Effectiveness of two antifolate prophylactic strategies against malaria in HIV-positive pregnant women in Bangui, Central African Republic: study protocol for a randomized controlled trial (MACOMBA)

Alexandre Manirakiza, Abdoulaye Sepou, Eugène Serdouma, Samuel Gondje, Ghislain Géraud Banthas Bata, Sandrine Moussa, Aude Boulay, Jean Methode Moyen, Olga Sakanga, Lenaig Le-Fouler, Mirdad Kazanji, Muriel Vray, Alexandre Manirakiza, Abdoulaye Sepou, Eugène Serdouma, Samuel Gondje, Ghislain Géraud Banthas Bata, Sandrine Moussa, Aude Boulay, Jean Methode Moyen, Olga Sakanga, Lenaig Le-Fouler, Mirdad Kazanji, Muriel Vray

Abstract

Background: Co-infection with malaria parasite and HIV is an emerging public health problem in tropical areas, particularly in pregnant women, and management of the concurrent effects of these two infections is challenging. Co-trimoxazole is a sulfamide preparation used to prevent opportunistic infections in HIV-infected patients, and many studies have reported that it has significant activity against malaria. As the efficacy of intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine (SP) against malaria is decreasing, co-trimoxazole might be an alternative for preventing malaria among HIV-infected populations. The aim of this study is to compare the effectiveness of SP-IPT, which is recommended for the prevention of malaria during pregnancy in the Central African Republic, with that of a daily dose of co-trimoxazole against P. falciparum infections among HIV-infected pregnant women in Bangui, the capital of the Central African Republic.

Methods/design: The MACOMBA study (MAternity and COntrol of Malaria-HIV co-infection in BAngui) is a multicentre open-label randomized clinical trial conducted at four maternity hospitals in Bangui. All HIV-infected pregnant women presenting for an antenatal clinic visit between the weeks 16 and 28 of amenorrhoea, with a CD4 count of more than 350 cells/mm3, will be eligible. All the women will provide written consent before being enrolled in the study and will then be randomly allocated to either SP-IPT (25 mg of sulfadoxine and 1.25 mg of pyrimethamine) or daily co-trimoxazole doses (960 mg per dose). The primary end-point is the placental malaria parasitaemia rate at delivery. Other main outcome measures include the number of malaria episodes during pregnancy, safety, and treatment compliance. Furthermore, the frequency of molecular resistance markers dhfr and dhps will be measured.

Discussion: In this trial, we seek to confirm whether co-trimoxazole is operationally suitable to replace SP-IPT in order to prevent malaria among pregnant women infected with HIV in the Central African Republic.

Trial registration: ClinicalTrials.gov Identifier: NCT01746199.

Figures

Figure 1
Figure 1
MACOMBA trial flowchart. 3TC: lamivudine; ACTs: artemisinin combined therapies; AZT: zidovudine; CTM: co-trimoxazole; DBS: dried blood spot; DBSd: dried blood spot for early diagnosis of HIV mother-to-child transmission; DOT: direct observed treatment; MTCTc: mother-to-child transmission of HIV and malaria parasite; NVP: nevirapine; PCRa, polymerase chain reaction for Plasmodium resistance markers; PCRb, nested species-specific polymerase chain reaction; RDT: rapid diagnostic test; SP: sulfadoxine-pyrimethamine; V1 to V5: follow-up visits; VL: viral load.

References

    1. Joint United Nations Programme on HIV/AIDS. Report on the global AIDS epidemic. Geneva; 2008.
    1. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006;367:1747–1757. doi: 10.1016/S0140-6736(06)68770-9.
    1. Butcher GA. HIV and malaria: a lesson in immunology? Parasitol Today. 1992;8:307–311. doi: 10.1016/0169-4758(92)90104-A.
    1. Martin-Blondel G, Soumah M, Camara B, Chabrol A, Porte L, Delobel P, Cuzin L, Berry A, Massip P, Marchou B. [Impact of malaria on HIV infection] Med Mal Infect. 2010;40:256–267. doi: 10.1016/j.medmal.2009.10.008.
    1. Whitworth J, Morgan D, Quigley M, Smith A, Mayanja B, Eotu H, Omoding N, Okongo M, Malamba S, Ojwiya A. Effect of HIV-1 and increasing immunosuppression on malaria parasitaemia and clinical episodes in adults in rural Uganda: a cohort study. Lancet. 2000;356:1051–1056. doi: 10.1016/S0140-6736(00)02727-6.
    1. ter Kuile FO, Parise ME, Verhoeff FH, Udhayakumar V, Newman RD, van Eijk AM, Rogerson SJ, Steketee RW. 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;Suppl 2:41–54.
    1. Steketee RW, Wirima JJ, Bloland PB, Chilima B, Mermin JH, Chitsulo L, Breman JG. Impairment of a pregnant woman's acquired ability to limit Plasmodium falciparum by infection with human immunodeficiency virus type-1. Am J Trop Med Hyg. 1996;Suppl 1:42–49.
    1. WHO/AFRO. A strategic framework for malaria prevention and control during pregnancy in the African region. Brazaville; 2004. Accessed on 20 July 2010 at [ ]
    1. Steketee RW, Wirima JJ, Slutsker L, Breman JG, Heymann DL. Comparability of treatment groups and risk factors for parasitemia at the first antenatal clinic visit in a study of malaria treatment and prevention in pregnancy in rural Malawi. Am J Trop Med Hyg. 1996;Suppl 1:17–23.
    1. Filler SJ, Kazembe P, Thigpen M, Macheso A, Parise ME, Newman RD, Steketee RW, Hamel M. Randomized trial of 2-dose versus monthly sulfadoxine-pyrimethamine intermittent preventive treatment for malaria in HIV-positive and HIV-negative pregnant women in Malawi. J Infect Dis. 2006;194:286–293. doi: 10.1086/505080.
    1. Mermin J, Ekwaru JP, Liechty CA, Were W, Downing R, Ransom R, Weidle P, Lule J, Coutinho A, Solberg P. Effect of co-trimoxazole prophylaxis, antiretroviral therapy, and insecticide-treated bednets on the frequency of malaria in HIV-1-infected adults in Uganda: a prospective cohort study. Lancet. 2006;367:1256–1261. doi: 10.1016/S0140-6736(06)68541-3.
    1. Thera MA, Sehdev PS, Coulibaly D, Traore K, Garba MN, Cissoko Y, Kone A, Guindo A, Dicko A, Beavogui AH, Djimde AA, Lyke KE, Diallo DA, Doumbo OK, Plowe CV. Impact of trimethoprim-sulfamethoxazole prophylaxis on falciparum malaria infection and disease. J Infect Dis. 2005;192:1823–1829. doi: 10.1086/498249.
    1. Bloland PB, Redd SC, Kazembe P, Tembenu R, Wirima JJ, Campbell CC. Co-trimoxazole for childhood febrile illness in malaria-endemic regions. Lancet. 1991;337:518–520. doi: 10.1016/0140-6736(91)91299-A.
    1. Hamel MJ, Holtz T, Mkandala C, Kaimila N, Chizani N, Bloland P, Kublin J, Kazembe P, Steketee R. Efficacy of trimethoprim-sulfamethoxazole compared with sulfadoxine-pyrimethamine plus erythromycin for the treatment of uncomplicated malaria in children with integrated management of childhood illness dual classifications of malaria and pneumonia. Am J Trop Med Hyg. 2005;73:609–615.
    1. Khalil IF, Ronn AM, Alifrangis M, Gabar HA, Jelinek T, Satti GM, Bygbjerg IC. Response of Plasmodium falciparum to cotrimoxazole therapy: relationship with plasma drug concentrations and dihydrofolatereductase and dihydropteroate synthase genotypes. Am J Trop Med Hyg. 2005;73:174–177.
    1. Sowunmi A, Fateye BA, Adedeji AA, Fehintola FA, Bamgboye AE, Babalola CP, Happi TC, Gbotosho GO. Effects of antifolates–co-trimoxazole and pyrimethamine-sulfadoxine–on gametocytes in children with acute, symptomatic, uncomplicated, Plasmodium falciparum malaria. Mem Inst Oswaldo Cruz. 2005;100:451–455. doi: 10.1590/S0074-02762005000400019.
    1. Forna F, McConnell M, Kitabire FN, Homsy J, Brooks JT, Mermin J, Weidle PJ. Systematic review of the safety of trimethoprim-sulfamethoxazole for prophylaxis in HIV-infected pregnant women: implications for resource-limited settings. AIDS reviews. 2006;8:24–36.
    1. Ronn AM, Msangeni HA, Mhina J, Wernsdorfer WH, Bygbjerg IC. High level of resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine in children in Tanzania. Trans R Soc Trop Med Hyg. 1996;90:179–181. doi: 10.1016/S0035-9203(96)90129-7.
    1. Roper C, Pearce R, Bredenkamp B, Gumede J, Drakeley C, Mosha F, Chandramohan D, Sharp B. Antifolate antimalarial resistance in southeast Africa: a population-based analysis. Lancet. 2003;361:1174–1181. doi: 10.1016/S0140-6736(03)12951-0.
    1. Menard D, Madji N, Manirakiza A, Djalle D, Koula MR, Talarmin A. Efficacy of chloroquine, amodiaquine, sulfadoxine-pyrimethamine, chloroquine-sulfadoxine-pyrimethamine combination, and amodiaquine-sulfadoxine-pyrimethamine combination in Central African children with noncomplicated malaria. Am J Trop Med Hyg. 2005;72:581–585.
    1. Menard D, Djalle D, Manirakiza A, Yapou F, Siadoua V, Sana S, Matsika-Claquin MD, Nestor M, Talarmin A. Drug-resistant malaria in Bangui, Central African Republic: an in vitro assessment. Am J Trop Med Hyg. 2005;73:239–243.
    1. Menard D, Djalle D, Yapou F, Manirakiza A, Talarmin A. Frequency distribution of antimalarial drug-resistant alleles among isolates of Plasmodium falciparum in Bangui, Central African Republic. Am J Trop Med Hyg. 2006;74:205–210.
    1. Menard D, Yapou F, Manirakiza A, Djalle D, Matsika-Claquin MD, Talarmin A. Polymorphisms in pfcrt, pfmdr1, dhfr genes and in vitro responses to antimalarials in Plasmodium falciparum isolates from Bangui, Central African Republic. Am J Trop Med Hyg. 2006;75:381–387.
    1. Kublin JG, Dzinjalamala FK, Kamwendo DD, Malkin EM, Cortese JF, Martino LM, Mukadam RA, Rogerson SJ, Lescano AG, Molyneux ME, Winstanley PA, Chimpeni P, Taylor TE, Plowe1 CV. Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J Infect Dis. 2002;185:380–388. doi: 10.1086/338566.
    1. Schleiermacher D, Rogier C, Spiegel A, Tall A, Trape JF, Mercereau-Puijalon O. Increased multiplicity of Plasmodium falciparum infections and skewed distribution of individual msp1 and msp2 alleles during pregnancy in Ndiop, a Senegalese village with seasonal, mesoendemic malaria. Am J Trop Med Hyg. 2001;64:303–309.
    1. Van Geertruyden JP, Menten J, Colebunders R, Korenromp E, D'Alessandro U. The impact of HIV-1 on the malaria parasite biomass in adults in sub-Saharan Africa contributes to the emergence of antimalarial drug resistance. Malar J. 2008;7:134. doi: 10.1186/1475-2875-7-134.
    1. Newman PM, Wanzira H, Tumwine G, Arinaitwe E, Waldman S, Achan J, Havlir D, Rosenthal PJ, Dorsey G, Clark TD, Deborah C. Placental malaria among HIV-infected and uninfected women receiving anti-folates in a high transmission area of Uganda. Malar J. 2009;8:254. doi: 10.1186/1475-2875-8-254.
    1. Malamba SS, Mermin J, Reingold A, Lule JR, Downing R, Ransom R, Kigozi A, Hunt BM, Hubbard A, Rosenthal PJ, Dorsey G. Effect of cotrimoxazole prophylaxis taken by human immunodeficiency virus (HIV)-infected persons on the selection of sulfadoxine-pyrimethamine-resistant malaria parasites among HIV-uninfected household members. Am J Trop Med Hyg. 2006;75:375–380.
    1. Khalil I, Ronn AM, Alifrangis M, Gabar HA, Satti GM, Bygbjerg IC. Dihydrofolatereductase and dihydropteroate synthase genotypes associated with in vitro resistance of Plasmodium falciparum to pyrimethamine, trimethoprim, sulfadoxine, and sulfamethoxazole. Am J Trop Med Hyg. 2003;68:586–589.
    1. Manirakiza A, Serdouma E, Heredeibona LS, Djalle D, Madji N, Moyen M, Soula G, Le Faou A, Delmont J. Rational case management of malaria with a rapid diagnostic test, Paracheck Pf(R), in antenatal health care in Bangui. Central African Republic. BMC Publ Health. 2012;12:482. doi: 10.1186/1471-2458-12-482.
    1. Ministère de la santé Publique, de la Population et de la Lutte contre le VIH/SIDA (République Centrafricaine) Politique nationale de la lutte contre le Paludisme. 2008.
    1. World Health Organization. Rapid Advice: use of antiretroviral drugs for treating pregnant women and preventing HIV Infection in infants. Geneva: WHO Press; 2009. Accessed 9 February 2010 at [ ]
    1. Ministère de la santé Publique, de la Population et de la Lutte contre le VIH/SIDA (République Centrafricaine) Prise en charge intégrée de la grossesse et de l’accouchementdans le contexte de la prévention de la transmission parents/enfants du VIH (PCIGA/PTPE) 2011.
    1. Joint United Nations Programme on HIV/AIDS. Guide du conseil du dépistage du VIH à l’initiative du soignant dans les établissements de santé. Geneva; 2007. Accessed 9 February 2010 at [ ]
    1. Snounou G, Singh B. In: Molecular Medicine, Malaria Methods and Protocols. Doolan D, editor. Totowa, NJ: Humana Press; 2002. Nested polymerase chain reaction analysis of Plasmodium Parasites; pp. 189–203.
    1. World Health Organization. Report on the global AIDS epidemic. Geneva; 2008. WHO Library Cataloguing in-publication Data. UNAIDS/08.25E/JC1510E ISBN 978 92 9 1737116. Accessed 9 February 2010 at [ ]
    1. Kattenberg JH, Tahita CM, Versteeg IA, Tinto H, TraoreCoulibaly M, D'Alessandro U, Schallig HD, Mens PF. Evaluation of antigen detection tests, microscopy, and polymerase chain reaction for diagnosis of malaria in peripheral blood in asymptomatic pregnant women in Nanoro, Burkina Faso. Am J Trop Med Hyg. 2012;87:251–256. doi: 10.4269/ajtmh.2012.12-0125.
    1. Plowe CV, Djimde A, Bouare M, Doumbo O, Wellems TE. Pyrimethamine and proguanil resistance-conferring mutations in Plasmodium falciparum dihydrofolatereductase: polymerase chain reaction methods for surveillance in Africa. Am J Trop Med Hyg. 1995;52:565–568.
    1. Dorton BJ, Mulindwa J, Li MS, Chintu NT, Chibwesha CJ, Mbewe F, Frenkel LM, Stringer JS, Chi BH. CD4+ cell count and risk for antiretroviral drug resistance among women using peripartum nevirapine for perinatal HIV prevention. BJOG. 2011;118:495–499. doi: 10.1111/j.1471-0528.2010.02835.x.
    1. Le Port A, Cottrell G, Echavanne C, Briand V, Bouraima A, Guerra J, Choudat I, Massougbodji A, Fayomi B, Migot-Nabias F, Garcia A, Cot M. Prevention of malaria during pregnancy: assessing the effect of the distribution of IPTp through the national policy in Benin. Am J Trop Med Hyg. 2011;84:270–275. doi: 10.4269/ajtmh.2011.10-0319.
    1. PACOME Research Team. Prevention of pregnancy-associated malaria in HIV-infected women: cotrimoxazole prophylaxis versus mefloquine (PACOME) ClinicalTrialsgov Identifier: NCT00970879. Accessed 24 December 2012 at [ ]
    1. MiPPAD Research Team. Evaluation of alternative antimalarial drugs for malaria in pregnancy (MiPPAD) ClinicalTrialsgov Identifier: NCT00811421. Accessed 24 December 2012 at [ ]

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren