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Very Early Combination Antiretroviral Therapy in Perinatal HIV Infection: Two Case Studies - "Mississippi" baby followup & 2nd case of infant that appears to have cleared HIV/remains on cART
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The two cases are a "signal that giving very early treatment to neonates really restricts HIV spread to the point where it is difficult to detect infection,"......Evidence is increasing that treating HIV-positive babies within a few hours of birth can dramatically restrict -- and perhaps eliminate -- infection, a researcher said here......The child -- unlike the Mississippi baby -- has been kept on therapy, so investigators can draw no conclusions about whether the virus has been beaten permanently, Persaud said..... there are no immediate plans to interrupt treatment for the Long Beach child, although her care team has initiated "conversations" about the issue with their institutional review board......If there is "some consensus" that the anti-HIV medications should be stopped, it would happen when the child reaches age 2, she said. In the Mississippi case, the stoppage was inadvertent, after the child was lost to follow-up.....Persaud added that plans are underway for a prospective international clinical trial involving 54 infants who will be treated at birth or very soon after, with planned treatment interruptions at age 2......The report is an additional signal that very early treatment might interrupt the "seeding" of the HIV reservoir, commented Elaine Abrams, MD, of Columbia University in New York City, who was not part of the study but who moderated a press conference at which some details were reported......."How limiting the reservoir will relate to remission and cure is still to be tested," she told MedPage Today. "What happens when this kid stops drugs -- and I suspect they eventually will -- will be interesting to see.".....Abrams noted that other studies have shown that starting therapy at 6 to 12 weeks of age is too late. "When you stop therapy at 2 years later, you get virus," she said. MedPageToday
Link to CROI webcast:
http://www.croiwebcasts.org/console/player/22149?mediaType=slideVideo&
Deborah Persuad concluded: "very early cART (31 hours of age) led to sustained HIV-1 remission for 23 months off cART in an infant who is now 41 months of age (Mississippi baby). In a 2nd infant, cART by 4 hours of life led to rapid clearance (within 6 days of life) of replicating virus & proviral DNA, supporting restriction of HIV-1 spread with very early cART. These 2 cases highlight challenges in the monitoring & future management of early-treated infants towards HIV-1 remission. Emphasizes the need for standardized approaches & development of sensitive lab markers to guide optimal management of very early treated HIV-1 infected infants toward viral remission."
"The Mississippi Child at 23 months off cART (age 41 months). A 2nd child, a 9 month old who received ART at 4 hours of age starting with a a 3 drug ART regimen followed by a 4 drug ART regimen remains on ART treatment.....the Mississippi baby remains in care using the20 copy assay HIV-RNA no target has been detected since off therapy since 18 mo of age, now 23 months off treatment. Child remains HIV-1 seronegative and has no HIV-1 specific CTL responses when last tested at 40 & 39 months of age. Using single-copy assay in John Mellors lab there is no detectable RNA in plasma at <1 copy/ml, when tested at 18, 21 and 22 months post-cART cessation when baby was 36, 39, and 40 months old, respectively.....we've done 3 co-culture latency assays looking for persistence of replication competent latent CD4 T-cell reservoir and on cultures of 17 to 2 million cells we are unable to recover replication competent virus....we continue to detect HIV-DNA at very low levels in this child's blood......Mississippi child remains in remission....replication competent resting T-cell reservoirs remain undetectable to date.....supports hypothesis that very early cART my form a barrier to very critical long-lived HIV-1 reservoir formation in perinatal infection that currently preclude cure.....it is intriguing that there is a persistent detection of proviral DNA in this child's peripheral blood cells, we're not sure if this is a real signal or at the assay's limits of detection and requires continued followup and study, it's important to point out the clinical relevance of this detection remains unclear but to date does not signify impending rebound viremia....we believe based on the maternal chimerism studies that this is an unlikely source....obviously the study remains limited we are still unable to amplify any sequence from the peripheral blood to confirm HIV-infection based on maternal sequence & infant similarities: low levels of HIV-1 persistence currently preclude phylogenetic confirmation of HIV-1 persistence, though efforts continue....the 2nd infant....this was a high-risk exposure infant: untreated maternal infection, maternal viral load near delivery=138,811 copies/ml; CD4=70 cells/mm3......at 4 hours of age infant was HIV-DNA positive, HIV-RNA at 36 hours of age showed 217 copies/ml, HV CSF RNA was positive at 6 days of age at 32 copies/mL....plasma viral load was undetectable by 11 days of age and remains undetable at 9 months of age....under ART treatment....child remains on ART....however, when looking at the non-induced proviral genomes in the culture obtained at 1 month of age we could detect in all 5 wells at days 7 & 14 the detection of HIV-DNA but not at a level we could amplify & sequence so its unclear what those signals mean nevertheless subsequent culture data has shown no detection of non-induced proviral genomes... .....proviral DNA was negative after 6 days of age & on cART and remains negative after 2.2 months...we've been unable to detect infectious virus child's resting CD4 T-cells at 1, 3 and 9 months.....proviral DNA remains low, at last testing at 9 months of age its <2 copies/ml....the child has zero-reverted and has become HIV-negative"
Program abstract:
75LB - Very Early Combination Antiretroviral Therapy in Perinatal HIV Infection: Two Case Studies
Deborah Persaud1, Audra Deveikis2, Hannah Gay3, Jagmohan Batra2, Tempe Chen2, David E. Michalik2, Kaitlin Rainwater-Lovett1, Carrie Ziemniak1, Katherine Luzuriaga4, Yvonne Bryson5
1Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD, United States, 2Pediatrics, Miller Children's Hospital, Long Beach, CA, United States, 3Pediatrics, University of Mississippi Medical Center, Jackson, MS, United States, 4Pediatrics, University of Massachusetts Medical School, Worcester, MA, United States, 5Pediatrics, UCLA School of Medicine, Los Angeles, CA, United States
Background: Combination Antiretroviral treatment (cART) by 31 hours of age led to HIV remission in the Mississippi Child where cART cessation did not
lead to rebound viremia. We report follow-up virologic and immunologic markers at 21 months off ART in the Mississippi Child and in a second perinatallyinfected
infant who started cART similar to that of the Mississippi Child (by four hours of age) and remains on cART through age 8 months.
Methodology: Standard HIV DNA and RNA tests were used to confirm infection and assess virologic responses to cART. HIV-specific immune responses
were assessed by ELISA, western blot and cytotoxic T-cell responses. CD4+ and CD8+ T cell percentages were enumerated by flow cytometry. Droplet
digital PCR (DDPCR) was used to quantify proviral burden in peripheral blood mononuclear cells (PBMCs), resting CD4+ T cells, activated CD4+ T cells
and monocytes. Replication-competent proviral genomes were identified using a limiting dilution viral outgrowth assay. Non-induced proviral genomes were
quantified by DDPCR of culture-negative wells.
Results: The Mississippi Child has remained in remission with undetectable plasma viremia (<20 copies/mL) and normal CD4+ and CD8+ T cell counts
at 39 months of age, 21 months after stopping cART. Trace proviral DNA is persistently detectable in PBMCs but replication competent HIV is not; noninduced proviruses were not detected in culture-negative wells. HIV-specific immune responses remain undetectable.
A second infant with high-risk exposure to HIV was started on cART at four hours of age. HIV infection was confirmed by positive peripheral blood HIV DNA
PCR at four hours of life and HIV RNA of 217 copies/mL at 36 hours of age. HIV RNA was detected in CSF at 32 copies/mL on DOL#6. Plasma HIV RNA
was undetectable on DOL#11 and remained undetectable through age 8 months. HIV DNA testing was negative by DOL#6, and remained undetectable
at DOL#47 and 67. Replication-competent HIV was not recovered from resting CD4+ T cells at 1 and 3 months of age; non-induced proviral genomes
were detected by DDPCR, in culture-negative wells, at one month but not age three months. At age 3 months, HIV antibody is indeterminate (western blot
reactivity to gp160). CD4+ T cell percentages remained normal for age.
Conclusions: Very early cART in an HIV-infected infant led to sustained HIV remission through 39 months of age, 21 months after stopping cART. In a
second infant, cART by four hours of life led to rapid clearance of replicating virus and an undetectable proviral DNA by clinical assays within 6 days of life,
supporting restriction of HIV spread with very early cART. Development of sensitive laboratory markers and standardized approaches will be necessary to
guide the optimal management of very early HIV treated infants in order to achieve remission.
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