Opinion
Malaria Parasite Clearance: What Are We Really Measuring?

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Highlights

  • The parasite clearance half-life is used to assess the efficacy of antimalarial drugs.

  • It is usually assumed that a parasite will be rapidly removed by the host after it is killed by a drug. This shapes our interpretation of the parasite clearance half-life.

  • The parasite clearance curve is not always measuring how quickly a drug kills parasites, because parasites that are killed may remain in circulation for some time.

  • Experimental approaches can be used to determine whether circulating parasites are viable or nonviable after treatment. These approaches allow us to assess how quickly parasites are killed.

  • Approaches that distinguish between viable and nonviable parasites would assist in better assessing the efficacy of antimalarials in vivo.

Antimalarial drugs are vital for treating malaria and controlling transmission. Measuring drug efficacy in the field requires large clinical trials and thus we have identified proxy measures of drug efficacy such as the parasite clearance curve. This is often assumed to measure the rate of drug activity against parasites and is used to predict optimal treatment regimens required to completely clear a blood-stage infection. We discuss evidence that the clearance curve is not measuring the rate of drug killing. This has major implications for how we assess optimal treatment regimens, as well as how we prioritise new drugs in the drug development pipeline.

Section snippets

Assessing Drug Efficacy in Malaria

Malaria was responsible for approximately 435 000 deaths in 2017 [1]. Mortality from malaria fell by 28% between 2010 and 2017 [1], in part because of the increased use of highly effective artemisinin-based therapies as the first-line treatment for malaria [2., 3., 4.]. However, artemisinin-resistant Plasmodium falciparum has been confirmed in a number of locations across South-East Asia, raising global concerns that malaria mortality will increase unless we can replace the current failing

Interpreting the Parasite Clearance Curve

The rate at which parasites disappear from a host’s circulation has been measured in a variety of ways (Box 1), and it is usually interpreted as a measure of the speed of drug activity. However, the rate of parasite clearance may not only depend on how quickly a drug acts, but also on how quickly drug-affected parasites are removed from circulation by the host [21., 22., 23., 24.]. To illustrate, let us imagine two extreme scenarios of drug action and parasite removal that have very different

Evidence for Drug Killing and Delayed Clearance

If the killing and delayed clearance scenario is correct, it implies that drugs act faster than we currently estimate by measuring the decline in parasitaemia alone, and that a population of killed parasites circulate for a period before removal. In this case, we would mistakenly classify some circulating parasites as ‘healthy’ in our measurements of parasite concentration (by microscopy or PCR), while in fact they are severely drug affected. We have recently investigated the viability of

Reinterpreting the Parasite Clearance Curve

It is clear from the evidence outlined that ‘parasite clearance’ is a composite measure, encapsulating both drug killing and rate of removal of drug-affected parasites from circulation. Thus, in a scenario where parasite numbers drop rapidly after treatment, there are a variety of possible scenarios that may cause this decline (Figure 1D,E). Figure 1E illustrates this, with contour lines showing the observed parasite clearance half-life for different combinations of the rates of drug killing

Implication 1: Delayed Clearance Confounds Forecasts of Drug Killing and Ideal Dosing Regimens

PK/PD models play a central role in drug development and dose-optimisation studies. In particular, PK/PD models are important for projecting the total fold reduction in parasite numbers following treatment with a candidate antimalarial drug [12,13]. It is important to understand the limitations of these models, because forecasts based on these will only ever be as accurate as the assumptions used to generate them. For example, a usual concern with forecasting drug killing forward is that it

Implication 2: Parasite Clearance Curve May Not Be the Optimal Method for Comparing Drug Killing Activity

Drug-affected parasites are not always immediately removed from circulation after they are killed by treatment. Therefore, our ability to compare drug killing between different drugs may be limited. If all drugs induced the same rate of removal of drug-affected parasites, then comparing drugs based on the rate of decline of total circulating parasite numbers may not be sensitive to differences in parasite killing rate [23]. For example, if two treatments induced killing at different rates, one

Translation to Clinical Efficacy: Lessons from the Artemisinins

Thus far we have highlighted that the key in vivo metric to assess the parasiticidal efficacy of a new candidate antimalarial drug – the parasite clearance half-life – is not measuring drug killing alone, and so may not be an ideal metric of parasiticidal efficacy. However, at this point it is worth considering whether parasiticidal efficacy and clinical efficacy may be best assessed in different ways. For example, if the presence of parasites (even dead ones) contributes to pathogenesis, then

Proposal to Measure Parasite Viability in Future Studies: Prospects and Challenges

To improve our understanding of drug efficacy and parasite viability after drug treatment in malaria we must improve and develop new methods for assessing parasite viability. By directly quantifying the viability of circulating parasites after drug treatment one will be able to understand whether the decline in circulating parasite concentration reflects drug killing activity, or whether it reflects host removal of drug-affected parasite. The question arises of how to assess viability?

Viability

Concluding Remarks

Artemisinin resistance is a growing threat to global efforts to eliminate malaria. This has driven a large global investment in the development of new antimalarial drugs and now is a critical moment in drug development efforts. How we assess and prioritise new compounds for development is a decision that may define the success of current drug-development campaigns. We advise caution in interpreting the parasite clearance curve as a measure of a drug’s killing rate. The use of the parasite

Acknowledgements

The complete list of authors includes those named in the author list, as well as the members of the Interdisciplinary Approaches to Malaria Consortium which includes Deborah Cromer, Maria Rebelo, Pengxing Cao, James M. McCaw, Julie A. Simpson, Jennifer A. Flegg, Danny W. Wilson, Nicholas M. Anstey, and James S. McCarthy. All authors contributed directly to the development of the ideas and writing of this publication. Spacing requirements precluded naming all authors explicitly in the author

Glossary

Clinical efficacy
a drug’s ability to improve clinical outcomes in patients. Examples of measures of clinical efficacy include the speed with which a drug resolves the patient’s symptoms (e.g., fever clearance time) and improvement in survival outcomes.
Delayed death
usually refers to the action of apicoplast inhibitors, such as doxycycline, which do not kill the current parasite stages, but damage daughter parasites, which are not able to establish infection in a new red blood cell once released.

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      This medicinal compound also acts as an anticancer agent [34–39]. However, it is more difficult to define and explain artemisinin resistance, typically knowing the fact that, following antimalarial treatment with an artemisinin derivative, parasites are removed from the bloodstream very differently involving the spleen [40–43]. Artemisinin is suggested to be a prodrug, and activation of artemisinin involves cleavage of the endoperoxide moiety by iron of heme; this process occurs within the erythrocytes and produces reactive oxygen species that attack the nucleophilic groups of parasitic proteins and lipids.

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      Careful evaluations of AS monotherapy trials have shown no associations of PCTs (or ring-stage clearance half-life) with recrudescences [24,55], and longer PCTs did not correspond to delayed resolutions of malaria fever [23,55]. Evidence that the clearance curve does not measure the rate of killing by the drug [56] is in accord with those evaluations. Likewise, various genetic markers and measures of parasite ART response in vitro ring-stage survival assays (RSAs, IC50s) have not associated with the recrudescences of monotherapy failure (Box 3).

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