Resistance to chloroquine is a major challenge in the treatment of falciparum malaria. In 1993, Malawi replaced chloroquine with sulfadoxine–pyrimethamine for malaria treatment. After the return of ...chloroquine-susceptible falciparum malaria to Malawi, investigators studied the reemergent clinical efficacy of chloroquine and found that it was approximately 99% effective.
After the return of chloroquine-susceptible falciparum malaria to Malawi, investigators studied the reemergent clinical efficacy of chloroquine and found that the drug was approximately 99% effective.
Malaria continues to be a leading killer of the world's poorest children. Six decades after chloroquine was widely deployed in a global program to eradicate malaria,
Plasmodium falciparum
continues to plague most of sub-Saharan Africa.
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Chloroquine resistance first emerged in Southeast Asia and South America in the late 1950s, and by the late 1970s, it had made its way to the African continent, where it contributed to increased transmission of malaria and deaths.
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In 1993, in response to high rates of treatment failure with chloroquine, Malawi became the first country in sub-Saharan Africa to replace chloroquine with the combination of . . .
Chemotherapy remains the only practicable tool to control falciparum malaria in sub-Saharan Africa, where >90% of the world's burden of malaria mortality and morbidity occurs. Resistance is rapidly ...eroding the efficacy of chloroquine, and the combination pyrimethamine–sulfadoxine is the most commonly chosen alternative. Resistant populations of
Plasmodium falciparum were selected extremely rapidly in Southeast Asia and South America. If this happens in sub-Saharan Africa, it will be a public health disaster because no inexpensive alternative is currently available. This article reviews the molecular mechanisms of this resistance and discusses how to extend the therapeutic life of antifolate drugs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Multidrug resistance is a major obstacle to the control of Plasmodium falciparum malaria, and its origins and modes of dissemination are imperfectly understood. In this study, haplotyping and ...microsatellite analysis of malaria from 5 regions of the South American Amazon support the conclusion that the parasite mutations conferring mid- and high-level resistance to the antifolate combination sulfadoxine-pyrimethamine have a common origin. Parasites harboring these mutations are also found to share drug-resistance alleles that confer a unique chloroquine resistance phenotype and to be similar at loci not linked to drug resistance, although not genetically identical. Since the 1980s, multidrug-resistant P. falciparum has spread in a north-northwest manner across the continent, from an origin likely in the lower Amazon. This study highlights the importance of continent-wide malaria-control policies and suggests that the containment of resistance to the next generation of therapies may be feasible
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Artemisinin-resistant Plasmodium falciparum malaria has been documented in southeast Asia and may already be spreading in that region. Molecular markers are important tools for monitoring the spread ...of antimalarial drug resistance. Recently, single-nucleotide polymorphisms (SNPs) in the PF3D7_1343700 kelch propeller (K13-propeller) domain were shown to be associated with artemisinin resistance in vivo and in vitro. The prevalence and role of K13-propeller mutations are poorly known in sub-Saharan Africa. K13-propeller mutations were genotyped by direct sequencing of nested polymerase chain reaction (PCR) amplicons from dried blood spots of pre-treatment falciparum malaria infections collected before and after the use of artemisinin-based combination therapy (ACT) as first-line therapy in Mali. Although K13-propeller mutations previously associated with delayed parasite clearance in Cambodia were not identified, 26 K13-propeller mutations were identified in both recent samples and pre-ACT infections. Parasite clearance time was comparable between infections with non-synonymous K13-propeller mutations and infections with the reference allele. These findings suggest that K13-propeller mutations are present in artemisinin-sensitive parasites and that they preceded the wide use of ACTs in Mali.
Despite the initiation in 1998 by the World Health Organization of a campaign to ‘Roll Back Malaria’, the rates of disease and death caused by Plasmodium falciparum malaria in sub-Saharan Africa are ...growing. Drug resistance has been implicated as one of the main factors in this disturbing trend. The efforts of international agencies, governments, public health officials, advocacy groups and researchers to devise effective strategies to deter the spread of drug resistant malaria and to ameliorate its heavy burden on the people of Africa have not succeeded. This review will not attempt to describe the regional distribution of drug resistant malaria in Africa in detail, mainly because information on resistance is limited and has been collected using different methods, making it difficult to interpret. Instead, the problems of defining and monitoring resistance and antimalarial drug treatment outcomes will be discussed in hopes of clarifying the issues and identifying ways to move forward in a more coordinated fashion. Strategies to improve measurement of resistance and treatment outcomes, collection and use of information on resistance, and potential approaches to deter and reduce the impact of resistance, will all be considered. The epidemiological setting and the goals monitoring determine how antimalarial treatment responses should be measured. Longitudinal studies, with incidence of uncomplicated malaria episodes as the primary endpoint, provide the best information on which to base treatment policy changes, while simpler standard in vivo efficacy studies are better suited for ongoing efficacy monitoring. In the absence of an ideal antimalarial combination regimen, different treatment alternatives are appropriate in different settings. But where chloroquine has failed, policy changes are long overdue and action must be taken now.
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FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
BackgroundHuman immunodeficiency virus (HIV) infection and malaria coexist in much of Africa. Previous studies differ in their findings on the interactions between the 2 infections MethodsAdults ...living with HIV infection in Blantyre, Malawi, were enrolled in a longitudinal observational study from September 2002 to August 2004. Malaria blood smears were obtained monthly and for any illness suggestive of malaria. Complete evaluations of all illness episodes were conducted, regardless of malaria smear results ResultsThe incidence of clinical malaria episodes was higher in participants with CD4 cell counts <200 cells/mm3 than in those with CD4 cell counts >500 cells/mm3. The trend was preserved when increasingly specific definitions of malaria disease were used. The prevalence of malaria infection was not associated with CD4 cell count. In per-visit analysis, lower CD4 cell counts were associated with higher incidences of pneumonia, sepsis, and tuberculosis but not of malaria. Severe malaria was rare, with only 3 cases in 591 person-years of observation. Parasite density and CD4 cell count were independent risk factors for fever ConclusionsProfoundly immunosuppressed adults with HIV infection require more-frequent treatment for uncomplicated malaria, but malaria infection and disease are less strongly associated with HIV-associated immunosuppression than are other opportunistic infections. Where malaria is common, the high incidence of fever found among immunosuppressed adults may lead to misclassification of illness episodes as malaria
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
BackgroundTrimethoprim-sulfamethoxazole (TS) prophylaxis is recommended for persons living with human immunodeficiency virus infection and acquired immunodeficiency syndrome in Africa. TS and the ...antimalarial combination sulfadoxine-pyrimethamine (SP) share mechanisms of action and resistance patterns, and concerns about the impact of TS resistance on SP efficacy have contributed to reluctance to implement TS prophylaxis in Africa MethodsTo determine whether TS prophylaxis impairs SP efficacy for treatment of uncomplicated falciparum malaria, we conducted a randomized, controlled, open-label study of TS prophylaxis. Two hundred and forty children 5–15 years old were randomized in a 2:1 fashion to receive either thrice-weekly TS for 12 weeks or no prophylaxis and were treated with SP for subsequent episodes of malaria. The incidence of malaria, SP efficacy, and the prevalence of parasite mutations that confer antifolate drug resistance were measured ResultsTS prophylaxis had a 99.5% protective efficacy against episodes of clinical malaria, with 97% efficacy against infection. Four SP treatment failures occurred in the control group, and none occurred in the TS group. No evidence was seen for selection by TS of antifolate resistance–conferring mutations in parasite dihydrofolate reductase or dihydropteroate synthase during subclinical infections ConclusionsIn this setting of low antifolate resistance, TS was highly effective in preventing falciparum malaria infection and disease and did not appear to select for SP-resistant parasites
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Plasmodium falciparum and Schistosoma haematobium are co-endemic parasitic diseases with worldwide distribution. Evidence suggests interactions occur between helminthic and malaria infections, ...although it is unclear whether this effect is beneficial or harmful to the host. Malian children 4-14 years of age with asymptomatic S. haematobium infection (SP) (n = 338) were prospectively matched by age, sex, and residence to children without schistosomiasis (SN) (n = 338) who were cleared of occult intestinal parasites, and followed-up for one malaria transmission season (25 weeks). The time to the first clinical malaria infection, incidence of malaria episodes, and parasitemia were recorded. Age associated protection from malaria in children with schistosomiasis was observed. SP children (4-8 years of age) compared with SN children demonstrated delayed time to first clinical malaria infection (74 versus 59 days; P = 0.04), fewer numbers of malaria episodes (1.55 versus 1.81 infections; P = 0.03) and lower geometric mean parasite densities (6,359 versus 9,874 asexual forms/mm(3); P = 0.07) at first infection. No association between schistosomiasis and P. falciparum malaria was observed in children 9-14 years of age. We conclude that underlying schistosomiasis is associated with protection against clinical falciparum malaria in an age-dependent manner.
Drug-resistant falciparum malaria is increasing in Africa and so methods to map resistance on a broad scale are needed. A molecular marker for chloroquine resistance, pfcrt T76, can be used for ...surveillance of clinical chloroquine resistance. The prevalence of pfcrt T76 and the prevalence of clinical chloroquine resistance and therapeutic failure were measured at sentinel sites and used to calculate age-adjusted genotype-resistance indices (GRIs) and genotype-failure indices (GFIs). We found stable GRIs and GFIs at different sites in Mali, West Africa. This model permits mapping of chloroquine resistance using molecular tools in rapid and simple cross-sectional surveys.
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DOBA, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SIK, UILJ, UKNU, UL, UM, UPCLJ, UPUK, VSZLJ
Combination drug therapy for malaria is recommended both to prevent and to overcome drug resistance. Drug combinations developed for use in Asia are being deployed in Africa, where higher rates of ...malaria affect the therapeutic and public health objectives of malaria chemotherapy as well as drug safety. Rational consideration of drug mechanisms, pharmacokinetics (PK), pharmacodynamics (PD), and malaria epidemiology should result in more effective combination regimens that retain therapeutic and prophylactic efficacy in the face of resistance.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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