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

HIV Infection Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02140255
• Other study ID #: IMPAACT P1115
• Secondary ID: UM1AI068632UM1AI
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: January 23, 2015
• Est. completion date: December 31, 2031

Study information

• Verified date: June 2024
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: Anne Coletti, MS
• Phone: 919-627-6445
• Email: acoletti[@]fhi360.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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 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.

Five 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.

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 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1120
• Est. completion date: December 31, 2031
• Est. primary completion date: January 31, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 48 Hours

Eligibility

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 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).

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.

Related Conditions & MeSH terms

• HIV Infection
• HIV Infections

Intervention

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.
• Nevirapine (NVP)
Administered orally. Dosed according to study step/participant's age/participant's weight.
• Lopinavir/Ritonavir (LPV/r)
Administered orally. Dosed according to study step and participant's age.
• Raltegravir (RAL)
Administered orally. Dosed according to study step and participant's age.
• VRC01
40 mg/kg administered subcutaneously.
• DTG
Administered orally. Dosed according to participant's weight.
• VRC07-523LS
40 mg/kg administered subcutaneously.

Locations

Country	Name	City	State
Argentina	Hosp. General de Agudos Buenos Aires Argentina NICHD CRS	Buenos Aires
Brazil	5073, School of Medicine Federal University Minas Gerais Clinical Research Site	Minas Gerais
Brazil	Hospital Nossa Senhora da Conceicao NICHD CRS	Porto Alegre	Rio Greande Do Sul
Brazil	5071, Instituto de Puericultura e Pediatria Martagao Gesteira Clinical Research Site	Rio De Janeiro
Brazil	5072, Hospital Federal dose Servidores do Estado Clinical Research Site	Rio De Janeiro
Brazil	5097, Hospital Geral de Nova Igaucu Clinical Research Site	Rio De Janeiro
Brazil	5074, University of Sao Paulo Clinical Research Site	São Paulo
Haiti	30022, Les Centres GHESKIO Clinical Research Site	Port-au-Prince
Kenya	5121, Kenya Medical Research Institute/Walter Reed Project Clinical Research Center Kericho Clinical Research Site	Kericho
Malawi	30301, Blantyre Clinical Research Site	Blantyre
Malawi	12001, Malawi Clinical Research Site	Lilongwe	Central
Puerto Rico	5129, University of Puerto Rico Gamma Project Clinical Research Site	San Juan
Puerto Rico	San Juan City Hosp. PR NICHD CRS	San Juan
Puerto Rico	University of Puerto Rico Pediatric HIV/AIDS Research Program CRS	San Juan
South Africa	30300, Umlazi Clinical Research Site	Durban	Kwa Zulu Natal
South Africa	Soweto IMPAACT CRS	Johannesburg	Gauteng
South Africa	Wits RHI Shandukani Research Centre CRS	Johannesburg	Gauteng
South Africa	8950, FAMCRU Clinical Research Site	Tygerberg	Western Cape
Tanzania	5118, Kilimanjaro Christian Medical Centre Clinical Research Site	Moshi
Thailand	5115, Siriraj Hospital Mahidol University Clinical Research Site	Bankok	Bangkoknoi
Thailand	5116, Chiangrai Prachanukroh Hospital Clinical Research Site	Chiang Mai
Uganda	31798, Baylor-Uganda Clinical Research Site	Kampala
Uganda	MU-JHU Care Limited CRS	Kampala
Uganda	MU-JHU Research Collaboration (MUJHU CARE LTD) CRS	Kampala
United States	Emory University School of Medicine NICHD CRS	Atlanta	Georgia
United States	5052, University of Colorado, Denver Clinical Research Site	Aurora	Colorado
United States	5092, Johns Hopkins Clinical Research Site	Baltimore	Maryland
United States	Boston Medical Center Ped. HIV Program NICHD CRS	Boston	Massachusetts
United States	5013, Jacobi Medical Center Clinical Research Site	Bronx	New York
United States	5114, Bronx Lebanon Hospital Center Clinical Research Site	Bronx	New York
United States	4001, Lurie Children's Hospital of Chicago Clinical Research Site	Chicago	Illinois
United States	5083, Rush University Cook County Hospital Clinical Research Site	Chicago	Illinois
United States	5055, South Florida CDTC Fort Lauderdale Clinical Research Site	Fort Lauderdale	Florida
United States	5128, Baylor College of Medicine/Texas Children's Hospital Clinical Research Site	Houston	Texas
United States	Texas Children's Hospital CRS	Houston	Texas
United States	5051, University of Florida Center for HIV/AIDS Research, Education and Service (UF CARES) Clinical Research Site	Jacksonville	Florida
United States	4601, University of California, San Diego Clinical Research Site	La Jolla	California
United States	5048, University of Southern California Clinical Research Site	Los Angeles	California
United States	5112, David Geffen School of Medicine at UCLA Clinical Research Site	Los Angeles	California
United States	6501, St Jude Children's Research Hospital Clinical Research Site	Memphis	Tennessee
United States	5127, Pediatric Perinatal HIV Clinical Research Site	Miami	Florida
United States	University of Miami CRS	Miami	Florida
United States	Philadelphia IMPAACT Unit CRS	Philadelphia	Pennsylvania
United States	Seattle Children's Research Institute CRS	Seattle	Washington
United States	Univ. of Washington NICHD CRS	Seattle	Washington
United States	5040, SUNY Stony Brook Clinical Research Site	Stony Brook	New York
Zambia	George CRS	Lusaka
Zimbabwe	30303, Saint Mary's Clinical Research Site	Chitungwiza
Zimbabwe	30306, Seke North Clinical Research Site	Chitungwiza
Zimbabwe	31890, Harare Family Care Clinical Research Site	Harare

Sponsors (3)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Mental Health (NIMH)

Countries where clinical trial is conducted

United States,  Zambia,  Zimbabwe,  Argentina,  Brazil,  Haiti,  Kenya,  Malawi,  Puerto Rico,  South Africa,  Tanzania,  Thailand,  Uganda, 

References & Publications (3)

Nelson BS, Tierney C, Persaud D, Jao J, Cotton MF, Bryson Y, Coletti A, Ruel TD, Spector SA, Reding C, Bacon K, Costello D, Perlowski C, Santos Cruz ML, Kosgei J, Majji S, Yin DE, Jean-Philippe P, Chadwick EG; IMPAACT P1115 Team. Infants Receiving Very Early Antiretroviral Therapy Have High CD4 Counts in the First Year of Life. Clin Infect Dis. 2023 Feb 8;76(3):e744-e747. doi: 10.1093/cid/ciac695. — View Citation

Persaud D, Bryson Y, Nelson BS, Tierney C, Cotton MF, Coletti A, Jao J, Spector SA, Mirochnick M, Capparelli EV, Costello D, Szewczyk J, Nicodimus N, Stranix-Chibanda L, Kekitiinwa AR, Korutaro V, Reding C, Carrington MN, Majji S, Yin DE, Jean-Philippe P, Chadwick EG. HIV-1 reservoir size after neonatal antiretroviral therapy and the potential to evaluate antiretroviral-therapy-free remission (IMPAACT P1115): a phase 1/2 proof-of-concept study. Lancet HIV. 2024 Jan;11(1):e20-e30. doi: 10.1016/S2352-3018(23)00236-9. Epub 2023 Dec 4. — View Citation

Ruel TD, Capparelli EV, Tierney C, Nelson BS, Coletti A, Bryson Y, Cotton MF, Spector SA, Mirochnick M, LeBlanc R, Reding C, Zimmer B, Persaud D, Bwakura-Dangarembizi M, Naidoo KL, Hazra R, Jean-Philippe P, Chadwick EG. Pharmacokinetics and safety of early nevirapine-based antiretroviral therapy for neonates at high risk for perinatal HIV infection: a phase 1/2 proof of concept study. Lancet HIV. 2021 Mar;8(3):e149-e157. doi: 10.1016/S2352-3018(20)30274-5. Epub 2020 Nov 23. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in HIV-specific immune response	As measured by %CD8+/DR+ T cells	Measured through Week 48
Other	Change in immune activation markers (%CD8+/DR+ T cells) response	As measured by HIV-specific antibodies and HIV-specific T cell responses	Measured through Week 48
Other	Change in DTG concentration among treated neonates and young infants	Based on laboratory evaluations	Measured through Week 24
Other	Change in VRC07-523LS concentration among treated neonates and young infants	Based on laboratory evaluations	Measured through Week 24
Other	Presence of ARV genotypic resistance to drugs taken		Measured through Week 48
Other	Presence of bNAb resistance as measured by inhibitory concentration		Measured through Week 48
Primary	Number of participants who achieve HIV remission	Defined as no confirmed HIV RNA greater than or equal to the limit of detection (LOD) through 48 weeks of treatment interruption	Measured through Week 48
Secondary	Frequency of Grade 3 or higher adverse events possibly, probably or definitely related to any component of the study regimen	Graded according to the DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017	Measured through Week 192
Secondary	Number of participants with viral suppression to consistent HIV-1 RNA less than LOD	Based on laboratory evaluations	Measured through Week 24
Secondary	Number of participants meeting all eligibility criteria for treatment interruption	As defined in criteria described in study protocol	Measured through Week 192
Secondary	Number of infants meeting the selected eligibility criteria for treatment interruption among infants who also met the viral suppression criteria for treatment interruption.	As defined in criteria described in the study protocol	Measured through Week 192
Secondary	Number of participants who experience HIV persistence	As measured by plasma viremia (single copy), droplet digital DNA, replication competent HIV reservoirs	Measured through Week 48

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