• Barriers to prompt and effective treatment of malaria in northern Sri Lanka.

      Reilley, B; Abeyasinghe, R; Pakianathar, M V; Medecins sans Frontieres, Colombo, Sri Lanka. (Wiley-Blackwell, 2002-09)
      BACKGROUND: For the past 18 years, northern Sri Lanka has been affected by armed ethnic conflict. This has had a heavy impact on displacement of civilians, health delivery services, number of health professionals in the area and infrastructure. The north of Sri Lanka has a severe malaria burden, with less than 5% of the national population suffering 34% of reported cases. Health care providers investigated treatment-seeking behaviour and levels of treatment failure believed to be the result of lack of adherence to treatment. METHODS: Pre- and post-treatment interviews with patients seeking treatment in the outpatient department (OPD) and focus groups. RESULTS: A total of 271 persons completed interviews: 54.4% sought treatment within 2 days of the onset of symptoms, and 91.9% self-treated with drugs with prior to seeking treatment, mainly with paracetamol. Self-treatment was associated with delaying treatment (RR 3.55, CI 1.23-10.24, P=0.002). In post-treatment interviews, self-reported default was 26.1%. The main reasons for not taking the entire regimen were side-effects (57.6%) and disappearance of symptoms (16.7%). Focus groups indicated some lack of confidence in chloroquine treatment and prophylaxis, and scant enthusiasm for prevention methods. CONCLUSIONS: A number of factors contribute to a lack of access and a lower quality of care for malaria: lack of medical staff and facilities because of the fighting; lack of confidence in treatment, and perception of malaria as a routine illness. Prevention efforts need to take into account certain beliefs and practices to be successful.
    • Case management of a multidrug-resistant Shigella dysenteriae serotype 1 outbreak in a crisis context in Sierra Leone, 1999-2000.

      Guerin, P J; Brasher, C; Baron, E; Mic, D; Grimont, F; Ryan, M; Aavitsland, P; Legros, D; Epicentre, 8 rue Saint Sabin, 75011 Paris, France. philippe.guerin@epicentre.msf.org (Elsevier, 2004-11)
      From December 1999 to the end of February 2000, 4218 cases of dysentery were reported in Kenema district, southeastern Sierra Leone, by a Médecins Sans Frontières team operating in this region. Shigella dysenteriae serotype 1 was isolated from the early cases. The overall attack rate was 7.5% but higher among children under 5 years (11.2%) compared to the rest of the population (6.8%) (RR = 1.6; 95% CI 1.5-1.8). The case fatality ratio was 3.1%, and higher for children under 5 years (6.1% vs. 2.1%) (RR = 2.9; 95% CI 2.1-4.1). A case management strategy based on stratification of affected cases was chosen in this resource-poor setting. Patients considered at higher risk of death were treated with a 5 day ciprofloxacin regimen in isolation centres. Five hundred and eighty-three cases were treated with a case fatality ratio of 0.9%. Patients who did not have signs of severity when seen by health workers were given hygiene advice and oral rehydration salts. This strategy was effective in this complex emergency.
    • Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial

      Smithuis, Frank; Kyaw, Moe Kyaw; Phe, Ohn; Win, Thein; Aung, Pyay Phyo; Oo, Aung Pyay Phyo; Naing, Arkar Linn; Nyo, Mya Yee; Myint, Naing Zaw Htun; Imwong, Mallika; Ashley, Elizabeth; Lee, Sue J; White, Nicholas J; Médecins Sans Frontières—Holland, Yangon, Myanmar; Medical Action Myanmar, Yangon, Myanmar; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Churchill Hospital, Oxford, UK (2010-09-09)
      BACKGROUND: Artemisinin-combination therapy (ACT) is recommended as first-line treatment of falciparum malaria throughout the world, and fixed-dose combinations are preferred by WHO; whether a single gametocytocidal dose of primaquine should be added is unknown. We aimed to compare effectiveness of four fixed-dose ACTs and a loose tablet combination of artesunate and mefloquine, and assess the addition of a single gametocytocidal dose of primaquine. METHODS: In an open-label randomised trial in clinics in Rakhine state, Kachin state, and Shan state in Myanmar (Burma) between Dec 30, 2008, and March 20, 2009, we compared the effectiveness of all four WHO-recommended fixed-dose ACTs (artesunate-mefloquine, artesunate-amodiaquine, dihydroartemisinin-piperaquine, artemether-lumefantrine) and loose artesunate-mefloquine in Burmese adults and children. Eligible patients were those who presented to the clinics with acute uncomplicated Plasmodium falciparum malaria or mixed infection, who were older than 6 months, and who weighed more than 5 kg. Treatments were randomised in equal numbers within blocks of 50 and allocation was in sealed envelopes. All patients were also randomly assigned to receive either a single dose of primaquine 0·75 mg base/kg or not. Patients were followed up for 63 days. Treatment groups were compared by analysis of variance and multiple logistic regression. The primary outcome was the 63 day recrudescence rate. This study is registered with clinicaltrials.gov, number NCT00902811. FINDINGS: 155 patients received artesunate-amodiaquine, 162 artemether-lumefantrine, 169 artesunate-mefloquine, 161 loose artesunate-mefloquine, and 161 dihydroartemisinin-piperaquine. By day 63 of follow-up, 14 patients (9·4%; 95% CI 5·7-15·3%) on artesunate-amodiaquine had recrudescent P falciparum infections, a rate significantly higher than for artemether-lumefantrine (two patients; 1·4%; 0·3-5·3; p=0·0013), fixed-dose artesunate-mefloquine (0 patients; 0-2·3; p<0·0001), loose artesunate-mefloquine (two patients; 1·3%; 0·3-5·3; p=0·0018), and dihydroartemisinin-piperaquine (two patients 1·3%; 0·3-5·2%; p=0·0012). Hazard ratios for re-infection (95% CI) after artesunate-amodiaquine were 3·2 (1·3-8·0) compared with the two artesunate-mefloquine groups (p=0·01), 2·6 (1·0-6-0) compared with artemether-lumefantrine (p=0·04), and 2·3 (0·9-6·0) compared with dihydroartemisinin-piperaquine (p=0·08). Mixed falciparum and vivax infections were common: 129 (16%) had a mixed infection at presentation and 330 (41%) patients had one or more episodes of Plasmodium vivax infection during follow-up. The addition of a single dose of primaquine (0·75 mg/kg) reduced P falciparum gametocyte carriage substantially: rate ratio 11·9 (95% CI 7·4-20·5). All regimens were well tolerated. Adverse events were reported by 599 patients, most commonly vomiting and dizziness. Other side-effects were less common and were not related to a specific treatment. INTERPRETATION: Artesunate-amodiaquine should not be used in Myanmar, because the other ACTs are substantially more effective. Artesunate-mefloquine provided the greatest post-treatment suppression of malaria. Adding a single dose of primaquine would substantially reduce transmission potential. Vivax malaria, not recurrent falciparum malaria, is the main complication after treatment of P falciparum infections in this region. FUNDING: Médecins sans Frontières (Holland) and the Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme.
    • Evaluation of three parasite lactate dehydrogenase-based rapid diagnostic tests for the diagnosis of falciparum and vivax malaria

      Ashley, Elizabeth A; Touabi, Malek; Ahrer, Margareta; Hutagalung, Robert; Htun, Khayae; Luchavez, Jennifer; Dureza, Christine; Proux, Stephane; Leimanis, Mara; Lwin, Myo Min; Koscalova, Alena; Comte, Eric; Hamade, Prudence; Page, Anne-Laure; Nosten, François; Guerin, Philippe J; Epicentre, Paris, France; Department of Microbiology, Hammersmith Hospital, Imperial College NHS Trust, London, UK; Médecins sans Frontières, Switzerland; Médecins sans Frontières, Myanmar; Research Institute for Tropical Medicine, Alabang, Muntinlupa City, Philippines; Shoklo Malaria Research Unit, Mae Sot, Thailand; Mahidol-Oxford Tropical Medicine Research Unit (MORU), Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, UK; Médecins sans Frontières Malaria Working Group, UK; Malaria Consortium, London, UK (2009-10-27)
      BACKGROUND: In areas where non-falciparum malaria is common rapid diagnostic tests (RDTs) capable of distinguishing malaria species reliably are needed. Such tests are often based on the detection of parasite lactate dehydrogenase (pLDH). METHODS: In Dawei, southern Myanmar, three pLDH based RDTs (CareStart Malaria pLDH (Pan), CareStart Malaria pLDH (Pan, Pf) and OptiMAL-IT)were evaluated in patients presenting with clinically suspected malaria. Each RDT was read independently by two readers. A subset of patients with microscopically confirmed malaria had their RDTs repeated on days 2, 7 and then weekly until negative. At the end of the study, samples of study batches were sent for heat stability testing. RESULTS: Between August and November 2007, 1004 patients aged between 1 and 93 years were enrolled in the study. Slide microscopy (the reference standard) diagnosed 213 Plasmodium vivax (Pv) monoinfections, 98 Plasmodium falciparum (Pf) mono-infections and no malaria in 650 cases. The sensitivities (sens) and specificities (spec), of the RDTs for the detection of malaria were- CareStart Malaria pLDH (Pan) test: sens 89.1% [CI95 84.2-92.6], spec 97.6% [CI95 96.5-98.4]. OptiMal-IT: Pf+/- other species detection: sens 95.2% [CI95 87.5-98.2], spec 94.7% [CI95 93.3-95.8]; non-Pf detection alone: sens 89.6% [CI95 83.6-93.6], spec 96.5% [CI95 94.8-97.7]. CareStart Malaria pLDH (Pan, Pf): Pf+/- other species: sens 93.5% [CI95 85.4-97.3], spec 97.4% [95.9-98.3]; non-Pf: sens 78.5% [CI95 71.1-84.4], spec 97.8% [CI95 96.3-98.7]. Inter-observer agreement was excellent for all tests (kappa > 0.9). The median time for the RDTs to become negative was two days for the CareStart Malaria tests and seven days for OptiMAL-IT. Tests were heat stable up to 90 days except for OptiMAL-IT (Pf specific pLDH stable to day 20 at 35 degrees C). CONCLUSION: None of the pLDH-based RDTs evaluated was able to detect non-falciparum malaria with high sensitivity, particularly at low parasitaemias. OptiMAL-IT performed best overall and would perform best in an area of high malaria prevalence among screened fever cases. However, heat stability was unacceptable and the number of steps to perform this test is a significant drawback in the field. A reliable, heat-stable, highly sensitive RDT, capable of diagnosing all Plasmodium species has yet to be identified.
    • In vivo parasitological measures of artemisinin susceptibility

      Stepniewska, Kasia; Ashley, Elizabeth; Lee, Sue J; Anstey, Nicholas; Barnes, Karen I; Binh, Tran Quang; D'Alessandro, Umberto; Day, Nicholas P J; de Vries, Peter J; Dorsey, Grant; Guthmann, Jean-Paul; Mayxay, Mayfong; Newton, Paul N; Olliaro, Piero; Osorio, Lyda; Price, Ric N; Rowland, Mark; Smithuis, Frank; Taylor, Walter R J; Nosten, François; White, Nicholas J; Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand; Shoklo Malaria Research Unit, Mae Sot, Thailand; Menzies School of Health Research and Royal Darwin Hospital, Darwin, Australia; Division of Clinical Pharmacology, Department of Medicine, University (2010-01-19)
      Parasite clearance data from 18,699 patients with falciparum malaria treated with an artemisinin derivative in areas of low (n=14,539), moderate (n=2077), and high (n=2083) levels of malaria transmission across the world were analyzed to determine the factors that affect clearance rates and identify a simple in vivo screening measure for artemisinin resistance. The main factor affecting parasite clearance time was parasite density on admission. Clearance rates were faster in high-transmission settings and with more effective partner drugs in artemisinin-based combination treatments (ACTs). The result of the malaria blood smear on day 3 (72 h) was a good predictor of subsequent treatment failure and provides a simple screening measure for artemisinin resistance. Artemisinin resistance is highly unlikely if the proportion of patients with parasite densities of <100,000 parasites/microL given the currently recommended 3-day ACT who have a positive smear result on day 3 is <3%; that is, for n patients the observed number with a positive smear result on day 3 does not exceed (n + 60)/24.
    • Supervised versus unsupervised antimalarial treatment with six-dose artemether-lumefantrine: pharmacokinetic and dosage-related findings from a clinical trial in Uganda.

      Checchi, F; Piola, P; Fogg, C; Bajunirwe, F; Biraro, S; Grandesso, F; Ruzagira, E; Babigumira, J; Kigozi, I; Kiguli, J; Kyomuhendo, J; Ferradini, L; Taylor, W R J; Guthmann, J P; Epicentre, Paris, France. francesco.checchi@lshtm.ac.uk (BioMed Central, 2006)
      BACKGROUND: A six-dose antimalarial regimen of artemether-lumefantrine (A/L) may soon become one of the most widely used drug combination in Africa, despite possible constraints with adherence and poor absorption due to inadequate nutrition, and a lack of pharmacokinetic and effectiveness data. METHODS: Within a trial of supervised versus unsupervised A/L treatment in a stable Ugandan Plasmodium falciparum transmission setting, plasma lumefantrine concentrations were measured in a subset of patients on day 3 (C [lum]day3) and day 7 (C [lum]day7) post-inclusion. Predictors of lumefantrine concentrations were analysed to show how both C [lum]day7 and the weight-adjusted lumefantrine dose affect 28-day recrudescence and re-infection risks. The implications of these novel findings are discussed in terms of the emergence of lumefantrine-resistant strains in Africa. RESULTS: C [lum]day3 and C [lum]day7 distributions among 241 supervised and 238 unsupervised patients were positively skewed. Unsupervised treatment and decreasing weight-adjusted lumefantrine dose were negatively associated with C [lum]day3. Unsupervised treatment and decreasing age showed strong negative associations with C [lum]day7. Both models were poorly predictive (R-squared < 0.25). There were no recrudescences in either arm, but decreasing lumefantrine dose per Kg resulted in up to 13-fold higher adjusted risks of re-infection. Re-infections occurred only among patients with C [lum]day7 below 400 ng/mL (p < 0.001). CONCLUSION: Maintaining the present six-dose regimen and ensuring high adherence and intake are essential to maximize the public health benefits of this valuable drug combination.