Modelling the drivers of the spread of Plasmodium falciparum hrp2 gene deletions in sub-Saharan Africa

Rapid diagnostic tests (RDTs) have transformed malaria diagnosis. The most prevalent P. falciparum RDTs detect histidine-rich protein 2 (PfHRP2). However, pfhrp2 gene deletions yielding false-negative RDTs, first reported in South America in 2010, have been confirmed in Africa and Asia. We developed a mathematical model to explore the potential for RDT-led diagnosis to drive selection of pfhrp2-deleted parasites. Low malaria prevalence and high frequencies of people seeking treatment resulted in the greatest selection pressure. Calibrating our model against confirmed pfhrp2-deletions in the Democratic Republic of Congo, we estimate a starting frequency of 6% pfhrp2-deletion prior to RDT introduction. Furthermore, the patterns observed necessitate a degree of selection driven by the introduction of PfHRP2-based RDT-guided treatment. Combining this with parasite prevalence and treatment coverage estimates, we map the model-predicted spread of pfhrp2-deletion, and identify the geographic regions in which surveillance for pfhrp2-deletion should be prioritised.

[1]  Jacob Bodilsen,et al.  [Plasmodium falciparum]. , 2022, Ugeskrift for laeger.

[2]  M. Gatton,et al.  Malaria rapid diagnostic test performance : results of WHO product testing of malaria RDTs : round 5 (2013) , 2018 .

[3]  C. Karema,et al.  False-negative malaria rapid diagnostic tests in Rwanda: impact of Plasmodium falciparum isolates lacking hrp2 and declining malaria transmission , 2017, Malaria Journal.

[4]  Mulugeta Russom,et al.  Rapid diagnostic tests failing to detect Plasmodium falciparum infections in Eritrea: an investigation of reported false negative RDT results , 2017, Malaria Journal.

[5]  Hannah C. Slater,et al.  Pfhrp2-Deleted Plasmodium falciparum Parasites in the Democratic Republic of the Congo: A National Cross-sectional Survey , 2016, The Journal of infectious diseases.

[6]  Oz Sahin,et al.  An integrated risk and vulnerability assessment framework for climate change and malaria transmission in East Africa , 2016, Malaria Journal.

[7]  Nigeria..  Nigeria Malaria Indicator Survey 2015 , 2016 .

[8]  P. Gething,et al.  Potential for reduction of burden and local elimination of malaria by reducing Plasmodium falciparum malaria transmission: a mathematical modelling study. , 2016, The Lancet. Infectious diseases.

[9]  L. Amoah,et al.  Plasmodium falciparum histidine rich protein-2 diversity and the implications for PfHRP 2: based malaria rapid diagnostic tests in Ghana , 2016, Malaria Journal.

[10]  U. Dalrymple,et al.  The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015 , 2015, Nature.

[11]  A. Ghani,et al.  Gradual acquisition of immunity to severe malaria with increasing exposure , 2015, Proceedings of the Royal Society B: Biological Sciences.

[12]  C. Shiff,et al.  Comparison of a PfHRP2-based rapid diagnostic test and PCR for malaria in a low prevalence setting in rural southern Zambia: implications for elimination , 2015, Malaria Journal.

[13]  A. M. de Oliveira,et al.  Prevalence of pfhrp2 and pfhrp3 gene deletions in Puerto Lempira, Honduras , 2015, Malaria Journal.

[14]  Peter Chiodini,et al.  Plasmodium falciparum parasites lacking histidine-rich protein 2 and 3: a review and recommendations for accurate reporting , 2014, Malaria Journal.

[15]  Neil M. Ferguson,et al.  Estimates of the changing age-burden of Plasmodium falciparum malaria disease in sub-Saharan Africa , 2014, Nature Communications.

[16]  A. M. de Oliveira,et al.  Multiple genetic origins of histidine-rich protein 2 gene deletion in Plasmodium falciparum parasites from Peru , 2013, Scientific Reports.

[17]  D. Rhodes,et al.  Superconductivity with extremely large upper critical fields in Nb$_{2}$Pd$_{0.81}$S$_{5}$ , 2013 .

[18]  S. Briolant,et al.  Pfhrp2 and pfhrp3 polymorphisms in Plasmodium falciparum isolates from Dakar, Senegal: impact on rapid malaria diagnostic tests , 2013, Malaria Journal.

[19]  Justin M. Cohen,et al.  Optimizing Investments in Malaria Treatment and Diagnosis , 2012, Science.

[20]  C. Karema,et al.  Sequence variation does not confound the measurement of plasma PfHRP2 concentration in African children presenting with severe malaria , 2012, Malaria Journal.

[21]  O. Doumbo,et al.  False-negative rapid diagnostic tests for malaria and deletion of the histidine-rich repeat region of the hrp2 gene. , 2012, The American journal of tropical medicine and hygiene.

[22]  P. Gething,et al.  Estimating the Number of Paediatric Fevers Associated with Malaria Infection Presenting to Africa's Public Health Sector in 2007 , 2010, PLoS medicine.

[23]  M. Perkins,et al.  A Large Proportion of P. falciparum Isolates in the Amazon Region of Peru Lack pfhrp2 and pfhrp3: Implications for Malaria Rapid Diagnostic Tests , 2010, PloS one.

[24]  A. Lambert,et al.  Allele fixation in a dynamic metapopulation: founder effects vs refuge effects. , 2009, Theoretical population biology.

[25]  Icf Macro.  Liberia Malaria Indicator Survey 2009 , 2009 .

[26]  J. Andersen,et al.  HDP—A Novel Heme Detoxification Protein from the Malaria Parasite , 2008, PLoS pathogens.

[27]  J. Baker,et al.  Genetic diversity of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) and its effect on the performance of PfHRP2-based rapid diagnostic tests. , 2005, The Journal of infectious diseases.

[28]  M. Foley,et al.  Histidine-rich protein 2 of the malaria parasite, Plasmodium falciparum, is involved in detoxification of the by-products of haemoglobin degradation. , 2001, Molecular and biochemical parasitology.

[29]  S. Ratan.  Review: The Rising Tide of Cultural Pluralism: The Nation-State at Bay edited by Crawford Young and The State of the World's Refugees: The Challenge of Protection by United Nations High Commissioner for Refugees , 1994 .

[30]  C. Dolea,et al.  World Health Organization , 1949, International Organization.

[31]  Target Audience.  False-negative RDT results and implications of new reports of P . falciparum histidine-rich protein 2 / 3 gene deletions , 2016 .

[32]  Gao Qi,et al.  Global technical strategy for malaria 2016–2030 , 2015 .

[33]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[34]  C. Vega.  United Nations High Commissioner for Refugees (UNHCR) , 2013 .

[35]  Diego F. Echeverry,et al.  Global sequence variation in the histidine-rich proteins 2 and 3 of Plasmodium falciparum: implications for the performance of malaria rapid diagnostic tests. , 2022 .

[36]  Organización Mundial de la Salud.  Guidelines for the treatment of malaria , 2010 .

[37]  J. Woolliams,et al.  What is Genetic Diversity , 2007 .