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Pharmacokinetic, Safety and Efficacy of
Darunavir/Ritonavir in HIV+ Pregnant Women
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program abstract
Reported by Jules Levin
17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, June 8-10, 2016, Washington DC
M. Le1, L. Blondel1, C. Charpentier2, S. Matheron3, R. Tubiana4, C. Soulié5, C. Borie6, A.G. Marcelin5, D. Descamps2, L. Mandelbrot7, G. Peytavin1
1Hôpital Bichat-Claude Bernard, Clinical PharmacoToxicology, Paris, France; 2Hôpital Bichat-Claude Bernard, Virology, Paris, France; 3Hôpital Bichat-Claude Bernard, Infectious Diseases, Paris, France; 4Hôpital Pitié-Salpétrière, Infectious Diseases, Paris, France; 5Hôpital Pitié-Salpétrière, Virology, Paris, France; 6Hôpital Robert Debré, Gyneco-obstetrics, Paris, France; 7Hôpital Louis Mourier, Gyneco-obstetrics, Colombes, France
Introduction: Darunavir/ritonavir (DRV/r) is the most popular protease inhibitor recommended to prevent the risk of HIV mother-to-child trans-mission. However, a decrease of DRV plasma exposure during the 3rd trimester which might put at risk the efficacy of the ARV strategy. The objectives were to assess maternal DRV plasma concentrations and to describe the safety and efficacy of DRV/r containing regimen.
Materials & Methods: A multicentre, cross-sectional, cohort was conducted from 2006 to 2015. HIV pregnant women receiving DRV/r (800/100mg QD or 600/100mg BID) containing regimen, with available demographics characteristics, plasma HIV-RNA (pVL) and CD4 count were enrolled. Switch from DRV/r QD to BID was recommended during pregnancy. Total and unbound DRV C24h and C12h were determined by UPLC-MS/MS at the three trimesters (Tn) of pregnancy and at delivery. Safety assessments and newborn data (weight, gestational age, APGAR score) were collected. Results are presented as medians (IQR).
Results: 220 pregnant women were included: aged 32 years old (28-36), 89% from sub-Saharan Africa, with HIV diagnosis since 7 years (6-12), 98% HIV-1 infected, 12% HBV+ and 4% HCV+ co-infected, 84% cART-experienced; ART backbone: 60% FTC/TDF, 15% ABC/3TC, 10% NRTIs+RAL, 5% ZDV/3TC, 5% DRV/r monotherapy. Before pregnancy, 149 women received DRV/r 800/100mg QD (among them,61 women switched to DRV/r 600/100mg BID during pregnancy) and 71 women received DRV/r 600/100mg BID ante-partum, throughout the period of pregnancy and post-partum. Before pregnancy (>6 months), BMI was 27 (23-30) kg/m² and CD4 nadir 270 (164-391) cells/mm3.
DRV plasma concentrations during pregnancy were: at T1, DRV C24h 1,574 ng/mL (1,101-2,033; n=33) and DRV C12h 2,088 (1,219-2,835; n=13); at T2, DRV C24h 1,144 ng/mL (743-1,605; n=81) and DRV C12h 2,174 ng/mL(1,534-2,812; n=49); at T3, DRV C24h 934 ng/mL (707-1,160; n=81) and DRV C12h 2,134 ng/mL (1,560-2,893; n=98); and at delivery, DRV C24h 853 ng/mL (479-1,617; n=30) and DRV C12h 2,033 ng/mL (1,081-2,793; n=53). DRV C24h was significantly lower at T2 and T3 than in T1 (-28%, p<0.05 and -41%, p<0.0001, respectively). DRV C12h was similar between T1, T2 and T3 (p=NS). At T3, 2% of DRV C12h and 12% of DRV C24h were < 550 ng/mL (10 fold protein adjusted EC50 for Wild-Type HIV). Cord blood/maternal ratio of DRV plasma concentration was 0.16 (0.07-0.42, n=91), consistently with previous studies. RTV C24h and C12h remained similar between the 3 trimesters. At birth, gestational age was 36 weeks (37-40): 20% <37 weeks and 4% <32 weeks, newborns' weight 2,910 gr (2,600-3,190; n=37), and APGAR score 10, and 84% of women presented pVL <50 copies/mL: 13% with 50< pVL< 400 copies/mL (69% receiving DRV/r 800/100mg QD) and 3% with pVL >400 copies/mL (40% receiving DRV/r 800/100mg QD). To date, no case of mother-to-child HIV transmission was observed.
Conclusions: In this population of mostly African HIV+ pregnant women, DRV/r containing regimen demonstrated a good virological efficacy at delivery. No significant impact of the pregnancy term was found on DRV C12h in contrast with DRV C24h, lower at T2 and T3.
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