key: cord-0291495-h27kaht6
authors: Zupko, R.; Nguyen, T. D.; Some, A. F.; Tran, T. N.-A.; Gerardin, J.; Dudas, P.; Giang, D. D. H.; Wesolowski, A.; Ouedraogo, J.-B.; Boni, M. F.
title: Long-term effects of increased adoption of artemisinin combination therapies in Burkina Faso
date: 2021-08-23
journal: nan
DOI: 10.1101/2021.08.20.21262380
sha: 4d4a8039d68fa7082560da77b0549db3d901ede3
doc_id: 291495
cord_uid: h27kaht6

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. To explore how the increased adoption of ACTs may affect the high-burden high-impact malaria setting of Burkina Faso, we added spatial structure to a validated individual-based stochastic model of P. falciparum transmission and evaluated long-term effects of increased ACT use. We explored how de novo emergence of artemisinin-resistant genotypes 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 reduce the long-run treatment failures. An MFT policy with equal deployment of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PPQ) may accelerate near-term drug resistance and treatment failure rates, 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 better long-term outcomes than using AL alone but may be difficult to implement in practice.

Despite the United Nations' Millennium Development Goals leading to substantial reductions in the global 42 burden of infectious disease, malaria remains a serious public health risk in many parts of Africa, Asia, and 43

South America. Plasmodium falciparum malaria remains holoendemic in at least eleven countries, mainly 44 in western and central Africa, and these countries have recently come under a WHO grouping called high-45 burden high-impact (HBHI) which recognizes that the most severely affected malaria-endemic countries 46 will require additional resources and greater policy imagination (WHO 2019, p. 24). The two primary 47 concerns in HBHI countries are high and widespread vectorial capacity and insufficient access to high- treatment distribution was modified to include private-market elimination, MFT, or both. We investigated 142 scenarios where immediate or gradual (phased in over ten years) implementation of MFT and private market 143 elimination occurred (see Supplemental Table 1) . 144

As expected, a focus solely upon the elimination of the private market results in an increase in the 145 frequency of 580Y due to the resulting increase in ACT usage (Fig. 3) . Under the rapid elimination scenario, 146 the national median frequency of 580Y rises to 0.106 (IQR 0.010 -0.113) by model year 2038, while under 147 a ten-year elimination strategy median 580Y frequency in 2038 is slightly lower at 0.085 (IRQ 0.081 -148 0.091). Elimination of the private market has a favorable outcome on treatment failures due to their 149 reduction in relation to the baseline scenario, with a rapid elimination resulting in a failure rate of 8.88% 150 (IRQ 8.80% -8.97%) in model year 2038 and a ten-year phase out resulting in a slightly lower rate of 8.58% 151 (IRQ 8.53% -8.65%). This reduction in treatment failures in comparison to the baseline configuration (23% 152 reduction for rapid elimination, and 26% reduction for ten-year phase-out), despite the higher 580Y 153 frequency, highlights the value in ensuring that individuals use highly efficacious treatments when 154 presenting with malaria. Note that the model predicts that the intermediate option (10-year phase-out) is the 155 best long-term approach for reducing treatment failures, highlighting the combined effects of artemisinin-156 resistance evolution and high-efficacy treatment access that need to be considered in long-term drug-157 resistance planning. 158

In contrast to the elimination of the private market, the model suggests that the introduction of MFT 159

with an equal distribution of AL and DHA-PPQ would have a negative effect on treatment failure rates due 160 to a more rapid acceleration in 580Y frequency (Fig. 4) year 2038 of 24.92% (IQR 24.58% -25.14%) and 580Y frequency of 0.532 (0.513 -0.545) by the end of 170 the simulation. This pattern of increased 580Y frequency is observed across all permutations of private 171 market elimination and MFT adoption rates (Table 1) . 172

This adverse MFT outcome is attributable to the increased usage of DHA-PPQ as the co-equal first-173 line therapy. Typically, MFT policies result in better long-term drug-resistance outcomes due to the 174 heterogeneous drug environments they create (Boni et al. 2008; Boni et al. 2016 ). However, these analyses 175 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted August 23, 2021. ; https://doi.org/10.1101/2021.08.20.21262380 doi: medRxiv preprint assume that all therapies distributed in an MFT policy are equally efficacious and have identical drug-176 resistance properties. This is not the case when comparing DHA-PPQ and AL, as piperaquine (PPQ) 177 resistance leads to higher levels of treatment failure when compared to lumefantrine resistance (Nguyen et 178 al. 2021) . In contrast to the baseline scenario with limited DHA-PPQ usage (5.1%), or the nominal increase 179 resulting from private market elimination (6.2%), introduction of MFT results in DHA-PPQ usage in 46.1% 180 of treatments when coupled with private market elimination (Supplemental Table 1 range from 60% to 90% AL use (Supplemental Table 1 ). When AL is used as a sole first-line therapy for 194 uncomplicated malaria, the 580Y frequency reaches 0.115 (IQR 0.109 -0.119) by model year 2038 with a 195 treatment failure rate below that of the status quo scenario of 9.16% (IQR 9.09% -9.21%). When MFT is 196 introduced using DHA-PPQ (10% of treatments) and AL (90%) the results by model year 2038 show a 197 small reduction in the 580Y frequency (0.111, IQR 0.103 -0.117) and treatment failure rate (9.14%, IQR 198 9.04% -9.22%) when compared to the AL as the sole first-line therapy. However, when the usage of DHA-199 PPQ is increased to 20% or higher, there is an increase in 580Y frequencies along with treatment failure 200 rates by model year 2038 (Table 1 , Fig.7) . is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 23, 2021. ; https://doi.org/10.1101/2021.08.20.21262380 doi: medRxiv preprint symptomatic/asymptomatic individuals during the rainy season, resulting in increased evolutionary 210 pressure favoring drug resistance due to a higher proportion of P. falciparum infections being treated. The 211 reason for the increase in the symptomatic/asymptomatic ratio during peak transmission likely results from 212 several factors, namely, (i) a lower population-average level of immunity at the beginning of the high 213 transmission season, (ii) possibility for multiple bites and repeat symptoms for individuals with low 214 immunity, and (iii) correlation between low biting attractiveness and low immunity which will skew the 215 ratio of bites on immunes/non-immunes from low to high transmission periods. Although the seasonal trend 216 in drug-resistance frequency was up during the rainy season and down or flat during the dry season, the 217 overall long-term trend remained upward with increasing drug resistance. 218 219 Discussion 220

While the evolution of drug resistance by the P. falciparum parasite is a pressing concern, in HBHI 221 countries drug resistance evolution is secondary to the need to increase access to and usage of ACTs. Once 222 access to ACTs is near universal, more attention should be turned towards the future impacts of drug 223 This study highlights the need for ACT partner-drug resistance awareness, particularly when partner-242 drug resistance has already been identified (Leroy et al. 2019 ). In the long term, drug resistance is expected 243 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 23, 2021. ; https://doi.org/10.1101/2021.08.20.21262380 doi: medRxiv preprint to evolve in all scenarios where population-level drug-use is sufficiently high, but resistance does not imply 244 complete loss of efficacy. For example, in the case of lumefantrine, the efficacy of AL remains high at 89% 245 on lumefantrine-resistant genotypes ); however, DHA-PPQ efficacy drops to 77% when 246 PPQ resistant parasites are present ). Ultimately, the partner drug moderates the pace at 247 which artemisinin resistance can emerge, rapid acquisition of resistance to the partner drug results in an 248 acceleration of artemisinin resistance due to usage of ACT as a 'de facto monotherapy' because of low 249 efficacy of the partner drug . MFT is not implemented, then this study suggests that the overall rate of treatment failures will go down as 253 the public switches to more efficacious treatments. While the selective pressure on the parasite will increase, 254 an increase in selective pressure is assumed regardless of intervention due to efforts to increase access to 255

ACTs. Furthermore, this study suggests that the timeframe for gaining benefits from private market 256 elimination may be quite broad. While elimination is unlikely outside of a model, phasing the private market 257 over ten years may be achievable. 258

Any modeling exercise is dependent upon assumptions and simplifications that may impact the results. resistance and an end to the current "calm before the storm" suggested by Conrad and Rosenthal (2019) . 291

This transition is inevitable. ACT access is likely to increase in the coming years, reducing case numbers 292 but increasing the selection pressure of artemisinin-resistant genotypes. Preparation, prevention, and 293 preemption during this high-risk period for drug-resistance emergence will be key to ensuring that first-line 294 treatment against P. falciparum continue working at high efficacy in the 2020s and 2030s. In order to calibrate the model for Burkina Faso, we started by first preparing geographic 306 information system (GIS) raster files for the country at the scale of 5km-by-5km pixels (or cells). These landscape, carrying any parasite colonies that they may be infected with as well. Data is collected from the 311 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 23, 2021. Table 6 ). The remaining five drug policy scenarios were designed to evaluate 372 the impact of various MFT mixes of AL and DHA-PPQ ranging from 100% AL to 50% AL by 10% 373 reductions in AL usage. Since the intent of these scenarios is to evaluate the impact of the MFT drug mixture 374 on the emergence of resistance, rapid private market elimination was used for all of them. 375 376 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 23, 2021. ; https://doi.org/10.1101/2021.08.20.21262380 doi: medRxiv preprint

Spatial raster files used in the simulation and long with intermediary files used for analysis and plot 378 generation can be found at https://github.com/bonilab/malariaibm-spatial-BurkinaFaso- CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 23, 2021. ; https://doi.org/10.1101/2021.08.20.21262380 doi: medRxiv preprint market, the treatment failure rate drops, which is expected given the elimination of less efficacious 587

treatments. Introduction of MFT plus elimination of the private market has a similar positive outcome; 588 however, this is rapidly offset by the increased treatment failure rate due to the increasing frequency of 589 plasmepsin-2,3 double-copy genotypes. 590 591 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) plasmepsin-2,3 genotypes after DHA-PPQ is introduced at high levels in 2021. Double-copy plasmepsin-2,3 genotypes (blue) are strongly selected 594

for after DHA-PPQ is introduced, which contrasts with the slower pace of 580Y evolution (orange). This rapid increase in the frequency of the 595 double-copy plasmepsin-2,3 genotypes result from the low efficacy of DHA-PPQ on these genotypes (77% efficacy on C580 and 42% on 580Y).

KNF genotypes (green) show the most resistance to lumefantrine, but the efficacy of AL on a KNF genotypes is 89% (C580) or 72% (580Y) making 597 the selection pressure exerted by AL weaker than the selection pressure exerted by DHA-PPQ. 598 599 Fig. 6: Comparison of plasmepsin-2,3 double-copy frequency under various drug policies. Under 600 policies of private market elimination, there is little effect on DHA-PPQ usage and thus low pressure on 601 plasmepsin-2,3 evolution. When MFT is introduced, the usage of DHA-PPQ increases substantially, 602

resulting in rapid selection of double-copy plasmepsin-2,3 genotypes. 603 604 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted August 23, 2021. ; https://doi.org/10.1101/2021.08.20.21262380 doi: medRxiv preprint loss of PPQ efficacy due to plasmepsin-2,3 double-copy emergence is correlated with the rate at which the 607 580Y frequency increases. 608 609 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted August 23, 2021. ; https://doi.org/10.1101/2021.08.20.21262380 doi: medRxiv preprint 

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