Frequent Emergence of Lamivudine and NNRTI Drug Resistance during Pregnancy-limited ART in the US
Roger Paredes*1,2, I Cheng3, D Kuritzkes1, R Tuomala1, and Women and Infants Study Group (WITS)
1Brigham and Women`s Hosp, Harvard Med Sch, Boston, MA, US; 2Fndns irsiCaixa and Lluita contra la SIDA, Univ Autonoma de Barcelona, Catalonia, Spain; and 3Clinical Trials & Surveys Corp, Baltimore, MD, US
Background: Pregnancy-limited (ART) drastically
reduces HIV-1 transmission to the newborn, but may select for antiretroviral
drug-resistance mutations (DRM) in exposed women.
Methods: We evaluated antiretroviral-naive,
HIV-1-infected pregnant women enrolled in the WITS cohort who received pregnancy-limited
ART between 1998 and 2004, and had 2- or 6-month postpartum plasma samples
available with HIV-1 RNA levels (viral load) >500 copies/mL. Postpartum
rates of DRM were assessed blindly using bulk sequencing of protease (PR) and
reverse transcriptase (RT), and allele-specific polymerase chain reaction (AS-PCR)
of the M184V, K103N, and D30N mutations (detection threshold 0.4%, 0.003%, and
0.1%, respectively). Factors associated with emergence of M184V, K103N, and
D30N were compared with χ2, Fisher’s exact test, or F-test, as
needed. Multivariate odds of developing M184V or K103N were evaluated using a General
Estimating Equations model (SAS procedure GENMOD).
Results: Of the 146 women who fulfilled the
inclusion criteria, the mean age was 26.7 (SD 5.23) years; 57.5% were black and
35.6% Hispanic; and 27.4% had a history of illicit drug use. Postpartum median
CD4+ counts were 575 (IQR 397 to 767) cells/mm3, median viral
load was 4780 (IQR 1352 to 18121) copies/mL. All women received, at least, zidovudine
(AZT) + lamivudine (3TC); 76% also received nelfinavir (NFV) and 8.2%
nevirapine (NVP). DRM data were available from 114 women (78%). By bulk
sequencing, NRTI-DRM rates in women receiving only AZT/3TC were: M41L = 5.0%,
D67N = 5.0%, K70R = 10.0%, M184V/I = 65.0% (95.0% by AS-PCR), and T215Y = 5.0%.
In women receiving 3 drugs, rates were: M41L = 1.1%, D67N = 1.1%, K70R = 1.1%,
M184V/I = 28.7% (51.6% by AS-PCR), and K219Q = 1.1%. NNRTI-DRM rates among
women receiving NVP were: K103N = 25% (37.5% by AS-PCR), Y188C = 12.5%. PI-DRM
rates in those receiving NFV were: D30N = 1.1% (1.1% by AS-PCR), and L90M = 1.1%.
In the multivariate analysis, variables associated with emergence of M184V were
triple vs dual pregnancy-limited ART (OR = 0.05, 95%CI 0.01 to 0.40, p <0.01),
and prolonged exposure to AZT (OR per additional month = 1.29, 95%CI 1.02 to 1.62,
p = 0.03). Variables associated with emergence of K103N were NVP use (OR
= 9.75, 95%CI 1.61 to 58.83, p = 0.01) and length of AZT/3TC (OR per
additional month = 1.46, 95%CI 1.05 to 2.02, p = 0.02).
Conclusions: Selection of 3TC and NNRTI resistance
is frequent during pregnancy-limited ART, but selection of PI resistance is
rare. Triple-drug pregnancy-limited ART decreases the odds for M184V selection.
Routine postpartum genotypic resistance testing may be useful to guide future
treatment decisions in mothers.