Benefits of using multiple first-line therapies against malaria

Abstract

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

Temporal and Seasonal Changes of Genetic Polymorphisms Associated with Altered Drug Susceptibility to Chloroquine, Lumefantrine, and Quinine in Guinea-Bissau between 2003 and 2012

“…The use of multiple first-line therapies that select for opposing genetic polymorphisms might therefore be of value. Furthermore, modeling has suggested that the use of multiple first-line therapies may prolong the total lifetime of the first-line drugs in use over that achieved with sequential use (39). Although by no means solid evidence, our findings of an increased pfcrt 76T frequency that probably reflects the increased prevalence of highly AL-susceptible P. falciparum (compared to that of 76K) when AL and quinine are used concurrently support that hypothesis.…”

Comparing the Impact of Artemisinin-Based Combination Therapies on Malaria Transmission in Sub-Saharan Africa

“…A limitation on the effectiveness of ACTs that remains to be addressed is the emergence and spread of P. falciparum resistance to artemisinin derivatives, partner drugs, or both. 26,27 Resistance may be of particular concern with regimens containing longer-acting partner drugs present at low levels for extended periods, such as is the case with piperaquine, and reports of reduced efficacy of DP are now emerging. 16,28 If resistance to ACTs spreads into sub-Saharan Africa, this will certainly alter the relative benefits of each regimen.…”

An Economic Evaluation of the Posttreatment Prophylactic Effect of Dihydroartemisinin–Piperaquine Versus Artemether–Lumefantrine for First-Line Treatment of Plasmodium falciparum Malaria Across Different Transmission Settings in Africa

“…In settings with lower endemicity and reinfection risk, the use of DP might be restricted to patients with a higher risk of malaria morbidity, such as young pediatric malaria patients, which might lead to additional benefits within the context of drug resistance through the use of multiple first-line treatment strategies. 28 A dispersible formulation of DP suitable for use in children between the ages of 6 months and 5 years is currently under development, and a targeted deployment of this drug can play an effective role in reducing the disease burden in children living in malariaendemic areas. …”