Some children who start antiretrovirals very early may control HIV after stopping treatment

A small proportion of children who start HIV treatment within the first two days of life may achieve ongoing viral suppression after stopping antiretrovirals, according to study results presented yesterday at the Conference on Retroviruses and Opportunistic Infections (CROI 2024). While these promising findings hold clues for HIV cure research, such early therapy is out of reach for many, and treatment interruption remains risky without careful monitoring.

Out of 54 children who acquired HIV in the womb and started combination antiretroviral therapy (ART) within 48 hours after birth, six had undetectable HIV and met other eligibility criteria for a closely monitored treatment interruption. Of these, four had sustained viral remission for at least a year.

“This study provides proof-of-concept that very early ART significantly curtails the viral reservoir,” Dr Deborah Persaud of Johns Hopkins University School of Medicine told reporters at a media briefing. “We think this is a really ground-breaking finding for the field of ART-free remission and cure for children.”

Rationale and results

Pregnant women with HIV who are not on ART have a 15% to 45% chance of passing the virus on during pregnancy, childbirth or breastfeeding. Taking antiretrovirals reduces the risk to less than 1%, but some women do not receive timely prenatal care or have access to treatment.

This was the case for the mother of the Mississippi Baby, who was not on treatment and had a detectable HIV viral load at the time of delivery. Due to the high risk of exposure, the infant started combination antiretrovirals 30 hours after birth, but she acquired the virus nonetheless. The child’s family stopped her treatment when she was 18 months old, but when she returned to care several months later, she still had viral suppression. This was unexpected, as HIV inserts its genetic blueprints into human cells soon after infection, establishing a long-lasting viral reservoir that is unreachable by antiretrovirals and usually invisible to the immune system.

Persaud described the case at CROI 2013 and in The New England Journal of Medicine, prompting global headlines about a possible cure. Extensive testing showed that the child’s plasma HIV RNA, HIV DNA in peripheral blood cells and HIV antibodies were undetectable. Unfortunately, though, the girl’s viral load ultimately rebounded after 27 months off treatment.

While disappointing, the case added to the evidence that starting treatment very early might limit the size of the viral reservoir and enable a functional cure, especially for children. To learn more, researchers launched a trial called IMPAACT P1115 (NCT02140255), funded by the US National Institutes of Health (NIH).

The study enrolled infants at high risk for in utero HIV acquisition in Brazil, Haiti, Thailand, the United States and several countries in sub-Saharan Africa. Because diagnosis can take time, the babies were pre-emptively started on combination antiretroviral therapy within 48 hours after birth.

At CROI 2022 and recently in The Lancet HIV, Persaud reported an analysis which included 54 babies born during 2015 to 2017 who were confirmed to have acquired HIV during gestation. They initially received AZT (Retrovir) or abacavir (Ziagen), lamivudine (Epivir) and nevirapine (Viramune), with lopinavir (Kaletra) added later.

Most of the children did not maintain full viral suppression, likely due to inconsistent adherence. But those who had an undetectable HIV RNA plasma viral load from 48 weeks onward were eligible for an analytic treatment interruption if they met the following criteria:

• not breastfeeding
• no detectable HIV DNA in peripheral blood cells (indicating a very small or non-existent viral reservoir)
• two consecutive negative HIV antibody tests (suggesting there may be no persistent virus to trigger an ongoing immune response)
• a normal CD4 count, and
• a CD4 percentage of at least 25.

The children who met these criteria had not yet stopped therapy at the time of that analysis, but Persaud presented updated results at CROI 2024.

Some advocates have raised questions about the ethics of treatment interruption for children, but Persaud explained that this is necessary because there are no known biomarkers that predict ART-free remission. She said that “mothers are very invested” in this research, and “this is something parents want for their children.”

Six children, all from sub-Saharan Africa, met the criteria and started a treatment interruption at a median age of 5.5 years. The researchers initially planned to take eligible children off treatment around age 2, but this was delayed due to the COVID-19 pandemic, Persaud noted. Four were girls and two were boys – an interesting finding, as recent research suggests that boys may be more likely than girls to maintain viral suppression off treatment.

Two of the six children – a girl and a boy – had relatively rapid viral rebound at three and eight weeks after stopping treatment. But the other four achieved ART-free remission, defined as no detectable plasma HIV RNA for at least 48 weeks. Lopinavir plasma levels were measured retrospectively to confirmed they were in fact off treatment. One of the girls maintained an undetectable viral load for 80 weeks before experiencing viral rebound. The others were still in remission at 48, 52 and 64 weeks.

All children who experienced viral rebound regained viral suppression after resuming treatment. Two developed acute retroviral syndrome (flu-like symptoms that arise as the immune system starts fighting the virus) and one had a low white blood cell count, but no other clinical or immunological events of concern were identified during or after treatment interruption.

Real-world implications

While these results are promising, the study does not reflect real-world conditions. The researchers were able to diagnose HIV within a strict time frame, start antiretrovirals very early and monitor the infants frequently. In contrast, babies typically start antiretrovirals weeks or months after birth, especially in low- and middle-income countries where the burden of HIV is greatest.

The study findings “point to the necessity of immediate neonatal testing and treatment initiation in health care settings for all infants potentially exposed to HIV in utero,” Persaud said in an NIH news release.

The researchers aim to identify biomarkers that could help predict the likelihood and timing of viral rebound after treatment interruption. Persaud noted that the criteria used so far are not fully predictive of ART-free remission, as two children deemed eligible experienced early viral rebound.

The children in this study received older antiretrovirals that were approved for paediatric use at the time. As the trial continues, the researchers plan to evaluate newer, more potent regimens, potentially including integrase inhibitors and broadly neutralising antibodies, Persaud told aidsmap.

“This remission was very much longer than we had anticipated,” said trial protocol chair Dr Ellen Chadwick of the Ann & Robert H. Lurie Children’s Hospital of Chicago. “We’re not surprised or crestfallen if they rebound because that’s what usually happens when medications are stopped. If we can get the virus to such low levels that we might be able to use some newer, innovative treatments to keep them from needing to be on medication every day, then we’re setting them up for success for long-term virologic control.”