Comparison of Efficacy and Safety of Infant Peri-exposure Prophylaxis With Lopinavir/Ritonavir Versus Lamivudine to Prevent HIV-1 Transmission by Breastfeeding

The ANRS 12174 study is a clinical trial that will compare the efficacy and safety of prolonged infant peri-exposure prophylaxis (PEP) with Lopinavir/Ritonavir (LPV/r) versus Lamivudine to prevent HIV-1 transmission through breast milk in children born to HIV-1-infected mothers not eligible for HAART and having benefited from perinatal antiretroviral (ART) regimens. The study will recruit 1500 mother-infant pairs in 4 African countries.

Study design:

PROMISE PEP is a multinational, randomised double-blind controlled clinical trial.

Intervention:

Infants will be randomised to receive LPV/r or 3TC twice daily from day seven (± 2 days) after birth until 4 weeks after cessation of breastfeeding (BF). We will recommend exclusive BF (EBF) up till including the 26th week of life followed by a relatively rapid (maximum of 8 weeks) cessation period. The maximum duration of PEP will thereby be 38 weeks.

Primary objective:

To compare the efficacy of infant LPV/r (40/10mg twice daily if 2-4kg and 80/20mg twice daily if \>4kg) vs. Lamivudine 7,5mg twice daily if 2-4kg, 25mg twice daily if 4-8kg and 50mg twice daily if \>8kg) from day 7 until 4 weeks after cessation of BF (maximum duration of prophylaxis: 50 weeks for a maximum duration of breastfeeding of 46 weeks) to prevent postnatal HIV-1 acquisition between 7 days and 50 weeks of age.

Secondary objectives:

* To assess the safety of long-term infant prophylaxis with LPV/r versus Lamivudine (including resistance, adverse events and growth) until 50 weeks.
* HIV-1-free survival until 50 weeks
* To build clinical trials capacity at the four study sites.

Main endpoint:

Acquisition of HIV-1 (as assessed by HIV-1 DNA PCR) between day 7 and 50 weeks of age

Study population:

HIV-uninfected infants at day 7 (± 2 days) born to HIV-1 infected mothers not eligible for HAART who choose to breastfeed their infants and who have benefited from the national prevention of mother to child transmission (PMTCT) program during pregnancy and delivery. The study will recruit 1500 mother-infant pairs in Burkina Faso, South Africa, Uganda and Zambia.

Study duration:

Infants will be followed up for 50 weeks and the total study duration is five years.

Expected outcome:

This study will inform on the relative advantages (efficacy) and drawbacks of two interventions to support HIV-1-infected women not eligible for HAART to safely breastfeed their babies. If found to be safe and efficacious, the regimens would avoid the existing contradiction between optimal infant feeding and the prevention of MTCT through breast milk. Clinical trial capacity development will improve the future quality of trials conducted in these countries.


Eligibility Criteria:
Inclusion Criteria: A baby will be included if she/he:

* is a singleton
* is breastfed at day 7 by her/his mother and her/his mother intends to continue breastfeeding for at least 6 months
* has a post-partum blood sample with a negative HIV-1 DNA PCR test result at day 7 (+/- 2 days)
* has received ART as part of PMTCT

and if the mother:

* has reached the local legal age for participating in medical research studies
* is shown to be HIV-1 infected (with or without HIV-2 infection) and is not eligible for HAART or is not taking HAART
* has received a perinatal antiretroviral prophylaxis during pregnancy and delivery,
* has a CD4 count above the threshold of HAART initiation in pregnant women according to the national recommendation in each site (minimum 230 cells/µL),
* resides within the study area and is not intending to move out of the area in the next year
* gives assent for the infant to participate and gives consent to participate

Exclusion Criteria:

* S/he presents clinical symptoms and/or biological abnormalities equal to or greater than grade II of the ANRS classification for adverse event on the day of enrolment
* S/he presents with serious congenital malformation(s)
* Her/his birth weight is lower than 2.0 kg
* Her/his antiretroviral prophylaxis is extending beyond day 7
* The mother has participated in the trial for a previous pregnancy
* S/he and her/his mother are participating in another clinical trial on the day of enrolment