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

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified December 2012 by Institut Pasteur
Sponsor:
Collaborator:
Institut Pasteur de Bangui
Information provided by (Responsible Party):
Institut Pasteur
ClinicalTrials.gov Identifier:
NCT01746199
First received: November 30, 2012
Last updated: November 14, 2013
Last verified: December 2012
  Purpose

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.


Condition Intervention Phase
Malaria in Pregnancy
HIV Infection
Drug: cotrimoxazole daily prophylaxis
Drug: sulphadoxine-pyrimethamine
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Comparative Study of Efficacy of Two Antifolates Prophylactic Strategies Against Malaria in HIV Positive Pregnant Women (MACOMBA Study)

Resource links provided by NLM:


Further study details as provided by Institut Pasteur:

Primary Outcome Measures:
  • placental parasitaemia [ Time Frame: at parturition ] [ Designated as safety issue: No ]
    microscopic observation and confirmation by Polymerase Chain Reaction (PCR)


Secondary Outcome Measures:
  • observance CTM prophylaxis [ Time Frame: until the end of pregnancy ] [ Designated as safety issue: No ]
  • occurrence of specific events related to the effectiveness of CTM prophylaxis and IPT-SP [ Time Frame: until the end of pregnancy ] [ Designated as safety issue: No ]

    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

  • occurence of adverse events [ Time Frame: until the end of pregnancy ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 300
Study Start Date: December 2013
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: cotrimoxazole daily prophylaxis
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®

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01746199

Contacts
Contact: Alexandre Manirakiza, MD + 236 70 93 05 79 amanirak@yahoo.fr
Contact: Muriel Vray, PhD + 33 1 40 61 39 82 muriel.vray@pasteur.fr

Locations
Central African Republic
Maternité de l'Hôpital communautaire Not yet recruiting
Bangui, Central African Republic
Maternité de l'Hôpital de l'Amitié Not yet recruiting
Bangui, Central African Republic
Maternité de la Gendarmerie Nationale Not yet recruiting
Bangui, Central African Republic
Maternité du centre de santé des Castors Not yet recruiting
Bangui, Central African Republic
Sponsors and Collaborators
Institut Pasteur
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
  More Information

No publications provided by Institut Pasteur

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Institut Pasteur
ClinicalTrials.gov Identifier: NCT01746199     History of Changes
Other Study ID Numbers: 2012-03
Study First Received: November 30, 2012
Last Updated: November 14, 2013
Health Authority: Central African Republic: Ministry of Public Health, Population and the fight against AIDS

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Malaria
Immune System Diseases
Immunologic Deficiency Syndromes
Lentivirus Infections
Parasitic Diseases
Protozoan Infections
RNA Virus Infections
Retroviridae Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases
Fanasil, pyrimethamine drug combination
Pyrimethamine
Sulfadoxine
Trimethoprim-Sulfamethoxazole Combination
Anti-Infective Agents
Anti-Infective Agents, Urinary
Antimalarials
Antiparasitic Agents
Antiprotozoal Agents
Enzyme Inhibitors
Folic Acid Antagonists
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Renal Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 30, 2014