BACKGROUND:

Integrase strand transfer inhibitors (INSTIs) are recommended components of initial antiretroviral therapy with two nucleoside reverse transcriptase inhibitors. Bictegravir is a novel, potent INSTI with a high in-vitro barrier to resistance and low potential as a perpetrator or victim of clinically relevant drug-drug interactions. We aimed to assess the efficacy and safety of bictegravir coformulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination versus coformulated dolutegravir, abacavir, and lamivudine.

METHODS:

We did this double-blind, multicentre, active-controlled, randomised controlled non-inferiority trial at 122 outpatient centres in nine countries in Europe, Latin America, and North America. We enrolled HIV-1 infected adults (aged ≥18 years) who were previously untreated (HIV-1 RNA ≥500 copies per mL); HLA-B*5701-negative; had no hepatitis B virus infection; screening genotypes showing sensitivity to emtricitabine, tenofovir, lamivudine, and abacavir; and an estimated glomerular filtration rate of 50 mL/min or more. Participants were randomly assigned (1:1), via a computer-generated allocation sequence (block size of four), 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, with matching placebo, once daily for 144 weeks. Randomisation was stratified by HIV-1 RNA (≤100 000 copies per mL, >100 000 to ≤400 000 copies per mL, or >400 000 copies per mL), CD4 count (<50 cells per μL, 50-199 cells per μL, or ≥200 cells per μL), and region (USA or ex-USA). Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to group assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 48, as defined by the US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. All participants who received one dose of study drug were included in primary efficacy and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02607930.

FINDINGS:

Between Nov 13, 2015, and July 14, 2016, we randomly assigned 631 participants to receive coformulated bictegravir, emtricitabine, and tenofovir alafenamide (n=316) or coformulated dolutegravir, abacavir, and lamivudine (n=315), of whom 314 and 315 patients, respectively, received at least one dose of study drug. At week 48, HIV-1 RNA less than 50 copies per mL was achieved in 92·4% of patients (n=290 of 314) in the bictegravir, emtricitabine, and tenofovir alafenamide group and 93·0% of patients (n=293 of 315) in the dolutegravir, abacavir, and lamivudine group (difference -0·6%, 95·002% CI -4·8 to 3·6; p=0·78), demonstrating non-inferiority of bictegravir, emtricitabine, and tenofovir alafenamide to dolutegravir, abacavir, and lamivudine. No individual developed treatment-emergent resistance to any study drug. Incidence and severity of adverse events was mostly similar between groups except for nausea, which occurred less frequently in patients given bictegravir, emtricitabine, and tenofovir alafenamide than in those given dolutegravir, abacavir, and lamivudine (10% [n=32] vs 23% [n=72]; p<0·0001). Adverse events related to study drug were less common with bictegravir, emtricitabine, and tenofovir alafenamide than with dolutegravir, abacavir, and lamivudine (26% [n=82] vs 40% [n=127]), the difference being driven by a higher incidence of drug-related nausea in the dolutegravir, abacavir, and lamivudine group (5% [n=17] vs 17% [n=55]; p<0·0001).

INTERPRETATION:

At 48 weeks, coformulated bictegravir, emtricitabine, and tenofovir alafenamide achieved virological suppression in 92% of previously untreated adults and was non-inferior to coformulated dolutegravir, abacavir, and lamivudine, with no treatment-emergent resistance. Bictegravir, emtricitabine, and tenofovir alafenamide was safe and well tolerated with better gastrointestinal tolerability than dolutegravir, abacavir, and lamivudine. Because coformulated bictegravir, emtricitabine, and tenofovir alafenamide does not require HLA B*5701 testing and provides guideline-recommended treatment for individuals co-infected with HIV and hepatitis B, this regimen might lend itself to rapid or same-day initiation of therapy in the clinical setting.

FUNDING:

Gilead Sciences.

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.

BACKGROUND:

Long-term effects of abacavir (ABC)-lamivudine (3TC), compared with tenofovir (TDF)-emtricitabine (FTC) with efavirenz (EFV) or atazanavir plus ritonavir (ATV/r), on bone mineral density (BMD) have not been analyzed.

METHODS:

A5224s was a substudy of A5202, in which HIV-infected treatment-naive participants were randomized and blinded to receive ABC-3TC or TDF-FTC with open-label EFV or ATV/r. Primary bone end points included Dual-emission X-ray absorbtiometry (DXA)-measured percent changes in spine and hip BMD at week 96. Primary analyses were intent-to-treat. Statistical tests used the factorial design and included linear regression, 2-sample t, log-rank, and Fisher's exact tests.

RESULTS:

Two hundred sixty-nine persons randomized to 4 arms of ABC-3TC or TDF-FTC with EFV or ATV/r. At baseline, 85% were male, and 47% were white non-Hispanic; the median HIV-1 RNA load was 4.6 log(10) copies/mL, the median age was 38 years, the median weight was 76 kg, and the median CD4 cell count was 233 cells/μL. At week 96, the mean percentage changes from baseline in spine and hip BMD for ABC-3TC versus TDF-FTC were -1.3% and -3.3% (P = .004) and -2.6% and -4.0% (P = .024), respectively; and for EFV versus ATV/r were -1.7% and -3.1% (P = .035) and -3.1% and -3.4% (P = .61), respectively. Bone fracture was observed in 5.6% of participants. The probability of bone fractures and time to first fracture were not different across components.

CONCLUSIONS:

Compared with ABC-3TC, TDF-FTC-treated participants had significantly greater decreases in spine and hip BMD, whereas ATV/r led to more significant losses in spine, but not hip, BMD than EFV. Clinical Trials Registration. NCT00118898.

The primary objective of this study is to evaluate the efficacy of switching to a fixed-dose combination (FDC) of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) versus continuing on a regimen consisting of boosted atazanavir (ATV) or darunavir (DRV) plus either emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC) in HIV-1 infected adults who are virologically suppressed.

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Background: The phase 3 randomized, active-controlled GS-US-380-1844 (NCT02603120) study evaluated switching to the single-Tablet regimen bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF) from dolutegravir (DTG), abacavir (ABC), and lamivudine (3TC) among people with HIV-1. Previously, results from the 48-week double-blind phase showed that switching to B/F/TAF was noninferior to remaining on DTG/ABC/3TC and that B/F/TAF was well tolerated. Here, we show the long-Term safety and efficacy of switching to B/F/TAF from DTG/ABC/3TC among people with HIV-1. Methods: Participants were virologically suppressed people with HIV-1 (HIV-1 RNA <50 copies/mL for ≥ 3 months prior to screening) receiving DTG/ABC/3TC at baseline. Participants were randomized 1:1 to switch to B/F/TAF or remain on DTG/ABC/3TC. Following 48 weeks of treatment with B/F/TAF or DTG/ABC/3TC in the double-blind phase, participants had the option to enter an open-label extension phase, during which they received B/F/TAF. Virologic, immunologic, and safety outcomes during treatment with B/F/TAF through the open-label extension up to 168 weeks, including preexisting and treatment-emergent resistance, were analyzed. Results: Among 547 participants in the all-B/F/TAF analysis set, virologic suppression (HIV-1 RNA<50copies/mL) was maintained in 99% to 100% of participants up to 168 weeks into B/F/TAF treatment, including in those with preexisting resistance; no treatment-emergent resistance was detected. CD4 cell counts remained stable during B/F/TAF treatment, with median (interquartile range) changes from baseline of-17 (-120, 65) cells/µL at week 48 and-9 (-100, 108) cells/µL at week 96. Safety and tolerability findings were consistent with previously reported findings up to week 48; most drug-related adverse events were grade 1 or 2 in severity; no new safety signals were identified. Conclusion: Switching to B/F/TAF from DTG/ABC/3TC was associated with continued high rates of virologic suppression up to week 168, with no treatment-emergent resistance. B/F/TAF was well tolerated throughout the study period. © 2025 the Author(s).

INTERVENTION:

Trade Name: Triumeq Pharmaceutical Form: Tablet CAS Number: 188062‐50‐2 Other descriptive name: ABACAVIR SULFATE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 600‐ Other descriptive name: DOLUTEGRAVIR SODIUM Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ INN or Proposed

INN:

LAMIVUDINE CAS Number: 134678‐17‐4 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 300‐ Trade Name: Dovato Pharmaceutical Form: Tablet Other descriptive name: DOLUTEGRAVIR SODIUM Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ INN or Proposed

INN:

LAMIVUDINE CAS Number: 134678‐17‐4 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 300‐

CONDITION:

Human immunodeficiency viruses (HIV) ; MedDRA version: 21.1 Level: PT Classification code 10067326 Term: Antiretroviral therapy System Organ Class: 10042613 ‐ Surgical and medical procedures Therapeutic area: Diseases [C] ‐ Virus Diseases [C02]

PRIMARY OUTCOME:

Main Objective: The aim of this study is to investigate if discontinuing abacavir by switching from a 3 drug regimen with with dolutegravir /abacavir/lamivudine to a 2 drug regimen with dolutegravir/lamivudine will cause changes in weight, and in metabolic and cardiac parameters in individuals infected with HIV. Primary end point(s): Primary outcome is defined by changes in body weight of more than 2 kg from baseline to week 48. Secondary Objective: Not applicable Timepoint(s) of evaluation of this end point: 48 weeks

SECONDARY OUTCOME:

Secondary end point(s): Safety; Virological control at 48 weeks of follow up as defined by a plasma HIV‐RNA <50 copies/ml; ; Selfrated health; • 12‐Item Short Form Survey (SF‐12); ; Metabolism; • Development of metabolic syndrome or diabetes; • Impaired insulin resistance and/or ß‐cell function determined by changes in HOMA‐IR; Changes in:; • Framingham Risk Score; • HbA1c, cholesterol total, HDL, LDL, VLDL, triglycerides; • Fat distribution evaluated as; o Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) determined by abdominal CT; o Hepatic steatosis: Development of steatosis or increase in steatosis from baseline (CT and liver elastography); o Fat distribution in trunk, limb and extremities measured by DEXA; ; ; Cardiac; Changes in from baseline to week 48 in:; • Blood pressure and pulse; • Cardiac magnetic resonance imaging (MRI); • Carotid artery intima‐media thickness (cIMT) measured by ultra sound; • Coronary artery calcium score (CACS); • N‐terminal pro‐B‐type natriuretic peptide (Pro‐BNP), Troponin T (TnT); ; Inflammation, endothelial function, platelet function and coagulation; Changes in from baseline to week 48 in:; • Inflammation: High‐sensitive C‐reactive protein, interleukin 1‐ and 6.; • Endothelial function: Vascular cell adhesion molecule 1 and intercellular adhesion molecule 1.; • Platelet function: soluble P‐selectin and soluble glycoprotein VI.; • Coagulation: D‐dimer, factor 2, 7 and 10 (extrinsic pathway) and fibrinogen; • General: Leucocytes, hemoglobin, platelets, creatinine, urea, sodium, potassium, bilirubin, alanine aminotransferase.; Timepoint(s) of evaluation of this end point: 48 weeks

INCLUSION CRITERIA:

‐ Individuals = 18 years old with ‐ Diagnosed HIV and ‐ At least 6 months of ongoing treatment with dolutegravir/ abacavir/lamivudine prior to inclusion ‐ No pre‐existing viral resistance mutations to lamivudine or to dolutegravir ‐ Plasma viral load (HIV‐RNA) < 50 copies/ml Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 84 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range

Background: Existing solid antiretroviral fixed-dose combination formulations are preferred over liquid formulations in children, but their suitability for neonates is unknown. We evaluated the pharmacokinetics and safety of paediatric abacavir–lamivudine fixed-dose dispersible tablets and ritonavir-boosted lopinavir granules in neonates. Methods: In this open-label, two-stage, single-arm, phase 1/2, pharmacokinetic and safety trial, generic abacavir– lamivudine (120:60 mg) double-scored dispersible tablets and lopinavir boosted with ritonavir (40:10 mg) granules were studied. Neonates exposed to HIV (≥37 weeks gestational age) of no more than 3 days of age with birthweights of 2000–4000 g were identified through routine care in a tertiary hospital in Cape Town, South Africa. In stage 1, the pharmacokinetics and safety of two single doses were assessed to select the multidose strategy for stage 2. Neonates received a single dose of abacavir–lamivudine (30:15 mg, a quarter of a tablet) and lopinavir boosted with ritonavir (40:10 mg - one sachet) orally between 3 days and 14 days of age, and a second dose of a quarter tablet of abacavir–lamivudine and lopinavir boosted with ritonavir (80:20 mg, two sachets) 10–14 days later in stage 1. The multidose strategy selected in stage 2 was a quarter of the abacavir–lamivudine (30:15 mg) fixed-dose dispersible tablet once per day and two sachets of the lopinavir boosted with ritonavir (80:20 mg) granules twice per day from birth to age 28 days. In both stages two intensive pharmacokinetic visits were done, one at less than 14 days of life (pharmacokinetics 1) and another 10–14 days later (pharmacokinetics 2). Safety visits were done 1–2 weeks after each pharmacokinetic visit. Primary objectives were to assess pharmacokinetics and safety of abacavir, lamivudine, and lopinavir. Pharmacokinetic endpoints were area under the concentration time curve (AUC), maximum concentration, and concentration at end of dosing interval in all participants with at least one evaluable pharmacokinetic visit. Safety endpoints included grade 3 or worse adverse events, and grade 3 or worse treatment-related adverse events, occurring between study drug initiation and end of study. This completed trial is registered with the Pan African Clinical Trials Registry (PACTR202007806554538). Findings: Between Aug 18, 2021, and Aug 18, 2022, 24 neonates were enrolled into the trial and received study drugs. Eight neonates completed stage 1, meeting interim pharmacokinetic and safety criteria. In stage 2, 16 neonates received study drugs. Geometric mean abacavir and lamivudine exposures (AUC0–24) were higher at 6–14 days (51·7 mg × h/L for abacavir and 17·2 mg × h/L for lamivudine) than at 19–24 days of age (25·0 mg × h/L and 11·3 mg × h/L), whereas they were similar for lopinavir over this period (AUC 0–12 58·5 mg × h/L vs 46·4 mg × h/L). Abacavir geometric mean AUC0–24 crossed the upper reference range at pharmacokinetics 1, but rapidly decreased. Lamivudine and lopinavir AUC0–tau were within range. No grade 2 or worse adverse events were related to study drugs. One neonate had a grade 1 prolonged corrected QT interval using the Fridericia method that spontaneously resolved. Interpretation: Abacavir–lamivudine dispersible tablets and ritonavir-boosted lopinavir granules in neonates were safe and provided drug exposures similar to those in young infants. Although further safety data are needed, this regimen presents a new option for HIV prevention and treatment from birth. Accelerating neonatal pharmacokinetic studies of novel antiretroviral therapies is essential for neonates to also benefit from state-of-the-art treatments. Funding: Unitaid.

BACKGROUND:

Although switching antiretroviral therapy (ART) in people with human immunodeficiency virus experiencing insomnia due to dolutegravir-related neurotoxicity is well founded upon evidence, there is a lack of proof in regard to the outcome of stopping dolutegravir-based ART in people without insomnia but reporting poor sleep quality.

METHODS:

This is a randomized, multicenter, open-label study to evaluate the reversibility of patient-reported sleep disturbances in patients on dolutegravir/lamivudine/abacavir without insomnia after switching to darunavir/cobicistat/emtricitabine/tenofovir alafenamide. The participants were randomized to switch ART at baseline or at week 4 and then completed 8 weeks of darunavir/cobicistat/emtricitabine/tenofovir alafenamide. Our primary objective was to compare changes in sleep quality between arms at week 4. Secondary objectives were to compare changes in mood and neuropsychiatric symptoms (NS) at week 4 and 4 and 8 weeks after switching to darunavir/cobicistat/emtricitabine/tenofovir alafenamide. The participants completed a survey, including the Pittsburgh Sleep Quality Index (PSQI), the Hospital Anxiety and Depression scale (HADS), and specific questions to explore NS, at each visit to assess those objectives.

RESULTS:

We included 72 participants. The results show that study arms were similar at baseline; however, at week 4, PSQI scores remained unchanged with dolutegravir/lamivudine/abacavir, whereas patients improved significantly after switching to darunavir/cobicistat/emtricitabine/tenofovir alafenamide. Similar differences between arms were also observed in HADS and NS changes. At weeks 4 and 8 after all participants switched to darunavir/cobicistat/emtricitabine/tenofovir alafenamide, we have observed significant improvements in PSQI and HAD scores and in NS.

CONCLUSIONS:

In patients reporting subclinical sleep disturbances without insomnia, switching from dolutegravir/lamivudine/abacavir to darunavir/cobicistat/emtricitabine/tenofovir alafenamide was associated with better sleep quality and improvements in mood and NS.

BACKGROUND:

The Raltegravir Switch for Toxicity or Adverse Events (RASTA) Study is a 2‐arm randomized pilot study exploring the safety and efficacy at 48 weeks of a treatment switch to raltegravir associated with tenofovir/emtricitabine or abacavir/lamivudine in patients with regimens with optimal virological control.

METHODS:

Patients treated with stable protease inhibitor (PI)‐, non‐nucleoside reverse transcriptase inhibitor (NNRTI)‐, or nucleoside reverse transcriptase inhibitor (NRTI)‐based regimens, with HIV‐RNA levels < 50 copies/ml for ≥ 3 months and a CD4 cell count > 200 cells/μl were eligible. Enrollment of 40 patients was planned: at baseline patients were randomized 1:1 to switch to raltegravir plus tenofovir/emtricitabine (arm A) or abacavir/lamivudine (arm B). Laboratory parameters, raltegravir plasma levels, self‐ reported adherence, quality of life parameters, neurocognitive performance, bone composition, and body fat distribution were monitored. Virological failure was defined as HIV‐RNA > 50 copies/ml on 2 consecutive determinations.

RESULTS:

After 48 weeks, 5/40 (12.5%) regimen discontinuations occurred: 2 were for low‐level viremia virological failure (both in arm A, at weeks 24 and 48) and 3 were for adverse events (neurological disturbances and skin rash in arm B; proximal tubulopathy in arm A). Overall, a significant CD4 increase was observed at weeks 36 and 48, and a significant decrease in total cholesterol, non‐high density lipoprotein cholesterol, and triglycerides was observed at each study visit. Physical health/satisfaction in therapy scores and neuropsychological performance improved. The lumbar column Z‐score improved, with no modification in other bone composition and fat distribution parameters.

CONCLUSIONS:

The investigated switch strategy was associated with rare virological failure. Improvements in lipid levels, quality of life measures, neuropsychological performance, and bone composition suggest good tolerability of raltegravir‐based regimens.