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Triple Combination Antiviral Drug (TCAD) Composed of Amantadine, Oseltamivir, and Ribavirin Impedes the Selection of Drug-Resistant Influenza A Virus

Journal Article · · PLoS ONE
 [1];  [2];  [2];  [2];  [2];  [3];  [4];  [5];  [5]
  1. Adamas Pharmaceuticals, Inc., Emeryville, CA (United States); DOE/OSTI
  2. Translational Genomics Research Inst., Flagstaff, AZ (United States)
  3. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  4. Oakland Univ., Rochester, MI (United States)
  5. Adamas Pharmaceuticals, Inc., Emeryville, CA (United States)
+ Show Author Affiliations
Widespread resistance among circulating influenza A strains to at least one of the anti-influenza drugs is a major public health concern. A triple combination antiviral drug (TCAD) regimen comprised of amantadine, oseltamivir, and ribavirin has been shown to have synergistic and broad spectrum activity against influenza A strains, including drug resistant strains. Here, we used mathematical modeling along with three different experimental approaches to understand the effects of single agents, double combinations, and the TCAD regimen on resistance in influenza in vitro, including: 1) serial passage at constant drug concentrations, 2) serial passage at escalating drug concentrations, and 3) evaluation of the contribution of each component of the TCAD regimen to the suppression of resistance. Consistent with the modeling which demonstrated that three drugs were required to suppress the emergence of resistance in influenza A, treatment with the TCAD regimen resulted in the sustained suppression of drug resistant viruses, whereas treatment with amantadine alone or the amantadine-oseltamivir double combination led to the rapid selection of resistant variants which comprised ,100% of the population. Furthermore, the TCAD regimen imposed a high genetic barrier to resistance, requiring multiple mutations in order to escape the effects of all the drugs in the regimen. Finally, we demonstrate that each drug in the TCAD regimen made a significant contribution to the suppression of virus breakthrough and resistance at clinically achievable concentrations. Taken together, these data demonstrate that the TCAD regimen was superior to double combinations and single agents at suppressing resistance, and that three drugs at a minimum were required to impede the selection of drug resistant variants in influenza A virus. The use of mathematical modeling with multiple experimental designs and molecular readouts to evaluate and optimize combination drug regimens for the suppression of resistance may be broadly applicable to other infectious diseases.
Research Organization:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1627494
Journal Information:
PLoS ONE, Journal Name: PLoS ONE Journal Issue: 12 Vol. 6; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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Avian influenza viruses that cause highly virulent infections in humans exhibit distinct replicative properties in contrast to human H1N1 viruses journal April 2016
The in vivo efficacy of neuraminidase inhibitors cannot be determined from the decay rates of influenza viral titers observed in treated patients journal January 2017
How to approach and treat viral infections in ICU patients journal November 2014
Simultaneous Detection of Oseltamivir- and Amantadine-Resistant Influenza by Oligonucleotide Microarray Visualization journal February 2013
Exploring virus release as a bottleneck for the spread of influenza A virus infection in vitro and the implications for antiviral therapy with neuraminidase inhibitors journal August 2017
Influenza treatment and prophylaxis with neuraminidase inhibitors: a review journal November 2013
Investigating Different Mechanisms of Action in Combination Therapy for Influenza journal October 2018
Oseltamivir (Tamiflu®) in the environment, resistance development in influenza A viruses of dabbling ducks and the risk of transmission of an oseltamivir-resistant virus to humans – a review journal January 2012
A Cutting-Edge View on the Current State of Antiviral Drug Development: A CUTTING-EDGE VIEW ON ANTIVIRALS journal March 2013
Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenzaa journal December 2018
Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenzaa journal March 2019
Combination Antiviral Therapy for Influenza: Predictions From Modeling of Human Infections journal March 2012
Continuing challenges in influenza: Continuing challenges in influenza journal May 2014

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