Is it time to refine HCC surveillance strategies in HCV cured patients?
Authors: Roberta D’Ambrosio, Pietro Lampertico
Journal: Hepatology (2022)

SEE ARTICLE ON PAGE 139 Since 2014, large‐scale use of direct‐acting antivirals (DAAs) to treat chronic HCV has progressively changed the epidemiological scenario worldwide. The excellent effectiveness and safety profiles of DAAs finally allowed for the treatment of the most infected persons, including those with cirrhosis, either compensated or not.[1] In those patients, sustained virological response (SVR) rates were similar to those of patients with milder stages of liver disease, progressively rising to nearly 99%.[1,2] Yet, in the interferon (IFN) era, the achievement of an SVR was associated with several clinical benefits, given how the risk of cirrhosis associated complications was significantly reduced.[3] The wide use of DAAs to cure large cohorts of patients with advanced liver disease and/or comorbidities, who were previously contraindicated to IFN‐based therapies, has recently livened up the debate on long‐term surveillance strategies and their cost‐effectiveness. Although the risk of hepatic decompensation remains low, also in patients with severe portal hypertension, before treatment,[1,4] the residual annual risk of de novo HCC has been estimated to be 2.0%–2.5% in SVR persons with cirrhosis following DAAs,[5] thus further supporting the need for post‐treatment surveillance in this subgroup of patients. Conversely, data on the residual risk of HCC in patients with F3 fibrosis are controversial, as long as recommendations from scientific societies are not univocal.[1,2,6] Given that the incidence of HCC is expected to rise over time in F3 and F4 cohorts, mainly attributable to extensive DAA use and population aging, individualized surveillance strategies are warranted in order to optimize patients' management and costs. In this issue of Hepatology, Lockart et al. evaluated the incidence of HCC in patients with advanced fibrosis (F3) or cirrhosis (F4) with an SVR to antivirals.[7] Their systematic review included 44 studies reporting data on 35,739 patients (29,444 with F4, 2201 with F3, and 4094 with F3‐F4) treated with either IFN (n = 2807) or DAAs (n = 19,663). Overall, HCC incidence was 1.7 per 100 person‐years during a follow‐up of at least 12 months. In F4 patients, overall risk of HCC was 2.1 (95% CI, 1.9–2.4) per 100 person‐years, higher in DAA treated than in IFN treated (2.5 [95% CI, 2.2–2.8] vs. 1.5 [95% CI, 1.0–2.1] per 100 person‐years), likely as a consequence of treatment selection bias and effectiveness. HCC risk was higher in patients with cirrhosis with past decompensation (adjusted rate ratio [aRR], 1.06; 95% CI, 1.01–1.12; p = 0.028) and older age (aRR, 1.32; 95% CI, 1.00–1.73; p = 0.048). The former finding is in line with previous studies that reported portal hypertension being associated with post‐SVR HCC.[5] Conversely, diabetes was not an independent predictor of HCC in this meta‐analysis, whereas other metabolic factors were not evaluated. The role of metabolic disorders on post‐treatment HCC risk probably needs additional investigations for several reasons. In fact, not all baseline metabolic risk factors have been collected in such studies. Then, not only diabetes, but also surrogate biomarkers of metabolic disorders, such as elevated gamma‐glutamyl transferase,[5,8] had been previously associated with HCC in some IFN‐ and DAA‐treated cohorts, thus suggesting that the dysmetabolic profile may have a role beyond single comorbidities. Another important finding of this meta‐analysis was that HCC risk was influenced by time elapsed from SVR achievement, given that it decreased over time. In F4 patients, risk of HCC was higher within the first 2 years after treatment completion compared to beyond this time point (2.7 vs. 1.9 per 100 person‐years), although both fell above the accepted yearly 1.5% HCC surveillance threshold. However, as clearly shown in Fig. 2B, all the five studies with a post‐SVR follow‐up exceeding 5 years showed a significantly lower HCC incidence, thus potentially arguing against universal HCC surveillance in these patients. However, in our view, these results require confirmation given that the overall number of patients enrolled in studies with long follow‐up is limited and who were mostly treated with IFN. Moreover, a few years ago, a large USA cohort study reported that in IFN‐treated patients with cirrhosis with baseline FIB‐4 ≥3.25, the annual risk of HCC remained above 2% even 10 years after SVR.[9] Until issues related to the long‐term risk of HCC are resolved, this meta‐analysis confirms the need for HCC surveillance, in line with international recommendations. It remains debatable whether predictive algorithms generated by the integrated analysis of pretreatment and time‐related factors may add useful information in terms of HCC risk stratification. Even more controversial is the issue of HCC surveillance in F3 patients. Lockhart et al. reported rates of HCC lower than the standard surveillance threshold, independently of treatment regimen (IFN vs. DAA, 0.4 [95% CI, 0.2–1.2] vs. 0.5 [95% CI, 0.3–0.8] per 100 person‐years). These data would definitively discourage one from applying lifelong HCC surveillance in this population, which is, however, not in line with EASL and APASL recommendations. We think that these findings need some considerations. First, data on the residual risk of HCC in F3 patients have historically been cautiously interpreted because of issues related to potential fibrosis underestimation. Already in the IFN era, identification of F3 patients was challenging because of the potential sampling error associated with liver biopsy. Currently, the extensive use of physical and serological noninvasive tests has further complicated matters, given that their ability to diagnose intermediate stages of fibrosis remains suboptimal.[10] To partially overcome this bias, the meta‐analysis included only studies where F3 fibrosis was defined according to the more accurate and validated staging tools, such as liver biopsy and transient elastography. However, liver stiffness measurement thresholds and ranges used to define advanced fibrosis in the meta‐analysis are heterogeneous and, in some cases, even overlapped those used to define cirrhosis.[10] Second, the number of studies reporting data on F3 patients is quite limited (three IFN and five DAAs), with those performed in the DAA era suffering from shorter follow‐up. Finally, the limited number of post‐SVR events may limit the robustness of the assessment of potential HCC predictors. Keeping these considerations in mind, it seems reasonable to wonder whether some F3 patients may face high (i.e., >1.5% per year) HCC risk following an SVR, given that they could potentially be worthy of HCC surveillance. Given that several factors may influence the risk of HCC occurrence in SVR patients, the development of algorithms for HCC risk stratification would help toward refining surveillance rules in order to personalize the surveillance strategies. They could be useful to identify: (1) patients at no or negligible risk of tumor development who could be eventually safely discontinued from surveillance; (2) F3 patients at high risk of de novo HCC for whom HCC surveillance could be indicated; and (3) F4 patients at very high risk of HCC, in whom HCC surveillance could even be intensified, although the usefulness of this strategy remains highly debated. Apart from baseline variables, which are already included in most predictive models, other variables, such as time‐related factors, could potentially influence the risk of HCC, especially in the long term. For example, the role of metabolic comorbidities with late post‐SVR onset and of other aging‐related factors has not been clearly investigated, yet; however, their identification could help to further refine HCC risk‐stratification models. This would be an issue also in HCV patients with pretreatment mild (F0‐F2) fibrosis, given the information gap relative to carcinogenesis even in patients with pure metabolic liver disease (i.e., NAFLD). In 2022, a decade after their development, DAAs have definitively changed the natural course of chronic HCV infection as well as the epidemiological scenario. For countries where DAAs are easily available and most patients had achieved a virological cure, the current challenge is to optimize post‐treatment HCC surveillance, thereby wisely balancing two priorities, to ensure early HCC diagnosis as well as saving resources. CONFLICT OF INTEREST Roberta D'Ambrosio has served in the capacity of speaking, teaching, and advisory boards for AbbVie, Gilead, and MSD; has consulted for AbbVie and Takeda; and has received research grants from AbbVie and Gilead. Pietro Lampertico has served on the advisory boards/speaker's bureaus for BMS, Roche, Gilead Sciences, GSK, AbbVie, MSD, Arrowhead, Alnylam, Janssen, Spring Bank, MYR, Eiger, Aligos, Antios, and Vir. AUTHOR CONTRIBUTIONS Roberta D'Ambrosio conception and design, acquisition of data, interpretation of data, drafting the article. Pietro Lampertico conception and design, acquisition of data, interpretation of data, drafting the article.