July 26, 2023—Roger Shapiro, professor of immunology and infectious diseases at Harvard T.H. Chan School of Public Health, has studied pediatric HIV as part of the Botswana Harvard Partnership since 1999. He recently led a study, published in Science Translational Medicine, of a potential alternative to antiretroviral treatment for children living with HIV.
Q: You called this study the Tatelo Study. Can you explain the name?
A: Tatelo means “the next thing” in Setswana, the language used in Botswana. We were studying what may be the “next thing” in treating HIV in children: broadly neutralizing antibodies. Otherwise known as bNAbs, these are special antibodies that target HIV. They’ve been used to control HIV replication in adults, but until now this strategy has not been studied in children. Our ultimate goal is to see if bNAbs can help deplete the HIV viral reservoir—the virus that can be found integrated into cells of the body—in a way that standard antiretroviral treatment (ART) cannot. There is hope that bNAbs may lead to an enhanced immune response against HIV, offering a path toward children being functionally cured of HIV.
Though bNAbs are expensive and complex to administer—making them challenging to implement in countries in Africa such as Botswana, where the burden of pediatric HIV is greatest—they offer other advantages over ART, too. They can be administered as infrequently as every two months, and caregivers in our study very much preferred them to daily ART, since it can be hard to give daily medication to children. bNAbs also appear to have less toxicity than ART, since they are essentially the same as antibodies that our own immune system makes. This is very important for children with HIV, who face both short-term and long-term toxicities from ART that can include anemia, altered growth patterns, and damage to their mitochondria.
Q: How did you study the effectiveness of bNAbs, and what did you find?
A: The Botswana Harvard Partnership’s experience conducting prior clinical trials in children with HIV allowed us to begin working in the bNAb space as soon as these new agents became available. And we had an existing cohort of early-treated children with low viral reservoirs who we thought would do really well with the antibodies—so that motivated us to propose the first study of this treatment in children.
We enrolled 25 of these children, ages two to six, in the clinical trial, all of whom had received ART from the first week of life through at least two years of age and were virally suppressed prior to entering the study. The children were treated with two different bNAbs, called VRC01LS and 10-1074, each given through intravenous injections every four weeks. The bNAbs were given in addition to ART for at least eight weeks, and then continued alone for up to 24 weeks.
Of the 25 children, 11 were able to remain virally suppressed during the 24 weeks of bNAbs alone. The bNAbs also had an excellent safety profile, with no concerning adverse events. For the 14 children with viral rebound, meaning a return of virus to their bloodstream while on bNAbs alone, we re-started ART very quickly since we were checking viral loads every one to two weeks. All these children re-suppressed on ART before the end of the study, and today, in long-term follow-up, all remain virally suppressed.
Q: How encouraging are these results?
A: The fact that nearly half of the children maintained viral suppression on bNAbs shows that bNAbs are a promising long-acting treatment option. Of course, nearly half isn’t good enough—but this is a first proof-of-concept. It’s similar to data from the early 1990s that showed promise around combinations of antiretrovirals. That research got us on the path to the more effective ART regimens we use today. One limitation of our study was that this was a special group of children who had started ART in the first week of life, and all had very low viral reservoirs to begin with—so we could not tell whether using bNAbs lowered their reservoirs even further. This limits our ability to tell whether bNAbs may help bring about a functional cure in some children.
We are still early in bnAb research, so each study, including this one, is moving the field forward. Further research using newer combinations of bNAbs with greater breadth and potency will build on the advancements we’ve already made. We also need a better understanding of which children may be able to control virus on their own after a period on intensive bNAb therapy. We can only do this by stopping all treatment in very carefully controlled trials. All of this is so new that we decided to be conservative about this study’s aims and only evaluate bNAbs as an alternate treatment to ART, rather than try to tackle the issue of which kids might be able to go off HIV treatment completely.
Now that we have learned from Tatelo, we plan to go further in the next study. Specifically, we plan to use a combination of three newer bNAbs that are broader and more potent, and select kids who meet the criteria Tatelo helped us discover for successful response to bNAbs. I think in this context we will see more than 90% of children maintaining viral suppression—matching the success rate of ART—and will be able to test the bNAbs’ effectiveness during a period off all treatment for some children. We hope this will put us on the road to prolonged periods off treatment—or even functional cure—for some children living with HIV.