World Health Organization guidelines for Prevention of HIV infection in infants in resource-limited settings recommend single dose nevirapine (SD-NVP) at onset of labor and to infants at 48-72 hours in addition to zidovudine (ZDV) from 28 weeks'gestation (ZDV28w/SD-NVP), for non immunocompromised women. While this regimen reduces perinatal HIV transmission to ?2%, post exposure resistance mutations to NVP in mothers and infected children raised concerns regarding future efficacy of Non Nucleoside Reverse Transcriptase Inhibitor (NNRTI) based treatments. In industrialized countries similarly low transmission rates are obtained using highly active antiretroviral therapy (HAART) regardless of women's immune status. Such regimens have not been rigorously compared for efficacy and safety with simpler regimens. With the increasing availability of protease inhibitors in resource limited settings and the concerns with use of SD- NVP, we propose to evaluate a simple HAART regimen, ZDV + ritonavir boosted lopinavir (ZDV+LPV/r28w), for prevention of mother to child HIV transmission (PMTCT) in a non-breastfeeding population. The primary objective of this study is to compare the efficacy, long term safety for infants and mothers, and feasibility of ZDV+LPV/r28w versus ZDV28w/SD-NVP for PMTCT. All infants will receive one week ZDV and will be formula fed. Secondary objectives are to: (1) evaluate the mortality, morbidity, CD4 evolution and time to treatment initiation in women up to 24 months after ZDV+LPV/r prophylaxis interruption;(2) assess the incidence of HIV resistance mutations in women after delivery and in HIV infected children;(3) study the pharmacokinetics of LPV/r in Thai pregnant women;and (4) monitor the virological response to ZDV+LPV/r. This multicenter, phase III, randomized, controlled trial will build upon an existing two-arm study, PHPT-5a, with a third arm to be compared with the reference arm (ZQV28w/SD-NVP). The revised study will enroll a total of 2097 consenting HIV-1 infected pregnant women, with CD4 count >250/mm3 (699 per arm including 5% non evaluable;alpha 5%;power: 80%;delta for non-inferiority testing between groups: 1.5%). The primary endpoint is infant HIV status based on confirmed DNA-PCR results at birth, 1, 2, 4 and 6 months. The study represents a collaborative effort of Harvard University, the Institut de Recherche pour le Developpement (France), the Thai Ministry of Public Health, and Mahidol and Chiang Mai Universities, through a network of 45 public hospitals in Thailand. If the simple ZDV+LPV/r28w regimen proves to be efficacious and safe for PMTCT, avoiding risks of resistance mutations to NNRTIs for both mothers and infected children and therefore preserving their future drug options, this study will have important public health imolications for industrialized and developing countries.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD056953-04
Application #
7848250
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Mofenson, Lynne M
Project Start
2007-08-10
Project End
2014-05-31
Budget Start
2010-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$348,934
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Cressey, Tim R; Punyawudho, Baralee; Le Coeur, Sophie et al. (2017) Assessment of Nevirapine Prophylactic and Therapeutic Dosing Regimens for Neonates. J Acquir Immune Defic Syndr 75:554-560
Sripan, Patumrat; Le Coeur, Sophie; Ingsrisawang, Lily et al. (2016) Contribution of different antiretroviral regimens containing zidovudine, lamivudine and ritonavir-boosted lopinavir on HIV viral load reduction during pregnancy. Antivir Ther 21:435-40
Sripan, Patumrat; Le Coeur, Sophie; Amzal, Billy et al. (2015) Modeling of In-Utero and Intra-Partum Transmissions to Evaluate the Efficacy of Interventions for the Prevention of Perinatal HIV. PLoS One 10:e0126647
Lallemant, Marc; Le Coeur, Sophie; Sirirungsi, Wasna et al. (2015) Randomized noninferiority trial of two maternal single-dose nevirapine-sparing regimens to prevent perinatal HIV in Thailand. AIDS 29:2497-507
Cressey, Tim R; Urien, Saik; Capparelli, Edmund V et al. (2015) Impact of body weight and missed doses on lopinavir concentrations with standard and increased lopinavir/ritonavir doses during late pregnancy. J Antimicrob Chemother 70:217-24
Cressey, Tim R; Jourdain, Gonzague; Rawangban, Boonsong et al. (2010) Pharmacokinetics and virologic response of zidovudine/lopinavir/ritonavir initiated during the third trimester of pregnancy. AIDS 24:2193-200