The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data.

BACKGROUND: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. METHODS: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. RESULTS: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. CONCLUSIONS: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.

Artesunate plus pyronaridine for treating uncomplicated Plasmodium falciparum malaria.

BACKGROUND: The World Health Organization (WHO) recommends that people with uncomplicated Plasmodium falciparum malaria are treated using Artemisinin-based Combination Therapy (ACT). ACT combines three-days of a short-acting artemisinin derivative with a longer-acting antimalarial which has a different mode of action. Pyronaridine has been reported as an effective antimalarial over two decades of use in parts of Asia, and is currently being evaluated as a partner drug for artesunate. OBJECTIVES: To evaluate the efficacy and safety of artesunate-pyronaridine compared to alternative ACTs for treating people with uncomplicated P. falciparum malaria. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; LILACS; ClinicalTrials.gov; the metaRegister of Controlled Trials (mRCT); and the WHO International Clinical Trials Search Portal up to 16 January 2014. We searched reference lists and conference abstracts, and contacted experts for information about ongoing and unpublished trials. SELECTION CRITERIA: Randomized controlled trials of artesunate-pyronaridine versus other ACTs in adults and children with uncomplicated P. falciparum malaria.For the safety analysis, we also included adverse events data from trials comparing any treatment regimen containing pyronaridine with regimens not containing pyronaridine. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and risk of bias, and extracted data. We combined dichotomous data using risk ratios (RR) and continuous data using mean differences (MD), and presented all results with a 95% confidence interval (CI). We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We included six randomized controlled trials enrolling 3718 children and adults. Artesunate-pyronaridine versus artemether-lumefantrineIn two multicentre trials, enrolling mainly older children and adults from west and south-central Africa, both artesunate-pyronaridine and artemether-lumefantrine had fewer than 5% PCR adjusted treatment failures during 42 days of follow-up, with no differences between groups (two trials, 1472 participants, low quality evidence). There were fewer new infections during the first 28 days in those given artesunate-pyronaridine (PCR-unadjusted treatment failure: RR 0.60, 95% CI 0.40 to 0.90, two trials, 1720 participants, moderate quality evidence), but no difference was detected over the whole 42 day follow-up (two trials, 1691 participants, moderate quality evidence). Artesunate-pyronaridine versus artesunate plus mefloquineIn one multicentre trial, enrolling mainly older children and adults from South East Asia, both artesunate-pyronaridine and artesunate plus mefloquine had fewer than 5% PCR adjusted treatment failures during 28 days follow-up (one trial, 1187 participants, moderate quality evidence). PCR-adjusted treatment failures were 6% by day 42 for these treated with artesunate-pyronaridine, and 4% for those with artesunate-mefloquine (RR 1.64, 95% CI 0.89 to 3.00, one trial, 1116 participants, low quality evidence). Again, there were fewer new infections during the first 28 days in those given artesunate-pyronaridine (PCR-unadjusted treatment failure: RR 0.35, 95% CI 0.17 to 0.73, one trial, 1720 participants, moderate quality evidence), but no differences were detected over the whole 42 days (one trial, 1146 participants, low quality evidence). Adverse effectsSerious adverse events were uncommon in these trials, with no difference detected between artesunate-pyronaridine and comparator ACTs. The analysis of liver function tests showed biochemical elevation were four times more frequent with artesunate-pyronaridine than with the other antimalarials (RR 4.17, 95% CI 1.38 to 12.62, four trials, 3523 participants, moderate quality evidence). AUTHORS' CONCLUSIONS: Artesunate-pyronaridine performed well in these trials compared to artemether-lumefantrine and artesunate plus mefloquine, with PCR-adjusted treatment failure at day 28 below the 5% standard set by the WHO. Further efficacy and safety studies in African and Asian children are required to clarify whether this combination is an option for first-line treatment.

WITHDRAWN: Azithromycin for treating uncomplicated typhoid and paratyphoid fever (enteric fever).

BACKGROUND: Review status: Current question - no update intended. Azithromycin treatments are included in the review: Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever). (Thaver D, Zaidi AKM, Critchley JA, Azmatullah A, Madni SA, Bhutta ZA. Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever). Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD004530. DOI: 10.1002/14651858.CD004530.pub3.)   This latter review is being updated, and will be published in late 2011.Enteric fever (typhoid and paratyphoid fever) is potentially fatal. Infection with drug-resistant strains of the causative organism Salmonella enterica serovar Typhi or Paratyphi increases morbidity and mortality. Azithromycin may have better outcomes in people with uncomplicated forms of the disease. OBJECTIVES: To compare azithromycin with other antibiotics for treating uncomplicated enteric fever. SEARCH STRATEGY: In August 2008, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2008, Issue 3), MEDLINE, EMBASE, LILACS, and mRCT. We also searched conference proceedings, reference lists, and contacted researchers and a pharmaceutical company. SELECTION CRITERIA: Randomized controlled trials comparing azithromycin with other antibiotics for treating children and adults with uncomplicated enteric fever confirmed by cultures of S. Typhi or Paratyphi in blood and/or stool. DATA COLLECTION AND ANALYSIS: Both authors independently extracted data and assessed the risk of bias. Dichotomous data were presented and compared using the odds ratio, and continuous data were reported as arithmetic means with standard deviations and were combined using the mean difference (MD). Both were presented with 95% confidence intervals (CI). MAIN RESULTS: Seven trials involving 773 participants met the inclusion criteria. The trials used adequate methods to generate the allocation sequence and conceal allocation, and were open label. Three trials exclusively included adults, two included children, and two included both adults and children; all were hospital inpatients. One trial evaluated azithromycin against chloramphenicol and did not demonstrate a difference for any outcome (77 participants, 1 trial). When compared with fluoroquinolones in four trials, azithromycin significantly reduced clinical failure (OR 0.48, 95% CI 0.26 to 0.89; 564 participants, 4 trials) and duration of hospital stay (MD -1.04 days, 95% CI -1.73 to -0.34 days; 213 participants, 2 trials); all four trials included people with multiple-drug-resistant or nalidixic acid-resistant strains of S. Typhi or S. Paratyphi. We detected no statistically significant difference in the other outcomes. Compared with ceftriaxone, azithromycin significantly reduced relapse (OR 0.09, 95% CI 0.01 to 0.70; 132 participants, 2 trials) and not other outcome measures. Few adverse events were reported, and most were mild and self limiting. AUTHORS' CONCLUSIONS: Azithromycin appears better than fluoroquinolone drugs in populations that included participants with drug-resistant strains. Azithromycin may perform better than ceftriaxone.

Improved malaria case management through the implementation of a health facility-based sentinel site surveillance system in Uganda.

BACKGROUND: Heath facility-based sentinel site surveillance has been proposed as a means of monitoring trends in malaria morbidity but may also provide an opportunity to improve malaria case management. Here we described the impact of a sentinel site malaria surveillance system on promoting laboratory testing and rational antimalarial drug use. METHODOLOGY/PRINCIPAL FINDINGS: Sentinel site malaria surveillance was established at six health facilities in Uganda between September 2006 and January 2007. Data were collected from all patients presenting to the outpatient departments including demographics, laboratory results, diagnoses, and treatments prescribed. Between the start of surveillance and March 2010, a total 424,701 patients were seen of which 229,375 (54%) were suspected of having malaria. Comparing the first three months with the last three months of surveillance, the proportion of patients with suspected malaria who underwent diagnostic testing increased from 39% to 97% (p<0.001). The proportion of patients with an appropriate decision to prescribe antimalarial therapy (positive test result prescribed, negative test result not prescribed) increased from 64% to 95% (p<0.001). The proportion of patients appropriately prescribed antimalarial therapy who were prescribed the recommended first-line regimen artemether-lumefantrine increased from 48% to 69% (p<0.001). CONCLUSIONS/SIGNIFICANCE: The establishment of a sentinel site malaria surveillance system in Uganda achieved almost universal utilization of diagnostic testing in patients with suspected malaria and appropriate decisions to prescribed antimalarial based on test results. Less success was achieved in promoting prescribing practice for the recommended first-line therapy. This system could provide a model for improving malaria case management in other health facilities in Africa.

Heterogeneities and consequences of Plasmodium species and hookworm coinfection: a population based study in Uganda.

BACKGROUND: Previous studies have suggested that helminth infection exacerbates malaria, but few existing epidemiological studies adequately control for infection heterogeneities and confounding factors. In this study, we investigate spatial and household heterogeneities, predictors, and consequences of Plasmodium species and hookworm coinfection in rural communities in Uganda. METHODS: A cross-sectional study was conducted among 1770 individuals aged 0-88 years in 4 villages. We recorded demographic, socioeconomic, and microgeographic factors during household surveys. We determined malaria parasitemia and hemoglobin concentration and collected stool samples on 2 consecutive days. For data analysis, we used a hierarchical, spatially explicit Bayesian framework. RESULTS: Prevalence of Plasmodium-hookworm coinfection was 15.5% overall and highest among school-aged children. We found strong evidence of spatial and household clustering of coinfection and an enduring positive association between Plasmodium-species and hookworm infection among preschool-aged children (odds ratio [OR], 2.36; 95% Bayesian credible interval [BCI], 1.26-4.30) and adults (OR, 2.09; 95% BCI, 1.35-3.16) but not among school-aged children. Coinfection was associated with lower hemoglobin level only among school-aged children. CONCLUSIONS: Plasmodium-hookworm coinfection exhibits marked age dependency and significant spatial and household heterogeneity, and among preschool-aged children and adults, occurs more than would be expected by chance. Such heterogeneities provide insight into factors underlying observed patterns and the design of integrated control strategies.

Heritability of Plasmodium parasite density in a rural Ugandan community.

Many factors influence variation in Plasmodium infection levels, including parasite/host genetics, immunity, and exposure. Here, we examine the roles of host genetics and exposure in determining parasite density, and test whether effects differ with age. Data for 1,711 residents of an eastern Ugandan community were used in pedigree-based variance component analysis. Heritability of parasite density was 13% (P < 0.001) but was not significant after controlling for shared household. Allowing variance components to vary between children (< 16 years) and adults (≥ 16 years) revealed striking age differences; 26% of variation could be explained by additively acting genes in children (P < 0.001), but there was no genetic involvement in adults. Domestic environment did not explain variation in children and explained 5% in adults (P = 0.09). Genetic effects are an important determinant of parasite density in children in this population, consistent with previous quantitative genetic studies of Plasmodium parasitaemia, although differences in environmental exposure play a lesser role.

Plasmodium infection and its risk factors in eastern Uganda.

BACKGROUND: Malaria is a leading cause of disease burden in Uganda, although surprisingly few contemporary, age-stratified data exist on malaria epidemiology in the country. This report presents results from a total population survey of malaria infection and intervention coverage in a rural area of eastern Uganda, with a specific focus on how risk factors differ between demographic groups in this population. METHODS: In 2008, a cross-sectional survey was conducted in four contiguous villages in Mulanda, sub-county in Tororo district, eastern Uganda, to investigate the epidemiology and risk factors of Plasmodium species infection. All permanent residents were invited to participate, with blood smears collected from 1,844 individuals aged between six months and 88 years (representing 78% of the population). Demographic, household and socio-economic characteristics were combined with environmental data using a Geographical Information System. Hierarchical models were used to explore patterns of malaria infection and identify individual, household and environmental risk factors. RESULTS: Overall, 709 individuals were infected with Plasmodium, with prevalence highest among 5-9 year olds (63.5%). Thin films from a random sample of 20% of parasite positive participants showed that 94.0% of infections were Plasmodium falciparum and 6.0% were P. malariae; no other species or mixed infections were seen. In total, 68% of households owned at least one mosquito although only 27% of school-aged children reported sleeping under a net the previous night. In multivariate analysis, infection risk was highest amongst children aged 5-9 years and remained high in older children. Risk of infection was lower for those that reported sleeping under a bed net the previous night and living more than 750 m from a rice-growing area. After accounting for clustering within compounds, there was no evidence for an association between infection prevalence and socio-economic status, and no evidence for spatial clustering. CONCLUSION: These findings demonstrate that mosquito net usage remains inadequate and is strongly associated with risk of malaria among school-aged children. Infection risk amongst adults is influenced by proximity to potential mosquito breeding grounds. Taken together, these findings emphasize the importance of increasing net coverage, especially among school-aged children.

Assessing the impact of indoor residual spraying on malaria morbidity using a sentinel site surveillance system in Western Uganda.

A single round of indoor residual spraying (IRS) using lambda-cyhalothrin was implemented in a district of Uganda with moderate transmission intensity in 2007. Individual patient data were collected from one health facility within the district 8 months before and 16 months after IRS. There was a consistent decrease in the proportion of patients diagnosed with clinical malaria after IRS for patients < 5 and > 5 years of age (52% versus 26%, P < 0.001 and 36% versus 23%, P < 0.001, respectively). There was a large decrease in the proportion of positive blood smears in the first 4 months after IRS for patients < 5 (47% versus 14%, P < 0.001) and > 5 (26% versus 9%, P < 0.001) years of age, but this effect waned over the subsequent 12 months. IRS was effective in reducing malaria morbidity, but this was not sustained beyond 1 year for the proportion of blood smears read as positive.

Use of the slide positivity rate to estimate changes in malaria incidence in a cohort of Ugandan children.

BACKGROUND: As malaria control efforts intensify, it is critical to monitor trends in disease burden and measure the impact of interventions. A key surveillance indicator is the incidence of malaria. Yet measurement of incidence is challenging. The slide positivity rate (SPR) has been used as a surrogate measure of malaria incidence, but limited data exist on the relationship between SPR and the incidence of malaria. METHODS: A cohort of 690 children aged 1-10 years at enrollment were followed for all their health care needs over a four-year period in Kampala, Uganda. All children with fever underwent laboratory testing, allowing us to measure the incidence of malaria and non-malaria fevers. A formula was derived to estimate relative changes in the incidence of malaria (rDeltaIm) based on changes in the SPR and the assumption that the incidence of non-malaria fevers was consistent over time. Observed and estimated values of rDeltaIm were compared over two, six, and 12 month time intervals after restricting the analysis to children contributing observation time between the ages of 4-10 years to control for aging of the cohort. RESULTS: Over the four-year observation period the incidence of malaria declined significantly from 0.93 episodes per person-year in 2005 to 0.39 episodes per person-year in 2008 (p < 0.0001) and the incidence of non-malaria fevers declined significantly from 2.31 episodes per person-year in 2005 to 1.31 episodes per person-year in 2008 (p < 0.0001). Younger age was associated with a significantly greater incidence of malaria and the incidence of malaria was significantly higher during seasonal peaks occurring each January-February and May-June. Changes in SPR produced reasonably accurate estimates of rDeltaIm over all time intervals. The average absolute difference in observed and estimated values of rDeltaIm was lower for six-month intervals (0.13) than it was for two-month (0.21) or 12 month intervals (0.21). CONCLUSION: Changes in SPR provided a useful estimate of changes in the incidence of malaria in a well defined cohort; however, a gradual decline in the incidence of non-malaria fevers introduced some bias in these estimates.

Efficacy of artesunate-amodiaquine for treating uncomplicated falciparum malaria in sub-Saharan Africa: a multi-centre analysis.

BACKGROUND: Artesunate and amodiaquine (AS&AQ) is at present the world's second most widely used artemisinin-based combination therapy (ACT). It was necessary to evaluate the efficacy of ACT, recently adopted by the World Health Organization (WHO) and deployed over 80 countries, in order to make an evidence-based drug policy. METHODS: An individual patient data (IPD) analysis was conducted on efficacy outcomes in 26 clinical studies in sub-Saharan Africa using the WHO protocol with similar primary and secondary endpoints. RESULTS: A total of 11,700 patients (75% under 5 years old), from 33 different sites in 16 countries were followed for 28 days. Loss to follow-up was 4.9% (575/11,700). AS&AQ was given to 5,897 patients. Of these, 82% (4,826/5,897) were included in randomized comparative trials with polymerase chain reaction (PCR) genotyping results and compared to 5,413 patients (half receiving an ACT). AS&AQ and other ACT comparators resulted in rapid clearance of fever and parasitaemia, superior to non-ACT. Using survival analysis on a modified intent-to-treat population, the Day 28 PCR-adjusted efficacy of AS&AQ was greater than 90% (the WHO cut-off) in 11/16 countries. In randomized comparative trials (n = 22), the crude efficacy of AS&AQ was 75.9% (95% CI 74.6-77.1) and the PCR-adjusted efficacy was 93.9% (95% CI 93.2-94.5). The risk (weighted by site) of failure PCR-adjusted of AS&AQ was significantly inferior to non-ACT, superior to dihydroartemisinin-piperaquine (DP, in one Ugandan site), and not different from AS+SP or AL (artemether-lumefantrine). The risk of gametocyte appearance and the carriage rate of AS&AQ was only greater in one Ugandan site compared to AL and DP, and lower compared to non-ACT (p = 0.001, for all comparisons). Anaemia recovery was not different than comparator groups, except in one site in Rwanda where the patients in the DP group had a slower recovery. CONCLUSION: AS&AQ compares well to other treatments and meets the WHO efficacy criteria for use against falciparum malaria in many, but not all, the sub-Saharan African countries where it was studied. Efficacy varies between and within countries. An IPD analysis can inform general and local treatment policies. Ongoing monitoring evaluation is required.

Improved malaria case management after integrated team-based training of health care workers in Uganda.

Malaria case management in Africa is characterized by presumptive treatment and substantial overtreatment. We evaluated an integrated team-based training program on malaria case management. Surveillance data 120 days before and after training were compared at eight health facilities in Uganda. After training, the proportion of patients with suspected malaria referred for blood smears increased from 38.3% to 54.6% (P=0.04) in persons<5 years of age years and from 34.1% to 53.4% (P=0.02) in those>or=5 years of age. The proportion of patients with negative blood smears prescribed antimalarial drugs decreased from 47.9% to 19.6% (P<0.001) in persons<5 years of age and from 38.8% to 15.6% (P<0.001) in those>or=5 years of age. Training did not improve the proportion of patients with positive blood smears prescribed antimalarial drugs, the proportion of patients prescribed appropriate antimalarial drugs, or the diagnostic accuracy of microscopy. Integrated team-based training may improve malaria case management and reduce the number of unnecessary antimalarial treatments.

Azithromycin for treating uncomplicated typhoid and paratyphoid fever (enteric fever).

BACKGROUND: Enteric fever (typhoid and paratyphoid fever) is potentially fatal. Infection with drug-resistant strains of the causative organism Salmonella enterica serovar Typhi or Paratyphi increases morbidity and mortality. Azithromycin may have better outcomes in people with uncomplicated forms of the disease. OBJECTIVES: To compare azithromycin with other antibiotics for treating uncomplicated enteric fever. SEARCH STRATEGY: In August 2008, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2008, Issue 3), MEDLINE, EMBASE, LILACS, and mRCT. We also searched conference proceedings, reference lists, and contacted researchers and a pharmaceutical company. SELECTION CRITERIA: Randomized controlled trials comparing azithromycin with other antibiotics for treating children and adults with uncomplicated enteric fever confirmed by cultures of S. Typhi or Paratyphi in blood and/or stool. DATA COLLECTION AND ANALYSIS: Both authors independently extracted data and assessed the risk of bias. Dichotomous data were presented and compared using the odds ratio, and continuous data were reported as arithmetic means with standard deviations and were combined using the mean difference (MD). Both were presented with 95% confidence intervals (CI). MAIN RESULTS: Seven trials involving 773 participants met the inclusion criteria. The trials used adequate methods to generate the allocation sequence and conceal allocation, and were open label. Three trials exclusively included adults, two included children, and two included both adults and children; all were hospital inpatients. One trial evaluated azithromycin against chloramphenicol and did not demonstrate a difference for any outcome (77 participants, 1 trial). When compared with fluoroquinolones in four trials, azithromycin significantly reduced clinical failure (OR 0.48, 95% CI 0.26 to 0.89; 564 participants, 4 trials) and duration of hospital stay (MD -1.04 days, 95% CI -1.73 to -0.34 days; 213 participants, 2 trials); all four trials included people with multiple-drug-resistant or nalidixic acid-resistant strains of S. Typhi or S. Paratyphi. We detected no statistically significant difference in the other outcomes. Compared with ceftriaxone, azithromycin significantly reduced relapse (OR 0.09, 95% CI 0.01 to 0.70; 132 participants, 2 trials) and not other outcome measures. Few adverse events were reported, and most were mild and self limiting. AUTHORS' CONCLUSIONS: Azithromycin appears better than fluoroquinolone drugs in populations that included participants with drug-resistant strains. Azithromycin may perform better than ceftriaxone.

Different methodological approaches to the assessment of in vivo efficacy of three artemisinin-based combination antimalarial treatments for the treatment of uncomplicated falciparum malaria in African children.

BACKGROUND: Use of different methods for assessing the efficacy of artemisinin-based combination antimalarial treatments (ACTs) will result in different estimates being reported, with implications for changes in treatment policy. METHODS: Data from different in vivo studies of ACT treatment of uncomplicated falciparum malaria were combined in a single database. Efficacy at day 28 corrected by PCR genotyping was estimated using four methods. In the first two methods, failure rates were calculated as proportions with either (1a) reinfections excluded from the analysis (standard WHO per-protocol analysis) or (1b) reinfections considered as treatment successes. In the second two methods, failure rates were estimated using the Kaplan-Meier product limit formula using either (2a) WHO (2001) definitions of failure, or (2b) failure defined using parasitological criteria only. RESULTS: Data analysed represented 2926 patients from 17 studies in nine African countries. Three ACTs were studied: artesunate-amodiaquine (AS+AQ, N = 1702), artesunate-sulphadoxine-pyrimethamine (AS+SP, N = 706) and artemether-lumefantrine (AL, N = 518).Using method (1a), the day 28 failure rates ranged from 0% to 39.3% for AS+AQ treatment, from 1.0% to 33.3% for AS+SP treatment and from 0% to 3.3% for AL treatment. The median [range] difference in point estimates between method 1a (reference) and the others were: (i) method 1b = 1.3% [0 to 24.8], (ii) method 2a = 1.1% [0 to 21.5], and (iii) method 2b = 0% [-38 to 19.3].The standard per-protocol method (1a) tended to overestimate the risk of failure when compared to alternative methods using the same endpoint definitions (methods 1b and 2a). It either overestimated or underestimated the risk when endpoints based on parasitological rather than clinical criteria were applied. The standard method was also associated with a 34% reduction in the number of patients evaluated compared to the number of patients enrolled. Only 2% of the sample size was lost when failures were classified on the first day of parasite recurrence and survival analytical methods were used. CONCLUSION: The primary purpose of an in vivo study should be to provide a precise estimate of the risk of antimalarial treatment failure due to drug resistance. Use of survival analysis is the most appropriate way to estimate failure rates with parasitological recurrence classified as treatment failure on the day it occurs.

Pharmacovigilance of antimalarial treatment in Uganda: community perceptions and suggestions for reporting adverse events.

OBJECTIVES: The deployment of new antimalarials in Africa provides an important opportunity to develop systems for pharmacovigilance. To inform strategies for reporting adverse events in Uganda, we investigated local perceptions and experiences with antimalarial treatment, and evaluated existing and potential systems for pharmacovigilance. METHODS: Focus group discussions (FGD) were conducted with community members and health workers from urban and rural Uganda exploring knowledge of fever/malaria, perceptions and expectations of treatment, understanding of adverse effects, and experiences with adverse events. Sessions were recorded, transcribed into English, and analysed using a coding scheme developed from pre-defined topics together with themes emerging from the data. RESULTS: Between April and July 2006, we conducted 25 FGDs; 16 with community members and nine with health workers. All respondents had extensive experience with malaria and its treatment. Community members commonly recognized adverse effects of antimalarial therapy. However, events were uncommonly reported, and certain events were often interpreted as signs of successful treatment. Community members often felt that the costs of reporting or seeking additional care outweighed the potential benefits. Health workers were unfamiliar with formal pathways for reporting, and were deterred by the additional work of reporting and fear of incrimination. Respondents provided suggestions for incentives and methods of reporting, emphasizing that pharmacovigilance should ideally encompass the public and private sector, and the community. CONCLUSIONS: To be successful, pharmacovigilance relying on voluntary reporting will require active participation of patients and health workers. Addressing the costs and benefits of reporting, and providing sensitization, training and feedback will be important.

Monitoring antimalarial safety and tolerability in clinical trials: a case study from Uganda.

BACKGROUND: New antimalarial regimens, including artemisinin-based combination therapies (ACTs), have been adopted widely as first-line treatment for uncomplicated malaria. Although these drugs appear to be safe and well-tolerated, experience with their use in Africa is limited and continued assessment of safety is a priority. However, no standardized guidelines for evaluating drug safety and tolerability in malaria studies exist. A system for monitoring adverse events in antimalarial trials conducted in Uganda was developed. Here the reporting system is described, and difficulties faced in analysing and interpreting the safety results are illustrated, using data from the trials. CASE DESCRIPTION: Between 2002 and 2007, eleven randomized, controlled clinical trials were conducted to compare the efficacy, safety, and tolerability of different antimalarial regimens for treatment of uncomplicated malaria in Uganda. The approach to adverse event monitoring was similar in all studies. A total of 5,614 treatments were evaluated in 4,876 patients. Differences in baseline characteristics and patterns of adverse event reporting were noted between the sites, which limited the ability to pool and analyse data. Clinical failure following antimalarial treatment confounded associations between treatment and adverse events that were also common symptoms of malaria, particularly in areas of lower transmission intensity. DISCUSSION AND EVALUATION: Despite prospectively evaluating for adverse events, limitations in the monitoring system were identified. New standardized guidelines for monitoring safety and tolerability in antimalarial trials are needed, which should address how to detect events of greatest importance, including serious events, those with a causal relationship to the treatment, those which impact on adherence, and events not previously reported. CONCLUSION: Although the World Health Organization has supported the development of pharmacovigilance systems in African countries deploying ACTs, additional guidance on adverse events monitoring in antimalarial clinical trials is needed, similar to the standardized recommendations available for assessment of drug efficacy.

Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treating uncomplicated malaria: a randomized trial to guide policy in Uganda.

BACKGROUND: Uganda recently adopted artemether-lumefantrine (AL) as the recommended first-line treatment for uncomplicated malaria. However, AL has several limitations, including a twice-daily dosing regimen, recommendation for administration with fatty food, and a high risk of reinfection soon after therapy in high transmission areas. Dihydroartemisinin-piperaquine (DP) is a new alternative artemisinin-based combination therapy that is dosed once daily and has a long post-treatment prophylactic effect. We compared the efficacy and safety of AL with DP in Kanungu, an area of moderate malaria transmission. METHODOLOGY/PRINCIPAL FINDINGS: Patients aged 6 months to 10 years with uncomplicated falciparum malaria were randomized to therapy and followed for 42 days. Genotyping was used to distinguish recrudescence from new infection. Of 414 patients enrolled, 408 completed follow-up. Compared to patients treated with artemether-lumefantrine, patients treated with dihydroartemisinin-piperaquine had a significantly lower risk of recurrent parasitaemia (33.2% vs. 12.2%; risk difference = 20.9%, 95% CI 13.0-28.8%) but no statistically significant difference in the risk of treatment failure due to recrudescence (5.8% vs. 2.0%; risk difference = 3.8%, 95% CI -0.2-7.8%). Patients treated with dihydroartemisinin-piperaquine also had a lower risk of developing gametocytaemia after therapy (4.2% vs. 10.6%, p = 0.01). Both drugs were safe and well tolerated. CONCLUSIONS/SIGNIFICANCE: DP is highly efficacious, and operationally preferable to AL because of a less intensive dosing schedule and requirements. Dihydroartemisinin-piperaquine should be considered for a role in the antimalarial treatment policy of Uganda. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN75606663.

Access to electronic health knowledge in five countries in Africa: a descriptive study.

BACKGROUND: Access to medical literature in developing countries is helped by open access publishing and initiatives to allow free access to subscription only journals. The effectiveness of these initiatives in Africa has not been assessed. This study describes awareness, reported use and factors influencing use of on-line medical literature via free access initiatives. METHODS: Descriptive study in four teaching hospitals in Cameroon, Nigeria, Tanzania and Uganda plus one externally funded research institution in The Gambia. Survey with postgraduate doctors and research scientists to determine Internet access patterns, reported awareness of on-line medical information and free access initiatives; semi structured interviews with a sub-sample of survey participants to explore factors influencing use. RESULTS: In the four African teaching hospitals, 70% of the 305 postgraduate doctors reported textbooks as their main source of information; 66% had used the Internet for health information in the last week. In two hospitals, Internet cafés were the main Internet access point. For researchers at the externally-funded research institution, electronic resources were their main source, and almost all had used the Internet in the last week. Across all 333 respondents, 90% had heard of PubMed, 78% of BMJ on line, 49% the Cochrane Library, 47% HINARI, and 19% BioMedCentral. HINARI use correlates with accessing the Internet on computers located in institutions. Qualitative data suggested there are difficulties logging into HINARI and that sometimes it is librarians that limit access to passwords. CONCLUSION: Text books remain an important resource for postgraduate doctors in training. Internet use is common, but awareness of free-access initiatives is limited. HINARI and other initiatives could be more effective with strong institutional endorsement and management to promote and ensure access.

Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment of malaria: a randomized trial.

OBJECTIVES: To compare the efficacy and safety of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) for treating uncomplicated falciparum malaria in Uganda. DESIGN: Randomized single-blinded clinical trial. SETTING: Apac, Uganda, an area of very high malaria transmission intensity. PARTICIPANTS: Children aged 6 mo to 10 y with uncomplicated falciparum malaria. INTERVENTION: Treatment of malaria with AL or DP, each following standard 3-d dosing regimens. OUTCOME MEASURES: Risks of recurrent parasitemia at 28 and 42 d, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections. RESULTS: Of 421 enrolled participants, 417 (99%) completed follow-up. The unadjusted risk of recurrent falciparum parasitemia was significantly lower for participants treated with DP than for those treated with AL after 28 d (11% versus 29%; risk difference [RD] 18%, 95% confidence interval [CI] 11%-26%) and 42 d (43% versus 53%; RD 9.6%, 95% CI 0%-19%) of follow-up. Similarly, the risk of recurrent parasitemia due to possible recrudescence (adjusted by genotyping) was significantly lower for participants treated with DP than for those treated with AL after 28 d (1.9% versus 8.9%; RD 7.0%, 95% CI 2.5%-12%) and 42 d (6.9% versus 16%; RD 9.5%, 95% CI 2.8%-16%). Patients treated with DP had a lower risk of recurrent parasitemia due to non-falciparum species, development of gametocytemia, and higher mean increase in hemoglobin compared to patients treated with AL. Both drugs were well tolerated; serious adverse events were uncommon and unrelated to study drugs. CONCLUSION: DP was superior to AL for reducing the risk of recurrent parasitemia and gametocytemia, and provided improved hemoglobin recovery. DP thus appears to be a good alternative to AL as first-line treatment of uncomplicated malaria in Uganda. To maximize the benefit of artemisinin-based combination therapy in Africa, treatment should be integrated with aggressive strategies to reduce malaria transmission intensity.