HIV -1 Infection
Conditions
Keywords
HIV, broadly neutralizing antibody, ePGT121v1-LS, viral load, safety, infant, children, VRC07-523-LS
Brief summary
The goal of this clinical trial is to learn if subcutaneous ePGT121v1-LS and VRC07-523-LS added to standard antiretroviral therapy (ART) is safe and helps improve HIV viral suppression in infants living with HIV in Mozambique and Cameroon. The study will also learn how the body processes ePGT121v1-LS and VRC07-523-LS and whether caregivers and health workers find this treatment approach acceptable. The main questions it aims to answer are: * Are ePGT121v1-LS and and VRC07-523-LS safe and well tolerated in infants living with HIV? * Does adding ePGT121v1-LS and VRC07-523-LS to standard ART increase the number of infants who achieve HIV viral suppression by week 48? * How long does it take participants receiving ePGT121v1-LS and VRC07-523-LS to achieve viral suppression compared with standard treatment alone? * How does ePGT121v1-LS and VRC07-523-LS behave in the body after repeated subcutaneous injections? Researchers will compare infants receiving ePGT121v1-LS and VRC07-523-LS plus ART to infants receiving standard ART plus placebo (saline) to see if ePGT121v1-LS improves HIV viral suppression. Participants will: * Continue taking standard oral ART. * Receive 4 subcutaneous injections of ePGT121v1-LS and VRC07-523-LS or placebo every 12 weeks. * Attend regular clinic visits for safety checks, blood tests, and HIV viral load monitoring. * Have follow-up visits for 48 weeks. * Participate in evaluations of treatment adherence and acceptability from the perspective of caregivers and health workers.
Detailed description
This Phase 1/2 clinical trial is designed to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of subcutaneous (SC) ePGT121v1-LS and VRC07-523-LS administered as adjunctive therapy to standard antiretroviral therapy (ART) in infants living with HIV (ILHIV) in South Africa. Although early ART initiation has significantly improved survival among infants with HIV, achieving sustained virological suppression during infancy remains challenging because of factors including limited pediatric formulations, adherence difficulties, high baseline viral loads, and treatment interruptions. Novel long-acting therapeutic strategies that simplify treatment delivery and enhance antiviral activity may improve outcomes in this vulnerable population. Broadly neutralizing antibodies (bNAbs) have shown antiviral activity in adults and children living with HIV and may provide additional benefits through prolonged antiviral coverage and immunomodulatory effects. ePGT121v1-LS is a long-acting bNAb directed against the V3 glycan supersite of the HIV-1 envelope and VRC07-523-LS is a bNAb against the CD4 binding site. The LS mutation extends antibody half-life and supports infrequent dosing schedules using SC administration. This study includes an initial safety lead-in phase followed by a randomized placebo-controlled phase evaluating ePGT121v1-LS and VRC07-523-LS in combination with standard ART. The trial will assess the safety profile and tolerability of repeated SC administrations and will characterize pharmacokinetic parameters following serial dosing in infants. In addition, the study will evaluate the antiviral effect of ePGT121v1-LS and VRC07-523-LS intensification therapy on HIV viral suppression during the first 48 weeks of follow-up. Exploratory analyses will further assess virological, immunological, and reservoir-related outcomes, including HIV-1 DNA dynamics, anti-drug antibodies, biomarkers and immune responses associated with bNAb exposure. Qualitative assessments will also evaluate the acceptability and feasibility of SC bNAb administration from the perspective of caregivers, healthcare workers, and stakeholders. The results of this study are intended to inform the development of future pediatric trials evaluating long-acting bNAb-based therapeutic strategies for infants living with HIV.
Interventions
Administration of subcutaneous ePGT121v1LS, 4 doses, separate 12 weeks away.
DRUGSaline (0.9% NaCl)
Administration of subcutaneous saline, 4 doses, separate 12 weeks away.
DRUGBroadly neutralizing antibody (bNAb) VRC07-523-LS
Administration of subcutaneous ePGT121v1LS, 4 doses, separate 12 weeks away.
Sponsors
Hospital Universitario 12 de Octubre
Africa Health Research Institute
PENTA Foundation
International AIDS Vaccine Initiative
University of Witwatersrand, South Africa
Radboud University Medical Center
Servicio Madrileño de Salud (SERMAS)
Eduardo Mondlane University
Fundaçao Ariel Glaser contra o SIDA Pediatrico
Centro de Investigação em Saúde de Manhiça
University of Rome Tor Vergata
Centre Pasteur du Cameroun
Barcelona Institute for Global Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Step 1 (safety lead-in): Non-randomized single arm with ePGT121v1-LS and VRC07-523-LS on top of antiretroviral therapy (ART). Step 2 (safety and efficacy): Double blind, randomized, parallel group with ePGT121v1-LS and VRC07-523-LS on top of ART compared to oral ART and placebo (saline).
Eligibility
Sex/Gender
ALL
Age
1 Days to 1 Years
Healthy volunteers
No
Inclusion criteria
* Infants from 1 to 365 days old at the time of enrolment. * Living with HIV-1, diagnosed with an approved assay detecting HIV nucleic acids in blood. * Weight \> 2.5 kg at enrolment. * ART-naïve or ≤ 30 days of triple ART at screening (not including prophylaxis in HIV-exposed). * Clinically stable and can be managed as outpatient (participants identified in-hospital can start the trial at their first routine visit). * Parent or legal guardian able to provide Informed consent (IC).
Exclusion criteria
* Participation in other concurrent research studies that, in the opinion of the principal investigator and central team, would interfere with the objectives of this study. * Previous receipt of bNAbs against HIV. * Serious Adverse Reactions (SARs) to the investigational medicinal product (IMP) or its components. * Intravenous (IV) immunoglobulins received within 90 days before IMP administration. * Any clinically significant acute or chronic illness or condition at screening that, in the opinion of the principal investigator/designee, renders the participant unfit to participate in the study or jeopardizes the safety or rights of the participant. Including, but not restricted to: * Evidence of active tuberculosis (TB) disease at the time of enrolment. * Life-threatening condition associated with a high risk of death within 30 days of enrolment, as determined by the study clinician. * Severe acute malnutrition with complications. * Severe neurological illness. * Hemodynamically significant severe congenital heart disease. * Active malignancies. * Life-threatening bleeding disorder. * Use of systemic immunosuppressive drugs within 30 days before first IMP administration. Not exclusionary: nasal steroid spray, inhaled steroids, topical steroids, a single course of oral/parenteral prednisone or equivalent at 2 mg/kg/day, and length of therapy \<14 days. * Unwillingness to have blood drawn * Unable to receive SC medications. * Chronic or recurrent urticaria or any other chronic dermatological condition that may be confused with local Adverse Reactions (ARs). Any social or medical condition in the caregivers that, in the judgement of the investigator, would interfere with protocol adherence, completion of the trial or assessment of safety.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety (Serious adverse events) | 48 weeks | Proportion of participants experiencing SAEs throughout the whole trial. |
| Virological suppression | 48 weeks | * Proportion of infants achieving virological suppression (plasma HIV-1 RNA \< 40 copies/mL) at week 48, as well as over the 48 week follow-up period. * Time to first virological suppression, defined as the time from randomization to the first post-baseline measurement of plasma HIV-1 RNA \< 40 copies/mL. |
| Time to virological suppression | 48 weeks | • Time to first virological suppression, defined as the time from randomization to the first post-baseline measurement of plasma HIV-1 RNA \< 40 copies/mL. |
| Tolerability of the treatment (participants who discontinue) | 48 weeks | • Proportion of participants who discontinue due to toxicity or tolerability issues. |
| Tolerability of the injection | 1 hour | • Median score of pain assessment scale after administration of bNAb (FLACC scale). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK profile of ePGT121v1-LS and of VRC07-523-LS | 12 weeks | Half-life |
| Time to sustained virological suppression | 48 weeks | Time from randomization to the first scheduled post-baseline visit at which HIV-1 RNA is \< 40 copies/mL, provided that all subsequent scheduled HIV-1 RNA measurements through week 48 also remain \< 40 copies/mL. |
| Longitudinal virological response | 48 weeks | Proportion of participants with HIV-1 RNA \< 40 copies/mL at weeks 12, 24, 36, and 48 will be recorded as the endpoint and log change in plasma HIV-1 RNA levels relative to baseline and subsequent pre-dose measurements. |
| Acceptability | 48 weeks | The acceptability will be assessed through a series of qualitative interviews and limited quantitative assessments. |
| Adverse events | 48 weeks | Number of and proportion of participants with solicited adverse event (AEs) and laboratory-related AEs. |
Contacts
CONTACTAlfredo Tagarro, PhD
Outcome results
None listed