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

NCT ID: NCT01746199

Last Updated: 2020-11-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 193 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-12-31
• Study Completion Date: 2019-12-31

Brief Summary

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.

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.

Conditions

Malaria in Pregnancy; HIV Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

cotrimoxazole daily prophylaxis

cotrimoxazole daily prophylaxis

Group Type: EXPERIMENTAL

cotrimoxazole daily prophylaxis

Intervention Type: DRUG

Intermittent Preventive sulphadoxine-pyrimethamine Treatment

Referent treatment given according WHO recommendations

Group Type: ACTIVE_COMPARATOR

sulphadoxine-pyrimethamine

Intervention Type: DRUG

Intermittent preventive sulphadoxine-pyrimethamine treatment

Interventions

cotrimoxazole daily prophylaxis

Intervention Type: DRUG

sulphadoxine-pyrimethamine

Intermittent preventive sulphadoxine-pyrimethamine treatment

Intervention Type: DRUG

Other Intervention Names

- CTM; - Sulfamethoxazole- trimethoprime; - Bactrim®; - SP; - sulfadoxine-pyrimethamine; - Fansidar®

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Institut Pasteur de Bangui

AMBIG

Sponsor Role: collaborator

Institut Pasteur

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Muriel Vray

Role: STUDY_DIRECTOR

Unité d'épidémiologie des maladies émergentes, Institut Pasteur Paris, France

Alexandre Manirakiza, MD

Role: PRINCIPAL_INVESTIGATOR

Unité d'Epidémiologie, Institut Pasteur de Bangui, Central African Republic

Mirdad Kazanji

Role: STUDY_CHAIR

Director of the Institut Pasteur de Bangui, Central African Republic

Locations

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

Bangui, , Central African Republic

Countries

Central African Republic

References

Pons-Duran C, Wassenaar MJ, Yovo KE, Marin-Carballo C, Briand V, Gonzalez R. Intermittent preventive treatment regimens for malaria in HIV-positive pregnant women. Cochrane Database Syst Rev. 2024 Sep 26;9(9):CD006689. doi: 10.1002/14651858.CD006689.pub3.

Reference Type: DERIVED

PMID: 39324693 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 23945130 (View on PubMed)

Other Identifiers

2012-03

Identifier Type: -

Identifier Source: org_study_id