The study will explore the effects of early intensive antiretroviral therapy (ART) with or without a broadly neutralizing antibody (bNAb) on achieving HIV remission (HIV RNA below the limit of detection of the assay) among infants living with HIV.

The purpose of this study is to explore the effects of early intensive antiretroviral therapy (ART) on achieving HIV remission (HIV RNA below the limit of detection of the assay) among infants living with HIV.

The study will enroll two cohorts. Cohort 1 will include infants born to a mother with presumed or confirmed HIV infection who received no or very limited antiretrovirals during pregnancy. Cohort 2 will include infants with at least one positive HIV nucleic acid test result from a sample collected within 48 hours of birth who initiated a qualifying ART regimen within 48 hours of birth.

Seven early intensive therapy regimens will be assessed. Regimen 1L will include 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus nevirapine (NVP) plus lopinavir/ritonavir (LPV/r). Regimen 2R will include 2 NRTIs plus NVP plus raltegravir (RAL). Regimen 2RV will include 2 NRTIs plus NVP plus RAL plus VRC01 monoclonal antibody. Regimen 3RD will include 2 NRTIs plus NVP plus RAL with subsequent switch to 2 NRTIs plus dolutegravir (DTG) upon reaching 28 days of age and 3 kg body weight. Regimen 3RDV7 will include 2 NRTIs plus NVP plus RAL plus VRC07-523LS with subsequent switch to 2 NRTIs plus DTG plus VRC07-523LS upon reaching 28 days of age and 3 kg body weight. Regimen 4D will include 2 NRTIs plus DTG. Regimen 4DV7 will include 2 NRTIs plus DTG plus VRC07-523LS.

The study will be conducted in four steps. In Step 1, Cohort 1 infants will be enrolled for evaluation of HIV infection and initiation of early intensive therapy within 48 hours of birth. Infants in whom in utero HIV infection is excluded will switch from the study regimen to standard perinatal prophylaxis per local guidelines within two weeks; these infants will continue in Step 1 safety monitoring for two additional weeks, undergo HIV testing at approximately 24 weeks of age, and then exit the study. Infants in whom in utero HIV infection is confirmed will enter Step 2 at least two weeks after enrollment in Step 1.

In Step 2, infants will receive the study regimen for up to 192 weeks. Beginning at Step 2 Week 84, children who achieved HIV RNA suppression by Week 24, and maintained suppression, thereafter, will be evaluated for possible analytic treatment interruption (ATI).

In Step 3, children in Step 2 who meet criteria for ATI will interrupt ART and be closely monitored for viral rebound for up to five years.

In Step 4, children who experience viral rebound in Step 3 or meet other Step 4 inclusion criteria will re-initiate ART and be closely monitored for viral re-suppression on ART until five years of age or six months after re-suppression, whichever is later.

Maternal Inclusion Criteria

1. Presumed or confirmed maternal HIV infection:

   • Mothers will be eligible to enroll with EITHER:

     • Presumed HIV infection defined as at least one positive rapid HIV antibody-based test result from a sample collected in the peripartum period. Presumed infection must be confirmed within 10 business days of enrollment OR
     • Confirmed HIV infection defined as positive results from two samples collected at different timepoints

2. Willing and able to provide written informed consent for participation of herself and her infant. The mother must be of legal age or circumstance to provide independent informed consent as determined by site standard operating procedures (SOPs) and consistent with IRB/EC policies and procedures. Otherwise, informed consent must be obtained from a legal guardian and the mother must provide written assent.

3. Was not previously enrolled in this study with another infant.

4. Did not receive ARVs during the current pregnancy.

5. Infant is eligible per inclusion criteria.

Infant Inclusion Criteria for Step 1

1. Less than or equal to 48 hours of age.
2. Greater than or equal to 37 weeks gestational age at birth (assessment of gestational age will be based on the best clinical estimate determined by date of last menstrual period, antenatal ultrasound, fundal height, or Ballard Score).
3. Greater than or equal to 2 kilograms (kg) at birth.
4. Able to take ARVs by mouth, nasogastric tube, or gastrostomy tube.
5. Has no clinically significant diseases (other than HIV infection) or clinically significant findings during review of medical history or physical examination prior to entry that, in the site investigator's opinion, would interfere with study participation or interpretation.
6. Mother is eligible per inclusion criteria.

Infant Inclusion Criteria for Step 2

1. Enrolled in Step 1.
2. Confirmed in utero HIV infection.
3. Able to take ARVs by mouth, nasogastric tube, or gastrostomy tube.
4. Has no clinically significant diseases (other than HIV infection) or clinically significant findings during review of medical history or physical examination prior to entry that, in the site investigator's opinion, would interfere with study participation or interpretation.
5. Mother (or legal guardian if applicable) is willing and able to provide written informed consent for child's participation in Step 2.

Infant Inclusion Criteria for Step 3

1. Enrolled in Step 2.

2. Has reached Step 2 Week 96.

3. Has the following results based on testing:

   • No confirmed plasma HIV RNA ≥200 copies/mL at Step 2 Week 24 and up to but excluding Step 2 Week 48.

   • No plasma HIV RNA detected at Step 2 Week 48 and thereafter, with two possible exceptions

     • (i) First possible exception: If HIV RNA is detected at or after Step 2 Week 48 with a result <200 copies/mL, testing will be repeated within three weeks (specimen collection for the confirmatory test must occur within three weeks of specimen collection for the initial test).
     • If no HIV RNA is detected on the confirmatory test, or if HIV RNA is detected with a result <200 copies/mL, the infant will be potentially eligible for Step 3 after an additional 48 weeks of follow-up in Step 2, provided no HIV RNA is detected on any subsequent tests in Step 2.
     • If HIV RNA is detected on the confirmatory test with a result ≥200 copies/mL, the infant will not be eligible for Step 3.
     • (ii) Second possible exception: If HIV RNA is detected after Step 2 Week 48 with a result \

Individual participant data that underlie results in the publication, after deidentification.

Beginning 3 months following publication and available throughout period of funding of the International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) Network by NIH

• 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.