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Specific Effects of ZDV, 3TC and LPV/r on HIV-1 RNA Viral Load During Pregnancy
Patumrat Sripan1, Sophie Le Coeur 5, Lily Ingsrisawang2, Tim R. Cressey3, Jean-Marc Tréluyer6, Naïm Bouazza4, Frantz Foissac4, Gonzague Jourdain3, Marc G. Lallemant3, Saïk Urien7
1 ED420, University of Paris Sud 11, Paris Descartes, Paris, France/PHPT-IRD UMI 174, Chiang Mai, Thailand/Department of Statistics, Faculty of Science, Kasetsart University, Bangkok, Thailand. 2 Department of Statistics, Faculty of Science, Kasetsart University, Bangkok, Thailand. 3 PHPT-IRD UMI 174, Faculty of Associated Medical Sciences, Chiang Mai University/Harvard School of Public Health, Chiang Mai, Thailand. 4 EA 08 Université Paris Descartes, Sorbonne Paris Cité, Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Paris, France. 5 Institut d'Etudes Démographiques, Institut de Recherche Pour le Développement (UMR 196 CEPED), Paris, France/Harvard School of Public Health, Boston, MA, USA/Faculty of Associated Medical Science, Chiang Mai University, Chiang Mai, Thailand. 6 EA 08 Université Paris Descartes, Sorbonne Paris Cité, Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Service de Pharmacologie Clinique, AP-HP, Groupe Hospitalier Paris Centre, CIC-0901 Inserm, Cochin-Necker, Paris, France. 7 EA 08 Université Paris Descartes, Sorbonne Paris Cité, Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, CIC-0901 Inserm, Cochin-Necker, Paris, France.
Background: HIV-infected women commonly receive zidovudine (ZDV) + lamivudine (3TC) + lopinavir/ritonavir (LPV/r) during pregnancy for the prevention of mother-to-child transmission (PMTCT) in Thailand. Our aims were to evaluate the role of 3TC added to ZDV+LPV/r and the specific effect of each drug on maternal HIV-1RNA viral load (VL) reduction for the PMTCT.
Methods: A total of 1,655 plasma VL levels from 702 pregnant women enrolled in the PHPT-5 perinatal HIV prevention trial in Thailand (NCT01511237, NCT00409591) were included. ART naïve pregnant women received either (1) ZDV only (plus nevirapine at onset of labor); (2) ZDV+LPV/r; or (3) ZDV+3TC+LPV/r. HIV-1 RNA VL time courses were analysed using non-linear mixed effect modelling and dependent on VL at treatment initiation and duration of treatments. An Emax response model was used to describe the impact of these ARV regimens on VL reduction during pregnancy. A mechanistically-based equation was developed to determine the contribution of each drug assuming ZDV and 3TC have the same target and mechanism of action, and the effect of LPV/r was added as a separate component.
Results: Of the 702 women, 278 (40%) received ZDV monotherapy, 146 (20%) ZDV+LPV/r and 278 (40%) ZDV+3TC+LPV/r during pregnancy. The maximum effect of each regimen on HIV-1 RNA VL was significantly different (p<0.02), with 1.67, 3.8 and 4.57 log10copies/mL reduction for ZDV alone, ZDV+LPV/r and ZDV+3TC+LPV/r, respectively. Time to reach half of maximum effect (T50) was significantly longer with ZDV alone compared with ZDV+3TC+LPV/r (p<0.001). However there was no significant difference between ZDV+LPV/r and ZDV+3TC+LPV/r (p=0.13). The mechanistically-based model estimated that 110 days of ZDV or 3TC were necessary to achieve half of ZDV or 3TC maximum effect on viral load suppression (maximum effect: minus 1.38 and 2.05 log10copies/mL, respectively) whereas only 10 days of LPV/r were necessary to achieve half of LPV/r maximum effect (maximum effect: minus 2.32 log10 copies/mL). Using the mean VL at treatment initiation (4.07 log10 copies/mL), the model indicated that the addition of 3TC reduced the time to undetectable VL (<50copies/mL) by 3 weeks: 7.3 weeks with ZDV+LPV/r compared with 4.4 weeks for ZDV+3TC+LPV/r assuming a common T50 for ZDV and 3TC.
Conclusions: The addition of 3TC to ZDV+LPV/r during pregnancy reduces time to reach undetectable VL in pregnant women, especially those with a high VL at treatment initiation and subsequent high risk of MTCT.