Antiretrovirals taken by pregnant women to prevent mother-to-child transmission are highly effective. But what of the minority of infants who still acquire HIV?
A study from South Africa presented today at the 12th International AIDS Society Conference on HIV Science (IAS 2023) in Brisbane, Australia shows that antiretrovirals can start to work as treatment for HIV-positive children even in the womb. The result can be, in some cases, young post-treatment controllers: children who will go on to maintain undetectable viral loads without taking antiretroviral therapy (ART).
Children are promising candidates for an HIV cure. The date they acquired HIV can be quite precisely estimated and ART can be started at birth. In addition, their immature immune systems contain fewer of the memory CD4 cells that form the reservoir of cells containing hidden HIV.
The study, presented by Dr Gabriela Cromhout of the University of KwaZulu-Natal, found evidence of differences in sex when it came to post-treatment control. Among 281 mother-baby pairs studied, there were five babies with persistently undetectable viral loads off ART. All five were boys, even though 60% of the babies in this prospective cohort study were girls.
In the last decade, there have been reports of several children who are post-treatment controllers, able to maintain an undetectable viral load for months to years off therapy, often after only a short course of ART. There was the Mississippi baby in 2012, a young girl who stayed off ART with an undetectable viral load for two years; a South African boy who, as of 2022, has stayed off ART for 12 of his 13 years with no detectable viral load; and a couple of other cases from France and from Texas.
Hypothesising that post-treatment control in children might be more common than we thought, Cromhout and colleagues set up a longitudinal cohort study currently containing 281 pairs of mothers with babies born with HIV. The babies were monitored from birth. The study started in 2015 and continues to date.
Dr Cromhout told aidsmap: “Approximately two-thirds of the transmissions in our study arose in mothers who only found out during the pregnancy that they had HIV. In some cases they started ART late into the pregnancy, even during labour. The remaining one-third had tested positive prior to the pregnancy but because of adherence problems, viral replication was not fully suppressed throughout the pregnancy.”
All the babies started ART at birth, but most had actually received it to some extent before, when their mothers started it: 92% of babies received ART from their mothers prior to birth via placental transfer. The average viral load in HIV-positive newborns was 155,000 before ART programmes started in South Africa in 2005. Now, giving ART to pregnant women has resulted in an average viral load at birth of 4600, with 14% of having an undetectable viral load, prior to any ART being given to the infants directly.
Cromhout continued: “I believe that this is one of the first studies that could potentially look at the way that ART is received by the foetus itself, and the effect on post treatment control.”
At first mothers and babies received regimens based on lopinavir boosted with ritonavir and then, from April 2020, on dolutegravir. The switch to dolutegravir resulted in a notable improvement in viral suppression, especially in boys. Average viral loads at birth were 6950 on lopinavir, but 1700 on dolutegravir, and below 1000 in boys. Only 10% of babies had baseline viral loads below 20 on lopinavir (8% in girls, 12% in boys), but 24% on dolutegravir (16% in girls, 33% in boys).
Antiretroviral adherence was monitored in mothers and, after birth, in babies using drug level monitoring. The viral characteristics tested for included sensitivity to the natural antiviral substances called type I inferferons, and the virus’s replicative capacity (ability to reproduce in lab-dish cells).
Thirty-six months after birth, 37% of mothers and babies had dropped out of the study. Of the remaining 63%, over a third (36.5%; 23% of the original group) had a persistently detectable viral load. But the remaining 63.5% (40% of the original group) had suppressed virus and nearly half of them (47.5%, 19% of the whole group) had had a persistently undetectable viral load (below 20) with no ‘blips’. Viral load was solely related to adherence after birth, not to viral load at birth.
Five babies, all of them boys, maintained viral loads below 20 despite not taking any ART, or very little, from at most two months after birth. So far they have had undetectable viral loads off ART from 3 to 19 months.
The child who has had an undetectable viral load for the longest, stopped taking ART at the age of 40 months (3 years 4 months) and has now just turned five. The other four resumed ART, but three are now enrolled in an analytic treatment interruption (ATI) study where they will be taken off ART under careful monitoring for a pre-defined period.
The boy who remains off ART had HIV antibody tests at 18, 24 and 37 months after birth, using the Western blot method. This detects separate HIV proteins and is very specific (few false positives) but can take a while to detect HIV seroconversion (the production of antibodies) especially in people with low viral loads. He was seronegative by Western blot in the first two tests but was positive for antibodies to five HIV proteins at week 37, despite having an undetectable viral load.
“This may indicate that there was some viral replication happening at 37 months, but that either this was a defective virus or short-lived viral blips were arising at times when blood samples were not being taken,” commented Dr Cromhout.
There were distinct differences in the types of viruses acquired by girls and boys. The HIV in girls tended to be resistant or at least less sensitive to type 1 interferons, meaning that these innate immune defences would not work so well against them (and maybe failed in the first place when they acquired HIV). On the other hand, they had rather low replicative capacity.
Boys’ HIV viruses tended to be sensitive to type 1 interferons, meaning that the immune defences would work well against them. On the other hand, they had high replicative capacity, maybe because only these viruses could get past the boys’ strong innate-immune response. However in the boys who maintained viral undetectability off ART, two had viruses with very low replicative capacity and two others lower than average (the fifth wasn’t tested).
“The reason we feel our study is important,” Dr Cromhout told aidsmap, “is primarily that reports of post-treatment control in children have been single cases; here we have five of them.
“Their viruses share similar characteristics in interferon response and replicative capacity, and the hypothesis is that these viral characteristics must have been driven by sex differences in the immune response during very early life.
“Girls in the womb naturally produce more type 1 interferon than boys, so have more activated CD4 T-cells to be targets for HIV. And because boys produce less interferon-1, there’s no selection for interferon-resistant viruses – so they get interferon-sensitive ones. And if they are interferon-sensitive, then only those with high replicative capacity survive. In some boys, these sensitive viruses do not survive – which would be consistent with what we are seeing in our ‘post treatment controllers’.”
If the type 1 interferon response is influencing the type of viruses that are being acquired by boys, then therapies that strengthen this response further might further narrow the range of viruses that could be transmitted and have a preventative effect, at least in children.
Cromhout G et al. Sustained aviraemia in the absence of anti-retroviral therapy in male children following in utero vertical HIV transmission. 12th IAS Conference on HIV Science, Brisbane, abstract OALBX0104, 2023.