A Sustained Viral Response Is Associated With Reduced Liver-Related Morbidity and Mortality in Patients With Hepatitis C Virus

doi:10.1016/j.cgh.2009.11.018

Clinical Gastroenterology and Hepatology

Volume 8, Issue 3, March 2010, Pages 280-288.e1

https://doi.org/10.1016/j.cgh.2009.11.018 Get rights and content

Background & Aims

The incidences of decompensated cirrhosis (defined by ascites, hepatic encephalopathy, or bleeding esophageal varices), hepatocellular carcinoma (HCC), and liver-related mortality among patients infected with hepatitis C virus (HCV) who achieve a sustained viral response (SVR), compared with patients who fail treatment (treatment failure), are unclear. We performed a meta-analysis to quantify the incidences of these outcomes.

Methods

This meta-analysis included observational cohort studies that followed HCV treatment failure patients; data were collected regarding the incidence of decompensated cirrhosis, HCC, or liver-related mortality and stratified by SVR status. Two investigators independently extracted data on patient populations, study methods, and results by using standardized forms. The agreement between investigators in data extraction was greater than 95%. Data analysis was performed separately for studies that enrolled only HCV patients with advanced fibrosis.

Results

We identified 26 appropriate studies for meta-analysis. Among treatment failure patients with advanced fibrosis, rates of liver-related mortality (2.73%/year; 95% confidence interval [CI], 1.38–4.080), HCC (3.22%/year, 95% CI, 2.02–4.42), and hepatic decompensation (2.92%/year; 95% CI, 1.61–4.22) were substantial. Patients with SVR are significantly less likely than patients who experienced treatment failure to develop liver-related mortality (relative risk [RR], 0.23; 95% CI, 0.10–0.52), HCC (RR, 0.21; 95% CI, 0.16–0.27), or hepatic decompensation (RR, 0.16; 95% CI, 0.04–0.59).

Conclusions

HCV patients with advanced fibrosis who do not undergo an SVR have substantial liver-related morbidity and mortality. Achieving SVR is associated with substantially lower liver-related morbidity and mortality.

Section snippets

Literature Search

A computer-assisted search with the Ovid interface to Medline was conducted to identify potentially relevant published articles. A search of the Medline database from 1966 to 2008 was performed by using the exploded (exp) medical subject heading (MeSH) terms (exp Hepatitis C) AND (exp Treatment Failure OR exp Retreatment OR exp Recurrence OR exp Drug Resistance OR keywords refractory, relapse, retreatment, nonrespond, non-respond, fail, unsuccess). The results of all searches were limited to

Results of Literature Search

The computer-assisted search yielded more than 2276 potentially relevant articles (Supplementary Figure 1). After initial review of titles and abstracts, 215 studies were potentially appropriate, and abstracts were reviewed in detail. One hundred four studies were potentially appropriate and underwent full manuscript review along with 3 additional studies identified through recursive literature searches. After application of the inclusion and exclusion criteria, 26 studies were included in our

Discussion

Physicians and HCV-infected patients should understand the likelihood of developing decompensated cirrhosis, HCC, and liver-related mortality after failing therapy to make appropriate decisions about whether to undergo retreatment. Prognostic data should be stratified on the basis of severity of hepatic fibrosis. Stratifying natural history data by stage of hepatic fibrosis is important because more advanced fibrosis is associated with higher rates of liver-related morbidity and mortality.³⁶

Acknowledgments

Drs Singal and Volk contributed equally to this work.

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Direct-acting antivirals sofosbuvir and daclatasvir attenuate carbon tetrachloride-induced liver fibrosis in mice
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Advanced liver fibrosis is a major risk for developing hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV) patients. Direct-acting antivirals (DAAs) which are used for treating HCV infection, produce more than 90% cure rate but do not seem to diminish the rate of occurrence or recurrence of HCC. This study aimed to investigate the effect of DAAs sofosbuvir (SOF) and daclatasvir (DAC) on carbon tetrachloride (CCl₄)-induced fibrotic changes in mice.
Eighty adult male Swiss albino mice were randomly allocated into 8 groups (10 mice/group): normal control group, SOF group (receiving SOF 80 mg/kg body weight (BW), oral gavage, daily), DAC group (receiving DAC 30 mg/kg BW, oral gavage, daily), SOF + DAC group (receiving a combination of both, daily), CCl4 model group (receiving CCl₄ 2 mL/kg BW, intraperitoneal twice weekly) and three CCl₄-intoxicated groups receiving either SOF or DAC or their combination. All CCl₄ groups received CCl₄ for 12 weeks followed by DAAs for another 12 weeks.
CCl₄-induced a significant elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and produced histopathological evidence of fibrosis and liver degeneration along with a significant increase (P ≤ 0.001) of the proliferation markers (proliferating cell nuclear antigen (PCNA) and Ki-67), hepatic stellate cells (HSCs) activation markers (alpha-smooth muscle actin (α-SMA) and glial fibrillary acidic protein (GFAP)), fibrosis marker (matrix metalloproteinase-9 (MMP-9)) and pro-inflammatory cytokine (tumor necrosis factor-alpha (TNF-α)). CCl₄-intoxicated mice treated with SOF, DAC, or their combination revealed a significant amelioration (P ≤ 0.001) of CCl₄-induced elevation of liver enzymes, fibrotic changes, and liver degeneration along with a significant attenuation (P ≤ 0.001) of CCl₄-induced upregulation of all tested markers. The effects of SOF, DAC, and their combination on liver enzymes were comparable while the effect of SOF + DAC combination on mitigating CCl₄-induced upregulation of the proliferation and HSCs activation markers was significantly stronger than either SOF or DAC alone. As for MMP-9 and TNF-α, the effects of DAC and SOF + DAC combination were comparable and both were more significant than that of SOF alone.
SOF and DAC may possess an antifibrotic effect that is independent of their role as antiviral agents against CCl₄-induced liver injury. This might exclude the role of DAAs in early occurrence or accelerated recurrence of HCC through the progression of the HCV patients' pre-existing fibrosis. However, HCC patients treated with DAAs should be closely monitored with continuous HCC surveillance during and post-therapy.
Incidence of liver- and non-liver-related outcomes in patients with HCV-cirrhosis after SVR
2022, Journal of Hepatology
As the long-term benefits of a sustained virological response (SVR) in HCV-related cirrhosis following direct-acting antiviral (DAA) treatment remain undefined, we assessed the incidence and predictors of liver-related events (LREs), non-liver-related events (NLREs) and mortality in DAA-treated patients with cirrhosis.
Consecutive patients with cirrhosis and SVR were enrolled in a longitudinal, single-center study, and divided into 3 cohorts: Cohort A (Child-Pugh A without a previous LRE), Cohort B (Child-Pugh B or Child-Pugh A with prior non-hepatocellular carcinoma [HCC] LREs), Cohort C (previous HCC).
A total of 636 patients with cirrhosis (median 65 years-old, 58% males, 89% Child-Pugh A) were followed for 51 (8-68) months (Cohort A n = 480, Cohort B n = 89, Cohort C n = 67). The 5-year estimated cumulative incidences of LREs were 10.4% in Cohort A vs. 32.0% in Cohort B (HCC 7.7% vs. 19.7%; ascites 1.4% vs. 8.6%; variceal bleeding 1.3% vs. 7.8%; encephalopathy 0 vs. 2.5%) vs. 71% in Cohort C (HCC only) (p <0.0001). The corresponding figures for NLREs were 11.7% in Cohort A vs. 17.9% in Cohort B vs. 17.5% in Cohort C (p = 0.32). The 5-year estimated probabilities of liver-related vs. non-liver-related deaths were 0.5% vs. 4.5% in Cohort A, 16.2% vs. 8.8% in Cohort B and 12.1% vs. 7.7% in Cohort C. The all-cause mortality rate in Cohort A was similar to the rate expected for the general population stratified by age, sex and calendar year according to the Human Mortality Database, while it was significantly higher in Cohort B.
Patients with cirrhosis and an SVR on DAAs face risks of liver-related and non-liver-related events and mortality; however, their incidence is strongly influenced by pre-DAA patient history.
In this large single-center study enrolling patients with hepatitis C virus (HCV)-related cirrhosis cured by direct-acting antivirals, pre-treatment liver disease history strongly influenced long-term outcomes. In patients with HCV-related cirrhosis, hepatocellular carcinoma was the most frequent liver-related complication after viral cure. Due to improved long-term outcomes, patients with cirrhosis after HCV cure are exposed to a significant proportion of non-liver-related events.
Should we continue surveillance for hepatocellular carcinoma and gastroesophageal varices in patients with cirrhosis and cured HCV infection?
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Hepatocellular carcinoma (HCC) and variceal bleeding are among the most common causes of liver-related mortality in patients with hepatitis C virus (HCV)-induced cirrhosis. Current guidelines recommend HCC and gastroesophageal varices (GEV) surveillance in patients with HCV infection and cirrhosis. However, since the recent introduction of direct-acting antivirals, most patients with cirrhosis are now cured of their chronic HCV infection. As virological cure is considered to substantially reduce the risk of cirrhosis-related complications, this review discusses the current literature concerning the surveillance of HCC and GEV in patients with HCV-induced cirrhosis with a focus on the setting following sustained virological response.
Clinical outcomes following DAA therapy in patients with HCV-related cirrhosis depend on disease severity
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HCV-infected patients with cirrhosis achieve high sustained virological response (SVR) rates with direct-acting antivirals (DAAs) even after hepatic decompensation. We aimed to assess the clinical outcome following DAAs among patients with compensated and decompensated cirrhosis in relation to SVR and changes in model for end-stage liver disease (MELD) score.
Consecutive DAA-treated chronic HCV-infected patients with cirrhosis from 4 hepatology clinics were included. The primary endpoint in survival analyses was clinical disease progression, defined as liver failure, hepatocellular carcinoma, liver transplantation or death.
In total, 868 patients were included with a median age of 59 (IQR 54–65) years; 719 (83%) with Child-Pugh A cirrhosis and 149 (17%) with Child-Pugh B/C cirrhosis. SVR was attained by 647 (90%) Child-Pugh A patients and 120 (81%) Child-Pugh B/C patients. During a median follow-up of 28 (IQR 20–36) months, 102 (14%) Child-Pugh A patients and 96 (64%) Child-Pugh B/C patients experienced clinical disease progression. SVR was independently associated with an improved event-free survival in patients with Child-Pugh A cirrhosis (adjusted hazard ratio [HR] 0.47; 95% CI 0.27–0.82, p = 0.007), but not in patients with Child-Pugh B/C cirrhosis (adjusted HR 1.23; 95% CI 0.67–2.26; p = 0.51). Twelve weeks post-DAAs, 28 (19%) patients with Child-Pugh B/C cirrhosis had ≥2-point MELD decline, but their 2-year event-free survival did not differ from those with a stable MELD (47.9%; 95% CI 28.7–67.1 vs. 48.9%; 95% CI 38.1–59.7, respectively, p = 0.99).
Among patients with chronic HCV infection, DAA-induced SVR was associated with a reduced risk of clinical disease progression in patients with Child-Pugh A cirrhosis but not in patients with Child-Pugh B/C cirrhosis. In Child-Pugh B/C cirrhosis, a ≥2-point MELD decline did not translate into improved clinical outcome.
Chronic HCV infection can be cured with antiviral therapy. In this study, we evaluated the long-term effects of antiviral therapy on liver-related complications in patients with cirrhosis. Our results suggest that patients with compensated cirrhosis who were cured of their HCV infection have a lower rate of complications. In contrast, the rate of complications was not related to virological cure among those with decompensated cirrhosis. While these patients seem to remain in need of liver transplantation, antiviral therapy may lower their priority on the liver transplantation waiting list.
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: Conflicts of interest The authors disclose the following: Dr Jensen has served on advisory boards for Abbott, Boehringer-Ingelheim, Vertex, Pharmasset, Roche, Tiboetc, Human Genome Sciences, and Globeimmune and has been an investigator for Boehringer-Ingelheim, Vertex, Roche, Tibotec, and Human Genome Sciences. Dr Di Bisceglie served on advisory boards for Roche, Idenix, Novartis, Vertex, Bristol-Meyers-Squibb, Anadys, and GlobeImmune; has received research support from Roche, Gilead Sciences, Idenix, Vertex, Bristol-Meyers-Squibb, GlobeImmune; and is a speaker for Novartis and a consultant for Bristol-Myers-Squibb, Abbott, Schering Plough, and Pharmasset. Dr Volk has served on an advisory boards for Onyx Pharmaceuticals and has received grant support from Vertex. Dr Singal has worked as a consultant for Vertex Pharmaceuticals and MD-Evidence. Dr Schoenfeld has worked as consultant for Vertex Pharmaceuticals and is a partner in MD-Evidence.

: Funding This research was funded by Vertex Pharmaceuticals.

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Original article—liver, pancreas, and biliary tractA Sustained Viral Response Is Associated With Reduced Liver-Related Morbidity and Mortality in Patients With Hepatitis C Virus

Background & Aims

Methods

Results

Conclusions

Section snippets

Literature Search

Results of Literature Search

Discussion

Acknowledgments

Gastroenterology

Gastroenterology

Control Clin Trials

J Infect Chemother

Hepatology

Lancet

Hepatology

J Hepatol

J Hepatol

Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease: Centers for Disease Control and Prevention

MMWR Recomm Rep

The prevalence of hepatitis C virus infection in the United States, 1999 through 2002

Ann Intern Med

The burden of hepatitis C in the United States

Hepatology

Estimating the future health burden of chronic hepatitis C and human immunodeficiency virus infections in the United States

J Viral Hepat

Cochrane systematic review: pegylated interferon plus ribavirin vs. interferon plus ribavirin for chronic hepatitis C

Aliment Pharmacol Ther

Diagnosis, management, and treatment of hepatitis C

Hepatology

Meta-analysis of observational studies in epidemiology: a proposal for reporting: Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group

JAMA

Long-term outcome after interferon therapy in elderly patients with chronic hepatitis C

Intervirology

Effects of interferon treatment response on liver complications of chronic hepatitis C: 9-year follow-up study

Am J Gastroenterol

Long-term follow up of chronic hepatitis C patients after alpha-interferon treatment: a functional study

J Gastroenterol Hepatol

Original article—liver, pancreas, and biliary tract
A Sustained Viral Response Is Associated With Reduced Liver-Related Morbidity and Mortality in Patients With Hepatitis C Virus