in IL-10-/mice. Archaea decreased in colitic IL-10-/mice and appear to associate with different bacterial species during active inflammation. These results indicate that the Archaea (methanogens) may serve as a biomarker for onset and progression of IBD. Further work on the diversity of methanogens as well as alterations in the concentration of methanogenic species is required to fully assess their biomarker potential.