Four children have remained free of detectable HIV for more than a year after their antiretroviral therapy (ART) was stopped to see if they could achieve HIV remission, according to a presentation today at the Conference on Retroviruses and Opportunistic Infections (CROI) in 2024 in Denver. . The children, who contracted HIV before birth, were enrolled in a clinical trial funded by the National Institutes of Health in which an ART regimen was started within 48 hours of birth and then closely monitored for safety. medications and HIV viral suppression. The results reported today follow planned ART interruptions once children met predefined virological and immunological criteria.
“These findings are clear evidence that very early treatment allows unique features of the neonatal immune system to limit HIV reservoir development, increasing the prospects for HIV remission,” said NIAID Director Jeanne Marrazzo, MD. , MPH. “The promising signals from this study are a beacon for the future science of HIV remission and underscore the indispensable roles of the global network of clinicians and study staff who implement pediatric HIV research with the utmost care.”
Advances in antiretroviral treatment have significantly reduced perinatal transmission of HIV, when a child acquires HIV while in the womb, during childbirth, or through consumption of milk from a lactating person. If transmission occurs, children should receive lifelong ART to control virus replication and protect their immune system from life-threatening complications. Typically, stopping treatment will lead to a rapid resumption of HIV replication and detectable virus in the blood within weeks. However, in 2013, a case report described an infant born with HIV in Mississippi who was initiated on treatment at 30 hours of age, was withdrawn from ART at 18 months of age, and remained in remission with no evidence of detectable HIV. for 27 months.
Building on the observation that very early ART initiation may limit the ability of HIV to establish latent virus reservoirs in infants, researchers began an early-stage proof-of-concept study of very early ART in infants conducted in Brazil, Haiti, Kenya, Malawi, Africa, Tanzania, Thailand, Uganda, United States, Zambia and Zimbabwe. Previous publications from the clinical study demonstrated that ART started within hours of birth was safe and effective in achieving and maintaining HIV suppression. A small subset of children achieved sustained HIV suppression and met other predefined study criteria for stopping ART. These criteria include a durable absence of HIV replication beginning at 48 weeks of ART initiation, no detectable antibodies near the time of ART discontinuation, and having a CD4+ T cell count (HIV’s primary immune cell target). ) similar to that of a child. without HIV. Children who met these criteria, were older than 2 years, and had stopped consuming human milk were eligible to discontinue ART.
The data presented at the CROI summarized the experience of six children, all 5 years old, who were eligible for ART discontinuation with close monitoring of their health and safety. Four of the six children experienced HIV remission, defined as the absence of virus replication for at least 48 weeks without ART. One of them experienced remission for 80 weeks, but then his HIV rebounded to detectable levels. Three others have been and remain in remission for 48, 52 and 64 weeks, respectively. However, two children did not experience remission and their HIV became detectable three and eight weeks after stopping ART, respectively. The two children whose HIV returned at eight and 80 weeks experienced mild acute retroviral syndrome (ARS) with symptoms including headache, fever, rash, swollen lymph nodes, tonsillitis, diarrhea, nausea and vomiting. One child had noticeably low levels of white blood cells, which are a type of immune cell. Both ARS and white blood cell deficiency resolved before or shortly after restarting ART. The three children who experienced viral rebound resumed HIV suppression at six, eight, and 20 weeks after restarting ART.
“This is the first study to rigorously replicate and extend the results seen in the Mississippi case report,” said the study’s lead virologist, Dr. Deborah Persaud, a professor of pediatrics at the Johns Hopkins University School of Medicine and director of the Division of Pediatrics. Infectious Diseases at Johns Hopkins Children’s Center, Baltimore. “These results are groundbreaking for HIV remission and cure research, and also point to the need for immediate neonatal testing and initiation of treatment in healthcare settings for all infants potentially exposed to HIV in utero.”
The latest findings show that very early initiation of ART has variable but favorable results in HIV control. Although ARS was generally mild and resolved in both cases, the authors cautioned that close monitoring of this potential event is needed in ongoing and future HIV remission research involving ART discontinuation. The children in this study took ART regimens with drugs that have been part of standard first-line therapy for decades. More research is being planned or conducted to understand how these observations might differ in children receiving newer, stronger generations of antiretroviral medications, and to identify biomarkers to predict the likelihood of HIV remission or rebound after ART discontinuation. Additional studies are also needed to understand the mechanisms by which neonatal immunity and very early initiation of ART limited the formation of HIV reservoirs and contributed to the remission observed in this study.
“ART changed the paradigm of HIV care, but treatment is a long road, especially for children who are lifelong HIV survivors,” said Adeodata Kekitiinwa, MBChB, MMed, associate clinical professor emeritus in the Department of Pediatrics at Baylor College of Medicine, registered investigator of the study. and clinical research site leader in Kampala, Uganda. “This trial brings us one step closer to realizing another paradigm shift in which our ART approach could be so effective that it could be used during one stage of life, rather than its entirety.”
This ongoing research is being conducted by the International Maternal, Pediatric, and Adolescent AIDS Clinical Trials Network (IMPAACT), which is funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, with co-funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH).
The research was led by study co-chairs Ellen Chadwick, MD, professor of pediatrics at Northwestern University Feinberg School of Medicine, and Yvonne Bryson, MD, professor of pediatrics at the David Geffen School of Medicine and Mattel Children’s Hospital. from UCLA, and director. of the Los Angeles Brazil AIDS Consortium. Dr. Kekitiinwa, Boniface Njau, MS, study coordinator at Kilimanjaro Christian Medical Center in Tanzania and Teacler Nematadzira, MBChB, site investigator at the University of Zimbabwe and University of California, San Francisco Collaborative Research Program, They continue to lead the study teams that oversee the children’s care. who experienced HIV remission. Jennifer Jao, MD, MPH, professor of pediatrics at Northwestern University Feinberg School of Medicine, has since taken on the role of co-chair of the study with Dr. Chadwick. The entire IMPAACT P1115 study team consists of hundreds of people at 30 NIAID- and NICHD-supported sites across the 11 study countries.