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

ABSTRACT: 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 (??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.

SUBMITTER: Goyal A

PROVIDER: S-EPMC5962520 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Goyal Ashish A Lurie Yoav Y Meissner Eric G EG Major Marian M Sansone Natasha N Uprichard Susan L SL Cotler Scott J SJ Dahari Harel H

Antiviral research 20170630

<h4>Background</h4>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 mathemati ...[more]

PMID: 28673800

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Project description:BACKGROUND & AIMS:It is unclear whether direct-acting antiviral (DAA) treatment-induced sustained virologic response (SVR) reduces the risk of hepatocellular carcinoma (HCC) in patients with HCV infection. Therefore, in the current study, our aim was to determine the impact of DAA-induced SVR on HCC risk. METHODS:We identified 62,354 patients who initiated antiviral treatment in the Veterans Affairs (VA) national healthcare system from 1 January 1999 to 31 December 2015, including 35,871 (58%) interferon (IFN)-only regimens, 4,535 (7.2%) DAA?+?IFN regimens, and 21,948 (35%) DAA-only regimens. We retrospectively followed patients until 15 June 2017 to identify incident cases of HCC. We used Cox proportional hazards regression to determine the association between SVR and HCC risk or between type of antiviral regimen (DAA-only vs. DAA?+?IFN vs. IFN-only) and HCC risk. RESULTS:We identified 3,271 incident cases of HCC diagnosed at least 180 days after initiation of antiviral treatment during a mean follow-up of 6.1 years. The incidence of HCC was highest in patients with cirrhosis and treatment failure (3.25 per 100 patient-years), followed by cirrhosis and SVR (1.97), no cirrhosis and treatment failure (0.87), and no cirrhosis and SVR (0.24). SVR was associated with a significantly decreased risk of HCC in multivariable models irrespective of whether the antiviral treatment was DAA-only (adjusted hazard ratio [AHR] 0.29; 95% CI 0.23-0.37), DAA?+?IFN (AHR 0.48; 95% CI 0.32-0.73) or IFN-only (AHR 0.32; 95% CI 0.28-0.37). Receipt of a DAA-only or DAA?+?IFN regimen was not associated with increased HCC risk compared with receipt of an IFN-only regimen. CONCLUSIONS:DAA-induced SVR is associated with a 71% reduction in HCC risk. Treatment with DAAs is not associated with increased HCC risk compared with treatment with IFN. LAY SUMMARY:It was unclear whether direct-acting antiviral treatment-induced sustained virologic response reduces the risk of liver cancer in patients with HCV infection. We demonstrated that eradication of HCV infection with direct-acting antiviral agents reduces the risk of liver cancer by 71%.

Project description:Direct acting antiviral (DAA) regimens of 12 weeks result in HCV clearance in vast majority of patients across genotypes. We previously demonstrated an ultra-short regimen of 4 weeks DAA cleared HCV in a subset of patients. Here, we hypothesized that individual level of antiviral immunity differentially influenced viral clearance and investigated biomarkers of a successful response. Cohorts of HCV patients treated for 4 weeks with DAA therapy who either achieved sustained virologic response (SVR) or relapsed were compared at baseline and at end of therapy (EOT) for immune cell phenotypes and HCV specific immunity. Higher levels of PD-1+ CD8+ and CD4+ T lymphocytes co-expressing inhibitory receptors (IR) were present at baseline and at EOT in HCV patients who eventually achieved SVR compared with those who relpased. HCV specific CD8+ T cells were predominantly contained within these IR expressing PD-1+ subsets. Patients in the SVR group had significantly higher CD8+ T cell degranulation in response to HCV peptides at baseline and higher levels of cytokine producing T cells at EOT time-point, relative to those who relapsed. In ex vivo cultures, PD-1+CD160+ CD8+ T cells had higher HCV specific degranulation and PD-1+2B4+ CD8+ T cells had higher cytokine expression (IFNγ+TNFα+ or IFNγ+CD107a+) compared with single or no IR expressing subsets, indicating higher virus specific functional capacity of these subsets. Receiver operating characteristics curve (ROC) for baseline circulating frequencies of PD-1+CD160+, PD-1+Tim-3+ CD8+ T cells and PD-1+CD160+, PD-1+Blimp-1+, PD-1-CTLA4+ CD4+ T cells respectively, had associated C-statistics of 0.8214 and 0.9451 for discriminatin of patients who successfully cleared HCV with 4 weeks treatment. Thus, PD-1+ virus-specific CD8+ T cell subsets with cytotoxic capacity are present in a subset of chronic HCV infected individuals that associate with ability to achieve SVR, indicating role of immunity in DAA mediated viral clearance with short duration therapy.

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

Publications

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

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