Very Early Intensive Treatment of Infants Living With HIV to Achieve HIV Remission

Very Early Intensive Treatment of Infants Living With HIV to Achieve HIV Remission: A Phase I/II Proof of Concept Study

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 ten 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 <LOD, the infant will be potentially eligible for Step 3 after an additional 48 weeks of follow-up in Step 2 with no RNA detected. There is no limit on the number of times HIV RNA may be detected with a result <LOD after Week 48. However, infants with detectable RNA with a result <LOD after Week 48 will not be considered for entry into Step 3 until after an additional 48 weeks of no RNA detected.
     • Participants may experience either or both exceptions at different timepoints during follow-up in Step 2.

4. If breastfed, must have permanently ceased breastfeeding, with no exposure to breast milk for at least six weeks prior to specimen collection for the testing specified in the criterion (#5) below.

5. Has met ALL of the following additional criteria while in Step 2, based on testing between Step 2 Week 84 and Step 2 Week 192 (inclusive):

   • Two consecutive negative HIV antibody tests by fourth generation ELISA at least eight weeks apart.
   • Two consecutive HIV DNA tests with no DNA detected in at least 850,000 PBMCs assayed at least eight weeks apart.
   • CD4 cell percentage greater than or equal to 25% and CD4 cell absolute count greater than or equal to the lower limit of normal for age (≥1000 cells/mL if 2 to less than 3 years of age; ≥750 cells/mL if 3 to less than 5 years of age; ≥500 cells/mL if 5 years of age or older).
   • Infant assessed by the site investigator or designee as expected to adhere to the Step 3 Schedule of Evaluations.
   • Mother (or legal guardian if applicable) willing and able to provide written informed consent for child's participation in Step 3 and Step 4.

6. No plasma HIV RNA detected by testing after criteria have been confirmed, with specimen collection for the assay within 14 days prior to Step 3 Entry.

Infant Inclusion Criteria for Step 4

1. Enrolled in Step 3.

2. Has met at least one of the following:

   • Plasma HIV RNA ≥LOD based on two assays.
   • Plasma HIV RNA ≥1000 copies/mL in the presence of fever or other sign or symptom of acute retroviral syndrome.
   • Confirmed or suspected diagnosis of acute retroviral syndrome.
   • Confirmed or suspected diagnosis of a new WHO Clinical Stage 3 or 4 condition.
   • Confirmed CD4 cell percentage less than 25% and CD4 cell absolute count less than the lower limit of normal for age (<1000 cells/mL if 2 to less than 3 years of age; <750 cells/mL if 3 to less than 5 years of age; <500 cells/mL if 5 years of age or older).
   • Otherwise assessed by the site investigator or designee, in consultation with the Clinical Management Committee (CMC), as having an indication to re-initiate treatment.