PRO: Patients With Hepatitis C Virus With Pretreatment Metavir Stage 3 Fibrosis Do Not Require Hepatocellular Carcinoma Surveillance After Sustained Virological Response

Watch a video presentation of this article Watch the interview with the author According to current American Association for the Study of Liver Diseases/Infectious Diseases Society of America (AASLD/IDSA) recommendations, HCV-infected patients with advanced fibrosis (Metavir stage 3) or cirrhosis (Metavir stage 4) should continue to undergo screening for HCC with biannual abdominal imaging after achieving an SVR.1 In this review, we argue that HCC screening after SVR should be discontinued in most, if not all, patients with pretreatment stage 3 fibrosis. Our argument rests on the current AASLD guideline statement that screening becomes cost-effective at a minimum annual HCC incidence rate of 1.5%.2 To evaluate the HCC risk in patients with Metavir 3 fibrosis, we draw on the data of the landmark “HALT-C” trial, the largest, prospective, controlled, randomized study of patients with HCV with biopsy-proven advanced fibrosis. In this trial, more than 1000 patients who had previously failed pegylated interferon (IFN) treatment were randomized to maintenance IFN or “no treatment” for 3.5 years, followed by several years of careful follow-up. In the subgroup of 313 untreated patients with stage 3 fibrosis, the annual HCC incidence was 0.97%, which is less than the 1.5% threshold3 (Fig. 1). The data from this study significantly weaken the argument in favor of continued HCC surveillance. Incidence of HCC in untreated patients with HCV with stage 3 fibrosis. A total of 313 patients with active infection were followed for a median duration of 6.1 years. The data were taken from the published HALT-C trial.3 The average annual HCC incidence rate was less than 1%. Furthermore, recent studies strongly suggest that HCC incidence rates are further reduced after SVR. For example, a retrospective analysis of pooled data from 153 European and Canadian patients with HCV with bridging fibrosis reported an annual incidence rate of HCC of 0.18% after SVR with IFN-based treatment, compared with 1.08% in patients with cirrhosis4 (Fig. 2). Only three patients with bridging fibrosis experienced HCC. Notably, all three patients had pretreatment thrombocytopenia, raising the possibility that they did in fact have cirrhosis before antiviral therapy.4 Long-term follow-up data with direct-acting antivirals (DAAs) are not yet available, but it appears highly unlikely that HCC rates after DAAs would exceed the approximately 1% reported in the HALT-C Metavir stage 3 control group, let alone approach the consensus screening threshold of 1.5%. HCC incidence in patients with stage 3 or 4 fibrosis after SVR. Data were taken from a recent publication by van der Meer.4 Patients with HCV with pretreatment stage 3 fibrosis (n = 153) or cirrhosis (n = 842) who had achieved SVR with IFN-based therapy were followed for up to 8 years. The dotted line represents the HCC threshold incidence rate of 1.5% per year. We acknowledge the possibility that some Metavir stage 3 patients at higher than average risk for development of HCC might benefit from continued HCC screening. Proposed high-risk features may include comorbidities such as diabetes, obesity, or clinical and demographic features such as ongoing alcohol use, advanced age, male sex, thrombocytopenia, HCV genotype 3, or chronically elevated serum alpha-fetoprotein.5, 6 It is worth noting that these proposed characteristics were identified retrospectively and by subgroup analysis, with individual hazard ratios that generally fell short of statistical significance. We doubt that properly powered, prospective observational studies will ever be performed to unequivocally settle this issue, especially given the current push not to delay antiviral therapy in patients with advanced fibrosis. We suggest that the decision whether to continue HCC surveillance in perceived high-risk patients, including those with multiple risk factors, will have to be individualized. With regard to Metavir stage 4 patients, three recent large studies evaluated the incidence of posttreatment HCC depending on whether patients did or did not achieve SVR.6-8 In the SVR groups, the annual incidence of HCC rates ranged from 0.76% to 1.39% (Fig. 2). Although the case for continued HCC surveillance may not be ironclad even in this group, the reported rates are close enough to the 1.5% threshold to justify this practice. In the absence of long-term follow-up studies with DAAs, our position is predicated on the assumption that DAA treatment, as compared with IFN-based therapy, will not raise the risk for HCC. This issue is currently hotly debated, after the publication of several retrospective case series reporting unexpectedly high HCC rates in DAA-treated patients with cirrhosis with SVR.9, 10 The validity of these reports has been questioned based on methodological flaws and by recent reports that failed to confirm such an effect. For example, a large meta-analysis of more than 6000 patients with HCV with previously treated HCC found no increase in HCC recurrence after DAA treatment.11 Similarly, a multivariate analysis of more than 5000 patients with HCV without prior HCC who were treated with sofosbuvir-containing regimens and 69,000 untreated controls demonstrated no association of DAA therapy with the development of new HCC.12 Based on these data, we conclude that the evidence for a “pro-HCC” role of DAAs is not convincing. However, successful DAA therapy in patients with decompensated cirrhosis will likely result in a new subgroup of patients with stabilized liver function and increased HCC risk as compared with patients with cirrhosis in the IFN era. Continued vigilance and careful HCC screening in these patients is sensible and supported by data. Our final argument pertains to the logistic implications of extending HCC screening to patients with stage 3 fibrosis. Current HCC screening rates in patients with HCV-related cirrhosis in the United States are less than 20%.13, 14 Because the prevalence rates of stage 3 and stage 4 fibrosis in the US population are within the same range (approximately 15% to 20% of all HCV-infected patients),15, 16 the inclusion of stage 3 patients would effectively double the screening workload. This would tax our limited screening resources, dilute our efforts, and reduce the overall effectiveness of HCC screening by overscreening lower-risk individuals. In conclusion, the available evidence indicates that HCC screening in patients with HCV with pretreatment Metavir stage 3 fibrosis is not cost-effective. We propose that HCC screening should not be instituted in such patients and that our effort should instead be redirected to the large and still growing cohort of patients with stage 4 disease.

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