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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 643
- 试验地点
- 35
- 主要终点
- Percentage of Mothers With HIV-1 RNA Viral Load Less Than 200 Copies/mL at Delivery
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
Arm 3: Maternal EFV/FTC/TDF
Mothers randomized to receive efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) during pregnancy, through delivery, and for 50 weeks postpartum.
干预措施: Efavirenz/emtricitabine/tenofovir disoproxil fumarate (Drug)
Arm 2: Maternal DTG+FTC/TDF
Mothers randomized to receive DTG plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) during pregnancy, through delivery, and for 50 weeks postpartum.
干预措施: Emtricitabine/tenofovir disoproxil fumarate (Drug)
Arm 1: Maternal DTG+FTC/TAF
Mothers randomized to receive dolutegravir (DTG) plus emtricitabine/tenofovir alafenamide (FTC/TAF) during pregnancy, through delivery, and for 50 weeks postpartum.
干预措施: Emtricitabine/tenofovir alafenamide (Drug)
Arm 2: Maternal DTG+FTC/TDF
Mothers randomized to receive DTG plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) during pregnancy, through delivery, and for 50 weeks postpartum.
干预措施: Dolutegravir (Drug)
Arm 1: Maternal DTG+FTC/TAF
Mothers randomized to receive dolutegravir (DTG) plus emtricitabine/tenofovir alafenamide (FTC/TAF) during pregnancy, through delivery, and for 50 weeks postpartum.
干预措施: Dolutegravir (Drug)
结局指标
主要结局
Percentage of Mothers With HIV-1 RNA Viral Load Less Than 200 Copies/mL at Delivery
时间窗: 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.
Percentage of Mother-infant Pairs With an Adverse Pregnancy Outcome
时间窗: Delivery
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)
Cumulative Probability of Women Experiencing Grade 3 or Higher Adverse Event
时间窗: From randomization up to 74 weeks
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.
Cumulative Probability of Infants Experiencing Grade 3 or Higher Adverse Event
时间窗: From birth through Week 50 postpartum
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.
次要结局
- Change in Maternal Weight Overall(Baseline to 50 weeks postpartum)
- Count of Mother-infant Pairs in the Classified Ranked Composite Safety Outcome(Birth through 50 weeks postpartum)
- Cumulative Probability of Infant HIV-infection(Birth through 50 weeks after birth)
- Cumulative Probability of Infant Deaths(Birth through 50 weeks after birth)
- Maternal Change in Creatinine Clearance(Baseline to 50 weeks postpartum)
- Infant Creatinine Clearance(Delivery and 26 weeks postpartum)
- Percentage of Mothers With HIV-1 ARV Drug Resistance Mutations at the Time of Maternal Virologic Failure(From 24 weeks after randomization through Week 50 postpartum)
- Count of Infants With HIV-1 Antiretroviral Drug Resistance Mutations at the Time of Infant HIV Diagnosis(From birth through 50 weeks postpartum)
- Percentage of Mother-Infant Pairs With Preterm Deliveries(Delivery)
- Percentage of Infants Born Small for Gestational Age(Birth)
- Change in Maternal Weight Antepartum(Baseline through before delivery (up to one day prior))
- Change in Maternal Weight Postpartum(Delivery to 50 weeks postpartum)
- 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)
- Percentage of Mother-Infant Pairs With an Adverse Pregnancy Outcome(Delivery)
- Cumulative Probability of Women Experiencing Grade 3 or Higher Adverse Event(From randomization up to 74 weeks)
- Cumulative Probability of Infants Experiencing Grade 3 or Higher Adverse Event(Birth through Week 50 postpartum)
- Percentage of Mother-infant Pairs With an Adverse Pregnancy Outcome or Major Congenital Anomaly(Delivery through 50 weeks postpartum)