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Association of HIV-1 Replication Capacity with HIV-1 Mother-to-Child Transmission among ART-naïve Malawian Women: NVAZ Trial
Susan H. Eshleman*1, S Chen2, Y Lie3, D Hoover4, S Hudelson1, S Fiscus5, C Petropoulos3, N Kumwenda2, T Taha2, N Parkin3, and the NVAZ study group
1Johns Hopkins Univ Sch of Med, Baltimore, MD, US; 2Johns Hopkins Univ, Bloomberg Sch of Publ Hlth, Baltimore, MD, US; 3Monogram Biosci, South San Francisco, CA, US; 4Rutgers Univ, Piscataway, NJ, US; and 5Univ of North Carolina at Chapel Hill, US
Background: HIV
pol
replication capacity is a potentially important determinant of viral fitness
and pathogenicity. We examined the association of
HIV-1 replication capacity and HIV-1 mother-to-child transmission among ART-
naïve Malawian women enrolled in the NVAZ late presenter trial. The subtype C
HIV-infected women in this trial did not receive any ART prophylaxis; infants
received single-dose nevirapine (sdNVP)
at birth, and were randomized to either receive or not receive 1 week of daily zidovudine (ZDV).
Methods: Plasma
samples were collected from women at delivery. Study subjects included 52 women
whose infants were HIV-1 infected at birth or during the first 6 to 8 weeks
after birth (transmitters) and 48 women whose infants remained uninfected 6 to 8
weeks after birth (nontransmitters); 54% of infants
received sdNVP only, and 46% of infants received sdNVP + ZDV. Replication capacity was determined using PhenoSense HIV (Monogram Biosciences). In this assay,
protease reverse transcriptase coding sequences from the test sample are
transferred to a subtype B resistance test vector, which is co-transfected into cells with a plasmid encoding a heterologous envelope protein. The efficiency of infection
in a single replication cycle is compared to that of a reference strain to
determine the replication capacity. A replication capacity of 100% indicates
that the replication capacity
of the resistance test vector is equal to the median of a wild type (drug
sensitive) virus population. For some analyses, replication capacity was log
transformed to remove skewness.
Results: The
mean replication capacity for the maternal plasma samples was 32% (standard
deviation = 20%). The mean replication capacity was higher for transmitters
35.3% vs non-transmitters 27.4% (p = 0.02, Wilcoxon test). In a multivariate model, a higher log10 replication
capacity was associated with HIV-1 transmission (OR = 6.60, 95%CI 1.23 to 35.31,
p = 0.03), adjusting for log10
delivery viral load (OR = 2.77, 95%CI 1.38 to 5.57, p = 0.0043), maternal age (OR = 1.01,
95%CI 0.88 to 1.16, p = 0.89), parity
(OR = 1.34, 95%CI 0.90 to 2.00, p = 0.15),
and infant regimen (OR = 0.61, 95%CI 0.23 to 1.61, p = 0.31).
Conclusions: In
unadjusted and multivariate models, higher HIV-1 replication capacity was associated
with HIV-1 mother-to-child transmission in Malawian women with subtype C whose
infants received either sdNVP
or sdNVP plus a short course of ZDV. Further studies
are needed to confirm the association of replication capacity and HIV-1
transmission in different HIV-1 subtypes and different clinical settings.
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