Nguyen Tran Dang, Zupko Robert J, Conrad Melissa D, Rukundo Gerald B, Farinha Carter C, Asua Victor D, Tran Kien Trung, Grace Deborah M, Rosenthal Philip J, Agaba Bosco B, Kamya Moses R, Opigo Jimmy, Boni Maciej F
Institute for Genomics and Evolutionary Medicine, Department of Biology, Temple University, Philadelphia, PA, USA.
Center for Infectious Disease Dynamics, Department of Biology, Pennsylvania State University, University Park, PA, USA.
medRxiv. 2025 May 18:2025.05.15.25327701. doi: 10.1101/2025.05.15.25327701.
The multiple emergences and continuing spread of partially artemisinin-resistant in Africa, where about 95% of malaria occurs, is a health challenge that requires urgent attention. The World Health Organization has developed a resistance response strategy that centers on enhancing surveillance, reducing drug pressure, and evaluating novel tools to slow resistance evolution which includes the deployment of multiple first-line therapies (MFT). Developing a specific resistance response is critical for Uganda, where four mutations are at local allele frequencies >0.20.
Using a previously validated Uganda-calibrated individual-based mathematical model of transmission and evolution, we evaluated 53 public-sector deployment strategies for artemisinin-based combination therapies (ACTs) aimed at reducing treatment failure and slowing the spread of alleles from 2025 to 2031. We assume that artemether-lumefantrine (AL) will continue to be used in the private sector.
A change of first-line therapy from AL to artesunate-amodiaquine (ASAQ) is projected to reduce treatment failures by 34.7% to 38.3% (90% range of simulation outcomes) over six years, while a change to dihydroartemisinin-piperaquine (DHA-PPQ) is projected to reduce treatment failures over the same period by 10.0% to 12.9%. This pessimistic projection for DHA-PPQ deployment rests on a model assumption - supported by clinical data from SE Asia - that piperaquine resistance evolution will lead to high rates of treatment failure. Optimal MFT deployments and cycling approaches are projected to reduce treatment failure counts by ~36% when compared to status quo AL use, an outcome similar to country-wide ASAQ deployment. MFT and cycling approaches are predicted to work best when ASAQ is recommended for a majority of malaria cases and DHA-PPQ for a smaller proportion of cases. Deployment of the triple ACT artemether-lumefantrine-amodiaquine has the potential to reduce treatment failures by ~42% if enacted immediately.
Increased adoption of and coverage with ASAQ is projected to play a large role in reducing malaria treatment failure counts in Uganda over the next six years. With continued AL use in the private sector, ASAQ and DHA-PPQ deployment in the public sector creates a public-private MFT mix of antimalarial use. DHA-PPQ deployment should be accompanied by real-time molecular surveillance for piperaquine-resistant genotypes.
在约95%的疟疾发生的非洲，部分青蒿素抗性疟原虫的多次出现及持续传播是一项亟需关注的健康挑战。世界卫生组织已制定了一项抗性应对策略，其核心是加强监测、减轻药物压力以及评估新工具以减缓抗性演变，其中包括采用多种一线治疗方案（MFT）。制定特定的抗性应对措施对乌干达至关重要，该国存在四种局部等位基因频率>0.20的突变。
我们使用先前经过验证的、针对乌干达校准的基于个体的传播与演变数学模型，评估了53种以青蒿素为基础的联合疗法（ACTs）的公共部门部署策略，旨在减少治疗失败情况并减缓2025年至2031年等位基因的传播。我们假设蒿甲醚-本芴醇（AL）将继续在私营部门使用。
预计将一线治疗方案从AL改为青蒿琥酯-阿莫地喹（ASAQ），在六年内可使治疗失败率降低34.7%至·38.3%（模拟结果的90%范围），而改为双氢青蒿素-哌喹（DHA-PPQ）预计同期可使治疗失败率降低10.0%至12.9%。对DHA-PPQ部署的这一悲观预测基于一个模型假设——东南亚的临床数据支持该假设——即哌喹抗性演变将导致高治疗失败率。与现状下使用AL相比，预计最佳的MFT部署和循环方法可使治疗失败病例数减少约36%，这一结果与全国范围内部署ASAQ相似。当大多数疟疾病例推荐使用ASAQ，较小比例病例推荐使用DHA-PPQ时，预计MFT和循环方法效果最佳。如果立即实施三联ACT蒿甲醚-本芴醇-阿莫地喹的部署，有可能使治疗失败率降低约42%。
预计在未来六年内，增加ASAQ的采用率和覆盖率将在减少乌干达疟疾治疗失败病例数方面发挥重要作用。由于私营部门继续使用AL，公共部门部署ASAQ和DHA-PPQ可形成公私合营的抗疟药物MFT组合。DHA-PPQ的部署应伴随对哌喹抗性基因型的实时分子监测。
