Efficacy of Antifolates Against Malaria in HIV-infected Pregnant Women and the Emergence of Induced Resistance in Plasmodium Falciparum (MACOMBA)

November 26, 2020 updated by: Institut Pasteur

Comparative Study of Efficacy of Two Antifolates Prophylactic Strategies Against Malaria in HIV Positive Pregnant Women (MACOMBA Study)

Given the resistance emergence of malaria in pregnant women receiving intermittent preventive treatment with sulfadoxine-pyrimethamine (IPT-SP) and the burden of this infection among pregnant women infected by HIV it is urgent to seek a more effective alternative treatment to optimize the prevention of malaria. Cotrimoxazole (CTM), actually administered daily as a prophylactic mean to opportunistic infections for HIV infected patients, showed encouraging results in preventing malaria in pregnant women. However, these results must be confirmed by randomized trials, particularly in pregnant women.

The main objective of this clinical trial is to compare the efficacy of cotrimoxazole (CTM), administered once daily with IPT-SP (3 curative doses spaced one month) on placental parasitaemia in pregnant women infected with HIV and cluster of differentiation 4 (CD4) > 350 cells/mm3.

The main hypothesis is based on the premise that cotrimoxazole is more effective than IPT-SP for placental parasitaemia. This might be due to the higher plasma concentration of cotrimoxazole attained with daily doses. If this hypothesis is proven, cotrimoxazole could be recommended as prophylaxis for HIV-positive pregnant women, whatever their CD4+ cell count. In this study, the investigators will also test the hypothesis that the strains of Plasmodium falciparum isolated from HIV-positive pregnant women express more dhfr and dhps resistance markers.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Ascertainment of HIV serological status has become a prerequisite for better prevention of malaria. Studies reported that cotrimoxazole reduces malaria episodes in adults (other than pregnant women), and in children. Furthermore, several studies showed a good clinical and parasitological response to cotrimoxazole in treated children. Therefore, preventive treatment with SP for all HIV+ patients (including pregnant women) who are receiving treatment containing cotrimoxazole is superfluous and is even contraindicated because of the increase risk of severe adverse reactions. Few studies, however, have described the efficacy of cotrimoxazole in the prevention of malaria in pregnant women, particularly in an area where the frequency of therapeutic failures with SP in cases of Plasmodium falciparum malaria is increasing.

The emergence and augmentation of the frequency of resistance of Plasmodium falciparum to SP, which has already been observed in numerous countries of sub-Saharan Africa and in the Central African Republic, challenges the short-term usefulness of this drug combination in the prevention of malaria in pregnant women. The resistance is due to accumulation of point mutations at various sites on the genes coding for dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps). The number of mutations correlates with the extent of resistance of Plasmodium falciparum to SP in vitro. In studies carried out in Bangui, the prevalence of therapeutic failure was estimated to be 23.8% after 14 days of follow-up among children with uncomplicated malaria, while the resistance of Plasmodium falciparum to pyrimethamine in vitro was reported to be 38.3%. The frequency of mutations in dhfr and dhps alleles is correlated with in vitro response of Plasmodium falciparum strains to SP.

Pregnancy and HIV infection increase the risk for emergence of mutated strains that are resistant to SP, because a wide variety of types and clones are found in parasitaemia in pregnant women (genetic diversity). Furthermore, some studies raised concern about the possible development of cross-resistance of Plasmodium falciparum to both cotrimoxazole and SP because of the similarity of their mode of action, although this hypothesis has not been proven.

The national malaria programme in the Central African Republic recommends the use of IPT-SP since 2006.

The investigators' main hypothesis is based on the premise that cotrimoxazole is more effective than SP for placental parasitaemia. This might be due to the higher plasma concentration of cotrimoxazole attained with daily doses. If this hypothesis is proven, cotrimoxazole could be recommended as prophylaxis for HIV+ pregnant women, whatever their CD4+ cell count. In this study, the investigators will also test the hypothesis that the strains of Plasmodium falciparum isolated from HIV+ positive pregnant women express more dhfr and dhps resistance markers.

Study Type

Interventional

Enrollment (Actual)

193

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Central African Republic
      • Bangui, Central African Republic
        • Maternité de l'Hôpital communautaire
      • Bangui, Central African Republic
        • Maternité de l'Hôpital de l'Amitié
      • Bangui, Central African Republic
        • Maternité de la Gendarmerie Nationale
      • Bangui, Central African Republic
        • Maternité du centre de santé des Castors

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • age ≥ 18 years
  • HIV positivity
  • gestational age between 16 and 28 weeks
  • CD4+ count > 350 cells/mm3 and no sign of WHO stage 2, 3 or 4;
  • agreement to attend all the antenatal consultations for the study
  • willingness to adhere to all requirements of the study (including HIV-1 voluntary counseling and testing)
  • signed informed consent

Exclusion Criteria:

  • psychological instability that could interfere with compliance;
  • hypersensitivity to sulfamides or dermatological disease(eczema, pemphigoid exanthema) that would increase the risk for severe reactions to the drugs being tested
  • severe anaemia (Hb<7 g/dl)and any other severe disease
  • known hepatic cardiac or renal disease

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: cotrimoxazole daily prophylaxis
Drug: cotrimoxazole daily prophylaxis
Other Names:
  • - CTM
  • - Sulfamethoxazole- trimethoprime
  • - Bactrim®
Active Comparator: Intermittent Preventive sulphadoxine-pyrimethamine Treatment
Referent treatment given according WHO recommendations
Drug: sulphadoxine-pyrimethamine
Intermittent preventive sulphadoxine-pyrimethamine treatment
Other Names:
  • - SP
  • - sulfadoxine-pyrimethamine
  • - Fansidar®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
placental parasitaemia
Time Frame: at parturition
microscopic observation and confirmation by Polymerase Chain Reaction (PCR)
at parturition

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
observance CTM prophylaxis
Time Frame: until the end of pregnancy
until the end of pregnancy
occurrence of specific events related to the effectiveness of CTM prophylaxis and IPT-SP
Time Frame: until the end of pregnancy

considered events :

  • maternal anemia (hemoglobinemia < 10g/dl)
  • incidence of malaria episodes during pregnancy
  • abortions, stillbirth, premature (birth <37 weeks of amenorrhea) and low birth weight (< 2500g)
  • placenta malaria and umbilical malaria transmission
until the end of pregnancy
occurence of adverse events
Time Frame: until the end of pregnancy
until the end of pregnancy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Institut Pasteur

Collaborators

Institut Pasteur de Bangui

Investigators

  • Study Director: Muriel Vray, Unité d'épidémiologie des maladies émergentes, Institut Pasteur Paris, France
  • Principal Investigator: Alexandre Manirakiza, MD, Unité d'Epidémiologie, Institut Pasteur de Bangui, Central African Republic
  • Study Chair: Mirdad Kazanji, Director of the Institut Pasteur de Bangui, Central African Republic

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 1, 2013

Primary Completion (Actual)

October 1, 2015

Study Completion (Actual)

December 1, 2019

Study Registration Dates

First Submitted

November 30, 2012

First Submitted That Met QC Criteria

December 6, 2012

First Posted (Estimate)

December 10, 2012

Study Record Updates

Last Update Posted (Actual)

November 30, 2020

Last Update Submitted That Met QC Criteria

November 26, 2020

Last Verified

November 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2012-03

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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