Elsevier

Antiviral Research

Volume 107, July 2014, Pages 23-30
Antiviral Research

Review
Reversal, maintenance or progression: What happens to the liver after a virologic cure of hepatitis C?

https://doi.org/10.1016/j.antiviral.2014.03.012Get rights and content

Highlights

  • Sustained virologic response leads to improvement in hepatic inflammation and fibrosis in CHC patients.

  • Stellate cells and monocyte-derived macrophages play key roles in fibrosis regression.

  • A subset of patients maintains inflammation and fibrosis years post-SVR.

  • Advanced fibrosis pretreatment is a risk factor for HCC post-SVR.

  • The mechanisms for persistent liver disease post-SVR remain unclear.

Abstract

A sustained virological response (SVR) from HCV (synonymous with virological cure) leads to decreased mortality, morbidity and improved quality of life, as well as a reduced incidence of liver disease progression, including liver failure, cirrhosis and hepatocellular carcinoma. Large clinical trials comparing pre- and post-treatment liver biopsies demonstrate improvements in inflammation as well as fibrosis score following SVR. However, a small subset of patients display persistent hepatic inflammation and/or progress to cirrhosis despite SVR. In addition to conferring a risk of fibrosis progression, advanced fibrosis pre-treatment is a major risk factor for post-SVR hepatocellular carcinoma. In this review, we discuss the mechanisms of fibrosis regression uncovered using experimental fibrosis models and highlight potential mechanisms in those few patients with fibrosis progression despite SVR. We also introduce current concepts of fibrosis-dependent tumorigenesis post-SVR in patients with advanced disease. This article forms part of a symposium in Antiviral Research on “Hepatitis C: next steps toward global eradication.”

Introduction

Hepatitis C virus (HCV) infection is a worldwide pandemic with an estimated 150–200 million people infected globally, and three to four million people newly infected each year as estimated by the WHO (World Health Organization). Its worldwide prevalence is ∼1.6–2% (Armstrong et al., 2006). Approximately 75–85% of all patients with acute HCV infection will develop chronic hepatitis C, which is defined as the persistence of HCV RNA >6 months (Thomas and Seeff, 2005). Because 2–30% of all patients with HCV progress to severe liver disease with fibrosis, cirrhosis or hepatocellular carcinoma over ∼30 years, HCV has been the leading cause for liver transplantation in the US (Thomas and Seeff, 2005).

Both host- as well as viral-factors determine the pace of disease progression. Host risk factors for advanced liver disease include duration of infection, age at infection (especially if acquired at >40 years of age), co-infection with HIV or HBV, obesity and alcohol consumption (Benhamou et al., 1999). Also, multiple host-specific genetic determinants associated with increased fibrosis progression have been identified, which include variants in the IFNGR2 (Nalpas et al., 2010), and PNPLA3 genes (Trepo et al., 2011, Valenti et al., 2011) among others (Patin et al., 2012, Huang et al., 2007, Huang et al., 2006). IL28B polymorphisms specifically have been associated not only with lower fibrosis progression rate in patients with non-1 HCV genotype (Bochud et al., 2012), but also as determinants in spontaneous or treatment-induced HCV clearance (see Balagopal et al., 2010 for review). Recently, there is also growing body of epidemiologic evidence demonstrating that coffee may attenuate fibrosis and HCC risk in HCV, however underlying mechanisms are not known (Freedman et al., 2009).

With the most recent approval of direct-acting antivirals (DAAs), for example simeprevir and sofosbuvir and others in the pipeline, the rates of a sustained virological response (SVR), and thus virological cure, have vastly increased across all HCV genotypes for treatment-naïve patients, as well as for treatment-experienced patients. This development is especially heartening for patients with cirrhosis, where cure has been difficult, and where side effects to interferon-based regimens were difficult to tolerate and often precipitated decompensation. Thus, interferon-free regimens now offer the prospect of treating this high-risk patient group while still achieving high SVR rates across all genotypes.

Clinical studies clearly establish that patients benefit from an SVR independent of their fibrosis stage. SVR leads to reduced mortality, morbidity, improved quality of life (Bernstein et al., 2002, John-Baptiste et al., 2009), and diminished risk of end-stage liver disease-associated complications (e.g., hepatic decompensation, HCC, bleeding, ascites) (Veldt et al., 2007, Cardoso et al., 2010, van der Meer et al., 2012); see also for excellent reviews (Thomas, 2013, Pearlman and Traub, 2011). Most patients demonstrate marked improvements in inflammation and fibrosis following SVR; however, in large clinical trials a minority of patients (7–13%) maintain their level of fibrosis or even progress to cirrhosis despite achieving SVR (Poynard et al., 2013, Poynard et al., 2002, Maylin et al., 2008) (see also Table 1). It is also vital to recognize that patients with advanced fibrosis remain at risk for HCC at least 8–10 years later despite virologic cure (Aleman et al., 2013).

The mechanisms of HCV-mediated liver injury and fibrosis during ongoing infection have been characterized in great detail in the past ∼25 years (see Schuppan et al., 2003, Teixeira et al., 2007, Mengshol et al., 2007). However, the mechanisms underlying improvement in these features after SVR are less well understood. Below we summarize the data from clinical trials that explore the outcomes and hepatic changes after SVR and data from pre-clinical (rodent) models where fibrosis regression has been studied. We also summarize what is currently known about the liver’s regenerative adaptation after SVR, which can return histology to normal in this setting.

Section snippets

What is SVR?

Sustained virologic response (SVR) is commonly used to estimate the success of HCV treatment and is defined as the proportion of patients achieving aviremia 24 weeks after completion of therapy. Although there is some support for the identification of SVR as early as 12 weeks after treatment (Zeuzem et al., 2003, Martinot-Peignoux et al., 2010), SVR after 24 weeks has remained the gold standard for therapeutic success, and translates into durable loss of viremia in the vast majority of patients (

Progression of fibrosis to cirrhosis even after SVR?

Overall, progression of liver fibrosis to cirrhosis is rare but can occur despite SVR. Based on a large pooled data set from 3010 naive patients, Poynard has estimated the prevalence at 7% (Poynard et al., 2002). Maylin et al. have analyzed 121 patients with pre and post-treatment liver biopsies and reported fibrosis progression in 12% patients after ruling out de novo infections or the existence of occult HCV via PCR of liver tissue (Maylin et al., 2008).

The presence of significant liver

Persisting risk for HCC after achieving SVR

There is clear evidence that patients with advanced fibrosis or cirrhosis who achieve SVR remain at heightened risk for HCC (Hirakawa et al., 2008, Yoshida et al., 1999, Yamashita et al., 2013, Maylin et al., 2008, van der Meer et al., 2012). In a meta-analysis that combined data from 30 studies, the incidence of HCC was 1.05% per person year in those with SVR compared to 3.3% in those patients without SVR (Morgan et al., 2013). In patients with advanced fibrosis (Ishak score 4–6) the

Conclusion

Rapid improvements in HCV therapies will greatly enhance the likelihood of SVR among all patient groups with HCV infection, including those traditionally considered ‘hard to treat’. Data from large trials underscore the importance of SVR in leading to improved mortality and reducing adverse outcomes, although fibrosis progression and de novo HCC still occur post-SVR in a small subset of patients. Moreover, HCV-infected patients, despite achieving SVR, remain at a higher health risk in

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