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.

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).

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

The main findings of the clinical trial will be submitted for publication in a peer reviewed journal within 12 months of study completion through an open access mechanism, or otherwise made available publicly in compliance with H2020 open access requirements.

Primary project raw data will be published in the project website. This approach is taken to protect in particular the interests of the endemic country researchers and institutions and in acknowledgment of the primary research oversight by endemic country ethics review boards. At no stage will data containing personal information of research participants be released.

Project metadata will be made available in formal reports to key stakeholders as soon as possible and to the wider public within 12 months after the end of the project. The announcement of the availability of the project metadata will be posted in the project website.

Open Access

Double blind placebo-controlled