A randomized open study to assess the efficacy and tolerability of dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Cambodia.

OBJECTIVES: To compare the efficacy and tolerability of dihydroartemisinin-piperaquine (DHA-PQP) with that of a 3-day regimen of mefloquine and artesunate (MAS3) for the treatment of uncomplicated falciparum malaria in Cambodia. METHOD: Randomized open-label non-inferiority study over 64 days. RESULTS: Four hundred and sixty-four patients were included in the study. The polymerase chain reaction genotyping-adjusted cure rates on day 63 were 97.5% (95% confidence interval, CI, 93.8-99.3) for DHA-PQP and 97.5% (95% CI, 93.8-99.3) for MAS3, P = 1. There were no serious adverse events, but significantly more episodes of vomiting (P = 0.03), dizziness (P = 0.002), palpitations (P = 0.04), and sleep disorders (P = 0.03) reported in the MAS3 treatment group, consistent with the side-effect profile of mefloquine. CONCLUSIONS: DHA-PQP was as efficacious as MAS3, but much better tolerated, making it more appropriate for use in a routine programme setting. This highly efficacious, safe and more affordable fixed-dose combination could become the treatment of choice for Plasmodium falciparum malaria in Cambodia

Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomised comparison.

BACKGROUND: Artemisinin-based combinations are judged the best treatments for multidrug-resistant Plasmodium falciparum malaria. Artesunate-mefloquine is widely recommended in southeast Asia, but its high cost and tolerability profile remain obstacles to widespread deployment. To assess whether dihydroartemisinin-piperaquine is a suitable alternative to artesunate-mefloquine, we compared the safety, tolerability, efficacy, and effectiveness of the two regimens for the treatment of uncomplicated falciparum in western Myanmar (Burma). METHODS: We did an open randomised comparison of 3-day regimens of artesunate-mefloquine (12/25 mg/kg) versus dihydroartemisinin-piperaquine (6.3/50 mg/kg) for the treatment of children aged 1 year or older and in adults with uncomplicated falciparum malaria in Rakhine State, western Myanmar. Within each group, patients were randomly assigned supervised or non-supervised treatment. The primary endpoint was the PCR-confirmed parasitological failure rate by day 42. Failure rates at day 42 were estimated by Kaplan-Meier survival analysis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN27914471. FINDINGS: Of 652 patients enrolled, 327 were assigned dihydroartemisinin-piperaquine (156 supervised and 171 not supervised), and 325 artesunate-mefloquine (162 and 163, respectively). 16 patients were lost to follow-up, and one patient died 22 days after receiving dihydroartemisinin-piperaquine. Recrudescent parasitaemias were confirmed in only two patients; the day 42 failure rate was 0.6% (95% CI 0.2-2.5) for dihydroartemisinin-piperaquine and 0 (0-1.2) for artesunate-mefloquine. Whole-blood piperaquine concentrations at day 7 were similar for patients with observed and non-observed dihydroartemisinin-piperaquine treatment. Gametocytaemia developed more frequently in patients who had received dihydroartemisinin-piperaquine than in those on artesunate-mefloquine: day 7, 18 (10%) of 188 versus five (2%) of 218; relative risk 4.2 (1.6-11.0) p=0.011. INTERPRETATION: Dihydroartemisinin-piperaquine is a highly efficacious and inexpensive treatment of multidrug-resistant falciparum malaria and is well tolerated by all age groups. The effectiveness of the unsupervised treatment, as in the usual context of use, equalled its supervised efficacy, indicating good adherence without supervision. Dihydroartemisinin-piperaquine is a good alternative to artesunate-mefloquine

The Frisians as a chosen people: religious-patriotic historiography in fifteenth-century Frisia

Collective identities and transnational networks in medieval and early modern Europe, 1000-180

Geographical distribution of selected and putatively neutral SNPs in Southeast Asian malaria parasites.

Loci targeted by directional selection are expected to show elevated geographical population structure relative to neutral loci, and a flurry of recent papers have used this rationale to search for genome regions involved in adaptation. Studies of functional mutations that are known to be under selection are particularly useful for assessing the utility of this approach. Antimalarial drug treatment regimes vary considerably between countries in Southeast Asia selecting for local adaptation at parasite loci underlying resistance. We compared the population structure revealed by 10 nonsynonymous mutations (nonsynonymous single-nucleotide polymorphisms [nsSNPs]) in four loci that are known to be involved in antimalarial drug resistance, with patterns revealed by 10 synonymous mutations (synonymous single-nucleotide polymorphisms [sSNPs]) in housekeeping genes or genes of unknown function in 755 Plasmodium falciparum infections collected from 13 populations in six Southeast Asian countries. Allele frequencies at known nsSNPs underlying resistance varied markedly between locations (F(ST) = 0.18-0.66), with the highest frequencies on the Thailand-Burma border and the lowest frequencies in neighboring Lao PDR. In contrast, we found weak but significant geographic structure (F(ST) = 0-0.14) for 8 of 10 sSNPs. Importantly, all 10 nsSNPs showed significantly higher F(ST) (P < 8 x 10(-5)) than simulated neutral expectations based on observed F(ST) values in the putatively neutral sSNPs. This result was unaffected by the methods used to estimate allele frequencies or the number of populations used in the simulations. Given that dense single-nucleotide polymorphism (SNP) maps and rapid SNP assay methods are now available for P. falciparum, comparing genetic differentiation across the genome may provide a valuable aid to identifying parasite loci underlying local adaptation to drug treatment regimes or other selective forces. However, the high proportion of polymorphic sites that appear to be under balancing selection (or linked to selected sites) in the P. falciparum genome violates the central assumption that selected sites are rare, which complicates identification of outlier loci, and suggests that caution is needed when using this approach

Treatment outcomes from the largest antiretroviral treatment program in Myanmar (Burma): a cohort analysis of retention after scale-up.

Article approval pendingAntiretroviral treatment (ART) coverage in Myanmar is well below average. This study describes retention and baseline predictors of prognosis from the largest ART program in the country

Cost effectiveness and resource allocation of Plasmodium falciparum malaria control in Myanmar: a modelling analysis of bed nets and community health workers.

BACKGROUND: Funding for malaria control and elimination in Myanmar has increased markedly in recent years. While there are various malaria control tools currently available, two interventions receive the majority of malaria control funding in Myanmar: (1) insecticide-treated bed nets and (2) early diagnosis and treatment through malaria community health workers. This study aims to provide practical recommendations on how to maximize impact from investment in these interventions. METHODS: A simple decision tree is used to model intervention costs and effects in terms of years of life lost. The evaluation is from the perspective of the service provider and costs and effects are calculated in line with standard methodology. Sensitivity and scenario analysis are undertaken to identify key drivers of cost effectiveness. Standard cost effectiveness analysis is then extended via a spatially explicit resource allocation model. FINDINGS: Community health workers have the potential for high impact on malaria, particularly where there are few alternatives to access malaria treatment, but are relatively costly. Insecticide-treated bed nets are comparatively inexpensive and modestly effective in Myanmar, representing a low risk but modest return intervention. Unlike some healthcare interventions, bed nets and community health workers are not mutually exclusive nor are they necessarily at their most efficient when universally applied. Modelled resource allocation scenarios highlight that in this case there is no "one size fits all" cost effectiveness result. Health gains will be maximized by effective targeting of both interventions

Geographic Resource Allocation Based on Cost Effectiveness: An Application to Malaria Policy.

Healthcare services are often provided to a country as a whole, though in many cases the available resources can be more effectively targeted to specific geographically defined populations. In the case of malaria, risk is highly geographically heterogeneous, and many interventions, such as insecticide-treated bed nets and malaria community health workers, can be targeted to populations in a way that maximises impact for the resources available. This paper describes a framework for geographically targeted budget allocation based on the principles of cost-effectiveness analysis and applied to priority setting in malaria control and elimination. The approach can be used with any underlying model able to estimate intervention costs and effects given relevant local data. Efficient geographic targeting of core malaria interventions could significantly increase the impact of the resources available, accelerating progress towards elimination. These methods may also be applicable to priority setting in other disease areas

CMV retinitis screening and treatment in a resource-poor setting: three-year experience from a primary care HIV/AIDS programme in Myanmar

Cytomegalovirus retinitis is a neglected disease in resource-poor settings, in part because of the perceived complexity of care and because ophthalmologists are rarely accessible. In this paper, we describe a pilot programme of CMV retinitis management by non-ophthalmologists. The programme consists of systematic screening of all high-risk patients (CD4 <100 cells/mm3) by AIDS clinicians using indirect ophthalmoscopy, and treatment of all patients with active retinitis by intravitreal injection of ganciclovir. Prior to this programme, CMV retinitis was not routinely examined for, or treated, in Myanmar