Evaluating the Efficacy and Safety of Dolutegravir-Containing Versus Efavirenz-Containing Antiretroviral Therapy Regimens in HIV-1-Infected Pregnant Women and Their Infants

NCT03048422 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: IMPAACT 201030129
• Study Type: interventional
• Target: 643
• Locations: 9 countries
• Sites: 21

Brief Summary

The purpose of this study was to compare the virologic efficacy and safety of three antiretroviral (ARV) regimens, dolutegravir plus emtricitabine/tenofovir alafenamide, dolutegravir plus emtricitabine/tenofovir disoproxil fumarate, and efavirenz/emtricitabine/tenofovir disoproxil fumarate in pregnant women living with HIV-1 and to compare the safety of these regimens for their infants.

Conditions

HIV Infections

Outcome Measures

Primary Outcomes (4)

• Percentage of Mothers With HIV-1 RNA Viral Load Less Than 200 Copies/mL at Delivery

  Percentage of mothers with plasma HIV-1 RNA viral load less than 200 copies/mL at delivery determined using real-time test results obtained at site laboratories. This outcome was evaluated in the non-inferiority (primary outcome) and superiority (secondary outcome) analyses. The intention-to-treat analysis included all randomized women who had viral load data available. The per-protocol analysis excluded women who modified randomized treatment (stopped, paused, switched, added any treatment) before viral load evaluation at delivery, with the exception of women who modified randomized treatment for use of a concomitant medication.

  Delivery

• Percentage of Mother-infant Pairs With an Adverse Pregnancy Outcome

  Percentage of mother-infant pairs with an adverse pregnancy outcome. Adverse pregnancy outcome includes spontaneous abortion (\<20 weeks gestation), stillbirth (≥20 weeks gestation), preterm delivery (\<37 completed weeks), or small for gestational age (\<10th percentile by INTERGROWTH 21st Standards)

  Delivery

• Cumulative Probability of Women Experiencing Grade 3 or Higher Adverse Event

  The Kaplan-Meier estimate of the cumulative probability of women experiencing grade 3 or higher adverse events, including events resulting in death due to any cause. Time to first maternal grade 3 or higher adverse event was defined as the first grade 3 or higher adverse event that occurred after randomization and before 74 weeks of follow-up. The timeframe of 74 weeks was determined by adding up 56 weeks of postpartum follow-up to the mean duration of antepartum follow-up, which was 18 weeks.

  From randomization up to 74 weeks

• Cumulative Probability of Infants Experiencing Grade 3 or Higher Adverse Event

  The Kaplan-Meier estimate of the cumulative probability of infants experiencing grade 3 or higher adverse events, including events resulting in death due to any cause.

  From birth through Week 50 postpartum

Secondary Outcomes (21)

• Percentage of Mothers With HIV-1 RNA Less Than 50 Copies/mL at Delivery Measured at Central Laboratory

  Delivery

• Percentage of Mothers With HIV-1 RNA Less Than 200 Copies/mL at 50 Weeks Postpartum

  50 weeks postpartum

• Time to First HIV-1 RNA Less Than 200 Copies/mL Through Delivery

  Randomization to delivery

• Percentage of Mothers With Virologic Success of HIV-1 RNA Less Than 200 Copies/mL at Delivery Based on FDA Snapshot Algorithm

  Delivery

• Percentage of Mothers With Virologic Success of HIV-1 RNA Less Than 200 Copies/mL at 50 Weeks Postpartum Based on FDA Snapshot Algorithm

  50 weeks postpartum

Study Arms (6)

Arm 1: Maternal DTG+FTC/TAF

EXPERIMENTAL

Mothers randomized to receive dolutegravir (DTG) plus emtricitabine/tenofovir alafenamide (FTC/TAF) during pregnancy, through delivery, and for 50 weeks postpartum.

Drug: Dolutegravir; Drug: Emtricitabine/tenofovir alafenamide

Arm 2: Maternal DTG+FTC/TDF

EXPERIMENTAL

Mothers randomized to receive DTG plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) during pregnancy, through delivery, and for 50 weeks postpartum.

Drug: Dolutegravir; Drug: Emtricitabine/tenofovir disoproxil fumarate

Arm 3: Maternal EFV/FTC/TDF

ACTIVE COMPARATOR

Mothers randomized to receive efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) during pregnancy, through delivery, and for 50 weeks postpartum.

Drug: Efavirenz/emtricitabine/tenofovir disoproxil fumarate

Arm 1 Infants

NO INTERVENTION

Infants born to women in Arm 1. Infants did not directly receive study intervention, but may have been exposed to the randomized treatment through placental or breastmilk transfer.

Arm 2 Infants

NO INTERVENTION

Infants born to women in Arm 2. Infants did not directly receive study intervention, but may have been exposed to the randomized treatment through placental or breastmilk transfer.

Arm 3 Infants

NO INTERVENTION

Infants born to women in Arm 3. Infants did not directly receive study intervention, but may have been exposed to the randomized treatment through placental or breastmilk transfer.

Interventions

Dolutegravir DRUG

One 50 mg DTG tablet was administered orally once daily

Also known as: DTG

Arm 1: Maternal DTG+FTC/TAF; Arm 2: Maternal DTG+FTC/TDF

Emtricitabine/tenofovir alafenamide DRUG

One fixed-dose combination tablet (FTC 200 mg/TAF 25 mg) was administered orally once daily

Also known as: FTC/TAF

Arm 1: Maternal DTG+FTC/TAF

Emtricitabine/tenofovir disoproxil fumarate DRUG

One fixed-dose combination tablet (FTC 200 mg/TDF 300 mg) was administered orally once daily

Also known as: FTC/TDF

Arm 2: Maternal DTG+FTC/TDF

Efavirenz/emtricitabine/tenofovir disoproxil fumarate DRUG

One fixed-dose combination tablet (EFV 600 mg/FTC 200 mg/TDF 300 mg) was administered orally once daily

Also known as: EFV/FTC/TDF

Arm 3: Maternal EFV/FTC/TDF

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Mother is able to provide written informed consent for her and her infant's participation in this study
• Mother has confirmed HIV-1 infection based on documented testing of two samples collected at different time points:
• Sample #1 may be tested using any of the following:
• Two rapid antibody tests from different manufacturers or based on different principles and epitopes
• One enzyme immunoassay (EIA) OR Western blot OR immunofluorescence assay OR chemiluminescence assay
• One HIV DNA polymerase chain reaction (PCR)
• One quantitative HIV RNA PCR (above the limit of detection of the assay)
• One qualitative HIV RNA PCR
• One total HIV nucleic acid test
• Sample #2 may be tested using any of the following:
• One rapid antibody test. If this option is used in combination with two rapid tests for Sample #1, at least one of the three rapid tests must be FDA-approved and the third rapid test must be from a third manufacturer or based on a third principle or epitope.
• One EIA OR Western blot OR immunofluorescence assay OR chemiluminescence assay
• One HIV DNA PCR
• One quantitative HIV RNA PCR (above the limit of detection of the assay)
• One qualitative HIV RNA PCR

You may not qualify if:

• Mother is currently incarcerated or involuntarily confined in a medical facility
• Mother is currently receiving:
• A psychoactive medication for treatment of a psychiatric illness
• Treatment for active tuberculosis
• Treatment for active hepatitis C infection
• Mother is expected to require treatment with interferon and/or ribavirin for hepatitis C infection during the study follow-up period
• Mother has a history of any of the following, as determined by the site investigator or designee based on maternal report and available medical records:
• Hypersensitivity or clinically significant adverse reaction to any of the ARVs included in the three study drug regimens (ever)
• Antiretroviral drug resistance mutations that would impact selection of ART regimen (ever)
• Clinically significant heart disease and/or known prolonged corrected QT (QTc) interval (ever)
• Suicidal ideation or attempt (ever)
• HIV-2 infection (ever)
• Zika virus infection, diagnosed or suspected, during the current pregnancy
• Receipt of any antiretroviral medication within six months prior to study entry, with two exceptions: receipt of any duration of TDF or FTC/TDF for pre-exposure prophylaxis or receipt of up to 14 days of ARVs during the current pregnancy
• Receipt of any prohibited medication within 14 days prior to study entry (see the protocol for more information)

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (21)

Univ. of Florida Jacksonville NICHD CRS

Jacksonville, Florida, 32209, United States

Location

Pediatric Perinatal HIV Clinical Trials Unit CRS

Miami, Florida, 33136, United States

Location

Gaborone CRS

Gaborone, South-East District, Botswana

Location

Molepolole CRS

Gaborone, Botswana

Location

SOM Federal University Minas Gerais Brazil NICHD CRS

Belo Horizonte, Minas Gerais, 30.130-100, Brazil

Location

Hospital Federal dos Servidores do Estado NICHD CRS

Rio de Janeiro, 20221-903, Brazil

Location

Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS

Rio de Janeiro, 21941-612, Brazil

Location

Hosp. Geral De Nova Igaucu Brazil NICHD CRS

Rio de Janeiro, 26030, Brazil

Location

Byramjee Jeejeebhoy Medical College (BJMC) CRS

Pune, Maharashtra, 411001, India

Location

Soweto IMPAACT CRS

Johannesburg, Gauteng, 1862, South Africa

Location

Wits RHI Shandukani Research Centre CRS

Johannesburg, Gauteng, 2001, South Africa

Location

Umlazi CRS

Durban, KwaZulu-Natal, 4001, South Africa

Location

Famcru Crs

Tygerberg, Western Cape, 7505, South Africa

Location

Kilimanjaro Christian Medical Centre (KCMC)

Moshi, Tanzania

Location

Siriraj Hospital ,Mahidol University NICHD CRS

Bangkok, Bangkoknoi, 10700, Thailand

Location

Chiangrai Prachanukroh Hospital NICHD CRS

Chiang Mai, 50100, Thailand

Location

Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS

Chiang Mai, 50200, Thailand

Location

Baylor-Uganda CRS

Kampala, Uganda

Location

Seke North CRS

Chitungwiza, Zimbabwe

Location

St Mary's CRS

Chitungwiza, Zimbabwe

Location

Harare Family Care CRS

Harare, Zimbabwe

Location

Related Publications (5)

• Lockman S, Brummel SS, Ziemba L, Stranix-Chibanda L, McCarthy K, Coletti A, Jean-Philippe P, Johnston B, Krotje C, Fairlie L, Hoffman RM, Sax PE, Moyo S, Chakhtoura N, Stringer JS, Masheto G, Korutaro V, Cassim H, Mmbaga BT, Joao E, Hanley S, Purdue L, Holmes LB, Momper JD, Shapiro RL, Thoofer NK, Rooney JF, Frenkel LM, Amico KR, Chinula L, Currier J; IMPAACT 2010/VESTED Study Team and Investigators. 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. Lancet. 2021 Apr 3;397(10281):1276-1292. doi: 10.1016/S0140-6736(21)00314-7.

  PMID: 33812487 RESULT

• Masheto G, Brummel SS, Ziemba L, Shepherd J, Mbengeranwa T, Igawa L, Coletti A, Mukura D, Rossouw L, Theron G, Krotje C, Jean-Philippe P, Chakhtoura N, Cassim H, Mathiba SR, Maena J, Murtaugh W, Fairlie L, Currier J, Hoffman R, Chinula L, Sax PE, Stranix-Chibanda L, Lockman S; IMPAACT 2010/VESTED Study Team and Investigators. Markers of Maternal Bone and Renal Toxicity Through 50 Weeks Postpartum: IMPAACT 2010 (VESTED) Trial. J Acquir Immune Defic Syndr. 2024 Oct 1;97(2):172-179. doi: 10.1097/QAI.0000000000003478.

  PMID: 39250651 DERIVED

• Eke AC, Brummel SS, Aliyu MH, Stranix-Chibanda L, Eleje GU, Ezebialu IU, Korutaro V, Wabwire D, Matubu A, Mbengeranwa T, Chakhtoura N, Chinula L, McCarthy K, Knowles K, Krotje C, Linton MF, Dooley KE, Sax PE, Brown T, Lockman S; IMPAACT 2010/VESTED Study Team. Lipid and Glucose Profiles in Pregnant Women With HIV on Tenofovir-based Antiretroviral Therapy. Clin Infect Dis. 2025 Mar 17;80(3):594-601. doi: 10.1093/cid/ciae441.

  PMID: 39219495 DERIVED

• Jacobson DL, Crider KS, DeMarrais P, Brummel S, Zhang M, Pfeiffer CM, Moore CA, McCarthy K, Johnston B, Mohammed T, Vhembo T, Kabugho E, Muzorah GA, Cassim H, Fairlie L, Machado ES, Ngocho JS, Shapiro RL, Serghides L, Chakhtoura N, Chinula L, Lockman S. Dolutegravir- Versus Efavirenz-Based Treatment in Pregnancy: Impact on Red Blood Cell Folate Concentrations in Pregnant Women and Their Infants. J Infect Dis. 2024 Nov 15;230(5):1224-1234. doi: 10.1093/infdis/jiae308.

  PMID: 38877762 DERIVED

• Chinula L, Ziemba L, Brummel S, McCarthy K, Coletti A, Krotje C, Johnston B, Knowles K, Moyo S, Stranix-Chibanda L, Hoffman R, Sax PE, Stringer J, Chakhtoura N, Jean-Philippe P, Korutaro V, Cassim H, Fairlie L, Masheto G, Boyce C, Frenkel LM, Amico KR, Purdue L, Shapiro R, Mmbaga BT, Patel F, van Wyk J, Rooney JF, Currier JS, Lockman S; IMPAACT 2010/VESTED Study Team and Investigators. 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. Lancet HIV. 2023 Jun;10(6):e363-e374. doi: 10.1016/S2352-3018(23)00061-9. Epub 2023 May 8.

  PMID: 37167996 DERIVED

Related Links

• Study website
• The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017, was used
• Intergrowth 21st Standards, including reference for infants small for gestational age
• FDA Snapshot algorithm
• Definition for major congenital anomalies
• Schwartz formula for calculating infant creatinine clearance

MeSH Terms

Conditions

HIV Infections

Interventions

dolutegravir; emtricitabine tenofovir alafenamide; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Tenofovir; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Emtricitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Drug Combinations; Pharmaceutical Preparations; Oxazines

Results Point of Contact

• Title: IMPAACT Clinicaltrials.gov Coordinator
• Organization: Family Health International (FHI 360)

IMPAACT.ctgov@fstrf.org

(919) 405-1429

Study Officials

• Shahin Lockman, MD, MSc

  Harvard T.H. Chan School of Public Health and Brigham and Women's Hospital

  STUDY CHAIR

• Lameck Chinula, MBBS, MMED, FCOG

  Kamuzu Central Hospital in Lilongwe, Malawi

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 7, 2017
• First Posted: February 9, 2017
• Study Start: January 19, 2018
• Primary Completion: October 3, 2020
• Study Completion: October 3, 2020
• Last Updated: November 21, 2022
• Results First Posted: November 10, 2021

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months following publication and available throughout period of funding of the International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) Network by NIH
• Access Criteria: * With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the IMPAACT Network. * For what types of analyses? To achieve aims in the proposal approved by the IMPAACT Network. * By what mechanism will data be made available? Researchers may submit a request for access to data using the IMPAACT "Data Request" form at: https://www.impaactnetwork.org/studies/submit-research-proposal. Researchers of approved proposals will need to sign an IMPAACT Data Use Agreement before receiving the data.

Locations

ZI (3); ZA (4); BO (2); IN (1); TA (1); BR (4); TH (3); UG (1); US (2)