- Category: Search for a Cure
- Published on Friday, 25 October 2013 00:00
- Written by Liz Highleyman
The case report of a child who remains free of detectable HIV more than 18 months after interrupting combination antiretroviral therapy (ART) that had been started within 2 days after birth has now been published in the New England Journal of Medicine. Experts have called this accidental experiment "proof-of-concept" that very early treatment may be able to cure HIV in some individuals.
Deborah Persaud from Johns Hopkins University School of Medicine made headlines at this year's Retrovirus conference in March when she presented a report about an infant born to an HIV positive mother who started combination ART very early, was lost to follow-up and taken off treatment, and was later found to have no evidence of replication-competent virus despite prolonged absence of ART. The case has since been cited among a handful of apparent cures, offering clues about how HIV might be eliminated or held in remission in a broader population.
The report in the October 23, 2013, advance online edition of the New England Journal of Medicine provides more details about the case.
The now 3-year-old girl was born to a woman with HIV in Mississippi who did not receive prenatal care, was not on ART, and had a low but detectable viral load (2423 copies/mL). The baby was delivered vaginally at 35 weeks and the mother gave birth before she could be given antiretroviral drugs to prevent mother-to-child transmission.
At 30 hours after birth the baby was started on standard 3-drug combination ART using nevirapine (Viramune), zidovudine (AZT, Retrovir), and lamivudine (3TC, Epivir). This case is unusual because typically only a single drug is given as extra protection to infants born to HIV positive mothers who receive prophylactic antiretrovirals during pregnancy and/or delivery.
Repeat testing revealed HIV RNA in the infant's blood plasma and HIV DNA in peripheral blood mononuclear cells (PBMCs), indicating that the baby had in fact been infected, probably during gestation. ART was therefore continued, with lopinavir/ritonavir (Kaletra) substituted for nevirapine at 1 week of age. The baby had detectable HIV RNA on 3 subsequent tests (at 6, 11, and 19 days of age) before achieving viral load suppression at 29 days, with a pattern of viral decline similar to that seen in treated adults.
The infant remained on ART and was not breast-fed during her first year of life, and adherence was deemed adequate based on prescription refill records. However, at 18 months the child began missing clinic visits. When she was brought back for care at 23 months, the mother reported that ART had been stopped at 18 months.
Nevertheless, the child continues to show undetectable HIV RNA in blood samples through 30 months of age at the time of the report. More extensive testing, including HIV DNA polymerase chain reaction tests, have failed to detect replication-competent virus, though isolated bits of HIV nucleic acid (viral genetic material) could still be found.
Neither the mother nor the child have immune markers suggesting they are natural "elite controllers." The child tests negative for HIV antibodies, has maintained a CD4 T-cell percentage within or above the normal range, and has experienced normal growth and development.
"This case suggests that very early ART in infants may alter the establishment and long-term persistence of HIV-1 infection," the researchers concluded. "[V]ery early ART may interfere with either the quantities or qualities of persistent reservoirs of replication-competent virus."
"The absence of rebound viremia, the undetectable replication-competent virus, the almost-complete disappearance of cell-associated HIV-1 DNA, and the absence of HIV-1-specific immune responses while the child was not receiving ART suggest that replication-competent HIV-1 reservoirs may not have been established or were markedly abated, if not extinguished," they elaborated in their discussion.This situation "closely mimics the virologic and immunologic biomarkers of the Berlin Patient" -- a man who has no detectable HIV after receiving a bone marrow transplant from a donor with a mutation that protects CD4 cells against viral entry -- at 5 years of follow-up.
"Our findings suggest that this child's remission is not a mere fluke but the likely result of aggressive and very early therapy that may have prevented the virus from taking a hold in the child's immune cells," Persaud said in a press release issued by Johns Hopkins. "Prompt antiviral therapy in newborns that begins within hours or days of exposure may help infants clear the virus and achieve long-term remission without the need for lifelong treatment by preventing such viral hideouts from forming in the first place."
"This case highlights the potential of prompt therapy to lead to long-term remission in those already infected by blocking the formation of the very viral reservoirs responsible for rekindling infection once treatment ceases," added senior author Katherine Luzuriaga from the University of Massachusetts. "This may be particularly true in infants, whose developing immune systems may be less amenable to the formation of long-lived virus-infected immune cells."
Following up on this accidental experiment, a National Institutes of Health study scheduled to start in early 2014 will test whether very early combination ART can produce similar remission in other HIV-infected infants.
"The big question, of course, is, 'Is the child cured of HIV infection?' The best answer at this moment is a definitive 'maybe'," wrote Scott Hammer from Columbia University in an accompanying editorial. "The child described by Persaud et al. may be unique, and thus we have to exercise caution before inferring general principles from this case report. This said, we are at the stage at which individual case reports can provide proofs of principle, stimulate hypotheses, and lead to carefully designed experimental therapeutic studies involving both adults and children that, we hope, will lead us down the road to the reduction or eradication of the HIV-1 reservoir."
- CROI 2013: Functional Cure of HIV-infected Infant after Early ART [VIDEO]
- CROI 2013: Case Report of a "Functional" HIV Cure in a Child
D Persaud, H Gay, C Ziemniak, K Luzuriaga, et al. Absence of Detectable HIV-1 Viremia after Treatment Cessation in an Infant. New England Journal of Medicine. October 23, 2013 (Epub ahead of print).
S Hammer. Baby Steps on the Road to HIV Eradication. New England Journal of Medicine. October 23, 2013 (Epub ahead of print).
Johns Hopkins Medicine. Child Born with HIV Still in Remission after 18 Months Off Treatment, Experts Report. Press release. October 23, 2013.