George Bedu-Addo

Efficacy and safety of a fixed-dose oral combination of pyronaridine-artesunate compared with artemether-lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria: a randomised non-inferiority trial

BACKGROUND There is a need for new artemisinin-based combination therapies that are convenient, effective, and safe. We compared the efficacy and safety of pyronaridine-artesunate with that of artemether-lumefantrine for treatment of uncomplicated P falciparum malaria. METHODS This phase 3, parallel-group, double-blind, randomised, non-inferiority trial was undertaken in seven sites in Africa and three sites in southeast Asia. In a double-dummy design, patients aged 3-60 years with uncomplicated P falciparum malaria were randomly assigned in a 2:1 ratio to receive pyronaridine-artesunate once a day or artemether-lumefantrine twice a day, orally for 3 days, plus respective placebo. Randomisation was done by computer-generated randomisation sequence in blocks of nine by study centre. Intervention tablets contained 180 mg pyronaridine and 60 mg artesunate; control tablets contained 20 mg artemether and 120 mg lumefantrine. Both treatments were given according to bodyweight. The primary efficacy outcome was PCR-corrected adequate clinical and parasitological response (ACPR) rate at day 28 in the per-protocol population. Non-inferiority was shown if the lower limit of the two-sided 95% CI for the difference between groups was greater than -5%. This study is registered with ClinicalTrials.gov, number NCT00422084. FINDINGS 1272 patients were randomly assigned to treatment (pyronaridine-artesunate, n=849; artemether-lumefantrine, n=423). The per-protocol population consisted of 784 patients in the pyronaridine-artesunate group and 386 patients in the artemether-lumefantrine group. PCR-corrected ACPR rate at day 28 was 99.5% (780 patients; 95% CI 98.7-99.9) in the pyronaridine-artesunate group and 99.2% (383 patients; 95% CI 97.7-99.8) in the artemether-lumefantrine group (treatment difference 0.3%, 95% CI -0.7 to 1.8; p=0.578). There were 509 (60.0%) adverse events in 849 patients assigned to pyronaridine-artesunate and 241 (57.0%) in 423 patients assigned to artemether-lumefantrine. The most frequent drug-related adverse event was eosinophilia (pyronaridine-artesunate, 53 events [6.2%]; artemether-lumefantrine 24 events [5.7%]). 21 (2.5%) patients in the pyronaridine-artesunate group and seven (1.7%) in the artemether-lumefantrine group discontinued study drugs or were withdrawn from the study. Mild and transient increases in alanine aminotransferase and aspartate aminotransferase concentrations were seen in the pyronaridine-artesunate group but not in the artemether-lumefantrine group. INTERPRETATION Efficacy of pyronaridine-artesunate was non-inferior to that of artemether-lumefantrine for treatment of uncomplicated falciparum malaria. Pyronaridine-artesunate should be considered for inclusion in malaria treatment programmes. FUNDING Shin Poong Pharmaceutical and the Medicines for Malaria Venture.

Diagnosis of Placental Malaria

ABSTRACT In a group of 596 delivering Ghanaian women, the sensitivities of peripheral blood thick film microscopy, ICT Malaria P.f/P.v test, and PCR in detecting microscopically confirmed placental Plasmodium falciparum infection were 42, 80, and 97%, respectively. In addition to the gross underestimation of placental malaria by peripheral blood film microscopy, submicroscopic infections were found to be a risk factor for maternal anemia.

Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock.

Adequate responses by our innate immune system toward invading pathogens were of vital importance for surviving infections, especially before the antibiotic era. Recently, a polymorphism in Mal (Ser180Leu, TIRAP rs8177374), an important adaptor protein downstream of the Toll-like receptor (TLR) 2 and 4 pathways, has been described to provide protection against a broad range of infectious pathogens. We assessed the functional effects of this polymorphism in human experimental endotoxemia, and we demonstrate that individuals bearing the TIRAP 180L allele display an increased, innate immune response to TLR4 and TLR2 ligands, but not to TLR9 stimulation. This phenotype has been related to an increased resistance to infection. However, an overshoot in the release of proinflammatory cytokines by TIRAP 180L homozygous individuals suggests a scenario of balanced evolution. We have also investigated the worldwide distribution of the Ser180Leu polymorphism in 14 populations around the globe to correlate the genetic makeup of TIRAP with the local infectious pressures. Based on the immunological, clinical, and genetic data, we propose that this mutation might have been selected in West Eurasia during the early settlement of this region after the out-of-Africa migration of modern Homo sapiens. This combination of functional and genetic data provides unique insights to our understanding of the pathogenesis of sepsis.

Bioavailability and Preliminary Clinical Efficacy of Intrarectal Artesunate in Ghanaian Children with Moderate Malaria

ABSTRACT We report the first detailed pharmacokinetic assessment of intrarectal (i.r.) artesunate (ARS) in African children. Artesunate was given intravenously (i.v.; 2.4 mg/kg of body weight) and i.r. (10 or 20 mg/kg formulated as 50- or 200-mg suppositories [Rectocaps]) in a crossover study design to 34 Ghanaian children with moderate falciparum malaria. The median relative bioavailability of dihydroartemisinin (DHA), the active antimalarial metabolite of ARS, was higher in the low-dose i.r. group (10 mg/kg) than in the high-dose i.r. group (20 mg/kg) (58 versus 23%; P = 0.018). There was wide interpatient variation in the area under the concentration-time curve after i.r. ARS administration (up to 9-fold in the high-dose group and 20-fold in the low-dose group). i.r. administered ARS was more rapidly absorbed in the low-dose group than the high-dose group (median [range] absorption half-lives, 0.7 h [0.3 to 1.24 h] versus 1.1 h [0.6 to 2.7 h] [P = 0.023]. i.r. administered ARS was eliminated with a median (range) half-life of 0.8 h (0.4 to 2.7 h) (low-dose group and 0.9 h (0.1 to 2.5 h) (high-dose group) (P = 1). The fractional clearances of DHA were 3.9, 2.6, and 1.5 liters/kg/h for the 20-mg/kg, 10-mg/kg and i.v. groups, respectively (P = 0.001 andP = 0.06 for the high-and low-dose i.r. groups compared with the i.v. groups, respectively). The median volumes of distribution for DHA were 1.5 liters kg (20 mg/kg, i.r. group), 1.8 liters/kg (10 mg/kg, i.r. group), and 0.6 liters/kg (i.v. group) (P< 0.05 for both i.r. groups compared with the i.v. group). Parasite clearance kinetics were comparable in all treatment groups. i.r. administered ARS may be a useful alternative to parenterally administered ARS in the management of moderate childhood malaria and should be studied further.

Evaluating health research capacity building: An evidence-based tool.

Bates and colleagues describe the development of a tool to assess capacity-building programs in health research, which they used in Kumasi, Ghana.

Diabetes mellitus type 2 in urban Ghana: characteristics and associated factors

BackgroundSub-Saharan Africa faces a rapid spread of diabetes mellitus type 2 (DM2) but its potentially specific characteristics are inadequately defined. In this hospital-based study in Kumasi, Ghana, we aimed at characterizing clinical, anthropometric, socio-economic, nutritional and behavioural parameters of DM2 patients and at identifying associated factors.MethodsBetween August 2007 and June 2008, 1466 individuals were recruited from diabetes and hypertension clinics, outpatients, community, and hospital staff. Fasting plasma glucose (FPG), serum lipids and urinary albumin were measured. Physical examination, anthropometry, and interviews on medical history, socio-economic status (SES), physical activity and nutritional behaviour were performed.ResultsThe majority of the 675 DM2 patients (mean FPG, 8.31 mmol/L) was female (75%) and aged 40-60 years (mean, 55 years). DM2 was known in 97% of patients, almost all were on medication. Many had hypertension (63%) and microalbuminuria (43%); diabetic complications occurred in 20%. Overweight (body mass index > 25 kg/m2), increased body fat (> 20% (male), > 33% (female)), and central adiposity (waist-to-hip ratio > 0.90 (male), > 0.85 (female)) were frequent occurring in 53%, 56%, and 75%, respectively. Triglycerides were increased (≥ 1.695 mmol/L) in 31% and cholesterol (≥ 5.17 mmol/L) in 65%. Illiteracy (46%) was high and SES indicators generally low. Factors independently associated with DM2 included a diabetes family history (adjusted odds ratio (aOR), 3.8; 95% confidence interval (95%CI), 2.6-5.5), abdominal adiposity (aOR, 2.6; 95%CI, 1.8-3.9), increased triglycerides (aOR, 1.8; 95%CI, 1.1-3.0), and also several indicators of low SES.ConclusionsIn this study from urban Ghana, DM2 affects predominantly obese patients of rather low socio-economic status and frequently is accompanied by hypertension and hyperlipidaemia. Prevention and management need to account for a specific risk profile in this population.

Rapid Increase in the Prevalence of Sulfadoxine-Pyrimethamine Resistance among Plasmodium falciparum Isolated from Pregnant Women in Ghana

Use of intermittent preventive treatment with sulfadoxine-pyrimethamine (SP) during pregnancy (IPTp-SP) has become policy in much of sub-Saharan Africa but crucially depends on the efficacy of SP. We assessed the frequency of the dhfr triple mutation among Plasmodium falciparum isolates obtained from pregnant Ghanaian women in 1998, 2000, and 2006. The prevalence of the triple mutation, which confers resistance to SP, doubled from 36% to 73% during the study period (P<.001). In 2006, the prevalence was virtually identical among women of early gestation and delivering women with or without a history of IPTp-SP use, indicating that such treatment did not select for mutant parasites. Nevertheless, IPTp-SP may be outdated by drug resistance before it is fully implemented.

Decline of placental malaria in southern Ghana after the implementation of intermittent preventive treatment in pregnancy.

BackgroundIntermittent preventive treatment in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) has been adopted as policy by many countries in sub-Saharan Africa. However, data on the post-implementation effectiveness of this measure are scarce.MethodsClinical and parasitological parameters were assessed among women delivering at a district hospital in rural southern Ghana in the year 2000 when pyrimethamine chemoprophylaxis was recommended (n = 839) and in 2006 (n = 226), approximately one year after the implementation of IPTp-SP. Examinations were performed in an identical manner in 2000 and 2006 including the detection of placental Plasmodium falciparum infection by microscopy, histidine-rich protein 2, and PCR.ResultsIn 2006, 77% of the women reported to have taken IPTp-SP at least once (26%, twice; 24%, thrice). In 2006 as compared to 2000, placental P. falciparum infection was reduced by 43–57% (P < 0.0001) and maternal anaemia by 33% (P = 0.0009), and median birth weight was 130 g higher (P = 0.02). In 2006, likewise, women who had taken ≥ 1 dose of IPTp-SP revealed less infection and anaemia and their children tended to have higher birth weights as compared to women who had not used IPTp-SP. However, placental P. falciparum infection was still observed in 11% (microscopy) to 26% (PCR) of those women who had taken three doses of IPTp-SP.ConclusionIn southern Ghana, placental malaria and maternal anaemia have declined substantially and birth weight has increased after the implementation of IPTp-SP. Likely, these effects can further be increased by improving IPTp-SP coverage and adherence. However, the remnant prevalence of infection in women having taken three doses of IPTp-SP suggests that additional antimalarial measures are needed to prevent malaria in pregnancy in this region.

Population kinetics, efficacy, and safety of dichloroacetate for lactic acidosis due to severe malaria in children.

The authors conducted a randomized, double‐blind, placebo‐controlled trial of intravenous dichloroacetate (DCA) for the purpose of treating lactic acidosis in 124 West African children with severe Plasmodium falciparum malaria. Lactic acidosis independently predicts mortality in severe malaria, and DCA stimulates the oxidative removal of lactate in vivo. A single infusion of 50 mg/kg DCA was well tolerated. When administered at the same time as a dose of intravenous quinine, DCA significantly increased the initial rate and magnitude of fall in blood lactate levels and did not interfere with the plasma kinetics of quinine. The authors developed a novel population pharmacokinetic‐pharmacodynamic indirect‐response model for DCA that incorporated characteristics associated with disease reversal. The model describes the complex relationships among antimalarial treatment procedures, plasma DCA concentrations, and the drugs lactate‐lowering effect. DCA significantly reduces the concentration of blood lactate, an independent predictor of mortality in malaria. Its prospective evaluation in affecting mortality in this disorder appears warranted.

Type 2 diabetes mellitus and increased risk for malaria infection.

A case–control study of 1,466 urban adults in Ghana found that patients with type 2 diabetes mellitus had a 46% increased risk for infection with Plasmodium falciparum. Increase in diabetes mellitus prevalence may put more persons at risk for malaria infection.