Long-term HIV Remission Case Raises More Questions than Answers
A French teenager with HIV who has managed to maintain an undetectable viral load for 12 years without antiretroviral treatment was a major topic of discussion at the 8th International AIDS Society Conference last month in Vancouver. While no one is calling this case a cure, it does raise some interesting questions about “post-treatment control” and may provide clues about how to achieve a functional cure or long-term HIV remission.
Asier Saez-Cirion from the Institut Pasteur in Paris described the case at a media briefing during the conference, and at the annual “Towards a Cure” pre-conference symposium.
The young woman, who is now 18, was infected with HIV before or during birth. Because her mother, who was first seen during late pregnancy, had a high viral load at the time of delivery, the baby was given preventive zidovudine (AZT) soon after birth. After finishing six weeks of zidovudine, her viral load rose to a high level, confirming that she was in fact infected. She then started combination antiretroviral therapy (ART) for treatment at three months of age.
When she was nearly six years old the child was withdrawn from care and lost to follow-up. When she came back a year later, her blood viral load was undetectable even though she wasn’t on ART. She stayed off treatment. At age 12 she had one substantial “blip” of viral replication (reaching about 500 copies/ml) but then returned to undetectable viral levels.
The young woman has now been off antiretroviral treatment for 12 years and has undetectable plasma viral load according to ultrasensitive tests that can measure down to 4 copies/ml. Her CD4 T-cell count also remains high and stable. But researchers can detect HIV DNA (viral genetic material) in her cells—and isolated cells can be reactivated to produce virus in the laboratory—showing that she has not been cured.
“This case is quite exceptional—that’s something we want to make very clear,” Saez-Cirion cautioned at the press briefing. “Most HIV-infected patients, either children or adults, even if they started treatment very early, if they stop treatment they will lose control of infection.”
“This young woman is still infected by HIV and it is impossible to predict how her state of health will change over time,” Jean-François Delfraissy, director of the French national AIDS Agency (ANRS), agreed. “Her case, though, constitutes a strong additional argument in favor of initiation of antiretroviral therapy as soon as possible after birth in all children born to seropositive mothers.”
What Does This Case Tell Us?
The past year saw some disappointing news in the quest for an HIV cure. In July 2014 researchers announced that the “Mississippi Baby”—a child who many experts thought might be cured of HIV—did in fact still carry the virus. Likewise, a pair of bone marrow transplant patients in Boston who showed no signs of HIV in their blood or cells while on ART experienced viral rebound several months after an experimental treatment interruption.
This leaves Timothy Brown, the Berlin Patient, as the only person who still appears to have been cured of HIV. Nearly a decade ago Brown received bone marrow transplants to treat leukemia, using stem cells from a donor with a naturally occurring mutation (CCR5-delta-32) that protects T-cells from HIV infection. Although Brown stopped ART during that process, his HIV did not return. After more than seven years of tests, researchers have not been able to detect replication-competent virus in his blood plasma, peripheral blood cells, or anywhere else they have looked.
Although the French teenager does not add to the ranks of people thought to be cured of HIV, she does join a small group of “post-treatment controllers” who appear able to control the virus after they stop antiretroviral treatment.
Saez-Cirion and his colleagues have been following a growing group of French adults, known as the VISCONTI cohort, who started treatment during acute or early HIV infection, interrupted therapy, and maintain undetectable plasma viral load. But they are not free of HIV DNA in their T-cells and elsewhere, like Brown.
Inspired by the VISCONTI group and the Mississippi Baby, Saez-Cirion’s team searched an ANRS database of pediatric patients with perinatal HIV infection and identified 100 who started treatment before the age of six month. Of these, 15 stopped ART while their viral load was very low or undetectable. In most of these cases viral rebound occurred within a year after treatment interruption. But one child maintained viral suppression for more than three years, and the teenager remains undetectable.
Saez-Cirion suggested that this is the first case of very long-term HIV remission in a person infected around the time of birth and treated early—about 10 years longer than the Mississippi Baby.
The young French woman and the VISCONTI cohort are not part of another rare group known as “elite controllers.” Those individuals have unusually strong immune responses that naturally keep HIV in check despite never taking antiretrovirals. The French teenager did have high viral load during periods off treatment as a baby, and she does not have various immune system markers characteristic of elite controllers.
“This girl has none of the genetic factors known to be associated with natural control of infection,” Saez-Cirion said. “Most likely she has been in virological remission for so long because she received a combination of antiretrovirals very soon after infection.”
The French teenager and some of the VISCONTI patients appear to have an unusually weak response to HIV, and their resting T-cells do not become activated and begin producing more virus. This may be desirable, as it avoids the persistent immune activation and inflammation usually seen in people with untreated HIV infection.
This feature of post-treatment controllers suggests that calming the immune system’s response to HIV—rather than strengthening it—may be one approach to achieving a functional cure.