Remdesivir-associated survival outcomes among immunocompromised patients hospitalized for COVID-19: real-world evidence from the Omicron dominant era.

BACKGROUND: Patients with immunocompromising conditions are at an increased risk for coronavirus disease 2019 (COVID-19)-related hospitalizations and mortality. Randomized clinical trials provide limited enrollment, if any, to inform outcomes of such patients treated with remdesivir. METHODS: Using the US PINC AI Healthcare Database, we identified adult patients with immunocompromising conditions, hospitalized for COVID-19 between December 2021 and February 2024. Primary outcome was all-cause inpatient mortality examined in propensity score (PS) matched patients in remdesivir versus non-remdesivir groups. Subgroup analyses were performed for patients with cancer, hematologic malignancies, and solid organ/hematopoietic stem cell transplant recipients. RESULTS: Of 28,966 patients included in the study, 16,730 (58%) received remdesivir during first two days of hospitalization. After PS matching, 8,822 patients in remdesivir and 8,822 patients in non-remdesivir group were analyzed. Remdesivir was associated with a significantly lower mortality among patients with no supplemental oxygen (aHR [95% CI]: 14-day, 0.73 [0.62-0.86]; 28-day, 0.79 [0.68-0.91]) and among those with supplemental oxygen (14-day, 0.75 [0.67-0.85]; 28-day, 0.78 [0.70-0.86]). Remdesivir was also associated with lower mortality in subgroups of patients with cancer, hematological malignancies (including leukemia, lymphoma, and multiple myeloma), and solid organ/hematopoietic stem cell transplantation. CONCLUSIONS: In this large cohort of patients with immunocompromising conditions hospitalized for COVID-19, remdesivir was associated with significant improvement in survival, including patients with varied underlying immunocompromising conditions. The integration of current real-world evidence into clinical guideline recommendations can inform clinical communities to optimize treatment decisions in the evolving COVID-19 era, extending beyond the conclusion of the public health emergency declaration.

Two 5-year studies of bictegravir/emtricitabine/tenofovir alafenamide in people with HIV: a plain-language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain-language summary of an article that reported on two studies of the medication bictegravir/emtricitabine/tenofovir alafenamide (shortened to B/F/TAF). B/F/TAF is a single pill containing three different drugs used to treat human immunodeficiency virus (known as HIV). The drugs work together to lower the levels of HIV (called viral load) in the body and make the virus undetectable in the blood. Researchers measured whether B/F/TAF was safe and effective when taken over 5 years in over 400 people in 10 countries who had never taken HIV medication before. WHAT WERE THE RESULTS?: After 5 years, almost all (99%) of the people who took B/F/TAF had an undetectable viral load. This does not mean that they were cured, but that the levels of HIV were so low that the tests used by researchers could not detect the virus in the blood. CD4 is a type of immune system cell. HIV causes CD4 cell numbers to decrease. On average, the number of CD4 cells increased by more than 300 cells per microliter (cells/µL) of blood over 5 years. This means that the immune system was improving. HIV is able to change its genes to escape the effects of the drugs. This is known as HIV resistance to treatment. Nine people had a viral load high enough to suggest that the drugs might not be working, but no resistance to B/F/TAF was seen. Some people (less than one in three) experienced medical problems thought to be linked to B/F/TAF treatment, known as side effects. The most common side effects were headache, diarrhea, nausea, tiredness (fatigue), dizziness, and difficulty falling or staying asleep (insomnia). On average, people's body weight increased by 3 kg in the first year of taking B/F/TAF. This might be because their general health improved after starting HIV treatment. Weight gained after that time was similar to the level of weight gain expected in the general population. Very few people (less than 1 in 100) stopped taking B/F/TAF because of side effects thought to have been caused by B/F/TAF. WHAT DO THE RESULTS MEAN?: B/F/TAF was effective at treating HIV in people who had never taken HIV medication before. Most (70%) people were still taking B/F/TAF after 5 years.Clinical Trial Registration: NCT02607930 (Study 1489); NCT02607956 (Study 1490) (ClinicalTrials.gov).

Lower mortality risk associated with remdesivir + dexamethasone versus dexamethasone alone for the treatment of patients hospitalized for COVID-19.

BACKGROUND: Treatment guidelines were developed early in the pandemic when much about COVID-19 was unknown. Given the evolution of SARS-CoV-2, real-world data can provide clinicians with updated information. The objective of this analysis was to assess mortality risk in patients hospitalized for COVID-19 during the Omicron period receiving remdesivir+dexamethasone versus dexamethasone alone. METHODS: A large, multicenter US hospital database was used to identify hospitalized adult patients, with a primary discharge diagnosis of COVID-19 also flagged as "present on admission" treated with remdesivir+dexamethasone or dexamethasone alone from December 2021 to April 2023. Patients were matched 1:1 using propensity score matching and stratified by baseline oxygen requirements. Cox proportional hazards model was used to assess time to 14- and 28-day in-hospital all-cause mortality. RESULTS: A total of 33 037 patients were matched, with most patients ≥65 years old (72%), White (78%), and non-Hispanic (84%). Remdesivir+dexamethasone was associated with lower mortality risk versus dexamethasone alone across all baseline oxygen requirements at 14 days (no supplemental oxygen charges: adjusted hazard ratio [95% CI]: 0.79 [0.72-0.87], low flow oxygen: 0.70 [0.64-0.77], high flow oxygen/non-invasive ventilation: 0.69 [0.62-0.76], invasive mechanical ventilation/extracorporeal membrane oxygen (IMV/ECMO): 0.78 [0.64-0.94]), with similar results at 28 days. CONCLUSIONS: Remdesivir+dexamethasone was associated with a significant reduction in 14- and 28-day mortality compared to dexamethasone alone in patients hospitalized for COVID-19 across all levels of baseline respiratory support, including IMV/ECMO. However, the use of remdesivir+dexamethasone still has low clinical practice uptake. In addition, these data suggest a need to update the existing guidelines.

Lipid and glucose profiles in pregnant women with HIV on tenofovir-based antiretroviral therapy.

OBJECTIVE: Tenofovir alafenamide (TAF)-based antiretroviral therapy (ART) regimens have been associated with adverse changes in lipid and glucose profiles compared with tenofovir disoproxil fumarate (TDF)-based ART, but data in pregnancy is limited. We evaluated metabolic markers in pregnant women with HIV after starting TAF- vs TDF-based ART. METHODS: We analyzed data within the IMPAACT 2010/VESTED trial, which demonstrated better pregnancy outcomes in pregnant women randomized to initiate TAF/Emtricitabine/Dolutegravir (TAF/FTC+DTG; n=217) or TDF/FTC+DTG (n=215). We measured non-fasting plasma concentrations of glucose, total-cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), lipoprotein (a), and triglycerides from samples collected eight weeks after enrollment. We employed linear regression models to estimate by-arm mean differences. RESULTS: 219 participants enrolled in the DTG arms in Zimbabwe and Uganda: 109 in the TAF/FTC+DTG and 110 in the TDF/FTC+DTG arms. At study entry, mean gestational age was 22.6 weeks, median HIV-1 RNA was 711 copies/mL, and mean age was 25.8 years. By eight weeks, mean total cholesterol was 12 mg/dL higher in women randomized to TAF/FTC+DTG versus TDF/FTC+DTG (95% CI 3.8, 21.1). Pregnant women in the TAF/FTC+DTG arm had higher mean LDL-C (7.1 mg/dL, 95% CI 0.2, 14.0), triglycerides (12.3 mg/dL, 95% CI 1.8, 22.7), lipoprotein (a) (7.3 mg/dL, 95% CI 1.1, 13.6), and lower mean HDL-C (2.8 mg/dL, 95% CI 0.1, 5.6) compared to the TDF/FTC+DTG arm. CONCLUSION: Pregnant women randomized to start TAF/FTC+DTG had higher lipids than those randomized to TDF/FTC+DTG within eight weeks of ART initiation. However, lipid levels were within normal reference ranges.

Markers of Maternal Bone and Renal Toxicity Through 50 Weeks Postpartum: IMPAACT 2010 (VESTED) Trial.

BACKGROUND: Safety data from randomized trials of antiretrovirals in pregnancy are scarce. We evaluated maternal bone and renal data from the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 2010 trial, which compared the safety and efficacy of 3 antiretroviral therapy regimens started in pregnancy: dolutegravir + emtricitabine/tenofovir alafenamide (DTG + FTC/TAF), dolutegravir + emtricitabine/tenofovir disoproxil fumarate (DTG + FTC/TDF), and efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). METHODS: A subset of participants underwent dual-energy X-ray absorptiometry scans at postpartum week 50 only. Maternal bone mineral density (BMD) Z-scores were compared between arms. Maternal creatinine was measured at enrolment and periodically through week 50 postpartum, and by-arm differences in average weekly change in estimated creatinine clearance were compared. RESULTS: Six hundred forty-three participants were randomized to DTG + FTC/TAF (N = 217) or DTG + FTC/TDF (N = 215) or EFV/FTC/TDF (N = 211). Median age = 27 years (IQR 23, 32), median CD4 count = 466 cells/mm3 (IQR 308, 624); 564 (88%) women enrolled in Africa and 479 (74%) breastfed. Week 50 postpartum dual-energy X-ray absorptiometry results from 154 women were included in the analysis. Hip and spine BMD was on average higher in women in the DTG + FTC/TAF and lower in the DTG + FTC/TDF and EFV/FTC/TDF arms, but no significant differences in BMD Z-scores were observed between treatment groups. The weekly rate of change in estimated creatinine clearance differed among treatment groups during the antepartum period, but not over the full study follow-up. CONCLUSIONS: Markers of bone and renal toxicity did not differ significantly through week 50 postpartum among women randomized to start DTG + FTC/TAF or DTG + FTC/TDF or EFV/FTC/TDF in pregnancy.

Nirmatrelvir-Ritonavir for Acute COVID-19 in Patients With Cardiovascular Disease and Postacute Sequelae of SARS-CoV-2 Infection.

Background: There is limited evidence of association of nirmatrelvir-ritonavir (NMV-r) and incidence of postacute sequelae of SARS-CoV-2 infection (PASC) in patients with pre-existing cardiovascular disease (CVD). Objectives: The objective of this study was to assess the association of NMV-r in nonhospitalized, vaccinated patients with pre-existing CVD and occurrence of PASC. Methods: We conducted a retrospective cohort study utilizing the TriNetX research network, including vaccinated patients with pre-existing CVD who developed COVID-19 between December 2021 and December 2022. Two cohorts were created based on NMV-r administration within 5 days of diagnosis: NMV-r and non-NMV-r cohort. The main outcome was presence of PASC, assessed between 30 to 90 days and 90 to 180 days after index COVID-19 infection. After propensity score matching, both cohorts were compared using t-test and chi-square test for continuous and categorical variables, respectively. Results: A total of 26,953 patients remained in each cohort after propensity score matching. Broadly defined PASC occurred in 6,925 patients (26%) in the NMV-r cohort vs 8,150 patients (30.6%) in the non-NMV-r cohort (OR: 0.80; 95% CI: 0.76-0.82; P < 0.001) from 30 to 90 days and in 6,692 patients (25.1%) as compared to 8,910 patients (33.5%) (OR: 0.25, 95% CI: 0.23-0.29; P < 0.001) from 90 to 180 days. Similarly, narrowly defined PASC occurred in 5,335 patients (20%) in the NMV-r cohort vs 6,271 patients (23.6%) in the non-NMV-r cohort between 30 and 90 days (OR: 0.81, 95% CI: 0.78-0.84, P < 0.001) and in 5,121 patients (19.2%) as compared to 6,964 patients (26.1%) (OR: 0.67, 95% CI: 0.64-0.70, P < 0.001) between 90 and 180 days. Conclusions: NMV-r in nonhospitalized vaccinated patients with pre-existing CVD with COVID-19 was associated with a reduction in PASC and health care utilization.

Antiretrovirals and Weight Change: Weighing the Evidence.

Body weight is influenced by an interplay of individual and environmental factors. In people with human immunodeficiency virus (HIV), weight is also influenced by disease status with loss accompanying disease progression that is reversed with effective antiretroviral therapy. Weight changes in comparative antiretroviral therapy trials differ by regimen, with greater gains observed with the integrase strand transfer inhibitors dolutegravir and bictegravir, particularly when coadministered with tenofovir alafenamide fumarate, compared with regimens that include agents such as tenofovir disoproxil fumarate that attenuate weight gain. We review weight changes in major randomized trials of preexposure prophylaxis and initial and switch HIV therapy, highlighting the challenges to assessing the role of antiretroviral therapy in weight change. This examination forms the basis for a model that questions assumptions regarding an association between integrase strand transfer inhibitors and tenofovir alafenamide fumarate and excessive weight gain and calls for more careful consideration of these data when making HIV treatment decisions.

Coronary Microcirculatory Dysfunction in People With HIV and Its Association With Antiretroviral Therapy.

BACKGROUND: HIV infection and abacavir-containing antiretroviral regimens are associated with vascular endothelial dysfunction and increased cardiovascular risk. Positron emission tomography (PET)-derived myocardial blood flow reserve (MBFR), the ratio of vasodilator stress to rest myocardial blood flow, is a well-validated measure of coronary microvascular health and marker of cardiovascular risk. Our objective was to compare MBFR among people with HIV (PWH) with matched non-HIV controls and to assess whether switching from dolutegravir/lamivudine/abacavir to the non-abacavir regimen bictegravir/emtricitabine/tenofovir alafenamide (TAF) would improve MBFR. METHODS AND RESULTS: Thirty-seven PWH were 1:2 matched on cardiovascular risk factors to 75 people without HIV, and MBFR corrected for differences in resting hemodynamics was compared in a cross-sectional design. PWH were majority men (68%) with a mean age of 56 years. Mean stress myocardial blood flow (1.83 mL/min per g [95% CI, 1.68-1.98] versus 2.40 mL/min per g [95% CI, 2.25-2.54]; P<0.001) and MBFR (2.18 [95% CI, 1.96-2.40] versus 2.68 [95% CI, 2.47-2.89]; P=0.002) was significantly lower in PWH than in people without HIV. In a single-arm, multicenter trial, a subset of 25 PWH who were virologically suppressed on dolutegravir/lamivudine/abacavir underwent positron emission tomography myocardial perfusion imaging at baseline and after switching to bictegravir/emtricitabine/TAF. MBFR was unchanged after switching to bictegravir/emtricitabine/TAF for a mean of 27 weeks (MBFR, 2.34 to 2.29; P=0.61), except in PWH with impaired MBFR at baseline (<2.00; N=6) in whom MBFR increased from 1.58 to 2.02 (P=0.02). CONCLUSIONS: PWH had reduced coronary microvascular function compared with controls without HIV. Coronary microvascular function did not improve after switching from dolutegravir/lamivudine/abacavir to bictegravir/emtricitabine/TAF. REGISTRATION: URL: https://www.clinicaltrials.gov; unique identifier: NCT03656783.

Projected Benefits of Long-Acting Antiretroviral Therapy in Nonsuppressed People With Human Immunodeficiency Virus Experiencing Adherence Barriers.

Background: In a demonstration project, long-acting, injectable cabotegravir-rilpivirine (CAB-RPV) achieved viral suppression in a high proportion of people with HIV (PWH) who were virologically nonsuppressed with adherence barriers. We projected the long-term impact of CAB-RPV for nonsuppressed PWH experiencing adherence barriers. Methods: Using the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) model, we compared 3 strategies: (1) standard of care oral integrase inhibitor-based ART (INSTI); (2) INSTI-based ART with supportive social services ("wraparound services" [WS]) (INSTI/WS); and (3) CAB-RPV with WS (CAB-RPV/WS). Model outcomes included viral suppression (%) and engagement in care (%) at 3 years, and life expectancy (life-years [LYs]). Base case cohort characteristics included mean age of 47y (standard deviation [SD], 10y), 90% male at birth, and baseline mean CD4 count 150/µL (SD, 75/µL). Viral suppression at 3 months was 13% (INSTI), 28% (INSTI/WS), and 60% (CAB-RPV/WS). Mean loss to follow-up was 28/100 person-years (PY) (SD, 2/100 PY) without WS and 16/100 PY (SD, 1/100 PY) with WS. Results: Projected viral suppression at 3 years would vary widely: 16% (INSTI), 38% (INSTI/WS), and 44% (CAB-RPV/WS). Life expectancy would be 7.4 LY (INSTI), 9.0 LY (INSTI/WS), and 9.4 LY (CAB-RPV/WS). Projected benefits over oral ART would be greater for PWH initiating CAB-RPV/WS at lower CD4 counts. Across plausible key parameter ranges, CAB-RPV/WS would improve viral suppression and life expectancy compared with oral INSTI strategies. Conclusions: These model-based results support that long-acting injectable CAB-RPV with extensive support services for nonsuppressed PWH experiencing adherence barriers is likely to increase viral suppression and improve survival. A prospective study to provide further evidence is needed.

Associations of Muscle Density and Area With Coronary Artery Plaque and Physical Function.

OBJECTIVE: Skeletal muscle quality and mass are important for maintaining physical function during advancing age. We leveraged baseline data from Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) to evaluate whether paraspinal muscle density and muscle area are associated with cardiac or physical function outcomes in people with HIV (PWH). METHODS: REPRIEVE is a double-blind randomized trial evaluating the effect of pitavastatin for primary prevention of major adverse cardiovascular events in PWH. This cross-sectional analysis focuses on participants who underwent coronary computed tomography at baseline. Lower thoracic paraspinal muscle density (Hounsfield units [HU]) and area (cm 2 ) were assessed on noncontrast computed tomography. RESULTS: Of 805 PWH, 708 had paraspinal muscle measurements. The median age was 51 years and 17% were natal female patients. The median muscle density was 41 HU (male) and 30 HU (female); area 13.2 cm 2 /m (male) and 9.9 cm 2 /m (female). In adjusted analyses, greater density (less fat) was associated with a lower prevalence of any coronary artery plaque, coronary artery calcium score >0, and high plaque burden ( P = 0.06); area was not associated with plaque measures. Among 139 patients with physical function measures, greater area (but not density) was associated with better performance on a short physical performance battery and grip strength. CONCLUSIONS: Among PWH, greater paraspinal muscle density was associated with a lower prevalence of coronary artery disease while greater area was associated with better physical performance. Whether changes in density or area are associated with changes in CAD or physical performance will be evaluated through longitudinal analyses in REPRIEVE.

Oral Nirmatrelvir and Ritonavir for Coronavirus Disease 2019 in Vaccinated, Nonhospitalized Adults Aged 18-50 Years.

BACKGROUND: The effects of nirmatrelvir/ritonavir (NMV/r [Paxlovid]) on coronavirus disease 2019 (COVID-19) outcomes in younger vaccinated adults are unclear. The objective of this study was to assess if NMV/r use in vaccinated adults aged ≤50 years is associated with improved outcomes and to identify beneficial and nonbeneficial subgroups. METHODS: In this cohort study, we generated 2 propensity-matched cohorts of 2547 patients from an 86 119-person cohort assembled from the TriNetX database. Patients in 1 cohort received NMV/r, and patients in the matched control cohort did not. The main outcome was composite of all-cause emergency department visits, hospitalization, and mortality. RESULTS: The composite outcome was detected in 4.9% of the NMV/r cohort and 7.0% of the non-NMV/r cohort (odds ratio, 0.683 [95% confidence interval, .540-.864]; P = .001), indicating a 30% relative risk reduction. The number needed to treat (NNT) for the primary outcome was 47. Subgroup analyses found significant associations for patients with cancer (NNT = 45), cardiovascular disease (NNT = 30), and both conditions (NNT = 16). No benefit was found for patients with only chronic lower respiratory disorders (asthma/chronic obstructive pulmonary disease [COPD]) or without serious comorbidities. Thirty-two percent of NMV/r prescriptions in the overall database were for 18- to 50-year-olds. CONCLUSIONS: NMV/r use in vaccinated adults aged 18-50 years, especially with serious comorbidities, was associated with reduced all-cause hospital visits, hospitalization, and mortality in the first 30 days of COVID-19 illness. However, NMV/r in patients without significant comorbidities or with only asthma/COPD had no association of benefit. Therefore, identifying high-risk patients should be a priority and overprescription should be avoided.

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.

Efficacy and safety of three antiretroviral therapy regimens started in pregnancy up to 50 weeks post partum: a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Drugs taken during pregnancy can affect maternal and child health outcomes, but few studies have compared the safety and virological efficacy of different antiretroviral therapy (ART) regimens. We report the primary safety outcomes from enrolment up to 50 weeks post partum and a secondary virological efficacy outcome at 50 weeks post partum of three commonly used ART regimens for HIV-1. METHODS: In this multicentre, open-label, randomised, controlled, phase 3 trial, we enrolled pregnant women aged 18 years or older with confirmed HIV-1 infection at 14-28 weeks of gestation. Women were enrolled at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Participants were randomly assigned (1:1:1) to one of three oral regimens: dolutegravir, emtricitabine, and tenofovir alafenamide; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; or efavirenz, emtricitabine, and tenofovir disoproxil fumarate. Up to 14 days of antepartum ART before enrolment was permitted. Women with known multiple gestation, fetal anomalies, acute significant illness, transaminases more than 2·5 times the upper limit of normal, or estimated creatinine clearance of less than 60 mL/min were excluded. Primary safety analyses were pairwise comparisons between ART regimens of the proportion of maternal and infant adverse events of grade 3 or higher up to 50 weeks post partum. Secondary efficacy analyses at 50 weeks post partum included a comparison of the proportion of women with plasma HIV-1 RNA of less than 200 copies per mL in the combined dolutegravir-containing groups versus the efavirenz-containing group. Analyses were done in the intention-to-treat population, which included all randomly assigned participants with available data. This trial was registered with ClinicalTrials.gov, NCT03048422. FINDINGS: Between Jan 19, 2018, and Feb 8, 2019, we randomly assigned 643 pregnant women to the dolutegravir, emtricitabine, and tenofovir alafenamide group (n=217), the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (n=215), and the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (n=211). At enrolment, median gestational age was 21·9 weeks (IQR 18·3-25·3), median CD4 count was 466 cells per µL (308-624), and median HIV-1 RNA was 903 copies per mL (152-5183). 607 (94%) women and 566 (92%) of 617 liveborn infants completed the study. Up to the week 50 post-partum visit, the estimated probability of experiencing an adverse event of grade 3 or higher was 25% in the dolutegravir, emtricitabine, and tenofovir alafenamide group; 31% in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group; and 28% in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (no significant difference between groups). Among infants, the estimated probability of experiencing at least one adverse event of grade 3 or higher by postnatal week 50 was 28% overall, with small and non-statistically significant differences between groups. By postnatal week 50, 14 infants whose mothers were in the efavirenz-containing group (7%) died, compared with six in the combined dolutegravir groups (1%). 573 (89%) women had HIV-1 RNA data available at 50 weeks post partum: 366 (96%) in the dolutegravir-containing groups and 186 (96%) in the efavirenz-containing group had HIV-1 RNA less than 200 copies per mL, with no significant difference between groups. INTERPRETATION: Safety and efficacy data during pregnancy and up to 50 weeks post partum support the current recommendation of dolutegravir-based ART (particularly in combination with emtricitabine and tenofovir alafenamide) rather than efavirenz, emtricitabine, and tenofovir disoproxil fumarate, when started in pregnancy. FUNDING: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.