Eradication of HCV in Patients With Cirrhosis Reduces Risk of Liver and Non-Liver Complications

In patients with HCV and compensated cirrhosis this analysis reported achieving sustained virologic response (SVR) reduced overall mortality and risk of death from liver-related and non–liver-related causes. Abstract and discussion provided below, click here to review full text article online in the January 2017 issue of Gastroenterology. 

Eradication of Hepatitis C Virus Infection in Patients With Cirrhosis Reduces Risk of Liver and Non-Liver Complications

Pierre Nahon Press enter key for correspondence information Press enter key to Email the author , Valérie Bourcier, Richard Layese, Etienne Audureau, Carole Cagnot, Patrick Marcellin, Dominique Guyader, Hélène Fontaine, Dominique Larrey, Victor De Lédinghen, Denis Ouzan, Fabien Zoulim, Dominique Roulot, Albert Tran, Jean-Pierre Bronowicki, Jean-Pierre Zarski, Vincent Leroy, Ghassan Riachi, Paul Calès, Jean-Marie Péron, Laurent Alric, Marc Bourlière, Philippe Mathurin, Sébastien Dharancy, Jean-Frédéric Blanc, Armand Abergel, Lawrence Serfaty, Ariane Mallat, Jean-Didier Grangé, Pierre Attali, Yannick Bacq, Claire Wartelle, Thông Dao, Yves Benhamou, Christophe Pilette, Christine Silvain, Christos Christidis, Dominique Capron, Brigitte Bernard-Chabert, David Zucman, Vincent Di Martino, Vincent Thibaut, Dominique Salmon, Marianne Ziol, Angela Sutton, Stanislas Pol, Françoise Roudot-Thoraval

DOI: http://dx.doi.org/10.1053/j.gastro.2016.09.009

Abstract

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 then with 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 outcome was 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.

Discussion Only
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This prospective study based on follow-up evaluation of 1323 treated patients with biopsy-proven, HCV-related cirrhosis sought to compare the outcome of patients with and without SVR. Although the inclusion of patients in whom histologic assessment of fibrosis was mandatory might have introduced selection biases, this rigorous approach strengthens the confidence in the drawn conclusions given the risk of incorrectly staging fibrosis using noninvasive tests. Not surprisingly, patients with SVR differed from those with active infection in many characteristics, which are the main predictive factors of response to interferon therapy. Indeed, most patients included in these analyses performed in January 2015 had access to an interferon-based regimen between 2006 and 2014 because DAAs only became available in February 2014 in France in the setting of an early access program for cirrhotic patients. As a consequence, if 315 patients were undergoing a DAA-based treatment at the time of analyses, only 179 of these regimens were assessable for SVR at end point. In a description of the CirVir cohort,15 baseline viral load was associated with an increased incidence of all complications. The present report, with the advantage of a longer follow-up period and by studying virologic clearance at end point as a time-dependent covariate after an interferon- or DAA-based regimen, now clearly shows that achieving SVR in HCV-infected cirrhotic patients leads to an improved prognosis. Overall, the present data were able to highlight specifically the independent influence of SVR on the incidence of liver complications, including HCC and mortality, and, interestingly, a positive impact on the occurrence of extrahepatic manifestations. These findings were supported further by multivariate Cox regressions performed in a propensity-matched population (Table 3), suggesting a lack of confounding by indication of treatment and capacity to achieve SVR. This point also was supported by the analysis of patients who achieved SVR after DAA, who seemed to have a similar outcome although older and with more impaired liver function (Supplementary Table 15). However, the achievement of SVR in DAA-treated patients is too recent to draw any definite conclusion on this point, and will require a longer follow-up evaluation of the CirVir cohort to be addressed adequately. Our study also highlighted specific risk factors for complications occurring after HCV eradication, particularly the influence of metabolic features on HCC development in case of viral clearance.

The hepatic benefit of HCV clearance was suggested by the initial description of the CirVir cohort14 because baseline viral load was associated with critical events occurring during the first 3 years of follow-up evaluation. The present data, by considering SVR as a time-dependent covariate over a longer follow-up period, provide a more accurate vision and stronger arguments on the expected clinical benefits on liver-related complications and death in case of HCV eradication. By rigorously analyzing the incidences of these complications in a competing risk framework, analysis of the CirVir cohort reports the precise rates of these events, particularly in patients with SVR, and confirms their dramatic decrease expected in forthcoming years, as predicted by modeling approaches.26 These incidences are indeed strikingly low in nonviremic patients, usually less than 1% per year, but nevertheless continue to exist and to justify periodic screening policies, particularly HCC (Figure 1A).27 Not surprisingly, these low rates of life-threatening events are translated into survival benefits, whether considering liver-related or extrahepatic mortality (Figure 4), thus delineating virologic cured HCV-related cirrhosis as a new clinical entity with specific risk factors for complications.

Except for lower levels of serum AFP that could be associated with HCV clearance, HCC characteristics did not differ according to SVR status (Supplementary Table 1). It is interesting to note that the few cases of HCC that developed in SVR patients occurred mainly in those with metabolic features (Figure 3). This could be explained by the known impact of diabetes and obesity in HCC development,28 as well as by progression of fibrosis despite viral eradication in patients presenting with comorbidities. Metabolic features, however, did not exert the same impact on HCC development in patients with active HCV replication, although the lack of systematic record regarding changes of all parameters over time in the CirVir cohort constitutes a limitation in interpretation of these data. Such observation might reflect that HCV-related hepatocarcinogenesis may be less related to the biological consequences of insulin resistance than a direct oncogenic role of the virus. The influence of alcohol consumption in the CirVir cohort is minimal because most patients with a previous high alcohol intake stopped drinking or drank only a limited amount of alcohol during follow-up evaluation (although an unreliable declaration cannot be excluded). This was not the case for metabolic features, which were present in nearly 60% of SVR patients (Figure 3). The extent to which the occurrence of HCC in this population was associated with a specific oncogenic process, or progression/nonregression of fibrosis despite viral eradication, warrants future studies because it could pave the way for the development of specific pharmacologic targets in this population.

One of the most striking results of our study was the decrease in non–liver-related mortality in patients with SVR. This must be analyzed carefully according to causes of death, mainly owing to BI, cardiovascular disease, and extrahepatic cancers, although the latter does not seem to be impacted by SVR. On the contrary, patients who achieved SVR had higher rates of extrahepatic malignancies (Table 2), an observation that might be related to the increased survival of this population (Figure 4). Until now, the possibility that the beneficial effects of SVR also result in reduced extrahepatic complications has been evoked only in retrospective studies focusing on an indirect end point, namely, all-cause mortality.6 Therefore, deciphering the consequences of HCV eradication upon the occurrence of major causes of extrahepatic death would better justify the use of costly antiviral therapy, such as expensive second-generation DAAs.29 This assumption is supported by the long-term observation of the CirVir cohort, because SVR was found to be an independent common predictor associated with a 2- to 5-fold reduction in all clinical complications (except for extrahepatic malignancies) (Figure 2C).

It is customary to consider BI as an extrahepatic complication, with the exception of SBP, classified in the present study as liver-related. Despite this conventional view, several studies, including data from the CirVir cohort,14 have shown that BIs in cirrhotic patients have prognostic significance; indeed, mortality is higher in patients who experienced a previous infection.30 As a consequence, decreasing BI occurrence in compensated cirrhosis would constitute a major step toward improvement of cirrhosis management: it is tempting to speculate that the clinical benefit of HCV clearance over the long term might be explained not only by slower liver function impairment (Figure 1B and 2B), but also by disruption of a vicious circle triggered by end-organ-dysfunction–related BI.31

The link between SVR and vascular events might be indirect (Figure 2A), and possibly a consequence of over-representation of metabolic syndrome in patients without SVR, as well as contraindications to interferon-based treatment in patients with cardiac failure or severe coronary disease. In this regard, our findings should be interpreted with full consideration of the observational nature of the present study, in which reverse causation processes could not be ruled out completely for the associations hypothesized between SVR status and the outcomes. Nevertheless, experimental and clinical data have highlighted the complex interplay between HCV and glucose or lipid metabolism, with possible extrahepatic consequences.32 However, although a higher incidence of vascular events has been reported in HCV-infected compared with uninfected patients,33 it still is not clear whether HCV infection per se and/or its interference with metabolic/inflammatory dysfunctions triggers vascular injury. Convincing evidence suggests that HCV may directly promote cardiovascular disease. In particular, a correlation between the severity of liver necroinflammation caused by HCV infection and cardiovascular morbidity has been shown, possibly modulated by viral clearance.34 Direct viral mechanisms, in addition to the negative impact of extensive fibrosis itself,35 appear to promote atherosclerosis, as suggested by higher serum HCV-RNA levels in patients with vascular conditions,36 or even by the presence of a positive HCV-RNA strand in carotid plaques of HCV-infected patients.37 The positive impact of SVR on cardiovascular events is underlined further by the lower incidence of MACE observed in these patients (Table 2 and Supplementary Figure 3). Taken together, these considerations lend a new perspective to HCV infection, which could be considered a systemic disease in the course of which physicians carefully must assess vascular risk, particularly in case of cirrhosis. The extent to which such a potential decrease in vascular events and mortality in case of SVR will modify access to expensive new DAAs now must be evaluated by cost-effectiveness analyses.38

In summary, an overall decrease in critical events, whether liver-related or owing to extrahepatic causes, was observed in patients with HCV compensated cirrhosis achieving virologic clearance. If confirmed by the longer follow-up evaluation of increasing numbers of DAA-treated patients, this population will define a new clinical entity with a completely different outcome and increased survival. Identifying patients who will develop life-threatening complications despite viral eradication39 that could be targeted selectively and in whom refinement of screening policies might be discussed constitutes a new challenge.

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