HIV: Apparent Cure in Infant Treated Early With Combo ART

Janis C. Kelly

October 24, 2013

An infant infected with HIV-1 and treated with combination antiretroviral therapy (ART) beginning at 30 hours of age remained healthy and had no detectable signs of the HIV-1 virus at age 30 months, despite having discontinued ART 12 months earlier.

"This case suggests that very early ART in infants may alter the establishment and long-term persistence of HIV-1 infection," write Deborah Persaud, MD, and colleagues in an article published online October 23 in the New England Journal of Medicine. Dr. Persaud is associate professor of pediatrics and infectious disease and director of the Infectious Disease Fellowship Program at Johns Hopkins University School of Medicine, Baltimore, Maryland.

Although rare cases of transient HIV infection in infants have been reported, the sole previously documented case of treatment-induced cure was the "Berlin Patient." That patient was an adult with acute myelogenous leukemia who had been treated with total ablative chemotherapy, radiation, therapy, and stem-cell transplantation with donor cells homozygous for CCR5-delta5, which produced graft-versus-host disease.

That approach was beneficial for the Berlin Patient but is unlikely to have broad clinical application. In contrast, the case reported by Dr. Persaud and colleagues involved eliminating the HIV reservoir in an infant treated with a fairly standard 3-drug antiviral regimen; the infant was later able to discontinue ART with no subsequent viral rebound.

According to Dr. Persaud, the infant was born at 35 weeks' gestation to a mother who had received no prenatal care and who was HIV-1-positive, as determined by rapid testing done during labor. The infant was born before antiretroviral prophylaxis could be administered to the mother. The mother's infection was later confirmed by Western blot. The child was not breast-fed.

The infant was treated, beginning at 30 hours after birth, with a 3-drug regimen of zidovudine, lamivudine, and nevirapine. Treatment was continued after detection of HIV-1 DNA in the child's peripheral blood mononuclear cells at 30 hours and detection of HIV-1 RNA in a blood sample collected at 31 hours, the standard diagnostic criteria for HIV-1 infection in an infant.

ART drove the plasma HIV-1 RNA level below detectable limits by the time the child was 29 days old.

During a clinic visit, when the child was 23 months of age, the mother reported that ART had been discontinued at age 18 months; pharmacy records showed that ART prescription had not been refilled since the child was 15 months old.

The authors write, "At the time of this report, the child had not received any antiretroviral drug through 30 months of age, and the plasma level of HIV-1 RNA had remained undetectable by routine clinical assays. Circulating HIV-1 antibodies have also not been detected."

The authors conclude, "This case suggests that very early ART may interfere with either the quantities or qualities of persistent reservoirs of replication-competent virus. Antiretroviral prophylaxis is routinely recommended for infants who have been exposed to HIV-1, with multidrug regimens recommended in high-risk cases. Furthermore, the initiation of ART in infected infants markedly reduces HIV-related mortality among infants and is recommended by the World Health Organization. This global standard may facilitate planned proof-of-concept studies of very early ART to modify persistent HIV-1 infection in infants, with an aim toward sparing them a lifetime of therapy."

In an accompanying editorial Scott M. Hammer, MD, writes, "The big question, of course, is, 'Is the child cured of HIV infection?' The best answer at this moment is a definitive 'maybe.' " Dr. Hammer is chief, Division of Infectious Diseases; the Harold C. Neu Professor of Medicine; and professor of epidemiology at the New York-Presbyterian/Columbia University Medical Center, New York City.

"The case study underlines the importance of an early [polymerase chain reaction (PCR)] test when there is a high risk of vertical transmission, coupled with preemptive combination antiretroviral therapy (cART). In many settings, cART for the baby would have been initiated much earlier than 30 hours of age (within first few hours of life). In high-prevalence settings, such as where I work (South Africa), the first PCR is usually done at 6 weeks, even though many infections could be diagnosed on day 1 of life. Data already show that delays in PCR, even to 6 weeks of age, are associated with much early morbidity, loss to follow-up, and mortality. Starting cART very early, even before the PCR result was available, was a key intervention," Mark F. Cotton, MBChB, told Medscape Medical News.

Dr. Cotton, who is from the Children's Infectious Diseases Clinical Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa, predicted that publication of this case report would renew the focus on testing infants on day 1 of life and on the use of very early combination ART.

"Remember, this is a unique case. The [Virological and Immunological Studies in Controllers After Treatment Interruption (VISCONTI)] study (which has now gathered 20 cases in adults) has been considered 'anecdotal' for years by many [American] specialists in this field. But I do believe that Persaud's report is of importance and adds something because I think children might be (functionally?) cured more easily than adults due to their particular 'immature' immune system. We also have such a pediatric case in the VISCONTI study. In fact, that particular case...looks like the Berlin Patient: No replicating virus can be found, and a very small amount of HIV-DNA was found only once," Laurent Hocqueloux, MD, told Medscape Medical News.

Dr. Hocqueloux is from the Infectious and Tropical Disease Service at Centre Hospitalier Régional in Orléans, France. He presented data from the VISCONTI study earlier this year at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, held in Kuala Lumpur, Malaysia.

"People infected by HIV have to be treated immediately. And to do this, they have to be diagnosed as soon as possible. So, test and treat as soon as possible," Dr. Hocqueloux added.

Dr. Persaud reported preliminary data from this study at the Conference on Retroviruses and Opportunistic Infections earlier this year.

Dr. Persaud reported receiving support from the National Institutes of Health and the Foundation for AIDS Research. One coauthor reported receiving support from the National Institutes of Health and the Foundation for AIDS Research and consulting fees from Tibotec. One coauthor reported consulting fees from Biota, Chimerix, Merck, Bristol-Myers Squibb, Gilead, Gen-Probe, and Monogram. The other study coauthors have disclosed no relevant financial relationships. Dr. Hammer reported consulting, research support, or advisory board fees from Merck, Bristol-Myers Squibb, MedImmune, Progenics, and SIGA. Dr. Cotton and Dr. Hocqueloux have disclosed no relevant financial relationships.

N Engl J Med. Published online October 23, 2013. Article full text, Editorial full text

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