A PHASE IV RANDOMIZED TRIAL TO EVALUATE THE VIROLOGIC RESPONSE AND PHARMACOKINETICS OF TWO DIFFERENT POTENT REGIMENS IN HIV INFECTED WOMEN INITIATING TRIPLE ANTIRETROVIRAL REGIMENS BETWEEN 28 AND 36 WEEKS OF PREGNANCY FOR THE PREVENTION OF MOTHER-TO-CHILD TRANSMISSION: NICHD P1081

DESIGN:                Multicenter two arm randomized open-label trial comparing the ability to achieve virologic suppression at delivery, tolerability, and safety.

SAMPLE SIZE:     334 evaluable mother-infant pairs (approximately 167 per arm), which is projected to require enrolling approximately 394 mother-infant pairs.

POPULATION:     Human Immunodeficiency Virus (HIV)-1 infected pregnant women with a gestational age between 28 and 36 weeks who are antiretroviral (ARV) naïve or have received short-course zidovudine (maximum of 8 weeks) only for prevention of mother-to-child transmission (PMTCT) in previous pregnancies, and their infants.

STRATIFY BY:    Gestational age at enrollment (28-30 weeks or 31-33 weeks or 34-36 weeks) and whether the women will use lamivudine/zidovudine or an alternative, locally supplied nucleoside reverse transcriptase inhibitor (NRTI) backbone.

REGIMEN:            Antepartum – Participants will be randomized 1:1

                                 Arm A: Lamivudine 150 mg/zidovudine 300 mg* twice daily (BID) + efavirenz 600 mg every night (QHS).

                                 Arm B: Lamivudine 150 mg/zidovudine 300 mg* BID + raltegravir 400 mg BID.

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                                 *Alternative, locally supplied NRTI backbone may be used in place of lamivudine/zidovudine with permission of protocol team obtained prior to randomization.

                                 Active labor:

                                 All participants will continue to receive study drugs during labor. In addition, in place of the oral fixed dose combination of lamivudine 150 mg/zidovudine 300 mg (or alternative NRTI backbone), participants may receive intravenous zidovudine, other dosing regimens of oral zidovudine, oral lamivudine and/or additional drugs during labor, according to local standard of care/guidelines.

                                 Infants:

                                 Infants will receive ARV according to specific local guidelines.

TREATMENT

DURATION:          All women will receive their randomized study regimen from study entry through delivery. Women who meet local guidelines for receiving antiretroviral therapy (ART) will continue triple ART after delivery according to local guidelines. These women can receive study supplied drugs for up to 8 weeks after delivery to facilitate the transition to local standard of care for treatment for maternal health and/or prevention of breast milk transmission. Women who do not meet local guidelines for receiving triple ART will stop study supplied drugs immediately after delivery. Women randomized to Arm A (efavirenz) may continue lamivudine/ zidovudine for a period of time after stopping efavirenz at the discretion of the local investigator.

STUDY

DURATION:          Women will be followed for 6 months after delivery. Infants will be followed until 6 months of age and may participate in an extension phase: developmental assessment of infants, lasting up to 4 years of age.

OBJECTIVES:       Primary Objectives:

1.                To compare the ability of two triple ARV regimens (one containing efavirenz and the other raltegravir) begun during the third trimester of pregnancy to achieve a viral load of < 200 copies/mL at the time of delivery.

2.                To compare the safety and tolerability of two triple ARV regimens (one containing efavirenz and the other raltegravir) begun during the third trimester of pregnancy.

Secondary Objectives:

1.                  To compare the kinetics of viral decay between the treatment regimens:

a.       Compare decay of plasma and vaginal HIV-1 RNA and DNA between the treatment regimens.

b.      Compare decay of plasma HIV-1 infectivity between the treatment regimens.

2.            To compare infant outcomes including stillbirth, premature birth, low birth weight, perinatal HIV transmission, neurodevelopmental outcomes and to compare (in HIV-infected infants) drug resistance between the two treatment regimens.

3.            To assess the baseline prevalence and selection of HIV-1 drug-resistance to the study drugs, using standard genotyping and ultrasensitive genotyping methods.

Exploratory Objectives:

1.      To describe the population pharmacokinetic (PK) parameters of efavirenz and raltegravir during the third trimester of pregnancy and postpartum using sparse sampling and to evaluate potential relationships between PK parameters, pharmacogenomics and viral load changes.

2.      To describe the maternal vaginal and infant nasopharyngeal and oropharyngeal microbiome environment and the potential association with adverse outcome in HIV exposed uninfected children.