Prevention of Pregnancy-associated Malaria in HIV-infected Women: Cotrimoxazole Prophylaxis Versus Mefloquine (PACOME)

Study Description

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Brief Summary:

The purpose of this study is to evaluate the efficacy of cotrimoxazole prophylaxis in prevention of malaria during pregnancy in HIV-infected women, compared to intermittent preventive treatment with mefloquine.

Condition or disease	Intervention/treatment	Phase
Malaria in Pregnancy; HIV Infections	Drug: cotrimoxazole; Drug: mefloquine	Phase 3

Detailed Description:

Malaria infection during pregnancy can have adverse effects on both mother and fetus, including maternal anaemia and low birth weight which are responsible for mother and infant mortality. It is a particular problem for women in their first and second pregnancies and for women who are HIV-positive. Maternal HIV infection potentiates many of these adverse effects. In HIV-infected women, the World Health Organization (WHO) advocates the use of insecticide-treated bednets, and drugs : If the CD4 cell count is below 350/mm3 or the HIV disease is in WHO stage 2, 3 or 4, cotrimoxazole prophylaxis for the prevention of pneumocystosis and toxoplasmosis is indicated, that is assumed to also protect those women from malaria. Otherwise, they have to receive at least three doses of intermittent preventive treatment (IPT), most commonly with sulfadoxine-pyrimethamine (SP) given at the antenatal care visits. If IPT with SP has been a subject of many investigations, cotrimoxazole efficacy has never been assessed in prevention of malaria during pregnancy.

The investigators aim to evaluate the efficacy of cotrimoxazole prophylaxis in prevention of malaria during pregnancy in HIV-infected women. The investigators postulate that cotrimoxazole prophylaxis is not inferior to IPT in all women, unrelated to their CD4 cell count. In the control arm, the investigators will use mefloquine as IPT. The safety and efficacy of this drug have already been assessed in HIV-negative patients (NCT00274235).

A randomized controlled trial will be conducted in five hospitals in Benin. Pregnant women will be enrolled both in the Antenatal Care unit and in the Infectious Diseases unit of each setting. All women will receive insecticide-treated bednets at enrolment. Randomization will be stratified by hospital and CD4 cell count range. Women assigned to cotrimoxazole will receive cotrimoxazole prophylaxis daily during all the course of pregnancy. Women assigned to mefloquine IPT will receive mefloquine three times during pregnancy. Women randomised in this arm and having a low CD4 cell count or an advanced HIV disease will also receive cotrimoxazole prophylaxis in prevention of HIV/AIDS opportunistic infections. Drug efficacy will be judged on the prevalence of placental malaria at delivery.

This study will contribute to updating the recommendations concerning the prevention of malaria during pregnancy in HIV-infected women.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	430 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Prevention
Official Title:	Prevention of Pregnancy-associated Malaria in HIV-infected Women : Randomised Controlled Trial Testing Cotrimoxazole Prophylaxis Versus Intermittent Preventive Treatment With Mefloquine
Study Start Date :	December 2009
Actual Primary Completion Date :	July 2012
Actual Study Completion Date :	December 2012

Arms and Interventions

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Arm	Intervention/treatment
Experimental: cotrimoxazole (high); CD4 cell count≥350/mm3	Drug: cotrimoxazole; 800 mg sulfamethoxazole and 160 mg trimethoprim daily, from 28 weeks of gestation until delivery
Active Comparator: mefloquine; CD4 cell count≥350/mm3	Drug: mefloquine; mefloquine 15 mg/Kg three times, between 16 and 28 weeks, 24 and 32 weeks, then 28 and 36 weeks of pregnancy
Experimental: cotrimoxazole (low); CD4 cell count<350/mm3	Drug: cotrimoxazole; 800 mg sulfamethoxazole and 160 mg trimethoprim daily, from 28 weeks of gestation until delivery
Active Comparator: mefloquine & cotrimoxazole; CD4 cell count<350/mm3	Drug: cotrimoxazole; 800 mg sulfamethoxazole and 160 mg trimethoprim daily, from 28 weeks of gestation until delivery Drug: mefloquine; mefloquine 15 mg/Kg three times, between 16 and 28 weeks, 24 and 32 weeks, then 28 and 36 weeks of pregnancy

Outcome Measures

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Primary Outcome Measures :

1. proportion of placental malaria (presence of parasites in the placental blood smear at delivery) [ Time Frame: delivery ]

Secondary Outcome Measures :

1. placental malaria mean parasite density at delivery [ Time Frame: delivery ]
2. proportion of low birth weight infants (<2500 g) and mean birth weight [ Time Frame: delivery ]
3. proportion of maternal anaemia (<11g/dl) and severe maternal anaemia (<8g/dl) at delivery and during pregnancy [ Time Frame: course of pregnancy and delivery ]
4. cord blood malaria infection at delivery (infant parasitemia) [ Time Frame: delivery ]
5. pre-term deliveries (< 37 weeks) [ Time Frame: delivery ]
6. spontaneous abortions (early:<28 weeks, late: ≥28 weeks) and still births [ Time Frame: course of pregnancy ]
7. congenital anomalies [ Time Frame: first 6 months of life ]
8. safety profile of the two treatments: proportion and detailed description of adverse effects in each treatment arm [ Time Frame: course of pregnancy (mother) anf first 6 months of life (infant) ]
9. Mother-to-child HIV transmission rate in each treatment arm [ Time Frame: 2 months after breastfeeding cessation ]
10. To document the effect of cotrimoxazole in reducing infections in HIV-infected women, we will measure the incidence of bacterial and parasitic infections (other than malaria) during pregnancy [ Time Frame: course of pregnancy ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Confirmed HIV seropositivity
• Permanent residency in the study catchment's area
• Confirmed pregnancy, gestational age< 28 weeks
• More than 18 years of age
• Karnofsky index ≥80
• Willingness to deliver at the hospital
• Written informed consent

Exclusion Criteria:

• History of allergy to study drugs : sulpha drugs, mefloquine, quinine
• History or presence of major illnesses : severe renal disease , severe hepatic disease, severe neuropsychiatric disease
• Mefloquine or halofantrine received within the 4 weeks prior to enrolment

Contacts and Locations

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Locations

Benin
Hôpital d'Instruction des Armées Camp Guézo
Cotonou, Benin
Hôpital de la Mère et de l'Enfant Lagune
Cotonou, Benin
Hôpital de zone de Suru Lere
Cotonou, Benin
Unviversity Hospital Hubert Koutoukou Maga
Cotonou, Benin
Clinique Louis Pasteur
Porto-Novo, Benin

Sponsors and Collaborators

Institut de Recherche pour le Developpement

Sidaction

Saint Antoine University Hospital

National University Hospital, Cotonou

Université d'Abomey-Calavi

Ministry of Health, Benin

Investigators

Principal Investigator:	Marcel D Zannou, Professor	Cotonou University Hospital & Faculté des Sciences de la Santé, Benin
Study Chair:	Pierre-Marie Girard, Professor	Saint Antoine Hospital, Assistance Publique-Hôpitaux se Paris
Study Director:	Michel Cot, MD, PHD	Institut de Recherche pour le Developpement

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Duvignaud A, Denoeud-Ndam L, Akakpo J, Agossou KV, Afangnihoun A, Komongui DG, Atadokpédé F, Dossou-Gbété L, Girard PM, Zannou DM, Cot M. Incidence of malaria-related fever and morbidity due to Plasmodium falciparum among HIV1-infected pregnant women: a prospective cohort study in South Benin. Malar J. 2014 Jul 4;13:255. doi: 10.1186/1475-2875-13-255.

Responsible Party:	Lise Denoeud-Ndam, MD, MPH, Institut de Recherche pour le Developpement
ClinicalTrials.gov Identifier:	NCT00970879 History of Changes
Other Study ID Numbers:	IRD-Sidaction-01
First Posted:	September 3, 2009
Last Update Posted:	January 23, 2013
Last Verified:	January 2013

Keywords provided by Lise Denoeud-Ndam, Institut de Recherche pour le Developpement:

malaria; pregnancy; HIV	prevention; cotrimoxazole; mefloquine

Additional relevant MeSH terms:

HIV Infections; Malaria; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Protozoan Infections	Parasitic Diseases; Mefloquine; Trimethoprim, Sulfamethoxazole Drug Combination; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents; Anti-Infective Agents, Urinary; Renal Agents; Anti-Bacterial Agents