Artemisinin combination therapies (ACTs) are highly effective at treating uncomplicated Plasmodium falciparum malaria, but the emergence of the new pfkelch13 R561H mutation in Rwanda, associated with delayed parasite clearance, suggests that interventions are needed to slow its spread. Using a Rwanda-specific spatial calibration of an individual-based malaria model, we evaluate 26 strategies aimed at minimizing treatment failures and delaying the spread of R561H after 3, 5 and 10 years. Lengthening ACT courses and deploying multiple first-line therapies (MFTs) reduced treatment failures after 5 years when compared to the current approach of a 3-d course of artemether–lumefantrine. The best among these options (an MFT policy) resulted in median treatment failure counts that were 49% lower and a median R561H allele frequency that was 0.15 lower than under baseline. New approaches to resistance management, such as triple ACTs or sequential courses of two different ACTs, were projected to have a larger impact than longer ACT courses or MFT; these were associated with median treatment failure counts in 5 years that were 81–92% lower than the current approach. A policy response to currently circulating artemisinin-resistant genotypes in Africa is urgently needed to prevent a population-wide rise in treatment failures.

Since their first detection in 2010, Plasmodium falciparum malaria parasites lacking the P. falciparum histidine-rich protein 2 gene (pfhrp2) have been observed in 40 of 47 surveyed countries, as documented by the World Health Organization. These genetic deletions reduce detection by the most widely used rapid diagnostic tests, prompting three countries to switch to alternative diagnostics. However, manufacturing of alternative rapid diagnostic tests has not been scaled up and there are no World Health Organization-prequalified combination tests that use P. falciparum Plasmodium lactate dehydrogenase. The continuing spread of pfhrp2 and/or pfhrp3 (pfhrp2/3) deletions threatens malaria control, creating an emerging public health crisis. Here we use mathematical modeling informed by current pfhrp2/3 deletion prevalence and a literature review to assess the global risk of pfhrp2 /3 deletions. We identify ten priority countries for surveillance and predict that the primary spread in Africa will move southward from the Horn of Africa through East Africa within 20 years. Despite variation in modeled timelines due to uncertainty in model parameters, four countries yet to switch rapid diagnostic tests are consistently classified as high risk under a range of model assumptions. This updated model offers refined predictions to guide pfhrp2/3 policy and prioritize future surveillance efforts and innovation.

Artemisinin combination therapies (ACTs) are the WHO-recommended first-line therapies for uncomplicated Plasmodium falciparum malaria. The emergence and spread of artemisinin-resistant genotypes is a major global public health concern due to the increased rate of treatment failures that result. This is particularly germane for WHO designated ‘high burden to high impact’ (HBHI) countries, such as Burkina Faso, where there is increased emphasis on improving guidance, strategy, and coordination of local malaria response in an effort to reduce the prevalence of P. falciparum malaria. To explore how the increased adoption of ACTs may affect the HBHI malaria setting of Burkina Faso, we added spatial structure to a validated individual-based stochastic model of P. falciparum transmission and evaluated the long-term effects of increased ACT use. We explored how de novo emergence of artemisinin-resistant genotypes, such as pfkelch13 580Y, may occur under scenarios in which private-market drugs are eliminated or multiple first-line therapies (MFT) are deployed. We found that elimination of private market drugs would result in lower treatment failures rates (between 11.98% and 12.90%) when compared to the status quo (13.11%). However, scenarios incorporating MFT with equal deployment of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PPQ) may accelerate near-term drug resistance (580Y frequency ranging between 0.62 to 0.84 in model year 2038) and treatment failure rates (26.69% to 34.00% in 2038), due to early failure and substantially reduced treatment efficacy resulting from piperaquine-resistant genotypes. A rebalanced MFT approach (90% AL, 10% DHA-PPQ) results in approximately equal long-term outcomes to using AL alone but may be difficult to implement in practice.

In the thirteen years since the first report of pfhrp2 -deleted parasites in 2010, the World Health Organization (WHO) has found that 40 of 47 countries surveyed worldwide have reported pfhrp2/3 gene deletions. Due to a high prevalence of pfhrp2/3 deletions causing false-negative HRP2 RDTs, in the last five years, Eritrea, Djibouti and Ethiopia have switched or started switching to using alternative RDTs, that target pan-specific-pLDH or P. falciparum specific-pLDH alone of in combination with HRP2. However, manufacturing of alternative RDTs has not been brought to scale and there are no WHO prequalified combination tests that use Pf-pLDH instead of HRP2 for P. falciparum detection. For these reasons, the continued spread of pfhrp2/3 deletions represents a growing public health crisis that threatens efforts to control and eliminate P. falciparum malaria. National malaria control programmes, their implementing partners and test developers desperately seek pfhrp2/3 deletion data that can inform their immediate and future resource allocation. In response, we use a mathematical modelling approach to evaluate the global risk posed by pfhrp2/3 deletions and explore scenarios for how deletions will continue to spread in Africa. We incorporate current best estimates of the prevalence of pfhrp2/3 deletions and conduct a literature review to estimate model parameters known to impact the selection of pfhrp2/3 deletions for each malaria endemic country. We identify 20 countries worldwide to prioritise for surveillance and future deployment of alternative RDT, based on quickly selecting for pfhrp2/3 deletions once established. In scenarios designed to explore the continued spread of deletions in Africa, we identify 10 high threat countries that are most at risk of deletions both spreading to and subsequently being rapidly selected for. If HRP2-based RDTs continue to be relied on for malaria case management, we predict that the major route for pfhrp2 deletions to spread is south out from the current hotspot in the Horn of Africa, moving through East Africa over the next 20 years. We explore the variation in modelled timelines through an extensive parameter sensitivity analysis and despite wide uncertainties, we identify three countries that have not yet switched RDTs (Senegal, Zambia and Kenya) that are robustly identified as high risk for pfhrp2/3 deletions. These results provide a refined and updated prediction model for the emergence of pfhrp2/3 deletions in an effort to help guide pfhrp2/3 policy and prioritise future surveillance efforts and innovation.