• 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; et al. (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.
    • Environmental risk factors for clinical malaria: a case-control study in the Grau region of Peru.

      Guthmann, J P; Hall, A J; Jaffar, S; Palacios, A; Lines, J; Llanos-Cuentas, A; Department of Infectious and Tropical Disease, Infectious Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, UK. jguthmann@epicentre.msf.org (2001)
      The role of environmental risk factors in clinical malaria has been studied mainly in Africa and Asia, few investigations have been carried out in Latin America. Field observations in northern coastal Peru, where the prevalence of malaria is high during the agricultural season, suggested that the risk of disease varied according to the characteristics of the house and the house environment. Environmental determinants of the risk of clinical malaria were therefore investigated through a case-control study: 323 clinical cases of malaria, recruited through community-based active case-finding, and 969 age-, sex- and village-matched controls were recruited into the study over a period of 12 months ending June 1997. Residual spraying of houses in the previous 6 months, living more than 100 m from a canal, a level of education equal to primary school or above and working in agriculture conferred significant protection from the risk of developing clinical malaria. The presence of spaces between the wall and roof in the subject's bedroom (eaves) and a house aged > 4 years statistically significantly increased the risk of disease. Based on these results we discuss possible control measures for malaria in this area of the country.
    • 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; et al. (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.
    • Falciparum Malaria and Climate Change in the Northwest Frontier Province of Pakistan.

      Bouma, M J; Dye, C; van der Kaay, H J; Medecins Sans Frontieres-Holland, Amsterdam, The Netherlands. (Published by: American Society of Tropical Medicine and Hygiene, 1996-08)
      Following a striking increase in the severity of autumnal outbreaks of Plasmodium falciparum during the last decade in the Northwest Frontier Province (NWFP) of Pakistan, the role of climatologic variables was investigated. A multivariate analysis showed that during the transmission season of P. falciparum, the amount of rainfall in September and October, the temperature in November and December, and the humidity in December were all correlated (r2 = 0.82) with two measures of P. falciparum, the falciparum rate (percent of slides examined positive for P. falciparum) since 1981 and the annual P. falciparum proportion (percent of all malaria infections diagnosed as P. falciparum) since 1978. Climatologic records since 1876 show an increase in mean November and December temperatures by 2 degrees C and 1.5 degrees C, respectively, and in October rainfall. Mean humidity in December has also been increasing since 1950. These climatologic changes in the area appear to have made conditions for transmission of P. falciparum more favorable, and may account for the increase in incidence observed in the NWFP in recent years.
    • Plasmodium vivax resistance to chloroquine in Dawei, southern Myanmar.

      Guthmann, J P; Pittet, A; Lesage, A; Imwong, M; Lindegardh, N; Min Lwin, M; Zaw, T; Annerberg, A; de Radiguès, X; Nosten, F; et al. (Wiley-Blackwell, 2008-01)
      OBJECTIVE: To assess the efficacy of chloroquine in the treatment of Plasmodium vivax malaria in in Dawei District, southern Myanmar. METHODS: Enrolled patients at Sonsinphya clinic >6 months of age were assessed clinically and parasitologically every week for 28 days. To differentiate new infections from recrudescence, we genotyped pre- and post-treatment parasitaemia. Blood chloroquine was measured to confirm resistant strains. RESULTS: Between December 2002 and April 2003, 2661 patients were screened, of whom 252 were included and 235 analysed. Thirty-four per cent (95% CI: 28.1-40.6) of patients had recurrent parasitaemia and were considered treatment failures. 59.4% of these recurrences were with a different parasite strain. Two (0.8%) patients with recurrences on day 14 had chloroquine concentrations above the threshold of 100 ng/ml and were considered infected with chloroquine resistant parasites. 21% of failures occurred during the first 3 weeks of follow-up: early recurrence and median levels of blood chloroquine comparable to those of controls suggested P. vivax resistance. CONCLUSIONS: Plasmodium vivax resistance to chloroquine seems to be emerging in Dawei, near the Thai-Burmese border. While chloroquine remains the first-line drug for P. vivax infections in this area of Myanmar, regular monitoring is needed to detect further development of parasite resistance.
    • 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; et al. (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.
    • 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; et al. (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.
    • Transmission of Plasmodium vivax in South-Western Uganda: Report of Three Cases in Pregnant Women

      Dhorda, Mehul; Nyehangane, Dan; Rénia, Laurent; Piola, Patrice; Guerin, Philippe J; Snounou, Georges; Epicentre, Mbarara, Uganda; Institut National de la Sante´ et de la Recherche Medicale,Paris, France; Universite´ Pierre et Marie Curie, Faculte´ de Me´decine Pitie´-Salpeˆ trie` re, Paris, France; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore; Epicentre, Paris, France; Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom (2011-05-13)
      Plasmodium vivax is considered to be rare in the predominantly Duffy negative populations of Sub-Saharan Africa, as this red blood cell surface antigen is essential for invasion by the parasite. However, despite only very few reports of molecularly confirmed P. vivax from tropical Africa, serological evidence indicated that 13% of the persons sampled in Congo had been exposed to P. vivax. We identified P. vivax by microscopy in 8 smears from Ugandan pregnant women who had been enrolled in a longitudinal study of malaria in pregnancy. A nested polymerase chain reaction (PCR) protocol was used to detect and identify the Plasmodium parasites present. PCR analysis confirmed the presence of P. vivax for three of the women and analysis of all available samples from these women revealed clinically silent chronic low-grade vivax infections for two of them. The parasites in one woman carried pyrimethamine resistance-associated double non-synonymous mutations in the P. vivax dihydrofolate reductase gene. The three women found infected with P. vivax were Duffy positive as were nine of 68 women randomly selected from the cohort. The data presented from these three case reports is consistent with stable transmission of malaria in a predominantly Duffy negative African population. Given the substantial morbidity associated with vivax infection in non-African endemic areas, it will be important to investigate whether the distribution and prevalence of P. vivax have been underestimated in Sub-Saharan Africa. This is particularly important in the context of the drive to eliminate malaria and its morbidity.