Akintunde Sowunmi

Comparison of chlorproguanil-dapsone with sulfadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in young African children: double-blind randomised controlled trial

BACKGROUND Increasing resistance to sulfadoxine-pyrimethamine is leading to a decline in its effectiveness. We aimed to assess the safety profile of chlorproguanil-dapsone (CD), and to compare the safety and efficacy of this drug with that of sulfadoxine-pyrimethamine (SP) as treatment for uncomplicated falciparum malaria. METHODS We undertook a double-blind, randomised trial in 1850 consecutively recruited children with uncomplicated falciparum malaria, pooling data from five African countries. Analyses were based on all randomised patients with available data. FINDINGS CD was significantly more efficacious than SP (odds ratio 3.1 [95% CI 2.0-4.8]); 1313 patients (96%) given CD and 306 (89%) given SP achieved acceptable clinical and parasitological response by day 14. Adverse events were reported in 46% and 50% of patients randomised to CD and SP, respectively (treatment difference -4.4%, [95% CI -10.1 to 1.3]). Haemoglobin in the CD group was significantly lower than in the SP group at day 7, a difference of -4 g/L (95% CI -6 to -2). Mean day 14 haemoglobin (measured only for the small number of patients whose day 7 data caused concern) was 94 g/L (92-96) and 97 g/L (92-102) after CD and SP, respectively. Glucose-6-phosphate dehydrogenase deficient patients on CD had greater odds than those on SP of having a fall of 20 g/dL or more in haemoglobin when baseline temperature was high. Methaemoglobinaemia was seen in the CD group (n=320, mean 0.4% [95% CI 0.4-0.4]) before treatment, 4.2% (95% CI 3.8-4.6) (n=301) at day 3, and 0.6% (0.6-0.7) (n=300) at day 7). INTERPRETATION CD had greater efficacy than SP in Africa and was well tolerated. Haematological adverse effects were more common with CD than with SP and were reversible. CD is a useful alternative where SP is failing due to resistance.

Selection of Plasmodium falciparum Multidrug Resistance Gene 1 Alleles in Asexual Stages and Gametocytes by Artemether-Lumefantrine in Nigerian Children with Uncomplicated Falciparum Malaria

ABSTRACT We assessed Plasmodium falciparum mdr1 (Pfmdr1) gene polymorphisms and copy numbers as well as P. falciparum Ca2+ ATPase (PfATPase6) gene polymorphisms in 90 Nigerian children presenting with uncomplicated falciparum malaria and enrolled in a study of the efficacy of artemether-lumefantrine (AL). The nested PCR-restriction fragment length polymorphism and the quantitative real-time PCR methodologies were used to determine the alleles of the Pfmdr1 and PfATPase6 genes and the Pfmdr1 copy number variation, respectively, in patients samples collected prior to treatment and at the reoccurrence of parasites during a 42-day follow-up. The Pfmdr1 haplotype 86N-184F-1246D was significantly associated (P < 0.00001) with treatment failures and was selected for among posttreatment samples obtained from patients with newly acquired or recrudescing infections (P < 0.00001; χ2 = 36.5) and in gametocytes (log rank statistic = 5; P = 0.0253) after treatment with AL. All pre- and posttreatment samples as well as gametocytes harbored a single copy of the Pfmdr1 gene and the wild-type allele (L89) at codon 89 of the PfATPase6 gene. These findings suggest that polymorphisms in the Pfmdr1 gene are under AL selection pressure. Pfmdr1 polymorphisms may result in reduction in the therapeutic efficacy of this newly adopted combination treatment for uncomplicated falciparum malaria in Saharan countries of Africa.

Prognostic risk factors and post mortem findings in cerebral malaria in children

We have examined the possible risk factors for poor prognosis in cerebral malaria in 61 Nigerian children in an area of high malaria transmission. The level of coma, decerebrate rigidity, hypoglycaemia, and high urea levels were indicators of poor prognosis. Pyrexia, vomiting, and anaemia did not influence prognosis. Post-mortem findings suggest gross cerebral oedema and raised intracranial pressure in 4 of 7 cases with petechial haemorrhages and small focal necrosis (Durcks granuloma).

Point mutations in the pfcrt and pfmdr-1 genes of Plasmodium falciparum and clinical response to chloroquine, among malaria patients from Nigeria

Abstract Chloroquine (CQ) resistance in Plasmodium falciparum has been associated with specific point mutations in the pfcrt and pfmdr-1 genes. In the present study, 30 children aged 1–12 years, who were all suffering from acute, uncomplicated, P. falciparum malaria in Ibadan, Nigeria, were evaluated to assess the association between these mutations and clinical outcome following treatment with CQ. The parasites, in blood samples collected pre-treatment and, in those who failed treatment, on the day symptoms re-occurred post-treatment, were genotyped using the polymorphic MSP1, MSP2 and GLURP loci and PCR-RFLP. The results showed that, pre-treatment, all 30 patients had polyclonal infections, the mean numbers of P. falciparum clones detected per infection being 2.6 with MSP1, 4.2 with MSP2 and 2.8 with GLURP. The T76 allele of pfcrt and the Y86 allele of pfmdr-1 were found in 53% and 40%, respectively, of the pre-treatment samples from the 15 patients who failed CQ treatment, but the Y1246 mutation in pfmdr-1 was never detected. Although the parasites from the two patients with high-grade (RIII) resistance to CQ had both of these point mutations, the presence of the T76 allele of pfcrt or the Y86 allele of pfmdr-1 (considered individually) could not be used to predict treatment outcome. However, a high frequency of clonal multiplicity may confound attempts to associate the point mutations in pfcrt or pfmdr-1 with clinical response to CQ. It remains unclear whether the present results represent the characteristics of the predominant parasite populations in the study area. Further studies are needed before the strength of the association between the point mutations identified as markers of drug resistance and clinical outcome can be accurately evaluated, in this and other regions of intense transmission.

Innate resistance to new antimalarial drugs in Plasmodium falciparum from Nigeria

The rapid dissemination of chloroquine-resistant Plasmodium falciparum in West Africa has been well documented and represents a significant health threat to autochthonous populations. The methodical development of alternative chemotherapeutic agents demands that dispensing new antimalarial drugs (mefloquine, halofantrine, and artemisinine [qinghaosu]) be closely monitored in order to protect their clinical utility. Indeed, mefloquine-resistant strains of P. falciparum have been reported. We present data from experiments in vitro on the innate resistance of P. falciparum isolates to mefloquine as well as a disturbing observation of transient resistance to artemisinine. The implications for the extended efficacy of these new antimalarial drugs are addressed.

Chlorproguanil−Dapsone−Artesunate versus Artemether−Lumefantrine: A Randomized, Double-Blind Phase III Trial in African Children and Adolescents with Uncomplicated Plasmodium falciparum Malaria

Background Chlorproguanil−dapsone−artesunate (CDA) was developed as an affordable, simple, fixed-dose artemisinin-based combination therapy for use in Africa. This trial was a randomized parallel-group, double-blind, double-dummy study to compare CDA and artemether−lumefantrine (AL) efficacy in uncomplicated Plasmodium falciparum malaria and further define the CDA safety profile, particularly its hematological safety in glucose-6-phosphate dehydrogenase (G6PD) -deficient patients. Methods and Findings The trial was conducted at medical centers at 11 sites in five African countries between June 2006 and August 2007. 1372 patients (≥1 to <15 years old, median age 3 years) with acute uncomplicated P. falciparum malaria were randomized (2∶1) to receive CDA 2/2.5/4 mg/kg once daily for three days (N = 914) or six-doses of AL over three days (N = 458). Non-inferiority of CDA versus AL for efficacy was evaluated in the Day 28 per-protocol (PP) population using parasitological cure (polymerase chain reaction [PCR]-corrected). Cure rates were 94.1% (703/747) for CDA and 97.4% (369/379) for AL (treatment difference –3.3%, 95%CI –5.6, −0.9). CDA was non-inferior to AL, but there was simultaneous superiority of AL (upper 95%CI limit <0). Adequate clinical and parasitological response at Day 28 (uncorrected for reinfection) was 79% (604/765) with CDA and 83% (315/381) with AL. In patients with a G6PD-deficient genotype (94/603 [16%] hemizygous males, 22/598 [4%] homozygous females), CDA had the propensity to cause severe and clinically concerning hemoglobin decreases: the mean hemoglobin nadir was 75 g/L (95%CI 71, 79) at Day 7 versus 97 g/L (95%CI 91, 102) for AL. There were three deaths, unrelated to study medication (two with CDA, one with AL). Conclusions Although parasitologically effective at Day 28, the hemolytic potential of CDA in G6PD-deficient patients makes it unsuitable for use in a public health setting in Africa. Trial Registration ClinicalTrials.gov NCT00344006

Evaluation of the relative efficacy of various antimalarial drugs in Nigerian children under five years of age suffering from acute uncomplicated falciparum malaria

A parallel group-randomized comparison of the therapeutic efficacy of chloroquine (CQ), amodiaquine (AM), quinine (QN), sulphadoxine-pyrimethamine (S-P), mefloquine 15 mg kg-1 (M15) and mefloquine 25 mg kg-1 (M25) in acute symptomatic uncomplicated falciparum malaria was carried out in 325 children under the age of five years in Ibadan, southwestern Nigeria, using the 28-day in vivo test. The parasitological cure rate, assessed only up to day 14, was 85% in the CQ group and 100% in the other groups. The mean parasite and fever clearance times were, respectively, 2.64 and 1.20 days in the CQ-sensitive subgroup, 2.32 and 1.13 days in the AM group, 2.27 and 1.17 days in the QN group, 2.23 and 1.76 days in the S-P group, 2.13 and 1.10 days in the M15 group, and 2.07 and 1.09 days in the M25 group. The CQ-treatment failures (seven of 46 patients) were successfully treated with 25 mg kg-1 mefloquine, with parasite and fever clearance times of 1.73 and 1.0 days respectively. The study shows that, in Nigeria, CQ is now less effective than AM, S-P, QN and M in acute falciparum malaria in the group most vulnerable to the infection (the under-five-year-olds).(ABSTRACT TRUNCATED AT 250 WORDS)

Activities of Amodiaquine, Artesunate, and Artesunate-Amodiaquine against Asexual- and Sexual-Stage Parasites in Falciparum Malaria in Children

ABSTRACT The activities of amodiaquine, artesunate, and artesunate-amodiaquine against asexual- and sexual-stage parasites were evaluated in 360 Nigerian children with uncomplicated Plasmodium falciparum malaria randomized to the standard dose regimens of the three drugs/combination. Clinical recovery from illness occurred in all children. There were no significant differences in fever clearance times. Patients treated with artesunate or artesunate-amodiaquine had significantly shorter parasite clearance times (1.4 ± 0.5 days or 1.4 ± 0.6 days versus 3.2 ± 2.3 days, P = 0.0001) and lower gametocyte carriage rates (3.3 or 1.7% versus 11.7%, P = 0.001) than those treated with amodiaquine alone. Gametocytemia was detected in 62 patients (11.7% before treatment and 5.6% after treatment). The pretreatment gametocyte sex ratio, which was female biased, increased significantly during the course of treatment with amodiaquine but not with artesunate and artesunate-amodiaquine. These results suggest that artesunate and artesunate-amodiaquine reduce gametocyte carriage and may reduce transmissibility in P. falciparum malaria by accelerating asexual clearance and influencing gametocyte sex ratio.

Effects of amodiaquine, artesunate, and artesunate-amodiaquine on Plasmodium falciparum malaria-associated anaemia in children.

The effects of amodiaquine, artesunate and artesunate-amodiaquine on Plasmodium falciparum malaria-associated anaemia (PfMAA) and the recovery from PfMAA were evaluated in 328 children with uncomplicated malaria randomized to the standard dose regimens of the three drug treatments. Overall, malaria-attributable fall in haematocrit (MAFH) before treatment was 4.8+/-2.8%, 95% confidence interval (CI) 4.4-5.2%, and was not significantly different between the treatment groups (P=0.31). An age <5 years and a history of illness >3d were independent predictors of MAFH before treatment >4%. Following treatment, drug-attributable fall in haematocrit (DAFH) was significantly higher in amodiaquine-treated children (4.6+/-2.9%, 2.8+/-1.8%, 3.0+/-1.8% for amodiaquine, artesunate, artesunate-amodiaquine, respectively, P<0.0001). The rate of DAFH was significantly lower in artesunate-treated children (1.4+/-0.9%, 0.7+/-0.6%, 1.0+/-0.6% per day for amodiaquine, artesunate and artesunate-amodiaquine, respectively, P<0.0001). The rate of rise in haematocrit from the nadir on days 3-7 was significantly higher in amodiaquine treated children (P=0.045). In anaemic children (n=68), the time elapsing from treatment to the attainment of a haematocrit > or =30%, the anaemia resolution time, and the proportion of anaemic children with complete resolution on day 14 were similar in all treatment groups (P=0.17 and 0.65, respectively). Artemisinin drugs may reduce the extent and rate of fall in PfMAA during treatment and may attenuate malaria-associated anaemia in children.

The relationship between the response of Plasmodium falciparum malaria to mefloquine in African children and its sensitivity in vitro

The clinical efficacy of two doses of mefloquine (15 and 25 mg/kg body weight) was evaluated in 85 children suffering from acute symptomatic falciparum malaria. The cure rate on day 28 was 100% in both groups. There was no significant difference (P > 0.05) in the mean parasite and fever clearance times in both groups (48.5 +/- 14.6 and 32.0 +/- 12.7 h respectively for the 25 mg/kg group and 49.0 +/- 15.1 and 30.0 +/- 13.3 h respectively for the 15 mg/kg group). There was also no significant difference (P > 0.05) in these values between children with hyperparasitaemia (53.6 +/- 11.1 and 36.0 +/- 17.0 h respectively) and those without hyperparasitaemia (49.1 +/- 13.6 and 31.8 +/- 14.6 h respectively). Recurrence of parasitaemia was observed after day 30 in 2 patients in the 15 mg/kg group and in 1 patient in the 25 mg/kg group. In vitro, 3 of 21 isolates showed reduced susceptibility to mefloquine, with minimum inhibitory concentrations (MIC) > 67 nM/litre. The MIC and 50%, 90% and 99% inhibitory concentrations were 200.8, 6.27, 31.7 and 119.6 nM/litre respectively. Four of 22 isolates were resistant to chloroquine (MIC > 108 nM/litre). Isolates that showed low sensitivity to mefloquine in vitro were sensitive to chloroquine in vitro, and the 4 that were resistant to chloroquine were sensitive to mefloquine. Irrespective of MIC and dose of mefloquine, parasitaemia cleared in all subjects in 96 h or less.(ABSTRACT TRUNCATED AT 250 WORDS)