Treatment of Uncomplicated Mutidrug-Resistant Falciparum Malaria with Artesunate-Atovaquine-Proguanil

Mahidol University, Krung Thep, Bangkok, Thailand
Clinical Infectious Diseases (Impact Factor: 8.89). 12/2002; 35(12):1498-504. DOI: 10.1086/344901
Source: PubMed


In an open-label trial carried out on the northwest border of Thailand, 1596 patients with uncomplicated multidrug-resistant falciparum malaria were randomly assigned to receive atovaquone-proguanil, atovaquone-proguanil-artesunate, or artesunate-mefloquine and were followed up for 42 days. All 3 regimens were highly effective and well tolerated. Fever duration and parasite clearance times were significantly shorter among patients who received artesunate (P<.001). Polymerase chain reaction genotyping confirmed that recrudescence occurred in 13 patients who received artesunate-mefloquine (2.4%), 5 who received atovaquone-proguanil-artesunate (0.9%), and 15 who received atovaquone-proguanil (2.8%). Adding artesunate to atovaquone-proguanil reduced the risk of failure 3-fold (95% confidence interval [CI], 1.1-8.2) and subsequent gametocyte carriage 21-fold (95% CI, 14-30). Gastrointestinal complaints in the first 48 h after initiation of treatment were more common among artesunate recipients, but after day 2, dizziness, sleep disturbance, nausea, vomiting, and anorexia were more common among mefloquine recipients (P< or =.014). Artesunate-atovaquone-proguanil is a highly effective and well-tolerated treatment for multidrug-resistant falciparum malaria.

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    • "Since PCR confirmation was not performed, parasites that were reappearing in this routine monitoring study could not be distinguished either as a recrudescent infection due to drug resistance, or re-infection from new parasites. A study carried out in north-western Thailand from 1995 to 2007 reported PCR-confirmed recrudescence in less than 5% of patients under MAS [5,16]. Even if the results of this study are not confirmed by PCR, the failure rate with MAS observed during the study period remains less than 10%. "
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    ABSTRACT: Background: The area along the Thai-Cambodian border is considered an epicenter of anti-malarial drug resistance. Recently, parasite resistance to artemisinin-based therapies has been reported in the area. The artemisinin resistance containment project was initiated in November 2008, with the aim to limit resistant parasites and eliminate malaria in this region. This study describes the response to artemisinin-based therapy among falciparum malaria patients in the area, using data from the malaria surveillance programmed under the containment project. Methods: The study was conducted in seven provinces of Thailand along the Thai-Cambodian border. Data of Plasmodium falciparum-positive patients during January 2009 to December 2011 were obtained from the electronic malaria information system (eMIS) Web-based reporting system. All P. falciparum cases were followed for 42 days, as the routine case follow-up protocol. The demographic characteristics of the patients were described. Statistical analysis was performed to determine the cure rate of the current standard anti-malarial drug regimen-mefloquine-artesunate combination therapy (MAS). The proportion of patients who remained parasite-positive at each follow-up day was calculated. In addition, factors related to the delayed parasite clearance on day-3 post-treatment, were explored. Results: A total of 1,709 P. falciparum-positive cases were reported during the study period. Almost 70% of falciparum cases received MAS therapy (n = 1,174). The majority of cases were males, aged between 31 and 50 years. The overall MAS cure rate was > 90% over the three-year period. Almost all patients were able to clear the parasite within 7 to 14 days post-treatment. Approximately 14% of patients undergoing MAS remained parasite-positive on day-3. Delayed parasite clearance was not significantly associated with patient gender, age, or citizenship. However, delayed parasite clearance varied across the study area.
    Full-text · Article · Aug 2012 · Malaria Journal
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    • "Some ACT failures have been observed in endemic areas. For instance, the failure rate after artemether– lumefantrine (AL) and artesunate–mefloquine (AM) treatments were about 18% in Tanzania and 2.4% in Thailand, respectively (van Vugt et al., 2002; Khim et al., 2005; Alker et al., 2007; Humphreys et al., 2007). Studies of the molecular mechanisms of plasmodial drug resistance are urgently needed. "
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    ABSTRACT: Despite global antimalarial measures, Plasmodium falciparum malaria remains a major public health problem. WHO has recommended the use of arteminisin-based combination therapy to limit the emergence of antimalarial drug resistance. However, ACT treatment failures have been linked to the selection of the wild types 86N genotype of P. falciparum multidrug resistance 1 (Pfmdr1) and the 76K genotype of P. falciparum chloroquine resistance (Pfcrt) genes. The aim of this study was to investigate the molecular impact of widespread implementation of artemether-lumefantrine and artesunate-mefloquine on local parasite population in Franceville, Gabon.
    Full-text · Article · Mar 2011 · Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases
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    • "Still, typing of cytb codon 268 has recently been suggested as a useful tool for the surveillance of atovaquone-proguanil resistance (Gil et al. 2003; Schwö bel et al. 2003). The combination atovaquone-proguanil is able to clear parasitaemia even in regions where proguanil alone is virtually ineffective (Looareesuwan et al. 1996; van Vugt et al. 2002). Proguanil inhibits the dihydrofolate reductase of the parasite only after hepatic conversion to its active metabolite, cycloguanil. "
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    ABSTRACT: Atovaquone-proguanil has recently been introduced for the treatment and prophylaxis of malaria. However, resistance of Plasmodium falciparum is increasingly reported. We assessed P. falciparum polymorphisms associated with resistance to atovaquone (cytochrome b, cytb) and to cycloguanil, the active compound of proguanil (dihydrofolate reductase, dhfr) in 100 isolates from northern Ghana. None of these exhibited cytb codon 268 mutations. Moreover, no dhfr V16A, S108T or I164L mutations linked with cycloguanil resistance were detected. However, dhfr triple mutants (S108N-I51L-C59R) conferring resistance to proguanil and sulphadoxine-pyrimethamine were seen in 51% of the isolates. In northern Ghana, P. falciparum cytb codon 268 mutations associated with atovaquone resistance are absent. Although proguanil appears to act synergistically with atovaquone in a way different from its antifolate property, the abundance of dhfr polymorphisms will likely compromise the prevention of dissemination of atovaquone-resistant parasites once emerged.
    Full-text · Article · Apr 2004 · Tropical Medicine & International Health
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