Snapshot Algorithm Research Articles

Durable Efficacy of Dolutegravir Plus Lamivudine in Antiretroviral Treatment-Naive Adults With HIV-1 Infection: 96-Week Results From the GEMINI-1 and GEMINI-2 Randomized Clinical Trials.

The 2-drug regimen dolutegravir + lamivudine was noninferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine in achieving HIV-1 RNA <50 copies/mL in treatment-naive adults in the 48-week primary analysis of the GEMINI trials. We present results from the prespecified 96-week secondary analyses. One hundred eighty-seven centers in 21 countries. GEMINI-1 and GEMINI-2 are identical, double-blind phase III studies. Participants with screening HIV-1 RNA ≤500,000 copies/mL were randomized 1:1 to once-daily dolutegravir + lamivudine or dolutegravir + tenofovir disoproxil fumarate/emtricitabine. At week 96, dolutegravir + lamivudine (N = 716) was noninferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine (N = 717) in achieving HIV-1 RNA <50 copies/mL (Snapshot algorithm; -10% noninferiority margin) in the pooled analysis (proportion of responders, 86.0% vs 89.5%, respectively; adjusted treatment difference [95% CI], -3.4% [-6.7 to 0.0007]), GEMINI-1 (-4.9% [-9.8 to 0.03]), and GEMINI-2 (-1.8% [-6.4 to 2.7]). Proportions of participants in the HIV-1 RNA ≥50 copies/mL Snapshot category were largely unchanged from week 48 to 96. Eleven participants taking dolutegravir + lamivudine and 7 taking dolutegravir + tenofovir disoproxil fumarate/emtricitabine met confirmed virologic withdrawal criteria through week 96; none had treatment-emergent resistance mutations. Dolutegravir + lamivudine had a lower rate of drug-related adverse events than dolutegravir + tenofovir disoproxil fumarate/emtricitabine (19.6% vs 25.0%; relative risk ratio, 0.78; 95% CI: 0.64 to 0.95). Renal and bone biomarker changes favored dolutegravir + lamivudine. Consistent with 48-week data, dolutegravir + lamivudine demonstrated long-term, noninferior efficacy vs dolutegravir + tenofovir disoproxil fumarate/emtricitabine without increased risk of treatment-emergent resistance, supporting its use in treatment-naive HIV-1-infected individuals.

2842. Durable Efficacy of Two-Drug Regimen (2DR) of Dolutegravir (DTG) plus Lamivudine (3TC) in Antiretroviral Treatment-Naïve Adults with HIV-1 Infection at 96 Weeks: Subgroup Analyses in the GEMINI Studies

BackgroundAt Weeks 48 and 96 in the GEMINI-1 and GEMINI-2 studies (Clinicaltrials.gov: NCT02831673 and NCT02831764), the 2DR of DTG+3TC was noninferior to the three-drug regimen of DTG + tenofovir/emtricitabine (TDF/FTC) in achieving plasma HIV-1 RNA < 50 c/mL in treatment-naïve adults.MethodsGEMINI-1 and 2 are identical, global, double-blind, multicenter Phase III studies. Participants with screening HIV-1 RNA ≤ 500.00 c/mL were randomized to once-daily DTG+3TC or DTG+TDF/FTC, stratified by plasma HIV-1 RNA and CD4+ cell count. The primary endpoint was the proportion of participants with plasma HIV-1 RNA < 50 c/mL at Week 48 (Snapshot algorithm). We present a secondary endpoint analysis of efficacy at Week 96 by baseline disease and demographic characteristics. For the overall population, estimates and confidence intervals were based on a stratified analysis using Cochran–Mantel–Haenszel weights.ResultsIn total, 714 and 719 adults were randomized and treated in GEMINI-1 and -2, respectively. Based on a 10% noninferiority margin, DTG+3TC was noninferior to DTG+TDF/FTC at Week 96 in both GEMINI-1 and -2 and in the pooled analysis. Response rates across baseline HIV-1 RNA subgroups were high and similar in both arms in the pooled analysis, including in participants with baseline HIV-1 RNA >100,000 c/mL (Table 1). Results were also generally consistent regardless of age, gender, or race. In the CD4+ ≤ 200 cells/mm3 subgroup, response rates were lower in the DTG+3TC group compared with DTG+TDF/FTC; most reasons for nonresponse were unrelated to virologic efficacy or treatment regimen. Across both studies, 11 participants on DTG+3TC and 7 on DTG+TDF/FTC met protocol-defined virologic withdrawal criteria through Week 96; none had treatment emergent integrase-strand-transfer-inhibitor or NRTI resistance mutations.ConclusionIn GEMINI-1 and 2, DTG+3TC was noninferior to DTG+TDF/FTC in treatment-naïve adults at Week 96, demonstrating durable efficacy. The results of subgroup analyses of efficacy at Week 96 were generally consistent with overall study results, and further demonstrate that DTG+3TC is an effective initial treatment for HIV-infected patients across a spectrum of disease characteristics and patient populations. The studies are ongoing. Disclosures All Authors: No reported Disclosures.

2490. Longer-Term Safety and Efficacy of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide in Virologically Suppressed Adults Living With HIV and End-Stage Renal Disease on Chronic Hemodialysis

BackgroundHIV treatment for individuals with end-stage renal disease (ESRD) on hemodialysis (HD) has previously required complex dose-adjusted regimens. We evaluated the safety and efficacy of single-tablet, once-daily elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) in people living with HIV (PLH) and ESRD on chronic HD.MethodsVirologically suppressed adult PLH with ESRD on chronic HD for ≥ 6 months were switched to open-label E/C/F/TAF 150/150/200/10 mg once daily for 96 weeks. Efficacy was assessed as the proportion of participants who maintained virologic suppression (HIV RNA < 50 copies/mL) using the snapshot algorithm. Safety and participant satisfaction were assessed throughout the study.ResultsWe enrolled 55 participants with median age 51 years (range 23–64) with median time on HD 6 years (range 1–17). In the per protocol analysis set, virologic suppression was maintained in 30 of 31 participants (96.8%, 95% CI [83.3%, 99.9%]) at week 96. In the full analysis set, virologic suppression was maintained in 30 of 55 participants (54.5%; 95% CI [40.6%, 68.0%]); one discontinued therapy due to lack of efficacy, and W96 data were unavailable for 24. Of the 24 participants lacking W96 data, 17 discontinued study drug early and 7 had missing data while on study drug; all had HIV RNA < 50 copies/mL at the last pre-week 96 check. Treatment-emergent AEs occurred in 53 (96.4%) participants, and study-drug-related AEs occurred in 7 (12.7%). Treatment-emergent AEs leading to premature study drug discontinuation occurred in 4 (7.3%) participants; two were considered study-drug-related (allergic pruritus and peripheral neuropathy in one participant each). No study-drug-related serious AEs were observed. 85.7% (30/35) of responding participants reported they were ‘much more satisfied’ with their regimen.ConclusionSingle-tablet, once-daily E/C/F/TAF was effective in maintaining virologic suppression in PLH on chronic HD over 96 weeks of follow-up. E/C/F/TAF was well tolerated and was associated with improved participant satisfaction. These data demonstrate that E/C/F/TAF is a safe and effective alternative to more complicated regimens in PLH on chronic HD, with the potential to improve patient satisfaction and quality of life.Disclosures All authors: No reported disclosures.

Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV

BackgroundTwo drugs under consideration for inclusion in antiretroviral therapy (ART) regimens for human immunodeficiency virus (HIV) infection are dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF). There are limited data on their use in low- and middle-income countries.MethodsWe conducted a 96-week, phase 3, investigator-led, open-label, randomized trial in South Africa, in which we compared a triple-therapy combination of emtricitabine (FTC) and DTG plus either of two tenofovir prodrugs — TAF (TAF-based group) or tenofovir disoproxil fumarate (TDF) (TDF-based group) — against the local standard-of-care regimen of TDF–FTC–efavirenz (standard-care group). Inclusion criteria included an age of 12 years or older, no receipt of ART in the previous 6 months, a creatinine clearance of more than 60 ml per minute (>80 ml per minute in patients younger than 19 years of age), and an HIV type 1 (HIV-1) RNA level of 500 copies or more per milliliter. The primary end point was the percentage of patients with a 48-week HIV-1 RNA level of less than 50 copies per milliliter (as determined with the Snapshot algorithm from the Food and Drug Administration; noninferiority margin, −10 percentage points). We report the primary (48-week) efficacy and safety data.ResultsA total of 1053 patients underwent randomization from February 2017 through May 2018. More than 99% of the patients were black, and 59% were female. The mean age was 32 years, and the mean CD4 count was 337 cells per cubic millimeter. At week 48, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group, findings that indicate that the DTG-containing regimens were noninferior to the standard-care regimen. The number of patients who discontinued the trial regimen was higher in the standard-care group than in the other two groups. In the per-protocol population, the standard-care regimen had equivalent potency to the other two regimens. The TAF-based regimen had less effect on bone density and renal function than the other regimens. Weight increase (both lean and fat mass) was greatest in the TAF-based group and among female patients (mean increase, 6.4 kg in the TAF-based group, 3.2 kg in the TDF-based group, and 1.7 kg in the standard-care group). No resistance to integrase inhibitors was identified in patients receiving the DTG-containing regimens.ConclusionsTreatment with DTG combined with either of two tenofovir prodrugs (TAF and TDF) showed noninferior efficacy to treatment with the standard-care regimen. There was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF, than with the standard-care regimen. (ADVANCE ClinicalTrials.gov number, NCT03122262.)

Dolutegravir-Based or Low-Dose Efavirenz–Based Regimen for the Treatment of HIV-1

BackgroundAn efavirenz-based regimen (with a 600-mg dose of efavirenz, known as EFV600) was the World Health Organization preferred first-line treatment for human immunodeficiency virus type 1 (HIV-1) infection until June 2018. Given concerns about side effects, dolutegravir-based and low-dose efavirenz–based combinations have been considered as first-line treatments for HIV-1 in resource-limited settings.MethodsWe conducted an open-label, multicenter, randomized, phase 3 noninferiority trial in Cameroon. Adults with HIV-1 infection who had not received antiretroviral therapy and had an HIV-1 RNA level (viral load) of at least 1000 copies per milliliter were randomly assigned to receive either dolutegravir or the reference treatment of low-dose efavirenz (a 400-mg dose, known as EFV400), combined with tenofovir and lamivudine. The primary end point was the proportion of participants with a viral load of less than 50 copies per milliliter at week 48, on the basis of the Food and Drug Administration snapshot algorithm. The difference between treatment groups was calculated, and noninferiority was tested with a margin of 10 percentage points.ResultsA total of 613 participants received at least one dose of the assigned regimen. At week 48, a viral load of less than 50 copies per milliliter was observed in 231 of 310 participants (74.5%) in the dolutegravir group and in 209 of 303 participants (69.0%) in the EFV400 group, with a difference of 5.5 percentage points (95% confidence interval [CI], −1.6 to 12.7; P<0.001 for noninferiority). Among those with a baseline viral load of at least 100,000 copies per milliliter, a viral load of less than 50 copies per milliliter was observed in 137 of 207 participants (66.2%) in the dolutegravir group and in 123 of 200 participants (61.5%) in the EFV400 group, with a difference of 4.7 percentage points (95% CI, −4.6 to 14.0). Virologic failure (a viral load of >1000 copies per milliliter) was observed in 3 participants in the dolutegravir group (with none acquiring drug-resistance mutations) and in 16 participants in the EFV400 group. More weight gain was observed in the dolutegravir group than in the EFV400 group (median weight gain, 5.0 kg vs. 3.0 kg; incidence of obesity, 12.3% vs. 5.4%).ConclusionsIn HIV-1–infected adults in Cameroon, a dolutegravir-based regimen was noninferior to an EFV400-based reference regimen with regard to viral suppression at week 48. Among participants who had a viral load of at least 100,000 copies per milliliter when antiretroviral therapy was initiated, fewer participants than expected had viral suppression. (Funded by Unitaid and the French National Agency for AIDS Research; NAMSAL ANRS 12313 ClinicalTrials.gov number, NCT02777229.)

Efficacy and safety of dolutegravir–rilpivirine for maintenance of virological suppression in adults with HIV-1: 100-week data from the randomised, open-label, phase 3 SWORD-1 and SWORD-2 studies

Primary analyses of the SWORD-1 and SWORD-2 trials at 48 weeks showed that switching to a two-drug regimen of dolutegravir plus rilpivirine was non-inferior to continuing a standard three-drug or four-drug antiretroviral regimen for maintenance of virological suppression in people with HIV-1. Here, we present efficacy and safety data from the 100-week analysis of the trials. SWORD-1 and SWORD-2 are identically designed, randomised, open-label phase 3 studies at 65 centres in 13 countries and 60 centres in 11 countries, respectively. Adults aged 18 years or older who were on a standard three-drug or four-drug antiretroviral therapy (ART) and had had fewer than 50 HIV-1 RNA copies per mL of plasma for at least 6 months were randomly assigned (1:1) to 50 mg dolutegravir plus 25 mg rilpivirine orally once daily (early-switch group) or to continue their standard regimen for 52 weeks before switching to the dolutegravir plus rilpivirine combination (ie, the late-switch group). In this analysis of week 100 data, the efficacy endpoint of interest was the proportion of participants with fewer than 50 copies of HIV-1 RNA per mL of plasma (per the US Food and Drug Administration snapshot algorithm). This outcome was assessed in all randomly assigned participants who received at least one dose of the study drug. Data were analysed after the last participant completed week 100 (Sept 15, 2017) and verified through the data cutoff (Nov 21, 2017). SWORD-1 and SWORD-2 are registered with ClinicalTrials.gov, numbers NCT02429791 and NCT02422797, respectively. 513 participants were randomly assigned to dolutegravir plus rilpivirine (ie, the early-switch group) and 511 to continue their standard ART regimen, 477 of whom then switched to dolutegravir plus rilpivirine at week 52 (ie, the late-switch group). At week 100, 456 (89% [95% CI 86-92]) of 513 participants in the early-switch group and 444 (93% [91-95]) of 477 in the late-switch group had fewer than 50 HIV-1 RNA copies per mL. Drug-related adverse events occurred in 103 (20%) participants in the early-switch group and 58 (12%) in the late-switch group. The most common drug-related adverse events were headache (11 participants in the early-switch group [2%] vs eight [2%] in the late-switch group) and nausea (eight [2%] vs five [1%]). The combination of dolutegravir plus rilpivirine sustained virological suppression of HIV-1, was associated with a low frequency of virological failure, and had a favourable safety profile, which support its use as a nucleoside reverse transcriptase inhibitor-sparing and protease inhibitor-sparing alternative to three-drug regimens that reduces overall exposure to ART. ViiV Healthcare and Janssen Pharmaceutica.

Low-dose ritonavir-boosted darunavir once daily versus ritonavir-boosted lopinavir for participants with less than 50 HIV RNA copies per mL (WRHI 052): a randomised, open-label, phase 3, non-inferiority trial

Pilot studies suggest that ritonavir-boosted darunavir could show high efficacy at doses below those currently approved. We investigated whether switch to 400 mg of darunavir boosted with 100 mg ritonavir once daily could show equivalent efficacy to continuation of ritonavir-boosted lopinavir (a protease inhibitor commonly used in low-income and middle-income countries) for individuals with HIV RNA suppression. In the WRHI 052 study, a randomised, parallel-group, open-label, non-inferiority phase 3 trial, adults who were HIV-1 positive were enrolled in Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa. Eligible participants were 18 years or older, who tolerated ritonavir-boosted lopinavir in combination with two nucleoside analogues (standard of care) for 6 months or more, and had plasma HIV-1 RNA of less than 50 copies per mL within 60 days of enrolment. We randomly assigned participants (1:1), using a computer-generated randomisation plan, to switch to darunavir (400 mg) boosted with ritonavir (100 mg) once daily or remain on ritonavir-boosted lopinavir (800 mg [plus 200 mg ritonavir]), with nucleoside analogues left unchanged. The primary endpoint was the proportion of patients with less than 50 HIV-1 RNA copies per mL at week 48 (US Food and Drug Administration snapshot algorithm; non-inferiority margin -4%). Primary and safety analyses included participants receiving at least one dose of darunavir boosted with ritonavir. This trial is registered with ClinicalTrials.gov, number NCT02671383. Between June 30, 2016, and June 15, 2017, 148 participants were assigned to ritonavir-boosted darunavir 400 mg and 152 continued on their lopinavir-containing regimen. Four (3%) patients in the darunavir group and three (2%) in the lopinavir group discontinued before week 48. At week 48, darunavir was non-inferior to lopinavir for the primary outcome (142 [96%] of 148 participants on darunavir had <50 HIV-1 RNA copies per mL vs 143 [94%] of 152 participants on lopinavir; difference 1·9% [95% CI -3·4 to 7·3]), with a predefined margin of -4%. More participants taking darunavir (30 [20%] participants) had drug-related adverse events than those on lopinavir (eight [5%]), but the adverse events were generally asymptomatic and resolved when switching back to lopinavir. Elevated liver transaminase in three (1%; one symptomatic) darunavir participants led to study withdrawal; all transaminase elevations resolved on restarting lopinavir. Low-dose ritonavir-boosted darunavir might be a safe and efficacious switch option to maintain HIV suppression for patients on lopinavir. However, an adequately powered and designed study in viraemic participants is needed. South African Medical Research Council, United States Agency for International Development, and US National Institute of Allergy and Infectious Diseases.

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

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. 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. 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. 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. 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

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. 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. 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. These week 96 data support bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people living with chronic HIV. Gilead Sciences, Inc.

Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed (DAWNING): an open-label, non-inferiority, phase 3b trial

Doubts exist regarding optimal second-line treatment options for HIV-1-infected patients in resource-limited settings. We assessed safety and efficacy of dolutegravir compared with ritonavir-boosted lopinavir, plus two nucleoside reverse transcriptase inhibitors (NRTIs) in adults in whom previous first-line antiretroviral therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two NRTIs has failed. DAWNING is a phase 3b, open-label, parallel-group, non-inferiority, active-controlled trial done at 58 sites in 13 countries. Eligible adults were aged at least 18 years and, during at least 6 months of treatment with a first-line treatment containing an NNRTI and two NRTIs, had virological failure (confirmed HIV-1 RNA ≥400 copies per mL). Participants were randomly assigned by a central randomisation system to receive oral dolutegravir (50 mg once daily) or ritonavir-boosted lopinavir (800 mg lopinavir plus 200 mg ritonavir once daily or 400 mg plus 100 mg twice daily), plus two investigator-selected NRTIs (at least one fully active based on resistance testing at screening). The primary outcome was the proportion of participants achieving viral suppression (defined as plasma HIV-1 RNA <50 copies per mL) at week 48 using the snapshot algorithm and a non-inferiority margin of -12%. The primary analysis was done in an intention-to-treat-exposed (ITT-E) population of participants who received at least one dose of study medication, according to original group assignment. Safety was analysed in all participants who received at least one dose of study drug, according to which drug was received. The study was registered at ClinicalTrials.gov, number NCT02227238, and viiv-studyregister.com, number 200304. Between Dec 11, 2014, and June 27, 2016, 968 adults were screened and 627 were randomly assigned to the dolutegravir group (n=312) or the ritonavir-boosted lopinavir group (n=315). Three patients in the ritonavir-boosted lopinavir group did not receive study medication and so 624 were included in the ITT-E population. At week 48, 261 (84%) of 312 participants in the dolutegravir group achieved viral suppression compared with 219 (70%) of 312 in the ritonavir-boosted lopinavir group (adjusted difference 13·8%; 95% CI 7·3-20·3). Non-inferiority was achieved on the basis of the 95% CI of the adjusted treatment difference having a lower bound greater than -12% (prespecified non-inferiority margin). Because the lower bound of the 95% CI is greater than zero (7·3%), superiority of dolutegravir was also concluded (p<0·0001). The safety profile for dolutegravir was favourable compared with that of ritonavir-boosted lopinavir. More grade 2-4 drug-related adverse events occurred with ritonavir-boosted lopinavir than dolutegravir (44 [14%] of 310 with ritonavir-boosted lopinavir vs 11 [4%] of 314 with dolutegravir), mainly driven by gastrointestinal disorders. When administered with two NRTIs, dolutegravir was superior to ritonavir-boosted lopinavir at 48 weeks and can be considered a suitable option for second-line treatment. ViiV Healthcare.

A More Faithful Formal Definition of the Desired Property for Distributed Snapshot Algorithms to Model Check the Property

The first distributed snapshot algorithm was invented by Chandy and Lamport: Chandy-Lamport distributed snapshot algorithm (CLDSA). Distributed snapshot algorithms are crucial components to make distributed systems fault tolerant. Such algorithms are extremely important because many modern key software systems are in the form of distributed systems and should be fault tolerant. There are at least two desired properties such algorithms should satisfy: 1) the distributed snapshot reachability property (called the DSR property) and 2) the ability to run concurrently with, but not alter, an underlying distributed system (UDS). This paper identifies subtle errors in a paper on formalization of the DSR property and shows how to correct them. We give a more faithful formal definition of the DSR property; the definition involves two state machines - one state machine M_UDS that formalizes a UDS and the other M_CLDSA that formalizes the UDS on which CLDSA is superimposed (UDS-CLDSA) - and can be used to more precise model checking of the DSR property for CLDSA. We also prove a theorem on equivalence of our new definition and an existing one that only involves M_CLDSA to guarantee the validity of the existing model checking approach. Moreover, we prove the second property, namely that CLDSA does not alter the behaviors of UDS.

553. A Retrospective Study to Evaluate the Safety and Efficacy of a Nucleoside-Sparing Regimen of Darunavir, Ritonavir, and Dolutegravir

BackgroundNucleoside reverse transcriptase inhibitors (NRTIs) may contribute to or exacerbate cardiovascular risk, bone loss, and renal dysfunction. Darunavir (DRV) and dolutegravir (DTG) have a high barrier to resistance and proven tolerability profile, but have not been well studied as part of an NRTI sparing regimen. The purpose of this study was to determine the real-world efficacy and safety of an NRTI-sparing regimen of boosted DRV and DTG.MethodsWe conducted a retrospective chart review (NCT03198884) of ~400 HIV+ patients at an urban Federally Qualified Health Center to identify those who started an NRTI-sparing regimen of ritonavir(r) boosted DRV and DTG once-daily (QD). Included subjects were 3 18 years of age, receiving DRV/r QD + DTG QD for 3 24 weeks, and had 48 weeks of laboratory data available. Subjects were excluded if they, missed >5 doses over 2 weeks prior study visit, or had missing laboratory data for 3 two study time points. The primary endpoints were the percent of patients with HIV-1 RNA <50 copies/mL at 48 weeks and the change in mean serum creatinine (SCr) from baseline to 48 weeks. Analysis used was the Snapshot algorithm and Wilcoxon signed rank testing, respectively. Additional secondary endpoints included changes in CD4+ cell counts, and incidence and severity of adverse events.ResultsTwenty subjects were identified for inclusion. The mean age of the cohort was 51 years with an average of 12.5 years of HIV seropositivity. The mean baseline CD4+ was 485 cells/mm3 with an HIV-1 RNA of 20,000 copies/mL. The percentage of subjects with HIV-1 RNA <50 copies increased from 45% at baseline to 95% at Week 48 (P = 0.002), 95% CI [2.24; NA], with one subject not having data in the 48-week window. There were no significant differences in SCr from baseline to 48 weeks (P = 0.5753) and no significant changes in CD4+ cell count from baseline at time points 24, 36 or 48 weeks. No subjects experienced virologic failure during the study period, or required genotypic resistance testing. No patients reported adverse events that led to discontinuation of the study regimen. ConclusionThe once daily regimen of boosted DRV and DTG was effective at achieving or maintaining virologic suppression with no significant adverse events. This regimen offers another viable option for patients unable to tolerate NRTIs.Disclosures J. Verna, Janssen Pharmaceuticals, Inc.: Investigator, Research support.

Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials

Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of -10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -2·6%, 95% CI -6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -0·7%, 95% CI -4·3 to 2·9), showing non-inferiority at a -10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference -1·7%, 95% CI -4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication. The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. ViiV Healthcare.

Switching to coformulated rilpivirine (RPV), emtricitabine (FTC) and tenofovir alafenamide from either RPV, FTC and tenofovir disoproxil fumarate (TDF) or efavirenz, FTC and TDF: 96‐week results from two randomized clinical trials

ObjectivesThe single‐tablet regimen rilpivirine, emtricitabine and tenofovir alafenamide (RPV/FTC/TAF) for treatment of HIV‐1‐infected adults was approved based on bioequivalence. We assessed the clinical efficacy, safety and tolerability of switching to RPV/FTC/TAF from either RPV/FTC/tenofovir disoproxil fumarate (TDF) or efavirenz (EFV)/FTC/TDF.MethodsWe conducted two distinct randomized, double‐blind, active‐controlled, noninferiority trials in participants taking RPV/FTC/TDF (Study 1216) and EFV/FTC/TDF (Study 1160). Each study randomized virologically suppressed (HIV‐1 RNA < 50 copies/mL) adults (1:1) to switch to RPV/FTC/TAF or continue their current regimen for 96 weeks. We evaluated efficacy as the proportion with HIV‐1 RNA < 50 copies/mL using the Food and Drug Administration snapshot algorithm and prespecified bone and renal endpoints at week 96.ResultsWe randomized and treated 630 participants in Study 1216 (RPV/FTC/TAF, n = 316; RPV/FTC/TDF, n = 314) and 875 in Study 1160 (RPV/FTC/TAF, n = 438; EFV/FTC/TDF, n = 437). In both studies, the efficacy of switching to RPV/FTC/TAF was noninferior to that of continuing baseline therapy at week 96, with respective percentages of patients with HIV RNA < 50 copies/mL being 89.2% versus 88.5% in Study 1216 [difference 0.7%; 95% confidence interval (CI) −4.3 to +5.8%] and 85.2% versus 85.1% in Study 1160 (difference 0%; 95% CI −4.8 to +4.8%). No participant on RPV/FTC/TAF developed treatment‐emergent resistance versus two on EFV/FTC/TDF and one on RPV/FTC/TDF. Compared with continuing baseline therapy, significant improvements in bone mineral density and renal tubular markers were observed in the RPV/FTC/TAF groups (P < 0.001).ConclusionsSwitching to RPV/FTC/TAF from RPV/FTC/TDF or EFV/FTC/TDF was safe and effective and improved bone mineral density and renal biomarkers up to 96 weeks with no cases of treatment‐emergent resistance.

Individual patient data meta-analysis of randomized controlled trials of dual therapy with a boosted PI plus lamivudine for maintenance of virological suppression: GeSIDA study 9717

Dual therapy (DT) with a ritonavir-boosted PI (PI/r) plus lamivudine has proven non-inferior (12% margin) to triple therapy (TT) with PI/r plus two nucleos(t)ide reverse transcriptase inhibitors [N(t)RTIs] in four clinical trials. It remains unclear whether DT is non-inferior based on the US FDA endpoint (virological failure with a margin of 4%) or in specific subgroups. We performed a systematic search (January 1990 to March 2017) of randomized controlled trials that compared switching of maintenance ART from TT to DT. The principal investigators were contacted and agreed to share study databases. The primary endpoint was non-inferiority of DT to TT based on the current FDA endpoint (4% non-inferiority margin for virological failure at week 48). We also analysed whether efficacy was modified by gender, active HCV infection and type of PI. Effect estimates and 95% CIs were calculated using generalized estimating equation-based models. We found 881 references that yielded eight articles corresponding to four clinical trials (1051 patients). At week 48, 4% of patients on DT versus 3.04% on TT had experienced virological failure (difference 0.9%; 95% CI -1.2% to 3.1%), and 84.7% of patients on DT versus 83.2% on TT had <50 copies of HIV RNA/mL (FDA snapshot algorithm) (difference 1.4%; 95% CI -2.8% to 5.8%). Gender, active HCV infection and type of PI had no effect on differences in treatment efficacy between DT and TT. DT was non-inferior to TT using both current and past FDA endpoints. The efficacy of DT was not influenced by gender, active HCV infection status, or type of PI.

Efficacy and safety of switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from boosted protease inhibitor-based regimens in virologically suppressed adults with HIV-1: 48 week results of a randomised, open-label, multicentre, phase 3, non-inferiority trial

Switching from therapy based on a boosted protease inhibitor to bictegravir, emtricitabine, and tenofovir alafenamide could avoid drug interactions and unwanted side-effects in virologically suppressed adults with HIV-1 infection, while maintaining a high barrier to resistance and providing a simplified once-daily, single-tablet regimen. Here, we report 48 week results of a phase 3 study investigating this switch. In this multicentre, randomised, open-label, active-controlled, non-inferiority, phase 3 trial, adults with HIV-1 infection were enrolled at 121 outpatient centres in ten countries. Eligible participants were aged 18 years or older, had an estimated glomerular filtration rate of 50 mL per min or higher, had been virologically suppressed (plasma HIV-1 RNA <50 copies per mL) for 6 months or more before screening, and were on a regimen consisting of boosted atazanavir or darunavir plus either emtricitabine and tenofovir disoproxil fumarate or abacavir and lamivudine. We randomly assigned participants (1:1), using a computer-generated randomisation sequence, to switch to co-formulated once-daily bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg), herein known as the bictegravir group, or to remain on their baseline boosted protease inhibitor regimen, herein known as the boosted protease inhibitor group, for 48 weeks. Randomisation was stratified by use of tenofovir disoproxil fumarate or abacavir at screening. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or higher at week 48 (by US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 4%. Efficacy and safety analyses included all participants who received at least one dose of study drug. This study is ongoing but not actively recruiting patients and is registered with ClinicalTrials.gov, number NCT02603107. Between Dec 2, 2015, and July 15, 2016, 578 participants were randomly assigned and 577 were treated (290 in the bictegravir group and 287 in the boosted protease inhibitor group). At week 48, five participants (2%) in the bictegravir group and five (2%) in the boosted protease inhibitor group had plasma HIV-1 RNA of 50 copies per mL or higher (difference 0·0%, 95·002% CI -2·5 to 2·5), thus switching to the bictegravir regimen was non-inferior to continued boosted protease inhibitor therapy. The overall incidence and severity of adverse events was similar between groups, although headache occurred more frequently in the bictegravir group than in the boosted protease inhibitor group. 233 (80%) participants in the bictegravir group and 226 (79%) in the boosted protease inhibitor group had an adverse event. Only two (1%) participants in the bictegravir group and one (<1%) in the boosted protease inhibitor group discontinued treatment because of adverse events. 54 participants (19%) in the bictegravir group had drug-related adverse events compared with six (2%) in the protease inhibitor group. Fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide might be a safe and efficacious alternative to continued boosted protease inhibitor therapy in adults with HIV-1 infection. Gilead Sciences.

Switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir plus abacavir and lamivudine in virologically suppressed adults with HIV-1: 48 week results of a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial

Bictegravir, co-formulated with emtricitabine and tenofovir alafenamide, has shown good efficacy and tolerability, and similar bone, renal, and lipid profiles to dolutegravir, abacavir, and lamivudine, in treatment-naive adults with HIV-1 infection, without development of treatment-emergent resistance. Here, we report 48-week results of a phase 3 study investigating switching to bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir, abacavir, and lamivudine in virologically suppressed adults with HIV-1 infection. In this multicentre, randomised, double-blind, active-controlled, non-inferiority, phase 3 trial, HIV-1-infected adults were enrolled at 96 outpatient centres in nine countries. Eligible participants were aged 18 years or older and on a regimen of 50 mg dolutegravir, 600 mg abacavir, and 300 mg lamivudine (fixed-dose combination or multi-tablet regimen); had an estimated glomerular filtration rate of 50 mL/min or higher; and had been virologically suppressed (plasma HIV-1 RNA <50 copies per mL) for 3 months or more before screening. We randomly assigned participants (1:1), using a computer-generated randomisation sequence, to switch to co-formulated bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg; herein known as the bictegravir group), or to remain on dolutegravir, abacavir, and lamivudine (herein known as the dolutegravir group), once daily for 48 weeks. The investigators, participants, study staff, and individuals assessing outcomes were masked to treatment assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or higher at week 48 (according to the US Food and Drug Administration snapshot algorithm); the prespecified non-inferiority margin was 4%. The primary efficacy and safety analyses included all participants who received at least one dose of study drug. This study is ongoing but not actively recruiting participants and is in the open-label extension phase, wherein participants are given the option to receive bictegravir, emtricitabine, and tenofovir alafenamide for an additional 96 weeks. This trial is registered with ClinicalTrials.gov, number NCT02603120. Between Nov 11, 2015, and July 6, 2016, 567 participants were randomly assigned and 563 were treated (282 received bictegravir, emtricitabine, and tenofovir alafenamide, and 281 received dolutegravir, abacavir, and lamivudine). Switching to the bictegravir regimen was non-inferior to remaining on dolutegravir, abacavir, and lamivudine for the primary outcome: three (1%) of 282 in the bictegravir group had HIV-1 RNA of 50 copies per mL or higher at week 48 versus one (<1%) of 281 participants in the dolutegravir group (difference 0·7%, 95·002% CI -1·0 to 2·8; p=0·62). Treatment-related adverse events were recorded in 23 (8%) participants in the bictegravir group and 44 (16%) in the dolutegravir group. Treatment was discontinued because of adverse events in six (2%) participants in the bictegravir group and in two (1%) participants in the dolutegravir group. The fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide might provide a safe and efficacious option for ongoing treatment of HIV-1 infection. Gilead Sciences.

Brief Report: Efficacy and Safety of Switching to Coformulated Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide (E/C/F/TAF) in Virologically Suppressed Women.

The integrase inhibitor regimen [elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (TDF)] demonstrated superior efficacy when compared with a protease inhibitor regimen [ritonavir-boosted atazanavir (ATV + RTV) and FTC/TDF] in 575 treatment-naive women at week 48. We investigated the efficacy, safety, and tolerability of switching to a TAF-based, single-tablet regimen containing elvitegravir, cobicistat, FTC, and tenofovir alafenamide (E/C/F/TAF) versus remaining on ATV + RTV plus FTC/TDF. After completing the initial randomized, blinded phase, virologically suppressed (HIV-1 RNA <50 copies/mL) women on ATV + RTV plus FTC/TDF were rerandomized (3:1) to receive open-label E/C/F/TAF versus remaining on their current regimen. The primary end point was proportion of participants with plasma HIV-1 RNA <50 copies per milliliter at week 48 (U.S. FDA snapshot algorithm), with a prespecified noninferiority margin of 12%. Safety [adverse events (AEs)] and tolerability were also assessed. Of 575 women originally randomized and treated in the blinded phase, 159 were rerandomized to switch to E/C/F/TAF and 53 to remain on ATV + RTV plus FTC/TDF. At week 48, virologic suppression was maintained in 150 (94%) of women on E/C/F/TAF and 46 (87%) on ATV + RTV plus FTC/TDF [difference 7.5% (95% confidence interval -1.2% to 19.4%)], demonstrating noninferiority of E/C/F/TAF to ATV + RTV and FTC/TDF. Incidence of AEs was similar between groups; study drug-related AEs were more common with E/C/F/TAF (11% versus 4%). Switching to E/C/F/TAF was noninferior to continuing ATV + RTV plus FTC/TDF in maintaining virologic suppression and was well tolerated at 48 weeks.

Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial

Doravirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with a pharmacokinetic profile supporting once-daily dosing, and potent in-vitro activity against the most common NNRTI-resistant HIV-1 variants. We compared doravirine with ritonavir-boosted darunavir, when both were given with two nucleoside reverse transcriptase inhibitors (NRTIs), in adults with previously untreated HIV-1 infection. In this randomised, controlled, double-blind, multicentre, non-inferiority trial, adults with HIV-1 infection were screened and enrolled at 125 clinical centres in 15 countries. Eligible participants (aged ≥18 years) were naive to antiretroviral therapy with plasma HIV-1 RNA of at least 1000 copies per mL at screening. Participants who had previously been treated for a viral infection other than HIV-1, those taking immunosuppressive drugs, and individuals with active acute hepatitis were excluded. Participants were randomly assigned (1:1) via an interactive voice and web response system to receive oral doravirine 100 mg or darunavir 800 mg plus ritonavir 100 mg once daily, with two investigator-selected NRTIs (tenofovir and emtricitabine or abacavir and lamivudine) for up to 96 weeks. Randomisation was stratified by HIV-1 RNA measurements at screening (≤100 000 vs >100 000 copies per mL) and the NRTI pair. Study participants, funding institution staff, investigators, and study site personnel were masked to treatment group assignment. The primary efficacy endpoint was the proportion of participants achieving HIV-1 RNA of less than 50 copies per mL at week 48 defined by the US Food and Drug Administration snapshot algorithm, with non-inferiority established if the lower bound of the two-sided 95% CI for the treatment difference (doravirine minus darunavir) was greater than -10 percentage points. All participants who received at least one dose of study drug were included in the primary efficacy and safety analyses. This trial is active, but not recruiting, and is registered with ClinicalTrials.gov, number NCT02275780. Between Dec 1, 2014, and Oct 20, 2015, 1027 participants were screened for eligibility, of whom 769 participants were randomly assigned to treatment (385 with doravirine and 384 with ritonavir-boosted darunavir). 56 participants discontinued treatment in the doravirine group compared with 71 in the darunavir group, mostly due to loss to follow-up. 383 participants who received doravirine and 383 who received darunavir were included in the primary efficacy analyses. At week 48, 321 (84%) participants in the doravirine group and 306 (80%) in the darunavir group achieved plasma HIV-1 RNA of less than 50 copies per mL (difference 3·9%, 95% CI -1·6 to 9·4), indicating non-inferiority of the doravirine regimen. The most common study drug-related adverse events were diarrhoea (21 [5%] of 383 participants in the doravirine group and 49 [13%] of 383 participants in the darunavir group), nausea (25 [7%] vs 29 [8%]), and headache (23 [6%] vs ten [3%]). 18 participants (six [2%] of 383 participants in the doravirine group vs 12 [3%] of 383 participants in the darunavir group) discontinued treatment due to adverse events, which were considered drug-related in four (1%) participants in the doravirine group and 8 (2%) participants in the darunavir group. Serious adverse events occurred in 19 (5%) of 383 participants in the doravirine group and 23 (6%) of 383 in the darunavir roup, and were considered study-drug related in one (<1%) participant of each group. In treatment-naive adults with HIV-1 infection, doravirine combined with two NRTIs might offer a valuable treatment option for adults with previously untreated HIV-1 infection. Merck & Co.

Tenofovir alafenamide plus emtricitabine versus abacavir plus lamivudine for treatment of virologically suppressed HIV-1-infected adults: a randomised, double-blind, active-controlled, non-inferiority phase 3 trial

Abacavir and tenofovir alafenamide offer reduced bone toxicity compared with tenofovir disoproxil fumarate. We aimed to compare safety and efficacy of tenofovir alafenamide plus emtricitabine with that of abacavir plus lamivudine. In this randomised, double-blind, active-controlled, non-inferiority phase 3 trial, HIV-1-positive adults (≥18 years) were screened at 79 sites in 11 countries in North America and Europe. Eligible participants were virologically suppressed (HIV-1 RNA <50 copies per mL) and on a stable three-drug regimen containing abacavir plus lamivudine. Participants were randomly assigned (1:1) by a computer-generated allocation sequence (block size 4) to switch to fixed-dose tablets of tenofovir alafenamide (10 mg or 25 mg) plus emtricitabine (200 mg) or remain on abacavir (600 mg) plus lamivudine (300 mg), with matching placebo, while continuing to take the third drug. Randomisation was stratified by the third drug (boosted protease inhibitor vs other drug) at screening. Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to treatment group. The primary endpoint was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 48 (assessed by snapshot algorithm), with a 10% non-inferiority margin. We analysed the primary endpoint in participants enrolled before May 23, 2016 (when target sample size was reached), and we analysed safety in all enrolled participants who received at least one dose of study drug (including patients enrolled after these dates). This study was registered with ClinicalTrials.gov, number NCT02469246. Study enrolment began on June 29, 2015, and the cutoff enrolment date for the week 48 primary endpoint analysis was May 23, 2016. 501 participants were randomly assigned and treated. At week 48, virological suppression was maintained in 227 (90%) of 253 participants receiving tenofovir alafenamide plus emtricitabine compared with 230 (93%) of 248 receiving abacavir plus lamivudine (difference -3·0%, 95% CI -8·2 to 2·0), showing non-inferiority. Few participants discontinued treatment because of adverse events: 12 (4%) of 280 participants in the tenofovir alafenimide plus emtricitabine group and nine (3%) of 276 in the abacavir plus lamivudine group. Three participants had serious, treatment-related adverse events: one each with renal colic and neutropenia in the tenofovir alafenamide plus emtricitabine group, and one myocardial infarction in the abacavir plus lamivudine group. There were no treatment-related deaths. Tenofovir alafenamide, in combination with emtricitabine and various third drugs, maintained high efficacy with a renal and bone safety profile similar to that of abacavir. In virologically suppressed patients, a regimen containing tenofovir alafenamide could be an alternative to those containing abacavir, without concern for new onset of renal or bone toxicities or hyperlipidaemia. Gilead Sciences Inc.