HIV Infection Clinical Trial
Official title:
Very Early Intensive Treatment of HIV-Infected Infants to Achieve HIV Remission: A Phase I/II Proof of Concept Study
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.
Status | Recruiting |
Enrollment | 905 |
Est. completion date | December 31, 2031 |
Est. primary completion date | January 31, 2028 |
Accepts healthy volunteers | No |
Gender | All |
Age group | N/A to 10 Days |
Eligibility | 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. |
Country | Name | City | State |
---|---|---|---|
Argentina | Hosp. General de Agudos Buenos Aires Argentina NICHD CRS | Buenos Aires | |
Brazil | SOM Federal University Minas Gerais Brazil NICHD CRS | Minas Gerais | |
Brazil | Hospital Nossa Senhora da Conceicao NICHD CRS | Porto Alegre | Rio Greande Do Sul |
Brazil | Hosp. Geral De Nova Igaucu Brazil NICHD CRS | Rio De Janeiro | |
Brazil | Hospital Federal dos Servidores do Estado NICHD CRS | Rio De Janeiro | |
Brazil | Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS | Rio De Janeiro | |
Brazil | Univ. of Sao Paulo Brazil NICHD CRS | São Paulo | |
Haiti | Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS | Port-au-Prince | |
Kenya | Kenya Medical Research Institute / Walter Reed Project Clinical Research Center, Kericho CRS | Kericho | |
Malawi | Blantyre CRS | Blantyre | |
Malawi | Malawi CRS | Lilongwe | Central |
Puerto Rico | IMPAACT/ Gamma Project/ UPR Pediatric HIV/AIDS Research CRS | 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 | Umlazi CRS | Durban | Kwa Zulu Natal |
South Africa | Soweto IMPAACT CRS | Johannesburg | Gauteng |
South Africa | Wits RHI Shandukani Research Centre CRS | Johannesburg | Gauteng |
South Africa | Famcru Crs | Tygerberg | Western Cape Province |
Tanzania | Kilimanjaro Christian Medical Centre (KCMC) | Moshi | |
Thailand | Siriraj Hospital ,Mahidol University NICHD CRS | Bankok | Bangkoknoi |
Thailand | Chiangrai Prachanukroh Hospital NICHD CRS | Chiang Mai | |
Uganda | Baylor-Uganda CRS | 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 | Univ. of Colorado Denver NICHD CRS | Aurora | Colorado |
United States | Johns Hopkins Univ. Baltimore NICHD CRS | Baltimore | Maryland |
United States | Boston Medical Center Ped. HIV Program NICHD CRS | Boston | Massachusetts |
United States | Bronx-Lebanon Hospital Center NICHD CRS | Bronx | New York |
United States | Jacobi Med. Ctr. Bronx NICHD CRS | Bronx | New York |
United States | Lurie Children's Hospital of Chicago (LCH) CRS | Chicago | Illinois |
United States | Rush Univ. Cook County Hosp. Chicago NICHD CRS | Chicago | Illinois |
United States | South Florida CDTC Ft Lauderdale NICHD CRS | Fort Lauderdale | Florida |
United States | Baylor College of Medicine/ Texas Children's Hospital NICHD CRS | Houston | Texas |
United States | Texas Children's Hospital CRS | Houston | Texas |
United States | Univ. of Florida Jacksonville NICHD CRS | Jacksonville | Florida |
United States | University of California, UC San Diego CRS- Mother-Child-Adolescent HIV Program | La Jolla | California |
United States | David Geffen School of Medicine at UCLA NICHD CRS | Los Angeles | California |
United States | Usc La Nichd Crs | Los Angeles | California |
United States | St. Jude Children's Research Hospital CRS | Memphis | Tennessee |
United States | Pediatric Perinatal HIV Clinical Trials Unit CRS | 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 | SUNY Stony Brook NICHD CRS | Stony Brook | New York |
Zambia | George CRS | Lusaka | |
Zimbabwe | Seke North CRS | Chitungwiza | |
Zimbabwe | St Mary's CRS | Chitungwiza | |
Zimbabwe | Harare Family Care CRS | Harare |
Lead Sponsor | Collaborator |
---|---|
National Institute of Allergy and Infectious Diseases (NIAID) | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) |
United States, Zambia, Zimbabwe, Argentina, Brazil, Haiti, Kenya, Malawi, Puerto Rico, South Africa, Tanzania, Thailand, Uganda,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
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 ART cessation | 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 288 | |
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 ART cessation | As defined in criteria described in study protocol | Measured through Week 288 | |
Secondary | Number of infants meeting the selected eligibility criteria for ART cessation among infants who also met the viral suppression criteria for ART cessation . | As defined in criteria described in the study protocol | Measured through Week 288 | |
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 | |
Secondary | Changes in immune activation markers (%CD8+/DR+ T cells) and HIV-specific immune responses | As measured by HIV-specific antibodies and HIV-specific T cell responses | Measured through Week 48 | |
Secondary | Change in RAL and VRC01 concentrations among treated neonates and young infants | Based on laboratory evaluations | Measured through Week 48 |
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