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Title: Modeling HCV cure after an ultra-short duration of therapy with direct acting agents

Journal Article · · Antiviral Research
 [1];  [2];  [3];  [4];  [5];  [5];  [6];  [6]
  1. Loyola Univ. Medical Center, Maywood, IL (United States). Program for Experimental and Theoretical Modeling; Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  2. Sha'are Zedek Medical Center, Jerusalem (Israel)
  3. Medical Univ. of South Carolina, Charleston, SC (United States). Dept. of Microbiology and Immunology; National Inst. of Health (NIH), Bethesda, MD (United States). national Inst. of Allergy and Infectious Diseases
  4. Food and Drug Administration, Silver Springs, MD (United States). Center for Biologics Evaluation and Research
  5. Loyola Univ. Medical Center, Maywood, IL (United States). Program for Experimental and Theoretical Modeling; Univ. of Illinois, Chicago, IL (United States). Dept. of Microbiology and Immunology
  6. Loyola Univ. Medical Center, Maywood, IL (United States). Program for Experimental and Theoretical Modeling

In cases of sustained-virological response (SVR or cure) after an ultra-short duration (≤ 27 days) of direct-acting antiviral (DAA)-based therapy, despite HCV being detected at end of treatment (EOT), have been reported. Established HCV mathematical models that predict the treatment duration required to achieve cure do not take into account the possibility that the infectivity of virus produced during treatment might be reduced. The aim of this study was to develop a new mathematical model that considers the fundamental and critical concept that HCV RNA in serum represents both infectious virus (Vi) and non-infectious virus (Vni) in order to explain the observation of cure with ultrashort DAA therapy. Established HCV models were compared to the new mathematical model to retrospectively explain cure in 2 patients who achieved cure after 24 or 27 days of paritaprevir, ombitasvir, dasabuvir, ritonavir and ribavirin or sofosbuvir plus ribavirin, respectively. Fitting established models with measured longitudinal HCV viral loads indicated that in both cases, cure would not have been expected without an additional 3–6 weeks of therapy after the actual EOT. In contrast, the new model fits the observed outcome by considering that in addition to blocking Vi and Vni production (ε~0.998), these DAA + ribavirin treatments further enhanced the ratio of Vni to Vi, thus increasing the log (Vni/Vi) from 1 at pretreatment to 6 by EOT, which led to <1 infectious-virus particle in the extracellular body fluid (i.e., cure) prior to EOT. This new model can explain cure after short duration of DAA + ribavirin therapy by suggesting that a minimum 6-fold increase of log (Vni/Vi) results from drug-induced enhancement of the Vni/Vi.

Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE; National Institutes of Health (NIH)
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1375871
Report Number(s):
LA-UR-17-20262
Journal Information:
Antiviral Research, Vol. 144, Issue C; ISSN 0166-3542
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 21 works
Citation information provided by
Web of Science

References (19)

Post-treatment control of HIV infection journal April 2015
HCV kinetic and modeling analyses indicate similar time to cure among sofosbuvir combination regimens with daclatasvir, simeprevir or ledipasvir journal June 2016
Triphasic decline of hepatitis C virus RNA during antiviral therapy journal January 2007
Modelling how ribavirin improves interferon response rates in hepatitis C virus infection journal December 2004
Development of a TaqMan assay for the six major genotypes of hepatitis C virus: Comparison with commercial assays journal January 2007
Non-A, Non-B Hepatitis in Chimpanzees and Marmosets journal December 1981
Modeling Early HCV Kinetics to Individualize Direct Acting Antivirals Treatment Duration in Patients with Advanced Cirrhosis journal January 2016
Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life journal February 2013
Hepatitis C virus cures after direct acting antiviral-related drug-induced liver injury: Case report journal January 2016
Mutagenic Effect of Ribavirin on Hepatitis C Nonstructural 5B Quasispecies In Vitro and During Antiviral Therapy journal March 2007
Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without Cirrhosis journal May 2014
Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study journal October 2016
Visualizing Hepatitis C Virus Infections in Human Liver by Two-Photon Microscopy journal October 2009
Mutation Rate of the Hepatitis C Virus NS5B in Patients Undergoing Treatment With Ribavirin Monotherapy journal May 2007
Previously Infected and Recovered Chimpanzees Exhibit Rapid Responses That Control Hepatitis C Virus Replication upon Rechallenge journal July 2002
Sustained Virologic Response for Chronic Hepatitis C Infection After 27 Days of Treatment with Sofosbuvir and Ribavirin journal January 2014
No scientific basis to restrict 8 weeks of treatment with ledipasvir/sofosbuvir to patients with hepatitis C virus RNA <6,000,000 IU/mL journal November 2015
A Comprehensive Hepatitis C Viral Kinetic Model Explaining Cure journal May 2010
Sporadic Reappearance of Minute Amounts of Hepatitis C Virus RNA After Successful Therapy Stimulates Cellular Immune Responses journal February 2011

Cited By (10)

Early HCV viral kinetics under DAAs may optimize duration of therapy in patients with compensated cirrhosis journal December 2018
A dynamical motif comprising the interactions between antigens and CD8 T cells may underlie the outcomes of viral infections posted_content February 2019
Interferon at the cellular, individual, and population level in hepatitis C virus infection: Its role in the interferon-free treatment era journal August 2018
Modelling how responsiveness to interferon improves interferon-free treatment of hepatitis C virus infection journal July 2018
A dynamical motif comprising the interactions between antigens and CD8 T cells may underlie the outcomes of viral infections journal August 2019
A dynamical motif comprising the interactions between antigens and CD8 T cells may underlie the outcomes of viral infections posted_content February 2019
Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct-acting antiviral agents journal June 2018
Modelling how responsiveness to interferon improves interferon-free treatment of hepatitis C virus infection journal July 2018
HCV kinetic and modeling analyses project shorter durations to cure under combined therapy with daclatasvir and asunaprevir in chronic HCV-infected patients journal December 2017
A Robust and Efficient Numerical Method for RNA-Mediated Viral Dynamics journal October 2017