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)
Alexandre ManirakizaAbdoulaye SépouEugène SerdoumaSamuel GondjéG BataSandrine MoussaAude BoulayJean Méthode MoyenOlga SakangaLenaig LeFoulerMirdad KazanjiMuriel Vray
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Co-infection with malaria parasite and HIV is an emerging public health problem in tropical areas, particularly in pregnant women, and management of the concurrent effects of these two infections is challenging. Co-trimoxazole is a sulfamide preparation used to prevent opportunistic infections in HIV-infected patients, and many studies have reported that it has significant activity against malaria. As the efficacy of intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine (SP) against malaria is decreasing, co-trimoxazole might be an alternative for preventing malaria among HIV-infected populations. The aim of this study is to compare the effectiveness of SP-IPT, which is recommended for the prevention of malaria during pregnancy in the Central African Republic, with that of a daily dose of co-trimoxazole against P. falciparum infections among HIV-infected pregnant women in Bangui, the capital of the Central African Republic. The MACOMBA study (MAternity and COntrol of Malaria-HIV co-infection in BAngui) is a multicentre open-label randomized clinical trial conducted at four maternity hospitals in Bangui. All HIV-infected pregnant women presenting for an antenatal clinic visit between the weeks 16 and 28 of amenorrhoea, with a CD4 count of more than 350 cells/mm3, will be eligible. All the women will provide written consent before being enrolled in the study and will then be randomly allocated to either SP-IPT (25 mg of sulfadoxine and 1.25 mg of pyrimethamine) or daily co-trimoxazole doses (960 mg per dose). The primary end-point is the placental malaria parasitaemia rate at delivery. Other main outcome measures include the number of malaria episodes during pregnancy, safety, and treatment compliance. Furthermore, the frequency of molecular resistance markers dhfr and dhps will be measured. In this trial, we seek to confirm whether co-trimoxazole is operationally suitable to replace SP-IPT in order to prevent malaria among pregnant women infected with HIV in the Central African Republic. ClinicalTrials.gov Identifier: NCT01746199 .Keywords:
Sulfadoxine
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Malaria prophylaxis
The in vivo efficacies of the Lao People's Democratic Republic (Laos) nationally recommended antimalarial agents—chloroquine and sulfadoxine-pyrimethamine—were assessed in a randomized, comparative trial that involved 100 patients with uncomplicated Plasmodium falciparum malaria who were followed for 42 days after starting treatment. Despite a shorter mean time to fever clearance associated with administration of chloroquine (mean time to clearance, 35.6 h; 95% confidence interval [CI], 26.3–45.0 h), compared with that associated with sulfadoxine-pyrimethamine (61.1 h; 95% CI, 50.9–71.3 h; P < .001), treatment failures were twice as frequent among patients receiving chloroquine therapy than among those receiving sulfadoxine-pyrimethamine therapy (36% vs. 18%; P = .02). Of 23 treatment failures, 10 (43%) were high grade. Treatment failure rates among children (age range, 5–15 years) were 4.9 times higher (95% CI, 2–12) than those among adults (P < .0001). Gametocytemia after antimalarial treatment was associated with receipt of sulfadoxine-pyrimethamine therapy and with treatment failure (P = .009). The efficacy of both chloroquine and sulfadoxine-pyrimethamine in Laos is unsatisfactory.
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Three recently isolated Thai strains of Plasmodium falciparum were tested in vitro for their response to pyrimethamine, sulfadoxine, and both compounds in combination. One isolate, FCK, was moderately tolerant to pyrimethamine whereas FCM3 and FCM5 were not affected by this compound at serum level, being 100 times less responsive than a sensitive strain from the Gambia when tested similarly. This low degree of response is evidently due to drug resistance. Sensitivity to sulfadoxine was low in the Thai isolates, but was also lower than expected in the Gambian strain. Possible causes of the poor response are discussed. Pyrimethamine in combination with sulfadoxine showed a synergistic effect; the effective doses were reduced by ten and three times, respectively.
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Eighteen patients with Plasmodium falciparum infection were studied in Port-au-Prince, Haiti, to monitor the response of the malaria parasite to sulfadoxine-pyrimethamine. In all infections the parasitaemia was cleared rapidly following treatment with standard dose of the drug combination; no recrudescence was observed during follow-up periods of 1 week (4 patients) and 4 weeks (14 patients). Parallel in vitro tests indicated that 5 of the 16 isolates successfully tested were resistant to pyrimethamine alone.
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Background: Mutations in parasite enzymes and sub-optimal dosing associated with poor quality drug administration are considered major causes of parasitological resistance to sulfadoxine-pyrimethamine in the treatment of malaria.Objectives: This study evaluated the effects of simvastatin in modulating parasitological response to sulfadoxine-pyrimethamine in the treatment of malaria.Methods: Malaria patients (n=60) diagnosed by thick blood film and confirmed using immunological tests were selected and informed written consent obtained.Patients were categorized into simvastatin plus sulfadoxinepyrimethamine (test) and sulfadoxine-pyrimethamine alone (control group).The University of Nigeria Teaching Hospital Research Ethics Committee reviewed the proposal and provided ethical clearance certification (NHREC/05/01/2008B).The WHO criteria was adopted in the assessment of parasitological response and patients followed up on days D0, D3, D7, D14 and D28 post-treatment.The analysis of data was done using GraphPad Prism 4.0 and data presented in tabular and graphical forms.Results: Revealed a statistically significant difference in parasitological response (p<0.05) between test and control groups.The mean value of low level resistance, RI was given as 8.5±0.76%,mid-level resistance, RII as 7.7±0.82%,high level parasitological resistance, RIII as 5.2±0.35% and the late parasitological failure, LPF as 3.4±0.29% in the test group.This contrasts with the value of RI given as 17.1±0.61%,RII as 22.6±0.85%,RIII as 15.2±0.76% and the LPF given as 11.4±0.15% in the control group. Conclusions:The implication of present study indicates that the enhanced parasitological response to sulfadoxine-pyrimethamine may be attributed to modulating effects of simvastatin use.
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This double-blind study is based on the treatment of 75 adult male patients suffering from Plasmodium falciparum malaria in Medellín, Colombia, a city in which there is no malaria transmission. The patients, who came from regions with high resistance to antimalarials, were divided into three groups receiving single-dose treatment as follows: a combination of 280 mg mefloquine, 800 mg sulfadoxine and 40 mg pyrimethamine; a combination of 420 mg mefloquine, 1200 mg sulfadoxine and 60 mg pyrimethamine; and a combination of 1500 mg sulfadoxine and 75 mg pyrimethamine. After treatment, follow-up examination was performed daily for I week and then weekly for another 3 weeks. The cure rate in the mefloquine groups (within the study period of 28 days) was 100%, and in the third group 75%. Normal blood levels of the administered drugs were found in 6 patients of the third group who were not cured; they were subsequently cured with a single dose of 1000 mg of mefloquine. Drug tolerance was good and no toxic effects were demonstrated in blood and urine examinations. While the doses in the drug combinations (containing mefloquine) gave very good results, we would recommend a slightly higher dose combination of mefloquine with sulfadoxine-pyrimethamine for the treatment of falciparum malaria in areas with a high prevalence of chloroquine resistance.
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Journal Article Double-blind dose finding study of mefloquine-sulfadoxine-pyrimethamine in children with acute falciparum malaria Get access X.B. Guo, X.B. Guo 1Malaria Research Unit, Guangzhou College of Traditional Chinese Medicine, Guangzhou, Guangdong, People's Republic of China Search for other works by this author on: Oxford Academic PubMed Google Scholar K. Arnold, K. Arnold ∗ 2Roche Asian Research Foundation, P.O. Box 98595, Tsimshatsui, Hong Kong ∗Author for correspondence. Search for other works by this author on: Oxford Academic PubMed Google Scholar L.C. Fu, L.C. Fu 1Malaria Research Unit, Guangzhou College of Traditional Chinese Medicine, Guangzhou, Guangdong, People's Republic of China Search for other works by this author on: Oxford Academic PubMed Google Scholar P.Q. Chen, P.Q. Chen 1Malaria Research Unit, Guangzhou College of Traditional Chinese Medicine, Guangzhou, Guangdong, People's Republic of China Search for other works by this author on: Oxford Academic PubMed Google Scholar G.Q. Li G.Q. Li 1Malaria Research Unit, Guangzhou College of Traditional Chinese Medicine, Guangzhou, Guangdong, People's Republic of China Search for other works by this author on: Oxford Academic PubMed Google Scholar Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 82, Issue 4, July-August 1988, Pages 538–540, https://doi.org/10.1016/0035-9203(88)90496-8 Published: 01 July 1988 Article history Received: 03 March 1988 Accepted: 18 March 1988 Published: 01 July 1988
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A study on the comparative efficacy of two antimalarial drugs, namely chloroquine and sulfadoxine/pyrimethamine combination in the treatment of falciparum malaria was carried out in Siaya District, Nyanza Province of Kenya. Children aged between six to sixty months attending Bondo sub-district hospital with a history of fever within 48 hours were screened for malaria parasites. Those found to have a parasite density of ≥1000 parasites/μl of blood were recruited and randomly allocated to two treatment regimens comprising of chloroquine at a total dose of 25mg/kg body weight given for three days and sulfadoxine/pyrimethamine combination given as 25mg/kg of sulfadoxine and 1.25mg/kg of pyrimethamine as a single dose. The children were followed on days 3, 7 and 14. A total of 92 children met the inclusion criteria and were allocated to treatment with either chloroquine or sulfadoxine/pyrimethamine combination. Of those on chloroquine, parasite clearance on days 3, 7 and 14 was 31.1%, 44.4% and 42.3% respectively, while sulfadoxine/pyrimethamine combination had a clearance of 70.2%, 91.5% and 95.7% respectively. The differences in the parasite clearance on each follow up days for both drugs were statistically significant (p < 0.0001). Other parameters which included fever and packed cell volume (PCV) were seen to improve significantly for the sulfadoxine/pyrimethamine combination than for chloroquine.
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Seventy Plasmodium falciparum isolates, collected from two geographically separate areas of Thailand, were tested for their in vitro responses to pyrimethamine, sulfadoxine, and a combination of these two drugs. The effects of pyrimethamine and pyrimethamine-sulfadoxine combinations against P. falciparum isolates were found to be significantly greater in a northern area where the combined drug was an effective therapeutic agent than in a south-eastern area, near the Thai-Kampuchean border, where the combined drug was no longer effective. However, the actions of sulfadoxine against parasites obtained from the two areas were not significantly different. There was no significant difference between the mean values of plasma 4-aminobenzoic acid (PABA) in falciparum malaria patients and in healthy controls. The test for PABA determinations used in this study gave positive readings with both PABA and sulfadoxine.
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