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  17th International Workshop
on Clinical Pharmacology of
HIV and Hepatitis Therapy
June 8-10, 2016, Washington DC
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Darunavir Troughs Lower in Trimesters 2 and 3 With Once-Daily Dosing
  17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, June 8-10, 2016, Washington DC
Mark Mascolini
Darunavir/ritonavir (DRV/r) taken once or twice daily during pregnancy kept viral loads below 400 copies at delivery in 96% of 220 women in France, and no woman transmitted HIV to her infant [1]. Darunavir trough concentrations were lower in the second and third trimester than in the first trimester with once-daily dosing, but not with twice-daily dosing.
Although DRV/r ranks as a leading choice for prevention of mother-to-child transmission, research shows lower darunavir plasma levels during the third trimester than earlier in pregnancy [2,3]. A multicenter French team conducted this cross-sectional study to determine maternal darunavir and ritonavir plasma levels throughout pregnancy and to assess their impact on viral load.
The study involved 220 pregnant women taking DRV/r once-daily (800/100 mg) or twice-daily (600/100 mg) during 2006-2015. No one was taking a CYP450 inducer. Median age stood at 32 years (interquartile range [IQR] 28 to 36), and 94% of women were from sub-Saharan Africa. The women had been diagnosed with HIV for a median of 6 years, and 83% had antiretroviral experience before pregnancy. Median body mass index stood at 27 kg/m(2) (IQR 23 to 30) before pregnancy, and median nadir CD4 count was 270 (IQR 164 to 391).
French national guidelines recommend switching from once-daily to twice-daily DRV/r during pregnancy. Among these 220 women, 149 (68%) took once-daily DRV/r, 88 (40%) took the once-daily dose throughout pregnancy, 61 (28%) switched to twice-daily dosing during pregnancy, and 71 (32%) took the twice-daily dose throughout pregnancy.
With the once-daily dose, darunavir trough (C24h/once-daily dosing) was significantly lower in the second trimester than the first (-27%, P < 0.05) and during the third trimester than the first (-40%, P < 0.0001). With the twice-daily dose, darunavir trough (C12h/twice-daily dosing) did not differ significantly between the first and later trimesters. Median darunavir C24h fell from 1574 ng/mL (IQR 1101 to 2033) in the first trimester, to 1144 ng/mL (IQR 743 to 1605) in the second trimester, to 934 ng/mL (IQR 707 to 1160) in the third trimester, and to 854 ng/mL (IQR 480 to 1617) at delivery. During the third trimester, 12% of darunavir C24h levels and 2% of C12h levels lay below 550 ng/mL (10-fold the protein-adjusted 50% effective concentration for wild-type [nonmutant] HIV). Ritonavir C24h and C12h remained similar in the three trimesters.
Median cord-to-maternal blood ratio for darunavir stood at 0.16 (IQR 0.07 to 0.42) overall and did not differ substantially with once-daily dosing (0.18) versus twice-daily dosing (0.14). Median gestational age measured 38 weeks (IQR 35 to 40), 20% of newborns had a gestational age less than 37 weeks, and 4% were less than 32 weeks. Median newborn weight measured 3160 g (IQR 2805 to 3487) and median APGAR score 10.
Most women, 82%, had a viral load below 50 copies in the third trimester and at delivery, while only 4% had a load above 400 copies. Median viral load at delivery among women with a load above 50 copies measured 109 copies (IQR 87 to 263). At the time of this presentation, no vertical HIV transmissions had occurred.
1. Le M, Blondel L, Charpentier C, et al. Pharmacokinetics, safety and efficacy of darunavir/ritonavir in HIV+ pregnant women. 17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, June 8-10, 2016, Washington DC. Abstract O1.
2. Stek A, Best BM, Wang J, Capparelli EV, et al. Pharmacokinetics of once versus twice daily darunavir in pregnant HIV-infected women. J Acquir Immune Defic Syndr. 2015;70:33-41.
3. Colbers A, Molto J, Ivanovic J, et al. Pharmacokinetics of total and unbound darunavir in HIV-1-infected pregnant women. J Antimicrob Chemother. 2015;70:534-542.