How could preventive therapy affect the prevalence of drug resistance? Causes and consequences

Various forms of preventive and prophylactic antimicrobial therapies have been proposed to combat HIV (e.g. pre-exposure prophylaxis), tuberculosis (e.g. isoniazid preventive therapy) and malaria (e.g. intermittent preventive treatment). However, the potential population-level effects of preventative therapy (PT) on the prevalence of drug resistance are not well understood. PT can directly affect the rate at which resistance is acquired among those receiving PT. It can also indirectly affect resistance by altering the rate at which resistance is acquired through treatment for active disease and by modifying the level of competition between transmission of drug-resistant and drug-sensitive pathogens. We propose a general mathematical model to explore the ways in which PT can affect the long-term prevalence of drug resistance. Depending on the relative contributions of these three mechanisms, we find that increasing the level of coverage of PT may result in increases, decreases or non-monotonic changes in the overall prevalence of drug resistance. These results demonstrate the complexity of the relationship between PT and drug resistance in the population. Care should be taken when predicting population-level changes in drug resistance from small pilot studies of PT or estimates based solely on its direct effects.

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Modeling Prevention of Malaria and Selection of Drug Resistance with Different Dosing Schedules of Dihydroartemisinin-Piperaquine Preventive Therapy during Pregnancy in Uganda

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01393-18 ◽

2018 ◽

Vol 63 (2) ◽

pp. e01393-18

Author(s):

Erika Wallender ◽

Nan Zhang ◽

Melissa Conrad ◽

Abel Kakuru ◽

Mary Muhindo ◽

...

Keyword(s):

Drug Resistance ◽

Intermittent Preventive Treatment ◽

Preventive Treatment ◽

Preventive Therapy ◽

Wild Type ◽

Content Type ◽

Mixed Effects Modeling ◽

Selection For ◽

Log Linear ◽

Selection Of

ABSTRACT Dihydroartemisinin-piperaquine (DHA-PQ) is under study for intermittent preventive treatment during pregnancy (IPTp), but it may accelerate selection for drug resistance. Understanding the relationships between piperaquine concentration, prevention of parasitemia, and selection for decreased drug sensitivity can inform control policies and optimization of DHA-PQ dosing. Piperaquine concentrations, measures of parasitemia, and Plasmodium falciparum genotypes associated with decreased aminoquinoline sensitivity in Africa (pfmdr1 86Y, pfcrt 76T) were obtained from pregnant Ugandan women randomized to IPTp with sulfadoxine-pyrimethamine (SP) or DHA-PQ. Joint pharmacokinetic/pharmacodynamic models described relationships between piperaquine concentration and the probability of genotypes of interest using nonlinear mixed effects modeling. An increase in the piperaquine plasma concentration was associated with a log-linear decrease in risk of parasitemia. Our models predicted that higher median piperaquine concentrations would be required to provide 99% protection against mutant infections than against wild-type infections (pfmdr1: N86, 9.6 ng/ml; 86Y, 19.6 ng/ml; pfcrt: K76, 6.5 ng/ml; 76T, 19.6 ng/ml). Comparing monthly, weekly, and daily dosing, daily low-dose DHA-PQ was predicted to result in the fewest infections and the fewest mutant infections per 1,000 pregnancies (predicted mutant infections for pfmdr1 86Y: SP monthly, 607; DHA-PQ monthly, 198; DHA-PQ daily, 1; for pfcrt 76T: SP monthly, 1,564; DHA-PQ monthly, 283; DHA-PQ daily, 1). Our models predict that higher piperaquine concentrations are needed to prevent infections with the pfmdr1/pfcrt mutant compared to those with wild-type parasites and that, despite selection for mutants by DHA-PQ, the overall burden of mutant infections is lower for IPTp with DHA-PQ than for IPTp with SP. (This study has been registered at ClinicalTrials.gov under identifier NCT02282293.)

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History of household member with tuberculosis or related death in newly diagnosed patients in India

Public Health Action ◽

10.5588/pha.19.0057 ◽

2020 ◽

Vol 10 (2) ◽

pp. 53-56

Author(s):

H. D. Shewade ◽

V. Gupta ◽

S. Satyanarayana ◽

S. S. Chadha ◽

S. Pandurangan ◽

...

Keyword(s):

Pulmonary Tuberculosis ◽

Preventive Treatment ◽

Population Level ◽

Household Member ◽

Newly Diagnosed ◽

Household Contacts ◽

Household Transmission ◽

Smear Positive Pulmonary Tuberculosis ◽

History Of ◽

Potential Population

Among new smear-positive pulmonary tuberculosis (TB) patients aged 15 years from marginalised populations in India, one in four had a history of a household member with TB and one in 10 had a TB-related death in the household. This contribution of household transmission to overall TB transmission provides evidence for a potential population-level benefit of TB preventive treatment for all household contacts (without active TB). Females with TB had a significantly higher household TB exposure than males. Targeted TB preventive treatment (if implemented in a phased manner) among female household contacts may be explored after considering other factors.

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Effect of Drug Pressure on Promoting the Emergence of Antimalarial-Resistant Parasites among Pregnant Women in Ghana

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02029-19 ◽

2020 ◽

Vol 64 (6) ◽

Cited By ~ 1

Author(s):

Bernard Tornyigah ◽

Romain Coppée ◽

Pascal Houze ◽

Kwadwo A. Kusi ◽

Bright Adu ◽

...

Keyword(s):

Drug Resistance ◽

Pregnant Women ◽

Marker Gene ◽

Intermittent Preventive Treatment ◽

Artemisinin Resistance ◽

Preventive Treatment ◽

Drug Pressure ◽

Gene Markers ◽

Content Type ◽

Artemisinin Derivatives

ABSTRACT The continuous spread of antimalarial drug resistance is a threat to current chemotherapy efficacy. Therefore, characterizing the genetic diversity of drug resistance markers is needed to follow treatment effectiveness and further update control strategies. Here, we genotyped Plasmodium falciparum resistance gene markers associated with sulfadoxine-pyrimethamine (SP) and artemisinin-based combination therapy (ACT) in isolates from pregnant women in Ghana. The prevalence of the septuple IRNI-A/FGKGS/T pfdhfr/pfdhps haplotypes, including the pfdhps A581G and A613S/T mutations, was high at delivery among post-SP treatment isolates (18.2%) compared to those of first antenatal care (before initiation of intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine [IPTp-SP]; 6.1%; P = 0.03). Regarding the pfk13 marker gene, two nonsynonymous mutations (N458D and A481C) were detected at positions previously related to artemisinin resistance in isolates from Southeast Asia. These mutations were predicted in silico to alter the stability of the pfk13 propeller-encoding domain. Overall, these findings highlight the need for intensified monitoring and surveillance of additional mutations associated with increased SP resistance as well as emergence of resistance against artemisinin derivatives.

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Prevalence of chloroquine and antifolate drug resistance alleles in Plasmodium falciparum clinical isolates from three areas in Ghana

AAS Open Research ◽

10.12688/aasopenres.12825.2 ◽

2018 ◽

Vol 1 ◽

pp. 1

Author(s):

James Abugri ◽

Felix Ansah ◽

Kwaku P. Asante ◽

Comfort N. Opoku ◽

Lucas A. Amenga-Etego ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Intermittent Preventive Treatment ◽

Preventive Treatment ◽

Chloroquine Resistance ◽

Nucleotide Polymorphisms ◽

Chloroquine Resistance Transporter ◽

Significant Difference ◽

Quadruple Mutant ◽

Study Sites

Background: The emergence and spread of resistance in Plasmodium falciparum to chloroquine (CQ) necessitated the change from CQ to artemisinin-based combination therapies (ACTs) as first-line drug for the management of uncomplicated malaria in Ghana in 2005. Sulphadoxine-pyrimethamine (SP) which was the second line antimalarial drug in Ghana, was now adopted for intermittent preventive treatment of malaria in pregnancy (IPTp). Methods: To examine the prevalence of molecular markers associated with CQ and antifolate drug resistance in Ghana, we employed restriction fragment length polymorphism polymerase chain reaction to genotype and compare single nucleotide polymorphisms (SNPs) in the P. falciparum chloroquine resistance transporter ( pfcrt, PF3D7_0709000), multidrug resistance ( pfmdr1, PF3D7_0523000), bifunctional dihydrofolate reductase-thymidylate synthase ( pfdhfr, PF3D7_0417200) and dihydropteroate synthase ( pfdhps, PF3D7_0810800) genes. Parasites were collected from children with malaria reporting to hospitals in three different epidemiological areas of Ghana (Accra, Kintampo and Navrongo) in 2012-2013 and 2016-2017. Results: The overall prevalence of the CQ resistance-associated pfcrt 76T allele was 8%, whereas pfmdr1 86Y and 184F alleles were present in 10.2% and 65.1% of infections, respectively. The majority of the isolates harboured the antifolate resistance-associated pfdhfr alleles 51I (83.4%), 59R (85.9 %) and 108N (90.5%). Pfdhps 437G and 540E were detected in 90.6% and 0.7% of infections, respectively. We observed no significant difference across the three study sites for all the polymorphisms except for pfdhps 437G, which was more common in Accra compared to Kintampo for the 2016-2017 isolates. Across both pfdhfr and pfdhps genes, a large proportion (61%) of the isolates harboured the quadruple mutant combination (I 51 R 59 N 108/ G 437). CQ resistance alleles decreased during the 12 years after CQ withdrawal, but an mediate SP resistance alleles increased. Conclusion: Surveillance of the prevalence of resistance alleles is necessary in monitoring the efficacy of antimalarial drugs.

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A Trial of the Efficacy, Safety and Impact on Drug Resistance of Four Drug Regimens for Seasonal Intermittent Preventive Treatment for Malaria in Senegalese Children

PLoS ONE ◽

10.1371/journal.pone.0001471 ◽

2008 ◽

Vol 3 (1) ◽

pp. e1471 ◽

Cited By ~ 65

Author(s):

Cheikh Sokhna ◽

Badara Cissé ◽

El Hadj Bâ ◽

Paul Milligan ◽

Rachel Hallett ◽

...

Keyword(s):

Drug Resistance ◽

Intermittent Preventive Treatment ◽

Preventive Treatment ◽

Drug Regimens

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Increasing Prevalence of a Novel Triple-Mutant Dihydropteroate Synthase Genotype in Plasmodium falciparum in Western Kenya

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04961-14 ◽

2015 ◽

Vol 59 (7) ◽

pp. 3995-4002 ◽

Cited By ~ 4

Author(s):

Naomi W. Lucchi ◽

Sheila Akinyi Okoth ◽

Franklin Komino ◽

Philip Onyona ◽

Ira F. Goldman ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Mutant Allele ◽

Double Mutant ◽

Intermittent Preventive Treatment ◽

Preventive Treatment ◽

Triple Mutant ◽

Western Kenya ◽

Content Type ◽

Dihydropteroate Synthase

ABSTRACTThe molecular basis of sulfadoxine-pyrimethamine (SP) resistance lies in a combination of single-nucleotide polymorphisms (SNPs) in two genes coding forPlasmodium falciparumdihydrofolate reductase (Pfdhfr) andP. falciparumdihydropteroate synthase (Pfdhps), targeted by pyrimethamine and sulfadoxine, respectively. The continued use of SP for intermittent preventive treatment in pregnant women in many African countries, despite SP's discontinuation as a first-line antimalarial treatment option due to high levels of drug resistance, may further increase the prevalence of SP-resistant parasites and/or lead to the selection of new mutations. An antimalarial drug resistance surveillance study was conducted in western Kenya between 2010 and 2013. A total of 203 clinical samples from children with uncomplicated malaria were genotyped for SNPs associated with SP resistance. The prevalence of the triple-mutantPfdhfrC50I51R59N108I164genotype and the double-mutantPfdhpsS436G437E540A581A613genotype was high. Two triple-mutantPfdhpsgenotypes, S436G437E540G581A613andH436G437E540A581A613, were found, with the latter thus far being uniquely found in western Kenya. The prevalence of the S436G437E540G581A613genotype was low. However, a steady increase in the prevalence of thePfdhpstriple-mutantH436G437E540A581A613genotype has been observed since its appearance in early 2000. Isolates with these genotypes shared substantial microsatellite haplotypes with the most common double-mutant allele, suggesting that this triple-mutant allele may have evolved locally. Overall, these findings show that the prevalence of theH436G437E540A581A613triple mutant may be increasing in this population and could compromise the efficacy of SP for intermittent preventive treatment in pregnant women if it increases the resistance threshold further.

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