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Children born with HIV and treated early with antiretroviral therapy (ART) continued to show elevated immune markers in adolescence, based on data presented at the International AIDS Society Conference on HIV Science.

Although universal early ART has improved long-term health outcomes for children with perinatal HIV, data on long-term effects of ART exposure are limited, wrote Claire Davies, PhD, a researcher at Stellenbosch University, Cape Town, South Africa, and colleagues.

“Prior to 2008-2009, antiretroviral therapy for children living with perinatal HIV was withheld until HIV disease was advanced,” Davies said in an interview.

“The reasoning was that ART, having been developed from cancer chemotherapy, had significant toxicity and it was thought best to spare infants from those toxicities until benefit clearly outweighed risk,” she said. In 2009, the landmark CHER trial showed that apparently well infants living with HIV who were given empiric ART soon after birth had approximately 400% better survival compared with those with no intervention.

“Immediate worldwide implementation of this intervention has led to emergence of an entirely new disease profile: Since 2009, early initiation of ART has been standard-of-care for perinatally-infected infants,” Davies told Medscape Medical News. “Since early-treated children living with HIV [CHIV] would then be spared from repeated opportunistic infections and years of ongoing HIV replication, it was hoped that they would also be spared from the enormous chronic inflammation that typically accompanied those infections,” she said. Chronic inflammation that persists over years is a powerful driver of cardiovascular disease (CVD), which leads to premature strokes and heart attacks in adulthood, she emphasized.

The researchers reviewed data from 185 individuals aged 7-16 years who were part of a study of early ART in South Africa. The study population included 65 CHIV and 118 HIV-unexposed children who served as control individuals. The CHIV began ART within 3 months of birth and were deemed clinically well at the time of blood testing for biomarkers.

The participants underwent a median of two measures of blood serum 4 years apart, yielding a total of 321 observations; 26 biomarkers were measured.

After adjusting for multiple variables, the CHIV group had significantly higher levels of C-reactive protein, soluble CD14 (a marker of monocyte activation), and vascular endothelial growth factor than the unexposed children.

The researchers also found specific effects in different age groups. Levels of Monocyte chemoattractant protein-1 (MCP-1), interleukin 6, and P-selectin in CHIV aged 6-8 years were significantly higher than matched control individuals, whereas MCP-1 was significantly higher in the CHIV group aged 13-16 years than control individuals. No other significant differences in biomarkers appeared between the groups.

When the current study began, it was entirely unknown whether early-treated children living with HIV would suffer from the same chronic inflammation and consequent premature CVD, or to what extent early lifelong ART might prevent CVD in these children as they grew, Davies told Medscape Medical News. “We hoped that by removing ongoing HIV replication and opportunistic infections, children living with HIV would be spared from the chronic inflammation that drives premature CVD in early adulthood,” she said.

The researchers had hoped to find that early ART had a greater impact on preventing chronic inflammation, but the results showed otherwise, said Davies. The data should alert clinicians to the increased risk for premature strokes and heart attacks in adulthood for children treated early with ART, she said.

For the study population treated with ART, their chronic inflammation can no longer be a result of ongoing HIV replication and opportunistic infections because these factors are no longer present, Davies told Medscape Medical News. “We now need to understand what is driving their ongoing chronic inflammation so that we can find treatments to help reduce it, and in so doing, reduce their risk of premature strokes and heart attacks in adulthood,” she said.

ART Alone is Not Enough

“While early ART dramatically improves long-term outcomes for children born with perinatal HIV, it remains unclear whether early ART alters the long-term inflammatory and immune activation profile,” said Jason E. Zucker, MD, an assistant professor of medicine and infectious diseases specialist at Columbia University Irving Medical Center, New York City, in an interview.

“These profiles are critical, as they are linked to future risk of noncommunicable diseases, such as cardiovascular and metabolic disorders,” said Zucker, who was not involved in the study. The current study fills a key gap by examining longitudinal biomarker data to assess persistent immune dysregulation in early treated children compared with uninfected control individuals, he said.

Zucker said he was slightly surprised by the findings of extensive immune activation and elevated biomarkers, into adolescence, especially those associated with monocyte activation. “The key takeaway is that early ART alone may not fully normalize immune activation in perinatally HIV-infected children,” he said. “The data underscore the need for long-term monitoring and potentially adjunctive interventions to mitigate inflammation and reduce future disease risk, even among virologically suppressed youth,” he added.

Some limitations of the study include the modest sample size and lack of any long-term clinical outcomes, Zucker told Medscape Medical News. “Biomarker assessments, while robust, do not confirm clinical endpoints such as actual cardiovascular events, and future research should track these cohorts longitudinally into adulthood to determine whether the observed immune profiles translate into actual disease, and explore therapeutic strategies,” he said.

This study was funded through the nonprofit Specialists in Global Health. The researchers had no financial conflicts to disclose. Zucker had no financial conflicts to disclose.