Treating people soon after they become infected might reduce the size of the initial HIV reservoir in their bodies.

Donald Bliss and Sriram Subramaniam, NIH

What can science learn from a child who has controlled HIV without drugs for more than 8 years?

PARIS—An HIV-infected child in South Africa who is controlling the virus without antiretroviral (ARV) drugs has reinvigorated the push to find ways to allow people to control the virus for prolonged periods without treatment.

The child, whose gender hasn't been revealed to help protect anonymity, was born to an HIV-infected mother and was given ARVs starting at 8 weeks old; the treatment was stopped at 40 weeks as part of a controlled clinical trial. Now, more than 8.5 years later, the virus hasn't rebounded and the child is doing fine, researchers reported here yesterday at an international AIDS conference. That doesn't mean the HIV infection has been cured, they stressed; the child still harbors low levels of the virus, invisible with standard tests but easily detected with ultrasensitive ones.

But the case may offer fresh clues to what makes long-term remission possible. In most people living with HIV who stop taking drugs, the virus comes roaring back within weeks. If long drug holidays were possible, it could simplify people’s lives, slash the costs of treatment, and reduce long-term side effects. And the research into what some call "sustained viral remission" could help inform the search for a complete cure.

So far there have only been two other reports of children whose virus remained undetectable for years after stopping treatment. Researchers think chances of long-term remission may increase if a patient starts treatment very soon after infection, as the South African child did.

The new case offers a unique study opportunity because it was part of a large clinical trial for which blood samples were stored at regular intervals. “It’s exciting that we’ve identified the child, as it could provide answers for the future,” says Mark Cotton, an HIV/AIDS clinical researcher at Stellenbosch University in South Africa who took part in the study, dubbed CHER. At the meeting, the team described genetic and immunologic studies to explain the remission, but said strong clues have not yet surfaced. “There’s a long way to go,” Cotton says.

But to some conference attendees, the case is a one-off that has echoes of the “Mississippi baby,” who had a similar history and received intense attention from scientists and the public alike—until the virus rebounded after 27 months off treatment. “Single-case reports have limited value now,” says Sharon Lewin, a leading HIV cure researcher and director of the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia. “We know it happens and we need to understand why. But I’m surprised there’s so much interest in this.” 

 It’s exciting that we’ve identified the child, as it could provide answers for the future.

Mark Cotton, Stellenbosch University

Very few people can control HIV without ARVs. These so-called “elite controllers” typically have genetic factors that predispose their immune systems to create unusually strong responses against HIV, without treatment. ARVs do the job very well, too, but the problem is that HIV can integrate and lie dormant in long-lived immune memory cells, ready to bounce back when therapy stops. To eliminate the virus—a complete cure—researchers have tried to shrink these reservoirs, so far with little progress.

But treating people shortly after they become infected might reduce the size of the initial reservoir, making it easier to drain. And even if it’s not possible to empty it, the amount of new virus emerging from a smaller reservoir might be so low that the immune system can contain it without drugs.

Asier Sáez-Cirión, a viral immunologist at the Pasteur Institute in Paris, has been following a group of 23 patients in France who started treatment shortly after becoming infected and whose virus had remained undetectable on standard tests for an average of 7 years. (They had been treated for 3 years on average but decided to stop for various reasons.) One person in the group, called the VISCONTI cohort, has gone without treatment for nearly 17 years. None of the patients had a genetic signature associated with elite controllers.

Many researchers paid little heed to the VISCONTI data when they were first reported in 2013 because it was a series of case reports, not a controlled study. “VISCONTI put the flag up and said there’s something going on, and many people thought it was rubbish and it doesn’t matter,” says clinical researcher John Frater of Oxford University in the United Kingdom. “But it wasn’t rubbish.”

Although Frater and co-workers weren’t looking to induce long-term remission, they conducted their own controlled study, called SPARTAC, of nearly 200 people who started treatment early. Treatment was halted in one group of participants after 12 weeks and in another after 48 weeks. One year later, the virus was undetectable in 14% of the people who had the 48-week treatment and in 4% of those who received the shorter one. The study, published in 2013, convinced Frater that early treatment can lead to long-term suppression in at least some people. (He hasn’t followed the patients since, and it’s not clear how they’re doing now.)

But limiting the reservoir by treating early won’t by itself lead to sustained viral remission, as underscored by another study presented at the meeting. Timothy Henrich of the University of California, San Francisco (UCSF), described a patient who started ARVs an estimated 10 days after becoming infected. He stayed on treatment for 34 months and had “nearly a complete loss” of HIV: Researchers couldn’t detect the virus “despite massive sampling” of his blood, bone marrow, spinal fluid, lymph nodes, ileum, and rectum. HIV did resurface, however, when they injected his blood into a “humanized” mouse, although the team was unable to confirm that the virus was real and not a contaminant. A mathematical model suggests the patient only had 200 infected cells left in his body. He decided to stop treatment and the virus rebounded 7.4 months later.

UCSF’s Steven Deeks, who collaborates with Henrich, says he thinks the key to sustained remission may be a tricky balance between using drugs early to keep the reservoir small and allowing the immune system to see enough HIV to develop a robust memory response for when the virus comes back. “If you start very early, as we did with our patient, you have only a few hundred infected cells, but the immune system did not have a chance to generate a protective response,” Deeks says. “If you start too late, you have a huge reservoir but an overwhelmed immune system.” He suggests the South African child and the VISCONTI patients may have had the right balance.

Anthony Fauci, the head of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, described a study that asked whether an HIV vaccine could boost the immune systems in infected people on ARVs whose virus was undetectable, hoping to help them achieve long-term remission when they stopped the drugs. One group of 15 received the vaccine, whereas the second was given a placebo. The strategy didn't work: The virus quickly rebounded in most everyone within a few weeks. But a handful of people stayed in remission for more than a year—some of them in the placebo group. The outcome emphasizes the importance of controlled trials, Fauci says: “If we had just given a vaccine without the control, we would have said, ‘Wow, look what we did.'”

Frater has one of several new, controlled studies on the drawing board that plan to stop ARVs in people who started treatment early and then intensively study them to see why a few have long-term remission. “What on Earth is driving this?” Frater asks. “If we think there’s a cure agenda, it will be really hard to move forward unless we understand this mechanism.”