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

This study will compare the virologic efficacy and safety of three ARV regimens in
HIV-1-infected pregnant women: 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 will also
compare the safety of these regimens for their infants.

At study entry, mothers will be 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 will complete study visits at study entry and every four weeks during pregnancy.
Study visits for mothers and their infants will occur at delivery and at 6, 14, 26, 38, and
50 weeks postpartum. Visits for mothers and infants will include physical examinations and
blood collection. Select study visits may include breast milk collection from mothers who
breast feed, 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.

Inclusion Criteria:

- Mother is at least 18 years of age and willing and 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

- 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