PURPOSE OF THE STUDY.
Until very recently, the only patient “cured” of HIV was the “Berlin patient,” an adult male treated for HIV-associated acute myeloid leukemia with stem cell transplantation from a donor who was intrinsically resistant to HIV. The donor carried homozygous mutations (delta32) in the chemokine receptor 5 gene, which is an essential co-receptor for HIV entry into most target cells. The present study reports on an infant who also may be cured with early, highly active antiretroviral therapy (ART) after documented perinatal infection.
A 35-week gestational age infant was born by normal vaginal delivery to an HIV-infected woman who received no prenatal care and who was not taking ART. ART was initiated in the infant at 30 hours of age with zidovudine, lamivudine, and nevirapine. At 1 week of age, this regimen was adjusted to zidovudine, lamivudine, and ritonavir-boosted lopinavir. The infant remained on ART for 18 months and was then lost to follow-up until 23 months of age. ART has been discontinued and, because of results from subsequent studies, has not been restarted.
Standard HIV polymerase chain reaction (PCR) assays and HIV antibody testing were used to diagnose and monitor the HIV-exposed infant. Peripheral blood mononuclear cell cultures were analyzed with PCR for virus DNA and with co-culture techniques for replication-competent virus. Lymphocyte subset analysis was conducted with standard flow cytometry, and HIV-specific T-cell responses were evaluated with intracellular cytokine generation assays.
During the first month of life and while receiving ART, the infant had elevated quantitative HIV RNA PCR measurements that declined to undetectable levels and remained there. Subsequently, although proviral DNA was detected at the limits of the assay at 26 months of age, plasma viral RNA was undetectable, and replication-competent virus could not be cultured at age 24 months. HIV antibody assays were not detected in the infant at or after 24 months of age, when maternal antibody would not confound the assays, and HIV-specific T-cell responses were not detected at age 28 months. CD4+ T-cell counts remain normal throughout the study.
Very early ART therapy in infants born at risk may abort HIV infection.
In patients with established HIV infection, effective ART drives the virus to “undetectable” levels, usually defined as <20/copies of viral RNA/mL of plasma. However, viremia persists in such patients at very low levels and as DNA pro-virus in peripheral blood mononuclear cells. Was this infant cured of HIV? According to the Centers for Disease Control and Prevention definition, the infant was “infected”: 2 positive PCR test results on at least 2 different blood specimens. The data presented demonstrated that after unintended discontinuation of therapy, the infant remained free of replication-competent HIV from at least 12 months of age. As the authors conclude, “very early ART in infants may alter the establishment and long term persistence of HIV-infection.” But why might this happen in a newborn when it has not been demonstrated in older patients except under the unique circumstances of the Berlin patient? HIV persistence depends on the establishment of a reservoir of infected cells. Recent studies suggest that this condition involves a specific population of “central memory T cells.” Perhaps very early therapy aborts or inhibits establishment of this reservoir or perhaps these cells have not fully matured to be infected in newborns. In any case, the present report suggests that very early therapy may prevent establishment of HIV in high-risk infants, and certainly this possibility is being studied intensively.
- Copyright © 2014 by the American Academy of Pediatrics