Risk of Hepatocellular Carcinoma After Sustained Virological Response in Veterans With Hepatitis C Virus Infection.
El-Serag HB., et al.
Hepatology 2016; 64:130-7

Abstract:
The long-term prognosis in terms of risk or predictors of developing hepatocellular carcinoma (HCC) among patients with sustained virological response (SVR) remains unclear.
We conducted a retrospective cohort study using data from the Veterans Affairs VA hepatitis C virus (HCV) Clinical Case Registry in patients with positive HCV RNA between October 1999 and August 2009 and follow-up through December 2010. HCV treatment (interferon with or without ribavirin) and SVR (RNA test negative at least 12 weeks after the end of treatment) were determined. We used Cox's proportional hazards models to calculate hazard ratios (HRs) for potential predictors (demographic, virological, and clinical) associated with HCC development post-SVR.
We identified 33,005 HCV-infected individuals who received treatment, of whom 10,817 achieved SVR. Among these patients, 100 developed new HCC during a total follow-up of 30,562 person-years for an overall incidence rate of 0.33% per year. Annual risk of HCC remained considerably high among patients with cirrhosis (1.39%) and those cured after age 64(0.95%). Patients with diabetes (adjusted HR 5 1.88; 1.21-2.91) or genotype 3 infection (adjusted HR 5 1.62; 0.96-2.734) were significantly more likely to develop HCC .

Conclusions:
Risk of HCC after HCV cure, though considerably reduced, remains relatively high at 0.33% per year. Older age and/or presence of cirrhosis at the time of SVR are associated with a high enough risk to warrant surveillance. Diabetes is also a risk factor for post-SVR HCC.

Expert's Commentary (Dr Jordan Feld, senior author)

With the development of highly effective direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection, the number of patients who achieve sustained virological response (SVR) is expected to increase enormously in coming years. Understanding how to follow these patients, particularly understanding the role of surveillance for hepatocellular carcinoma (HCC) will become increasingly important. Numerous small studies have reported the occurrence of HCC post-SVR, primarily in patients with cirrhosis prior to treatment, leading current guidelines to recommend continued HCC surveillance in cirrhotic patients after viral clearance. However, precise estimates on the risk of HCC post-SVR and identification of risk factors to help guide surveillance algorithms have been lacking. This study provides useful date on a huge cohort of patients treated at Veterans Affairs Hospitals (VA) in the US. The study nicely confirms that SVR is associated with a marked reduction in HCC incidence and helps identify risk factors in the 100 patients who developed HCC in follow-up. Not surprisingly, the authors fond that cirrhosis at the time of treatment, whether identified in the chart or diagnosed by APRI, was the strongest risk factor for HCC. It would have been nice to tease this apart in more detail. Most clinicians do not follow those without cirrhosis after SVR. Understanding if any of these patients are indeed at risk for HCC is critically important. The authors showed that the incidence of HCC was much lower in those without cirrhosis but it would have been helpful if they had gone to greater lengths to confirm the absence of cirrhosis in all of these cases. Given the relatively small numbers involved, a detailed chart review would have been feasible and may have identified important other risk factors or more likely would have found missed cirrhosis in all or the majority. Importantly, they also showed that increasing age is associated with HCC and that incidence is steady over time, at least for the first number of years. This is quite important and perhaps counter-intuitive, because many might have assumed that the longer one was out from viral clearance, the lower the risk of HCC development. However, while time free of HCV may be important, increasing age is also important and these risks obviously go in the opposite direction. This has important clinical implications because it means that clinicians cannot discharge patients from follow-up after a fixed number of years since SVR. This is the largest study to look at HCC post-SVR to date but unfortunately, even with the huge number of patients followed, beyond those without cirrhosis, it was not possible to identify a group who do not need follow-up post-SVR. The most important message is therefore that we need to treat early to prevent cirrhosis. Hopefully as we continue to cure huge numbers of cirrhotic patients, we will start to figure out if non-invasive tools or other factors may identify a group with a low enough risk of HCC to forgo surveillance, but until then, these data nicely confirm that we have to follow all cirrhotics indefinitely even after viral cure.

Jordan Feld MD MPH, University of Toronto, Ontario, Canada