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Background: Bictegravir is a potent integrase strand-transfer inhibitor (INSTI) with a high genetic barrier to resistance. Bictegravir, coformulated with emtricitabine and tenofovir alafenamide, is recommended by key European and US HIV treatment guidelines as the preferred single-tablet regimen for adults and adolescents. The aim of this study was to assess the pharmacokinetics, safety, and efficacy of switching to this regimen in virologically suppressed children and adolescents with HIV., Methods: In this single-arm, open-label trial, we enrolled virologically suppressed children and adolescents (aged 6 to <18 years) with HIV at 22 hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants had a bodyweight of at least 25 kg, were virologically suppressed (HIV-1 RNA <50 copies per mL) on a stable ART regimen for at least 6 months before screening, had a CD4 count of at least 200 cells per μL, and an estimated glomerular filtration rate of at least 90 mL/min per 1·73 m 2 by the Schwartz formula at screening. All participants received the fixed-dose regimen of coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg once daily. Pharmacokinetic analysis was used for dosing confirmation, and results compared with adult values. The primary outcomes were area under the curve at the end of the dosing interval (AUC tau ) and concentration at the end of the dosing interval (C tau ) of bictegravir, and incidence of treatment-emergent adverse events and laboratory abnormalities at week 24. Efficacy and safety analyses included all participants who received at least one dose of study drug. We report the 48-week results. This study is registered with ClinicalTrials.gov, NCT02881320., Findings: Between Sept 29, 2016 and Feb 16, 2018, we enrolled 102 participants. 100 participants received bictegravir, emtricitabine, and tenofovir alafenamide (cohort 1 [adolescents aged 12 to <18 years], n=50; cohort 2 [children aged 6 to <12 years], n=50). The mean bictegravir AUC tau was 89 100 ng × h/mL (coefficient of variation 31·0%) in adolescents (cohort 1) and 128 000 ng × h/mL (27·8%) in children (cohort 2). Compared with adults, bictegravir C tau was 35% lower in adolescents and 11% lower in children. The 90% CIs of both parameters were within the predefined pharmacokinetic equivalence boundary and within overall range of exposures observed in adults and deemed to be safe and efficacious (geometric least-squares mean ratio [GLSM] 86·3% [90% CI 80·0-93·0] for AUC tau and 65·4% [58·3-73·3] for C tau in adolescents; GLSM 125% [90% CI 117-134] for AUC tau and 88·9% [80·6-98·0] for C tau for children). Bictegravir, emtricitabine, and tenofovir alafenamide was well tolerated; most adverse events were grade 2 or less in severity and no study drug-related serious adverse events were reported. One participant discontinued study drug due to adverse events (grade 2 insomnia and anxiety). Virological suppression (HIV-1 RNA <50 copies per mL) was maintained by all 100 participants at week 24 and by 98 (98%) of 100 at week 48; no participants had treatment-emergent resistance., Interpretation: In adolescents and children with HIV, the bictegravir, emtricitabine, and tenofovir alafenamide single-tablet regimen was well tolerated and maintained virological suppression. Our data support the treatment of HIV in adolescents and children with this single-tablet regimen. At present, the single-tablet regimen is recommended as first-line treatment in the USA for adolescents and as an alternative regimen in children and has the potential to represent an important regimen in the paediatric population., Funding: Gilead Sciences., Competing Interests: Declaration of interests AHG reports that his institution holds a Clinical Trials Agreement with Gilead to support the clinical trials sponsored by Gilead, including those that contributed to data shared in this manuscript; no direct payment was made to AHG. CAR has received research grant support and payment for attending scientific meetings from Gilead. KC reports research support from Gilead. HMax, PW, DP, SM, MSY, HG, HMar, DMB, and CP are or were employees of Gilead at the time of this analysis and report and hold stock interest in the company. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with tenofovir disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir alafenamide versus emtricitabine and tenofovir disoproxil fumarate for HIV prevention., 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 regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and tenofovir disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine (200 mg) and tenofovir disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and tenofovir alafenamide to emtricitabine and tenofovir disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02842086, and is no longer recruiting., Findings: Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and tenofovir alafenamide was non-inferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19-1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06-0·33]), and 15 participants in the emtricitabine and tenofovir disoproxil fumarate group (0·34 infections per 100 person-years [0·19-0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and tenofovir disoproxil fumarate group). Emtricitabine and tenofovir alafenamide was superior to emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints., Interpretation: Daily emtricitabine and tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and tenofovir disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and tenofovir disoproxil fumarate., Funding: Gilead Sciences., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The presence of transmitted drug resistance mutations (TDRMs) in antiretroviral treatment (ART)-naive patients can adversely affect the outcome of ART., Methods: Resistance testing was conducted in 6704 ART-naive subjects predominantly from the United States and Europe in 9 clinical studies conducted by Gilead Sciences from 2000 to 2013., Results: The presence of TDRMs increased during this period (from 5.2% to 11.4%), primarily driven by an increase in nonnucleoside reverse-transcriptase (RT) inhibitor (NNRTI) resistance mutations (from 0.3% to 7.1%), particularly K103N/S (increase from 0.3% to 5.3%). Nucleoside/nucleotide RT inhibitor mutations were found in 3.1% of patients. Only 1 patient had K65R (0.01%) and 7 had M184V/I (0.1%), despite high use of tenofovir disoproxil fumarate (TDF), emtricitabine, and lamivudine and potential transmission of resistance to these drugs. At least 1 thymidine-analogue mutations was present in 2.7% of patients with 0.07% harboring T215Y/F and 2.7% harboring T215 revertant mutations (T215rev). Patients with the combination of M41L + L210W + T215rev showed full human immunodeficiency virus RNA suppression while receiving a TDF- or tenofovir alafenamide-containing regimen., Conclusions: There was an overall increase of TDRMs among patients enrolling in clinical trials from 2000 through 2013, driven primarily by an increase in NNRTI resistance. However, the presence of common TDRMs, including thymidine-analogue mutations/T215rev, showed no impact on response to TDF- or tenofovir alafenamide-containing regimens., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background.: The presence of transmitted drug-resistance mutations (TDRM) in antiretroviral (ARV) treatment-naïve patients can adversely affect the outcome of ARV therapy.Methods.: Resistance testing was conducted in 6704 ARV-naïve subjects predominantly from the U.S. and Europe in 9 Gilead clinical studies from 2000 to 2013.Results.: The presence of TDRM increased during this period (5.2% to 11.4%), primarily driven by non-nucleoside RT inhibitor resistance mutations (NNRTI; 0.3% to 7.1%), particularly K103N/S (0.3% to 5.3%). NRTI mutations were found in 3.1% of patients. Only 1 patient had K65R (0.01%) and 7 patients had M184V/I (0.1%) despite high use of tenofovir disoproxil fumarate (TDF), emtricitabine, and lamivudine and potential transmission of resistance to these drugs. One or more thymidine analog mutations (TAMs) were present in 2.7% of patients with 0.07% harboring T215Y/F and 2.7% harboring T215 revertant mutations (T215rev). Patients with the combination of M41L+L210W+T215rev showed full HIV RNA suppression while receiving a TDF- or tenofovir alafenamide (TAF)-containing regimen.Conclusions.: There was an overall increase of TDRMs among patients enrolling in clinical trials from 2000 through 2013 driven primarily by an increase in NNRTI-R. However, the presence of common TDRMs, including TAMs/T215rev, showed no impact on response to TDF- or TAF-containing regimens. [ABSTRACT FROM AUTHOR]

Background In the DISCOVER PrEP trial, emtricitabine/tenofovir alafenamide (F/TAF) was noninferior to emtricitabine/tenofovir disoproxil fumarate (F/TDF) for HIV prevention. Here we report the bone safety outcomes of F/TAF and F/TDF. Methods Men who have sex with men (MSM) and transgender women (TGW) at risk of HIV were randomized 1:1 to receive blinded F/TDF or F/TAF, taken once daily. Those on PrEP with F/TDF were eligible to enroll. Bone densitometry (DXA) of the hip and spine were performed in a subset of participants (BMD subset). Fracture events were compared in all study participants. Week 48 data are presented. Results 5387 participants were enrolled in the main study, with 383 included in the BMD subset. In the BMD subset, the median age was 37 (IQR 29, 46); 0.8% were TGW, 9.4% were black, and 20.6% were Hispanic or Latinx. Fifty-three BMD subset participants were on baseline F/TDF PrEP at enrollment, 26 of whom were randomized to F/TAF. F/TAF was associated with more favorable changes in hip and spine BMD compared with F/TDF (Table 1); these differences were similar when participants on baseline PrEP were excluded. Participants age <35 on F/TAF gained BMD, whereas those on F/TDF lost BMD (Table 1). BMD decreases of ≥3% were less frequent in the F/TAF group than the F/TDF group at the hip (3.8% vs. 18.4%, P < 0.001) and spine (10.1% vs. 26.9%, P < 0.001). Osteopenia was more frequently diagnosed in the spine in participants on F/TDF compared with F/TAF (Figure 1, P = 0.007); but not in the hip. Fracture event frequency was the same (53 [2.0%] per group, P = 1.00). One pathological fracture was reported in the F/TAF group compared with two in the F/TDF group (P = 0.57). In participants on baseline F/TDF PrEP, those randomized to F/TAF had significantly improved hip BMD compared with baseline (median percent change 1.13 [IQR −0.86, 3.47], P = 0.027), while spine BMD was unchanged. Conclusion Through 48 weeks, DXA subset participants taking F/TAF for PrEP had significantly less change in BMD than those taking F/TDF, and were less likely to develop spine osteopenia. The incidence of fracture was similar, and pathological fractures were rare. F/TAF for PrEP is effective and has a superior bone safety profile compared with F/TDF. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background In the DISCOVER PrEP trial, emtricitabine/tenofovir alafenamide (F/TAF) was noninferior to emtricitabine/tenofovir disoproxil fumarate (F/TDF) for HIV prevention. Here, we report on the renal outcomes of F/TAF and F/TDF among all DISCOVER participants and in those on baseline F/TDF PrEP who were randomized to F/TAF. Methods In total, 5387 men who have sex with men (MSM) and transgender women (TGW) at risk for HIV were randomized 1:1 to receive blinded F/TDF or F/TAF taken once daily (full cohort). Of these, 905 were on F/TDF PrEP at enrollment; of whom, 465 were randomized to F/TAF. Renal function and safety assessments included urinalysis (UA), estimated glomerular filtration rate (eGFRCG), urine protein:creatinine (Cr) ratio (UPCR), markers of proximal tubular function (β2-microglobulin:Cr ratio [β2M:Cr] and retinol-binding protein:Cr ratio [RBP:Cr]) and investigator-reported renal adverse events (AEs). Week 48 data are presented. Results In the full cohort, F/TAF was associated with more favorable changes in eGFRCG, β2M:Cr, and RBP:Cr compared with F/TDF (Table 1). Treatment-emergent proteinuria by UA was more common with F/TDF than F/TAF (24.3% vs. 21.3% P = 0.009), as were treatment-emergent elevations in UPCR >200 mg/g (35 [1.5%] vs. 16 [0.7%], P = 0.005). Compared with F/TDF, participants taking F/TAF had numerically fewer study drug-related renal AEs, severe study drug-related renal AEs, and discontinuations due to renal AEs (Table 2). Proximal renal tubulopathy (Fanconi syndrome) was reported in one participant in the F/TDF arm and none in the F/TAF arm. In participants on F/TDF PrEP at enrollment who were randomized to F/TAF, statistically significant increases in eGFRCG were apparent as early as week 4 (Table 1 and Figure 1), as were decreases in tubular proteinuria (Table 1). Renal biomarker changes in PrEP-naïve participants mirrored those in the full cohort. Conclusion Through 48 weeks, MSM and TGW taking F/TAF for PrEP had significantly better measures of renal function and fewer study-drug-related renal AEs compared with those taking F/TDF; switching from F/TDF to F/TAF was associated with improvements in eGFRCG and tubular function biomarkers. F/TAF for PrEP is effective and has a superior renal safety profile compared with F/TDF. Disclosures All Authors: No reported Disclosures. [ABSTRACT FROM AUTHOR]