Treating Newborns: Timing Is Everything

©iStock.com/UygarGeographic
©iStock.com/UygarGeographic

Should babies infected with HIV in utero be put on anti-HIV drugs immediately after birth? Can very early treatment allow some children to eventually control the virus on their own? HAI researchers are helping to answer those questions.

When HIV-infected women receive antiretroviral (ARV) drugs early enough during pregnancy, their chance of passing HIV to their infants can be dramatically reduced so that nearly all babies are born HIV-free. But infants born to mothers who are not taking ARVs have a much greater chance of becoming infected.

This was the case with the so-called “Mississippi baby,” born in a U.S. clinic in 2010. When the infant was just 30 hours old, a doctor put the newborn on ARVs before knowing if the baby had HIV. Because ARVs carry a risk of harmful side effects, doctors don’t usually prescribe these drugs unless a baby has tested positive for HIV. In Mississippi, lab tests came back several days later indicating that the baby did indeed have HIV. Subsequent tests confirmed her infection.

The baby stayed on ARVs for 18 months, but stopped treatment when her mother stopped follow-up care. After five months, the baby returned to care and was tested again for HIV. Here’s where things get interesting: the baby showed no sign of HIV infection. Doctors did not restart her ARVs, but monitored her closely. The toddler celebrated her third birthday with no detectable virus. Newspaper headlines heralded a possible cure for AIDS. There was a surge of optimism in the HIV research world. Then, shortly before the child’s fourth birthday, detectable levels of HIV were found in her blood. The virus had rebounded. The girl was put back on ARVs to suppress her virus.

When the news was announced in early July, Dr. Anthony Fauci, head of HIV/AIDS research at the National Institutes of Health (NIH), issued a statement. “Certainly, this is a disappointing turn of events for this young child . . . and the HIV/AIDS research community. Scientifically, this development reminds us that we still have much more to learn about the intricacies of HIV infection and where the virus hides in the body. The NIH remains committed to moving forward with research on a cure for HIV infection.”

A cure for HIV has been maddeningly elusive. Once the virus enters the body, it quickly forms reservoirs in certain tissues, including lymph nodes, the gut, and the brain. Though ARVs work well to control the virus, they don’t eradicate it from these reservoirs. If a person stops taking ARVs, latent virus in the reservoirs begins to replicate and the virus rapidly returns. In the case of the Mississippi baby, researchers had hoped that either the reservoirs never had a chance to form, or that very low levels of HIV would allow the child’s immune system to control the virus and that she could stay off treatment indefinitely.

Viral rebound in the Mississippi baby was a step backward, but not all the way to the drawing board. Although cure remains the ultimate goal, researchers are now asking whether starting treatment very early in life may allow for better treatment outcomes, and possibly periods of time off treatment, even if a lasting cure is not likely. Dr. Roger Shapiro, an HAI researcher not involved with the Mississippi case, is conducting a research study on early infant treatment of HIV in Botswana. Shapiro’s earlier work made groundbreaking contributions in preventing HIV-infected mothers from passing the virus to their babies. While neonatal HIV infection has almost been eliminated in the U.S., in sub-Saharan Africa, nearly 1000 babies are born with HIV every day.

Dr. Roger Shapiro, photo by Kent Dayton
Dr. Roger Shapiro, photo by Kent Dayton

In his new study, 30 babies born with HIV will be put on treatment right after birth. “The early treatment approach depends on rapid turnaround,” said Shapiro. ARVs will only be given to babies who test positive. He hopes to get HIV test results back within 24 hours of delivery. “Our goal is to start treatment by the second day of life.”

The second big challenge confronting Shapiro and his team is giving the babies the right amount of medicine. “In terms of dosing, we don’t have a lot of knowledge about treating neonates,” said Shapiro. Drugs are mixed with syrup that’s put into a small syringe and squirted into the baby’s mouth. “Babies in the first week of life have been treated before, but it’s not common. There is some uncertainty about getting the doses right,” said Shapiro. “We are being very, very careful.”

The study also hopes to test whether children who achieve an undetectable viral level after a course of ARV treatment will be able to remain HIV-free without treatment for an extended period of time. If a child has been on treatment for 96 weeks and virus is undetectable, the young patient may stop treatment and be carefully monitored for 96 more weeks to see if the virus returns. If it does, the child will immediately restart treatment.

Prior to any treatment interruption, Shapiro and his colleagues must receive approval from a Data Safety Monitoring Board (DSMB) and two Institutional Review Boards (IRBs) to ensure that the highest ethical standards are applied and the latest scientific evidence is taken into account. If some or many of the children are able to remain off treatment for weeks, months, or even years, then we will be much closer to understanding how viral reservoirs are established and how treatment in early infancy may be different than at other times in life. And possibly closer to a cure.

As Dr. Shapiro notes, “The benefits of starting treatment early in life may be far-reaching for these children. Minimizing the amount of virus in their bodies may allow for better treatment response and more durable treatment success at times in their lives when staying on medicines may be a challenge, such as adolescence.”

“This is the culmination of our work to find solutions for infants and children impacted by HIV/AIDS,” said Dr. Max Essex, Chair of HAI. “If this work leads to strategies to cure or control HIV infection, that would make a huge difference. Children would not have to experience the lifelong health challenges associated with chronic HIV and the medicine necessary to treat it.”

Much was haphazard about the case of the Mississippi baby, but much was also learned. Though HIV eventually rebounded in one girl, that won’t necessarily be the case for all children. As NIH’s Fauci stressed, “Now we must direct our attention to understanding why that is and determining whether the period of sustained remission in the absence of therapy can be prolonged even further.”

Shapiro’s study, designed and implemented with the highest standards, will provide answers to pressing questions in pediatric AIDS research. He and his team hope to start testing newborns later this year. Preliminary results should be available in three years, with more conclusive answers in about five. Though this is a challenging trial to conduct, the outcome could have a profound positive effect on the life-long health of babies infected with HIV.