• Artemether-Lumefantrine to treat Malaria in pregnancy is associated with reduced placental Haemozoin deposition compared to Quinine in a randomized controlled trial

      Muehlenbachs, Atis; Nabasumba, Carolyn; McGready, Rose; Turyakira, Eleanor; Tumwebaze, Benon; Dhorda, Mehul; Nyehangane, Dan; Nalusaji, Aisha; Nosten, Franois; Guerin, Philippe J; Piola, Patrice; Department of Pathology, University of Washington, Box 357470, 1959 NE Pacific Street, Seattle, WA, USA. amuehlen@u.washington.edu (2012-05-03)
      Data on efficacy of artemisinin-based combination therapy (ACT) to treat Plasmodium falciparum during pregnancy in sub-Saharan Africa is scarce. A recent open label, randomized controlled trial in Mbarara, Uganda demonstrated that artemether-lumefantrine (AL) is not inferior to quinine to treat uncomplicated malaria in pregnancy. Haemozoin can persist in the placenta following clearance of parasites, however there is no data whether ACT can influence the amount of haemozoin or the dynamics of haemozoin clearance.
    • 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.
    • Chloroquine, sulfadoxine-pyrimethamine and amodiaquine efficacy for the treatment of uncomplicated Plasmodium falciparum malaria in Upper Nile, south Sudan.

      van den Broek, I; Gatkoi, T; Lowoko, B; Nzila, A; Ochong, E; Keus, K; Médecins sans Frontières-Holland, South Sudan-Section, P. O. Box 4064, Nairobi, Kenya. ingrid_vandenbroek@yahoo.com (Elsevier, 2008-01-31)
      The current first-line and second-line drugs for Plasmodium falciparum malaria in South Sudan, chloroquine and sulfadoxine-pyrimethamine (SP), were evaluated and compared with amodiaquine, in an MSF-Holland-run clinic in eastern Upper Nile, South Sudan from June to December 2001. Patients with uncomplicated malaria and fever were stratified by age group and randomly allocated to one of 3 treatment regimes. A total of 342 patients was admitted and followed for 14 d after treatment. The dropout rate was 10.2%. Of those who completed the study, 104 were treated with chloroquine (25 mg/kg, 3 d), 102 with SP (25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine, single dose) and 101 with amodiaquine (25 mg/kg, 3 d). Adequate clinical response was observed in 88.5% of patients treated with chloroquine, 100% of patients treated with SP and 94.1% of patients treated with amodiaquine. In children aged < 5 years, the success rate was lower: 83.3% for chloroquine and 93.0% for amodiaquine. In adults no treatment failures were found, but children aged 5-15 years showed intermediate levels. In addition, we determined the initial genotypes of dhfr and dhps of 44 isolates from the SP-treated group and > 80% were found to be wild type for dhfr and 100% for dhps. Two percent of isolates had a single mutation and 16% had double mutations of dhfr. These data are in full agreement with the clinical effectiveness of SP. A change in malaria treatment protocols for South Sudan is recommended.
    • Comparison of chloroquine, sulfadoxine/pyrimethamine, mefloquine and mefloquine-artesunate for the treatment of falciparum malaria in Kachin State, North Myanmar.

      Smithuis, F; Shahmanesh, M; Kyaw, M K K; Savran, O; Lwin, S; White, N J; Medecins sans Frontieres-Holland, Yangon, Myanmar. (Wiley-Blackwell, 2004-11)
      Multi-drug resistant falciparum malaria is widespread in Asia. In Thailand, Cambodia and Vietnam the national protocols have changed largely to artesunate combined treatment regimens but elsewhere in East and South Asia chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) are still widely recommended by national malaria control programmes. In Kachin State, northern Myanmar, an area of low seasonal malaria transmission, the efficacy of CQ (25 mg base/kg) and SP (1.25/25 mg/kg), the nationally recommended treatments at the time, were compared with mefloquine alone (M; 15 mg base/kg) and mefloquine combined with artesunate (MA; 15:4 mg/kg). An open randomized controlled trial enrolled 316 patients with uncomplicated Plasmodium falciparum malaria, stratified prospectively into three age-groups. Early treatment failures (ETF) occurred in 41% (32/78) of CQ treated patients and in 24% of patients treated with SP (18/75). In young children the ETF rates were 87% after CQ and 35% after SP. Four children (two CQ, two SP) developed symptoms of cerebral malaria within 3 days after treatment. By day 42, failure rates (uncorrected for reinfections) had increased to 79% for CQ and 81% for SP. ETF rates were 2.5% after treatment with M and 3.9% after treatment with MA (P > 0.2). Overall uncorrected treatment failure rates at day 42 following M and MA were 23% and 21%, respectively. Chloroquine and SP are completely ineffective for the treatment of falciparum malaria in northern Myanmar. Mefloquine treatment is much more effective, but three day combination regimens with artesunate will be needed for optimum efficacy and protection against resistance.
    • Drug resistance in Plasmodium falciparum from the Chittagong Hill Tracts, Bangladesh.

      van den Broek, I; van der Wardt, S; Talukder, L; Chakma, S; Brockman, A; Nair, S; Anderson, T C; Médecins sans Frontières-Holland, Gulshan, Dhaka, Bangladesh. ingrid.van.den.braek@london.msf.org (Wiley-Blackwell, 2004-06)
      OBJECTIVE: To assess the efficacy of antimalarial treatment and molecular markers of Plasmodium falciparum resistance in the Chittagong Hill Tracts of Bangladesh. METHODS: A total of 203 patients infected with P. falciparum were treated with quinine 3 days plus sulphadoxine/pyrimethamine (SP) combination therapy, and followed up during a 4-week period. Blood samples collected before treatment were genotyped for parasite mutations related to chloroquine (pfcrt and pfmdr1 genes) or SP resistance (dhfr and dhps). RESULTS: Of 186 patients who completed follow-up, 32 patients (17.2%) failed to clear parasitaemia or became positive again within 28 days after treatment. Recurring parasitaemia was related to age (chi(2) = 4.8, P < 0.05) and parasite rates on admission (t = 3.1, P < 0.01). PCR analysis showed that some of these cases were novel infections. The adjusted recrudescence rate was 12.9% (95% CI 8.1-17.7) overall, and 16.6% (95% CI 3.5-29.7), 15.5% (95% CI 8.3-22.7) and 6.9% (95% CI 0.4-13.4) in three age groups (<5 years, 5-14, > or =15). The majority of infections carried mutations associated with chloroquine resistance: 94% at pfcrt and 70% at pfmdr. Sp-resistant genotypes were also frequent: 99% and 73% of parasites carried two or more mutations at dhfr and dhps, respectively. The frequency of alleles at dhfr, dhps and pfmdr was similar in cases that were successfully treated and those that recrudesced. CONCLUSIONS: The clinical trial showed that quinine 3-days combined to SP is still relatively effective in the Chittagong Hill Tracts. However, if this regimen is continued to be widely used, further development of SP resistance and reduced quinine sensitivity are to be expected. The genotyping results suggest that neither chloroquine nor SP can be considered a reliable treatment for P. falciparum malaria any longer in this area of Bangladesh.
    • 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.
    • Evaluation of Three Rapid Tests for Diagnosis of P. Falciparum and P. Vivax Malaria in Colombia.

      van den Broek, I; Hill, O; Gordillo, F; Angarita, B; Hamade, P; Counihan, H; Guthmann, J P; Médecins sans Frontières (MSF), London, UK. ingrid_vandenbroek@yahoo.com (2006-12)
      The diagnostic capacity of three malaria rapid diagnostic tests (RDTs), NOW-Malaria-ICT, OptiMAL-IT, and Paracheck-Pf, was evaluated against expert microscopy in Colombia. We tested 896 patients, of whom microscopy confirmed 139 P. falciparum, 279 P. vivax, and 13 mixed P.f/P.v infections and 465 negatives. Paracheck-Pf and NOW-malaria-ICT were more accurate in detecting P. falciparum (sensitivities 90.8% and 90.1%, respectively) in comparison with Optimal-IT (83.6%). NOW showed an acceptable Pf detection rate at low densities (< 500/microL), but resulted in a higher proportion of false positives. For P. vivax diagnosis, Optimal-IT had a higher sensitivity than NOW (91.0% and 81.4%, respectively). The choice between the two Pf/Pv detecting RDTs balances P. falciparum and P. vivax detection rates. Considering some degree of P. falciparum overtreatment and failure to detect all P. vivax cases as more acceptable than missing some cases of P. falciparum, we recommend careful implementation of NOW-malaria-ICT in areas where microscopy is lacking. The price is however still a constraint.
    • Identifying malaria control issues: a district hospital-based evaluation.

      Kimerling, M; Houth, H; Hilderbrand, K; Goubert, L; MSF Holland-Belgium, Phnom Penh, Cambodia. (1995-12)
      Chuk district hospital is centrally located in a rural malarious region in southern Cambodia. It was the site of a hospital-based evaluation (KAP assessment and in vivo i.v. quinine/oral tetracycline drug study) done to identify relevant issues for establishing a rational malaria control strategy. The KAP assessment identified the young, male forest worker as the highest risk group. Of 112 study patients, 73% were male and 82% reported various forest activities. The primary reason found for patient delay (8.9 days) in seeking hospital care was self-treatment at home (N = 102, 91%) with drugs purchased through private sellers (104/105). Using the 7-day WHO field test methodology, resistance rates were calculated (N = 22); S1/R1, 73%; R1, 9%; R2, 0%; R3, 18%. A modified version of the 7-day test was used to calculate its utility in this particular rural setting. It showed a negative predictive value of 93% and a positive predictive value of 71%. The case fatality rate for the study period was 2.7%. Information from this study, which correlates a confirmed malaria diagnosis with prior patient behavior and response to anti-malarial therapy, is intended for realizing the goals set forth by the national malaria control program.
    • Improving the Specificity of Plasmodium falciparum Malaria Diagnosis in High-Transmission Settings with a Two-Step Rapid Diagnostic Test and Microscopy Algorithm

      Murungi, M; Fulton, T; Reyes, R; Matte, M; Ntaro, M; Mulogo, E; Nyehangane, D; Juliano, J; Siedner, M; Boum, Y; Boyce, R (American Society for Microbiology, 2017-05)
      Poor specificity may negatively impact rapid diagnostic test (RDT)-based diagnostic strategies for malaria. We performed real-time PCR on a subset of subjects who had undergone diagnostic testing with a multiple-antigen (histidine-rich protein 2 and pan-lactate dehydrogenase pLDH [HRP2/pLDH]) RDT and microscopy. We determined the sensitivity and specificity of the RDT in comparison to results of PCR for the detection of Plasmodium falciparum malaria. We developed and evaluated a two-step algorithm utilizing the multiple-antigen RDT to screen patients, followed by confirmatory microscopy for those individuals with HRP2-positive (HRP2+)/pLDH-negative (pLDH-) results. In total, dried blood spots (DBS) were collected from 276 individuals. There were 124 (44.9%) individuals with an HRP2+/pLDH+ result, 94 (34.1%) with an HRP2+/pLDH- result, and 58 (21%) with a negative RDT result. The sensitivity and specificity of the RDT compared to results with real-time PCR were 99.4% (95% confidence interval [CI], 95.9 to 100.0%) and 46.7% (95% CI, 37.7 to 55.9%), respectively. Of the 94 HRP2+/pLDH- results, only 32 (34.0%) and 35 (37.2%) were positive by microscopy and PCR, respectively. The sensitivity and specificity of the two-step algorithm compared to results with real-time PCR were 95.5% (95% CI, 90.5 to 98.0%) and 91.0% (95% CI, 84.1 to 95.2), respectively. HRP2 antigen bands demonstrated poor specificity for the diagnosis of malaria compared to that of real-time PCR in a high-transmission setting. The most likely explanation for this finding is the persistence of HRP2 antigenemia following treatment of an acute infection. The two-step diagnostic algorithm utilizing microscopy as a confirmatory test for indeterminate HRP2+/pLDH- results showed significantly improved specificity with little loss of sensitivity in a high-transmission setting.
    • 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.
    • Influence of rapid malaria diagnostic tests on treatment and health outcome in fever patients, Zanzibar: a crossover validation study

      Msellem, Mwinyi I; Mårtensson, Andreas; Rotllant, Guida; Bhattarai, Achuyt; Strömberg, Johan; Kahigwa, Elizeus; Garcia, Montse; Petzold, Max; Olumese, Peter; Ali, Abdullah; Björkman, Anders; Malaria Control Programme, Ministry of Health and Social Welfare, Zanzibar, Tanzania; Infectious Diseases Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Division of International Health, Department of Public Health Sciences, Karolinska Institutet, Stockholm; Medecins Sans Frontieres, Dar es Salaam, Tanzania; World Health Organization (WHO) Country Office, Dar es Salaam, Tanzania; Nordic School of Public Health, Gothenburg, Sweden; Global Malaria Programme, WHO, Geneva, Switzerland (2009-04-28)
      BACKGROUND: The use of rapid diagnostic tests (RDTs) for Plasmodium falciparum malaria is being suggested to improve diagnostic efficiency in peripheral health care settings in Africa. Such improved diagnostics are critical to minimize overuse and thereby delay development of resistance to artemisinin-based combination therapies (ACTs). Our objective was to study the influence of RDT-aided malaria diagnosis on drug prescriptions, health outcomes, and costs in primary health care settings. METHODS AND FINDINGS: We conducted a cross-over validation clinical trial in four primary health care units in Zanzibar. Patients of all ages with reported fever in the previous 48 hours were eligible and allocated alternate weeks to RDT-aided malaria diagnosis or symptom-based clinical diagnosis (CD) alone. Follow-up was 14 days. ACT was to be prescribed to patients diagnosed with malaria in both groups. Statistical analyses with multilevel modelling were performed. A total of 1,887 patients were enrolled February through August 2005. RDT was associated with lower prescription rates of antimalarial treatment than CD alone, 361/1005 (36%) compared with 752/882 (85%) (odds ratio [OR] 0.04, 95% confidence interval [CI] 0.03-0.05, p<0.001). Prescriptions of antibiotics were higher after RDT than CD alone, i.e., 372/1005 (37%) and 235/882 (27%) (OR 1.8, 95%CI 1.5-2.2, p<0.001), respectively. Reattendance due to perceived unsuccessful clinical cure was lower after RDT 25/1005 (2.5%), than CD alone 43/882 (4.9%) (OR 0.5, 95% CI 0.3-0.9, p = 0.005). Total average cost per patient was similar: USD 2.47 and 2.37 after RDT and CD alone, respectively. CONCLUSIONS: RDTs resulted in improved adequate treatment and health outcomes without increased cost per patient. RDTs may represent a tool for improved management of patients with fever in peripheral health care settings. TRIAL REGISTRATION: (Clinicaltrials.gov) NCT00549003.
    • Malaria in camps for internally-displaced persons in Uganda: evaluation of an insecticide-treated bednet distribution programme.

      Spencer, S; Grant, A D; Piola, P; Tukpo, K; Okia, M; Garcia, M; Salignon, P; Genevier, C; Kiguli, J; Guthmann, J P; Médecins Sans Frontières, 4 rue Saint Sabin, 75011 Paris, France. (ElsevierWiley-Blackwell, 2004-12)
      Malaria is a key health problem among displaced populations in malaria-endemic areas. Mass distribution of insecticide-treated bednets (ITN) to prevent malaria is often carried out in complex emergencies, but there are few data on the outcome or operational effectiveness of such programmes. In June 2001, Medecins Sans Frontieres completed a mass distribution of ITNs (Permanet) to internally displaced persons in Bundibugyo, southwest Uganda, distributing one to four nets per household, and aiming to provide coverage for all residents. In July 2002, we did a cross-sectional survey using three-stage cluster sampling to evaluate the programme. A total of 1245 individuals from 835 households were interviewed. An ITN was present in 75.6% (95% CI 72.7-78.5) of the households, but only 56.5% (95% CI 52.3-60.4) of individuals were sleeping under an ITN, and nets were often damaged. The prevalence of malarial parasitaemia was 11.2% (95% CI 9.4-13.0), and was significantly lower in ITN users compared to non-users (9.2% vs. 13.8%, relative risk [RR] 0.63, 95% CI 0.46-0.87); ITNs with severe damage remained effective (RR for severely damaged net 0.58, 95% CI 0.35-0.98). There was no significant difference in haemoglobin concentration between ITN users and non-users.
    • Malaria, malnutrition and MSF. Médecins Sans Frontières.

      Evans, D; Médecins Sans Frontières, Glebe, NSW. office@sydney.msf.org (Medical Society of Australia, 2008-02-21)
      This is a personal account of my brief time in Burundi as a volunteer doctor with Médecins Sans Frontières (MSF) at the beginning of 2001. Burundi is a small nation in central Africa (bounded by the Democratic Republic of Congo, Rwanda and Tanzania) which has suffered from problems between the Hutu and Tutsi "ethnic groups", similar to those for which Rwanda is better known. Unlike Rwanda, the war between government troops and rebel forces continues in Burundi. MSF has been in Burundi since 1992, providing basic healthcare, nutrition programs, surgical services and epidemiological intervention. In late 2000, a malaria epidemic began in Burundi's highland regions where transmission is normally low, and thus the population largely not immune. Malnutrition rates also increased and MSF rapidly expanded its usual program in an attempt to control these new health problems.
    • Plasmodium falciparum: sensitivity in vivo to chloroquine, pyrimethamine/sulfadoxine and mefloquine in western Myanmar.

      Smithuis, F; Monti, F; Grundl, M; Oo, A Z; Kyaw, T T; Phe, O; White, N J; Artsen Zonder Grenzen, Médecins Sans Frontières-Holland, Yangon, Myanmar, Thailand. (Elsevier, 2008-02-07)
      In Rakhine State, on the western border of Myanmar, the efficacy of chloroquine (CQ) and pyrimethamine/ sulfadoxine (PS), the current treatments for uncomplicated Plasmodium falciparum malaria in this area, was evaluated in an open comparative study of 289 patients, stratified prospectively into 3 age groups. Chloroquine treatment was associated with more rapid clinical recovery (P = 0.03), but the overall cure rates were worse than for PS treatment; failure to clear parasitaemia or recrudescence within 14 d occurred in 72% (102/141) of cases treated with CQ compared to 47% (69/148) of those who received PS (P < 0.0001, adjusted for age). Failure rates at day 28 increased to 82% (116/141) in the CQ group and 67% (99/148) in the PS group (P = 0.003). The risk of treatment failure was significantly higher in children under 15 years old than in adults for both CQ (relative risk [RR] = 2.6; 95% confidence interval [95% CI] 1.3-5.2) and PS (RR = 2.2; 95% CI 1.4-3.3). Mefloquine (15 mg base/kg) proved to be highly effective as a treatment for CQ and PS resistant P. falciparum; only 2 of 75 patients (3%) had early treatment failures (< or = day 7), and the overall failure rate by day 42 was 7%. There is a very high level of chloroquine and PS resistance in P.falciparum on the western border of Myanmar, but mefloquine was effective in the area.
    • A randomized open study to assess the efficacy and tolerability of dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Cambodia.

      Janssens, B; Van Herp, M; Goubert, L; Chan, S; Uong, S; Nong, S; Socheat, D; Brockman, A; Ashley, E A; Van Damme, W; Médecins Sans Frontières, Phnom Penh, Cambodia. b.janssens@bigfoot.com (Wiley-Blackwell, 2007-02)
      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.
    • Ranking malaria risk factors to guide malaria control efforts in African highlands

      Protopopoff, Natacha; Van Bortel, Wim; Speybroeck, Niko; Van Geertruyden, Jean-Pierre; Baza, Dismas; D'Alessandro, Umberto; Coosemans, Marc; Department of Parasitology, Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium; Medecins Sans Frontieres Brussels, Belgium; Department of Animal Health, Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium; School of Public Health, Universite Catholique de Louvain, Brussels, Belgium; Programme de Lutte contre les Maladies Transmissibles et Carentielles, Ministry of Health, Bujumbura, Burundi; Department of Biomedical Sciences, Faculty of Pharmaceutical, Veterinary and Biomedical Sciences, University of Antwerp, Antwerp, Belgium (2009-11-25)
      INTRODUCTION: Malaria is re-emerging in most of the African highlands exposing the non immune population to deadly epidemics. A better understanding of the factors impacting transmission in the highlands is crucial to improve well targeted malaria control strategies. METHODS AND FINDINGS: A conceptual model of potential malaria risk factors in the highlands was built based on the available literature. Furthermore, the relative importance of these factors on malaria can be estimated through "classification and regression trees", an unexploited statistical method in the malaria field. This CART method was used to analyse the malaria risk factors in the Burundi highlands. The results showed that Anopheles density was the best predictor for high malaria prevalence. Then lower rainfall, no vector control, higher minimum temperature and houses near breeding sites were associated by order of importance to higher Anopheles density. CONCLUSIONS: In Burundi highlands monitoring Anopheles densities when rainfall is low may be able to predict epidemics. The conceptual model combined with the CART analysis is a decision support tool that could provide an important contribution toward the prevention and control of malaria by identifying major risk factors.
    • Rapid malaria diagnostic tests vs. clinical management of malaria in rural Burkina Faso: safety and effect on clinical decisions. A randomized trial

      Bisoffi, Zeno; Sirima, Bienvenu Sodiomon; Angheben, Andrea; Lodesani, Claudia; Gobbi, Federico; Tinto, Halidou; Van den Ende, Jef; Centre for Tropical Diseases, Sacro Cuore Hospital, Negrar (Verona), Italy; Centre National de Recherche et de Formation sur le Paludisme, Ministry of Health, Ouagadougou, Burkina Faso; Medecins sans Frontieres, Democratic Republic of Congo; Centre Muraz, Bobo Dioulasso, Burkina Faso; Projet AnKaHeresso, Bobo Dioulasso, Burkina Faso; Department of Clinical Sciences, Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium (2009-02-15)
      OBJECTIVES: To assess if the clinical outcome of patients treated after performing a Rapid Diagnostic Test for malaria (RDT) is at least equivalent to that of controls (treated presumptively without test) and to determine the impact of the introduction of a malaria RDT on clinical decisions. METHODS: Randomized, multi-centre, open clinical trial in two arms in 2006 at the end of the dry and of the rainy season in 10 peripheral health centres in Burkina Faso: one arm with use of RDT before treatment decision, one arm managed clinically. Primary endpoint: persistence of fever at day 4. Secondary endpoints: frequency of malaria treatment and of antibiotic treatment. RESULTS: A total of 852 febrile patients were recruited in the dry season and 1317 febrile patients in the rainy season, and randomized either to be submitted to RDT (P_RTD) or to be managed presumptively (P_CLIN). In both seasons, no significant difference was found between the two randomized groups in the frequency of antimalarial treatment, nor of antibiotic prescription. In the dry season, 80.8% and 79.8% of patients with a negative RDT were nevertheless diagnosed and treated for malaria, and so were 85.0% and 82.6% negative patients in the rainy season. In the rainy season only, both diagnosis and treatment of other conditions were significantly less frequent in RDT positive vs. negative patients (48.3% vs. 61.4% and 46.2% vs. 59.9%, P = 0.00 and 0.00, respectively). CONCLUSION: Our study was inconclusive on RDT safety (clinical outcome in the two randomized groups), because of an exceedingly and unexpectedly low compliance with the negative test result. Further research is needed on best strategies to promote adherence and on the safety of a test based strategy compared with the current, presumptive treatment strategy.
    • Relapses of Plasmodium vivax infection usually result from activation of heterologous hypnozoites.

      Imwong, M; Snounou, G; Pukrittayakamee, S; Tanomsing, N; Kim, J R; Nandy, A; Guthmann, J P; Nosten, F; Carlton, J; Looareesuwan, S; Nair, S; Sudimack, D; Day, N P J; Anderson, T J C; White, N J; Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. (Infectious Diseases Society of America and University of Chicago Press, 2007-04-01)
      BACKGROUND: Relapses originating from hypnozoites are characteristic of Plasmodium vivax infections. Thus, reappearance of parasitemia after treatment can result from relapse, recrudescence, or reinfection. It has been assumed that parasites causing relapse would be a subset of the parasites that caused the primary infection. METHODS: Paired samples were collected before initiation of antimalarial treatment and at recurrence of parasitemia from 149 patients with vivax malaria in Thailand (n=36), where reinfection could be excluded, and during field studies in Myanmar (n=75) and India (n=38). RESULTS: Combined genetic data from 2 genotyping approaches showed that novel P. vivax populations were present in the majority of patients with recurrent infection (107 [72%] of 149 patients overall [78% of patients in Thailand, 75% of patients in Myanmar {Burma}, and 63% of patients in India]). In 61% of the Thai and Burmese patients and in 55% of the Indian patients, the recurrent infections contained none of the parasite genotypes that caused the acute infection. CONCLUSIONS: The P. vivax populations emerging from hypnozoites commonly differ from the populations that caused the acute episode. Activation of heterologous hypnozoite populations is the most common cause of first relapse in patients with vivax malaria.