Evaluation of the safety and efficacy of dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in HIV-infected pregnant women: protocol of a multicentre, two-arm, randomised, placebo-controlled, superiority clinical trial (MAMAH project)

Raquel González, Tacilta Nhampossa, Ghyslain Mombo-Ngoma, Johannes Mischlinger, Meral Esen, André-Marie Tchouatieu, Clara Pons-Duran, Lia Betty Dimessa, Bertrand Lell, Heimo Lagler, Laura Garcia-Otero, Rella Zoleko Manego, Myriam El Gaaloul, Sergi Sanz, Mireia Piqueras, Esperanca Sevene, Michael Ramharter, Francisco Saute, Clara Menendez, Raquel González, Tacilta Nhampossa, Ghyslain Mombo-Ngoma, Johannes Mischlinger, Meral Esen, André-Marie Tchouatieu, Clara Pons-Duran, Lia Betty Dimessa, Bertrand Lell, Heimo Lagler, Laura Garcia-Otero, Rella Zoleko Manego, Myriam El Gaaloul, Sergi Sanz, Mireia Piqueras, Esperanca Sevene, Michael Ramharter, Francisco Saute, Clara Menendez

Abstract

Introduction: Malaria infection during pregnancy is an important driver of maternal and neonatal health especially among HIV-infected women. Intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine 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. Dihydroartemisinin-piperaquine (DHA-PPQ) has been shown to improve antimalarial protection, constituting a promising IPTp candidate. This trial's objective is to determine if monthly 3-day IPTp courses of DHA-PPQ added to daily CTXp are safe and superior to CTXp alone in decreasing the proportion of peripheral malaria parasitaemia at the end of pregnancy.

Methods and analysis: This is a multicentre, two-arm, placebo-controlled, individually randomised trial in HIV-infected pregnant women receiving CTXp and antiretroviral treatment. A total of 664 women will be enrolled at the first antenatal care clinic visit in sites from Gabon and Mozambique. Participants will receive an insecticide-treated net, and they will be administered monthly IPTp with DHA-PPQ or placebo (1:1 ratio) as directly observed therapy from the second trimester of pregnancy. Primary study outcome is the prevalence of maternal parasitaemia at delivery. Secondary outcomes include prevalence of malaria-related maternal and infant outcomes and proportion of adverse perinatal outcomes. Participants will be followed until 6 weeks after the end of pregnancy and their infants until 1 year of age to also evaluate the impact of DHA-PPQ on mother-to-child transmission of HIV. The analysis will be done in the intention to treat and according to protocol cohorts, adjusted by gravidity, country, seasonality and other variables associated with malaria.

Ethics and dissemination: The protocol was reviewed and approved by the institutional and national ethics committees of Gabon and Mozambique and the Hospital Clinic of Barcelona. Project results will be presented to all stakeholders and published in open-access journals.

Trial registration number: NCT03671109.

Keywords: HIV & AIDS; clinical trials; epidemiology; maternal medicine; tropical medicine.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
MAMAH trial design. ANC, antenatal care; ARVs, antiretroviral drugs; CTX, cotrimoxazole; DHA-PPQ, dihydroartemisinin–piperaquine; ITNs, insecticide- treated nets; MAMAH, Improving maternal Health by Reducing Malaria in African HIV Women.

References

    1. WHO . World malaria report 2020. WHO, 2020. Available: [Accessed March 2021].
    1. Mombo-Ngoma G, Mackanga JR, González R, et al. . Young adolescent girls are at high risk for adverse pregnancy outcomes in sub-Saharan Africa: an observational multicountry study. BMJ Open 2016;6:e011783. 10.1136/bmjopen-2016-011783
    1. WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group, Dahal P, d'Alessandro U, et al. . Clinical determinants of early parasitological response to acts in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data. BMC Med 2015;13:212. 10.1186/s12916-015-0445-x
    1. Desai M, ter Kuile FO, Nosten F, et al. . Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis 2007;7:93–104. 10.1016/S1473-3099(07)70021-X
    1. Menéndez C, D'Alessandro U, ter Kuile FO. Reducing the burden of malaria in pregnancy by preventive strategies. Lancet Infect Dis 2007;7:126–35. 10.1016/S1473-3099(07)70024-5
    1. Menendez C, Ordi J, Ismail MR, et al. . The impact of placental malaria on gestational age and birth weight. J Infect Dis 2000;181:1740–5. 10.1086/315449
    1. Bardají A, Sigauque B, Sanz S, et al. . Impact of malaria at the end of pregnancy on infant mortality and morbidity. J Infect Dis 2011;203:691–9. 10.1093/infdis/jiq049
    1. Desai M, Hill J, Fernandes S, et al. . Prevention of malaria in pregnancy. Lancet Infect Dis 2018;18:e119–32. 10.1016/S1473-3099(18)30064-1
    1. UNAIDS/WHO . Global report: UNAIDS report on the global AIDS epidemic 2013. UNAIDS(JC2502/1/E: WHO Library Cataloguing-in-Publication Data, 2013.
    1. WHO . Malaria and HIV interactions and their implications for public health policy WHO. WHO, 2005.
    1. Kwenti TE. Malaria and HIV coinfection in sub-Saharan Africa: prevalence, impact, and treatment strategies. Res Rep Trop Med 2018;9:123–36. 10.2147/RRTM.S154501
    1. ter Kuile FO, Parise ME, Verhoeff FH, et al. . The burden of co-infection with human immunodeficiency virus type 1 and malaria in pregnant women in sub-Saharan Africa. Am J Trop Med Hyg 2004;71:41–54. 10.4269/ajtmh.2004.71.41
    1. González R, Ataíde R, Naniche D, et al. . HIV and malaria interactions: where do we stand? Expert Rev Anti Infect Ther 2012;10:153–65. 10.1586/eri.11.167
    1. WHO . Intermittent preventive treatment of malaria in pregnancy using Sulfadoxine-Pyrimethamine (IPTp-SP). updated who policy recommendation. WHO, 2012. Available:
    1. WHO . Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection recommendations for a public health approach June 2013. WHO, 2013.
    1. Sevene E, González R, Menéndez C. Current knowledge and challenges of antimalarial drugs for treatment and prevention in pregnancy. Expert Opin Pharmacother 2010;11:1277–93. 10.1517/14656561003733599
    1. Ward SA, Sevene EJP, Hastings IM, et al. . Antimalarial drugs and pregnancy: safety, pharmacokinetics, and pharmacovigilance. Lancet Infect Dis 2007;7:136–44. 10.1016/S1473-3099(07)70025-7
    1. Menéndez C, Bardají A, Sigauque B, et al. . Malaria prevention with IPTp during pregnancy reduces neonatal mortality. PLoS One 2010;5:e9438. 10.1371/journal.pone.0009438
    1. Eisele TP, Larsen DA, Anglewicz PA, et al. . Malaria prevention in pregnancy, birthweight, and neonatal mortality: a meta-analysis of 32 national cross-sectional datasets in Africa. Lancet Infect Dis 2012;12:942–9. 10.1016/S1473-3099(12)70222-0
    1. González R, Sevene E, Jagoe G, et al. . A public health paradox: the women most vulnerable to malaria are the least protected. PLoS Med 2016;13:e1002014. 10.1371/journal.pmed.1002014
    1. González R, Desai M, Macete E, et al. . Intermittent preventive treatment of malaria in pregnancy with mefloquine in HIV-infected women receiving cotrimoxazole prophylaxis: a multicenter randomized placebo-controlled trial. PLoS Med 2014;11:e1001735. 10.1371/journal.pmed.1001735
    1. WHO . Guidelines for the treatment of malaria. 2nd edn. WHO, 2010.
    1. Rijken MJ, McGready R, Boel ME, et al. . Dihydroartemisinin-piperaquine rescue treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy: a preliminary report. Am J Trop Med Hyg 2008;78:543–5. 10.4269/ajtmh.2008.78.543
    1. Pekyi D, Ampromfi AA, et al. , PREGACT Study Group . Four artemisinin-based treatments in African pregnant women with malaria. N Engl J Med 2016;374:913–27. 10.1056/NEJMoa1508606
    1. Desai M, Gutman J, L'lanziva A, et al. . Intermittent screening and treatment or intermittent preventive treatment with dihydroartemisinin-piperaquine versus intermittent preventive treatment with sulfadoxine-pyrimethamine for the control of malaria during pregnancy in Western Kenya: an open-label, three-group, randomised controlled superiority trial. Lancet 2015;386:2507–19. 10.1016/S0140-6736(15)00310-4
    1. Kakuru A, Jagannathan P, Muhindo MK, et al. . Dihydroartemisinin-Piperaquine for the prevention of malaria in pregnancy. N Engl J Med 2016;374:928–39. 10.1056/NEJMoa1509150
    1. Gutman J, Kovacs S, Dorsey G, et al. . Safety, tolerability, and efficacy of repeated doses of dihydroartemisinin-piperaquine for prevention and treatment of malaria: a systematic review and meta-analysis. Lancet Infect Dis 2017;17:184–93. 10.1016/S1473-3099(16)30378-4
    1. Natureeba P, Kakuru A, Muhindo M, et al. . Intermittent preventive treatment with Dihydroartemisinin-Piperaquine for the prevention of malaria among HIV-infected pregnant women. J Infect Dis 2017;216:29–35. 10.1093/infdis/jix110
    1. Schulz KF, Altman DG, Moher D, et al. . Consort 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann Intern Med 2010;152:726–32. 10.7326/0003-4819-152-11-201006010-00232
    1. González R, Munguambe K, Aponte J, et al. . High HIV prevalence in a southern semi-rural area of Mozambique: a community-based survey. HIV Med 2012;13:581–8. 10.1111/j.1468-1293.2012.01018.x
    1. Manego RZ, Mombo-Ngoma G, Witte M, et al. . Demography, maternal health and the epidemiology of malaria and other major infectious diseases in the rural department Tsamba-Magotsi, Ngounie Province, in central African Gabon. BMC Public Health 2017;17:130. 10.1186/s12889-017-4045-x
    1. Caron M, Lekana-Douki SE, Makuwa M, et al. . Prevalence, genetic diversity and antiretroviral drugs resistance-associated mutations among untreated HIV-1-infected pregnant women in Gabon, central Africa. BMC Infect Dis 2012;12:64. 10.1186/1471-2334-12-64
    1. Lahuerta M, Aparicio E, Bardaji A, et al. . Rapid spread and genetic diversification of HIV type 1 subtype C in a rural area of southern Mozambique. AIDS Res Hum Retroviruses 2008;24:327–35. 10.1089/aid.2007.0134
    1. WHO . Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection 2016. In: Reccomendations for a public health approach. 2nd edn. World Health Organization, 2016.
    1. González R, Mombo-Ngoma G, Ouédraogo S, et al. . Intermittent preventive treatment of malaria in pregnancy with mefloquine in HIV-negative women: a multicentre randomized controlled trial. PLoS Med 2014;11:e1001733. 10.1371/journal.pmed.1001733
    1. Menéndez C, Bardají A, Sigauque B, et al. . A randomized placebo-controlled trial of intermittent preventive treatment in pregnant women in the context of insecticide treated nets delivered through the antenatal clinic. PLoS One 2008;3:e1934. 10.1371/journal.pone.0001934
    1. Ballard JL, Khoury JC, Wedig K, et al. . New Ballard score, expanded to include extremely premature infants. J Pediatr 1991;119:417–23. 10.1016/S0022-3476(05)82056-6
    1. Gladstone M, Lancaster GA, Umar E, et al. . The Malawi developmental assessment tool (MDAT): the creation, validation, and reliability of a tool to assess child development in rural African settings. PLoS Med 2010;7:e1000273. 10.1371/journal.pmed.1000273
    1. Koura KG, Boivin MJ, Davidson LL, et al. . Usefulness of child development assessments for low-resource settings in francophone Africa. J Dev Behav Pediatr 2013;34:486–93. 10.1097/DBP.0b013e31829d211c
    1. Prado EL, Abubakar AA, Abbeddou S, et al. . Extending the developmental milestones checklist for use in a different context in sub-Saharan Africa. Acta Paediatr 2014;103:447–54. 10.1111/apa.12540
    1. Ismail MR, Ordi J, Menendez C, et al. . Placental pathology in malaria: a histological, immunohistochemical, and quantitative study. Hum Pathol 2000;31:85–93. 10.1016/S0046-8177(00)80203-8
    1. Pharmalys . Pharmalys CRO, 2021. Available: [Accessed July 2021].
    1. Zou G. A modified poisson regression approach to prospective studies with binary data. Am J Epidemiol 2004;159:702–6. 10.1093/aje/kwh090
    1. Zou GY, Donner A. Extension of the modified poisson regression model to prospective studies with correlated binary data. Stat Methods Med Res 2013;22:661–70. 10.1177/0962280211427759
    1. NHREC . Guidelines for community Advisory groups. NHREC, 2012. Available: [Accessed April 2021].
    1. EMA . Guideline for good clinical practice E6 (R2). EMA, 2015. Available: [Accessed April 2021].
    1. Alonso PL, Sacarlal J, Aponte JJ, et al. . Efficacy of the RTS, S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Lancet 2004;364:1411–20. 10.1016/S0140-6736(04)17223-1
    1. UNAIDS . Mozambique country fact sheet, 2015. Available: [Accessed Feb 2017].
    1. Sylla EH, Kun JF, Kremsner PG. Mosquito distribution and entomological inoculation rates in three malaria-endemic areas in Gabon. Trans R Soc Trop Med Hyg 2000;94:652–6. 10.1016/S0035-9203(00)90219-0
    1. Ministère-de-la-Santé-et-de-la-Prévoyance-sociale-Gabon . Rapport national sur La Réponse Au VIH/SIDA 2014, 2015. Available: [Accessed Feb 7].
    1. Mourou J-R, Coffinet T, Jarjaval F, et al. . Malaria transmission in Libreville: results of a one year survey. Malar J 2012;11:40. 10.1186/1475-2875-11-40

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