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ACTG 5153s: Pharmacokinetic Exposure and Virological Response in HIV-1-infected Pregnant Women Treated with PI
Francesca Aweeka*1, C Tierney2, A Stek3, X Sun2, S Cohn4, R Coombs5, P Lizak1, A Kmack6, K Klingman7, and B Sha8
1Univ of California, San Francisco, US; 2Statistical & Data Analysis Ctr, Harvard Sch of Publ Hlth, Boston, MA, US; 3Univ of Southern California, Los Angeles, US; 4Univ of Rochester, NY, US; 5Univ of Washington, Seattle, US; 6Frontier Sci & Tech Res Fndn, Amherst, NY, US; 7Div of AIDS, NIAID, NIH, Bethesda, MD, US; and 8Rush Univ Med Ctr, Chicago, IL, US
Background: Pregnancy may lead to reduced protease inhibitor (PI)
levels leading clinicians to modify dosages. We studied the pharmacokinetics
and pharmacodynamics of boosted lopinavir/rotinavir (LPV/r) and nelfinavir
(NFV) to assess whether the area under the plasma concentration versus time
curve (AUC) is altered in pregnancy and whether changes in exposure affect
HIV-1 virologic control.
Methods: We enrolled pregnant women ≥13 years of
age between 22 to 30 weeks’ gestation who expected to be on stable LPV/r or NFV
for ≥8 weeks at delivery as part of protocol A5150. Pharmacokinetics
evaluations for LPV, ritonavir (RTV), NFV, and its active M8 metabolite
occurred at 36 weeks gestation and 6 and 24 weeks postpartum. Ante- and post-partum
were compared using the difference of the postpartum to AP log-scaled AUC.
Plasma HIV-1 RNA levels were measured.
Results: For this pharmacokinetics analysis, 10 women
(5 black non-Hispanic and 3 Hispanic) contributed to LPV/r and 9 (1 black
non-Hispanic and 8 Hispanic) to NFV. Geometric mean AUC0-6h (95%CI)
for LPV were 26.5 (17.0 to 41.4) and 41.9 (26.1 to 67.5) h*µg/mL at 36 weeks’
gestation and 6 weeks’ post-partum, respectively; within-subject geometric mean
ratio (GMR) 0.60 (0.25 to 1.43); p = 0.19.
(Insufficient data precluded 24 weeks post-partum). For RTV, 36 weeks’
gestation values were significantly lower, with geometric mean of 0.99 (0.58 to
1.68) compared with 2.5 (1.4 to 4.6) µg*h/mL at 6 weeks post-partum (GMR 0.36, 0.14
to 0.92; p = 0.04). For NFV, values
did not differ significantly during pregnancy compared to 6 (GMR 1.01, 0.64 to
1.62; p = 0.95) or 24 weeks post-partum
(GMR 0.77, 0.53 to 1.12; p = 0.13).
For month 8, ante-partum values did not differ significantly from 6 weeks post-partum
(GMR 0.42, 0.12 to 1.53; p = 0.14),
however, they were significantly lower than 24 weeks postpartum with means of
1.3 (0.68 to 2.5) and 4.5 (2.1, 9.7), respectively (GMR 0.32, 0.19 to 0.56; p = 0.003). In the LPV/r group, at 36 weeks’
gestation, 6 of 10 had a viral load <200 copies/mL (10 of 10 <2000
copies/mL) and 6 weeks post-partum 9 of 10 had a viral load <200 copies/mL.
In the NFV group at 36 weeks’ gestation 7 of 9 had a viral load <200 copies/mL
(9 of 9 <2600 copies/mL) and 6 weeks post-partum 8 of 9 had a viral load
<200 copies/mL. The baby’s HIV status was negative for all 18 subjects with
data.
Conclusions: RTV and month 8 AUC had significantly lower
exposure during pregnancy with a trend toward diminished exposure for LPV, but
not for NFV. Despite variability in ART exposure, subjects sustained virologic
control. These results suggest dosage adjustments for protease inhibitors (PI)
during pregnancy, and may not be necessary for the majority of patients.
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