Mapping the prevalence of molecular markers of Plasmodium falciparum artemisinin partial resistance in Africa: a systematic review and spatiotemporal modelling study.

内容摘要

Plasmodium falciparum kelch13(k13) mutations in Africa signal emerging artemisinin partial resistance (ART-R), endangering malaria control by undermining artemisinin-based combination therapies (ACTs). Sparse surveillance obscures whether rising k13 ART-R prevalence reflects local emergence or geographical expansion. We aimed to model and infer high-resolution spatiotemporal prevalence of k13 ART-R mutations, as well as mdr1 and crt mutations (markers of reduced susceptibility to ACT partner drugs), to inform public health policy. For this systematic review and modelling analysis, we searched PubMed, Ovid MEDLINE, and Web of Science databases for English-language primary studies reporting malaria resistance, conducted in Africa, reporting pretreatment P falciparum samples with genotyping of k13 (all codons), mdr1 N86Y, or crt K76T, and that provided sufficient survey time and location metadata and complete, primary data, published between Sept 25, 2014, and July 9, 2025, with data extracted from full-text reports. Studies identified during the systematic review were added to 11 privately held datasets that met the same eligibility criteria but were unpublished at the time of review to give the augmented systematic review. Studies from the augmented systematic review were added to existing data from the Worldwide Antimalarial Resistance Network molecular surveyor (WWARN), MalariaGEN Pf8, and the WHO malaria threats map (WHO MTM), with any duplicates removed. The integrated dataset was harmonised by use of a standardised data schema. We estimated the continuous prevalence of each mutation using a spatiotemporal Gaussian process model and summarised with median and 95% credible intervals over posterior draws. The study was registered with PROSPERO (CRD42024593923). We identified 1119 articles during the database search, with 120 studies included in the final analysis. These were augmented with 11 privately held datasets. In total, the augmented systematic review identified 131 unique studies. Data from public repositories (WWARN, Pf8, and WHO MTM) provided an additional 447 studies after removal of duplicates. The final dataset included 93 887 samples sequenced at target k13 positions and 185 099 samples sequenced for either k13, crt K76T, or mdr1 N86Y, drawn from 578 studies encompassing 3848 distinct surveys across 47 African countries. Modelling showed distinct emergences of k13 R561H in Rwanda, k13 A675V and C469Y in Uganda, and k13 R622I in Ethiopia and Eritrea. The highest predicted prevalence of k13 mutations in 2024 was observed in Northern Province, Rwanda, at 62·2% (95% credible interval 3·9-98·6), increasing from 0·2% (0·0-0·7) in 2012 at an average annual increase of 5·2 percentage points. Modelling indicated a rapid transition from localised k13 ART-R mutation emergence to entrenched regional hot spots covering most of Uganda and Rwanda, and similarly at the border of Ethiopia, Eritrea, and Sudan. Prevalence of mdr1 N86Y, a marker of partner-drug amodiaquine reduced susceptibility, is fading, but crt K76T remains prevalent in the Horn of Africa. The rapid, multicentric expansion of k13 ART-R mutations in east Africa threatens ACT efficacy, especially where k13 and markers of reduced susceptibility to partner drugs, such as mdr1 N86Y, or crt K76T, co-occur. This study provides an updated k13 ART-R mutation database and high-resolution resistance maps with uncertainty quantification, supporting targeted surveillance to identify hot spots and prioritise therapeutic efficacy studies. US National Institutes of Health.