Clinical trial NCT03870438: Prevention of Mother-to-child Transmission of HIV-1 Using a Responsive Intervention
Official title: Prevention of Mother-to-child Transmission of HIV-1: Programme Evaluation and Innovative Responsive Intervention Integrated in the Expanded Programme of Immunization. PROMISE-EPI Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV-1
Keywords: HIV-1
PMTCT
Point of Care
PrEP
Zambia
Burkina Faso
Expanded Program of Immunization (EPI)
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: University Teaching Hospital, Lusaka, Zambia
name: Centre Muraz
name: Institut National de la Santé Et de la Recherche Médicale, France
name: University of Bergen
First posted: 2019-03-12
Enrollment: 1506
Sex: FEMALE
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase III, Randomized Control Trial, parallel, open-label, multi-country and multi-centre trial
Primary purpose: PREVENTION

Brief summary: The second visit of the Expanded Programme of Immunization when the child is 2 months old (EPI-2) represents a unique opportunity to link the EPI and PMTCT programmes and to introduce preventive and therapeutic rescue interventions in order to: 1) Assess the efficacy of the PMTCT cascade up to 2 months postpartum; 2) Allow at least 80% of HIV-1-infected infants identified at the second EPI visit who were not involved in HIV care to initiate ARVs at the earliest, but no later than 2 months after confirmation of HIV diagnosis; 3) Reduce HIV-1 transmission to less than 3% between 2 and 12 months among exposed children who completed the second EPI visit

Detailed description: In the vast majority of sub-Saharan African countries, all mothers attend an immunization (EPI) visit when their child is 6 to 8 weeks old (the first EPI visit for BCG and OPV0 vaccination, takes place at childbirth).

This study primarily aims at utilizing existing strategies to prevent postnatal HIV-1 transmission through optimizing the use of lamivudine as pre-exposure prophylaxis (PrEP) for at risk children. For this purpose, the study will use recently marketed diagnostic point of care (POC) tests at the first level of care for maternal HIV-1 viral load and early infant diagnosis (EID). This POC early infant diagnosis will also allow optimizing treatment of HIV-infected infants by offering to all the benefits of an early ART initiation.

The hypothesis is that the second visit for routine vaccination (Expanded Program of Immunization visit 2: EPI-2) represents a unique opportunity to link EPI and PMTCT programs and introduce rescue preventive and therapeutic interventions. The EPI visit will allow an opportunity to:

1. Assess the efficacy of the PMTCT cascade.
2. Identify HIV-1-infected children early and refer them for early initiation of treatment
3. Provide their children with an antiretroviral drug that can protect them from HIV-1, irrespective of their mother's adherence to ART as part of the Phase III Randomized Controlled Trial.

The Phase III RCT will be testing a rescue preventive intervention among HIV-1-uninfected children exposed to HIV-1 by their HIV-1-infected breastfeeding mothers against a control routine Option B+ implementation.

Following a brief questionnaire and counselling on ART adherence and breastfeeding, participant mothers aged 15 years or older who meet eligibility criteria will be randomized to the control or intervention arms at a 1:1 ratio.

The phase III Randomised Controlled Trial (RCT) testing a rescue preventive intervention among HIV-1-uninfected children exposed to HIV-1 by their HIV-1-infected breastfeeding mothers against a control routine Option B+ implementation.

In the control arm, routine Option B+ national guidelines including HIV-1 plasmatic viral load testing will be adhered to as part of the clinics' usual practice. Visits will take place at 6-8 weeks, 6 and 12 months post-partum to collect samples from the mother for the analysis of viral load results at 12 months. In addition, at 6-8 weeks, 6 and 12 months post-partum, POC tests will be done for the diagnosis of HIV-1 in their infants (by HIV-1 DNA PCR) and results will be shared within 2 hours. Children infected with HIV-1 will be referred to the National Programme for confirmed diagnosis and immediate ART.

The intervention arm aims at reducing the risk of HIV transmission for infants exposed to large amounts of HIV-1 through breastfeeding, which correlates with the maternal plasma viral load. At 6-8 weeks post-partum, a venous blood sample will be taken from the mothers to assess their viral load using a GenXpert® HIV RNA POC test. Concomitantly, a capillary blood sample will be taken from the child for the detection of HIV-1 (by HIV-1 DNA PCR). Children infected with HIV-1 will be referred to the National Programme for confirmed HIV diagnosis and immediate ART.

For children that are not HIV-1 infected in the intervention arm, the results on the mother's viral load will guide the next steps:

- Mothers with a detectable plasma viral load (≥ 1000 copies/mL) will receive reinforced counselling on ART adherence.

In addition, their child will be initiated on PrEP, lamivudine syrup (7.5 mg twice daily if 2 to 4 kg; 25 mg twice a day if weight \<8 kg; and 50 mg twice a day if weight \>8 kg). Mothers will come with their child to the study site every month (at M3, M4, M5, M7, M8, M9, M10 and M11) to collect drug supplies, safety follow-up, child's PrEP adherence adherence and counselling, mother's ART adherence and reporting. In Zambia, high risk HIV negative infants on a 12-week prophylactic regimen and are still taking ART at this visit, their first day of the study prophylaxis administration will take place at Month 3.

- Mothers with an undetectable viral loads (\<1000 copies/mL) will continue receiving ART adherence counselling. However, the children of these mothers will not be initiated on PrEP on the study at 6-8 weeks of age. However, because ART compliance declines rapidly over time within the first year of initiation, additional monitoring on the viral load of the mother and the diagnosis of the child will take place at 6 months: If the maternal plasmatic viral load is ≥ 1000 copies/mL, the child will be initiated on PrEP, lamivudine syrup (7.5 mg twice daily if 2 to 4 kg; 25 mg twice a day if weight \<8 kg; and 50 mg twice a day if weight \>8 kg), until the baby is 12 months old or until the confirmed end of breastfeeding. Breastfeeding will be considered to be ceased if the mother confirms she is no longer breastfeeding for 2 consecutive monthly visits.

Children infected with HIV-1 will be referred to the National Programme for confirmed diagnosis and immediate ART.

Eligibility criteria: For HIV+ women who give consent, the measurement of their HIV-1 viral load and the detection of HIV-1 DNA in their children will be assessed.

Inclusion Criteria:

A mother/infant pair will be included in the Phase III trial if the infant:

* Is a singleton
* Is breastfed at 2 months and the mother intends to continue breastfeeding for at least 4 months (until her child is 6 months old)
* Has a negative HIV-1 PCR POC test at 2 months of age
* Has a mother who:
* Is the accompanying person to visit 2 of the EPI
* Is 15 years of age or older (in Zambia) and 20 years of age or older (in Burkina Faso) or
* If between 15 and 19 years of age (inclusive) in Burkina Faso, and is accompanied by a referent adult of her choice representing her interests and the interests of the child (parent, family member or guardian, member of an association, etc.)
* Has been confirmed to be infected with HIV-1 (with or without HIV-2)
* Has signed the consent form to participate For the mother in Zambia, the consent must be signed by herself and a witness; For the mother in Burkina Faso, the consent must be signed by herself and a witness (if illiterate) and/or a referent adult (if under 20 years of age in Burkina Faso).

For the child in Zambia, the consent must be signed by the mother. For the child in Burkina Faso, the consent must be signed by the mother and/or a referent adult (if under 20 years of age in Burkina Faso. In Burkina Faso, both parents need to sign the consent unless the mother exercises sole parental authority or if obtaining the father's consent is likely to endanger the mother and her child. In Zambia, the mother exercises sole parental authority.

Exclusion Criteria:

A mother-child couple will not be included if the child:

* Has clinical symptoms or biological abnormalities of DAIDS classification 3 or 4 for adverse events on the day of inclusion
* Has a severe congenital malformation
* Has a known allergy to the study drug or its components
* Takes emtricitabine concomitantly
* Has a mother who:
* Lives outside the study area or intending to move from the area within the next 12 months
* Is participating in another clinical trial

Primary outcomes:
measure: Prevention of HIV-1 transmission from HIV-1-positive mothers to their breastfeeding children
timeFrame: 12 months
Secondary outcomes:
measure: Assessment of PMTCT cascade
timeFrame: 2 months
measure: Access to ART for HIV-1 positive children
timeFrame: 6 months
measure: Evaluation of the diagnostic performance of plasma HIV viral load in comparison to breastmilk viral load to identify infants at risk of transmission at 6-8 weeks, 6 months and 12 months
timeFrame: 6-8 weeks, 6 months, 12 months
measure: Evaluation of the efficacy for all the participants of the intervention arm and the comparison arm sub-population following the 2020 Zambian guidelines implementation:
timeFrame: 12 months
measure: Evaluation of the efficacy for all the participants of the intervention arm and the comparison arm sub-population following the 2020 Zambian guidelines implementation:
timeFrame: 12 months
measure: Evaluation of the safety for all the participants of the intervention arm and the comparison arm sub-population following the 2020 Zambian guidelines implementation
timeFrame: 12 months
measure: Evaluation of the efficacy for all the participants of the intervention arm and the comparison arm sub-population before the introduction of the 2020 Zambian guidelines (including Burkina Faso control arm)
timeFrame: 12 months
measure: Evaluation of the efficacy for all the participants of the intervention arm and the comparison arm sub-population before the introduction of the 2020 Zambian guidelines (including Burkina Faso control arm)
timeFrame: 12 months
measure: Evaluation of the safety for all the participants of the intervention arm and the comparison arm sub-population before the introduction of the 2020 Zambian guidelines (including Burkina Faso control arm)
timeFrame: 12 months
Other outcomes:
Locations:
city: Bobo-Dioulasso
country: Burkina Faso
facility: CSPS and CMA of Do and Dafra districts
city: Ouagadougou
country: Burkina Faso
facility: CSPS and CMA of Baskuy and Boulmiougou districts
city: Lusaka
country: Zambia
facility: Bauleni
city: Lusaka
country: Zambia
facility: Chaisa
city: Lusaka
country: Zambia
facility: Chilenje Level 1 hospital
city: Lusaka
country: Zambia
facility: Matero Main
Study officials:
affiliation: Institut National de la Santé Et de la Recherche Médicale, France
name: Philippe Van de Perre, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nagot N, Kankasa C, Tumwine JK, Meda N, Hofmeyr GJ, Vallo R, Mwiya M, Kwagala M, Traore H, Sunday A, Singata M, Siuluta C, Some E, Rutagwera D, Neboua D, Ndeezi G, Jackson D, Marechal V, Neveu D, Engebretsen IMS, Lombard C, Blanche S, Sommerfelt H, Rekacewicz C, Tylleskar T, Van de Perre P; ANRS 12174 Trial Group. 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. Lancet. 2016 Feb 6;387(10018):566-573. doi: 10.1016/S0140-6736(15)00984-8. Epub 2015 Nov 19.
citation: Mennecier A, Kankasa C, Fao P, Moles JP, Eymard-Duvernay S, Mwiya M, Kania D, Chunda-Liyoka C, Sakana L, Rutagwera D, Tassembedo S, Wilfred-Tonga MM, Mosqueira B, Tylleskar T, Nagot N, Van de Perre P; ANRS 12397 Study group. Design and challenges of a large HIV prevention clinical study on mother-to-child transmission: ANRS 12397 PROMISE-EPI study in Zambia and Burkina Faso. Contemp Clin Trials. 2021 Jun;105:106402. doi: 10.1016/j.cct.2021.106402. Epub 2021 Apr 17.