CROI 2013: First Glimpse of A Pediatric HIV Cure?
An infant who started anti-HIV drugs within hours after birth appears to have been functionally cured of HIV infection, according to researchers presenting data this week at the 20th Conference on Retroviruses and Opportunistic Infections.
Setting off a storm of questions during a March 3 press conference, Deborah Persaud, MD, of Johns Hopkins University School of Medicine outlined several factors that make this infant’s case remarkable.
The child’s mother tested HIV positive during labor and had not previously been on antiretroviral therapy. HIV testing of the slightly premature infant was conducted earlier than usual: Using technology that detects HIV’s own genetic material rather than antibodies to the virus, two HIV tests were performed within the first two days of the baby’s life. Both tests came back positive. At just 31 hours old, the infant’s viral load was roughly 20,000 copies/mL.
The pediatrician in charge of the child prescribed AZT, lamivudine, and nevirapine, the standard triple-drug combination used to prevent HIV acquisition in infants whose mothers were diagnosed during labor. But in this case, there was a twist: The doctor upped the nevirapine to a twice-daily dose, which Persaud noted is the level used to treat HIV-positive pediatric patients.
Persaud explained that ordinarily it can take four to six weeks to identify HIV infection in an infant and then initiate therapy. In this case, however, treatment was initiated early. Very early, in fact: just 30 hours after birth.
Why does this matter? In the earliest days following HIV infection, the virus hijacks CD4 cells (key players in the immune system) and uses them to replicate. It also establishes “viral reservoirs” in CD4 cells that are in a resting state; these cells are not “on duty” in the immune system, and are essentially invisible to other immune system cells whose job is to destroy infected cells.
These reservoirs of hard-to-reach virus represent a major obstacle to eradicating HIV from the body. And because the HIV in these reservoirs is not actively replicating, it is not susceptible to antiretroviral drugs, which work only by interrupting various stages in the viral lifecycle. But could starting anti-HIV therapy during this early stage of infection result in fewer viral reservoirs? Recent research suggests the answer may be yes, and that’s the answer Persaud and colleagues are banking on.
Less than a month after starting extremely early antiretroviral therapy, the infant’s viral load was undetectable (below 20 copies/mL for the test used), showing the treatment was working. The child continued to do well on treatment until around 18 months of age, but was then lost to care for several weeks. (“It’s not uncommon for kids to be lost to follow-up,” said Persaud.)
When the child was brought back for medical visits at just shy of two years old, the antiretroviral meds had been discontinued for five months—yet the child had an undetectable viral load.
In the several months since, researchers have been unable to detect any “replication-competent” virus—that is, HIV that can make more copies of itself—in blood samples, and the child remains off HIV therapy at age two and a half.
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The research team has discovered very small traces of HIV’s genetic material in samples of the child’ blood plasma and cells, but they are unsure as yet whether this represents what Persaud referred to as “assay noise,” a “genetic footprint” left behind by the virus, or evidence of actual viral replication.
Many questions remain to be answered, but the child’s good health and the team’s lack of detection of any replication-competent virus convince Persaud that she and her colleagues have “proof of concept” of a pediatric functional cure.
One man, Timothy Ray Brown (formerly known as the “Berlin Patient”), famously experienced a functional cure when, as part of a last-resort treatment for leukemia, he received a stem cell transplant from a donor whose immune system cells were essentially immune to HIV. (Read more about Timothy Brown’s amazing story.)
“We believe this is our Timothy Brown case,” Persaud said. While acknowledging that it’s early days for this single case, she and her team are confident: “We believe that perhaps the initiation of very early antiretroviral therapy prevented the formation of the viral reservoirs in central memory CD4 T cells that are the barriers to cure, and [this] really sets the stage for the pediatric cure agenda going forward.”
Persaud added that this case shows that drugs already tested and approved for pediatric HIV therapy—drugs already deemed safe for children—can be employed as part of a functional cure for infants who were perinatally infected with HIV (that is, infected at birth). The International Maternal Pediatric Adolescent AIDS Clinical Trials group, she said, is now designing studies to try to replicate this apparent functional cure.
Responding to a press member’s question about previous reports of children who seem to have spontaneously cleared HIV infection, Persaud referred to an extensive genetic investigation, published in 1998, of five different studies with over 1,500 HIV-positive mothers. The analysis determined, she said, that of the 42 cases reported of HIV-diagnosed infants reverting to an HIV-negative status, 99% were attributable due to “laboratory mishap,” such as mislabeling or contamination of samples.
The case reported today, Persaud said, is “the first well-documented functional cure of a perinatally infected child.”
Reilly O’Neal is the editor of BETA.
Frenkel, L. and others. Genetic evaluation of suspected cases of transient HIV-1 infection of infants. Science 280 (5366): 1073–1077. May 15, 1998.
Persaud, D. and others. Functional HIV cure after very early ART of an infected infant. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta. March 3–6, 2013. Abstract #48LB.