Universal Use of EFV-TDF-FTC and AZT-3TC-LPV/r Combinations for HIV-1 PMTCT in Pregnant and Breastfeeding Women : a Phase 3 Trial

Study Overview
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Brief Summary
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To assess the maternal and infant safety of a single daily fixed-dose combination of TDF/FTC/EFV (Atripla®), compared to the association of LPV/r (Kaletra® or Aluvia®) and 3TC/ZDV (Combivir®) given to African women to prevent overall MTCT in populations practicing breastfeeding.

Detailed Description
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The prevention of MTCT during pregnancy and through breastfeeding exposure remains challenging to date in most resource-limited settings. Peripartum HIV transmission is already amenable to ARV interventions. These ARV regimens, partially efficacious are insufficiently used despite their apparent simplicity. The postnatal transmission via breastfeeding remains a serious additional threat. This is a multicentric, non-inferiority, randomized controlled trial aiming at assessing the maternal and infant safety of a single daily fixed-dose combination of TDF/FTC/EFV (Atripla®), compared to the association of LPV/r (Kaletra® or Aluvia®) and 3TC/ZDV (Combivir®) given to African women (in Cote d'Ivoire an in Zambia) to prevent MTCT overall in breastfeeding population. The fixed-dose combination of Tenofovir/Emtricitabine/Efavirenz (TDF/FTC/EFV or Atripla®) is a highly effective HAART combination and the simplest ARV regimen currently available in resource-limited settings and is therefore likely to become soon the lead first-line HAART regimen for adults in such settings. Its anticipated widespread prescription in women of childbearing age requires the proper documentation of its use in pregnancy and during breastfeeding. The combination of ZDV/3TC (Combivir®) and Lopinavir/ritonavir (LPV/r) (Kaletra® or Aluvia®) is chosen as a reference regimen as it is one of the most commonly used first-line HAART for adults and the reference regimen for PMTCT in industrialised settings. The maternal ARV regimen will be initiated as soon as possible from 20 weeks of gestation until at least the cessation of breastfeeding (with the advice to cease at six months). The decision to stop or continue the maternal ARV regimen after breastfeeding cessation will be based on the baseline maternal CD4 count and the maternal clinical stage at baseline and/or at breastfeeding cessation. A woman with a baseline CD4 <500 cells/ml will always be proposed to continue her treatment after breastfeeding cessation. A woman with a baseline CD4 count >500 will be asked to stop her treatment after breastfeeding cessation unless she has reached the WHO clinical stage IV at that time. Infants will receive daily Zidovudine syrup from birth during the first week of life, or an updated ARV post-exposure prophylaxis recommended by WHO when women receive HAART.

Official Title
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Safety and Efficacy of the Universal Use of EFV-TDF-FTC and AZT-3TC-LPV/r Combinations in Pregnant and Breastfeeding Women to Prevent mother-to Child Transmission of HIV-1 o, Resource-limited Settings: A Multicentre Randomized Phase 3 Clinical Trial

Conditions
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HIV Infection, Pregnancy, Breastfeeding, HIV Infections

Intervention / Treatment
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* Drug: Efavirenz-Tenofovir-Emtricitabine
* Drug: Zidovudine-Lamivudine-Lopinavir/Ritonavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: being pregnant, presenting in at least the 20th week of pregnancy and no later than 2 weeks before the expected term; at least 18 years of age; diagnosed as infected with HIV-1 only; not currently taking any ARV drugs; having not been exposed to NVP in the 6 months preceding enrolment; willing to breastfeed their forthcoming child; residing and planning to continue to reside within the predefined catchment areas until 12 months after delivery; being able to give informed consent for enrolment in the study; lacking any medical contraindication to any of the proposed ARV medications; and accepting the principle of being randomized to receive one of the ARV regimens evaluated within the study, to prevent MTCT and for their own health when required. Exclusion Criteria: presenting within 2 weeks before the expected term; currently taking ARV drugs; having been exposed to NVP in the 6 months preceding enrolment; not willing to breastfeed their forthcoming child; having severe renal insufficiency (creatin clearance < 60ml/min); diagnosed as infected with HIV-2 only or dually infected HIV-1 and HIV-2; hemoglobin < 7 g/dL in the month preceding inclusion HBs Ag positive Women meeting one of the three last exclusion criteria (HIV-2 infection or co-infection, hemoglobin < 7 g/dL, HBs Ag positive) will not be randomized but will all received Atripla and be followed-up in an ancillary open cohort according the same procedures and agenda.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Atripla (R)<br> | Drug: Efavirenz-Tenofovir-Emtricitabine<br>* Atripla (R) : Efavirenz 600 mg - Tenofovir 300 mg - Emtricitabine 200 mg; Dosage : 1 pill/day<br>|
| Active Comparator: Combivir (R) + Kaletra (R) or Aluvia (R)<br> | Drug: Zidovudine-Lamivudine-Lopinavir/Ritonavir<br>* Combivir (R) : Zidovudine 300 mg - Lamivudine 150 mg Dosage : 1 pill twice a day Kaletra (R) or Aluvia (R) : Lopinavir 200 mg / Ritonavir 50 mg Dosage : 2 or 3 pills twice a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cumulative occurence of : -adverse pregnancy outcomes (spontaneous abortion, stillbirth, congenital abnormality requiring surgical correction in children < 1 yr of age); -paediatric HIV infection; -infant mortality |  | at 6 and 12 months following delivery/birth | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| occurence of grade 4 events in treated women, and of grade 3 or 4 events in ARV-exposed infants |  | at 6 and 12 months following delivery/birth | 
| frequency of virological failure (>300 copies/mL) and viral resistance profile |  | at 6 month and 12 months post-delivery | 
| frequency of premature delivery (<37 weeks) and frequency of low birth weight (<2500 g) |  | at delivery/birth | 
| cumulative incidence of paediatric HIV infection |  | at 12 months after delivery | 
| tolerability of the ARV combination in treated women |  | at 6 and 12 months following delivery/birth | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, pregnancy, breastfeeding, PMTCT, ARV treatment, treatment naive