617
Acquisition and Archiving of Non-Nucleoside Reverse Transcriptase Inhibitor-resistant HIV-1 Variants during Mother-to-Child Transmission in US-born Infants
Deborah Persaud*1, P Palumbo2, C Ziemniak1, P Havens3, E Chadwick4, and Pediatric AIDS Clin Trials Group P1030 Team
1Johns Hopkins Univ Sch of Med, Baltimore, MD, US; 2Univ of Med and Dentistry of New Jersey, Newark, US; 3Children's Hosp of Wisconsin, Milwaukee, US; and 4Northwestern Univ Children's Memorial Hosp, Chicago, IL, US
Background: Non-nucleoside
reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 occurs in at least 65%
of women and 46% of infants receiving single-dose nevirapine (NVP) for
prevention of mother-to-child transmission (PMTCT). The extent to which these drug-resistant
HIV-1 variants become permanently archived in long-lived viral reservoirs is
unknown.
Methods: We evaluated,
longitudinally, persistence of NNRTI-resistant HIV-1 in U.S. infants
with perinatally acquired HIV-1 infection, who were enrolled in a multi-center,
open-label, phase I/II trial of lopinavir/ritonavir (LPV/r) for early treatment
of HIV-1 infection. From June 2002 until November 2004, 17 of the 24 HIV-1-infected
children enrolled in the trial had taken a study drug for at least 24 weeks, 13
for 48 weeks and 6 for 96 weeks. A limiting dilution culture assay of purified
resting CD4+ T cells that allows for analysis of HIV-1 variants in
individual cells was done at 24, 48, and 96 weeks of treatment.
Replication-competent viral clones were genotyped and assessed for resistance
mutations, which were correlated with antiretroviral drug exposure. Maternal
treatment histories were not collected.
Results: Of the 17 children,
13 received prophylaxis with zidovudine (AZT) (median of 4 weeks; range 2 to 8
weeks). Of these infants, 3 received NVP, 1 of whom received a combination of AZT/lamivudine
(3TC)/NVP. No infant received NVP during HAART. A total of 116 viral isolates
were recovered from 16 of the 17 infants, and drug-resistant HIV-1 was detected
in the resting CD4+ T cell reservoir in 6 of 16 (38%) infants. NNRTI-resistant
HIV-1 was detected in 4 of 16 (25%) infants at a median of 24 weeks of HAART
and persisted as long as 2 years of effective HAART. The NNRTI-mutations
detected were: K103S (1), V106I/Y188H (1), V106A/Y188C (1), G190A (1). Only 1 of
these 4 infants had a history of NVP prophylaxis. The non-NNRTI-resistance
mutations detected were M184V (3) and, in 1 infant, M41L/T215Y.
Conclusions: NNRTI-resistant
HIV-1 acquired through MTCT or selection during immediate postpartum
chemoprophylaxis becomes permanently archived in latent viral reservoirs in
some infants. K103N, one of the more common mutations associated with NVP prophylaxis
for PMTCT, was not detected in this cohort. The presence of these
NNRTI-resistant variants does not preclude treatment success with LPV-based
HAART.
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