Chemoprevention strategies reduce malaria disease and death, but the efficacy of anti-malarial drugs used for chemoprevention is perennially threatened by drug resistance. This review examines the ...current impact of chemoprevention on the emergence and spread of drug resistant malaria, and the impact of drug resistance on the efficacy of each of the chemoprevention strategies currently recommended by the World Health Organization, namely, intermittent preventive treatment in pregnancy (IPTp); intermittent preventive treatment in infants (IPTi); seasonal malaria chemoprevention (SMC); and mass drug administration (MDA) for the reduction of disease burden in emergency situations. While the use of drugs to prevent malaria often results in increased prevalence of genetic mutations associated with resistance, malaria chemoprevention interventions do not inevitably lead to meaningful increases in resistance, and even high rates of resistance do not necessarily impair chemoprevention efficacy. At the same time, it can reasonably be anticipated that, over time, as drugs are widely used, resistance will generally increase and efficacy will eventually be lost. Decisions about whether, where and when chemoprevention strategies should be deployed or changed will continue to need to be made on the basis of imperfect evidence, but practical considerations such as prevalence patterns of resistance markers can help guide policy recommendations.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Antifolate antimalarial drugs interfere with folate metabolism, a pathway essential to malaria parasite survival. This class of drugs includes effective causal prophylactic and therapeutic agents, ...some of which act synergistically when used in combination. Unfortunately, the antifolates have proven susceptible to resistance in the malaria parasite. Resistance is caused by point mutations in dihydrofolate reductase and dihydropteroate synthase, the two key enzymes in the folate biosynthetic pathway that are targeted by the antifolates. Resistance to these drugs arises relatively rapidly in response to drug pressure and is now common worldwide. Nevertheless, antifolate drugs remain first-line agents in several sub-Saharan African countries where chloroquine resistance is widespread, at least partially because they remain the only affordable, effective alternative. New antifolate combinations that are more effective against resistant parasites are being developed and in one case, recently introduced into use. Combining these antifolates with drugs that act on different targets in the parasite should greatly enhance their effectiveness as well as deter the development of resistance. Molecular epidemiological techniques for monitoring parasite drug resistance may contribute to development of strategies for prolonging the useful therapeutic life of this important class of drugs.
The interruption of malaria transmission worldwide is one of the greatest challenges for international health and development communities. The current expert view suggests that, by aggressively ...scaling up control with currently available tools and strategies, much greater gains could be achieved against malaria, including elimination from a number of countries and regions; however, even with maximal effort we will fall short of global eradication. The Malaria Eradication Research Agenda (malERA) complements the current research agenda--primarily directed towards reducing morbidity and mortality--with one that aims to identify key knowledge gaps and define the strategies and tools that will result in reducing the basic reproduction rate to less than 1, with the ultimate aim of eradication of the parasite from the human population. Sustained commitment from local communities, civil society, policy leaders, and the scientific community, together with a massive effort to build a strong base of researchers from the endemic areas will be critical factors in the success of this new agenda.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chloroquine-Resistant Malaria Wellems, Thomas E.; Plowe, Christopher V.
The Journal of infectious diseases,
09/2001, Letnik:
184, Številka:
6
Journal Article
Recenzirano
The development of chloroquine as an antimalarial drug and the subsequent evolution of drug-resistant Plasmodium strains had major impacts on global public health in the 20th century. In P. ...falciparum the cause of the most lethal human malaria, chloroquine resistance is linked to multiple mutations in PfCRT, a protein that likely functions as a transporter in the parasite’s digestive vacuole membrane. Rapid diagnostic assays for PfCRT mutations are already employed as surveillance tools for drug resistance. Here, we review recent field studies that support the central role of PfCRT mutations in chloroquine resistance. These studies suggest chloroquine resistance arose in ⩾4 distinct geographic foci and substantiate an important role of immunity in the outcomes of resistant infections after chloroquine treatment. P. vivax which also causes human malaria, appears to differ from P. falciparum in its mechanism of chloroquine resistance. Investigation of the resistance mechanisms and of the role of immunity in therapeutic outcomes will support new approaches to drugs that can take the place of chloroquine or augment its efficiency
Vaccine-Resistant Malaria Plowe, Christopher V
New England journal of medicine/The New England journal of medicine,
11/2015, Letnik:
373, Številka:
21
Journal Article
Recenzirano
Odprti dostop
To ensure efficacy against wild poliovirus, Jonas Salk methodically classified circulating polio strains before choosing three to use in his inactivated vaccine.
1
Several other successful vaccines ...against viruses and bacteria have likewise included immunogen variants that were selected through careful assessments of pathogen genetic diversity and strain-specific protective immunity.
In contrast, virtually all vaccines against the malaria parasite
Plasmodium falciparum
, including RTS,S/AS01, have been designed with the use of genetic sequences that are derived from a single, well-characterized reference strain thought to be of West African origin — 3D7. In light of the extreme diversity of malaria parasites, could . . .
The evolution of drug-resistant malaria Plowe, Christopher V.
Transactions of the Royal Society of Tropical Medicine and Hygiene,
04/2009, Letnik:
103, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Molecular epidemiological investigations have uncovered the patterns of emergence and global spread of
Plasmodium falciparum resistance to chloroquine and sulfadoxine-pyrimethamine. Malaria parasites ...highly resistant to chloroquine and pyrimethamine spread from Asian origins to Africa, at great cost to human health and life. If artemisinin-resistant falciparum malaria follows the same pattern, renewed efforts to eliminate and eradicate malaria will be gravely threatened. This paper, adapted from a talk given in honour of Professor Malcolm Molyneux in Liverpool in September 2008, reviews the rise and fall of clinically important forms of drug-resistant falciparum malaria and considers how lessons learned from studying the evolution of drug-resistant malaria can be applied to efforts to prevent and deter resistance.
More details about human movement patterns are needed to evaluate relationships between daily travel and malaria risk at finer scales. A multiagent mobility simulation model was built to simulate the ...movements of villagers between home and their workplaces in 2 townships in Myanmar.
An agent-based model (ABM) was built to simulate daily travel to and from work based on responses to a travel survey. Key elements for the ABM were land cover, travel time, travel mode, occupation, malaria prevalence, and a detailed road network. Most visited network segments for different occupations and for malaria-positive cases were extracted and compared. Data from a separate survey were used to validate the simulation.
Mobility characteristics for different occupation groups showed that while certain patterns were shared among some groups, there were also patterns that were unique to an occupation group. Forest workers were estimated to be the most mobile occupation group, and also had the highest potential malaria exposure associated with their daily travel in Ann Township. In Singu Township, forest workers were not the most mobile group; however, they were estimated to visit regions that had higher prevalence of malaria infection over other occupation groups.
Using an ABM to simulate daily travel generated mobility patterns for different occupation groups. These spatial patterns varied by occupation. Our simulation identified occupations at a higher risk of being exposed to malaria and where these exposures were more likely to occur.
The Threat of Artemisinin-Resistant Malaria Dondorp, Arjen M; Fairhurst, Rick M; Slutsker, Laurence ...
New England journal of medicine/The New England journal of medicine,
09/2011, Letnik:
365, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Since the 1970s, when Chinese researchers demonstrated the artemisinins' antimalarial potency, artemisinin-based combination therapy has become key to malaria control. But reduced susceptibility of
...Plasmodium falciparum
to artemisinin is now being seen in some places.
In the 1970s, Chinese government scientists working on a secret “Project 523” developed a new class of potent antimalarial drugs, the artemisinins or qinghaosu derivatives. In mostly unpublished work that has just been recognized by a 2011 Lasker Award to Tu Youyou, researchers in China isolated the active compounds from the plant
Artemisia annua,
tested them in mice, analyzed the chemical structure of the artemisinins, and demonstrated their high potency and rapid efficacy in human trials. Although they were widely used in China during the 1980s, only in the 1990s did the artemisinins come to wider global attention in the . . .
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.
Mutational analysis of the Plasmodium falciparum kelch 13 (k13) gene is routinely performed to track the emergence and spread of artemisinin resistance. Surveillance of resistance markers has been ...impeded by the difficulty of extracting sufficient DNA from low parasite density infections common in low-transmission settings, such as Southeast Asia. This problem can be overcome by collecting large volumes of venous blood. Efficient methods for extracting and amplifying k13 from dried blood spots (DBS) would facilitate resistance surveillance.
Methods for k13 amplification from standard Whatman 3MM DBS (stored for 14 days at 28 °C with 80% relative humidity) were optimized by systematically testing different extraction conditions. Conditions that improved parasite DNA recovery as assessed by quantitative polymerase chain reaction (PCR) of 18S rDNA were then tested for their impact on k13 PCR amplification.
The optimized protocol for amplification of k13 from DBS is markedly more sensitive than standard methods using commercial kits. Using this method, k13 was successfully amplified from laboratory-created DBS samples with parasite densities as low as 500 parasites/mL. Importantly, the method recovers both DNA and RNA, making it compatible with RNA-based ultrasensitive techniques currently in use.
The optimized DBS protocol should facilitate drug resistance surveillance, especially in low-transmission settings where clinical malaria infections with high parasite densities are rare.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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