ATLANTA — Until recently, the medical community held a consensus that children born with HIV might be obliged to take antiretroviral drugs for the rest of their lives. But the announcement made last week that an infant in rural Mississippi who stopped receiving medicine at 18 months of age and has since lived for a year with no measurable viral RNA in the blood is prompting HIV experts to question the conventional wisdom.
“It’s definitely paradigm shifting,” says Deborah Persaud, a pediatric infectious disease physician at the Johns Hopkins Children’s Center in Baltimore who presented the Mississippi case here at the Conference on Retroviruses and Opportunistic Infections (CROI) on 4 March. However, a trial that involves drug cessation is fraught with ethical and medical difficulties, so the next steps going forward remain unclear.
Persaud and other HIV specialists plan to meet over three days in May at a leadership retreat of the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) group, an investigator network funded by the US National Institutes of Health (NIH), to discuss how best to test if and when antiretroviral therapy can be halted for children born with HIV who achieve undetectable levels of the virus in their blood. “We need community input on this,” Persaud says. “If we develop careful strategies, we could probably come up with a consensus approach in a couple of months.”
From Berlin to Mississippi
A prime benefit of going off antiretrovirals is the avoidance of drug-induced side effects, ranging from metabolic complications to bone demineralization to kidney failure. This is especially true for young people who could be on these medications from birth. Yet, before the Mississippi baby, no one had ever achieved a ‘functional cure’ from HIV—meaning undetectable viral replication and no disease progression in the absence of drugs—off the back of antiretroviral therapy alone. (Timothy Brown, the so-called ‘Berlin patient’, achieved this state, but only after a bone-marrow transplant with donor cells invulnerable to HIV replaced all of his native immune cells, a procedure deemed too risky for most HIV-positive individuals.)
The key to the baby’s functional cure, researchers believe, was probably the unconventionally aggressive treatment administered to the newborn in the first days of life: a trio of antiretroviral agents given twice daily starting from around 30 hours after birth. By giving these drugs before the infant had the chance to develop any memory T cells—the place where HIV goes to hide—this may have prevented the virus from establishing the latent reservoir that typically thwarts efforts at fully eliminating HIV from the body.
In contrast, most babies born to HIV-positive mothers today receive only a ‘prophylactic’ course of antiretroviral drugs to prevent infection. This typically involves fewer agents and less frequent dosing. Full treatment regimens are then given only after a positive diagnosis, which can take up to six weeks in many parts of the developing world.
Yet, in the case of the Mississippi baby, Hannah Gay, a pediatric HIV specialist at the University of Mississippi Medical Center in Jackson, put the newborn on the more aggressive regimen even before the tests came back showing that the child was infected. She did so out of the concern over the possibility of mother-to-child transmission, as the mother had never received prenatal care nor antiretroviral treatment. In fact, her HIV-positive status was only revealed to doctors while she was in labor. Following the baby’s diagnosis six days later, Gay maintained this intensive protocol with a slightly different drug cocktail going forward. Drug withdrawal was never planned. But after 18 months on the regimen, the child’s family stopped treatment for unspecified reasons. Surprisingly to Gay and her colleagues, the virus never rebounded.
“It’s always good to have your thinking jolted,” says Katherine Luzuriaga, of the University of Massachusetts Medical School in Worcester, who collaborated with Presaud and Gay in analyzing the Mississippi baby’s blood work.
Could other babies—around 1,000 of whom are newly infected globally each day with HIV—treated in a similar way now be functionally cured of their infection? A month ago, most researchers would have said no. Now, they’re not so sure.
Emily Erbelding, deputy director of the Division of AIDS at the NIH’s National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, which partially funds IMPAACT, thinks the answer could be ‘yes’. “There might be some window of opportunity where antiretroviral therapy alone can just knock down viral replication and maybe prevent any significant reservoir from being established—that’s the hypothesis,” she told Nature Medicine. “It’s probably our highest priority for research in children, as far as HIV goes, to figure out how to test that and to see if this case can be replicated. The hope is that we can cure kids from HIV.”
Before investigating the possibility of drug cessation, however, Persaud, Luzuriaga and their IMPAACT colleagues want to first test the risks and benefits of aggressive treatment from birth for babies at high probability of HIV infection. “What we want to do is see is if we can replicate the Mississippi case” in infants whose mothers for some reason did not take the standard preventative antiretrovirals during pregnancy, says Paul Palumbo, a pediatrician at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, and vice-chair of the clinical trials network. The team is now writing up a clinical protocol for a pilot study that would include about two dozen babies born in these circumstances.
The impetus for that study doesn’t come from just the Mississippi baby, though. Inspiration is also being drawn from some of the first children to ever receive so-called ‘highly active antiretroviral therapy’ (HAART), a combination of at least three drugs designed to suppress HIV replication, in the mid-1990s. Reporting at CROI, researchers showed that, of five individuals who were started on a triple drug regimen before three months of age and have since received the medications for an average of 16 years, four now have no detectable levels of viral replication or HIV-specific antibodies in their bloodstream.
Looking ahead, “it may be reasonable to consider a trial off therapy for these kids,” says Luzuriaga, who led the study. But first, she and her team would like to conduct more studies using ultrasensitive assays to be absolutely sure the now-teenagers have cleared all of the virus that can replicate from their bodies before withdrawing the drugs and risking the possibility of viral rebound.
There is some precedent for stopping drug treatment in children with HIV. For instance, William Borkowsky, of New York University School of Medicine, and his colleagues previously tested the idea of cyclically weaning kids off of HAART for progressively longer and longer intervals, with the hope that periodically exposing children to their own viral strains would serve as a type of ‘autologous vaccine’ to build up HIV-specific immune responses. It worked to some extent, but RNA levels of the virus never dropped precipitously (AIDS Res. Hum. Retroviruses. 24, 401–411, 2008). At last year’s CROI, a team led by Mark Cotton of Stellenbosch University in South Africa also presented data showing that HIV-infected infants first given HAART before three months of age could safely stop taking their drugs after one or two years of treatment, although the majority of such kids had to restart therapy after less than a two-year drug holiday. Importantly, neither study raised any major red flags in terms of safety. Still, “the bottom line,” says Palumbo, “is you always see some evidence of the virus post-drug withdrawal.”
Perhaps a strategy of early, aggressive treatment before drug withdrawal would be different. And should the approach prove successful, it could spare thousands of babies a lifetime of drug therapy. But, as David Margolis, a molecular virologist and clinical investigator at the University of North Carolina at Chapel Hill, points out, there remains a more effective—and proven— strategy to avoid HIV infection in children: “It’s better to treat the mother” during pregnancy.