• Polymorphisms in Plasmodium falciparum Chloroquine Resistance Transporter and Multidrug Resistance 1 Genes: Parasite Risk Factors that Affect Treatment Outcomes for P. falciparum Malaria after Artemether-Lumefantrine and Artesunate-Amodiaquine

      Venkatesan, Meera; Gadalla, Nahla B; Stepniewska, Kasia; Dahal, Prabin; Nsanzabana, Christian; Moriera, Clarissa; Price, Ric N; Mårtensson, Andreas; Rosenthal, Philip J; Dorsey, Grant; et al. (2014-07-21)
      Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001: were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.
    • Population Pharmacokinetics of Lumefantrine in Pregnant and Nonpregnant Women With Uncomplicated Plasmodium falciparum Malaria in Uganda

      Kloprogge, F; Piola, P; Dhorda, M; Muwanga, S; Turyakira, E; Apinan, S; Lindegårdh, N; Nosten, F; Day, N P J; White, N J; et al. (2013)
      Pregnancy alters the pharmacokinetic properties of many antimalarial compounds. The objective of this study was to evaluate the pharmacokinetic properties of lumefantrine in pregnant and nonpregnant women with uncomplicated Plasmodium falciparum malaria in Uganda after a standard fixed oral artemether-lumefantrine treatment. Dense venous (n = 26) and sparse capillary (n = 90) lumefantrine samples were drawn from pregnant patients. A total of 17 nonpregnant women contributed with dense venous lumefantrine samples. Lumefantrine pharmacokinetics was best described by a flexible absorption model with multiphasic disposition. Pregnancy and body temperature had a significant impact on the pharmacokinetic properties of lumefantrine. Simulations from the final model indicated 27% lower day 7 concentrations in pregnant women compared with nonpregnant women and a decreased median time of 0.92 and 0.42 days above previously defined critical concentration cutoff values (280 and 175 ng/ml, respectively). The standard artemether-lumefantrine dose regimen in P. falciparum malaria may need reevaluation in nonimmune pregnant women.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e83; doi:10.1038/psp.2013.59; advance online publication 13 November 2013.
    • Population Pharmacokinetics of Piperaquine after Two Different Treatment Regimens with Dihydroartemisinin-Piperaquine in Patients with Plasmodium falciparum Malaria in Thailand.

      Tarning, J; Ashley, E A; Lindegardh, N; Stepniewska, K; Phaiphun, L; Day, N P J; McGready, R; Ashton, M; Nosten, F; White, N J; et al. (American Society for Microbiology, 2008-03)
      The population pharmacokinetics of piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria treated with two different dosage regimens of dihydroartemisinin-piperaquine were characterized. Piperaquine pharmacokinetics in 98 Burmese and Karen patients aged 3 to 55 years were described by a two-compartment disposition model with first-order absorption and interindividual random variability on all parameters and were similar with the three- and four-dose regimens. Children had a lower body weight-normalized oral clearance than adults, resulting in longer terminal elimination half-lives and higher total exposure to piperaquine (area under the concentration-time curve from 0 to 63 days [AUC(day 0-63)]). However, children had lower plasma concentrations in the therapeutically relevant posttreatment prophylactic period (AUC(day 3-20)) because of smaller body weight-normalized central volumes of distribution and shorter distribution half-lives. Our data lend further support to a simplified once-daily treatment regimen to improve treatment adherence and efficacy and indicate that weight-adjusted piperaquine doses in children may need to be higher than in adults.
    • Predictors of the Quality of Health Worker Treatment Practices for Uncomplicated Malaria at Government Health Facilities in Kenya.

      Zurovac, D; Rowe, A K; Ochola, S A; Noor, A M; Midia, B; English, M; Snow, R W; Médecins Sans Frontières-France, P.O. Box 39719, Nairobi, Kenya. dzurovac@wtnairobi.mimcom.net (Published by Oxford University Press, 2004-10)
      BACKGROUND: When replacing failing drugs for malaria with more effective drugs, an important step towards reducing the malaria burden is that health workers (HW) prescribe drugs according to evidence-based guidelines. Past studies have shown that HW commonly do not follow guidelines, yet few studies have explored with appropriate methods why such practices occur. METHODS: We analysed data from a survey of government health facilities in four Kenyan districts in which HW consultations were observed, caretakers and HW were interviewed, and health facility assessments were performed. The analysis was limited to children 2-59 months old with uncomplicated malaria. Treatment was defined as recommended (antimalarial recommended by national guidelines), a minor error (effective, but non-recommended antimalarial), or inappropriate (no effective antimalarial). RESULTS: We evaluated 1006 consultations performed by 135 HW at 81 facilities: 567 children received recommended treatment, 314 had minor errors, and 125 received inappropriate treatment (weighted percentages: 56.9%, 30.4%, and 12.7%). Multivariate logistic regression analysis revealed that programmatic interventions such as in-service malaria training, provision of guidelines and wall charts, and more frequent supervision were significantly associated with better treatment quality. However, neither in-service training nor possession of the guideline document showed an effect by itself. More qualified HW made more errors: both major and minor errors (but generally more minor errors) when second-line drugs were in stock, and more major errors when second-line drugs were not in stock. Child factors such as age and a main complaint of fever were also associated with treatment quality. CONCLUSIONS: Our results support the use of several programmatic strategies that can redress HW deficiencies in malaria treatment. Targeted cost-effectiveness trials would help refine these strategies and provide more precise guidance on affordable and effective ways to strengthen and maintain HW practices.
    • Prevalence and Diagnostics of Congenital Malaria in Rural Burundi, a Cross-Sectional Study

      Stassijns, J; van den Boogaard, W; Pannus, P; Nkunzimana, A; Rosanas-Urgell, A (BioMed Central, 2016-08-30)
      Congenital malaria, defined as the presence of asexual forms of malaria parasites in the peripheral blood during the first 7 days of life, remains a neglected area of research. Knowledge gaps exist about prevalence and management of malaria in this age group. The objective of this study was to evaluate the prevalence of congenital malaria and the validity of a rapid diagnostic test (RDT) for its diagnosis in rural Burundi.
    • Prevalence of malaria and anemia among pregnant women residing in malaria-endemic forest villages in India

      Qureshi, Ihtesham Aatif; Arlappa, Nimmathota; Qureshi, Mohtashim Arbaab (Elsevier, 2014-07-19)
    • Prevalence of malaria infection among under five year tribal children residing in malaria endemic forest villages

      Qureshi, Ihtesham; Qureshi, Mohtashim; Gudepu, Rohit; Arlappa, Nimmathota (F1000Research, 2014-11-20)
    • 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.
    • A randomized trial comparing the efficacy of four treatment regimens for uncomplicated falciparum malaria in Assam state, India.

      Campbell, P; Baruah, S; Narain, K; Rogers, C C; Medecins sans Frontieres-Holland, India Section, R.G. Baruah Road, Guwahati, Assam 781024, India. patricia10334@yahoo.com (Elsevier, 2006-02)
      A four-arm drug sensitivity study compared chloroquine, sulfadoxine-pyrimethamine (SP), mefloquine and mefloquine-artesunate in Sonitpur and Karbi Anglong districts in Assam state, India. Two criteria were used to ascertain outcome: success of clinical treatment and parasitologic cure. In Sonitpur, at 14 days, there were 36/56 early and late treatment failures plus late parasitologic failures to chloroquine and 16/56 for SP. In Karbi Anglong, combined treatment failure at 14 days was 16/56 to chloroquine and 8/60 to SP. Mefloquine and mefloquine-artesunate demonstrated 93.9% and 93.6% sustained responses respectively at 42 days. High failure rates to both chloroquine and SP preclude the use of these drugs as first-line treatment for uncomplicated falciparum malaria in this region. A mefloquine-artesunate combination presents an effective alternative utilizing the currently recommended higher dose of mefloquine.
    • 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.
    • Ready-to-use therapeutic food for Catch-up Growth in children after an episode of Plasmodium Falciparum Malaria: an open randomised controlled trial

      van der Kam, S; Swarthout, T; Niragira, O; Froud, A; Sompwe, E M; Mills, C; Roll, S; Tinnemann, P; Shanks, L; Médecins Sans Frontières, Amsterdam, The Netherlands. saskia.vd.kam@amsterdam.msf.org (2012-04-25)
      Catch-up growth after an infection is essential for children to maintain good nutritional status. To prevent malnutrition, WHO recommends that children are given one additional healthy meal per day during the 2 weeks after onset of illness. We investigated to what extent ready-to-use therapeutic food (RUTF) promotes catch-up growth in children after an acute, uncomplicated episode of Plasmodium falciparum malaria.
    • Real-time PCR/MCA assay using fluorescence resonance energy transfer for the genotyping of resistance related DHPS-540 mutations in Plasmodium falciparum

      Mens, Petra F; van Overmeir, Chantal; Bonnet, Maryline; Dujardin, Jean-Claude; d'Alessandro, Umberto; Prince Leopold Institute of Tropical Medicine, Department of Parasitology, Antwerp, Belgium; Koninklijk Instituut voor de Tropen/Royal Tropical Institute, KIT Biomedical Research, Amsterdam, The Netherlands; Epicentre, Paris, France (2008-03-17)
      BACKGROUND: Sulphadoxine-pyrimethamine has been abandoned as first- or second-line treatment by most African malaria endemic countries in favour of artemisinin-based combination treatments, but the drug is still used as intermittent preventive treatment during pregnancy. However, resistance to sulphadoxine-pyrimethamine has been increasing in the past few years and, although the link between molecular markers and treatment failure has not been firmly established, at least for pregnant women, it is important to monitor such markers. METHODS: This paper reports a novel sensitive, semi-quantitative and specific real-time PCR and melting curve analysis (MCA) assay using fluorescence resonance energy transfer (FRET) for the detection of DHPS-540, an important predictor for SP resistance. FRET/MCA was evaluated using 78 clinical samples from malaria patients and compared to PCR-RFLP. RESULTS: Sixty-two samples were in perfect agreement between both assays. One sample showed a small wild type signal with FRET/MCA that indicates a polyclonal infection. Four samples were not able to generate enough material in both assays to distinguish mutant from wild-type infection, six samples gave no signal in PCR-RFLP and five samples gave no amplification in FRET/MCA. CONCLUSION: FRET/MCA is an effective tool for the identification of SNPs in drug studies and epidemiological surveys on resistance markers in general and DHPS-540 mutation in particular.
    • 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.
    • The relationship between the haemoglobin concentration and the haematocrit in Plasmodium falciparum malaria.

      Lee, S J; Stepniewska, K; Anstey, N; Ashley, E; Barnes, K; Binh, T Q; D'Alessandro, U; Day, N; de Vries, P J; Dorsey, G; et al. (BioMed Central, 2008-08)
      BACKGROUND: Malaria is a very important cause of anaemia in tropical countries. Anaemia is assessed either by measurement of the haematocrit or the haemoglobin concentration. For comparisons across studies, it is often necessary to derive one measure from the other. METHODS: Data on patients with slide-confirmed uncomplicated falciparum malaria were pooled from 85 antimalarial drug trials conducted in 25 different countries, to assess the haemoglobin/haematocrit relationship at different time points in malaria. Using a linear random effects model, a conversion equation for haematocrit was derived based on 3,254 measurements from various time points (ranging from day 0 to day 63) from 1,810 patients with simultaneous measurements of both parameters. Haemoglobin was also estimated from haematocrit with the commonly used threefold conversion. RESULTS: A good fit was obtained using Haematocrit = 5.62 + 2.60 * Haemoglobin. On average, haematocrit/3 levels were slightly higher than haemoglobin measurements with a mean difference (+/- SD) of -0.69 (+/- 1.3) for children under the age of 5 (n = 1,440 measurements from 449 patients). CONCLUSION: Based on this large data set, an accurate and robust conversion factor both in acute malaria and in convalescence was obtained. The commonly used threefold conversion is also valid.
    • Responding to the evidence for the management of severe malaria

      Ford, Nathan P.; de Smet, Martin; Kolappa, Kavitha; White, Nicholas J. (2011-09)
    • A review of the WHO malaria rapid diagnostic test product testing programme (2008–2018): performance, procurement and policy

      Cunningham, J; Jones, S; Gatton, M; Barnwell, J; Cheng, Q; Chiodini, P; Glenn, J; Gonzalez, I; Kosack, C; Nhem, S; et al. (Springer Science and Business Media LLC, 2019-12-02)
      Malaria rapid diagnostic tests (RDTs) emerged in the early 1990s into largely unregulated markets, and uncertain field performance was a major concern for the acceptance of tests for malaria case management. This, combined with the need to guide procurement decisions of UN agencies and WHO Member States, led to the creation of an independent, internationally coordinated RDT evaluation programme aiming to provide comparative performance data of commercially available RDTs. Products were assessed against Plasmodium falciparum and Plasmodium vivax samples diluted to two densities, along with malaria-negative samples from healthy individuals, and from people with immunological abnormalities or non-malarial infections. Three measures were established as indicators of performance, (i) panel detection score (PDS) determined against low density panels prepared from P. falciparum and P. vivax wild-type samples, (ii) false positive rate, and (iii) invalid rate, and minimum criteria defined. Over eight rounds of the programme, 332 products were tested. Between Rounds 1 and 8, substantial improvements were seen in all performance measures. The number of products meeting all criteria increased from 26.8% (11/41) in Round 1, to 79.4% (27/34) in Round 8. While products submitted to further evaluation rounds under compulsory re-testing did not show improvement, those voluntarily resubmitted showed significant increases in P. falciparum (p = 0.002) and P. vivax PDS (p < 0.001), with more products meeting the criteria upon re-testing. Through this programme, the differentiation of products based on comparative performance, combined with policy changes has been influential in the acceptance of malaria RDTs as a case-management tool, enabling a policy of parasite-based diagnosis prior to treatment. Publication of product testing results has produced a transparent market allowing users and procurers to clearly identify appropriate products for their situation, and could form a model for introduction of other, broad-scale diagnostics.
    • Risk associated with asymptomatic parasitaemia occurring post-antimalarial treatment

      Olliaro, P; Pinoges, L; Checchi, F; Vaillant, M; Guthmann, J P; UNICEF/UNDP/World Bank/WHO Special Programme on Research and Training in Tropical Diseases (TDR), Geneva, Switzerland. Centre for Tropical Medicine and Vaccinology, University of Oxford, Oxford, UK. Epicentre, Paris, France. Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK. Centre de Recherches Publiques (CRP)-Santé, Luxembourg. (2008-01)
      OBJECTIVE: Parasites may recur asymptomatically after initial clearance by antimalarial treatment. Current guidelines recommend treatment only when patients develop symptoms or at the end of follow-up. We wanted to assess prospectively the probability of becoming symptomatic and the risks of this practice. METHODS: We analysed data collected in 13 trials of uncomplicated paediatric malaria conducted in eight sub-Saharan African countries. These studies followed all cases of post-treatment asymptomatic parasitaemia until they developed symptoms or to the end of the 28-day follow-up period, at which time parasite genotypes were compared to pre-treatment isolates to distinguish between recrudescences and new infections. RESULTS: There were 425 asymptomatic recurrences after 2576 treatments with either chloroquine, sulfadoxine/pyrimethamine or amodiaquine, of which 225 occurred by day 14 and 200 between day 15 and day 28. By day 28, 42% developed fever (median time to fever = 5 days) and 30% remained parasitaemic but afebrile, while 23% cleared their parasites (outcome unknown in 4%). Young age, parasitaemia >/=500 parasites/microl; onset of parasitaemia after day 14, and treatment with amodiaquine were the main variables associated with higher risk of developing fever. CONCLUSION: In areas of moderate to intense transmission, asymptomatic recurrences of malaria after treatment carry a substantial risk of becoming ill within a few days and should be treated as discovered. Young children are at higher risk. The higher risk carried by cases occurring in the second half of follow-up may be explained by falling residual drug levels.
    • The risk of Plasmodium vivax parasitaemia after P. falciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network

      Hossain, MS; Commons, RJ; Douglas, NM; Thriemer, K; Alemayehu, BH; Amaratunga, C; Anvikar, AR; Ashley, EA; Asih, PBS; Carrara, VI; et al. (Public Library of Science, 2020-11-19)
      Background: There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial. Methods and findings: A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0-29.0 years; range = 0-80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9-33.4) after AL, 14.1% (95% CI 10.8-18.3) after AA, 7.4% (95% CI 6.7-8.1) after AM, and 4.5% (95% CI 3.9-5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6-43.3), 42.4% (95% CI 34.7-51.2), 22.8% (95% CI 21.2-24.4), and 12.8% (95% CI 11.4-14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0-19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6-8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4-3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0-1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4-2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high. Conclusions: In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas.
    • Safety and efficacy of dihydroartemisinin-piperaquine in falciparum malaria: a prospective multi-centre individual patient data analysis.

      Zwang, Julien; Ashley, Elizabeth A; Karema, Corine; D'Alessandro, Umberto; Smithuis, Frank; Dorsey, Grant; Janssens, Bart; Mayxay, Mayfong; Newton, Paul; Singhasivanon, Pratap; et al. (2009-07-15)
      BACKGROUND: The fixed dose antimalarial combination of dihydroartemisinin-piperaquine (DP) is a promising new artemisinin-based combination therapy (ACT). We present an individual patient data analysis of efficacy and tolerability in acute uncomplicated falciparum malaria, from seven published randomized clinical trials conducted in Africa and South East Asia using a predefined in-vivo protocol. Comparator drugs were mefloquine-artesunate (MAS3) in Thailand, Myanmar, Laos and Cambodia; artemether-lumefantrine in Uganda; and amodiaquine+sulfadoxine-pyrimethamine and artesunate+amodiaquine in Rwanda. METHODS AND FINDINGS: In total 3,547 patients were enrolled: 1,814 patients (32% children under five years) received DP and 1,733 received a comparator antimalarial at 12 different sites and were followed for 28-63 days. There was no significant heterogeneity between trials. DP was well tolerated with 1.7% early vomiting. There were less adverse events with DP in children and adults compared to MAS3 except for diarrhea; ORs (95%CI) 2.74 (2.13 to 3.51) and 3.11 (2.31 to 4.18), respectively. DP treatment resulted in a rapid clearance of fever and parasitaemia. The PCR genotype corrected efficacy at Day 28 of DP assessed by survival analysis was 98.7% (95%CI 97.6-99.8). DP was superior to the comparator drugs in protecting against both P.falciparum recurrence and recrudescence (P = 0.001, weighted by site). There was no difference between DP and MAS3 in treating P. vivax co-infections and in suppressing the first relapse (median interval to P. vivax recurrence: 6 weeks). Children under 5 y were at higher risk of recurrence for both infections. The proportion of patients developing gametocytaemia (P = 0.002, weighted by site) and the subsequent gametocyte carriage rates were higher with DP (11/1000 person gametocyte week, PGW) than MAS3 (6/1000 PGW, P = 0.001, weighted by site). CONCLUSIONS: DP proved a safe, well tolerated, and highly effective treatment of P.falciparum malaria in Asia and Africa, but the effect on gametocyte carriage was inferior to that of MAS3.