Clinical trial NCT03048422: Evaluating the Efficacy and Safety of Dolutegravir-Containing Versus Efavirenz-Containing Antiretroviral Therapy Regimens in HIV-1-Infected Pregnant Women and Their Infants
Official title: Phase III Study of the Virologic Efficacy and Safety of Dolutegravir-Containing Versus Efavirenz-Containing Antiretroviral Therapy Regimens in HIV-1-Infected Pregnant Women and Their Infants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2017-02-09
Enrollment: 643
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: This study compared the virologic efficacy and safety of three ARV regimens in pregnant women living with HIV: dolutegravir (DTG) plus emtricitabine/tenofovir alafenamide (FTC/TAF), DTG plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), and efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). The study also compared the safety of these regimens for their infants.

At study entry, mothers were randomly assigned to either receive DTG plus FTC/TAF (Arm 1), DTG plus FTC/TDF (Arm 2), or EFV/FTC/TDF (Arm 3) during pregnancy, through delivery, and for 50 weeks postpartum.

Mothers completed study visits at study entry and every four weeks during pregnancy. Study visits for mothers and their infants occurred at delivery and at 6, 14, 26, 38, and 50 weeks postpartum. Visits for mothers and infants included physical examinations and blood collection. Select study visits also included breast milk collection from mothers who breastfed, hair and urine collection, ultrasound scans, pregnancy testing, contraception counseling, and, for a subset of participants, dual energy x-ray absorptiometry (DXA) scans for mothers and their infants.

For pregnancy outcome measures, mothers and infants were evaluated together as mother-infant pairs, with any outcome between the two counting as an event (for example, if an infant was born small for gestational age, this would be a pregnancy outcome event for the mother-infant pair). For all other outcome measures, women and infants were evaluated separately.

Eligibility criteria: Inclusion Criteria:

* 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
  * One total HIV nucleic acid test.
  * See the protocol for more information on this inclusion criterion.
* At screening, mother is ART-naive, defined as having not received prior antiretroviral therapy other than ARVs received during prior pregnancies or prior periods of breastfeeding (i.e., receipt of any single, dual, or triple ARV regimen during prior time-limited periods of pregnancy and breastfeeding is permitted). Receipt of up to 14 days of ARVs during the current pregnancy is permitted prior to study entry so that initiation of ARVs during the current pregnancy is not delayed during the study screening period. Note: Non-study ART may be initiated in the current pregnancy prior to initiation of the study screening process. For eligible participants, enrollment must occur within 14 days of non-study ART initiation. Note: Receipt of ARVs during a prior pregnancy or prior period of breastfeeding must have concluded at least six months prior to study entry. Receipt of TDF or FTC/TDF for pre-exposure prophylaxis at any time in the past is not exclusionary (even if received within six months prior to study entry).
* At screening, mother has the following laboratory test results (based on testing of samples collected within 14 days prior to study entry):

  * Grade 1 or lower (less than 2.5 times upper limit of normal \[ULN\]) alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
  * Grade 2 or lower (less than or equal to 1.8 times ULN) creatinine
  * Grade 2 or lower (greater than or equal to 60 mL/min) estimated creatinine clearance (CrCl; Cockcroft-Gault formula). See the protocol for guidance on severity grading. Laboratory tests may be repeated during the study screening period, with the latest result used for eligibility determination.
* At screening and at study entry, no evidence of multiple gestation or fetal anomalies, as assessed by best available method
* At study entry, gestational age of 14-28 weeks, defined as greater than 13 weeks plus six days and less than 28 completed weeks gestation, estimated by best available method. Note: For this inclusion criterion and the previous inclusion criterion, fetal ultrasound is preferred but not required for purposes of eligibility determination. If ultrasound cannot be performed during the study screening period prior to study entry, it must be performed within 14 days after study entry. As further explained in the protocol, enrolled participants will not be withdrawn from the study based on ultrasound findings obtained after study entry.
* At study entry, mother expects to remain in the geographic area of the study site during pregnancy and for 50 weeks postpartum \[Eligibility criteria added per Letter of Amendment 1 to V2; July 2018\]:
* At study entry, mother reports that she does not wish to become pregnant again for at least 50 weeks after her current pregnancy and that she is willing to use effective contraception during this period. Effective contraception may include surgical sterilization (i.e., hysterectomy, bilateral oophorectomy, tubal ligation, or salpingectomy) or any of the following methods:

  * Contraceptive intrauterine device (IUD) or intrauterine system (IUS)
  * Subdermal contraceptive implant
  * Progestogen injections
  * Progestogen only oral contraceptive pills
  * Combined estrogen and progestogen oral contraceptive pills
  * Percutaneous contraceptive patches
  * Contraceptive vaginal rings
  * Note: IUDs, IUSs, implants, and injections are strongly recommended due to their lower failure rates with typical use. Male or female condom use is recommended with all contraceptive methods for dual protection against pregnancy and to avoid transmission of HIV and other sexually transmitted infections.

Exclusion Criteria:

* 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)
  * Clinically significant acute illness requiring systemic treatment and/or hospitalization (i.e., major medical condition that is likely to lead to hospitalization and/or to an adverse pregnancy outcome) within 14 days prior to study entry
  * Unstable liver disease (defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice) or known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) within 14 days prior to study entry
  * Note: Testing to rule out HIV-2 infection is not required.
* Mother or fetus has any other condition that, in the opinion of the site investigator or designee, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives

Primary outcomes:
measure: Percentage of Mothers With HIV-1 RNA Viral Load Less Than 200 Copies/mL at Delivery
timeFrame: Delivery
measure: Percentage of Mother-infant Pairs With an Adverse Pregnancy Outcome
timeFrame: Delivery
measure: Cumulative Probability of Women Experiencing Grade 3 or Higher Adverse Event
timeFrame: From randomization up to 74 weeks
measure: Cumulative Probability of Infants Experiencing Grade 3 or Higher Adverse Event
timeFrame: From birth through Week 50 postpartum
Secondary outcomes:
measure: Percentage of Mothers With HIV-1 RNA Less Than 50 Copies/mL at Delivery Measured at Central Laboratory
timeFrame: Delivery
measure: Percentage of Mothers With HIV-1 RNA Less Than 200 Copies/mL at 50 Weeks Postpartum
timeFrame: 50 weeks postpartum
measure: Time to First HIV-1 RNA Less Than 200 Copies/mL Through Delivery
timeFrame: Randomization to delivery
measure: Percentage of Mothers With Virologic Success of HIV-1 RNA Less Than 200 Copies/mL at Delivery Based on FDA Snapshot Algorithm
timeFrame: Delivery
measure: Percentage of Mothers With Virologic Success of HIV-1 RNA Less Than 200 Copies/mL at 50 Weeks Postpartum Based on FDA Snapshot Algorithm
timeFrame: 50 weeks postpartum
measure: Percentage of Mother-Infant Pairs With an Adverse Pregnancy Outcome
timeFrame: Delivery
measure: Cumulative Probability of Women Experiencing Grade 3 or Higher Adverse Event
timeFrame: From randomization up to 74 weeks
measure: Cumulative Probability of Infants Experiencing Grade 3 or Higher Adverse Event
timeFrame: Birth through Week 50 postpartum
measure: Percentage of Mother-infant Pairs With an Adverse Pregnancy Outcome or Major Congenital Anomaly
timeFrame: Delivery through 50 weeks postpartum
measure: Count of Mother-infant Pairs in the Classified Ranked Composite Safety Outcome
timeFrame: Birth through 50 weeks postpartum
measure: Cumulative Probability of Infant HIV-infection
timeFrame: Birth through 50 weeks after birth
measure: Cumulative Probability of Infant Deaths
timeFrame: Birth through 50 weeks after birth
measure: Maternal Change in Creatinine Clearance
timeFrame: Baseline to 50 weeks postpartum
measure: Infant Creatinine Clearance
timeFrame: Delivery and 26 weeks postpartum
measure: Percentage of Mothers With HIV-1 ARV Drug Resistance Mutations at the Time of Maternal Virologic Failure
timeFrame: From 24 weeks after randomization through Week 50 postpartum
measure: Count of Infants With HIV-1 Antiretroviral Drug Resistance Mutations at the Time of Infant HIV Diagnosis
timeFrame: From birth through 50 weeks postpartum
measure: Percentage of Mother-Infant Pairs With Preterm Deliveries
timeFrame: Delivery
measure: Percentage of Infants Born Small for Gestational Age
timeFrame: Birth
measure: Change in Maternal Weight Antepartum
timeFrame: Baseline through before delivery (up to one day prior)
measure: Change in Maternal Weight Postpartum
timeFrame: Delivery to 50 weeks postpartum
measure: Change in Maternal Weight Overall
timeFrame: Baseline to 50 weeks postpartum
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: Univ. of Florida Jacksonville NICHD CRS
state: Florida
city: Miami
country: United States
facility: Pediatric Perinatal HIV Clinical Trials Unit CRS
state: Florida
city: Gaborone
country: Botswana
facility: Gaborone CRS
state: South-East District
city: Gaborone
country: Botswana
facility: Molepolole CRS
city: Belo Horizonte
country: Brazil
facility: SOM Federal University Minas Gerais Brazil NICHD CRS
state: Minas Gerais
city: Rio De Janeiro
country: Brazil
facility: Hospital Federal dos Servidores do Estado NICHD CRS
city: Rio de Janeiro
country: Brazil
facility: Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS
city: Rio de Janeiro
country: Brazil
facility: Hosp. Geral De Nova Igaucu Brazil NICHD CRS
city: Pune
country: India
facility: Byramjee Jeejeebhoy Medical College (BJMC) CRS
state: Maharashtra
city: Johannesburg
country: South Africa
facility: Soweto IMPAACT CRS
state: Gauteng
city: Johannesburg
country: South Africa
facility: Wits RHI Shandukani Research Centre CRS
state: Gauteng
city: Durban
country: South Africa
facility: Umlazi CRS
state: Kwa Zulu Natal
city: Tygerberg
country: South Africa
facility: Famcru Crs
state: Western Cape Province
city: Moshi
country: Tanzania
facility: Kilimanjaro Christian Medical Centre (KCMC)
city: Bangkok
country: Thailand
facility: Siriraj Hospital ,Mahidol University NICHD CRS
state: Bangkoknoi
city: Chiang Mai
country: Thailand
facility: Chiangrai Prachanukroh Hospital NICHD CRS
city: Chiang Mai
country: Thailand
facility: Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
city: Kampala
country: Uganda
facility: Baylor-Uganda CRS
city: Chitungwiza
country: Zimbabwe
facility: Seke North CRS
city: Chitungwiza
country: Zimbabwe
facility: St Mary's CRS
city: Harare
country: Zimbabwe
facility: Harare Family Care CRS
Study officials:
affiliation: Harvard T.H. Chan School of Public Health and Brigham and Women's Hospital
name: Shahin Lockman, MD, MSc
role: STUDY_CHAIR
affiliation: Kamuzu Central Hospital in Lilongwe, Malawi
name: Lameck Chinula, MBBS, MMED, FCOG
role: STUDY_CHAIR
References:
citation: 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.