• In vivo assessment of drug efficacy against Plasmodium falciparum malaria: duration of follow-up.

      Stepniewska, K; Taylor, W R J; Mayxay, M; Price, R; Smithuis, F; Guthmann, J P; Barnes, K; Myint, H Y; Adjuik, M; Olliaro, P; et al. (2004-11)
      To determine the optimum duration of follow-up for the assessment of drug efficacy against Plasmodium falciparum malaria, 96 trial arms from randomized controlled trials (RCTs) with follow-up of 28 days or longer that were conducted between 1990 and 2003 were analyzed. These trials enrolled 13,772 patients, and participating patients comprised 23% of all patients enrolled in RCTs over the past 40 years; 61 (64%) trial arms were conducted in areas where the rate of malaria transmission was low, and 58 (50%) trial arms were supported by parasite genotyping to distinguish true recrudescences from reinfections. The median overall failure rate reported was 10% (range, 0 to 47%). The widely used day 14 assessment had a sensitivity of between 0 and 37% in identifying treatment failures and had no predictive value. Assessment at day 28 had a sensitivity of 66% overall (28 to 100% in individual trials) but could be used to predict the true failure rate if either parasite genotyping was performed (r(2) = 0.94) or if the entomological inoculation rate was known. In the assessment of drug efficacy against falciparum malaria, 28 days should be the minimum period of follow-up.
    • In Vivo Efficacy of Artesunate-Amodiaquine and Artemether-Lumefantrine for the Treatment of Uncomplicated Falciparum Malaria: an Open-Randomized, Non-Inferiority Clinical Trial in South Kivu, Democratic Republic of Congo

      de Wit, M; Funk, AL; Moussally, K; Nkuba, DA; Siddiqui, R; Bil, K; Piriou, E; Bart, A; Bahizi Bizoza, P; Bousema, T (BioMed Central (Springer Science), 2016)
      Between 2009 and 2012, malaria cases diagnosed in a Médecins sans Frontières programme have increased fivefold in Baraka, South Kivu, Democratic Republic of the Congo (DRC). The cause of this increase is not known. An in vivo drug efficacy trial was conducted to determine whether increased treatment failure rates may have contributed to the apparent increase in malaria diagnoses.
    • 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; et al. (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.
    • Independent Origin of Plasmodium falciparum Antifolate Super-Resistance, Uganda, Tanzania, and Ethiopia.

      Alifrangis, Michael; Nag, Sidsel; Schousboe, Mette L; Ishengoma, Deus; Lusingu, John; Pota, Hirva; Kavishe, Reginald A; Pearce, Richard; Ord, Rosalynn; Lynch, Caroline; et al. (2014-08)
      Super-resistant Plasmodium falciparum threatens the effectiveness of sulfadoxine-pyrimethamine in intermittent preventive treatment for malaria during pregnancy. It is characterized by the A581G Pfdhps mutation on a background of the double-mutant Pfdhps and the triple-mutant Pfdhfr. Using samples collected during 2004-2008, we investigated the evolutionary origin of the A581G mutation by characterizing microsatellite diversity flanking Pfdhps triple-mutant (437G+540E+581G) alleles from 3 locations in eastern Africa and comparing it with double-mutant (437G+540E) alleles from the same area. In Ethiopia, both alleles derived from 1 lineage that was distinct from those in Uganda and Tanzania. Uganda and Tanzania triple mutants derived from the previously characterized southeastern Africa double-mutant lineage. The A581G mutation has occurred multiple times on local Pfdhps double-mutant backgrounds; however, a novel microsatellite allele incorporated into the Tanzania lineage since 2004 illustrates the local expansion of emergent triple-mutant lineages.
    • 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; et al. (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.
    • Intermittent Preventive Treatment for Malaria Among Children in a Refugee Camp in Northern Uganda: Lessons Learned

      Coldiron, M; Lasry, E; Bouhenia, M; Das, D; Okui, P; Nyehangane, D; Mwanga, J; Langendorf, C; Elder, G; Salumu, L; et al. (BioMed Central, 2017-05-23)
      Northern Uganda hosts a large population of refugees from South Sudan, and malaria is one of the major health problems in the area. In 2015, intermittent preventive treatment for malaria (IPTc) was implemented in two refugee camps among children aged 6 months to 14 years. Three distributions of dihydroartemisinin-piperaquine (DP) were conducted at 8-week intervals. The first dose was directly administered at IPTc distribution sites and the second and third doses were given to caregivers to administer at home. A multi-faceted evaluation was implemented, including coverage surveys, malaria prevalence surveys, reinforced surveillance, and pharmacovigilance. Programme coverage exceeded 90% during all three distributions with a total of 40,611 participants. Compared to same period during the previous year (only available data), the incidence of malaria in the target populations was reduced (IRR 0.73, 95% CI 0.69-0.77 among children under 5 years old; IRR 0.70, 95% CI 0.67-0.72 among children aged 5-14 years). Among those not targeted for intervention, the incidence between the 2 years increased (IRR 1.49, 95% CI 1.42-1.56). Cross-sectional surveys showed a prevalence of parasitaemia (microscopy or PCR) of 12.9-16.4% (95% CI 12.6-19.3) during the intervention, with the highest prevalence among children aged 5-14 years, but with a large increase 8 weeks after the final distribution. A total of 57 adverse events were reported during the intervention period, including one severe adverse event (death from varicella). Adverse events were of mild to moderate severity, and were mainly dermatologic and gastrointestinal. This is the first documentation of an IPTc programme in a refugee camp. The positive impact of DP on the incidence of malaria, together with its favourable safety profile, should lead to further use of IPTc in similar settings. Expanding coverage groups and decreasing intervals between distributions might provide more benefit, but would need to be balanced with the operational implications of a broader, more frequent distribution schedule.
    • Internal quality control of the malaria microscopy diagnosis for 10 laboratories on the Thai-Myanmar border.

      Hemme, F; Gay, F; Medecins Sans Frontières, French Section, Mae Sot, Thailand. (1998-09)
      On the Thai-Myanmar border, where multidrug resistance to anti-malaria medications is a major problem, a quality control program for diagnostic laboratories has been set up. This study examines the "passive" screening performed in 10 laboratories. Monthly evaluation of the quality of thick and thin smear practice, Giemsa staining and microscopy took place during the year 1994. Considering the general context and the methodology applied, the evaluation of performance and strategy of the malaria diagnostic test showed satisfactory results for all 10 laboratories. Performance of technics = 64% (62-66) to 96% (95-97); Sensitivity = 92.6 (91.5-95.5) to 96.6% (95.8-99.0); Specificity = 93.5% (91.4-95.5) to 98.3% (97.6-99.0); Predictive Positive Value = 92.0% (90.9-93.1) to 98.3% (97.6-99.0); Predictive Negative Value = 94.3% (93.0-95.6) to 98.5% (98.0-99.0). The study underlines the importance of a reliable quality control method for microscopy diagnosis of malaria in hyperendemic areas, with Plasmodium falciparum as the main species. A high level of input from the international laboratory technician, performing training, follow-up and evaluation was required. The need for adequate training of national technicians and supervisors, especially regarding long-term sustainability, is stressed. The type of program presented can be used as a model for similar projects in developing countries.
    • Last line of defence

      de Smet, M (2009-06-20)
    • Local Constraints to Access Appropriate Malaria Treatment in the Context of Parasite Resistance in Cambodia: a Qualitative Study

      Verschuere, J; Decroo, T; Lim, D; Kindermans, JM; Nguon, C; Huy, R; Alkourdi, Y; Peeters Grietens, K; Gryseels, C (BioMed Central, 2017-02-17)
      Despite emerging drug resistance in Cambodia, artemisinin-based combination therapy (ACT) is still the most efficacious therapy. ACT is available free of charge in the Cambodian public sector and at a subsidized rate in the private sector. However, un- and mistreated cases in combination with population movements may lead to the further spread of resistant parasites, stressing the importance of understanding how the perceived aetiology of malaria and associated health-seeking behaviour may delay access to appropriate treatment. A qualitative study explored these factors after an epidemiological survey confirmed parasite resistance in Preah Vihear province.
    • Long-lasting insecticide-treated net usage in eastern Sierra Leone - the success of free distribution.

      Gerstl, Sibylle; Dunkley, Sophie; Mukhtar, Ahmed; Maes, Peter; De Smet, Martin; Baker, Samuel; Maikere, Jacob; Médecins Sans Frontières-United Kingdom, London, UK. (2010-02-09)
      Summary Objective Médecins Sans Frontières (MSF) runs a malaria control project in Bo and Pujehun districts (population 158 000) that includes the mass distribution, routine delivery and demonstration of correct use of free, long-lasting insecticide-treated nets (LLINs). In 2006/2007, around 65 000 LLINs were distributed. The aim of this follow-up study was to measure LLIN usage and ownership in the project area. Methods Heads of 900 randomly selected households in 30 clusters were interviewed, using a standardized questionnaire, about household use of LLINs. The condition of any LLIN was physically assessed. Results Of the 900 households reported, 83.4% owning at least one LLIN. Of the 16.6% without an LLIN, 91.9% had not participated in the MSF mass distribution. In 94.1% of the households reporting LLINs, the nets were observed hanging correctly over the beds. Of the 1135 hanging LLINs, 75.2% had no holes or 10 or fewer finger-size holes. The most common source of LLINs was MSF (75.2%). Of the 4997 household members, 67.2% reported sleeping under an LLIN the night before the study, including 76.8% of children under 5 years and 73.0% of pregnant women. Conclusion Our results show that MSF achieved good usage with freely distributed LLINs. It is one of the few areas where results almost achieve the new targets set in 2005 by Roll Back Malaria to have at least 80% of pregnant women and children under 5 years using LLINs by 2010.
    • Low efficacy of the combination artesunate plus amodiaquine for uncomplicated falciparum malaria among children under 5 years in Kailahun, Sierra Leone.

      Grandesso, F; Hagerman, A; Kamara, S; Lam, E; Checchi, F; Balkan, S; Scollo, G; Durand, R; Guthmann, J P; Epicentre, Paris, France. (Wiley-Blackwell, 2006-07)
      OBJECTIVE: In 2004, Sierra Leone adopted artesunate plus amodiaquine as first-line antimalarial treatment. We evaluated the efficacy of this combination in Kailahun, where a previous study had shown 70.2% efficacy of amodiaquine in monotherapy. METHODS: Method and outcome classification of the study complied with WHO guidelines. Children 6-59 months with uncomplicated malaria were followed-up for 28 days. PCR genotyping was used to distinguish recrudescence from reinfection. Reinfections were reclassified as cured. RESULTS: Of 172 children who were referred to the study clinic, 126 satisfied inclusion criteria and were enrolled. No early treatment failures were reported. The day 14, efficacy was 98.2% (95% CI: 93.8-99.8). Of 65 recurrent parasitaemias analysed by PCR, 17 were recrudescences. The PCR-adjusted day 28 efficacy was 84.5% (95% CI: 76.4-90.7). All true failures occurred in the last 8 days of follow-up. Of 110 children who completed the 28-day follow-up, 54 (49.1%) experienced a novel infection. CONCLUSION: The efficacy of this combination was disappointing. The high reinfection rate suggested little prophylactic effect. In Kailahun a more efficacious combination might be necessary in the future. The efficacy of AS + AQ needs to be monitored in Kailahun and in the other regions of Sierra Leone.
    • Low referral completion of rapid diagnostic test-negative patients in community-based treatment of malaria in Sierra Leone.

      Thomson, Anna; Khogali, Mohammed; de Smet, Martin; Reid, Tony; Mukhtar, Ahmed; Peterson, Stefan; von Schreeb, Johan; Division of Global Health, Karolinska Institutet, Stockholm, Sweden. anna.thomson@stockholm.msf.org. (2011-05)
    • Malaria in an Internally Displaced Persons Camp in the Democratic Republic of the Congo

      Brooks, H; Jean Paul, M; Claude, K; Houston, S; Hawkes, M (Oxford University Press, 2017-08-01)
    • 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; et al. (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 in pregnancy: a call for a safe, efficient, and patient-centred approach to first-trimester treatment.

      Rao, VB; Jensen, TO; Jimenez, BC; Robays, J; Lasry, E; Sterk, E; de Smet, M (Elsevier, 2018-06-06)
    • Malaria in the Nuba Mountains of Sudan: baseline genotypic resistance and efficacy of the artesunate plus sulfadoxine-pyrimethamine and artesunate plus amodiaquine combinations.

      Hamour, S; Melaku, Y; Keus, K; Wambugu, J; Atkin, S; Montgomery, J; Ford, N; Hook, C; Checchi, F; Médecins Sans Frontières, Plantage Middenlaan 14, 1018 DD Amsterdam, The Netherlands. (Elsevier, 2005-07)
      Both northern and southern Sudan are deploying artemisinin-based combinations against uncomplicated Plasmodium falciparum malaria (artesunate+sulfadoxine-pyrimethamine [AS+SP] in the north, artesunate+amodiaquine [AS+AQ] in the south). In 2003, we tested the efficacy of 3 day AS+SP and AS+AQ regimens in vivo in the isolated, seasonally endemic Nuba Mountains region (the first study of AS combinations in southern Sudan). We also analysed pre-treatment blood samples for mutations at the P. falciparum chloroquine transporter (Pfcrt) gene (associated with CQ resistance), and at the dihydrofolate reductase (Dhfr) gene (associated with pyrimethamine resistance). Among 161 randomized children under 5 years, PCR-corrected cure rates after 28 days were 91.2% (52/57, 95% CI 80.7-97.1) for AS+SP and 92.7% (51/55, 95% CI 82.4-98.0) for AS+AQ, with equally rapid parasite and fever clearance. The Pfcrt K76T mutation occurred in 90.0% (144/160) of infections, suggesting CQ would work poorly in this region. Overall, 82.5% (132/160) carried mutations at Dhfr (N51I, C59R or S108N, but not I164L), but triple mutants (more predictive of in vivo SP failure) were rare (3.1%). CQ use should be rapidly discontinued in this region. SP resistance may propagate rapidly, and AS+AQ is likely to be a better long-term option, provided AQ use is limited to the combination.
    • Malaria is an uncommon cause of adult sepsis in south-western Uganda

      Auma, Mary A; Siedner, Mark J; Nyehangane, Dan; Nalusaji, Aisha; Nakaye, Martha; Mwanga-Amumpaire, Juliet; Muhindo, Rose; Wilson, L Anthony; Boum, Yap; Moore, Christopher C; et al. (BioMed Central, 2013-05-01)
      Malaria is often considered a cause of adult sepsis in malaria endemic areas. However, diagnostic limitations can make distinction between malaria and other infections challenging. Therefore, the objective of this study was to determine the relative contribution of malaria to adult sepsis in south-western Uganda.
    • Malaria PCR Detection in Cambodian Low-Transmission Settings: Dried Blood Spots Versus Venous Blood Samples

      Canier, Lydie; Khim, Nimol; Kim, Saorin; Eam, Rotha; Khean, Chanra; Loch, Kaknika; Ken, Malen; Pannus, Pieter; Bosman, Philippe; Stassijns, Jorgen; et al. (American Society of Tropical Medicine and Hygiene, 2015-01-05)
      In the context of malaria elimination, novel strategies for detecting very low malaria parasite densities in asymptomatic individuals are needed. One of the major limitations of the malaria parasite detection methods is the volume of blood samples being analyzed. The objective of the study was to compare the diagnostic accuracy of a malaria polymerase chain reaction assay, from dried blood spots (DBS, 5 μL) and different volumes of venous blood (50 μL, 200 μL, and 1 mL). The limit of detection of the polymerase chain reaction assay, using calibrated Plasmodium falciparum blood dilutions, showed that venous blood samples (50 μL, 200 μL, 1 mL) combined with Qiagen extraction methods gave a similar threshold of 100 parasites/mL, ∼100-fold lower than 5 μL DBS/Instagene method. On a set of 521 field samples, collected in two different transmission areas in northern Cambodia, no significant difference in the proportion of parasite carriers, regardless of the methods used was found. The 5 μL DBS method missed 27% of the samples detected by the 1 mL venous blood method, but most of the missed parasites carriers were infected by Plasmodium vivax (84%). The remaining missed P. falciparum parasite carriers (N = 3) were only detected in high-transmission areas.
    • Malaria surveillance among the displaced Karen population in Thailand April 1984 to February 1989, Mae Sot, Thailand.

      Decludt, B; Pecoul, B; Biberson, P; Lang, R; Imivithaya, S; Medecins sans Frontieres, Paris, France. (1991-12)
      Right from the arrival of the displaced Karen people in Thailand, Médecins sans Frontières (MSF) identified malaria as the top priority problem. A program of patient care based on the coupled laboratory/dispensary was set up in April 1984. Immediately a system of surveillance of morbidity and mortality from malaria was set up. This study consisted of analysing data gathered over a period of five years. During this time, the displaced population increased from 9,000 to 20,000. Analysis of the trends shows a hyperendemic situation with an annual incidence rate of 1,067 per thousand in 1984. This figure was 600 per thousand in 1988. 1,500 blood smears were checked each month and the positive predictive value of clinical suspicion was 45% on average. Plasmodium falciparum represented 80% of infections. The malaria case fatality ratio over the course of the last two years of surveillance was 0.3%. Five years observation show that the fight against malaria in this region can be based on the development of curative services and laboratories.
    • 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.