Efficacy and safety of dolutegravir with emtricitabine and tenofovir alafenamide fumarate or tenofovir disoproxil fumarate, and efavirenz, emtricitabine, and tenofovir disoproxil fumarate HIV antiretroviral therapy regimens started in pregnancy (IMPAACT 2010/VESTED): a multicentre, open-label, randomised, controlled, phase 3 trial

Lockman, Shahin; Brummel, Sean; Ziemba, Lauren; Stranix‐Chibanda, Lynda; McCarthy, Katie; Coletti, Anne; Jean‐Philippe, Patrick; Johnston, Ben; Krotje, Chelsea; Fairlie, Lee; Hoffman, Risa M.; Sax, Paul E.; Moyo, Sikhulile; Chakhtoura, Nahida; Stringer, Jeffrey S. A.; Masheto, Gaerolwe; Korutaro, Violet; Cassim, Haseena; Mmbaga, Blandina T; João, Esaú; Hanley, Sherika; Purdue, Lynette; Holmes, Lewis B.; Momper, Jeremiah D.; Shapiro, Roger; Thoofer, Navdeep; Rooney, James F.; Frenkel, Lisa M.; Amico, K Rivet; Chinula, Lameck; Currier, Judith S.; Best, Brookie M.; Blanchette, Cheryl; Browning, Renee; Cheng, Yifei; Fox, Andee; Jaliaah, Nagawa; Knowles, Kevin R.; Mirochnick, Mark; Murtaugh, William; Patras, Emmanuel; Pinilla, Mauricio; Wyk, Jean van; Whalen, Frances

doi:10.1016/s0140-6736(21)00314-7

Cited by 115 publications

(116 citation statements)

References 30 publications

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“…This combination remains the most common treatment prescribed to Zambian adults but is likely to be replaced over time by dolutegravir-containing regimens. The IMPAACT 2010 trial 29 found a lower composite risk of early pregnancy loss, stillbirth, preterm delivery, or small for gestational age among women newly starting a combination of dolutegravir, tenofovir alafenamide fumarate, and efavirenz in preg nancy compared with those newly starting the regimen used in our trial (24•1% vs 32•7%, p=0•047). Therefore, our findings might not be generalisable if dolutegravir replaces efavirenz as first line treatment.…”

Section: Discussionmentioning

confidence: 54%

Weekly 17 alpha-hydroxyprogesterone caproate to prevent preterm birth among women living with HIV: a randomised, double-blind, placebo-controlled trial

et al. 2021

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Background Women with HIV face an increased risk of preterm birth. 17 alpha-hydroxyprogesterone caproate (17P) has been shown in some trials to reduce early delivery among women with a history of spontaneous preterm birth. We investigated whether 17P would reduce this risk among women with HIV. MethodsWe did a randomised, double-blind, placebo-controlled trial in pregnant women with HIV at the University Teaching Hospital and Kamwala District Health Centre in Lusaka, Zambia. Eligible patients were women aged 18 years or older with confirmed HIV-1 infection, viable intrauterine singleton pregnancy at less than 24 weeks of gestation, and were receiving or intending to commence antiretroviral therapy during pregnancy. Exclusion criteria were major uterine or fetal anomaly; planned or in situ cervical cerclage; evidence of threatened miscarriage, preterm labour, or ruptured membranes at screening; medical contraindication to 17P; previous participation in the trial; or history of spontaneous preterm birth. Eligible participants provided written informed consent and were randomly assigned (1:1) to receive 250 mg intramuscular 17P or placebo once per week, starting between 16 and 24 weeks of gestation until delivery, stillbirth, or reaching term (37 weeks). Participants and study staff were masked to assignment, except for pharmacy staff who did random assignment and prepared injections but did not interact with participants. The primary outcome was a composite of delivery before 37 weeks or stillbirth at any gestational age. Patients attended weekly visits for study drug injections and antenatal care. We estimated the absolute and relative difference in risk of the primary outcome and safety events between treatment groups by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03297216, and is complete.Findings Between Feb 7, 2018 and Jan 13, 2020, we assessed 1042 women for inclusion into the study. 242 women were excluded after additional assessments, and 800 eligible patients were enrolled and randomly assigned to receive intramuscular 17P (n=399) or placebo (n=401). Baseline characteristics were similar between groups. Adherence to study drug injections was 98% in both groups, no patients were lost to follow-up, and the final post-partum visit was on Aug 6, 2020. 36 (9%) of 399 participants assigned to 17P had preterm birth or stillbirth, compared with 36 (9%) of 401 patients assigned to placebo (risk difference 0•1, 95% CI -3•9 to 4•0; relative risk 1•0, 95% CI 0•6 to 1•6; p=0•98). Intervention-related adverse events were reported by 140 (18%) of 800 participants and occurred in similar proportions in both randomisation groups. No serious adverse events were reported.Interpretation Although 17P seems to be safe and acceptable to participants, available data do not support the use of the drug to prevent preterm birth among women whose risk derives solely from HIV infection. The low risk of preterm birth in both randomisation groups warrants further investigation.Funding US National Institutes ...

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Section: Discussionmentioning

confidence: 54%

Weekly 17 alpha-hydroxyprogesterone caproate to prevent preterm birth among women living with HIV: a randomised, double-blind, placebo-controlled trial

et al. 2021

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“… 76 , 77 Recent randomised controlled trials of ART regimens initiated during pregnancy showed that DTG-based ART had superior virological efficacy compared to EFV-based ART, and that a regimen containing DTG, emtricitabine and tenofovir alafenamide fumarate had the lowest rate of adverse pregnancy outcomes. 78 , 79 We found that PI-ART is associated with an increased risk of SGA and VSGA, but not PTB or other perinatal outcomes. However, no significant differences in perinatal outcomes were found between LPV/r, ATV/r, and DRV/r.…”

Section: Discussionmentioning

confidence: 66%

Adverse perinatal outcomes associated with protease inhibitor-based antiretroviral therapy in pregnant women living with HIV: A systematic review and meta-analysis

et al. 2022

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“…Organizations have begun to apply these ethical considerations in promoting research to generate pregnancy‐specific evidence [44,45] and identifying optimal drug regimens [3], modelling how ethics can serve to justify research priorities and shift presumptions going forward. Researchers and pharmaceutical companies working to advance innovative trials involving pregnant people [46–49] can also use these considerations to guide future studies.…”

Section: Discussionmentioning

confidence: 99%

Ending the evidence gap for pregnancy, HIV and co‐infections: ethics guidance from the PHASES project

et al. 2021

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Introduction While pregnant people have been an important focus for HIV research, critical evidence gaps remain regarding prevention, co‐infection, and safety and efficacy of new antiretroviral therapies in pregnancy. Such gaps can result in harm: without safety data, drugs used may carry unacceptable risks to the foetus or pregnant person; without pregnancy‐specific dosing data, pregnant people face risks of both toxicity and undertreatment; and delays in gathering evidence can limit access to beneficial next‐generation drugs. Despite recognition of the need, numerous barriers and ethical complexities have limited progress. We describe the process, ethical foundations, recommendations and applications of guidance for advancing responsible inclusion of pregnant people in HIV/co‐infections research. Discussion The 26‐member international and interdisciplinary Pregnancy and HIV/AIDS: Seeking Equitable Study (PHASES) Working Group was convened to develop ethics‐centred guidance for advancing timely, responsible HIV/co‐infections research with pregnant people. Deliberations over 3 years drew on extensive qualitative research, stakeholder engagement, expert consultation and a series of workshops. The guidance, initially issued in July 2020, highlights conceptual shifts needed in framing research with pregnant people, and articulates three ethical foundations to ground recommendations: equitable protection from drug‐related risks, timely access to biomedical advances and equitable respect for pregnant people's health interests. The guidance advances 12 specific recommendations, actionable within the current regulatory environment, addressing multiple stakeholders across drug development and post‐approval research, and organized around four themes: building capacity, supporting inclusion, achieving priority research and ensuring respect. The recommendations describe strategies towards ethically redressing the evidence gap for pregnant people around HIV and co‐infections. The guidance has informed key efforts of leading organizations working to advance needed research, and identifies further opportunities for impact by a range of stakeholder groups. Conclusions There are clear pathways towards ethical inclusion of pregnant people in the biomedical research agenda, and strong agreement across the HIV research community about the need for – and the promise of – advancing them. Those who fund, conduct, oversee and advocate for research can use the PHASES guidance to facilitate more, better and earlier evidence to optimize the health and wellbeing of pregnant people and their children.

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Cited by 115 publications

References 30 publications

Weekly 17 alpha-hydroxyprogesterone caproate to prevent preterm birth among women living with HIV: a randomised, double-blind, placebo-controlled trial

Weekly 17 alpha-hydroxyprogesterone caproate to prevent preterm birth among women living with HIV: a randomised, double-blind, placebo-controlled trial

Adverse perinatal outcomes associated with protease inhibitor-based antiretroviral therapy in pregnant women living with HIV: A systematic review and meta-analysis

Ending the evidence gap for pregnancy, HIV and co‐infections: ethics guidance from the PHASES project

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