Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication.
Van der Meer AJ, et al.
J Hepatology 2017; 66:485-93
Background & Aims:
The risk of hepatocellular carcinoma (HCC) is reduced but not eradicated among patients with hepatitis C virus (HCV)-induced advanced hepatic fibrosis who attained sustained viral response (SVR). We aimed to assess the risk of cirrhosis-related complications in this specific group of patients.
Methods:
Data from previously reported Western cohort studies including patients with chronic HCV infection and bridging fibrosis or cirrhosis who attained SVR were pooled for survival analyses on the individual patient level. The primary endpoint was HCC and the secondary endpoint was clinical disease progression, defined as liver failure, HCC or death.
Results:
Included were 1000 patients with SVR. Median age was 52.7 (IQR 45.1–59.7) years, 676 (68%) were male and 842 (85%) had cirrhosis. Median follow-up was 5.7 (IQR 2.9–8.0) years. Fifty-one patients developed HCC and 101 had clinical disease progression. The cumulative 8-year HCC incidence was 1.8 (95% CI 0.0–4.3) among patients with bridging fibrosis and 8.7% (95% CI 6.0–11.4) among those with cirrhosis (p = 0.058). Within the cirrhosis group, the 8-year HCC incidence was 2.6% (95% CI 0.0–5.5) among patients <45 years, 9.7% (95% CI 5.8–13.6) among patients from 45–60 years, and 12.2% (95% CI 5.3–19.1) among patients >60 years of age at start of therapy (p = 0.006). Multivariable Cox analyses indicated that higher age, lower platelet count and diabetes mellitus were independently associated with development of HCC. After 8 years 4.2% (95% CI 0.1–8.3) of patients with bridging fibrosis and 15.8% (95% CI 12.3–19.3) of patients with cirrhosis experienced clinical disease progression (p = 0.007).
Conclusions:
Patients with HCV-induced cirrhosis and SVR showed an annual risk of approximately 1% for HCC and 2% for clinical disease progression. Therefore, to prevent HCC surveillance, chronic HCV infection should preferably be treated before cirrhosis has developed.
Patients with cirrhosis who were able to eradicate their chronic HCV infection remain at substantial risk of primary liver cancer. The risk of liver cancer increases with higher age, laboratory makers suggesting more severe liver disease, and presence of diabetes mellitus. Also after successful antiviral therapy patients with HCV-induced cirrhosis should thus remain included in follow-up for early detection of liver cancer.
Expert's Commentary (Dr Jordan Feld, senior author)
As we continue to cure patients with HCV, we are trying to identify those we can discharge from our practices. This paper reports on the extension of a long-term follow-up study we have been doing in patients with advanced liver disease. Our focus this time was to understand the risk of HCC after sustained virological response (SVR). For me, there were 3 critical findings. Firstly, HCC was extremely rare in patients without cirrhosis at baseline. Only 3 cases were reported in patients with F3 fibrosis prior to treatment and on careful inspection, all 3 had low platelet counts and may well have progressed to cirrhosis between the time of liver biopsy and treatment. This is relevant because it means that we probably do not need to follow those without cirrhosis once they achieve SVR. The second point of interest is the strong effect of increasing age. On first inspection, one might conclude that young patients do not require surveillance because of their low risk of HCC. However, if we look closely at the cumulative incidence curves in both those under 45 and 45-60 years at the time of treatment, the slope of the curves do not level off as we might have expected, but actually seem to increase with continued follow-up. I might have expected that the further patients got out from SVR, in other words the longer they were virus-free, the lower the risk of HCC. Yet these results suggest that for young patients, the risk continues to increase as they age. There is certainly a concern that after many years of ‘negative ultrasounds' patients and physicians may get surveillance-fatigue and think it is less important. These data suggest the opposite is true and as patients age we have to be even more vigilant. Finally, these data confirm the importance of diabetes as an important risk factor pre-SVR and now post-SVR as well. Collectively all 3 points further the case for early treatment, prior to the development of cirrhosis (and possibly diabetes), thus avoiding the need for potentially very prolonged follow-up post-SVR.
Jordan Feld MD MPH, University of Toronto, Ontario, Canada
