Clinical trial NCT02140255: Very Early Intensive Treatment of Infants Living With HIV to Achieve HIV Remission
Official title: Very Early Intensive Treatment of Infants Living With HIV to Achieve HIV Remission: A Phase I/II Proof of Concept Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: HIV Infection
Keywords: HIV Remission
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Institute of Mental Health (NIMH)
First posted: 2014-05-16
Enrollment: 1120
Sex: ALL
Maximum age (years): 48
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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.

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 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of participants who achieve HIV remission
timeFrame: Measured through Week 48
Secondary outcomes:
measure: Frequency of Grade 3 or higher adverse events possibly, probably or definitely related to any component of the study regimen
timeFrame: Measured through Week 192
measure: Number of participants with viral suppression to consistent HIV-1 RNA less than LOD
timeFrame: Measured through Week 24
measure: Number of participants meeting all eligibility criteria for treatment interruption
timeFrame: Measured through Week 192
measure: Number of infants meeting the selected eligibility criteria for treatment interruption among infants who also met the viral suppression criteria for treatment interruption.
timeFrame: Measured through Week 192
measure: Number of participants who experience HIV persistence
timeFrame: Measured through Week 48
Other outcomes:
measure: Change in HIV-specific immune response
timeFrame: Measured through Week 48
measure: Change in immune activation markers (%CD8+/DR+ T cells) response
timeFrame: Measured through Week 48
measure: Change in DTG concentration among treated neonates and young infants
timeFrame: Measured through Week 24
measure: Change in VRC07-523LS concentration among treated neonates and young infants
timeFrame: Measured through Week 24
measure: Presence of ARV genotypic resistance to drugs taken
timeFrame: Measured through Week 48
measure: Presence of bNAb resistance as measured by inhibitory concentration
timeFrame: Measured through Week 48
Locations:
city: La Jolla
country: United States
facility: 4601, University of California, San Diego Clinical Research Site
state: California
city: Los Angeles
country: United States
facility: 5048, University of Southern California Clinical Research Site
state: California
city: Los Angeles
country: United States
facility: 5112, David Geffen School of Medicine at UCLA Clinical Research Site
state: California
city: Aurora
country: United States
facility: 5052, University of Colorado, Denver Clinical Research Site
state: Colorado
city: Fort Lauderdale
country: United States
facility: 5055, South Florida CDTC Fort Lauderdale Clinical Research Site
state: Florida
city: Jacksonville
country: United States
facility: 5051, University of Florida Center for HIV/AIDS Research, Education and Service (UF CARES) Clinical Research Site
state: Florida
city: Miami
country: United States
facility: 5127, Pediatric Perinatal HIV Clinical Research Site
state: Florida
city: Miami
country: United States
facility: University of Miami CRS
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine NICHD CRS
state: Georgia
city: Chicago
country: United States
facility: 5083, Rush University Cook County Hospital Clinical Research Site
state: Illinois
city: Chicago
country: United States
facility: 4001, Lurie Children's Hospital of Chicago Clinical Research Site
state: Illinois
city: Baltimore
country: United States
facility: 5092, Johns Hopkins Clinical Research Site
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center Ped. HIV Program NICHD CRS
state: Massachusetts
city: Bronx
country: United States
facility: 5114, Bronx Lebanon Hospital Center Clinical Research Site
state: New York
city: Bronx
country: United States
facility: 5013, Jacobi Medical Center Clinical Research Site
state: New York
city: Stony Brook
country: United States
facility: 5040, SUNY Stony Brook Clinical Research Site
state: New York
city: Philadelphia
country: United States
facility: Philadelphia IMPAACT Unit CRS
state: Pennsylvania
city: Memphis
country: United States
facility: 6501, St Jude Children's Research Hospital Clinical Research Site
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hospital CRS
state: Texas
city: Houston
country: United States
facility: 5128, Baylor College of Medicine/Texas Children's Hospital Clinical Research Site
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Research Institute CRS
state: Washington
city: Seattle
country: United States
facility: Univ. of Washington NICHD CRS
state: Washington
city: Buenos Aires
country: Argentina
facility: Hosp. General de Agudos Buenos Aires Argentina NICHD CRS
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora da Conceicao NICHD CRS
state: Rio Greande Do Sul
city: Minas Gerais
country: Brazil
facility: 5073, School of Medicine Federal University Minas Gerais Clinical Research Site
city: Rio De Janeiro
country: Brazil
facility: 5072, Hospital Federal dose Servidores do Estado Clinical Research Site
city: Rio De Janeiro
country: Brazil
facility: 5071, Instituto de Puericultura e Pediatria Martagao Gesteira Clinical Research Site
city: Rio De Janeiro
country: Brazil
facility: 5097, Hospital Geral de Nova Igaucu Clinical Research Site
city: São Paulo
country: Brazil
facility: 5074, University of Sao Paulo Clinical Research Site
city: Port-au-Prince
country: Haiti
facility: 30022, Les Centres GHESKIO Clinical Research Site
city: Kericho
country: Kenya
facility: 5121, Kenya Medical Research Institute/Walter Reed Project Clinical Research Center Kericho Clinical Research Site
city: Lilongwe
country: Malawi
facility: 12001, Malawi Clinical Research Site
state: Central
city: Blantyre
country: Malawi
facility: 30301, Blantyre Clinical Research Site
city: San Juan
country: Puerto Rico
facility: 5129, University of Puerto Rico Gamma Project Clinical Research Site
city: San Juan
country: Puerto Rico
facility: University of Puerto Rico Pediatric HIV/AIDS Research Program CRS
city: San Juan
country: Puerto Rico
facility: San Juan City Hosp. PR NICHD CRS
city: Johannesburg
country: South Africa
facility: Soweto IMPAACT CRS
state: Gauteng
city: Johannesburg
country: South Africa
facility: Wits RHI Shandukani Research Centre CRS
state: Gauteng
city: Durban
country: South Africa
facility: 30300, Umlazi Clinical Research Site
state: Kwa Zulu Natal
city: Tygerberg
country: South Africa
facility: 8950, FAMCRU Clinical Research Site
state: Western Cape
city: Moshi
country: Tanzania
facility: 5118, Kilimanjaro Christian Medical Centre Clinical Research Site
city: Bankok
country: Thailand
facility: 5115, Siriraj Hospital Mahidol University Clinical Research Site
state: Bangkoknoi
city: Chiang Mai
country: Thailand
facility: 5116, Chiangrai Prachanukroh Hospital Clinical Research Site
city: Kampala
country: Uganda
facility: 31798, Baylor-Uganda Clinical Research Site
city: Kampala
country: Uganda
facility: MU-JHU Care Limited CRS
city: Kampala
country: Uganda
facility: MU-JHU Research Collaboration (MUJHU CARE LTD) CRS
city: Lusaka
country: Zambia
facility: George CRS
city: Chitungwiza
country: Zimbabwe
facility: 30303, Saint Mary's Clinical Research Site
city: Chitungwiza
country: Zimbabwe
facility: 30306, Seke North Clinical Research Site
city: Harare
country: Zimbabwe
facility: 31890, Harare Family Care Clinical Research Site
Study officials:
affiliation: Northwestern University Feinberg School of Medicine and Ann & Robert Lurie Children's Hospital of Chicago
name: Ellen Chadwick, MD
role: STUDY_CHAIR
affiliation: Northwestern University Feinberg School of Medicine and Ann & Robert Lurie Children's Hospital of Chicago
name: Jennifer Jao, MD
role: STUDY_CHAIR
References:
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.
citation: 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.
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.