Regression of HCV cirrhosis: Time will tell

Abstract

Potential conflict of interest: Nothing to report. SEE ARTICLE ON PAGE 1683 Supported by the Yale Liver Center (National Institutes of Health grant P30 DK34989). In patients who have chronic hepatitis C virus (HCV), one of the goals of viral elimination is to prevent progression across the different stages of disease, thereby preventing the development of clinically relevant outcomes. Viral elimination in chronic hepatitis C has been shown to prevent progression to more advanced stages of fibrosis/cirrhosis. Furthermore, in patients with compensated cirrhosis, viral elimination has been shown to prevent or delay the development of varices, decompensation, and hepatocellular carcinoma. In fact, these patients have been shown to have a life expectancy similar to that of the general population. However, regression of the disease is also an important outcome—perhaps even more important—and this will depend on the stage of chronic liver disease at the time of initiation of antiviral therapy (Fig. 1).Figure 1: Conceptual framework of the stages of chronic HCV defined by histology and portal pressure (HVPG) with the theoretical possibilities of regression and clinical decompensation after SVR. Abbreviations: CLD, chronic liver disease; CSPH, clinically significant portal hypertension; HE, hepatic encephalopathy; HVPG, hepatic venous pressure gradient; NA, not applicable; SVR, sustained virological response (viral elimination); VH, variceal hemorrhage. *Patients with varices and/or collaterals have, by definition, CSPH. **Assumes that no other injurious agents (alcohol, fat) are present.In chronic liver disease with only mild/moderate fibrosis, one assumes that because fibrogenesis and vascular/parenchymal alterations that lead to cirrhosis are ongoing and incomplete, viral elimination (in the absence of concomitant injurious agents/conditions) will eventually lead to regression to a normal liver. In the sickest patients, those with decompensated cirrhosis, regression would be to a compensated stage, as demonstrated in patients with decompensated HCV cirrhosis in whom HCV elimination has led to recompensation (that is, return to a compensated stage) and delisting from the transplant list.1 However, in patients with decompensated cirrhosis, stromal and vascular alterations in the liver are likely irreversible, and it would be essentially impossible for the liver to regress to a noncirrhotic stage.2 It is patients with compensated cirrhosis in whom regression to a noncirrhotic stage is a possibility. Regression of fibrosis in HCV‐compensated cirrhosis has been described after viral elimination with interferon‐based therapy.3 What is still undefined is the subgroup of patients with compensated cirrhosis in whom regression to a noncirrhotic stage is possible and the substage at which regression will be unlikely (i.e., the point of no return) and how to determine whether such regression has occurred not only histologically but also clinically (i.e., eliminating risk of cirrhosis‐related clinical events). In a position paper published in Hepatology that correlated the clinical, hemodynamic, histological, and biological aspects of chronic liver disease/cirrhosis, we postulated that the stage at which compensated cirrhosis may not be reversible is the stage of clinically significant portal hypertension (CSPH), defined as a hepatic venous pressure gradient (HVPG) of at least 10 mm Hg2 (Fig. 1). This was based on evidence showing that, in patients with compensated cirrhosis and mild portal hypertension (HVPG >5 but <10 mmHg), fibrous septa were more frequently thin, whereas in those with CSPH, fibrous septa were mostly thick,4 in a pattern that has been classified as “predominantly progressive”5 and is unlikely to regress. These concepts are being increasingly explored now that therapies for HCV lead to viral elimination in most patients. In this issue of Hepatology, Mauro et al.6 investigate fibrosis regression in a relatively large group of patients (n = 112) with posttransplant recurrent HCV with at least stage F1 fibrosis (METAVIR system) before therapy and with repeat liver biopsy 12 months after viral elimination. Fibrosis regression (defined by decrease by one METAVIR stage or more) occurred in 67% of patients overall but occurred in a larger percentage (72%‐85%) of patients without cirrhosis (F1‐F3) compared with patients who had cirrhosis (F4) at baseline, 43% of whom had fibrosis regression. Importantly, regression to a nonfibrotic stage (F0) was observed in 72% of patients with F1 fibrosis, 39% of patients with F2 fibrosis, 15% of patients with F3 fibrosis, and in no patients with F4 fibrosis at baseline. Of the 37 patients with cirrhosis, 92% remained at F4 fibrosis or decreased to F3 fibrosis—that is, most remained with advanced fibrosis. However, almost half of the patients with cirrhosis in the cohort had a history of decompensation and, when analyzed jointly with compensated patients, they find that prior dec