Malaria transmission intensity and the rate of spread of chloroquine resistant Plasmodium falciparum: Why have theoretical models generated conflicting results?

Talisuna, AO; Erhart, Annette; Samarasinghe, Saumya Madushani; Overmeir, Chantal Van; Speybroeck, Niko; D’Alessandro, Umberto

doi:10.1016/j.meegid.2005.06.003

Cited by 21 publications

(21 citation statements)

References 31 publications

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“…Prophylactic drug treatment has the same effect in this experimental model (37). These data, together with correlational field data consistent with crowding and competitive release (24)(25)(26)(27)(28)(29), demonstrate that in-host competition could be an important determinant of the strength of drug selection for resistance in malaria populations. Competitive release of resistance after chemotherapy of mixed infections would greatly accelerate the evolution of resistance and may account for the depressingly short useful lifespans of some antimalarial compounds (4).…”

Section: Discussionsupporting

confidence: 70%

“…For malaria, there is direct evidence of the cocirculation of multiple Plasmodium clones in both acute and persistent human infections, including the coexistence of resistant and sensitive clones (18)(19)(20)(21)(22)(23). A body of correlational epidemiological evidence is consistent with crowding effects in human malaria infections (24)(25)(26)(27)(28), and some patterns of drug resistance in Africa are more readily explained by invoking competitive release (11,29). However, unambiguous experimental evidence of competitive release cannot be ethically obtained from human infections.…”

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confidence: 99%

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Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model

Wargo

Huijben

Roode

et al. 2007

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

169

205

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Malaria infections frequently consist of mixtures of drug-resistant and drug-sensitive parasites. If crowding occurs, where clonal population densities are suppressed by the presence of coinfecting clones, removal of susceptible clones by drug treatment could allow resistant clones to expand into the newly vacated niche space within a host. Theoretical models show that, if such competitive release occurs, it can be a potent contributor to the strength of selection, greatly accelerating the rate at which resistance spreads in a population. A variety of correlational field data suggest that competitive release could occur in human malaria populations, but direct evidence cannot be ethically obtained from human infections. Here we show competitive release after pyrimethamine curative chemotherapy of acute infections of the rodent malaria Plasmodium chabaudi in laboratory mice. The expansion of resistant parasite numbers after treatment resulted in enhanced transmission-stage densities. After the elimination or near-elimination of sensitive parasites, the number of resistant parasites increased beyond that achieved when a competitor had never been present. Thus, a substantial competitive release occurred, markedly elevating the fitness advantages of drug resistance above those arising from survival alone. This finding may explain the rapid spread of drug resistance and the subsequently brief useful lifespans of some antimalarial drugs. In a second experiment, where subcurative chemotherapy was administered, the resistant clone was only partly released from competitive suppression and experienced a restriction in the size of its expansion after treatment. This finding raises the prospect of harnessing in-host ecology to slow the spread of drug resistance.competition ͉ evolution of drug resistance ͉ Plasmodium chabaudi ͉ transmission ͉ in-host ecology

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Section: Discussionsupporting

confidence: 70%

mentioning

confidence: 99%

Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model

Wargo

Huijben

Roode

et al. 2007

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

169

205

View full text Add to dashboard Cite

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“…A substantial body of epidemiological evidence is consistent with crowding effects within infections, whereby the population densities of individual genotypes are suppressed when other genotypes are present (15,16,(23)(24)(25)(26)(27)(28)(29)(30)(31). For example, parasite densities are unrelated to the number of clones per host, and high turnover rates are observed in mixed-genotype infections.…”

Section: Aims Of Patient Treatmentmentioning

confidence: 94%

“…The impact of this competitive release on the rate of spread of resistance can be very substantial, as was first recognized by Hastings and colleagues (58)(59)(60). Where multiclone infections dominate, this within-host ecology can be the primary determinant of the speed at which resistance spreads, and a far more important selective force than the simple survival advantage conferred by resistance (25,27,(58)(59)(60)(61)(62).…”

Section: Aims Of Patient Treatmentmentioning

confidence: 99%

The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy

Read

Day

Huijben

2011

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

245

295

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The evolution of drug-resistant pathogens is a major challenge for 21st century medicine. Drug use practices vigorously advocated as resistance management tools by professional bodies, public health agencies, and medical schools represent some of humankind's largest attempts to manage evolution. It is our contention that these practices have poor theoretical and empirical justification for a broad spectrum of diseases. For instance, rapid elimination of pathogens can reduce the probability that de novo resistance mutations occur. This idea often motivates the medical orthodoxy that patients should complete drug courses even when they no longer feel sick. Yet “radical pathogen cure” maximizes the evolutionary advantage of any resistant pathogens that are present. It could promote the very evolution it is intended to retard. The guiding principle should be to impose no more selection than is absolutely necessary. We illustrate these arguments in the context of malaria; they likely apply to a wide range of infections as well as cancer and public health insecticides. Intuition is unreliable even in simple evolutionary contexts; in a social milieu where in-host competition can radically alter the fitness costs and benefits of resistance, expert opinion will be insufficient. An evidence-based approach to resistance management is required.

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“…In Uganda, the prevalence of HIV is estimated to be 6.4% in adults and 0.7% in children, 1 The transmission intensity of malaria in Tororo, Uganda, the site of the study, is very high, with a parasite prevalence of 91% among children 2-9 years of age 2 and an entomologic inoculation rate of 562 infectious bites per person per year. 3 Past evidence has demonstrated that clinical malaria is more likely to develop in HIV-infected patients than in those who are uninfected, [4][5][6] with an estimated 10% of clinical malaria in Africa attributable to concurrent HIV infection.…”

Section: Introductionmentioning

confidence: 99%

Plasmodium falciparum Dihydrofolate Reductase and Dihyropteroate Synthase Mutations and the Use of Trimethoprim-Sulfamethoxazole Prophylaxis among Persons Infected with Human Immunodeficiency Virus

Malamba

Sandison²,

Lule³

et al. 2010

The American Journal of Tropical Medicine and Hygiene

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Abstract. A prospective cohort design was used to measure the association between daily cotrimoxazole-prophylaxis and infection with Plasmodium falciparum containing mutations associated with antifolate resistance among persons infected with human immunodeficiency virus (HIV) in Tororo and Busia District, in eastern Uganda. Of 149 cases of P. falciparum parasitemia diagnosed, 147 (99%) (smears from participants taking prophylaxis = 91 and smears from those not taking cotrimoxazole prophylaxis = 56) were successfully assessed for mutations in the dihydrofolate reductase ( dhfr ) and dihydropteroate synthase ( dhps ) mutations associated with antifolate resistance. Prevalences of the dhfr pure triple mutant (74% and 70%; P = 0.71), the dhps pure double mutant (95% and 88%; P = 0.21), and the dhfr/dhps pure quintuple mutant (73% and 64%; P = 0.36), were not significantly different between those taking and those not taking cotrimoxazole-prophylaxis, respectively. The overall prevalence of the pure quintuple mutant in this study was 69%, which is among the highest in Africa. Although resistance rates of P. falciparum to antifolate drugs are high, cotrimoxazole-prophylaxis in HIV-infected persons was not associated with a higher prevalence of mutations associated with antifolate resistance.

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Malaria transmission intensity and the rate of spread of chloroquine resistant Plasmodium falciparum: Why have theoretical models generated conflicting results?

Cited by 21 publications

References 31 publications

Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model

Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model

The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy

Plasmodium falciparum Dihydrofolate Reductase and Dihyropteroate Synthase Mutations and the Use of Trimethoprim-Sulfamethoxazole Prophylaxis among Persons Infected with Human Immunodeficiency Virus

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