Researchers Describe First ‘Functional HIV Cure’ in an Infant, Benefits of Early Therapy

News tips from the 20th annual conference on retroviruses and opportunistic infections (croi), march 3-6, Atlanta. Two separate reports by a team of researchers from Johns Hopkins Children’s Center, the University of Mississippi Medical Center and the University of Massachusetts Medical School show that prompt initiation of antiretroviral therapy (ART) in HIV-infected newborns not only curbs the formation of hard-to-treat viral reservoirs but, in doing so, may lead to so-called “functional cure.” In contrast to a sterilizing cure — a complete eradication of all viral traces from the body — a functional cure occurs when viral presence is so minimal, it remains undetectable by standard clinical tests, yet discernible by ultrasensitive methods. Results of both studies were presented March 3 and 4 at the 20th annual Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta.The first report describes the case of an infant who underwent remission of HIV infection after receiving ART within 30 hours of birth. Johns Hopkins virologist Deborah Persaud, M.D., lead author on the report, and University of Massachusetts Medical School immunologist Katherine Luzuriaga, M.D., headed a team of laboratory

investigators. Pediatric HIV specialist Hannah Gay, M.D., associate professor of pediatrics at the University of Mississippi Medical Center, provided treatment to the baby. The child described in the current report was born to an HIV-infected mother and received combination antiretroviral treatment beginning 30 hours after birth. A series of tests showed progressively diminishing viral presence in the infant’s blood, until the virus reached undetectable levels 29 days after birth. The infant remained on antivirals until 18 months of age, at which point the child was lost to follow-up for a while and, the researchers say, stopped treatment. Ten months after discontinuation of treatment, the child underwent repeated standard blood tests, none of which detected HIV presence in the blood. A test for HIV-specific antibodies — the standard clinical indicator of HIV infection — also remained negative throughout. Currently, high-risk newborns — those born to mothers with poorly controlled infections or whose mothers’ HIV status is discovered around the time of delivery — receive a combination  of antivirals at prophylactic doses to prevent infection for six weeks and start therapeutic doses if and once infection is diagnosed. But this particular case, the investigators say, may change the current practice because it highlights the curative potential of very early ART. Prompt antiviral therapy in newborns — one that begins within days of exposure —  appears to work by halting the formation of viral hideouts, the dormant cells responsible for reigniting the infection in most HIV patients within weeks of stopping therapy, the researchers say. And because prompt antiviral therapy in a newborn may prevent such reservoirs from forming in the first place, it can help infants “clear” the

virus and achieve-long term remission without lifelong treatment. This is precisely what they believe happened in this case. The investigators say they deem the child described in the report “functionally cured,” a condition that occurs when a patient achieves and maintains long-term viral remission without lifelong treatment and standard clinical tests fail to detect HIV replication in the blood. Specialists say natural viral suppression without treatment is an exceedingly rare phenomenon observed in less than half a percent of HIV-infected adults, known as “elite controllers,” whose immune systems are able to rein in viral replication and keep the virus at clinically undetectable levels. HIV experts have long sought a way to help all HIV patients achieve such elite-controller status. The new case, the researchers say, may be that long-sought game-changer because it suggests prompt ART in newborns can do just that. “We believe prompt ART may actually push infants into the elite responder category by preventing the formation of latent viral reservoirs — the sleeper cells responsible for reigniting the infection in the majority of patients once they stop taking antivirals,” Persaud says.The investigators caution they don’t have enough data to recommend change right now to the current practice of treating high-risk infants with prophylactic doses instead of therapeutic ones, but this infant’s case provides the rationale to start proof-of-principle studies in all high-risk newborns. “Our next step is to find out if this is a highly unusual response to very early antiretroviral therapy or something we can actually replicate in other high-risk newborns,” says Persaud, who is also the scientific chair of the HIV Cure Committee of the International Maternal, Pediatric, Adolescent Clinical AIDS Trials (IMPAACT) network, a consortium of researchers and institutions that was critical in

spearheading the earliest clinical trials of mother-to-child transmission and early treatment of infants 15 years ago. A single case of sterilizing cure also has been reported so far, the investigators note. It occurred in an HIV-positive man treated with a bone marrow transplant for leukemia. The bone marrow cells came from a donor with a rare genetic mutation of the white blood cells that renders some people resistant to HIV, a benefit that transferred to the recipient.  However, HIV experts agree that such a complex treatment approach is neither feasible nor practical for the 33 million people worldwide infected with HIV.“Complete viral eradication on a large scale is our long-term goal but, for now, remains out of reach, and our best chance may come from aggressive, timely and precisely targeted use of antiviral therapies in high-risk newborns as a way to achieve functional cure,” Luzuriaga says. Despite the promise this approach holds for infected newborns, the researchers say preventing mother-to-child transmission remains the primary goal. “Prevention really is the best cure, and we already have proven strategies that can prevent 98 percent of newborn infections by identifying and treating HIV-positive pregnant women,” says Gay, the pediatric HIV expert who provided treatment to the infant.The second report, a small study of teens infected with HIV at birth, further clarifies the mechanism believed to be at play in the functionally cured infant described in the first report.The report describes nine teenagers receiving antiretroviral therapy, but five of whom started treatment around 2 months of age. Ultrasensitive testing showed extremely low viral DNA levels in the blood of the five teens who received early ART, compared with the blood of the four teens who initiated ART later in childhood. Using sophisticated laboratory techniques, researchers were unable to

detect dormant viral cells capable of replication from the early-treated teens. By contrast, such viral cells were readily cultured from the blood of the late-treated teens. Four of the five early-treated teens showed no HIV-specific antibodies on standard testing, but antibodies were detected in the blood of all four who started treatment late.“Taken together, the findings of our two studies show that very early ART in infants prevents the development of long-term viral reservoirs, and in doing so, may put newborns on a path to long-term remission and on the road to a functional cure,” Persaud says.“Our goal is to use these data to craft future therapeutic approaches that will ultimately spare children a lifetime of therapy,” Luzuriaga adds. The work was supported by the National Institutes of Health, by amfAR, the Foundation for AIDS Research and by the Department of Health and Human Services.Related Information: International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network  Conference on Retroviruses and Opportunistic Infections (CROI). Founded in 1912 as the children’s hospital of the Johns Hopkins Medical Institutions, the Johns Hopkins Children’s Center offers one of the most comprehensive pediatric medical programs in the country, with nearly 95,000 patient visits and some 9,000 admissions each year. Hopkins Children’s is consistently ranked among the top children’s hospitals in the nation. Hopkins Children’s is Maryland’s largest children’s hospital and the only state-designated Trauma Service and Burn Unit for pediatric patients. It has recognized Centers of Excellence in dozens of pediatric subspecialties, including allergy, cardiology, cystic fibrosis, gastroenterology, nephrology, neurology, neurosurgery, oncology, pulmonary, and transplant. News from: Johns Hopkins University

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