Novel anti-malarial drug strategies to prevent artemisinin partner drug resistance: A model-based analysis

Abstract

Emergence of resistance to artemisinin and partner drugs in the Greater Mekong Subregion has made elimination of malaria from this region a global priority; it also complicates its achievement. Novel drug strategies such as triple artemisinin combination therapies (ACTs) and chemoprophylaxis have been proposed to help limit resistance and accelerate elimination. The objective of this study was to better understand the potential impacts of triple ACTs and chemoprophylaxis, using a mathematical model parameterized using data from Cambodia. We used a simple compartmental model to predict trends in malaria incidence and resistance in Cambodia from 2020–2025 assuming no changes in transmission since 2018. We assessed three scenarios: a status quo scenario with artesunate-mefloquine (ASMQ) as treatment; a triple ACT scenario with dihydroartemisinin-piperaquine (DP) plus mefloquine (MQ) as treatment; and a chemoprophylaxis scenario with ASMQ as treatment plus DP as chemoprophylaxis. We predicted MQ resistance to increase under the status quo scenario. Triple ACT treatment reversed the spread of MQ resistance, but had no impact on overall malaria incidence. Joint MQ-PPQ resistance declined under the status quo scenario for the baseline parameter set and most sensitivity analyses. Compared to the status quo, triple ACT treatment limited spread of MQ resistance but also slowed declines in PPQ resistance in some sensitivity analyses. The chemoprophylaxis scenario decreased malaria incidence, but increased the spread of strains resistant to both MQ and PPQ; both effects began to reverse after the intervention was removed. We conclude that triple ACTs may limit spread of MQ resistance in the Cambodia, but would have limited impact on malaria incidence and might slow declines in PPQ resistance. Chemoprophylaxis could have greater impact on incidence but also carries higher risks of resistance. Aggressive strategies to limit transmission the GMS are needed to achieve elimination goals, but any intervention should be accompanied by monitoring for drug resistance.

Expert perspectives on the introduction of Triple Artemisinin-based Combination Therapies (TACTs) in Southeast Asia: a Delphi study

“…Our results indicate that malaria experts do acknowledge that the introduction of TACT is a valid approach to mitigate drug-resistant falciparum malaria, to protect current antimalarial drugs, and to reduce the risk of resistance spreading to other continents and regions. In support of these perspectives are recent studies showing the efficacy of TACTs to treat multidrug-resistant falciparum malaria [ 14 ] while further mathematical modelling studies are required to determine its potential in protecting drug compounds and mitigating the spread of resistance [ 13 , 34 , 35 ]. Modeling studies could also inform about implications of introducing TACTs on transmission intensity and on achieving the malaria elimination ambitions in Southeast Asia [ 36 ], although the latter was considered to be a not-relevant item by malaria experts in the present study.…”

“…Indeed, these statements can be considered controversial and to our knowledge, there is no scientific evidence supporting them. The expert panel also assigned low relevance to the post-treatment prophylactic effect of TACTs [ 34 ] and to the potential of TACTs to reduce vivax malaria incidence, indicating that experts either disagree with the statements or that they are only considered minor advantages.…”

Evidence for the early emergence of piperaquine-resistant Plasmodium falciparum malaria and modeling strategies to mitigate resistance

“…Those studies, however, had not modeled how treatment regimens, parasite densities and drug pharmacokinetics affect parasite evolution. Other models have incorporated drug-drug interactions, pharmacokinetics and fixed resistance thresholds to assess how resistance to specific components of a triple ACT might impact treatment efficacy [75], or how resistance might spread in areas of triple ACT use [76]. Those models did not account for parasite fitness that is integral in shaping the parasite resistance landscape.…”

Artemisinin and multidrug-resistant Plasmodium falciparum – a threat for malaria control and elimination

“…Triple artemisinin-based combination therapies (TACTs) provide another promising option that could be rapidly deployed. TACTs are combinations of an artemisinin derivative and two partner drugs selected based on their elimination half-lives and observed parasite resistance profiles to ensure mutual protection [ 60 , 64 , 65 ▪▪ , 66 ]. Two such TACTs, artemether-lumefantrine with amodiaquine and dihydroartemisinin-piperaquine with mefloquine have been shown to be well tolerated and highly efficacious in Thailand, Cambodia and Vietnam where dihydroartemisinin-piperaquine failed in nearly 50% of patients [ 48 ▪ ].…”