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1.  Linking international clinical research with stateless populations to justice in global health 
BMC Medical Ethics  2014;15:49.
Background
In response to calls to expand the scope of research ethics to address justice in global health, recent scholarship has sought to clarify how external research actors from high-income countries might discharge their obligation to reduce health disparities between and within countries. An ethical framework—‘research for health justice’—was derived from a theory of justice (the health capability paradigm) and specifies how international clinical research might contribute to improved health and research capacity in host communities. This paper examines whether and how external funders, sponsors, and researchers can fulfill their obligations under the framework.
Methods
Case study research was undertaken on the Shoklo Malaria Research Unit’s (SMRU) vivax malaria treatment trial, which was performed on the Thai-Myanmar border with Karen and Myanmar refugees and migrants. We conducted nineteen in-depth interviews with trial stakeholders, including investigators, trial participants, community advisory board members, and funder representatives; directly observed at trial sites over a five-week period; and collected trial-related documents for analysis.
Results
The vivax malaria treatment trial drew attention to contextual features that, when present, rendered the ‘research for health justice’ framework’s guidance partially incomplete. These insights allowed us to extend the framework to consider external research actors’ obligations to stateless populations. Data analysis then showed that framework requirements are largely fulfilled in relation to the vivax malaria treatment trial by Wellcome Trust (funder), Oxford University (sponsor), and investigators. At the same time, this study demonstrates that it may be difficult for long-term collaborations to shift the focus of their research agendas in accordance with the changing burden of illness in their host communities and to build the independent research capacity of host populations when working with refugees and migrants. Obstructive factors included the research funding environment and staff turnover due to resettlement or migration.
Conclusions
Our findings show that obligations for selecting research targets, research capacity strengthening, and post-trial benefits that link clinical trials to justice in global health can be upheld by external research actors from high-income countries when working with stateless populations in LMICs. However, meeting certain framework requirements for long-term collaborations may not be entirely feasible.
doi:10.1186/1472-6939-15-49
PMCID: PMC4085396  PMID: 24969638
International clinical research; Global justice; Research ethics; Health capability paradigm; Shoklo malaria research unit
2.  Population Pharmacokinetic Assessment of the Effect of Food on Piperaquine Bioavailability in Patients with Uncomplicated Malaria 
Previously published literature reports various impacts of food on the oral bioavailability of piperaquine. The aim of this study was to use a population modeling approach to investigate the impact of concomitant intake of a small amount of food on piperaquine pharmacokinetics. This was an open, randomized comparison of piperaquine pharmacokinetics when administered as a fixed oral formulation once daily for 3 days with (n = 15) and without (n = 15) concomitant food to patients with uncomplicated Plasmodium falciparum malaria in Thailand. Nonlinear mixed-effects modeling was used to characterize the pharmacokinetics of piperaquine and the influence of concomitant food intake. A modified Monte Carlo mapped power approach was applied to evaluate the relationship between statistical power and various degrees of covariate effect sizes of the given study design. Piperaquine population pharmacokinetics were described well in fasting and fed patients by a three-compartment distribution model with flexible absorption. The final model showed a 25% increase in relative bioavailability per dose occasion during recovery from malaria but demonstrated no clinical impact of concomitant intake of a low-fat meal. Body weight and age were both significant covariates in the final model. The novel power approach concluded that the study was adequately powered to detect a food effect of at least 35%. This modified Monte Carlo mapped power approach may be a useful tool for evaluating the power to detect true covariate effects in mixed-effects modeling and a given study design. A small amount of food does not affect piperaquine absorption significantly in acute malaria.
doi:10.1128/AAC.02318-13
PMCID: PMC4023753  PMID: 24449770
3.  Ancillary Care: From Theory to Practice in International Clinical Research 
Public Health Ethics  2013;6(2):154-169.
How international research might contribute to justice in global health has not been substantively addressed by bioethics. This article describes how the provision of ancillary care can link international clinical research to the reduction of global health disparities. It identifies the ancillary care obligations supported by a theory of global justice, showing that Jennifer Ruger’s health capability paradigm requires the delivery of ancillary care to trial participants for a limited subset of conditions that cause severe morbidity and mortality. Empirical research on the Shoklo Malaria Research Unit’s (SMRU) vivax malaria treatment trial was then undertaken to demonstrate whether and how these obligations might be upheld in a resource-poor setting. Our findings show that fulfilment of the ancillary care obligations is feasible where there is commitment from chief investigators and funders and is strongly facilitated by SMRU’s dual role as a research unit and medical non-governmental organization.
doi:10.1093/phe/pht015
PMCID: PMC3712402  PMID: 23864908
4.  Triangular test design to evaluate tinidazole in the prevention of Plasmodium vivax relapse 
Malaria Journal  2013;12:173.
Background
There are very few drugs that prevent the relapse of Plasmodium vivax malaria in man. Tinidazole is a 5-nitroimidazole approved in the USA for the treatment of indications including amoebiasis and giardiasis. In the non-human primate relapsing Plasmodium cynomolgi/macaque malaria model, tinidazole cured one of six macaques studied with an apparent mild delay to relapse in the other five of 14–28 days compared to 11–12 days in controls. One study has demonstrated activity against P. vivax in man. Presented here are the results of a pilot phase II, randomized, open-label study conducted along the Thai-Myanmar border designed to evaluate the efficacy of tinidazole to prevent relapse of P. vivax when administered with chloroquine.
Methods
This study utilized a modified triangular test sequential analysis which allows repeated statistical evaluation during the course of enrolment while maintaining a specified power and type 1 error and minimizing recruitment of subjects. Enrolment was to be halted when a pre-specified success/failure ratio was surpassed. The study was designed to have a 5% type 1 error and 90% power to show whether tinidazole would produce a relapse rate of less than 20% or greater than 45% through Day 63 of weekly follow-up after initiation of treatment and initial parasite clearance with 3 days of an oral weight based dosing of chloroquine and five days of 2 grams/day of tinidazole.
Results
All subjects cleared their parasitaemia by Day 3. Six of the first seven subjects treated with tinidazole relapsed prior to Day 63 (average Day 48.3 (range 42–56)). This exceeded the upper boundary of the triangular test and enrolment to receive tinidazole was halted. A concurrent cohort of five subjects definitively treated with standard doses of primaquine and chloroquine (historically 100% effective) showed no episodes of recurrent P. vivax parasitaemia during the 63-day protocol specified follow-up period.
Conclusions
Tinidazole is ineffective in preventing relapse of P. vivax at the dose used. The macaque relapsing model appeared to correctly predict outcome in humans. Use of the modified triangular test allowed minimal enrolment and limited unnecessary exposure to the study drug and reduced costs. This adds weight to the ethical and economic advantages of this study design to evaluate similarly situated drugs.
Trial registration
ClinicalTrials.gov NCT00811096
doi:10.1186/1475-2875-12-173
PMCID: PMC3671156  PMID: 23718705
Malaria; Plasmodium vivax; Tinidazole; Relapse; Triangular test; Sequential analysis
5.  Malaria Burden and Artemisinin Resistance in the Mobile and Migrant Population on the Thai–Myanmar Border, 1999–2011: An Observational Study 
PLoS Medicine  2013;10(3):e1001398.
Francois Nosten and colleagues evaluate malaria prevalence and incidence in the mobile population on the Myanmar side of the border with Thailand between 1999 and 2011, and also assess resistance to artemisinin.
Background
The Shoklo Malaria Research Unit has been working on the Thai–Myanmar border for 25 y providing early diagnosis and treatment (EDT) of malaria. Transmission of Plasmodium falciparum has declined, but resistance to artesunate has emerged. We expanded malaria activities through EDT and evaluated the impact over a 12-y period.
Methods and Findings
Between 1 October 1999 and 30 September 2011, the Shoklo Malaria Research Unit increased the number of cross-border (Myanmar side) health facilities from two to 11 and recorded the number of malaria consultations. Changes in malaria incidence were estimated from a cohort of pregnant women, and prevalence from cross-sectional surveys. In vivo and in vitro antimalarial drug efficacy were monitored. Over this period, the number of malaria cases detected increased initially, but then declined rapidly. In children under 5 y, the percentage of consultations due to malaria declined from 78% (95% CI 76–80) (1,048/1,344 consultations) to 7% (95% CI 6.2–7.1) (767/11,542 consultations), p<0.001. The ratio of P. falciparum/P. vivax declined from 1.4 (95% CI 1.3–1.4) to 0.7 (95% CI 0.7–0.8). The case fatality rate was low (39/75,126; 0.05% [95% CI 0.04–0.07]). The incidence of malaria declined from 1.1 to 0.1 episodes per pregnant women-year. The cumulative proportion of P. falciparum decreased significantly from 24.3% (95% CI 21.0–28.0) (143/588 pregnant women) to 3.4% (95% CI 2.8–4.3) (76/2,207 pregnant women), p<0.001. The in vivo efficacy of mefloquine-artesunate declined steadily, with a sharp drop in 2011 (day-42 PCR-adjusted cure rate 42% [95% CI 20–62]). The proportion of patients still slide positive for malaria at day 3 rose from 0% in 2000 to reach 28% (95% CI 13–45) (8/29 patients) in 2011.
Conclusions
Despite the emergence of resistance to artesunate in P. falciparum, the strategy of EDT with artemisinin-based combination treatments has been associated with a reduction in malaria in the migrant population living on the Thai–Myanmar border. Although limited by its observational nature, this study provides useful data on malaria burden in a strategically crucial geographical area. Alternative fixed combination treatments are needed urgently to replace the failing first-line regimen of mefloquine and artesunate.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
According to latest figures, the World Health Organization estimates that there are over 200 million cases of malaria each year, with over three-quarters of a million deaths. Several Plasmodium parasites cause malaria (the most serious being Plasmodium falciparum) and are transmitted to people through the bites of infected night-flying mosquitoes. Malaria transmission can be prevented by using insecticides to control the mosquitoes and by sleeping under insecticide-treated bed nets. However, in Southeast Asia the effectiveness of these measures is limited. Treating infected people with antimalarial drugs, particularly with artemisinin-based combination treatments (ACTs), is a key strategy in reducing the deaths and disability caused by malaria. However, progress is now threatened by the emergence in Southeast Asia of P. falciparum isolates that are resistant to artesunate (a common component of ACT). This development is concerning, as resistance to the artemisinin family of drugs, of which artesunate is a member, could trigger a resurgence in malaria in many parts of the world and compromise the progress made in the treatment of severe malaria.
Why Was This Study Done?
P. falciparum resistance to artemisinin has been confirmed in the area around the border between Thailand and Myanmar. Malaria control in this border area is particularly challenging, as there is a reservoir of malaria in Myanmar (where the disease burden is higher than in Thailand), frequent population movement, and differences in adequate control measures on the two sides of the border. In this study the authors evaluated malaria prevalence and incidence in the mobile population on the Myanmar side of the border between 1 October 1999 and 30 September 2011 to assess whether increasing access to early diagnosis and treatment with ACT was associated with a decline in the malaria burden.
What Did the Researchers Do and Find?
The Shoklo Malaria Research Unit (SMRU) has been working on the Thai–Myanmar border for 25 years providing early diagnosis and treatment of malaria and has extended its services from two to 11 health care facilities (health posts) on the Myanmar side of the border over the past few years. In order to evaluate any changes in the malaria burden since the expansion of services, the researchers recorded the number of consultations in all SMRU clinics and health posts with confirmed malaria diagnosis and tracked changes in the prevalence of malaria in the population on the Myanmar side of the border (via cross-sectional surveys in villages). The researchers also assessed the incidence of malaria in a cohort of pregnant women living on both sides of the border and monitored antimalarial drug efficacy over this time period.
The researchers found that although the mobile population on the Thai side of the border remained constant, the population in villages covered by the clinics and health posts in the border area increased four-fold. Over the time period, the researchers found that the number of confirmed malaria cases (P. falciparum) increased initially, rising from just over 5,000 in 2000 to a peak of 13,764 in 2006, and then declined to just over 3,500 in 2011. A striking finding was the predominance of infections in young adult males (50,316/90,321; 55.7%). Encouragingly, the percentage of consultations due to malaria in children under five years fell from 78% to 7%, and the incidence of malaria declined from 1.1 to 0.1 episodes per pregnant woman-year. In addition, the proportion of patients admitted to hospital with severe disease was stable, and the number of deaths from malaria remained extremely low, with an overall case fatality rate of 0.05%. The researchers also found that the ratio of P. falciparum to P. vivax infections declined from 1.4 to 0.7, and the prevalence of P. falciparum decreased from 24.3% to 3.4%. However, worryingly, in the small number of patients undertaking drug efficacy tests, the drug efficacy of artesunate declined steadily, with the proportion of patients still infected with malaria at day 3 of treatment increasing from 0% in 2000 to 28% in 2011.
What Do These Findings Mean?
These findings indicate that despite the emergence of resistance to artesunate in P. falciparum, and the decline in the efficacy of ACT, the strategy of early diagnosis and treatment with ACTs has been associated with a reduction in malaria in the population living on the Thai–Myanmar border. Furthermore, these findings suggest that an aggressive strategy based on early detection and treatment of cases, combined with vector control and information, could be the way forward to eliminate malaria. Although there were only a small number of patients involved in drug efficacy tests in 2011, this study shows that alternative fixed combination treatments are needed urgently to replace the failing first-line regimen of mefloquine and artesunate.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001398.
More information about the Shoklo Malaria Research Unit is available
The World Health Organization website has more information about antimalarial drug efficacy and drug resistance
The Bill & Melinda Gates Foundation website tells the malaria resistance story
doi:10.1371/journal.pmed.1001398
PMCID: PMC3589269  PMID: 23472056
6.  Effect of High-Dose or Split-Dose Artesunate on Parasite Clearance in Artemisinin-Resistant Falciparum Malaria 
New treatment strategies are needed for artemisinin-resistant falciparum malaria. This randomized trial shows that neither increasing nor splitting the standard once-daily artesunate dose reverses the markedly reduced parasite clearance rate in patients with artemisinin-resistant falciparum malaria.
Background. The emergence of Plasmodium falciparum resistance to artemisinins on the Cambodian and Myanmar-Thai borders poses severe threats to malaria control. We investigated whether increasing or splitting the dose of the short-half-life drug artesunate improves parasite clearance in falciparum malaria in the 2 regions.
Methods. In Pailin, western Cambodia (from 2008 to 2010), and Wang Pha, northwestern Thailand (2009–2010), patients with uncomplicated falciparum malaria were randomized to oral artesunate 6 mg/kg/d as a once-daily or twice-daily dose for 7 days, or artesunate 8 mg/kg/d as a once-daily or twice-daily dose for 3 days, followed by mefloquine. Parasite clearance and recrudescence for up to 63 days of follow-up were assessed.
Results. A total of 159 patients were enrolled. Overall median (interquartile range [IQR]) parasitemia half-life (half-life) was 6.03 (4.89–7.28) hours in Pailin versus 3.42 (2.20–4.85) hours in Wang Pha (P = .0001). Splitting or increasing the artesunate dose did not shorten half-life in either site. Pharmacokinetic profiles of artesunate and dihydroartemisinin were similar between sites and did not correlate with half-life. Recrudescent infections occurred in 4 of 79 patients in Pailin and 5 of 80 in Wang Pha and was not different between treatment arms (P = .68).
Conclusions. Increasing the artesunate treatment dose up to 8 mg/kg/d or splitting the dose does not improve parasite clearance in either artemisinin resistant or more sensitive infections with P. falciparum.
Clinical Trials Registration. ISRCTN15351875.
doi:10.1093/cid/cis958
PMCID: PMC3563392  PMID: 23175556
artemisinins; drug resistance; Plasmodium falciparum; neutropenia; reticulocytopenia
7.  Artemisinin Resistance in Plasmodium falciparum Malaria 
The New England journal of medicine  2009;361(5):455-467.
BACKGROUND
Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai–Cambodian border, historically a site of emerging antimalarial-drug resistance.
METHODS
In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance.
RESULTS
We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate–mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P = 0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco–endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups.
CONCLUSIONS
P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.)
doi:10.1056/NEJMoa0808859
PMCID: PMC3495232  PMID: 19641202
8.  A major genome region underlying artemisinin resistance in malaria 
Science (New York, N.y.)  2012;336(6077):79-82.
Evolving resistance to artemisinin-based compounds threatens to derail attempts to control malaria. Resistance has been confirmed in western Cambodia, has recently emerged in western Thailand, but is absent from neighboring Laos. Artemisinin resistance results in reduced parasite clearance rates (CR) following treatment. We used a two-phase strategy to identify genome region(s) underlying this ongoing selective event. Geographical differentiation and haplotype structure at 6,969 polymorphic SNPs in 91 parasites from Cambodia, Thailand and Laos identified 33 genome regions under strong selection. We screened SNPs and microsatellites within these regions in 715 parasites from Thailand, identifying a selective sweep on chr 13 that shows strong association (P=10-6-10-12) with slow CR, illustrating the efficacy of targeted association for identifying the genetic basis of adaptive traits.
doi:10.1126/science.1215966
PMCID: PMC3355473  PMID: 22491853
9.  Community engagement on the Thai–Burmese border: rationale, experience and lessons learnt 
International health  2010;2(2):123-129.
Community engagement is increasingly promoted in developing countries, especially in international health research, but there is little published experience. The Shoklo Malaria Research Unit (SMRU) conducts research with refugees, migrant workers, displaced people, and day migrants on the Thai-Burmese border, and has recently facilitated the set up of the Tak Province Border Community Ethics Advisory Board (T-CAB). Valuable lessons have been learnt from consultation with the T-CAB especially in the area of participant recruitment and the informed consent process. A lot of new research questions have emerged from consultation with the T-CAB. This paper describes our experience, lessons learnt and the unique challenges faced working with the T-CAB from its initial conception to date. We conclude that consultation with the T-CAB has made improvements in our research in particular operational and ethical aspects of our studies.
doi:10.1016/j.inhe.2010.02.001
PMCID: PMC3442337  PMID: 22984375
Community engagement; Community advisory board; Ethics; Community; Migrants; Border population
10.  Effect of Early Detection and Treatment on Malaria Related Maternal Mortality on the North-Western Border of Thailand 1986–2010 
PLoS ONE  2012;7(7):e40244.
Introduction
Maternal mortality is high in developing countries, but there are few data in high-risk groups such as migrants and refugees in malaria-endemic areas. Trends in maternal mortality were followed over 25 years in antenatal clinics prospectively established in an area with low seasonal transmission on the north-western border of Thailand.
Methods and Findings
All medical records from women who attended the Shoklo Malaria Research Unit antenatal clinics from 12th May 1986 to 31st December 2010 were reviewed, and maternal death records were analyzed for causality. There were 71 pregnancy-related deaths recorded amongst 50,981 women who attended antenatal care at least once. Three were suicide and excluded from the analysis as incidental deaths. The estimated maternal mortality ratio (MMR) overall was 184 (95%CI 150–230) per 100,000 live births. In camps for displaced persons there has been a six-fold decline in the MMR from 499 (95%CI 200–780) in 1986–90 to 79 (40–170) in 2006–10, p<0.05. In migrants from adjacent Myanmar the decline in MMR was less significant: 588 (100–3260) to 252 (150–430) from 1996–2000 to 2006–2010. Mortality from P.falciparum malaria in pregnancy dropped sharply with the introduction of systematic screening and treatment and continued to decline with the reduction in the incidence of malaria in the communities. P.vivax was not a cause of maternal death in this population. Infection (non-puerperal sepsis and P.falciparum malaria) accounted for 39.7 (27/68) % of all deaths.
Conclusions
Frequent antenatal clinic screening allows early detection and treatment of falciparum malaria and substantially reduces maternal mortality from P.falciparum malaria. No significant decline has been observed in deaths from sepsis or other causes in refugee and migrant women on the Thai–Myanmar border.
doi:10.1371/journal.pone.0040244
PMCID: PMC3399834  PMID: 22815732
11.  Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study 
Lancet  2012;379(9830):1960-1966.
Summary
Background
Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand–Myanmar (Burma) border.
Methods
In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≥4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms.
Findings
3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5–2·7) in 2001, to 3·7 h (3·6–3·8) in 2010, compared with a mean of 5·5 h (5·2–5·9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≥6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010.
Interpretation
Genetically determined artemisinin resistance in P falciparum emerged along the Thailand–Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2–6 years.
Funding
The Wellcome Trust and National Institutes of Health.
doi:10.1016/S0140-6736(12)60484-X
PMCID: PMC3525980  PMID: 22484134
12.  Refugee and Migrant Women's Views of Antenatal Ultrasound on the Thai Burmese Border: A Mixed Methods Study 
PLoS ONE  2012;7(4):e34018.
Background
Antenatal ultrasound suits developing countries by virtue of its versatility, relatively low cost and safety, but little is known about women’s or local provider’s perspectives of this upcoming technology in such settings. This study was undertaken to better understand how routine obstetric ultrasound is experienced in a displaced Burmese population and identify barriers to its acceptance by local patients and providers.
Methodology/Principal Findings
Qualitative (30 observations, 19 interviews, seven focus group discussions) and quantitative methods (questionnaire survey with 644 pregnant women) were used to provide a comprehensive understanding along four major themes: safety, emotions, information and communication, and unintended consequences of antenatal ultrasound in refugee and migrant clinics on the Thai Burmese border. One of the main concerns expressed by women was the danger of childbirth which they mainly attributed to fetal malposition. Both providers and patients recognized ultrasound as a technology improving the safety of pregnancy and delivery. A minority of patients experienced transitory shyness or anxiety before the ultrasound, but reported that these feelings could be ameliorated with improved patient information and staff communication. Unintended consequences of overuse and gender selective abortions in this population were not common.
Conclusions/Significance
The results of this study are being used to improve local practice and allow development of explanatory materials for this population with low literacy. We strongly encourage facilities introducing new technology in resource poor settings to assess acceptability through similar inquiry.
doi:10.1371/journal.pone.0034018
PMCID: PMC3325974  PMID: 22514615
13.  Randomized, Double-Blind, Placebo-Controlled Trial of Monthly versus Bimonthly Dihydroartemisinin-Piperaquine Chemoprevention in Adults at High Risk of Malaria 
Intermittent preventive treatment (IPT) is increasingly used to reduce malaria morbidity and mortality in children and pregnant women. The efficacy of IPT depends on the pharmacokinetic and pharmacodynamic properties of the antimalarial drugs used. Healthy adult male volunteers whose occupation put them at high risk of malaria on the Northwest border of Thailand were randomized to receive a 3-day-treatment dose of dihydroartemisinin-piperaquine monthly (DPm) or every 2 months (DPalt) or an identical placebo with or without fat (6.4g/dose) over a 9-month period. All volunteers were monitored weekly. One thousand adults were recruited. Dihydroartemisinin-piperaquine was well tolerated. There were 114 episodes of malaria (49 Plasmodium falciparum, 63 P. vivax, and 2 P. ovale). The protective efficacy against all malaria at 36 weeks was 98% (95% confidence interval [CI], 96% to 99%) in the DPm group and 86% (95% CI, 81% to 90%) in the DPalt group (for both, P < 0.0001 compared to the placebo group). As a result, the placebo group also had lower hematocrits during the study (P < 0.0001). Trough plasma piperaquine concentrations were the main determinant of efficacy; no malaria occurred in participants with a trough concentration above 31 ng/ml. Neither plasma piperaquine concentration nor efficacy was influenced by the coadministration of fat. DPm is safe to use and is effective in the prevention of malaria in adult males living in an area where P. vivax and multidrug-resistant P. falciparum malaria are endemic.
doi:10.1128/AAC.05877-11
PMCID: PMC3294930  PMID: 22252804
14.  Dihydroartemisinin-Piperaquine Versus Chloroquine in the Treatment of Plasmodium vivax Malaria in Thailand: A Randomized Controlled Trial 
The efficacy of chloroquine in the treatment of Plasmodium vivax malaria is declining on the Northwestern border of Thailand. This randomized controlled trial in 500 adults and children shows that dihydroartemisinin-piperaquine is a safe and effective alternative treatment.
Background. Chloroquine (CQ) remains the treatment of choice for Plasmodium vivax malaria. Initially confined to parts of Indonesia and Papua, resistance of P. vivax to CQ seems to be spreading, and alternative treatments are required.
Methods. We conducted a randomized controlled study to compare the efficacy and the tolerability of CQ and dihydroartemisinin-piperaquine (DP) in 500 adults and children with acute vivax malaria on the Northwestern border of Thailand.
Results. Both drugs were well tolerated. Fever and parasite clearance times were slower in the CQ than in the DP group (P < .001). By day 28, recurrent infections had emerged in 18 of 207 CQ recipients compared with 5 of 230 treated with DP (relative risk, 4.0; 95% confidence interval [CI], 1.51–10.58; P = .0046). The cumulative risk of recurrence with P. vivax at 9 weeks was 79.1% (95% CI, 73.5%–84.8%) in patients treated with CQ compared with 54.9% (95% CI, 48.2%–61.6%) in those receiving DP (hazard ratio [HR], 2.27; 95% CI, 1.8–2.9; P < .001). Children <5 years old were at greater risk of recurrent P. vivax infection (74.4%; 95% CI, 63.2%–85.6%) than older patients (55.3% [95% CI, 50.2%–60.4%]; HR, 1.58 [95% CI, 1.1–2.2]; P = .005). In vitro susceptibility testing showed that 13% of the tested isolates had a CQ median inhibitory concentration >100 nmol/L, suggesting reduced susceptibility.
Conclusions. The efficacy of CQ in the treatment of P. vivax infections is declining on the Thai-Myanmar border. DP is an effective alternative treatment.
Clinical Trials Registration. ISRCTN87827353.
doi:10.1093/cid/cir631
PMCID: PMC3193831  PMID: 22002979
15.  A Small Amount of Fat Does Not Affect Piperaquine Exposure in Patients with Malaria▿† 
Dihydroartemisinin-piperaquine is a new, highly effective, and well-tolerated combination treatment for uncomplicated falciparum malaria. The lipophilic characteristic of piperaquine suggests that administration together with fat will increase the oral bioavailability of the drug, and this has been reported for healthy volunteers. This pharmacokinetic study monitored 30 adult patients with uncomplicated falciparum malaria for 4.5 months to evaluate the effects of the concomitant intake of fat on the total piperaquine exposure. The fixed-drug combination of dihydroartemisinin-piperaquine was given with water to fasting patients (n = 15) or was coadministered with 200 ml milk containing 6.4 g fat (n = 15). The drug combination was generally well tolerated, and there were no severe adverse effects reported for either group during the study. Total piperaquine exposure (area under the concentration-time curve from zero to infinity [AUC0-∞]; results are given as medians [ranges]) were not statistically different between fed (29.5 h · μg/ml [20.6 to 58.7 h · μg/ml]) and fasting (23.9 h · μg/ml [11.9 to 72.9 h · μg/ml]) patients, but the interindividual variation was reduced in the fed group. Overall, none of the pharmacokinetic parameters differed statistically between the groups. Total piperaquine exposure correlated well with the day 7 concentrations in the fasted group, but the fed group showed a poor correlation. In conclusion, the coadministration of 6.4 g fat did not have any significant effect on piperaquine pharmacokinetics in the treatment of uncomplicated malaria.
doi:10.1128/AAC.00279-11
PMCID: PMC3165307  PMID: 21709087
16.  Exploring the Contribution of Candidate Genes to Artemisinin Resistance in Plasmodium falciparum▿  
The reduced in vivo sensitivity of Plasmodium falciparum has recently been confirmed in western Cambodia. Identifying molecular markers for artemisinin resistance is essential for monitoring the spread of the resistant phenotype and identifying the mechanisms of resistance. Four candidate genes, including the P. falciparum mdr1 (pfmdr1) gene, the P. falciparum ATPase6 (pfATPase6) gene, the 6-kb mitochondrial genome, and ubp-1, encoding a deubiquitinating enzyme, of artemisinin-resistant P. falciparum strains from western Cambodia were examined and compared to those of sensitive strains from northwestern Thailand, where the artemisinins are still very effective. The artemisinin-resistant phenotype did not correlate with pfmdr1 amplification or mutations (full-length sequencing), mutations in pfATPase6 (full-length sequencing) or the 6-kb mitochondrial genome (full-length sequencing), or ubp-1 mutations at positions 739 and 770. The P. falciparum CRT K76T mutation was present in all isolates from both study sites. The pfmdr1 copy numbers in western Cambodia were significantly lower in parasite samples obtained in 2007 than in those obtained in 2005, coinciding with a local change in drug policy replacing artesunate-mefloquine with dihydroartemisinin-piperaquine. Artemisinin resistance in western Cambodia is not linked to candidate genes, as was suggested by earlier studies.
doi:10.1128/AAC.00032-10
PMCID: PMC2897287  PMID: 20421395
17.  Changes in the Treatment Responses to Artesunate-Mefloquine on the Northwestern Border of Thailand during 13 Years of Continuous Deployment 
PLoS ONE  2009;4(2):e4551.
Background
Artemisinin combination treatments (ACT) are recommended as first line treatment for falciparum malaria throughout the malaria affected world. We reviewed the efficacy of a 3-day regimen of mefloquine and artesunate regimen (MAS3), over a 13 year period of continuous deployment as first-line treatment in camps for displaced persons and in clinics for migrant population along the Thai-Myanmar border.
Methods and Findings
3,264 patients were enrolled in prospective treatment trials between 1995 and 2007 and treated with MAS3. The proportion of patients with parasitaemia persisting on day-2 increased significantly from 4.5% before 2001 to 21.9% since 2002 (p<0.001). Delayed parasite clearance was associated with increased risk of developing gametocytaemia (AOR = 2.29; 95% CI, 2.00–2.69, p = 0.002). Gametocytaemia on admission and carriage also increased over the years (p = 0.001, test for trend, for both). MAS3 efficacy has declined slightly but significantly (Hazards ratio 1.13; 95% CI, 1.07–1.19, p<0.001), although efficacy in 2007 remained well within acceptable limits: 96.5% (95% CI, 91.0–98.7). The in vitro susceptibility of P. falciparum to artesunate increased significantly until 2002, but thereafter declined to levels close to those of 13 years ago (geometric mean in 2007: 4.2 nM/l; 95% CI, 3.2–5.5). The proportion of infections caused by parasites with increased pfmdr1 copy number rose from 30% (12/40) in 1996 to 53% (24/45) in 2006 (p = 0.012, test for trend).
Conclusion
Artesunate-mefloquine remains a highly efficacious antimalarial treatment in this area despite 13 years of widespread intense deployment, but there is evidence of a modest increase in resistance. Of particular concern is the slowing of parasitological response to artesunate and the associated increase in gametocyte carriage.
doi:10.1371/journal.pone.0004551
PMCID: PMC2641001  PMID: 19234601
18.  Clinically uncomplicated Plasmodium falciparum malaria with high schizontaemia: A case report 
Malaria Journal  2008;7:57.
Background
The treatment options for acute Plasmodium falciparum malaria are based on the clinician classifying the patient as uncomplicated or severe according to the clinical and parasitological findings. This process is not always straightforward.
Case presentation
An adult male presented to a clinic on the western border of Thailand with a physical examination and P. falciparum trophozoite count (1.2% of infected red blood cells, IRBC) from malaria blood smear, consistent with a diagnosis of uncomplicated P. falciparum infection. However, the physician on duty treated the patient for severe malaria based on the reported P. falciparum schizont count, which was very high (0.3% IRBC), noticeably in relation to the trophozoite count and schizont:trophozoite ratio 0.25:1. On intravenous artesunate, the patient deteriorated clinically in the first 24 hours. The trophozoite count increased from 1.2% IRBC at baseline to 20.5% IRBC 18 hours following the start of treatment. By day three, the patient recovered and was discharged on day seven having completed a seven-day treatment with artesunate and mefloquine.
Conclusion
The malaria blood smear provides only a guide to the overall parasite biomass in the body, due to the ability of P. falciparum to sequester in the microvasculature. In severe malaria, high schizont counts are associated with worse prognosis. In low transmission areas or in non-immune travelers the presence of schizonts in the peripheral circulation is an indication for close patient supervision. In this case, an unusually high schizont count in a clinically uncomplicated patient was indicative of potential deterioration. Prompt treatment with intravenous artesunate is likely to have been responsible for the good clinical outcome in this case.
doi:10.1186/1475-2875-7-57
PMCID: PMC2365953  PMID: 18402713

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