Children born with HIV have persistent inflammation markers linked to heart disease

Two studies of children with HIV presented at the 13th International AIDS Society Conference on HIV Science (IAS 2025) in Kigali, Rwanda showed that even if they are on antiretroviral therapy (ART) and have fully suppressed viral loads, they carry markers of chronic immune activation that could lead to premature cardiovascular disease and other non-AIDS-defining conditions.

One of the studies linked this to the amount of intact proviral DNA they carry in their ‘reservoir’ cells; as other studies have previously shown, this was significantly lower in children who received ART shortly after birth.

Children born with HIV have elevated levels of some pro-inflammatory proteins

Claire Davies of Stellenbosch University in Cape Town, South Africa said that little was previously known about the long-term inflammatory profile of children born with HIV and whether early ART and sustained viral suppression were able to prevent chronic immune activation going into adolescence.

She compared levels of 28 biomarkers in 68 children born with HIV with levels in 121 HIV-negative children from the same communities and with similar backgrounds. Most children entered the study between seven and nine years of age, with some followed up to age 16.

The HIV-positive children had all received early ART, at less than three months’ age, and had near-normal CD4 counts (average: 893). Ninety-three per cent were virally suppressed at the time their bloods were taken. Of the 28 biomarkers, 12 were markers of inflammation and of increases in certain kinds of white blood cell; five were associated with vascular growth and atherosclerosis (hardening of the arteries); and four with the metabolism of fats and glucose.

She found raised levels of six of the biomarkers in the children living with HIV, compared to the HIV-negative children. CRP 76% was higher and IL-6 15% higher; CRP is a general maker of inflammation in hospital blood tests and IL-6 stimulates the liver to release it. VEGF (vascular endothelial growth factor) was 37% higher: this stimulates the growth of new blood vessels and is a causative factor in some malignancies and in some eye diseases.

In addition, the levels of some other chemicals had a relationship with age. Levels of the S100 calcium binding proteins, which are markers of gut inflammation, were heightened in all ages but especially in children aged 13-16 (up 87%) while the inflammation marker TNF-alpha was raised by 24%, but only in the over-13s.

Sex also had an influence. Levels of adiponectin, which is involved in the metabolism of fats and glucose, were higher by 16%, but only in boys. While levels of MCP-1 (monocyte chemoattractant protein), which increases the levels of monocytes – a type of white blood cells crucial in repairing injury – were 27% higher in the HIV-positive children, this only reached statistical significance in boys.

Davies hypothesised that early damage to regulatory T-cells caused by perinatally acquired HIV persists into adolescence, but said that causation could be multifactorial. Microbial translocation (‘leaky gut syndrome’) could be one cause, and ongoing inflammation caused by circulating defective virus another. The levels of many of the proinflammatory chemicals were correlated and seemed to reinforce each other.

Another interesting factor could be ART toxicity. At the time the data were collected, almost all of the children were all on zidovudine, lamivudine and boosted lopinavir, whereas paediatric regimens based on dolutegravir are now more often used. A few were also on nevirapine, and it would be interesting to perform the same study on children taking ART with different metabolic profiles.

In answer to a question, Davies said that the same immune dysregulation was not always observed in adults who achieved prolonged viral suppression, and that HIV might therefore cause more long-term harm to infants’ immune systems than to those acquiring it as adults.

Earlier treatment and a smaller reservoir are associated with less immune dysregulation in children

The size of the HIV reservoir may also have an influence. In another study, Dr Fatima Kakkar of the University of Montreal found raised levels of inflammation markers CRP and the immunomodulators IL-6, IL-18 (which is involved in producing the natural antiviral protein interferon-gamma) and IL-1-beta (which is a general immune activator involved in inducing fevers) in children born with HIV.

The children she studied had important differences from the South Africans in Davies’ study. They were Canadian and mostly teenagers who had entered the study at an average age of nearly 14, and were then followed for five years. Half of them were female and 81% were virally suppressed when they entered the cohort.

The study looked at the relationship between the time of ART initiation, the size of the HIV reservoir, and biomarker levels. Reservoir size was measured in 121 of the 225 children in the cohort through two methods: quantifying intracellular proviral DNA levels and inducing intracellular RNA production.

The analysis considered four groups of the 121 children. The smallest, numbering 10 children, had started ART below the age of six months and had been virally suppressed on their first regimen for over five years. Thirty children had also been virally suppressed on their first regimen for over five years but had started ART later. Twenty-nine children had not achieved viral suppression on their first regimen but had become virally suppressed for over five years on subsequent regimens. The remaining 52 had started at varying ages and had only achieved viral suppression for two to five years.

The children starting suppressive ART before six months had significantly smaller reservoirs, averaging about 12.6 HIV DNA copies per million CD4 cells. In contrast, the children in the other three groups averaged 56 to 79 copies per million cells, with no significant difference between groups.

Inducible RNA was much more variable. It averaged 2.5 copies in the early-treated group if they did not have CMV (cytomegalovirus, a common virus that can induce inflammation too) and between 10 and 100 copies in the other groups. While no child in the early-treated group had inducible RNA of more than 100 copies, in the second and third groups it ranged up to 1000 copies, while in the fourth, less-suppressed group a few had up to a million copies. However, there were children in all four groups where no induced RNA was detectable.

Younger age at ART initiation, duration of ART and duration of viral suppression were all strongly associated with reservoir size, as were levels of CRP and IL-6, IL-18 and IL-1-beta, but not TNF-alpha, interferon-gamma or VEGF.

Kakkar hypothesised that the reservoir size drives the higher levels of inflammatory proteins, but she acknowledged the possibility of reverse causation – that higher inflammation could lead to increased subclinical viral replication and thus larger reservoir size. As with many other studies, the lesson seemed to be: children born with HIV benefit most from starting treatment as early as possible and achieving rapid viral suppression.