Clinical trial NCT00640263: Comparison of Efficacy and Safety of Infant Peri-exposure Prophylaxis With Lopinavir/Ritonavir Versus Lamivudine to Prevent HIV-1 Transmission by Breastfeeding
Official title: A Randomised Controlled Trial Comparing the Efficacy of Infant Peri-exposure Prophylaxis With Lopinavir/Ritonavir (LPV/r) Versus Lamivudine to Prevent HIV-1 Transmission by Breastfeeding
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: HIV-1
Breastfeeding
Prevention
lamivudine
lopinavir/ritonavir
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: European and Developing Countries Clinical Trials Partnership (EDCTP)
name: The Research Council of Norway
name: Swedish International Development Cooperation Agency (SIDA)
name: Université Montpellier
name: University of Bergen
First posted: 2008-03-21
Enrollment: 1500
Sex: ALL
Minimum age (years): 5
Maximum age (years): 9
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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

Primary outcomes:
measure: Acquisition of HIV-1 (as determined by HIV-1 DNA PCR)
timeFrame: between day 7 and 50 weeks of age
Secondary outcomes:
measure: HIV-1 free survival
timeFrame: at 50 weeks of age
measure: HIV-1 free survival
timeFrame: at one year of age
measure: safety of long-term prophylaxis
timeFrame: until 50 weeks of age
measure: safety of long-term prophylaxis
timeFrame: until one year of age
Other outcomes:
Locations:
city: Ouagadougou
country: Burkina Faso
facility: Université de Ouagadougou
city: East London
country: South Africa
facility: East London Hospital Complex
city: Kampala
country: Uganda
facility: Dept of Paediatrics and Child Health, Makerere University
city: Lusaka
country: Zambia
facility: Dept of Paediatrics and Child Health, School of Medicine, University of Zambia
Study officials:
affiliation: University of Montpellier, France
name: Philippe Vande Perre, MD, PhD
role: STUDY_CHAIR
affiliation: Centre For International Health
name: Thorkild Tylleskär, MD, PhD
role: STUDY_CHAIR
affiliation: University of Ouagadougou, Burkina Faso
name: Nicolas Meda, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Dept of Paediatrics and Child Health, Makerere University, Uganda
name: James K Tumwine, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Dept of Paediatrics and Child Health, School of Medicine, University of Zambia
name: Chipepo Kankasa, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: East London Hospital Complex
name: Justus Hofmeyer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Uppsala University, Uppsala, Sweden
name: Eva-Charlotte Ekström, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Necker Enfants Malades, Université Paris V (EA 3620)
name: Stephane Blanche, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kourtis AP, Jamieson DJ, de Vincenzi I, Taylor A, Thigpen MC, Dao H, Farley T, Fowler MG. Prevention of human immunodeficiency virus-1 transmission to the infant through breastfeeding: new developments. Am J Obstet Gynecol. 2007 Sep;197(3 Suppl):S113-22. doi: 10.1016/j.ajog.2007.03.003.
citation: Birungi N, Fadnes LT, Engebretsen IMS, Tumwine JK, Astrom AN; for ANRS 12174 AND 12341 study groups. Antiretroviral treatment and its impact on oral health outcomes in 5 to 7 year old Ugandan children: A 6 year follow-up visit from the ANRS 12174 randomized trial. Medicine (Baltimore). 2020 Sep 25;99(39):e22352. doi: 10.1097/MD.0000000000022352.
citation: Birungi N, Fadnes LT, Engebretsen IMS, Lie SA, Tumwine JK, Astrom AN; ANRS 12174 and 12341 study groups. Caries experience and oral health related quality of life in a cohort of Ugandan HIV-1 exposed uninfected children compared with a matched cohort of HIV unexposed uninfected children. BMC Public Health. 2020 Mar 30;20(1):423. doi: 10.1186/s12889-020-08564-1.
citation: Montoya-Ferrer A, Sanosyan A, Fayd'herbe de Maudave A, Pisoni A, Bollore K, Moles JP, Peries M, Tylleskar T, Tumwine JK, Ndeezi G, Gorgolas M, Nagot N, van de Perre P, Tuaillon E. Clinical and Biological Factors Associated With Early Epstein-Barr Virus Infection in Human Immunodeficiency Virus-Exposed Uninfected Infants in Eastern Uganda. Clin Infect Dis. 2021 Mar 15;72(6):1026-1032. doi: 10.1093/cid/ciaa161.
citation: Birungi N, Fadnes LT, Engebretsen IMS, Lie SA, Tumwine JK, Astrom AN; ANRS 12174 and 12341 study groups. Association of maternal HIV-1 severity with dental caries: an observational study of uninfected 5- to 7-yr-old children of HIV-1-infected mothers without severe immune suppression. Eur J Oral Sci. 2020 Feb;128(1):46-54. doi: 10.1111/eos.12669. Epub 2020 Jan 29.
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citation: Blanche S, Tylleskar T, Peries M, Kankasa C, Engebretsen I, Meda N, Tumwine JK, Singata-Madliki M, Mwiya M, Van de Perre P, Nagot N; ANRS 12174 Trial Group. Growth in HIV-1-exposed but uninfected infants treated with lopinavir-ritonavir versus lamivudine: a secondary analysis of the ANRS 12174 trial. Lancet HIV. 2019 May;6(5):e307-e314. doi: 10.1016/S2352-3018(18)30361-8. Epub 2019 Feb 24.
citation: Some EN, Engebretsen IMS, Nagot N, Meda N, Lombard C, Vallo R, Peries M, Kankasa C, Tumwine JK, Hofmeyr GJ, Singata M, Harper K, Van De Perre P, Tylleskar T; ANRS 12174 Trial Group. Breastfeeding patterns and its determinants among mothers living with Human Immuno-deficiency Virus -1 in four African countries participating in the ANRS 12174 trial. Int Breastfeed J. 2017 May 2;12:22. doi: 10.1186/s13006-017-0112-2. eCollection 2016.
citation: Foissac F, Blume J, Treluyer JM, Tylleskar T, Kankasa C, Meda N, Tumwine JK, Singata-Madliki M, Harper K, Illamola SM, Bouazza N, Nagot N, Van de Perre P, Blanche S, Hirt D. Are Prophylactic and Therapeutic Target Concentrations Different?: the Case of Lopinavir-Ritonavir or Lamivudine Administered to Infants for Prevention of Mother-to-Child HIV-1 Transmission during Breastfeeding. Antimicrob Agents Chemother. 2017 Jan 24;61(2):e01869-16. doi: 10.1128/AAC.01869-16. Print 2017 Feb.
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citation: Nagot N, Kankasa C, Meda N, Hofmeyr J, Nikodem C, Tumwine JK, Karamagi C, Sommerfelt H, Neveu D, Tylleskar T, Van de Perre P; PROMISE-PEP group. Lopinavir/Ritonavir versus Lamivudine peri-exposure prophylaxis to prevent HIV-1 transmission by breastfeeding: the PROMISE-PEP trial Protocol ANRS 12174. BMC Infect Dis. 2012 Oct 6;12:246. doi: 10.1186/1471-2334-12-246.