Neutralization, effector function and immune imprinting of Omicron variants.

Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain1 (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting.

Bictegravir/emtricitabine/tenofovir alafenamide as initial treatment for HIV-1: five-year follow-up from two randomized trials.

Background: Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is a single-tablet regimen recommended for HIV-1 treatment. The safety and efficacy of B/F/TAF as initial therapy was established in two Phase 3 studies: 1489 (vs dolutegravir [DTG]/abacavir/lamivudine) and 1490 (vs DTG + F/TAF). After 144 weeks of randomized follow-up, an open-label extension evaluated B/F/TAF to 240 weeks. Methods: Of 634 participants randomized to B/F/TAF, 519 completed the double-blinded treatment, and 506/634 (80%) chose the 96-week open-label B/F/TAF extension, which was completed by 444/506 (88%) participants. Efficacy was based on the secondary outcome of the proportion of participants with HIV-1 RNA <50 copies/mL at Week 240 by missing = excluded and missing = failure methods. All 634 participants who were randomized to B/F/TAF and received at least one dose of B/F/TAF were included in efficacy and safety analyses. (Study 1489: ClinicalTrials.govNCT02607930; EudraCT 2015-004024-54. Study 1490: ClinicalTrials.govNCT02607956; EudraCT 2015-003988-10). Findings: Of those with available virologic data, 98.6% (95% CI [97.0%-99.5%], 426/432) maintained HIV-1 RNA <50 copies/mL at Week 240 (missing = excluded); when missing virologic data were considered as failure, 67.2% (95% CI [63.4%-70.8%], 426/634) maintained HIV-1 RNA <50 copies/mL. Mean (SD) change in CD4+ count from baseline was +338 (236.2) cells/µL. No treatment-emergent resistance to B/F/TAF was detected. Adverse events led to drug discontinuation in 1.6% (n = 10/634) of participants (n = 5 with events considered drug-related). No discontinuations were due to renal adverse events. Median (IQR) total cholesterol increased 21 (1,42) mg/dL from baseline; the change in total cholesterol:HDL was 0.1 (-0.5,0.6). Median (IQR) weight change from baseline was +6.1 kg (2.0, 11.7) at Week 240. In Study 1489, hip and spine bone mineral density mean percent changes from baseline were ≤0.6%. Interpretation: Through 5 years of follow-up, B/F/TAF maintained high rates of virologic suppression with no treatment-emergent resistance and rare drug discontinuations due to adverse events. These results demonstrate the durability and safety of B/F/TAF in people with HIV. Funding: Gilead Sciences.

Brief Report: Comparative Analysis of Pre-existing HIV Drug Resistance Mutations in Proviral DNA Using Next-Generation Sequencing and Routine HIV RNA Genotyping.

BACKGROUND: We investigated whether deep sequencing of archived HIV DNA of antiretroviral-naive persons with acute/early HIV infection could identify transmitted drug resistance mutations (DRM), per the IAS drug resistance algorithm, which are not detected by routine bulk (consensus) sequencing. METHODS: Deep sequencing of HIV DNA from peripheral blood mononuclear cells and consensus sequencing from concurrent blood plasma (BP) was performed from antiretroviral (ART)-naive adults with recent infection. We compared the prevalence of low-frequency (2%-20%) and high-frequency (>20%) nonnucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI), and protease inhibitor (PI) DRM. RESULTS: Overall, 190 individuals were included, 72 (37.9%) with acute, 20 (10.5%) with very early, and 98 (51.6%) with recent HIV infection. Although all DRM detected in plasma appeared in archived proviral DNA, 9 high-frequency mutations were only detected in HIV DNA. These included 3 NRTI mutations, 4 NNRTI mutations, 1 PI mutation, and 1 H221Y (associated rilpivirine resistance) mutation. When considering DRM <20%, 11 NNRTI, 7 NRTI, 6 PI, and 3 F227L (associated doravirine resistance) mutations were found exclusively in HIV DNA. Interestingly, although 2 high-frequency M184V appeared in both DNA and RNA, low-frequency M184I were exclusive to HIV DNA (n = 6). No participants experienced virologic failure after initiating ART during the median 25.39 ± 3.13 months of follow-up on treatment. CONCLUSION: Although most high-frequency DRMs were consistently detected in HIV RNA and HIV DNA, the presence of low-frequency DRM in proviral DNA may be relevant for clinicians because these mutations could become dominant under drug selection pressure.

Therapeutic and vaccine-induced cross-reactive antibodies with effector function against emerging Omicron variants.

Currently circulating SARS-CoV-2 variants acquired convergent mutations at receptor-binding domain (RBD) hot spots. Their impact on viral infection, transmission, and efficacy of vaccines and therapeutics remains poorly understood. Here, we demonstrate that recently emerged BQ.1.1. and XBB.1 variants bind ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1 and XBB.1 RBDs bound to human ACE2 and S309 Fab (sotrovimab parent) explain the altered ACE2 recognition and preserved antibody binding through conformational selection. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1, the variant displaying the greatest loss of neutralization. Moreover, in several donors vaccine-elicited plasma antibodies cross-react with and trigger effector functions against Omicron variants despite reduced neutralizing activity. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring persistent immune imprinting. Our findings suggest that this previously overlooked class of cross-reactive antibodies, exemplified by S309, may contribute to protection against disease caused by emerging variants through elicitation of effector functions.

High efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide in people with suppressed HIV and preexisting M184V/I.

OBJECTIVE: We investigated the prevalence of preexisting M184V/I and associated risk factors among clinical trial participants with suppressed HIV and evaluated the impact of M184V/I on virologic response after switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF). DESIGN: Participant data were pooled from six clinical trials investigating the safety and efficacy of switching to B/F/TAF in virologically suppressed people with HIV. METHODS: Preexisting drug resistance was assessed by historical genotypes and/or baseline proviral DNA genotyping. Virologic outcomes were determined by last available on-treatment HIV-1 RNA. Stepwise selection identified potential risk factors for M184V/I in a multivariate logistic regression model. RESULTS: Altogether, 2034 participants switched treatment regimens to B/F/TAF and had follow-up HIV-1 RNA data, and 1825 of these participants had baseline genotypic data available. Preexisting M184V/I was identified in 182 (10%), mostly by baseline proviral DNA genotype ( n  = 167). Most substitutions were M184V ( n  = 161) or M184V/I mixtures ( n  = 10). Other resistance substitutions were often detected in addition to M184V/I ( n  = 147). At last on-treatment visit, 98% (179/182) with preexisting M184V/I and 99% (2012/2034) of all B/F/TAF-treated participants had HIV-1 RNA less than 50 copies/ml, with no treatment-emergent resistance to B/F/TAF. Among adult participants, factors associated with preexisting M184V/I included other resistance, black race, Hispanic/Latinx ethnicity, lower baseline CD4 + cell count, advanced HIV disease, longer duration of antiretroviral therapy, and greater number of prior third agents. CONCLUSION: M184V/I was detected in 10% of virologically suppressed clinical trial participants at study baseline. Switching to B/F/TAF demonstrated durable efficacy in maintaining viral suppression, including in those with preexisting M184V/I.

Forgiveness of INSTI-Containing Regimens at Drug Concentrations Simulating Variable Adherence In Vitro.

The integrase strand transfer inhibitor (INSTI)-based regimens bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), dolutegravir (DTG)+FTC/TAF, DTG/lamivudine (3TC), and DTG/rilpivirine (RPV) are all approved for treatment of HIV-infected patients, with various limitations. Here, time to in vitro viral breakthrough (VB) and resistance barrier using simulated human drug exposures at either full or suboptimal treatment adherence to each regimen were compared. At drug concentrations corresponding to full adherence and 1 missed dose (Cmin and Cmin-1), no VB occurred with any regimen. At Cmin-2, VB occurred only with DTG+3TC, with emergent resistance to both drugs. At Cmin-3, VB occurred with all regimens: 100% of DTG+3TC cultures had VB by day 12, and <15% of BIC+FTC+TAF, DTG+FTC+TAF, and DTG+RPV cultures had VB. Emergent reverse transcriptase (RT) or integrase (IN) resistance was seen with DTG+RPV and DTG+3TC but not with BIC+FTC+TAF or DTG+FTC+TAF. At Cmin-4, 100% VB occurred with DTG+3TC and DTG+FTC+TAF by day 12, while 94% VB occurred with DTG+RPV by day 25 and only 50% VB occurred with BIC+FTC+TAF by day 35. Emergent Cmin-4 drug resistance was seen with all regimens but at differing frequencies; DTG+RPV had the most cultures with resistance. Emergent resistance was consistent with clinical observations. Overall, under high adherence conditions, no in vitro VB or resistance development occurred with these INSTI-based regimens. However, when multiple missed doses were simulated in vitro, BIC+FTC+TAF had the highest forgiveness and barrier to resistance of all tested regimens. Compared to DTG+3TC and DTG+FTC+TAF, DTG+RPV had higher forgiveness but lower resistance barrier after several simulated missed doses.

Brief Report: Bictegravir/Emtricitabine/Tenofovir Alafenamide Efficacy in Participants With Preexisting Primary Integrase Inhibitor Resistance Through 48 Weeks of Phase 3 Clinical Trials.

BACKGROUND: Preexisting drug resistance limits the utility of HIV antiretroviral therapy. Studies have demonstrated safety and efficacy of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), including in patients with M184V/I substitutions. SETTING: We investigated virologic outcomes through 48 weeks of B/F/TAF treatment in individuals with preexisting primary integrase strand transfer inhibitor resistance (INSTI-R). METHODS: Preexisting INSTI-R was retrospectively evaluated from 7 B/F/TAF studies. INSTI-R was assessed by historical genotypes and/or baseline RNA or DNA sequencing. Viral loads were measured at all visits. RESULTS: Preexisting primary INSTI-R substitutions were detected in 20 of the 1907 participants (1.0%). The 20 participants were predominantly male (75%), were Black (65%), had HIV-1 subtype B (85%), and had baseline median CD4 counts of 594 cells/mm3 and median age of 52 years. Most of the participants (n = 19) were virologically suppressed at baseline and had one primary INSTI-R substitution, E92G, Y143C/H, S147G, Q148H/K/R, N155S, or R263K, +/-secondary substitutions. All suppressed participants maintained virologic suppression throughout 48 weeks without any viral blips. One treatment-naive participant had virus with Q148H+G140S that was fully sensitive to bictegravir but only partially to dolutegravir (phenotype <2.5-fold change and >4-fold change, respectively). With a baseline viral load of 30,000 copies/mL, this participant was virologically suppressed by week 4 and maintained <50 copies/mL through week 48. CONCLUSIONS: This small cohort with primary INSTI-R achieved and/or maintained virologic suppression through 48 weeks of B/F/TAF treatment. Consistent with the potent in vitro activity of bictegravir against most INSTI-R patterns, B/F/TAF may be a potential treatment option for patients with select preexisting INSTI-R, if confirmed by further studies.

Three-year study of pre-existing drug resistance substitutions and efficacy of bictegravir/emtricitabine/tenofovir alafenamide in HIV-1 treatment-naive participants.

OBJECTIVES: Two Phase 3, randomized, double-blind, active-controlled studies of initial HIV-1 treatment demonstrated that bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) was non-inferior to dolutegravir/abacavir/lamivudine (DTG/ABC/3TC; Study 1489) or to DTG+F/TAF (Study 1490) through 144 weeks. In both studies, there was no emergent resistance to study drugs. Here, the 3 year resistance analysis and impact of baseline resistance substitutions on treatment response are described. METHODS: Population sequencing of HIV-1 protease and reverse transcriptase (RT) was performed at screening. Retrospective baseline next generation sequencing of protease, RT and integrase (IN) was analysed at a ≥ 15% cutoff. Resistance analyses were performed on participants with confirmed viral rebound of HIV-1 RNA ≥200 copies/mL through Week 144 or last visit who did not resuppress to <50 copies/mL while on study drug. RESULTS: Transmitted primary drug resistance substitutions were present in the following proportions of participants: integrase strand transfer inhibitor (INSTI) resistance (-R) in 1.3% (17/1270) of participants; NRTI-R in 2.7% (35/1274); NNRTI-R in 14.1% (179/1274); and PI-R in 3.5% (44/1274). These pre-existing resistance substitutions not associated with study drug did not affect treatment outcomes. One participant in the B/F/TAF group had pre-existing bictegravir and dolutegravir resistance substitutions (Q148H+G140S in integrase) at baseline and suppressed and maintained HIV-1 RNA <50 copies/mL through Week 144. In total, 21 participants qualified for resistance testing [1.3% (8/634) B/F/TAF; 1.9% (6/315) DTG/ABC/3TC; 2.2% (7/325) DTG+F/TAF]; none had emergent resistance to study drugs. CONCLUSIONS: Treatment with B/F/TAF, DTG/ABC/3TC, or DTG+F/TAF achieved high, durable rates of virological suppression in HIV-1 treatment-naive participants. The presence of pre-existing resistance substitutions did not affect treatment outcomes, and there was no treatment-emergent resistance.

Switching to Bictegravir, Emtricitabine, and Tenofovir Alafenamide in Virologically Suppressed Adults With Human Immunodeficiency Virus.

BACKGROUND: Bictegravir (B)/emtricitabine (F)/tenofovir alafenamide (TAF) is guideline-recommended treatment for human immunodeficiency virus type 1 (HIV-1). We evaluated whether people receiving dolutegravir (DTG) plus F/TAF or F/TDF (tenofovir disoproxil fumarate) with viral suppression can switch to B/F/TAF without compromising safety or efficacy, regardless of preexisting nucleoside reverse transcriptase inhibitor (NRTI) resistance. METHODS: In this multicenter, randomized, double-blinded, active-controlled, noninferiority trial, we enrolled adults who were virologically suppressed for ≥6 months before screening (with documented/suspected NRTI resistance) or ≥3 months before screening (with no documented/suspected NRTI resistance) on DTG plus either F/TDF or F/TAF. We randomly assigned (1:1) participants to switch to B/F/TAF or DTG + F/TAF once daily for 48 weeks, each with matching placebo. The primary endpoint was proportion of participants with plasma HIV-1 RNA ≥50 copies/mL at week 48 (snapshot algorithm); the prespecified noninferiority margin was 4%. RESULTS: Five hundred sixty-seven adults were randomized; 565 were treated (284 B/F/TAF, 281 DTG + F/TAF). At week 48, B/F/TAF was noninferior to DTG + F/TAF, as 0.4% (1/284) vs 1.1% (3/281) had HIV-1 RNA ≥50 copies/mL (difference, -0.7% [95.001% confidence interval {CI}, -2.8% to 1.0%]). There were no significant differences in efficacy among participants with suspected or confirmed prior NRTI resistance (n = 138). No participant had treatment-emergent drug resistance. Median weight change from baseline at week 48 was +1.3 kg (B/F/TAF) vs +1.1 kg (DTG + F/TAF) (P = .46). Weight change differed by baseline NRTIs (+2.2 kg [F/TDF] and +0.6 kg [F/TAF], P < .001), with no differences between B/F/TAF and DTG + F/TAF. CONCLUSIONS: The single-tablet regimen B/F/TAF is a safe, effective option for people virologically suppressed on DTG plus either F/TDF or F/TAF, including in individuals with preexisting resistance to NRTIs. CLINICAL TRIALS REGISTRATION: NCT03110380.

Simulating HIV Breakthrough and Resistance Development During Variable Adherence to Antiretroviral Treatment.

BACKGROUND: Barriers to lifelong HIV-1 suppression by antiretrovirals include poor adherence and drug resistance; regimens with higher tolerance to missed doses (forgiveness) would be beneficial to patients. To model short-term nonadherence, in vitro experiments monitoring viral breakthrough (VB) and resistance development were conducted. METHODS: HIV breakthrough experiments simulated drug exposures at full adherence or suboptimal adherence to bictegravir+emtricitabine+tenofovir alafenamide (BIC+FTC+TAF) or dolutegravir + lamivudine (DTG+3TC). MT-2 cells were infected with wild-type or low frequency M184V HIV-1, exposed to drug combinations, monitored for VB, and rebound virus was deep sequenced. Drug concentrations were determined using human plasma-free adjusted clinical trough concentrations (Cmin), at simulated Cmin after missing 1 to 3 consecutive doses (Cmin - 1 or Cmin - 2, and Cmin - 3) based on drug or active metabolite half-lives. RESULTS: Cultures infected with wild-type or low frequency M184V HIV-1 showed no VB with BIC+FTC+TAF at drug concentrations corresponding to Cmin, Cmin - 1, or Cmin - 2 but breakthrough did occur in 26 of 36 cultures at Cmin - 3, where the M184V variant emerged in one culture. Experiments using DTG + 3TC prevented most breakthrough at Cmin concentrations (9/60 had breakthrough) but showed more breakthroughs as drug concentrations decreased (up to 36/36) and variants associated with resistance to both drugs emerged in some cases. CONCLUSIONS: These in vitro VB results suggest that the high potency, long half-lives, and antiviral synergy provided by the BIC/FTC/TAF triple therapy regimen may protect from viral rebound and resistance development after short-term lapses in drug adherence.

Switching to Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) From Dolutegravir (DTG)+F/TAF or DTG+F/Tenofovir Disoproxil Fumarate (TDF) in the Presence of Pre-existing NRTI Resistance.

BACKGROUND: Study 4030 was a phase 3, randomized, double-blinded study of 565 HIV-1 RNA-suppressed participants switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) or dolutegravir (DTG)+F/TAF. Nucleoside reverse transcriptase inhibitor (NRTI), non-NRTI, and protease inhibitor resistance (-R) was allowed, but integrase strand transfer inhibitor-R was excluded. Here, we describe the detailed resistance analysis. METHODS: Historical plasma HIV-1 RNA genotypes and baseline proviral DNA genotypes were analyzed. Documented or investigator-suspected NRTI-R was grouped for stratification into 3 categories of level of resistance. Viral blips were assessed through week 48. Virologic failures had genotypic and phenotypic resistance analyses at week 48, confirmed failure, or last visit, if HIV-1 RNA did not resuppress to <50 copies/mL while on study drug. RESULTS: In total, 83% (470/565) of participants had baseline genotypic data available with NRTI-R detected in 24% (138/565), including 5% (30/565) with K65R/E/N or ≥3 thymidine analog mutations and 19% (108/565) with other NRTI-R mutations. M184V/I was present in 14% (81/565). Pre-existing integrase strand transfer inhibitor-R mutations were found in 4% (20/565) of participants. Primary non-NRTI-R and protease inhibitor-R mutations were present in 21% (118/565) and 7% (38/565) of participants. High rates of viral suppression were maintained in all groups through week 48; blips were observed in only 15 participants (2.7%). Three participants met criteria for resistance analysis (all in DTG+F/TAF arm); none developed treatment-emergent resistance to study drugs. CONCLUSIONS: Participants with baseline NRTI resistance, much of which was previously undocumented, maintained suppression 48 weeks after switching to B/F/TAF or DTG+F/TAF triple therapy. Blips and virologic failure were uncommon using either regimen, with no treatment-emergent resistance.

Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir-containing regimens for initial treatment of HIV-1 infection: week 144 results from two randomised, double-blind, multicentre, phase 3, non-inferiority trials.

BACKGROUND: In the primary week-48 analyses of two phase 3 studies, coformulated bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to a dolutegravir-containing regimen in treatment-naive people with HIV. We report week-144 efficacy and safety results from these studies. METHODS: We did two double-blind, active-controlled studies (now in open-label extension phase). Study 1 randomly assigned (1:1) HLA-B*5701-negative adults without hepatitis B virus co-infection to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg, or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg once daily. Study 2 randomly assigned (1:1) adults to bictegravir, emtricitabine, and tenofovir alafenamide, or dolutegravir 50 mg given with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg. We previously reported non-inferiority at the primary endpoint. Here, we report the week-144 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 144, by US Food and Drug Administration Snapshot algorithm, analysed in the same manner. These studies were registered with ClinicalTrials.gov, NCT02607930 and NCT02607956. FINDINGS: 629 participants were randomly assigned and treated in study 1 (314 to bictegravir, emtricitabine, and tenofovir alafenamide, and 315 to dolutegravir, abacavir, and lamivudine) and 645 in study 2 (327 to bictegravir, emtricitabine, and tenofovir alafenamide, 325 to dolutegravir, emtricitabine, tenofovir alafenamide). At week 144, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to both dolutegravir-containing regimens for efficacy. In study 1, 256 (82%) of 314 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 265 (84%) of 315 in the dolutegravir, abacavir, and lamivudine group (difference -2·6%, 95% CI -8·5 to 3·4). In study 2, 262 (82%) of 320 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 273 (84%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (difference -1·9%, -7·8 to 3·9). In both studies, no participant had treatment-emergent resistance to study drugs up to week 144. All treatment regimens were well tolerated with additional exposure. Adverse events that led to study drug discontinuation were reported for no participants in the bictegravir, emtricitabine, and tenofovir alafenamide group versus five (2%) of 315 in the dolutegravir, abacavir, and lamivudine group (study 1), and six (2%) of 320 in the bictegravir, emtricitabine, and tenofovir alafenamide versus six (2%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (study 2). In study 1, statistically significant differences were observed in median changes from baseline in fasting total cholesterol (14 mg/dL vs 10 mg/dL; p=0·034), direct LDL (21 mg/dL vs 14 mg/dL; p=0·004), and total cholesterol to HDL ratio (-0·1 vs -0·3; p=0·007) at week 144; no differences were observed between groups in study 2. Weight gain was seen across all treatment groups in both studies, with no differences in median changes from baseline in weight at week 144 for either study. INTERPRETATION: These long-term data support the use of bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people with HIV, with no emergent resistance. FUNDING: Gilead Sciences.

Switching to Fixed-Dose Bictegravir, Emtricitabine, and Tenofovir Alafenamide (B/F/TAF) in Virologically Suppressed HIV-1 Infected Women: A Randomized, Open-Label, Multicenter, Active-Controlled, Phase 3, Noninferiority Trial.

BACKGROUND: Bictegravir, coformulated with emtricitabine/tenofovir alafenamide as a fixed-dose combination (B/F/TAF), is recommended for treatment of HIV-1-infection. Multiple studies of B/F/TAF in treatment-naive and virologically suppressed cohorts have shown high efficacy and tolerability with no treatment-emergent resistance through 48 weeks. Participants in these studies have been predominantly men. We report 48-week results from a phase 3 study evaluating switching to B/F/TAF, specifically in a globally distributed trial population of women. METHODS: In this multicenter, randomized, open-label, active-controlled, noninferiority trial (ClinicalTrials.gov NCT02652624), women living with HIV who were virologically suppressed (HIV-1 RNA levels <50 copies/mL) on a regimen containing either TAF or tenofovir disoproxil fumarate were randomly assigned (1:1) to switch to B/F/TAF (50/200/25 mg) or stay on baseline regimen (SBR) once daily for 48 weeks. Primary endpoint was proportion of participants with plasma HIV-1 RNA ≥50 copies/mL at week 48 (U.S. Food and Drug Administration snapshot algorithm); prespecified noninferiority margin was 4%. FINDINGS: We randomized 472 participants and treated 470 (234 B/F/TAF, 236 SBR). Switching to B/F/TAF was noninferior to SBR for the primary outcome, as 1.7% (4/234) vs 1.7% (4/236) had HIV-1 RNA ≥50 copies/mL at week 48 (difference 0.0%, 95.001% confidence interval: -2.9% to 2.9%). No individual receiving B/F/TAF developed treatment-emergent resistance. Both treatments were well-tolerated; no participant discontinued treatment because of an adverse event. INTERPRETATION: Fixed-dose combination B/F/TAF provides a safe and efficacious option for ongoing treatment of HIV in women. This study contributes important data on safety, tolerability, and outcomes of antiretroviral therapy among women living with HIV.

Bictegravir combined with emtricitabine and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial.

BACKGROUND: Bictegravir co-formulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination is recommended for treatment of HIV-1-infection and might be better tolerated than other integrase inhibitor-based single-tablet regimens, but long-term outcomes data are not available. We assessed the efficacy, safety and tolerability of bictegravir, emtricitabine, and tenofovir alafenamide compared with co-formulated dolutegravir, abacavir, and lamivudine at week 96. METHODS: This ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial was done at 122 outpatient centres in nine countries. We enrolled adults (aged ≥18 years) living with HIV who were treatment naive and HLA-B*5701 negative, did not have hepatitis B virus infection, and had an estimated glomerular filtration rate of at least 50 mL/min. We randomly assigned participants (1:1) to receive co-formulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg (the bictegravir group) or co-formulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (the dolutegravir group), each with matching placebo, once daily for 144 weeks. Treatment allocation was masked to all participants and investigators. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. We previously reported the primary endpoint. Here, we report the week 96 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 96 by US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. This study was registered with ClinicalTrials.gov, number NCT02607930. FINDINGS: Between Nov 13, 2015, and July 14, 2016, we screened 739 participants, of whom 108 were excluded and 631 enrolled and randomly assigned to bictegravir, emtricitabine, and tenofovir alafenamide (n=316) or dolutegravir, abacavir, and lamivudine (n=315). Two participants in the bictegravir group did not receive at least one dose of their assigned drug and were excluded from analyses. At week 96, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to dolutegravir, abacavir, and lamivudine, with 276 (88%) of 314 participants in the bictegravir group versus 283 (90%) of 315 participants in the dolutegravir group achieving HIV-1 RNA less than 50 copies per mL (difference -1·9%; 95% CI -6·9 to 3·1). The most common adverse events were nausea (36 [11%] of 314 for the bictegravir group vs 76 [24%] of 315 for the dolutegravir group), diarrhoea (48 [15%] vs 50 [16%]), and headache (41 [13%] vs 51 [16%]). 36 (11%) participants in the bictegravir group versus 39 (12%) participants in the dolutegravir group had a serious adverse event. Two individuals died in the bictegravir group (recreational drug overdose and suicide, neither of which was treatment related) and none died in the dolutegravir group. No participants discontinued because of adverse events in the bictegravir group compared with five (2%) of 315 in the dolutegravir group. Study drug-related adverse events were reported for 89 (28%) participants in the bictegravir group and 127 (40%) in the dolutegravir group. INTERPRETATION: These week 96 data support bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people living with HIV-1 with no emergent resistance. FUNDING: Gilead Sciences, Inc.

Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial.

BACKGROUND: The single-tablet regimen consisting of bictegravir, emtricitabine, and tenofovir alafenamide is recommended for treatment of HIV-1 infection on the basis of data from 48 weeks of treatment. Here, we examine the longer-term efficacy, safety, and tolerability of bictegravir, emtricitabine, and tenofovir alafenamide compared with dolutegravir plus co-formulated emtricitabine and tenofovir alafenamide at week 96. METHODS: This ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial was done at 126 outpatient centres in ten countries. We enrolled treatment-naive adults (aged ≥18 years) with HIV-1 infection who had an estimated glomerular filtration rate of at least 30 mL/min and sensitivity to emtricitabine and tenofovir. People with chronic hepatitis B or C infection, or both, and those who had used antivirals previously for prophylaxis were allowed. We randomly assigned participants (1:1) to receive treatment with either co-formulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg (the bictegravir group) or dolutegravir 50 mg with co-formulated emtricitabine 200 mg and tenofovir alafenamide 25 mg (the dolutegravir group), each with matching placebo, once daily for 144 weeks. Treatment allocation was masked to all participants and investigators. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. We previously reported the primary endpoint. Here, we report the week 96 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 96 by US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. This study was registered with ClinicalTrials.gov, number NCT02607956. FINDINGS: Between Nov 13, 2015, and July 14, 2016, we screened 742 individuals, of whom 657 were enrolled. 327 participants were assigned to the bictegravir group and 330 to the dolutegravir group. Of these, 320 in the bictegravir group and 325 in the dolutegravir group received at least one dose of study drug. At week 96, HIV-1 RNA less than 50 copies per mL was achieved by 269 (84%) of 320 participants in the bictegravir group and 281 (86%) of 325 in the dolutegravir group (difference -2·3%, 95% CI -7·9 to 3·2), demonstrating non-inferiority of the bictegravir regimen compared with the dolutegravir regimen. Both treatments continued to be well tolerated through 96 weeks; 283 (88%) of 320 participants in the bictegravir group and 288 (89%) of 325 in the dolutegravir group had any adverse event and 55 (17%), and 33 (10%) had any serious adverse event. The most common adverse events were diarrhoea (57 [18%] of 320 in the bictegravir group vs 51 [16%] of 325 in the dolutegravir group) and headache (51 [16%] of 320 vs 48 [15%] of 325). Deaths were reported for three (1%) individuals in each group (one cardiac arrest, one gastric adenocarcinoma, and one hypertensive heart disease and congestive cardiac failure in the bictegravir group and one unknown causes, one pulmonary embolism, and one lymphoma in the dolutegravir group); none were considered to be treatment related. Adverse events led to discontinuation in six (2%) participants in the bictegravir group and five (2%) in the dolutegravir group; one of these events in the bictegravir group versus four in the dolutegravir group occurred between weeks 48 and 96. Study drug-related adverse events were reported for 64 (20%) participants in the bictegravir group and 92 (28%) in the dolutegravir group. INTERPRETATION: These week 96 data support bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people living with chronic HIV. FUNDING: Gilead Sciences, Inc.

Resistance Analysis of Bictegravir-Emtricitabine-Tenofovir Alafenamide in HIV-1 Treatment-Naive Patients through 48 Weeks.

In clinical studies GS-US-380-1489 (study 1489) and GS-US-380-1490 (study 1490), bictegravir-emtricitabine-tenofovir alafenamide (B-F-TAF), dolutegravir-abacavir-lamivudine (DTG-ABC-3TC), and dolutegravir plus emtricitabine-tenofovir alafenamide (DTG+F-TAF) treatment achieved high rates of virologic suppression in HIV-1 treatment-naive participants through week 48. Preexisting primary drug resistance was present at levels of 1.3% integrase strand transfer inhibitor resistance (INSTI-R), 2.7% nucleoside reverse transcriptase inhibitor resistance (NRTI-R), 14.1% nonnucleoside reverse transcriptase inhibitor resistance (NNRTI-R), and 3.5% protease inhibitor resistance (PI-R) in the 1,274 participants from these studies. These mutations did not affect treatment outcomes. Resistance analyses in 13 virologic failures found no emergent resistance to study drugs.