Monitoring and deterring drug-resistant malaria in the era of combination therapy

Malaria Section, Center for Vaccine Development, University of Maryland School of Medicine, 685 W. Baltimore Street, Baltimore, MD 21201, USA.
The American journal of tropical medicine and hygiene (Impact Factor: 2.7). 01/2008; 77(6 Suppl):160-9.
Source: PubMed


As chloroquine and sulfadoxine-pyrimethamine (SP) are replaced by more effective artemisinin-based combination therapies (ACTs), strategies for monitoring (and, if possible, deterring) drug-resistant malaria must be updated and optimized. In vitro methods for measuring resistance will be critical for confirming and characterizing resistance to ACTs. Molecular markers are useful for tracking the emergence and dissemination of resistance and guiding treatment policy where resistance is low or moderate. Genomic approaches may help identify molecular markers for resistance to artemisinins and their partner drugs. Studies of reported ACT treatment failure should include assessing factors other than resistance that affect efficacy, including pharmacokinetics. Longitudinal clinical trials are particularly useful for comparing the benefits and risks of repeated treatment in high transmission settings. The malaria research and control community should not fail to exploit this opportunity to apply the lessons of the last 50 years to extend the useful therapeutic lives of ACTs.

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    • "Plasmodium falciparum has repeatedly proven ability for mounting resistance to any anti-malarial drug regimen upon wider use, including current ones [2-7]. To avert potential resurgence owing to treatments that are no longer effective, not only are new anti-malarials needed, but also public health strategies that will minimize or delay drug resistance escalation [8,9]. "
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    ABSTRACT: The emergence of parasite drug resistance, especially Plasmodium falciparum, persists as a major obstacle for malaria control and elimination. To develop effective public health containment strategies, a clear understanding of factors that govern the emergence and spread of resistant parasites in the field is important. The current study documents selection for chloroquine-sensitive malaria parasites by wild Anopheles arabiensis in southern Zambia. In a 2,000-sq km region, mosquitoes were collected from human sleeping rooms using pyrethrum spray catches during the 2006 malaria transmission season. After morphological examination and molecular confirmation, vector mosquitoes were dissected to separate head and thorax from the abdominal section, followed by PCR screening for P. falciparum infection. Human residents of all ages were tested for P. falciparum parasitaemia by microscopy and PCR. Plasmodium falciparum infections were genotyped at the chloroquine resistance-conferring amino acid codon 76 of the PfCRT gene, using PCR and restriction enzyme digestion. In the human population there was nearly 90% prevalence of the chloroquine-resistant PfCRT K76T mutant, with no significant differences in polymorphism among smear-positive and smear-negative (submicroscopic) infections (p = 0.323, n = 128). However, infections in both abdominal and salivary gland phases of the An. arabiensis vector exhibited wild type K76-bearing parasites with up to 9X higher odds (OR (95% CI): 9 (3.7-20.2), p < 0.0005, n = 125), despite having been acquired from humans within a few weeks. Anopheles arabiensis selects for wild-type K76-bearing P. falciparum during both abdominal and salivary gland phases of parasite development. The rapid vectorial selection, also recently seen with antifolate resistance, is evidence for parasite fitness cost in the mosquito, and may underpin regional heterogeneity in the emergence, spread and waning of drug resistance. Understanding the nature and direction of vector selection could be instrumental for rational curtailment of the spread of drug resistance in integrated malaria control and elimination programmes.
    Malaria Journal 12/2013; 12(1):453. DOI:10.1186/1475-2875-12-453 · 3.11 Impact Factor
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    • "Molecular studies probably provide the earliest warning signs of resistance to the SP component of AS+SP [9,10]. For operational reasons, until recently there have been no molecular data on P. falciparum SP resistance markers in isolates obtained within the borders of Afghanistan. "
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    ABSTRACT: Artesunate plus sulphadoxine-pyrimethamine (AS+SP) is now first-line treatment for Plasmodium falciparum infection in several south Asian countries, including Afghanistan. Molecular studies provide a sensitive means to investigate the current state of drug susceptibility to the SP component, and can also provide information on the likely efficacy of other potential forms of artemisinin-combination therapy. During the years 2007 to 2010, 120 blood spots from patients with P. falciparum malaria were obtained in four provinces of Afghanistan. PCR-based methods were used to detect drug-resistance mutations in dhfr, dhps, pfcrt and pfmdr1, as well as to determine copy number of pfmdr1. The majority (95.5%) of infections had a double mutation in the dhfr gene (C59R, S108N); no mutations at dhfr positions 16, 51 or 164 were seen. Most isolates were wild type across the dhps gene, but five isolates from the provinces of Kunar and Nangarhar in eastern Afghanistan had the triple mutation A437G / K540E / A581G; all five cases were successfully treated with three receiving AS+SP and two receiving dihydroartemisinin-piperaquine. All isolates showed the pfcrt SVNMT chloroquine resistance haplotype. Five of 79 isolates had the pfmdr1 N86Y mutation, while 52 had pfmdr1 Y184F; positions 1034, 1042 and 1246 were wild type in all isolates. The pfmdr1 gene was not amplified in any sample. This study indicates that shortly after the adoption of AS+SP as first-line treatment in Afghanistan, most parasites had a double mutation haplotype in dhfr, and a small number of isolates from eastern Afghanistan harboured a triple mutation haplotype in dhps. The impact of these mutations on the efficacy of AS+SP remains to be assessed in significant numbers of patients, but these results are clearly concerning since they suggest a higher degree of SP resistance than previously detected. Further focused molecular and clinical studies in this region are urgently required.
    Malaria Journal 03/2013; 12(1):96. DOI:10.1186/1475-2875-12-96 · 3.11 Impact Factor
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    • "Malaria is a mosquito-borne disease responsible for approximately 216 million human infections and an estimated 655,000 deaths annually, with most deaths occurring in African children [1]. Novel therapeutic intervention methods and other ways to complement or replace existing malaria control methods are a necessity to combat malaria especially when drug-resistant parasites and mosquitoes resistant to commonly used insecticides are a continuing issue and there is no effective malaria vaccine available [2-5]. New bio-informatics analyses of the Plasmodium genome and proteome have provided opportunities to identify and search for protein candidates that potentially can serve as effective targets for vaccines, drug therapy, and/or novel mosquito control methods. "
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    ABSTRACT: Background Efforts to control malaria are demanding due to drug-resistant parasites, insecticide-resistant mosquitoes and poor health infrastructure in malaria-endemic countries. Therefore, the research and development of additional malaria control methods are crucial. For host-parasite interactions, surface antigens and secreted proteins are likely to be involved in infectivity and invasion of host tissues and therefore can be effective targets for control by vaccines, drug therapy, or novel mosquito control methods. In an effort to identify and characterize genes that may have a role in host-parasite interaction, this study describes the expression profile of Plasmodium falciparum PF3D7_1363700. Methods A P. falciparum gene, PF3D7_1363700, was identified by a search of the annotated Plasmodium genome database. Protein alignments of PF3D7_1363700 orthologues from various Plasmodium species were performed to demonstrate protein similarity. Transcript expression profiles of PF3D7_1363700 were determined via reverse-transcriptase PCR and protein expression was investigated by immunofluorescence assays, western blot analysis and green fluorescent trafficking studies. Results The PF3D7_1363700 protein demonstrates significant similarity with orthologues in other Plasmodium species and appears to be unique to Apicomplexans. The PF3D7_1363700 transcription profile demonstrated expression during the intra-erythrocytic, oocyst sporozoite, and salivary gland sporozoite stages while the PF3D7_1363700 protein was only detected during the intra-erythrocytic stages. Conclusions This research utilized an in silico approach to identify a well-conserved protein known as PF3D7_1363700. By molecular, biochemical and cellular analyses, PF3D7_1363700 was discovered to be an intra-erythrocytic-specific stage protein that is unique to Apicomplexans.
    Malaria Journal 02/2013; 12(1):66. DOI:10.1186/1475-2875-12-66 · 3.11 Impact Factor
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