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

Abstract

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 (V i) and non-infectious virus (V ni) 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 V i and V ni productionmore » (ε~0.998), these DAA + ribavirin treatments further enhanced the ratio of V ni to V i, thus increasing the log (V ni/V i) 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 (V ni/V i) results from drug-induced enhancement of the V ni/V i.« less

Authors:
 [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
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH)
OSTI Identifier:
1375871
Report Number(s):
LA-UR-17-20262
Journal ID: ISSN 0166-3542
Grant/Contract Number:
AC52-06NA25396
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Antiviral Research
Additional Journal Information:
Journal Volume: 144; Journal Issue: C; Journal ID: ISSN 0166-3542
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; Biological Science

Citation Formats

Goyal, Ashish, Lurie, Yoav, Meissner, Eric G., Major, Marian, Sansone, Natasha, Uprichard, Susan L., Cotler, Scott J., and Dahari, Harel. Modeling HCV cure after an ultra-short duration of therapy with direct acting agents. United States: N. p., 2017. Web. doi:10.1016/j.antiviral.2017.06.019.
Goyal, Ashish, Lurie, Yoav, Meissner, Eric G., Major, Marian, Sansone, Natasha, Uprichard, Susan L., Cotler, Scott J., & Dahari, Harel. Modeling HCV cure after an ultra-short duration of therapy with direct acting agents. United States. doi:10.1016/j.antiviral.2017.06.019.
Goyal, Ashish, Lurie, Yoav, Meissner, Eric G., Major, Marian, Sansone, Natasha, Uprichard, Susan L., Cotler, Scott J., and Dahari, Harel. 2017. "Modeling HCV cure after an ultra-short duration of therapy with direct acting agents". United States. doi:10.1016/j.antiviral.2017.06.019.
@article{osti_1375871,
title = {Modeling HCV cure after an ultra-short duration of therapy with direct acting agents},
author = {Goyal, Ashish and Lurie, Yoav and Meissner, Eric G. and Major, Marian and Sansone, Natasha and Uprichard, Susan L. and Cotler, Scott J. and Dahari, Harel},
abstractNote = {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.},
doi = {10.1016/j.antiviral.2017.06.019},
journal = {Antiviral Research},
number = C,
volume = 144,
place = {United States},
year = 2017,
month = 6
}

Journal Article:
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  • Systematic studies were made of afterglow effects on light flash duration in nanosecond discharges in Ar, He, and N gases. The discharge circuit was placed in a quartz window chamber filled with gas to 25 atm pressure. The discharge current was recorded at 10/sup -9/ sec and discharge emission at 3 x 10/ sup -3/ sec. The afterglow duration was determined as the difference between the light flash duration measured at 1/3 maximum intensity and the total discharge current duration. (R.V.J.)
  • In order to shorten the course of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, we examined the antiviral efficacy and safety of 3 weeks of response-guided therapy with an NS3 protease inhibitor and dual NS5A inhibitor–NS5B nucleotide analogue. In this open-label, phase 2a, single centre study, Chinese patients with chronic HCV genotype 1b infection without cirrhosis were randomly allocated by a computer program to one of three treatment groups (sofosbuvir, ledipasvir, and asunaprevir; sofosbuvir, daclatasvir, and simeprevir; or sofosbuvir, daclatasvir, and asunaprevir) until six patients in each group (1:1:1) achieved an ultrarapid virological response (plasma HCV RNAmore » <500 IU/mL by day 2, measured by COBAS TaqMan HCV test, version 2.0). Patients with an ultrarapid virological response received 3 weeks of therapy. Patients who did not achieve an ultrarapid response were switched to sofosbuvir and ledipasvir for either 8 weeks or 12 weeks. Furthermore, the primary endpoint was the proportion of patients with a sustained virological response at 12 weeks (SVR12) after treatment completion, analysed in the intention-to-treat population. All patients who achieved an ultrarapid virological response were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02470858. Between April 5, 2015, and April 15, 2015, 26 eligible patients were recruited. 12 patients were assigned to sofosbuvir, ledipasvir, and asunaprevir; six to sofosbuvir, daclatasvir, and simeprevir; and eight to sofosbuvir, daclatasvir, and asunaprevir. Six patients in each group achieved an ultrarapid virological response (18 [69%]). All patients with an ultrarapid virological response who were given 3 weeks of triple therapy achieved SVR12. The most common adverse events were fatigue (one [17%] of six patients receiving sofosbuvir, ledipasvir, and asunaprevir; one [17%] of six patients receiving sofosbuvir, daclatasvir, and simeprevir; and two [33%] of six patients receiving sofosbuvir, daclatasvir, and asunaprevir) and headache (one [17%] patient in each group). There were no patients who experienced any serious adverse events. In this proof-of-concept study, all patients with chronic HCV without cirrhosis who achieved an ultrarapid virological response on triple direct-acting antiviral regimens by day 2 and received 3 weeks of treatment were cured, with excellent tolerability. By shortening the duration of therapy from the currently recommended 12 weeks to 3 weeks, we could drastically reduce the cost of therapy and the rate of adverse events. Further large-scale studies should be done to confirm our findings.« less
  • Five commercially available nitropolyclyclic aromatic hydrocarbons (nitro-PAH), namely, 4-nitrobiphenyl, 2-nitrofluorene, 9-nitroanthracene, 1-nitropyrene, and 2,7-dinitrofluorene, were exposed under restricted sunlight in the open air. The direct-acting mutagenicities of the samples after an exposure of 45 days were measured in order to compare them with those of the original samples in the Ames Salmonella typhimurium bioassay. It was found that the mutagenicities of some nitro-PAH do not change significantly while the mutagenicities of others increase or decrease after exposure. A preliminary study of nitro-PAH reaction products after exposure using GC, GC/MS, and FT-IR is also reported.