January 26, 2011

Liver International
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.
Volume 31, Issue Supplement s1, pages 18–22, January 2011

Alfredo Alberti

Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02378.x
© 2011 John Wiley & Sons A/S

Author Information
Department of Histology, Microbiology and Medical Biotechnologies, Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy

* Correspondence: Correspondence Prof. Alfredo Alberti, Department of Histology, Microbiology and Medical Biotechnologies, Venetian Institute of Molecular Medicine, University of Padova, Via Orus 2, 35100 Padova, Italy Tel: +39 049 821 2293 Fax: +39 049 821 1826 e-mail: alfredo.alberti@gmail.com

Keywords:
cirrhosis progression; decompensation; fibrosis; HCC; modelling; natural history; outcomes; remission

Abstract

A sustained virological response (SVR), defined as undetectable hepatitis C virus (HCV)-RNA 24 weeks after withdrawal from therapy (SVR-24w), is the primary endpoint of antiviral therapy in chronic hepatitis C. There is solid evidence that patients who reach this target will remain virus free during long-term follow-up, with a risk of late HCV recurrence of <2% in published series using the most stringent criteria for assessing the virological response during and after antiviral therapy. Long-term observational studies indicate that SVR-24w has a profound impact on the natural course of chronic hepatitis C in relation to biochemical and histological remission of liver disease and improvement in quality of life. The effects of successful antiviral therapy on clinical endpoints such as the development of end-stage liver disease, its severe complications and liver-related mortality have been more difficult to ascertain because of the heterogeneity of the initial staging and rate of progression of chronic hepatitis C. However, most available data suggest that SVR following antiviral therapy reduces the risk of progression to cirrhosis and may prevent the development of severe liver complications and improve survival, at least in successfully treated patients who have already progressed to significant liver fibrosis or early cirrhosis. Outcome modelling suggests that these effects might also include HCV patients treated with milder forms of liver damage.

The primary endpoint of antiviral therapy for chronic hepatitis C is achieving sustained virological response (SVR), defined as undetectable hepatitis C virus (HCV)-RNA in serum 24 weeks after stopping antiviral therapy (SVR-24w). This is the endpoint used in all clinical trials to assess therapeutic interventions as well as by clinicians treating patients. This is because a large body of evidence exists that SVR-24w is an excellent surrogate endpoint to identify a permanent virological cure in most patients, with a clear clinical benefit in many of them. While it has been fairly easy to show that SVR-24w is associated with an extremely low risk of persistent HCV or recurrence during longer follow-up, data on the impact of SVR for more specific clinical endpoints have been limited by the heterogeneity of the initial presentation and rate and speed of chronic hepatitis C disease progression.

It is clear from studies on the natural history of HCV that a minority of patients with chronic infection develop significant life-long clinical complications, and it is also well known that current clinical practice has extended the indication to start antiviral therapy to patients with the mild or moderate hepatitis C, whose risk of progression is often difficult to define. When these patients receive antiviral therapy, data show that SVR improves quality of life and reduces the risk of histological progression. Although there is no direct evidence, outcome modelling suggests that there may be significant effects on clinical complications and survival in a subgroup of patients at risk of more rapid disease progression. On the other hand, solid evidence shows that the risk of developing end-stage liver disease, portal hypertension and hepatocellular carcinoma (HCC) is reduced in patients with more advanced liver disease or cirrhosis who achieve SVR with antiviral therapy.

In this chapter, we briefly discuss the data on the impact of SVR on long-term HCV eradication as well as on biochemical, histological and clinical outcomes in patients with hepatitis C depending on the phase of liver disease when therapy was begun.

Sustained virological response and long-term eradication of hepatitis C virus

There is good evidence that HCV permanently disappears from serum when antiviral therapy is successful. Most experts consider this to be the expression of complete and permanent viral eradication, while data on a persistent occult form of HCV in the liver and/or peripheral blood mononuclear cells (PBMC) are not fully convincing. Because HCV-RNA may be negative in serum during and at the end of antiviral therapy and reactivate after treatment withdrawal in a subgroup of patients with incomplete clearance (relapsers), viral negativity must be confirmed during off-therapy follow-up to confirm a definitive cure of hepatitis C. SVR is the primary goal of antiviral therapy in chronic hepatitis C and is classically defined as the absence, by the most sensitive polymerase chain reaction assay, of HCV-RNA in serum, 24 weeks after therapy has been withdrawn (SVR-24w) (1). This has been the definition since standard interferon (IFN) monotherapy was implemented and remained valid for IFN plus ribavirin combination therapy and more recently for pegylated interferon (PEG-IFN) plus ribavirin combination regimens. The SVR-24w definition of response to therapy will be maintained when new strategies of HCV treatment, including direct antiviral agents, are introduced into clinical practice. Indeed, most published studies as well as extensive clinical experience show that an absence of HCV-RNA in serum 6 months after therapy is the best indicator of HCV clearance, whatever the HCV genotype, patient characteristics, type and duration of treatment. This has been confirmed in several studies evaluating the long-term virological profile in large cohorts of patients treated with different schedules of IFN-based therapies and tested for HCV recurrence several months or years after having achieved SVR-24w.

Recently, Welker and Zeuzem (2) reviewed available data on the rates of late virological relapse in hepatitis C patients treated with IFN (or PEG-IFN) therapy with a sustained response based on the 24 week off-therapy rule. The authors identified 44 studies, including more than 4200 patients who had been followed up to 108 months after the end of therapy. Overall, late virological relapses were rare (3%). There was considerable heterogeneity among the different studies, with some of the smaller series reporting the highest rates of HCV recurrence. On the other hand, the larger series and those with the most stringent criteria to define SVR conclude that negative HCV-RNA in serum 24 weeks after the end of therapy is associated with a durable response and no recurrence of HCV during follow-up in more than 98% of cases.

Some studies have suggested that HCV-RNA may persist in the liver and/or in PBMC in patients who achieve SVR after antiviral therapy and with undetectable HCV-RNA in serum (3, 4). The significance of these findings is uncertain but most available data suggest that they are not clinically significant, at least in the immunocompetent host.

Thus, patients achieving SVR-24w with antiviral therapy can be considered clinically cured of viral infection, with an extremely low risk of late virological recurrence. If this occurs, reinfection rather than a ‘true’ relapse could be suspected and should be evaluated carefully.

Recently, it has been proposed that a 12-week post-treatment follow-up might be as relevant as 24 weeks to determine the sustained virological response in patients with hepatitis C virus receiving PEG-IFN and ribavirin (5).

Biochemical outcomes after sustained virological response

Alanine transaminase (ALT)/aspartate aminotransferase (AST) levels markedly improve in most patients who achieve SVR with antiviral therapy and permanently normalize in many (6, 7). The mean ALT and AST activities after therapy are significantly lower than the pretreatment baseline levels even in HCV carriers who began antiviral therapy with ‘normal’ ALT levels (8). Indeed, eradication of HCV by antiviral therapy in these cases is associated with a significant improvement in liver enzyme levels, which decrease from pretreatment ‘high normal’ to post-treatment ‘low normal’ levels. These findings suggest the presence of ongoing marginal liver disease activity even in HCV carriers with ‘normal’ range ALT levels, in agreement with histological findings of inflammation and fibrosis in around 15–25% of these patients (9).

On the other hand, liver enzymes may not normalize completely in patients with cirrhosis who achieve SVR. The discrepancy between biochemical and virological outcomes does not exclude a clinical benefit and is probably a sign of profound irreversible changes in hepatocyte metabolism from advanced cirrhosis.

As a general rule, other causes of liver damage (coinfections, alcohol, drugs, metabolic abnormalities) should be investigated in patients who achieve SVR with antiviral therapy but still have elevated ALT and/or AST.

Histological outcomes after sustained virological response

Many studies have described the histological outcome following antiviral therapy for chronic hepatitis C and have clearly identified some major differences among non-responders, partial responders, relapsers and sustained responders (10–15). Although the benefit to disease activity and progression with a partial or a transient virological response remains controversial, these studies clearly confirm that SVR is associated with histological improvement in disease activity and associated fibrosis. Liver steatosis is also improved when it is directly linked to HCV as for HCV-3.

The type and degree of histological benefit after SVR is highly dependent on pretreatment activity, the stage of liver disease and the interval between end of therapy and liver biopsy. Improvement in liver inflammation is more evident when a liver biopsy is obtained years rather than months after the end of therapy. The effect of time is even more evident for the regression of liver fibrosis. Available studies indicate that liver inflammation resolves in most, if not all, patients after SVR while improvement in fibrosis (regression) is found in 25–80%, worsening (progression) in only 0–12, and 16–68% remain stable. These results are significantly different from those in patients who do not achieve SVR. Table 1 describes some studies that have evaluated histological outcome after SVR using paired liver biopsies before and at different intervals after antiviral therapy. Available cumulative data on progression to cirrhosis have indicated that the risk after 1–10 years is reduced from 7–10% in non-responders to 0.5–1% in sustained responders, although it should be emphasized that patients who achieve SVR might have a milder and less progressive form of liver disease compared with non-responders.

Reversal of histological cirrhosis has been reported in patients achieving SVR with antiviral therapy. Although in most patients the benefit was limited to regression to METAVIR stage 3, i.e. advanced fibrosis with bridging, a histological sampling error cannot be excluded, other patients have been shown to achieve more marked and permanent histological benefit with regression from signs of cirrhosis to minimal-mild fibrosis.

Recent non-invasive markers of liver fibrosis, such as the FibroTest and FibroScan, have become important new tools for the management of patients with chronic hepatitis C. Results in patients receiving antiviral therapy have confirmed a marked improvement in liver fibrosis indexes following SVR (16, 17). Further validation for the optimized use of these methods during and after antiviral therapy is ongoing in several centres.

Sustained virological response and clinical outcomes

Morbidity and mortality in chronic hepatitis C infection are mainly associated with the complications of cirrhosis and the development of HCC, as well as an increased risk in liver-related deaths. It is therefore essential to assess the impact of SVR on these clinical outcomes. Because of the heterogeneity of the clinical presentation of chronic HCV infection, the slow and unpredictable progression and the lack of longitudinal studies of adequate size and duration, the impact of antiviral therapy and SVR on liver-related complications and mortality has been difficult to determine, especially in patients with milder forms of HCV-related liver disease. Although the endpoint of SVR is clearly associated with reduced histological disease progression in these patients, there is no clear evidence that this will result in reduced morbidity and mortality. At present, many patients with mild chronic hepatitis C are treated with antiviral therapy, especially younger patients or those infected with easy to clear HCV genotypes.

High SVR rates are achieved in these patients and outcome modelling also suggests that successful antiviral therapy could reduce the clinical burden of their disease. On the other hand, there are also convincing results associating a marked improvement in quality of life with SVR after antiviral therapy. This effect is largely independent of the stage of disease when treatment is begun (18). The clinical benefit associated with HCV clearance at any stage of chronic HCV infection is supported by recent results in a large population-based survey by Omland and Krarup (19), showing that overall life-long mortality as well as liver-and HCC-related mortality were significantly lower in HCV patients who showed a clearance of viraemia than in those with chronic viraemia.

Unlike the data for patients with milder forms of chronic hepatitis C, several studies have clearly shown that antiviral therapy with SVR is associated with a marked improvement in clinical outcomes in patients with advanced fibrosis or compensated cirrhosis. Indeed, most studies show that ascites, hepatic encephalopathy, jaundice or gastrointestinal bleeding are extremely rare after SVR has been achieved. Development of hepatocellular carcinoma is also significantly reduced, but patients with cirrhosis who clear HCV during antiviral therapy are still at a risk of developing HCC. Although the risk is certainly much lower than in age/gender/race-matched patients with active disease, continued monitoring is recommended. One of the most recent reports on the impact of combination PEG-IFN and ribavirin therapy on clinical outcome and complications in patients with chronic hepatitis C and advanced fibrosis is that of Cardoso et al. (20). These authors describe long-term outcomes in 307 patients with chronic hepatitis C and advanced fibrosis (127 cases) or cirrhosis (180 cases) treated with PEG-IFN plus ribavirin and followed up for a mean 3–5 years after treatment. SVR-24w was found in 33% of the cases, with no significant differences between patients with advanced fibrosis (37%) and cirrhosis (30%). During follow-up, the incidence of liver-related complications, HCC and liver-related deaths per 100 person – years was 0.63, 1.24 and 0.61, respectively, in patients with SVR and 4.16, 5.85 and 3.66, respectively, in patients without SVR. The difference for each outcome was statistically significant (P<0.001 by log-rank test). Multivariate analysis confirmed that SVR protected against progression to liver complications, HCC and liver-related deaths, with the relative risk in the absence of SVR ranging between 3.06 and 4.73. These results confirm those of several previous studies based on cohorts of patients treated with standard IFN, standard IFN plus ribavirin or PEG-IFN plus ribavirin, showing that antiviral treatment provides a definitive clinical advantage to patients with compensated cirrhosis who tolerate treatment and achieve an SVR.

Another recent study published by Bruno et al. (21) reported the effect of antiviral therapy and SVR on portal hypertension in HCV patients with cirrhosis. The authors reported results in 218 patients with cirrhosis who were untreated or treated with IFN-α-based therapy and followed up for a median 11.4 years. All patients had compensated cirrhosis when therapy began without oesophageal varices. Endoscopic monitoring was performed at 3-year intervals. None of the patients who achieved SVR developed oesophageal varices during follow-up compared with 32% of untreated patients and 39% of treated patients who did not achieve SVR, showing that SVR clinically improved the development of portal hypertension.

In conclusion, SVR improves the clinical outcomes in patients with chronic hepatitis C and advanced fibrosis or compensated cirrhosis. On the other hand, most studies assessing whether a partial response or long-term maintenance therapy with PEG-IFN without viral eradication is beneficial have failed to demonstrate any significant improvement in clinical outcomes (22, 23).

Conflicts of interest

The author has declared no potential conflicts.

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