The efficacy of chloroquine for the treatment of acute, uncomplicated,<i>Plasmodium falciparum</i>malaria in Laos

Guthmann, Jean Paul; Kasparian, Saro; Phetsouvanh, Rattanaxay; Nathan, Nathalie; García, Miguel del Fresno; Phompida, Samalane; Brockman, Alan; Gastellu, M.; Legros, Dominique

doi:10.1179/000349802125001654

Cited by 18 publications

(14 citation statements)

References 18 publications

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“…The proportion of chloroquine-and sulfadoxine-pyrimethamine-resistant cases in this study was comparable to that in previously published reports in Laos with a 128-day followup period [1,3]. A recent study with a 14-day follow-up period in Attapeu (figure 1) found early treatment failure or late treatment failure among 45% and 18% of patients, respectively, treated with chloroquine and sulfadoxine-pyrimethamine [4].…”

Section: Discussionsupporting

confidence: 91%

Chloroquine versus Sulfadoxine-Pyrimethamine for Treatment of Plasmodium falciparum Malaria in Savannakhet Province, Lao People's Democratic Republic: An Assessment of National Antimalarial Drug Recommendations

Mayxay

Newton

Khanthavong

et al. 2003

Clinical Infectious Diseases

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The in vivo efficacies of the Lao People's Democratic Republic (Laos) nationally recommended antimalarial agents--chloroquine and sulfadoxine-pyrimethamine-were assessed in a randomized, comparative trial that involved 100 patients with uncomplicated Plasmodium falciparum malaria who were followed for 42 days after starting treatment. Despite a shorter mean time to fever clearance associated with administration of chloroquine (mean time to clearance, 35.6 h; 95% confidence interval [CI], 26.3-45.0 h), compared with that associated with sulfadoxine-pyrimethamine (61.1 h; 95% CI, 50.9-71.3 h; P<.001), treatment failures were twice as frequent among patients receiving chloroquine therapy than among those receiving sulfadoxine-pyrimethamine therapy (36% vs. 18%; P=.02). Of 23 treatment failures, 10 (43%) were high grade. Treatment failure rates among children (age range, 5-15 years) were 4.9 times higher (95% CI, 2-12) than those among adults (P<.0001). Gametocytemia after antimalarial treatment was associated with receipt of sulfadoxine-pyrimethamine therapy and with treatment failure (P=.009). The efficacy of both chloroquine and sulfadoxine-pyrimethamine in Laos is unsatisfactory.

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Section: Discussionsupporting

confidence: 91%

Chloroquine versus Sulfadoxine-Pyrimethamine for Treatment of Plasmodium falciparum Malaria in Savannakhet Province, Lao People's Democratic Republic: An Assessment of National Antimalarial Drug Recommendations

Mayxay

Newton

Khanthavong

et al. 2003

Clinical Infectious Diseases

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“…Clinical resistance spread much more slowly in Laos, and CQ remains the first-line drug against malaria in this country. Recent clinical trials indicate unsatisfactory cure rates for CQ and only now are policy changes being considered (Guthmann et al 2002;Mayxay et al 2003;Schwobel et al 2003). Molecular marker data are consistent with the clinical data.…”

Section: Introductionsupporting

confidence: 65%

Selection strength and hitchhiking around two anti-malarial resistance genes

et al. 2005

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Neutral mutations may hitchhike to high frequency when they are situated close to sites under positive selection, generating local reductions in genetic diversity. This process is thought to be an important determinant of levels of genomic variation in natural populations. The size of genome regions affected by genetic hitchhiking is expected to be dependent on the strength of selection, but there is little empirical data supporting this prediction. Here, we compare microsatellite variation around two drug resistance genes (chloroquine resistance transporter ( pfcrt), chromosome 7, and dihydrofolate reductase (dhfr), chromosome 4) in malaria parasite populations exposed to strong (Thailand) or weak selection (Laos) by anti-malarial drugs. In each population, we examined the point mutations underlying resistance and length variation at 22 (chromosome 4) or 25 (chromosome 7) microsatellite markers across these chromosomes. All parasites from Thailand carried the K76T mutation in pfcrt conferring resistance to chloroquine (CQ) and 2-4 mutations in dhfr conferring resistance to pyrimethamine. By contrast, we found both wild-type and resistant alleles at both genes in Laos. There were dramatic differences in the extent of hitchhiking in the two countries. The size of genome regions affected was smaller in Laos than in Thailand. We observed significant reduction in variation relative to sensitive parasites for 34-64 kb (2-4 cM) in Laos on chromosome 4, compared with 98-137 kb (6-8 cM) in Thailand. Similarly, on chromosome 7, we observed reduced variation for 34-69 kb (2-4 cM) around pfcrt in Laos, but for 195-268 kb (11-16 cM) in Thailand. Reduction in genetic variation was also less extreme in Laos than in Thailand. Most loci were monomorphic in a 12 kb region surrounding both genes on resistant chromosomes from Thailand, whereas in Laos, even loci immediately proximal to selective sites showed some variation on resistant chromosomes. Finally, linkage disequilibrium (LD) decayed more rapidly around resistant pfcrt and dhfr alleles from Laos than from Thailand. These results demonstrate that different realizations of the same selective sweeps may vary considerably in size and shape, in a manner broadly consistent with selection history. From a practical perspective, genomic regions containing resistance genes may be most effectively located by genome-wide association in populations exposed to strong drug selection. However, the lower levels of LD surrounding resistance alleles in populations under weak selection may simplify identification of functional mutations.

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“…CQ has been abandoned in treating falciparum malaria in China in late 1970s, but remained as the first-line drug treating uncomplicated falciparum malaria in Laos and Myanmar until the policy changes to ACT in 2005 (Smithuis et al, 2004; Mayxay et al, 2007b). In numerous surveys carried out within the last decade in Laos, significant in vitro resistance to CQ has been observed and levels of treatment failure reached unacceptable levels (Pillai et al, 2001; Guthmann et al, 2002; Berens et al, 2003; Mayxay et al, 2007a). In the area immediately bordering Yunnan, high-grade CQ resistance was also prevalent (Yang et al, 1997; Dittrich et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Monitoring Plasmodium falciparum chloroquine resistance in Yunnan Province, China, 1981–2006

Yang¹,

Yang²,

Yang³

et al. 2008

Acta Tropica

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The emergence and spread of drug resistant malaria parasites are an important factor contributing to the global resurgence of malaria, demonstrating the essence of drug resistance surveillance in endemic areas. In the malarious border regions of Yunnan Province, China, we have selected three study sites to monitor in vitro and in vivo resistance of Plasmodium falciparum parasites to chloroquine (CQ) from 1981 to 2006. In vitro studies using the microtest clearly showed high-degree of CQ resistance in the early 1980s, when CQ was replaced by artemether monotherapy for falciparum malaria. In subsequent in vitro surveys performed in the early 1990s and 2003-2004, we found reductions in both the concentrations inhibiting 50% parasite growth (IC 50 s) and the percentage of resistant parasites at all study sites, although the degrees of the reduction varied among sites. Even though amodiaquine has never been used in this area, there were consistently high levels of resistance to this drug, confirming cross resistance between CQ and amodiaquine. In vivo clinical studies were consistent with the results of the in vitro assays. The overall rate of resistant clinical cases decreased from 97% in 1981-1983 to 40% in 2005-2006. Collectively, whereas a general trend of reduction in CQ resistance was observed in Yunnan, variations among sites existed in this relatively small area, probably as the result of both geographical heterogeneity of malaria epidemiology in Yunnan and different levels of CQ resistance in neighboring countries.

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The efficacy of chloroquine for the treatment of acute, uncomplicated,Plasmodium falciparummalaria in Laos

Cited by 18 publications

References 18 publications

Chloroquine versus Sulfadoxine-Pyrimethamine for Treatment of Plasmodium falciparum Malaria in Savannakhet Province, Lao People's Democratic Republic: An Assessment of National Antimalarial Drug Recommendations

Chloroquine versus Sulfadoxine-Pyrimethamine for Treatment of Plasmodium falciparum Malaria in Savannakhet Province, Lao People's Democratic Republic: An Assessment of National Antimalarial Drug Recommendations

Selection strength and hitchhiking around two anti-malarial resistance genes

Monitoring Plasmodium falciparum chloroquine resistance in Yunnan Province, China, 1981–2006

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