Primary Care Corner with Geoffrey Modest MD: Hepatoma surveillance after hep c treatment

by Dr Geoffrey Modest

The American Gastroenterological Association just published a clinical practice update on the care of hepatitis C patients who achieve a sustained virologic response (SVR) after direct-acting antiviral therapy (DAA). See Their recommendations:

— Reconfirm SVR at 48 weeks post-DAA treatment. Studies have found that <1% of patients relapse after SVR at 24 weeks (SVR24, though SVR12 at 12 weeks is now more commonly checked). These are real relapses, not reinfections, and seem to be independent of viral genotype or particular type of patient. But this low rate of relapses still justify checking [and presumably treating]. The European Assn for the Study of the Liver also recommends the 48 week SVR check.

— Continue surveillance for hepatocellular carcinoma (HCC) with liver imaging +/- serum AFP 2x/year indefinitely in all patients with stage 3 fibrosis or cirrhosis post-SVR (but not in those with stage 0-2 fibrosis). AFP screening is now considered optional or adjunctive per most current guidelines. There are HCC cases found >5 years post-SVR in patients with interferon-based regimens, so at this point there is no recommendation as to when/if we can stop. Also, there are documented cases of HCC in those with F0-F2 fibrosis, though it is unclear from these reports whether there might have been other reasons for HCC (NASH, alcohol…).  For these F0-F2 patients, they do comment that “some clinicians might choose to obtain a final ultrasound during the year after SVR following DAA therapy”. Of course, one issue here is that biopsies may miss higher fibrosis regions, and liver elastography is operator-dependent and may not correlate with the (also imperfect) biopsy. See article below for some suggestive evidence that DAA could actually increase the likelihood of HCC.

–endoscopic screening for esophagogastric varices should be done in all patients with cirrhosis, independent of SVR. And it should be repeated at 2-3 years if no varices or small varices are present initially. This can be stopped after the second screening if no varices are found and there are no risk factors for progressive cirrhosis, on an individual patient basis. They also suggest that for those with small varices on initial exam (where no treatment is necessary), no further screening is necessary if followup endoscopy after 2-3 years shows unchanged or smaller varices.

–it is okay to check fibrosis with noninvasive tools (eg liver elastography) on an individual basis, but “improved fibrosis measurements should not alter the frequency of HCC surveillance at the present time”. [so, I’m not sure why we would do this…..]

–and, patients who achieve SVR should be counseled about minimizing risk of liver injury (alcohol, fatty liver, heptotoxins), and should be evaluated for these if serum liver enzymes are elevated. They note: “no safe limits for alcohol consumption has been established post-SVR and, therefore, avoidance of significant alcohol intake should be recommended for all patients, and complete abstinence is prudent in patients with advanced liver fibrosis or cirrhosis.” Diabetes is also a risk factor for HCC in those with hepatitis C, including those with HCC post-SVR and in non-cirrhotic patients, though there are insufficient data evaluating the benefit diabetes control or decreasing fatty liver disease.



The data are mixed on the effect of DAA for hepatitis C on the development of HCC, though older studies did find a reduction with interferon-based therapies (decreased all-cause mortality, liver-related mortality, need for liver transplant, variceal bleeding, as well as HCC, where a pooled study found a 76% decrease). A recent letter in Gastroenterology presented the results of a retrospective study of 66 cirrhotic patients treated with DAA in 2015-6 at the University of Alabama, with SVR in 61 (92%).  The above clinical guidelines cite a baseline HCC rate of 1-4%/year in those with cirrhosis. In this study, they found that 9% of patients developed de novo HCC within 6 months of DAA therapy (1/2 of whom developed HCC during DAA therapy), and another 3% having new indeterminate lesions (see There have been other studies finding either higher or lower incidence of post-SVR HCC; the variability of results may reflect the predominance of different genotypes in the different studies, the degree of cirrhosis/Child-Pugh class, as well as selection biases/imaging modalities to assess HCC (eg, ultrasound missing smaller lesions, especially in cirrhotic patients)/etc.)  But this and some other studies reinforce, at least for now, the need to continue surveillance for HCC in those with cirrhosis and treated effectively with DAA. The above clinical guidelines suggest NOT doing enhanced surveillance in the immediate post-SVR period, though this study did find that 1/2 the patients with HCC developed it during therapy.  Why would there be differences in HCC in those getting DAA vs interferon-based regiments of yore?? One thought is that SVR after DAA leads to down-regulation of cytokines (including endogenous interferon) which may have anti-tumor effects.


so, these studies suggest a few conclusions:

— we should be checking SVR one year after treatment, and not just at 12 or 24 weeks

— we should continue with HCC surveillance in those with SVR for the indeterminate future, per the usual 6-monthly schedule

— and it does not seem to make sense to rely on ultrasound or liver elastography to assess regression of cirrhosis as a means to decrease this HCC surveillance at this point.