title: Extended pre-exposure prophylaxis with lopinavir-ritonavir versus lamivudine to prevent HIV-1 transmission through breastfeeding up to 50 weeks in infants in Africa (ANRS 12174): a randomised controlled trial.
abstract: BACKGROUND
  Strategies to prevent postnatal mother-to-child transmission of HIV-1 in Africa, including infant prophylaxis, have never been assessed past 6 months of breastfeeding, despite breastfeeding being recommended up to 12 months after birth. We aimed to compare the efficacy and safety of infant prophylaxis with the two drug regimens (lamivudine or lopinavir-ritonavir) to prevent postnatal HIV-1 transmission up to 50 weeks of breastfeeding.
  
  
  METHODS
  We did a randomised controlled trial in four sites in Burkina Faso, South Africa, Uganda, and Zambia in children born to HIV-1-infected mothers not eligible for antiretroviral therapy (CD4 count >350 cells per μL). An independent researcher electronically generated a randomisation schedule; we then used sequentially numbered envelopes to randomly assign (1:1) HIV-1-uninfected breastfed infants aged 7 days to either lopinavir-ritonavir or lamivudine (paediatric liquid formulations, twice a day) up to 1 week after complete cessation of breastfeeding or at the final visit at week 50. We stratified the randomisation by country and used permuted blocks of four and six. We used a study label on drug bottles to mask participants, study physicians, and assessors to the treatment allocation. The primary outcome was infant HIV-1 infection between age 7 days and 50 weeks, diagnosed every 3 months with HIV-1 DNA PCR, in the modified intention-to-treat population (all who attended at least one follow-up visit). This trial is registered with ClinicalTrials.gov, number NCT00640263.
  
  
  RESULTS
  Between Nov 16, 2009, and May 7, 2012, we enrolled and randomised 1273 infants and analysed 1236; 615 assigned to lopinavir-ritonavir or 621 assigned to lamivudine. 17 HIV-1 infections were diagnosed in the study period (eight in the lopinavir-ritonavir group and nine in the lamivudine group), resulting in cumulative HIV-1 infection of 1.4% (95% CI 0.4-2.5) and 1.5% (0.7-2.5), respectively. Infection rates did not differ between the two drug regimens (hazard ratio [HR] of lopinavir-ritonavir versus lamivudine of 0.90, 95% CI 0.35-2.34; p=0.83). Clinical and biological severe adverse events did not differ between groups; 251 (51%) infants had a grade 3-4 event in the lopinavir-ritonavir group compared with 246 (50%) in the lamivudine group.
  
  
  CONCLUSIONS
  Infant HIV-1 prophylaxis with lopinavir-ritonavir was not superior to lamivudine and both drugs led to very low rates of HIV-1 postnatal transmission for up to 50 weeks of breastfeeding. Infant pre-exposure prophylaxis should be extended until the end of HIV-1 exposure and mothers should be informed about the persistent risk of transmission throughout breastfeeding.
  
  
  BACKGROUND
  INSERM/National Agency for Research on AIDS and Viral Hepatitis (including funds from the Total Foundation), European Developing Countries Clinical Trials Partnership, Research Council of Norway.
authors.affiliation: INSERM U 1058, Montpellier, France; Université Montpellier, Montpellier, France; CHU Montpellier, Montpellier, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Nagot
authors.affiliation: University of Zambia, School of Medicine, Department of Paediatrics and Child Health, University Teaching Hospital, Lusaka, Zambia.
authors.forename: Chipepo
authors.initials: C
authors.lastname: Kankasa
authors.affiliation: Department of Paediatrics and Child Health, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
authors.forename: James K
authors.initials: JK
authors.lastname: Tumwine
authors.affiliation: Centre of International Research for Health, Faculty of Health Sciences, University of Ouagadougou, Ouagadougou, Burkina Faso.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Meda
authors.affiliation: Effective Care Research Unit, Cecilia Makiwane Hospital, East London Hospital Complex, East London, South Africa; School of Public Health, University of the Western Cape, South Africa.
authors.forename: G Justus
authors.initials: GJ
authors.lastname: Hofmeyr
authors.affiliation: INSERM U 1058, Montpellier, France; Université Montpellier, Montpellier, France.
authors.forename: Roselyne
authors.initials: R
authors.lastname: Vallo
authors.affiliation: University of Zambia, School of Medicine, Department of Paediatrics and Child Health, University Teaching Hospital, Lusaka, Zambia.
authors.forename: Mwiya
authors.initials: M
authors.lastname: Mwiya
authors.affiliation: Department of Paediatrics and Child Health, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
authors.forename: Mary
authors.initials: M
authors.lastname: Kwagala
authors.affiliation: Centre of International Research for Health, Faculty of Health Sciences, University of Ouagadougou, Ouagadougou, Burkina Faso.
authors.forename: Hugues
authors.initials: H
authors.lastname: Traore
authors.affiliation: Effective Care Research Unit, Cecilia Makiwane Hospital, East London Hospital Complex, East London, South Africa; School of Public Health, University of the Western Cape, South Africa.
authors.forename: Amwe
authors.initials: A
authors.lastname: Sunday
authors.affiliation: Effective Care Research Unit, Cecilia Makiwane Hospital, East London Hospital Complex, East London, South Africa; School of Public Health, University of the Western Cape, South Africa.
authors.forename: Mandisa
authors.initials: M
authors.lastname: Singata
authors.affiliation: University of Zambia, School of Medicine, Department of Paediatrics and Child Health, University Teaching Hospital, Lusaka, Zambia.
authors.forename: Chafye
authors.initials: C
authors.lastname: Siuluta
authors.affiliation: Centre of International Research for Health, Faculty of Health Sciences, University of Ouagadougou, Ouagadougou, Burkina Faso.
authors.forename: Eric
authors.initials: E
authors.lastname: Some
authors.affiliation: University of Zambia, School of Medicine, Department of Paediatrics and Child Health, University Teaching Hospital, Lusaka, Zambia.
authors.forename: David
authors.initials: D
authors.lastname: Rutagwera
authors.affiliation: Centre of International Research for Health, Faculty of Health Sciences, University of Ouagadougou, Ouagadougou, Burkina Faso.
authors.forename: Desire
authors.initials: D
authors.lastname: Neboua
authors.affiliation: Department of Paediatrics and Child Health, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
authors.forename: Grace
authors.initials: G
authors.lastname: Ndeezi
authors.affiliation: School of Public Health, University of the Western Cape, South Africa.
authors.forename: Debra
authors.initials: D
authors.lastname: Jackson
authors.affiliation: INSERM U 1058, Montpellier, France; Université Montpellier, Montpellier, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Maréchal
authors.affiliation: INSERM U 1058, Montpellier, France; Université Montpellier, Montpellier, France.
authors.forename: Dorine
authors.initials: D
authors.lastname: Neveu
authors.affiliation: Centre for International Health, University of Bergen, Bergen, Norway.
authors.forename: Ingunn M S
authors.initials: IMS
authors.lastname: Engebretsen
authors.affiliation: Biostatistics Unit, Medical Research Council of South Africa, Cape Town, South Africa.
authors.forename: Carl
authors.initials: C
authors.lastname: Lombard
authors.affiliation: University of Paris V, Department of Paediatrics, URC/CIC Necker-Cochin, Hôpital Necker, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blanche
authors.affiliation: Centre for International Health, University of Bergen, Bergen, Norway; Centre for Intervention Science in Maternal and Child Health, Centre for International Health, University of Bergen, Bergen, Norway; Department of International Public Health, Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Halvor
authors.initials: H
authors.lastname: Sommerfelt
authors.affiliation: French National Institute of Health and Medical Research-National Agency for Research on AIDS and Viral Hepatitis (INSERM-ANRS), Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Rekacewicz
authors.affiliation: Centre for International Health, University of Bergen, Bergen, Norway.
authors.forename: Thorkild
authors.initials: T
authors.lastname: Tylleskär
authors.affiliation: INSERM U 1058, Montpellier, France; Université Montpellier, Montpellier, France; CHU Montpellier, Montpellier, France. Electronic address: p-van_de_perre@chu-montpellier.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Van de Perre
mesh_terms: D017954:Africa South of the Sahara; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D001942:Breast Feeding; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission; D015497:HIV-1; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control*; D019259:Lamivudine / Q000008:administration & dosage; D061466:Lopinavir / Q000008:administration & dosage; D065129:Pre-Exposure Prophylaxis / Q000379:methods*; D019438:Ritonavir / Q000008:administration & dosage
chemical_list: D019380:Anti-HIV Agents; D061466:Lopinavir; D019259:Lamivudine; D019438:Ritonavir