2022-08-29 ペンシルベニア州立大学(PennState)
様々なレベルのマラリア流行と既存のパートナー薬剤耐性、さらにジヒドロアルテミシニン-ピペラキン、アルテスネート-アモジアキン、アルテメター-ルメファントリンなどの抗マラリア併用療法へのアクセスの度合いをモデルで検討した。
研究チームは、パートナーである薬剤耐性マラリア原虫の遺伝子型の頻度が高いほど、これらの原虫の間でアルテミシニン耐性が早期に確立されることを見出した。すべてのモデルにおいて,パートナー薬剤耐性マラリア原虫の頻度が平均で 10 倍になると,パートナー薬剤が完全に作用する場合よりも 2 ～ 12 年早くアルテミシニンの効力が失われることになる.3つの薬剤の組み合わせのうち、ジヒドロアルテミシニン-ピペラキンは、パートナー薬剤の耐性化の影響を最も受けやすく、アルテミシニン耐性の進化を加速させるものであることがわかった。特に、パートナー薬剤耐性頻度が低い場合でも、アルテミシニン耐性の確立時間が大幅に短縮されることが確認された。
<関連情報>
- https://www.psu.edu/news/eberly-college-science/story/partner-drug-resistance-accelerates-resistance-first-line-malaria-drug/
- https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(22)00155-0/fulltext
アルテミシニン併用療法に対する既存のパートナー薬剤耐性は、アルテミシニン耐性の出現と拡大を促進する:コンセンサスモデリング研究 Pre-existing partner-drug resistance to artemisinin combination therapies facilitates the emergence and spread of artemisinin resistance: a consensus modelling study
Oliver J Watson, Bo Gao, Tran Dang Nguyen, Thu Nguyen-Anh Tran, Melissa A Penny, Prof David L Smith, Lucy Okell, Ricardo Aguas, Maciej F Boni
The Lancet Microbe Published:August 02, 2022
DOI:https://doi.org/10.1016/S2666-5247(22)00155-0
Summary
Background
Artemisinin-resistant genotypes of Plasmodium falciparum have now emerged a minimum of six times on three continents despite recommendations that all artemisinins be deployed as artemisinin combination therapies (ACTs). Widespread resistance to the non-artemisinin partner drugs in ACTs has the potential to limit the clinical and resistance benefits provided by combination therapy. We aimed to model and evaluate the long-term effects of high levels of partner-drug resistance on the early emergence of artemisinin-resistant genotypes.
Methods
Using a consensus modelling approach, we used three individual-based mathematical models of Plasmodium falciparum transmission to evaluate the effects of pre-existing partner-drug resistance and ACT deployment on the evolution of artemisinin resistance. Each model simulates 100 000 individuals in a particular transmission setting (malaria prevalence of 1%, 5%, 10%, or 20%) with a daily time step that updates individuals’ infection status, treatment status, immunity, genotype-specific parasite densities, and clinical state. We modelled varying access to antimalarial drugs if febrile (coverage of 20%, 40%, or 60%) with one primary ACT used as first-line therapy: dihydroartemisinin–piperaquine (DHA-PPQ), artesunate–amodiaquine (ASAQ), or artemether–lumefantrine (AL). The primary outcome was time until 0·25 580Y allele frequency for artemisinin resistance (the establishment time).
Findings
Higher frequencies of pre-existing partner-drug resistant genotypes lead to earlier establishment of artemisinin resistance. Across all models, a 10-fold increase in the frequency of partner-drug resistance genotypes on average corresponded to loss of artemisinin efficacy 2–12 years earlier. Most reductions in time to artemisinin resistance establishment were observed after an increase in frequency of the partner-drug resistance genotype from 0·0 to 0·10.
Interpretation
Partner-drug resistance in ACTs facilitates the early emergence of artemisinin resistance and is a major public health concern. Higher-grade partner-drug resistance has the largest effect, with piperaquine resistance accelerating the early emergence of artemisinin-resistant alleles the most. Continued investment in molecular surveillance of partner-drug resistant genotypes to guide choice of first-line ACT is paramount.
Funding
Schmidt Science Fellowship in partnership with the Rhodes Trust; Bill & Melinda Gates Foundation; Wellcome Trust.
