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.
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

November 30, 2012
November 14, 2013
December 2013
October 2015   (final data collection date for primary outcome measure)
placental parasitaemia [ Time Frame: at parturition ] [ Designated as safety issue: No ]
microscopic observation and confirmation by Polymerase Chain Reaction (PCR)
Same as current
Complete list of historical versions of study NCT01746199 on ClinicalTrials.gov Archive Site
  • 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 ]
Same as current
Not Provided
Not Provided
 
Efficacy of Antifolates Against Malaria in HIV-infected Pregnant Women and the Emergence of Induced Resistance in Plasmodium Falciparum
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.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
  • Malaria in Pregnancy
  • HIV Infection
  • Drug: cotrimoxazole daily prophylaxis
    Other Names:
    • - CTM
    • - Sulfamethoxazole- trimethoprime
    • - Bactrim®
  • Drug: sulphadoxine-pyrimethamine
    Intermittent preventive sulphadoxine-pyrimethamine treatment
    Other Names:
    • - SP
    • - sulfadoxine-pyrimethamine
    • - Fansidar®
  • Experimental: cotrimoxazole daily prophylaxis
    cotrimoxazole daily prophylaxis
    Intervention: Drug: cotrimoxazole daily prophylaxis
  • Active Comparator: Intermittent Preventive sulphadoxine-pyrimethamine Treatment
    Referent treatment given according WHO recommendations
    Intervention: Drug: sulphadoxine-pyrimethamine
Manirakiza A, Sepou A, Serdouma E, Gondje S, Bata GG, Moussa S, Boulay A, Moyen JM, Sakanga O, Le-Fouler L, Kazanji M, Vray M. 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). Trials. 2013 Aug 14;14:255. doi: 10.1186/1745-6215-14-255.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Not yet recruiting
300
Not Provided
October 2015   (final data collection date for primary outcome measure)

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
Female
18 Years and older
No
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
Central African Republic
 
NCT01746199
2012-03
Yes
Institut Pasteur
Institut Pasteur
Institut Pasteur de Bangui
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
Institut Pasteur
December 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP