Biology subjects

Tran, T. N.-A.

Publications and source records attributed to Tran, T. N.-A..

5 recordsLinked to original sources

bioRxiv2024

Effects of recombination on multi-drug resistance evolution in Plasmodium falciparum malaria

When multiple beneficial alleles are present in a population but not linked together in any one individual, there is no general evolutionary result that determines whether recombination will speed up or slow down the emergence and evolution of genotypes carrying multiple beneficial alleles. Translated to infectious disease control, this evolutionary uncertainty means that when multiple types of drug resistance are present we do not know whether recombination will act more strongly to (1) bring together single-resistant genotypes into multi-drug resistant (MDR) genotypes, or (2) break apart MDR genotypes into single-resistant genotypes. In this paper, we introduce a new version of an established and validated individual-based malaria transmission model where we have added individual mosquito bites, interrupted feeding by mosquitoes, 25 drug-resistance related loci, and individual recombination events of different Plasmodium falciparum genotypes inside the mosquito. Recombination among P. falciparum genotypes in this model occurs from two sources of variation, multi-clonal infections and interrupted feeding by mosquitoes, and we show that 80% to 97% of MDR recombinant falciparum genotypes are projected to occur from single uninterrupted bites on hosts with multi-clonal infections (for malaria prevalence > 5%). Increases in the models interrupted feeding rate slowly increase the number of recombination events occurring from interrupted feeds. A comparison of drug-resistance management strategies with this new model shows that, over a 15-year timeframe, triple artemisinin-combination therapies (ACT) strategies show the largest reductions in treatment failures and the longest delays until artemisinin resistance reaches a critical 1% threshold. Multiple first-line therapies (MFT) are second best under these criteria, and ACT cycling approaches are third best. MFT strategies generate a greater diversity of recombinant genotypes but fewer recombination events generating MDR and slower emergence of these recombinant MDR genotypes.

evolutionary biology↗

bioRxiv2023

Role of Seasonal Importation and Random Genetic Drift on Selection for Drug-Resistant Genotypes of Plasmodium falciparum in High Transmission Settings

Historically Plasmodium falciparum has followed a pattern of drug resistance first appearing in low transmission settings before spreading to high transmission settings. Several features of low-transmission regions are hypothesized as explanations: higher chance of symptoms and treatment seeking, better treatment access, less within-host competition among clones, and lower rates of recombination. Here, we test whether importation of drug-resistant parasites is more likely to lead to successful emergence and establishment in low-transmission or high-transmission periods of the same epidemiological setting, using a spatial, individual-based stochastic model of malaria and drug-resistance evolution calibrated for Burkina Faso. Upon controlling for the timing of importation of drug-resistant genotypes and examination of key model variables, we found that drug-resistant genotypes imported during the low transmission season were, (1) more susceptible to stochastic extinction due to the action of random genetic drift, and (2) more likely to lead to establishment of drug resistance when parasites are able to survive early stochastic loss due to drift. This implies that rare importation events are more likely to lead to establishment if they occur during a high-transmission season, but that constant importation (e.g., neighboring countries with high levels of resistance) may produce a greater risk during low-transmission periods.

genetics↗

bioRxiv2022

Assessing emergence risk of double-resistant and triple-resistant genotypes of Plasmodium falciparum

Delaying and slowing antimalarial drug resistance evolution is a priority for the World Health Organization and for National Malaria Control Programs in malaria-endemic countries. Until novel therapies become available, the mainstay of antimalarial treatment will continue to be artemisinin combination therapy (ACT), with artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine the three primary therapies deployed worldwide. Deployment of ACTs can be optimized to minimize evolutionary pressure for drug resistance by deploying them as a set of co-equal multiple first-line therapies (MFT) rather than rotating therapies in and out of use. Here, we consider one potential detriment of MFT policies, namely, that the simultaneous deployment of multiple ACTs could drive the evolution of different resistance alleles concurrently and that these resistance alleles could then be brought together by recombination into double-resistant or triple-resistant parasites. Using an individual-based Plasmodium falciparum transmission model, we compare MFT and cycling policies over 20-year periods in malaria transmission settings ranging from 0.1% to 25% Plasmodium falciparum prevalence (PfPR2-10). We define a total risk measure for multi-drug resistance (MDR) by summing the area under the genotype-frequency curves (AUC) of double- and triple-resistant genotypes. When PfPR [≥] 1%, total MDR risk as measured by AUC is 4% to 90% lower under MFT policies than under cycling policies, irrespective of whether resistance is imported or emerges de novo. When PfPR = 0.1%, there is little statistical difference in MDR risk between MFT and cycling.

evolutionary biology↗

bioRxiv2021

Pre-existing partner-drug resistance facilitates the emergence and spread of artemisinin resistance: a consensus modelling study

BackgroundArtemisinin-resistant genotypes have now emerged a minimum of five 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. MethodsUsing a consensus modelling approach with three individual-based mathematical models of Plasmodium falciparum transmission, we evaluate the effects of pre-existing partner-drug resistance and ACT deployment on artemisinin resistance evolution. We evaluate settings where dihydroartemisinin-piperaquine (DHA-PPQ), artesunate-amodiaquine (ASAQ), or artemether-lumefantrine (AL) are deployed as first-line therapy. We use time until 0.25 artemisinin resistance allele frequency (the establishment time) as the primary outcome measure. FindingsHigher frequencies of pre-existing partner-drug resistant genotypes lead to earlier establishment of artemisinin resistance. Across all scenarios and pre-existing frequencies of partner-drug resistance explored, a 0.10 increase in partner-drug resistance frequency on average corresponded to 0.7 to 5.0 years loss of artemisinin efficacy. However, the majority of reductions in time to artemisinin establishment were observed after the first increment from 0.0 to 0.10 partner-drug resistance genotype frequency. InterpretationPartner-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 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. FundingBill and Melinda Gates Foundation; Wellcome Trust.

genetics↗

bioRxiv2021

Antimalarial mass drug administration in large populations and the evolution of drug resistance

Mass drug administration (MDA) with antimalarials has been shown to reduce prevalence and interrupt transmission in small populations, in populations with reliable access to antimalarial drugs, and in populations where sustained improvements in diagnosis and treatment are possible. Effective MDA eliminates drug-resistant parasites which has the long-term benefit of extending the useful therapeutic life of first-line therapies for all populations, not just the focal population where MDA was carried out. However, in order to plan elimination measures effectively, it is necessary to characterize the conditions under which failed MDA could exacerbate resistance. We use an individual-based stochastic model of Plasmodium falciparum transmission to evaluate this risk in large populations (>40K) where access to antimalarial treatments may not be uniformly high and where re-importation of drug-resistant parasites may be common. We find that drug-resistance evolution can be accelerated by MDA when all three of the following conditions are met: (1) strong genetic bottlenecking that falls short of elimination, (2) re-importation of resistant genotypes, and (3) continued selection pressure during routine case management post-MDA. Accelerated resistance levels are not immediate but follow the rebound of malaria cases post-MDA, if this is allowed to occur. Crucially, resistance is driven by the selection pressure during routine case management post-MDA and not the selection pressure exerted during the MDA itself. Second, we find that increasing treatment coverage post-MDA increases the probability of local elimination in low-transmission regions (PfPR < 2%) in scenarios with both low and high levels of drug-resistance importation. This emphasizes the importance of preparation and planning to ensure that MDA has a high probability of leading to elimination, and the necessity of supporting public health infrastructure to provide high coverage of diagnosis and treatment post-MDA.

evolutionary biology↗