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

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Recruiting

CT.gov ID

NCT02140255

Collaborator

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)

905

Enrollment

Locations

Arms

203.2

Duration (Months)

19.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The study will 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.

Condition or Disease	Intervention/Treatment	Phase
HIV Infection	Drug: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Drug: Nevirapine (NVP) Drug: Lopinavir/Ritonavir (LPV/r) Drug: Raltegravir (RAL) Drug: VRC01	Phase 1/Phase 2

Detailed Description

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 288 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 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.

HIV-uninfected infants will be followed for 12 weeks. HIV-infected infants will be followed for up to 288 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

905 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jan 23, 2015

Anticipated Primary Completion Date :

Jan 31, 2028

Anticipated Study Completion Date :

Dec 31, 2031

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1, Regimen 1L: 2 NRTIs + NVP + LPV/r Participants will receive 2 NRTIs + NVP + LPV/r.	Drug: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Chosen by the site investigator and dosed according to World Health Organization (WHO) or individual country or local standard guidelines. Drug: Nevirapine (NVP) Administered orally. Dosed according to study step/participant's age/participant's weight. Drug: Lopinavir/Ritonavir (LPV/r) Administered orally. Dosed according to study step and participant's age.
Experimental: Cohort 2, Regimen 1L: 2 NRTIs + NVP + LPV/r Participants will receive 2 NRTIs + NVP + LPV/r.	Drug: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Chosen by the site investigator and dosed according to World Health Organization (WHO) or individual country or local standard guidelines. Drug: Nevirapine (NVP) Administered orally. Dosed according to study step/participant's age/participant's weight. Drug: Lopinavir/Ritonavir (LPV/r) Administered orally. Dosed according to study step and participant's age.
Experimental: Cohort 1, Regimen 2R: 2 NRTIs + NVP + RAL Participants will receive 2 NRTIs + NVP + RAL.	Drug: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Chosen by the site investigator and dosed according to World Health Organization (WHO) or individual country or local standard guidelines. Drug: Nevirapine (NVP) Administered orally. Dosed according to study step/participant's age/participant's weight. Drug: Raltegravir (RAL) Administered orally. Dosed according to study step and participant's age.
Experimental: Cohort 2, Regimen 2R: 2 NRTIs + NVP + RAL Participants will receive 2 NRTIs + NVP + RAL.	Drug: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Chosen by the site investigator and dosed according to World Health Organization (WHO) or individual country or local standard guidelines. Drug: Nevirapine (NVP) Administered orally. Dosed according to study step/participant's age/participant's weight. Drug: Raltegravir (RAL) Administered orally. Dosed according to study step and participant's age.
Experimental: Cohort 1, Regimen 2RV: 2 NRTIs + NVP + RAL + VRC01 Participants will receive 2 NRTIs + NVP + RAL + VRC01.	Drug: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Chosen by the site investigator and dosed according to World Health Organization (WHO) or individual country or local standard guidelines. Drug: Nevirapine (NVP) Administered orally. Dosed according to study step/participant's age/participant's weight. Drug: Raltegravir (RAL) Administered orally. Dosed according to study step and participant's age. Drug: VRC01 40 mg/kg administered subcutaneously

Outcome Measures

Primary Outcome Measures

Number of participants who achieve HIV remission [Measured through Week 48]
Defined as no confirmed HIV RNA greater than or equal to the limit of detection (LOD) through 48 weeks of ART cessation

Secondary Outcome Measures

Frequency of Grade 3 or higher adverse events possibly, probably or definitely related to any component of the study regimen [Measured through Week 288]
Graded according to the DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017
Number of participants with viral suppression to consistent HIV-1 RNA less than LOD [Measured through Week 24]
Based on laboratory evaluations
Number of participants meeting all eligibility criteria for ART cessation [Measured through Week 288]
As defined in criteria described in study protocol
Number of infants meeting the selected eligibility criteria for ART cessation among infants who also met the viral suppression criteria for ART cessation . [Measured through Week 288]
As defined in criteria described in the study protocol
Number of participants who experience HIV persistence [Measured through Week 48]
As measured by plasma viremia (single copy), droplet digital DNA, replication competent HIV reservoirs
Changes in immune activation markers (%CD8+/DR+ T cells) and HIV-specific immune responses [Measured through Week 48]
As measured by HIV-specific antibodies and HIV-specific T cell responses
Change in RAL and VRC01 concentrations among treated neonates and young infants [Measured through Week 48]
Based on laboratory evaluations

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 10 Days

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 288:
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.
Must have met at least one of the following:
Plasma HIV RNA greater than or equal to LOD based on 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).
Confirmed CD4 cell percentage less than 25% or CD4 cell absolute count less than the lower limit of normal for age
Confirmed or suspected diagnosis of a new WHO Clinical Stage 3 or 4 condition
Confirmed or suspected diagnosis of acute retroviral syndrome
Otherwise assessed by the site investigator or designee, in consultation with the Clinical Management Committee (CMC), as having an indication to re-initiate treatment
Note: Regardless of any of the above, 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, UC San Diego CRS- Mother-Child-Adolescent HIV Program	La Jolla	California	United States	92093-0672
2	Usc La Nichd Crs	Los Angeles	California	United States	90089
3	David Geffen School of Medicine at UCLA NICHD CRS	Los Angeles	California	United States	90095-1752
4	Univ. of Colorado Denver NICHD CRS	Aurora	Colorado	United States	80045
5	South Florida CDTC Ft Lauderdale NICHD CRS	Fort Lauderdale	Florida	United States	33316
6	Univ. of Florida Jacksonville NICHD CRS	Jacksonville	Florida	United States	32209
7	Pediatric Perinatal HIV Clinical Trials Unit CRS	Miami	Florida	United States	33136
8	Emory University School of Medicine NICHD CRS	Atlanta	Georgia	United States	30322
9	Rush Univ. Cook County Hosp. Chicago NICHD CRS	Chicago	Illinois	United States	60612
10	Lurie Children's Hospital of Chicago (LCH) CRS	Chicago	Illinois	United States	60614-3393
11	Johns Hopkins Univ. Baltimore NICHD CRS	Baltimore	Maryland	United States	21287
12	Boston Medical Center Ped. HIV Program NICHD CRS	Boston	Massachusetts	United States	02118
13	Bronx-Lebanon Hospital Center NICHD CRS	Bronx	New York	United States	10457
14	Jacobi Med. Ctr. Bronx NICHD CRS	Bronx	New York	United States	10461
15	SUNY Stony Brook NICHD CRS	Stony Brook	New York	United States	11794
16	Philadelphia IMPAACT Unit CRS	Philadelphia	Pennsylvania	United States	9104
17	St. Jude Children's Research Hospital CRS	Memphis	Tennessee	United States	38105-3678
18	Texas Children's Hospital CRS	Houston	Texas	United States	77030-2399
19	Seattle Children's Research Institute CRS	Seattle	Washington	United States	98101
20	Univ. of Washington NICHD CRS	Seattle	Washington	United States	98195
21	Hosp. General de Agudos Buenos Aires Argentina NICHD CRS	Buenos Aires		Argentina	C1221ADC
22	Hospital Nossa Senhora da Conceicao NICHD CRS	Porto Alegre	Rio Greande Do Sul	Brazil	91350-200
23	SOM Federal University Minas Gerais Brazil NICHD CRS	Minas Gerais		Brazil	30.130-100
24	Hospital Federal dos Servidores do Estado NICHD CRS	Rio De Janeiro		Brazil	20221-903
25	Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS	Rio De Janeiro		Brazil	21941-612
26	Hosp. Geral De Nova Igaucu Brazil NICHD CRS	Rio De Janeiro		Brazil	26030
27	Univ. of Sao Paulo Brazil NICHD CRS	São Paulo		Brazil	14049-900
28	Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS	Port-au-Prince		Haiti	HT-6110
29	Kenya Medical Research Institute / Walter Reed Project Clinical Research Center, Kericho CRS	Kericho		Kenya	20200
30	Malawi CRS	Lilongwe	Central	Malawi
31	Blantyre CRS	Blantyre		Malawi
32	University of Puerto Rico Pediatric HIV/AIDS Research Program CRS	San Juan		Puerto Rico	00935
33	San Juan City Hosp. PR NICHD CRS	San Juan		Puerto Rico	00936
34	Soweto IMPAACT CRS	Johannesburg	Gauteng	South Africa	1862
35	Wits RHI Shandukani Research Centre CRS	Johannesburg	Gauteng	South Africa	2001
36	Umlazi CRS	Durban	Kwa Zulu Natal	South Africa	4001
37	Famcru Crs	Tygerberg	Western Cape Province	South Africa	7505
38	Kilimanjaro Christian Medical Centre (KCMC)	Moshi		Tanzania
39	Siriraj Hospital ,Mahidol University NICHD CRS	Bankok	Bangkoknoi	Thailand	10700
40	Chiangrai Prachanukroh Hospital NICHD CRS	Chiang Mai		Thailand	50100
41	Baylor-Uganda CRS	Kampala		Uganda
42	MU-JHU Care Limited CRS	Kampala		Uganda
43	MU-JHU Research Collaboration (MUJHU CARE LTD) CRS	Kampala		Uganda
44	George CRS	Lusaka		Zambia	10101
45	Seke North CRS	Chitungwiza		Zimbabwe
46	St Mary's CRS	Chitungwiza		Zimbabwe
47	Harare Family Care CRS	Harare		Zimbabwe

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

Study Chair: Yvonne Bryson, MD, University of California, Los Angeles
Study Chair: Ellen Chadwick, MD, Northwestern University Feinberg School of Medicine and Ann & Robert Lurie Children's Hospital of Chicago