Eradication of hepatitis C virus infection in patients with cirrhosis reduces risk of liver and non-liver complications
Nahon P, et al, for the ANRS CO12 CirVir Group
Gastroenterology 2017; 152:142-156.

Background & Aims : We performed a prospective study to investigate the effects of a sustained viral response (SVR) on outcomes of patients with hepatitis C virus (HCV) infection and compensated cirrhosis.

Methods : We collected data from 1323 patients included in the prospective Agence Nationale pour la Recherche sur le SIDA et les hépatites virales (ANRS) viral cirrhosis (CirVir) cohort, recruited from 35 clinical centers in France from 2006 through 2012. All patients had HCV infection and biopsy-proven cirrhosis, were Child–Pugh class A, and had no prior liver complications. All patients received anti-HCV treatment before or after inclusion (with interferon thenwith direct antiviral agents) and underwent an ultrasound examination every 6 months, as well as endoscopic evaluations. SVR was considered as a time-dependent covariate; its effect on outcomewas assessed by the Cox proportional hazard regression method. We used a propensity score to minimize confounding by indication of treatment and capacity to achieve SVR.

Results : After a median follow-up period of 58.2 months, 668 patients (50.5%) achieved SVR. SVR was associated with a decreased incidence of hepatocellular carcinoma (hazard ratio [HR] compared with patients without an SVR, 0.29; 95% confidence interval [CI], 0.19–0.43; P < .001) and hepatic decompensation (HR, 0.26; 95% CI, 0.17–0.39; P < .001). Patients with SVRs also had a lower risk of cardiovascular events (HR, 0.42; 95% CI, 0.25–0.69; P . .001) and bacterial infections (HR, 0.44; 95% CI, 0.29–0.68; P < .001). Metabolic features were associated with a higher risk of hepatocellular carcinoma in patients with SVRs, but not in patients with viremia. SVR affected overall mortality (HR, 0.27 compared with patients without SVR; 95% CI, 0.18–0.42; P < .001) and death from liver-related and non–liver-related causes. Similar results were obtained in a propensity score-matched population.

Conclusions : We confirmed a reduction in critical events, liver-related or not, in a prospective study of patients with HCV infection and compensated cirrhosis included in the CirVir cohort who achieved an SVR. We found an SVR to reduce overall mortality and risk of death from liver-related and non–liver-related causes. A longer follow-up evaluation is required to accurately describe and assess specific risk factors for complications in this population.

Expert's Commentary

The French ANRS CO12 CirVir prospective cohort is highly informative since based on a rigorous approach : 1. prospective multicentric inclusion of viral-infected compensated patients ; 2. biopsy-proven cirrhosis avoiding the risk of incorrectly staging fibrosis using noninvasive tests ; 3. systematic data collection of clinical events ensuring quality of analyses on a long follow-up period and 4. multivariate Cox regressions performed in a propensity matched population suggesting a lack of confounding by indication of treatment and capacity to achieve SVR. There was evidence that SVR had a positive impact in this large population of 1323 cirrhotic individuals : viral clearance significantly reduced the entire spectrum of liver-related complications (cirrhosis decompensation, bacterial infection, hepatocellular carcinoma); this translated in a significant improvement of the 5-year survival (95.2% vs 84.5%; HR, 0.27; IQR, 0.18–0.42; P < .001) and reduction in liver- and extra-hepatic-related mortality (5-year specific survival, 97.8% vs 91.8%; HR, 0.19; IQR, 0.10–0.36; P < 0.001 ; 97.6% vs 93.4%; HR, 0.44; IQR, 0.24–0.82; P <0 .010, respectively).  The incidence of complications was indeed strikingly low in nonviremic patients, usually less than 1% per year, but continued to occur: periodic screening policies, particularly HCC, remain mandatory. Interestingly, analyses took particularly into account the influence of comorbidities which appear indeed as the next therapeutic challenge since the metabolic syndrome (and we may speculate that it is also true for chronic alcohol consumption which was not a concern in this cohort) was associated with a persisting risk of occurrence of HCC which disappeared one year after SVR in those patients without metabolic syndrome who achieved SVR.

A limitation of the study is that results were mainly obtained with interferon-based therapy. We cannot exclude that the immunomodulatory and antifibrotic properties of interferon may not allow a complete translation of the results in DAA-treated patients. However, the analysis of the first patients treated by second-generation DAAs found a similar outcome although thoe patients were older and with more impaired liver function. We can speculate that SVR rather than the treatment per se impact the clinical benefits.

In summary, in the long-term observation of the CirVir cohort, SVR was an independent common predictor associated with a 2- to 5-fold reduction in all clinical complications (except for extrahepatic malignancies which should conduct to an extended re-analysis over time)

Pr Stanislas Pol
Université Paris Descartes; Hepatology Department, Cochin hospital, APHP
INSERM U-818 and UMS-20, Institut Pasteur, Paris, France