Very Early Intensive Treatment of HIV-Infected Infants to Achieve HIV Remission

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
HIV-infected infants.

The study will enroll two cohorts. Cohort 1 will include infants at high risk for in utero
HIV infection. Cohort 2 will include in utero HIV-infected, ART-started infants.

Three 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.

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 final HIV testing at
approximately 12 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, Cohort 1 infants identified with in utero HIV infection and Cohort 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, with no HIV
RNA detected at or after Week 48, will be evaluated for possible treatment cessation.

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

In Step 4, children who experience viral rebound in Step 3 will re-start 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.

HIV-uninfected infants will be followed for 12 weeks. HIV-infected infants will be followed
for up to 192 weeks in Step 2 (on ART); those entering Step 3 will be followed for primary
endpoint ascertainment at 48 weeks and for up to a total of five years (off ART) in this
step.

Maternal Inclusion Criteria, Cohort 1 and Cohort 2

- Mothers will be eligible to enroll with EITHER:

- Presumed HIV infection defined as greater than or equal to one positive rapid HIV
antibody test obtained in the peripartum period. Maternal infection must be
confirmed, with confirmatory results available within 10 business days of
enrollment (see below). OR

- Confirmed HIV infection defined as positive results from two samples collected at
different time points. All samples tested must be whole blood, serum or plasma.
More information on this criterion is available in the protocol.

- Willing and able to provide written informed consent for participation of herself and
her infant (Step 1 and/or Step 2 as applicable). The mother must be of an age to
provide legal informed consent as defined by the country in which she resides. If not,
informed consent must be obtained from a legal guardian.

Maternal Inclusion Criteria, Cohort 1 Only

- Infant eligible and enrolled in Cohort 1

- No receipt of ARVs during the current pregnancy

- Note: Maternal receipt of ARVs prior to the current pregnancy (including NVP) or
during labor and/or the intrapartum period (within five days prior to delivery)
of the current pregnancy is permissible.

Maternal Inclusion Criteria, Cohort 2 Only

- Infant eligible and enrolled in Cohort 2

- Note: Maternal receipt of ARVs during the current pregnancy and/or the
intrapartum period for the current pregnancy is permissible.

Infant Inclusion Criteria, Step 1, Evaluation and Initial Treatment of High-Risk Infants

- Less than or equal to 48 hours of age

- Greater than or equal to 36 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)

- Greater than or equal to 2 kg at birth

- Mother with presumed or confirmed HIV infection per criteria above.

- Mother did not receive ARVs during the current pregnancy per criteria above.

- Able to take ARVs by mouth, nasogastric tube, or gastrostomy tube

Infant Inclusion Criteria, Step 2, Management of Infants with Confirmed in utero HIV
Infection

- Able to take ARVs by mouth, nasogastric tube, or gastrostomy tube.

- Cohort 1 Only

- Must have been enrolled in Step 1

- Confirmed in utero HIV infection (see study protocol for more information)

- Cohort 2 Only

- Less than or equal to 10 days of age

- Greater than or equal to 36 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)

- Greater than or equal to 2 kg at birth

- Mother with presumed or confirmed HIV infection per criteria above

- At least one NAT positive for HIV infection on a sample drawn within 48 hours of
birth

- Received first dose of ART within 48 hours of birth on a regimen including 2
NRTIs and at least one other agent (e.g., NVP, RAL, LPV/r)

- Dosing of each agent in the regimen should be based on current dosing
guidelines (WHO or individual country or local standard guidelines)

- NVP dosing must be at least equivalent to current country or local standard
dosing guidelines for prophylaxis

- The FDA recommends avoiding LPV/r in infants less than 14 days of age or
less than 42 weeks postmenstrual age

- ART regimen (described in criteria above) was taken daily from date of initiation
until study entry

- Other than the exception in the next bullet point for NVP, each agent in the
regimen must be taken daily from the date of initiation

- NVP should ideally be taken daily from the date of initiation and must be
taken on at least two of the first five days of life (i.e., it is acceptable
for NVP to not be taken on up to three of the first five days of life)

Infant Inclusion Criteria, Step 3, Treatment Cessation

- Note: The criteria in this section may be modified in response to expert panel review.

- Must have been enrolled in Step 2.

- Must have reached Step 2 Week 96.

- Must have the following based on testing at the local CLIA-certified (US sites) or
VQA-certified (non-US sites) laboratory:

- No confirmed plasma HIV RNA greater than or equal to 200 copies/mL at Step 2 Week
24 and up to but excluding Step 2 Week 48 (see the study protocol for procedural
guidance related to this criterion) AND

- No plasma HIV RNA detected at Step 2 Week 48 and thereafter

- Note: Sample dilution for HIV RNA assays should not occur at or after Step 2
Week 24. In the event that an adequate sample volume cannot be collected at
a given study visit, the infant should return to the clinic on a different
day within the allowable visit window for a repeat specimen collection
attempt. If the repeat attempt is unsuccessful, or if for any reason sample
dilution is unavoidable, the infant may be considered for entry into Step 3
as long as dilution occurs only once at or after Step 2 Week 24 and the HIV
RNA assays immediately preceding and immediately following the diluted assay
are not performed with a diluted sample and provide results that otherwise
meet criteria for entry into Step 3.

- 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
criterion below.

- Must have met ALL of the following additional criteria while in Step 2, obtained at
greater than or equal to Step 2 Week 84 and less than or equal to Step 2 Week 192:

- Two consecutive negative HIV antibody tests by fourth generation enzyme-linked
immunosorbent assay (ELISA) (performed in the study's designated central
laboratory) at least 8 weeks apart

- Two consecutive HIV DNA tests with no DNA detected in at least 850,000 PBMCs
assayed (performed in the study's designated central laboratory) at least 8 weeks
apart

- Note: One million PBMCs should ideally be assayed; to accommodate variable
specimen volumes and cell counts, however, a minimum of 850,000 PBMCs
assayed is acceptable.

- No plasma HIV RNA detected at the time of the second consecutive negative HIV DNA
test (based on testing performed in the study's designated VQA-certified central
laboratory)

- 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 (i.e., 1000 cells/mL
if 2-3 years of age, greater than or equal to 750 cells/mL if 3-4 years of age)

- Infant assessed by the site investigator or designee as expected to comply with
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

- No plasma HIV RNA detected by testing performed at the local CLIA-certified (US sites)
or VQA-certified (non-US sites) laboratory, after criteria above have been confirmed,
with specimen collection for the assay within 14 days prior to Step 3 Entry.

Infant Inclusion Criteria, Step 4, Treatment Re-Initiation

- Must have been enrolled in Step 3.

- Plasma HIV RNA greater than or equal to LOD based on by standard quantitative testing
performed at the local CLIA-certified (US sites) or VQA-certified (non-US sites)
laboratory after ART cessation (see the study protocol for procedural guidance related
to this criterion).

- Note: Regardless of HIV RNA test results, any child enrolled in Step 3 may
re-initiate ART at the request of his or her parent or guardian; any such child
is eligible for inclusion in Step 4.

Infant Exclusion Criteria, Step 1 and Step 2

- Any 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 investigator's opinion, would interfere with study participation or
interpretation.