Introducción
Two monoclonal antibodies appeared safe and tolerable when administered alone or in combination to newborns exposed to HIV, according to a proof-of-concept study presented at the International AIDS Society Conference on HIV Science in Kigali, Rwanda.
Over 28 days of safety observation, infants who received either or both antibodies CAP256V2LS or VRC07-523LS experienced only grade 1-2 adverse events (AEs), except for five grade 3 AEs and two grade 4 AEs that resolved on their own, reported Gabriella Scarlatti, MD, PhD, of I.R.C.C.S. Ospedale San Raffaele in Milan. The four serious AEs that occurred were unrelated to the drug and resolved.
Importancia del estudio
Joseph McGowan, MD, of Northwell Health in Manhasset, New York, told MedPage Today that the strategy of using broadly neutralizing monoclonal antibodies (bNAbs) in newborns has precedent in, for example, the prevention of respiratory syncytial virus (RSV).
“This study is important preliminary work to develop an HIV prevention strategy that can be widely implemented globally in areas of high HIV incidence,” said McGowan, who was not involved in the research. “Having a passive means of PEP [pre-exposure prophylaxis] to allow a mother living with HIV to breastfeed can improve the health and safety of the newborn.”
The public health community has known since 1994 how to prevent vertical transmission of HIV, yet 120,000 children acquired HIV via vertical transmission in 2024, Scarlatti said.
“We know that more or less 50% of these transmission events occur through breast milk,” she stated. “That’s where we have to prevent them.” Transmission occurs because mothers are on antiretroviral therapy (ART) but not adequately suppressed; are not on ART; have their ART interrupted; or acquire HIV themselves during pregnancy or the breastfeeding period, Scarlatti said.
Procedimiento del ensayo
“We believe that broadly neutralizing antibodies are an option for postnatal vertical transmission, but obviously we have to figure out how many,” she said, so her group decided to start with two that target “different regions of the HIV envelope to increase the breadth and the potency,” as previous in vitro research had shown.
The phase I trial involved three steps. First, 40 infants exposed to HIV who were born without HIV were randomly assigned in groups of eight to receive escalating subcutaneous doses of either CAP256V2LS or VRC07-523LS within 96 hours after birth. The three arms of CAP256V2LS consisted of doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg, and the two VRC07-523LS arms included doses of 20 mg/kg or 30 mg/kg. All infants were from one of two institutions in Durban, South Africa.
During this step, one infant receiving 10 mg/kg of CAP256V2LS, four infants receiving 20 mg/kg of VRC07-523LS, and three infants receiving 30 mg/kg of VRC07-523LS experienced erythema and/or induration in the 15 minutes after administration, but it resolved within an hour.
The second step, following data review from the first step, involved a sixth arm of eight additional infants who received a 60-mg dose of CAP256V2LS and a 90-mg dose of VRC07-523LS within 96 hours after birth. In the third step, these infants received another dose of both antibodies, at 120 mg each, at age 3 months to cover them during the breastfeeding period.
Four infants receiving the first dose experience bilateral pain 4 hours after administration, and one infant vomited at 1 hour after the second dose’s administration.
Resultados del seguimiento
Over 6 months of follow-up, 298 AEs occurred, including 117 in those receiving CAP256V2LS, 82 in those receiving VRC07-523LS, 43 after the first dose in the eight infants who received both antibodies, and 54 after the second dose in those eight infants. These AEs were distributed fairly evenly across all the groups and were mostly common childhood illnesses.
“Think about nappy rashes, colds, whatsoever comes to your mind that happens in 6 to 9 months of babies’ lives,” Scarlatti said. Importantly, she said, they were mild or moderate and mostly unrelated to the study drug.
There were 11 AEs probably or possibly related to the drug. In the single-antibody arms, these included elevated aspartate aminotransferase (AST) in an infant receiving 10 mg/kg of CAP256V2LS; unusual and persistent fussiness in an infant receiving 20 mg/kg of CAP256V2LS; and elevated AST and alanine aminotransferase (ALT) in an infant receiving 20 mg/kg of VRC07-523LS. In the combined antibodies arm, one infant had unusual irritability after the first dose, and one child had anemia, while five had a low absolute neutrophil count after the second dose.
Datos farmacocinéticos
The pharmacokinetic data “are promising, but different from adults,” Scarlatti said. In the combined antibodies arm, the time to maximum concentration was 1 day, the half-life of CAP256V2LS was 24.5 days, and the half-life of VRC07-523LS was 44 days. The Cmax was 160.8 micrograms/mL for CAP256V2LS and 69.3 micrograms/mL for VRC07-523LS. The researchers conducted simulations that confirmed the fixed dose and repeat dose at 3 months would achieve the “potential efficacy target.”
“We think that [bNAbs] might be a magic bullet to eliminate postnatal transmission,” Scarlatti said, and administration can be easily integrated into routine child health services, and bNAbs could also “provide rescue cover for infants of mothers with recent HIV acquisition,” she said.
Scarlatti noted that among the questions that remain are which antibodies to use, how many, and what the target efficacy concentration needs to be.
Conclusiones y próximos pasos
McGowan said the bNAbs appeared safe, with reactions that would be expected, such as injection site reactions and rash.
“Issues that will need to be addressed going further include identifying bNAbs that are protective against the HIV subtypes in the priority population, use of combinations of bNAbs that would be effective even if pre-treatment screening for susceptibility were not done, assessing efficacy in the period after newborn oral PEP has been completed, monitoring for anti-drug antibody, and determining any long-term vaccinial effect of monoclonals,” he said.
Disclaimer: This information is intended for educational purposes only and should not be considered as medical advice. Consult with a healthcare professional for any medical concerns.
Fuente: https://www.medpagetoday.com/meetingcoverage/ias/116589
Join the doctors who get the most relevant medical news, curated by specialty, every week — no spam, unsubscribe anytime.
