History, Dynamics, and Public Health Importance of Malaria Parasite Resistance

Talisuna, Ambrose; Bloland, Peter B.; D’Alessandro, Umberto

doi:10.1128/cmr.17.1.235-254.2004

Cited by 268 publications

(248 citation statements)

References 203 publications

(166 reference statements)

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“…For more than 50 years chloroquine (CQ) was a frontline therapy, but resistant strains have emerged worldwide [2,3]. The development of affordable alternatives to CQ has been slow [4].…”

Section: Introductionmentioning

confidence: 99%

Chloroquine-resistant isoforms of the Plasmodium falciparum chloroquine resistance transporter acidify lysosomal pH in HEK293 cells more than chloroquine-sensitive isoforms

Reeves

Liebelt

Lakshmanan

et al. 2006

Molecular and Biochemical Parasitology

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The emergence of chloroquine-resistant Plasmodium falciparum malaria imperils the lives of millions of people in Africa, Southeast Asia and South America. Chloroquine resistance is associated with mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT). We expressed chloroquine sensitive (HB3) and resistant (Dd2) pfcrt alleles in HEK293 human embryonic kidney cells. PfCRT localized to the lysosomal limiting membrane and was not detected in the plasma membrane. We observed significant acidification of lysosomes containing PfCRT HB3 and Dd2, with Dd2 acidifying significantly more than HB3. A mutant HB3 allele expressing the K76T mutation (earlier found to be key for chloroquine resistance) acidified to the same extent as Dd2, whereas the acidification of a Dd2 allele expressing the T76K "back mutation" was significantly less than Dd2. Thus, the amino acid at position 76 is both an important determinant of chloroquine resistance in parasites and of lysosomal acidification following heterologous expression. PfCRT may be capable of modulating the pH of the parasite digestive vacuole, and thus chloroquine availability. Chloroquine accumulation and glycyl-phenylalanine-2-naphthylamide-induced release of lysosomal Ca 2+ stores were unaffected by PfCRT expression. Cytoplasmic domain mutations did not alter PfCRT sorting to the lysosomal membrane. This heterologous expression system will be useful to characterize PfCRT protein structure and function, and elucidate its molecular role in chloroquine resistance.

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“…For more than 50 years chloroquine (CQ) was a frontline therapy, but resistant strains have emerged worldwide [2,3]. The development of affordable alternatives to CQ has been slow [4].…”

Section: Introductionmentioning

confidence: 99%

Chloroquine-resistant isoforms of the Plasmodium falciparum chloroquine resistance transporter acidify lysosomal pH in HEK293 cells more than chloroquine-sensitive isoforms

Reeves

Liebelt

Lakshmanan

et al. 2006

Molecular and Biochemical Parasitology

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“…[1][2][3] More than 40 countries in Africa have now adopted ACT as their first line treatment recommendation for uncomplicated malaria. 4 Beyond the difficulties of changing national treatment policies, a key bench mark of successful policy implementation, and thus effectiveness, is that the recommended drugs are available at the point of care.…”

mentioning

confidence: 99%

Malaria Drug Shortages in Kenya: A Major Failure to Provide Access to Effective Treatment

Kangwana¹,

Memusi²,

Snow³

et al. 2009

The American Journal of Tropical Medicine and Hygiene

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Abstract. A key bench mark of successful therapeutic policy implementation, and thus effectiveness, is that the recommended drugs are available at the point of care. Two years after artemether-lumefathrine (AL) was introduced for the management of uncomplicated malaria in Kenya, we carried out a cross-sectional survey to investigate AL availability in government facilities in seven malaria-endemic districts. One of four of the surveyed facilities had none of the four AL weight-specific treatment packs in stock; three of four facilities were out of stock of at least one weight-specific AL pack, leading health workers to prescribe a range of inappropriate alternatives. The shortage was in large part caused by a delayed procurement process. National ministries of health and the international community must address the current shortcomings facing antimalarial drug supply to the public sector.The widespread failure of chloroquine and sulfadoxine pyrimethamine (SP) in the treatment of malaria in Africa during the late 1990s resulted in a turbulent public health debate, which led to universal acceptance that mono-therapies that failed to cure up to one in four patients should be replaced by highly efficacious artemisinin-based combination therapy (ACT). 1-3 More than 40 countries in Africa have now adopted ACT as their first line treatment recommendation for uncomplicated malaria. 4 Beyond the difficulties of changing national treatment policies, a key bench mark of successful policy implementation, and thus effectiveness, is that the recommended drugs are available at the point of care. [5][6][7] In most countries, ACTs are supplied only to the public, formal health sector managed by the government and its mission sector partners. In 2006, Kenya implemented a change in malaria treatment policy in all public facilities from SP to the ACT artemetherlumefantrine (AL), largely supported by the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM). 7 Two years after AL introduction, we carried out a crosssectional survey to investigate AL availability in government facilities. From August 18 through October 2, 2008, 164 facilities (115 dispensaries, 30 health centers, and 19 hospitals) were assessed in seven districts in Nyanza, Western, and Coast Provinces, Kenya, that were highly endemic for malaria. At each facility, information was collected on the availability of AL packs for the four patient weight groups either through direct review of stock cards or through phone interviews. Health workers were also asked what they prescribed in the absence of AL.One (25.6%) of four of the surveyed facilities had none of the four AL weight-specific treatment packs in stock, with such complete stockouts more common in dispensaries (30.4%) than in health centers (20.0%) and hospitals (5.3%). Furthermore, three (75.0%) of four facilities were out of stock of at least one weight-specific AL pack (Table 1 ). It was particularly worrying that packs for the youngest age group, the group most at risk of malaria mortality, were absent...

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“…that cause malaria. The evolution and worldwide spread of resistance to chloroquine (CQ) over the past 50 years (1) and the subsequent failure of sulfadoxinepyrimethamine (SP) (1,2) have created a crisis for many African nations and other malaria-endemic countries (3). A number of these countries have adopted the highly effective artemisinin-based combination therapies (ACTs) as their first-line therapy for uncomplicated malaria, but ACTs are not yet widely available.…”

mentioning

confidence: 99%

Benefits of using multiple first-line therapies against malaria

Boni

Smith

Laxminarayan

2008

Proc. Natl. Acad. Sci. U.S.A.

132

124

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Despite the availability of many drugs and therapies to treat malaria, many countries' national policies recommend using a single first-line therapy for most clinical malaria cases. To assess whether this is the best strategy for the population as a whole, we designed an evolutionary-epidemiological modeling framework for malaria and compared the benefits of different treatment strategies in the context of resistance evolution. Our results show that the population-wide use of multiple first-line therapies (MFT) against malaria yields a better clinical outcome than using a single therapy or a cycling strategy where therapies are rotated, either on a fixed cycling schedule or when resistance levels or treatment failure become too high. MFT strategies also delay the emergence and slow the fixation of resistant strains (phenotypes), and they allow a larger fraction of the population to be treated without trading off future treatment of cases that may be untreatable because of high resistance levels. Earlier papers have noted that cycling strategies have the disadvantage of creating a less temporally variable environment than MFT strategies, making resistance evolution easier for the parasite. Here, we illustrate a second feature of parasite ecology that impairs the performance of cycling policies, namely, that cycling policies degrade the mean fitness of the parasite population more quickly than MFT policies, making it easier for new resistant types to invade and spread. The clinical benefits of using multiple first-line therapies against malaria suggest that MFT policies should play a key role in malaria elimination and control programs. drug resistance ͉ epidemiology ͉ evolution ͉ treatment strategies ͉ cost of resistance

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History, Dynamics, and Public Health Importance of Malaria Parasite Resistance

Cited by 268 publications

References 203 publications

Chloroquine-resistant isoforms of the Plasmodium falciparum chloroquine resistance transporter acidify lysosomal pH in HEK293 cells more than chloroquine-sensitive isoforms

Chloroquine-resistant isoforms of the Plasmodium falciparum chloroquine resistance transporter acidify lysosomal pH in HEK293 cells more than chloroquine-sensitive isoforms

Malaria Drug Shortages in Kenya: A Major Failure to Provide Access to Effective Treatment

Benefits of using multiple first-line therapies against malaria

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