New Clues about Viral Rebound in Mississippi Child Thought Cured of HIV

alt

Clinicians involved in the care of a child many once hoped was cured of HIV have published details about the case in the February 15 New England Journal of Medicine. The authors found that the virus that eventually returned after the girl had been off antiretroviral therapy for more than 2 years was identical to her mother's viral strain.

Katherine Luzuriaga from University of Massachusetts Medical School, Hannah Gay from the University of Mississippi Medical Center, and Deborah Persaud from Johns Hopkins School of Medicine have been providing updates about the child formerly known as the "Mississippi Baby" for the past 2 years.

Persaud first reported at the 2013 Conference on Retroviruses and Opportunistic Infections (CROI) that an HIV-infected baby who started combination antiretroviral therapy (ART) very soon after birth was maintaining an undetectable viral load after being withdrawn from care and taken off treatment.

The baby was born in 2010 to a mother who did not receive prenatal care and was diagnosed with HIV when she presented for delivery. She went into labor prematurely and there was not enough time to start prophylactic antiretrovirals to prevent mother-to-child transmission.

Due to the risk of infection, the infant was started on a 3-drug combination ART regimen around 30 hours after birth, and she soon reached an undetectable viral load. Sensitive tests showed that the baby was HIV-infected herself -- not just carrying antibodies from her mother -- and she remained on ART for 18 months with good viral suppression. At that time, the child began to miss appointments and her caretakers took her off treatment. When she was brought back into care at age 2 -- after being off antiretrovirals for several months -- she surprisingly still had undetectable plasma viral load.

Over the next year the child underwent extensive testing, which failed to find HIV RNA in her blood plasma. Bits of HIV DNA could intermittently be detected in peripheral blood cells, at a level of about 3 copies per million cells, but she had no apparent replication-competent virus. In addition, the girl also had normal CD4 and CD8 cell counts and no detectable HIV-specific antibodies or HIV-targeted T-cells. Yet she did not have markers suggesting she was a natural "elite controller."

Persaud reported further details of the case at the 2014 CROI in March, convincing many experts that the child was the second known person to be cured of HIV, after Timothy Brown, the Berlin Patient.

Unfortunately, after 28 months of sustained remission, the team reported shortly before the International AIDS Conferencein July 2014 that the child -- now age 4 -- was found to have detectable HIV viral load during a routine clinical visit. At this point she also had detectable HIV antibodies and a declining CD4 cell level indicating that replicating virus was causing immune damage. The girl was then put back on ART, her viral load was rapidly suppressed, her CD4 cells rose, and she remains in generally good health.

As the researchers report in their letter to the editor in the New England Journal of Medicine, the Mississippi child had no identifiable risk factors for HIV reinfection, such as breast-feeding or sexual abuse. Genetic sequencing of the girl's virus -- which could not be done until viral rebound occurred -- revealed that it was 99% identical to viral samples from her mother collected 24 months after delivery. The girl's virus had very little variability (0.1% diversity), as expected after a prolonged absence of viral replication.

"In conclusion, the return of HIV-1 viremia after a substantial period of viral quiescence is consistent with the model of HIV-1 latency in which long-lived resting memory CD4+ T cells were generated during routine immunologic memory formation, though other reservoirs are also possible," the authors wrote. "The findings in this case and others provide insight on how very early treatment may restrict but not eradicate HIV-1 reservoirs."

The case of the Mississippi child shows that HIV establishes a viral reservoir very soon after infection. Starting antiretroviral treatment a day after birth was not enough to prevent viral rebound, though it did appear to allow prolonged remission. However, the researchers think the Mississippi child was infected sometime during gestation, rather than during delivery, so treatment was not actually as early as it might seem.

A study now underway (IMPAACT P1115) hopes to treat nearly 500 infants as soon as possible after perinatal infection, with ART alone or combined with immunotherapeutic strategies, in an effort to learn more about sustained remission, or a "functional cure."

Until these studies are completed, "initiation of ART as early as possible in infants and continuation without interruption seem prudent," the authors recommended.

2/20/15

Reference

K Luzuriaga, H Gay, C Ziemniak, D Persaud, et al. Viremic Relapse after HIV-1 Remission in a Perinatally Infected Child. New England Journal of Medicine 372(8):786-788. February 19, 2015.