Long-term Outcome of Chronic Hepatitis C After Sustained Virological Response to Interferon-based Therapy

Alimentary Pharmacology & Therapeutics

Long-term Outcome of Chronic Hepatitis C After Sustained Virological Response to Interferon-based Therapy

C. Koh, T. Heller, V. Haynes-Williams, K. Hara, X. Zhao, J. J. Feld, D. E. Kleiner, Y. Rotman, M. G. Ghany, T. J. Liang, J. H. Hoofnagle

Aliment Pharmacol Ther. 2013;37(9):887-894.

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Abstract and Introduction
Materials and Methods
Results
Discussion

References

The initial 5 of 10 patients treated with antiviral therapy in 1986 at the NIH for chronic HCV achieved an SVR and had both biochemical and histological evidence of improvement in the year following treatment.[26] These five patients have now been followed up for more than 20 years and remain HCV RNA-negative and have normal or near-normal serum enzyme levels.[28] Liver biopsies on these patients 10 years after initial therapy showed resolution of the disease activity and regression of fibrosis in some.[35] After this initial study, patients at the NIH were enrolled in various therapeutic trials for chronic hepatitis C. As of 2003, a total of 103 patients had achieved an SVR, all in response to interferon-based therapy. The duration of subsequent follow-up in these 103 patients varied from a few months to as long as 23 years. In this cohort, three patients relapsed, and the remaining 100 patients had markedly improved liver tests at the time of follow-up evaluation and none had clinical evidence of advanced cirrhosis, hepatic decompensation or end-stage liver disease. These findings indicate that an SVR from interferon-based therapies for chronic HCV is usually durable and associated with improvement in biomarkers of disease, a favourable long-term prognosis and lack of evidence of progression of liver disease.

Similar findings after SVR in chronic HCV have been published in other cohorts.[15–20, 36–39] However, the current analysis extends this experience to more than 20 years after therapy. Importantly, while patients who achieved an SVR did not develop progressive liver disease, at least one case of HCC still occurred. In this cohort, one patient who had cirrhosis before treatment developed HCC despite having had an SVR 12 years previously. The occurrence of HCC after SVR has been reported in several cohorts, although the rate of liver cancer appears to be far less than occurs among untreated patients with advanced fibrosis or cirrhosis due to chronic hepatitis C.[19, 20, 36, 37] Such findings suggest that patients with an SVR should continue to have regular surveillance for HCC if they had histological evidence of cirrhosis before treatment.

A shortcoming of this study is the lack of a control group of patients with chronic hepatitis C who were not treated or a comparison group of patients who were treated but did not achieve an SVR. However, it was not feasible or considered ethical to randomise patients to therapy vs. no therapy and follow them for an indefinite period. In early controlled trials of interferon for hepatitis C, some patients were not treated for the initial 1–2 years after randomisation.[27] However, the controls from those studies were subsequently offered therapy on an open-label basis and some achieved an SVR and are a part of this analysis. Since 1992 and the approval of interferon as therapy of hepatitis C, all large 'controlled' trials of treatment have compared one interferon-based regimen to another and patients were not given placebo or randomised to no therapy.

Another approach to assessment of the possible benefit of an SVR is to compare patients who achieve an SVR to those who relapse or do not respond. However, multiple studies have shown that patients who have an SVR have a durable loss of HCV RNA and are less likely to have advanced fibrosis or cirrhosis.[5–7, 27] For these reasons, such comparisons require careful balancing of risk factors. Among the 262 patients treated in at this centre, the majority of the non responders were retreated at one time or another, with differing regimens and often at different institutions.

Use of transient elastography, a non-invasive marker for hepatic fibrosis, suggested that 41% of the cohort had residual evidence of fibrosis at the time of last follow-up 3–23 years after SVR. The elevated elastography scores were not associated with residual abnormalities of serum aminotransferase levels but were more likely to be abnormal in patients who had advanced fibrosis or cirrhosis before treatment. This suggests that some degree of fibrosis persists despite the resolution of disease activity as assessed by serum enzymes. Slight decreases in platelet counts at the time of final follow-up also correlated with the initial liver histology. Elastography scores were not available from before treatment, but improvements in other markers of advanced disease (platelet count, direct bilirubin, immunoglobulin levels) suggest that SVR may be associated with subsequent improvement in portal hypertension and perhaps partial regression of fibrosis. These findings suggest that the greatest benefit from successful eradication of HCV may be in non-cirrhotic patients, but that even patients with advanced disease, gain a benefit from treatment.

In summary, with continued follow-up of patients with chronic hepatitis C for up to 23 years after achieving sustained clearance of HCV RNA, progressive liver disease was not seen. Among patients who had advanced fibrosis and cirrhosis before being treated, evidence from platelet counts and transient elastography suggested the persistence of some degree of hepatic fibrosis and a low but continued risk for HCC.

Of Interest

Clin Infect Dis. (2013) doi: 10.1093/cid/cit234 First published online: April 24, 2013

A risk for hepatocellular carcinoma still persists long-term after sustained virological response in patients with hepatitis C associated liver cirrhosis
                 

+ Author Affiliations

1. ¹Department of Gastroenterology and Hepatology
2. ²Department of Infectious Diseases, Karolinska Institutet
3. ³Department of Medicine, Skåne University Hospital
4. ⁴Department of Infectious Diseases, Skåne University Hospital
5. ⁵Department of Clinical Epidemiology, Karolinska University Hospital, Sweden

1. Correspondence to: Soo Aleman, Department of Gastroenterology and Hepatology, and Infectious Diseases, Karolinska University Hospital, at Karolinska Institute, 171 76 Stockholm, Sweden, Phone: +46 8 517 72741, Fax: +46 8 517 700 00, E-mail: soo.aleman@ki.se

1. Alternate corresponding author: Rolf Hultcrantz, Department of Gastroenterology and Hepatology, Karolinska University Hospital, 171 76 Stockholm, Sweden, Phone: +46 8 517 00 00, E-mail: rolf.hultcrantz@ki.se 

Abstract
Background. 
The long-term effect of sustained virological response (SVR) to antiviral therapy on the risk to develop hepatocellular cancer (HCC), liver complications, liver-related deaths and overall death in hepatitis C (HCV) infected patients with liver cirrhosis is not fully known.

 

Methods. 
These risks were evaluated during long-term follow-up in in 351 patients with HCV related cirrhosis. 110 with SVR, 193 with non-SVR and 48 untreated patients were included in a multi-center cohort which was initiated 2001 and prospectively followed-up for a mean 5.3 ±SD 2.8 years. Complementary follow-up data from national registries were used to minimize the loss of patients during follow-up.
                 

Results. 

Six patients with SVR developed HCC at 0.04, 0.64, 2.4, 7.4, 7.4 and 7.6 years after achieving SVR. The incidence of HCC, any liver complication, liver-related and overall death per 100 person-years was significantly lower in SVR time with 1.0, 0.9, 0.7, 1.9, compared to 2.3, 3.2, 3.0, 4.1 and 4.0, 4.9, 4.5, 5.1 in non-SVR and untreated time, respectively. The long-term consequences did not decline significantly after more than 3-year versus during the first 3-year of follow-up.
                 

Conclusions. 

The risk for HCC, liver decompensation, and death in patients with liver cirrhosis related to HCV was markedly reduced after SVR, but a long-term risk to develop HCC remains for up to 8 years. Cirrhotic patients with HCV who achieve SVR should therefore maintain long-term surveillance for HCC. Future studies aimed to better identify those with remaining long-term risk for HCC are needed.

http://cid.oxfordjournals.org/content/early/2013/04/23/cid.cit234.abstract