Improving Maternal heAlth by Reducing Malaria in African HIV Women
- Conditions
- MalariaHIV/AIDSPregnancy Related
- Interventions
- Drug: Dihydroartemisinin-piperaquine (DHA-PPQ)Drug: Placebo Oral Tablet
- Registration Number
- NCT03671109
- Lead Sponsor
- Barcelona Institute for Global Health
- Brief Summary
Trial to evaluate the safety and efficacy of DHA-PPQ for Intermittent Preventive Treatment (IPTp) in HIV-infected pregnant women receiving cotrimoxazole prophylaxis (CTXp) and antiretroviral (ARV) drugs and using long lasting insecticide treated nets will be conducted in Mozambique and Gabon where malaria and HIV infection are moderate to highly prevalent. In addition, the possibility for a PK interaction between DHA-PPQ and ARV drugs will be assessed in a sub-sample of participants. Women will receive ARV therapy according to national guidelines and their infants will be followed until one year of age to evaluate the impact of DHA-PPQ on MTCT-HIV.
- Detailed Description
Background
Intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) is recommended for malaria prevention in HIV-uninfected women but it is contraindicated in those HIV-infected on cotrimoxazole prophylaxis (CTXp) due to potential adverse effects. A recent trial showed that an effective antimalarial added to CTXp and long-lasting insecticide treated nets (LLITNs) in HIV-infected pregnant women improves malaria prevention and maternal health. However, the antimalarial used -mefloquine- was not well tolerated and it was associated with an increase in HIV viral load at delivery and a two-fold increased risk of MTCT-HIV. These findings highlight the need to find alternative drugs with better tolerability and safety profile to prevent malaria in this vulnerable group and to further study the pharmacological interactions between antimalarials and antiretrovirals (ARVs).
Dihydroartemisinin-piperaquine (DHA-PPQ), because of its long half-life and good tolerability has been shown to improve antimalarial protection in HIV-uninfected pregnant women, constituting the most promising candidate for IPTp in HIV-infected pregnant women. However, there is limited information on the pharmacokinetics of DHA-PPQ with concomitant use of ARV drugs and CTX, particularly in pregnant women.
Objectives
1. To evaluate the safety, tolerability and efficacy of DHA-PPQ as IPTp for malaria prevention in HIV-infected pregnant women receiving daily CTXp and ARV drugs
2. To assess the effect of DHA-PPQ as IPTp on mother to child transmission of HIV
3. To study the effects of DHA-PPQ on the pharmacokinetics of clinically relevant doses of ARV drugs used for prevention of MTCT and treatment of HIV infection
4. To evaluate the effectiveness of CTXp in clearing malaria parasites in HIV-infected pregnant women
Methods
The trial has been designed as a randomized double blind placebo-controlled superiority trial to evaluate the safety and efficacy of DHA-PPQ as IPTp in HIV-infected pregnant women taking daily CTXp and ARV drugs. The trial sites are located in Central and South Eastern sub-Saharan Africa (Gabon and Mozambique), where HIV prevalence among pregnant women ranges from 6 to 29%.
Based on previous estimations at the study sites and assuming a prevalence of peripheral parasitaemia at delivery of 7.5% with CTXp, it is estimated that 298 women per arm will be required to detect with 80% power a significant (p\<0.05) decrease of 5% or more in the prevalence of peripheral parasitaemia in the CTXp+IPTp-DHA-PPQ group. In order to allow for 10% losses to follow up, it is calculated that 332 women/study arm will need to be recruited (total n=664). Furthermore, assuming a 5% MTCT-HIV in the control group, this sample size will have an 80% power to detect at the 5% level of significance, 2.2 times difference in the risk of MTCT-HIV.
The trial will have two study arms; HIV-infected pregnant women participating in the trial will be randomized to receive either:
1. Monthly doses of IPTp-DHA-PPQ over three days plus daily ARVs and cotrimoxazole prophylaxis
2. Monthly doses of IPTp-placebo over three days plus daily ARVs and cotrimoxazole prophylaxis
Women will receive ARV therapy according to national guidelines and their infants will be followed until one year of age to evaluate the impact of DHA-PPQ on MTCT-HIV.
Participants will be asked to visit the ANC monthly and to deliver at the study health facilities. Adherence to CTX prophylaxis and ARV therapy, as well as use of the LLITNs use will be assessed monthly at the scheduled antenatal care (ANC) clinic visits.
Pharmacokinetic (PK) sub-study The possibility for a PK interaction between DHA-PPQ and ARV drugs will be assessed in a sub-sample of participants (n=200).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 666
- Permanent resident in the study area
- Gestational age at the first antenatal visit ≤ 28 weeks
- HIV seropositive status
- Agreement to deliver in the study site's maternity(ies) wards
- Residence outside the study area or planning to move out in the following 10 months from enrolment
- Gestational age at the first antenatal visit > 28 weeks of pregnancy
- Known history of allergy to CTX
- Known history of allergy or contraindications to DHA-PPQ
- Participating in other intervention studies
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description IPTp-DHA-PPQ Dihydroartemisinin-piperaquine (DHA-PPQ) Monthly IPTp-DHA-PPQ over three days plus daily ARVs and cotrimoxazole prophylaxis IPTp-Placebo Placebo Oral Tablet Monthly IPTp-placebo over three days plus daily ARVs and cotrimoxazole prophylaxis
- Primary Outcome Measures
Name Time Method Maternal parasitaemia at delivery Delivery Presence of Plasmodium falciparum (P. falciparum) asexual parasites of any density in peripheral blood (determined by microscopy)
- Secondary Outcome Measures
Name Time Method Incidence of clinical malaria During first year of life Incidence of all-cause admissions On average six months follow up during pregnancy Incidence of all-cause outpatient attendances On average six months follow up during pregnancy Frequency and severity of adverse events On average six months follow up during pregnancy Mean haemoglobin concentration At delivery Prevalence of submicroscopic P. falciparum peripheral parasitaemia At delivery Prevalence of anaemia (Hb<11 g/dL) At delivery Prevalence of severe anaemia (Hb<7 g/dL) At delivery Mean CD4+ T cell counts levels At delivery Proportion of women with detectable HIV viral load At delivery Prevalence of placental P. falciparum infection At delivery Prevalence of P. falciparum peripheral parasitaemia at the post-partum visit On average 42 days after end of pregnancy (post-partum visit) Maternal mortality rate On average six months follow up during pregnancy and 42 days after end of pregnancy (post-partum visit) Prevalence of P. falciparum parasitaemia in cord blood At birth Prevalence of neonatal anaemia Neonatal period ( in first 28 days of life) Mean birth weight At birth Prevalence of low birth weight (<2500 g) At birth Mean gestational age at birth At birth Prevalence of prematurity At birth Prevalence of embryo and foetal losses On average six months follow up during pregnancy Prevalence of small for gestational age At birth Frequency of congenital malformations At birth Neonatal mortality rate During neonatal period (during first 28 days of life) Frequency of mother to child transmission of HIV at one and at 12 months of age During first year of life Infant mortality rate During first year of life Composite adverse pregnancy outcome Birth LBW, miscarriage, stillbirth, prematurity
Composite malaria outcome: proportion of participants with malaria infection diagnosed From enrolment until one month after end of pregnancy (on average seven months of study follow up of women, depending on gestational age at inclusion) Any malaria confirmed infection during follow up, delivery and post-partum period (blood smear, malaria PCR, placental infection)
Composite maternal malaria and anemia: proportion of particiapnts diganosed either with malaria or anemia At delivery
Trial Locations
- Locations (2)
Centre de Recherches Médicales de Lambaréné (CERMEL)
🇬🇦Lambaréné, Gabon
Centro de Investigação em Saúde de Manhiça (CISM)
🇲🇿Manhiça, Mozambique