Early Neutralizing Antibodies in Infants Living With HIV to Enhance Their Life (2)

A Phase 1/2 Trial Evaluating the Safety, Pharmacokinetics, and Antiviral Activity of Subcutaneous ePGT121v1-LS in Combination With VRC07-523LS, Added to Standard Antiretroviral Therapy in Infants Living With HIV

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.

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.

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.