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HCC surveillance after SVR in patients with F3/F4 fibrosis
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Dec 7 2020 Jnl of Hepatology
HCV eradication by antiviral treatment reduces but does not eliminate HCC risk. Patients with established cirrhosis require HCC surveillance "indefinitely" after sustained virologic response (SVR) because they appear to have a high risk of HCC even many years after SVR. Patients without established or known cirrhosis may still require surveillance after SVR if they have a sufficiently high HCC risk. In all patients who achieve SVR, the key question is how we can reliably estimate HCC risk, and the change in HCC risk over time, to determine whether the patient might benefit from HCC surveillance. HCC risk is one of the most important factors that should inform decisions of whether and how to screen for HCC. Promising strategies for estimating HCC risk include simplified scoring systems (such as fibrosis-4), liver elastography and multivariable HCC risk calculators. Such tools may enable risk stratification and individualised, risk-based surveillance strategies ("precision HCC screening") in the future.
Eradication of HCV by antiviral treatment reduces but does not eliminate the risk of hepatocellular carcinoma (HCC). In particular, patients with advanced fibrosis (F3) or cirrhosis (F4), have a substantial residual risk of HCC that remains after viral eradication. In patients with cirrhosis, the residual HCC risk after sustained virologic response (SVR) is high enough that there is currently universal agreement that these patients need to continue HCC surveillance. Patients with F3 fibrosis are difficult to stage reliably in a non-invasive manner and have a lower HCC risk than those with cirrhosis, making HCC surveillance decisions harder. In all patients who achieve SVR, the key question is how we can reliably estimate HCC risk, since HCC risk is the key determinant of the cost-effectiveness of screening. Exciting frontiers for current and future research are how HCC risk might decline (or not) as years accrue after HCV eradication, how to estimate HCC risk in individual patients and how to incorporate estimates of HCC risk into risk-based, individualised surveillance strategies. Patients, providers and healthcare systems also desperately need guidance as to whether HCC surveillance can ever be safely discontinued after HCV eradication in patients with cirrhosis, or whether these patients are committed to lifelong surveillance. Does HCC risk decline over time after SVR and can we ever safely discontinue HCC surveillance?
It is tempting to assume that HCC risk would gradually decline after SVR in patients with cirrhosis or advanced fibrosis as the liver remodels, eventually reaching a low enough level that HCC surveillance would no longer be warranted. Unfortunately, studies have demonstrated that annual HCC risk continues to be >2% for up to 10 years after SVR in patients with cirrhosis and a FIB-4 score ≥3.25 30,42(Fig. 5). Even patients without pre-treatment cirrhosis continue to have a substantial annual HCC risk >1% if their FIB-4 score is >3.25.30
Therefore, based on current data, patients with pre-treatment cirrhosis or those without cirrhosis but with FIB-4 >3.25 before and after treatment should continue to undergo HCC surveillance "indefinitely". This is a great strain on healthcare systems that already have relatively low rates of HCC surveillance. There is a great need to develop dynamic tools that incorporate changes over time in age, liver stiffness, FIB-4 score or blood-based biomarkers to calculate changes in HCC risk in order to identify those patients who have attained a sufficiently low HCC risk at a certain time point after SVR and can safely discontinue HCC surveillance.
Patients without established/known cirrhosis may still require surveillance after SVR if they have a sufficiently high HCC risk, such as patients with FIB-4 ≥3.25.
Risk after SVR is the most important factor driving HCC surveillance decisions
It is imperative to estimate HCC risk after SVR because it is the most important factor in determining the cost-effectiveness of an HCC surveillance programme. Only patients who are destined to develop HCC can possibly benefit from HCC surveillance. All other patients can only experience the costs and potential harms of HCC surveillance including financial costs as well as the potential harms of screening anxiety, incidental findings, subsequent confirmatory imaging studies and invasive tests such as liver biopsy. 22
Assuming that HCC surveillance is effective in reducing HCC-related mortality, it has been shown that the cost of screening per quality-adjusted life year (QALY) decreases almost exponentially with increasing HCC risk (incidence) (Fig. 3).
Future directions: Risk stratification and risk-based surveillance strategies
We currently we have a "one-size-fits-all" HCC surveillance strategy, whereby surveillance is recommended based on the presumed stage of fibrosis and all patients are recommended to undergo surveillance by the same relatively ineffective strategy (ultrasonography +/− serum AFP) irrespective of their underlying risk of HCC. An alternative, risk-based surveillance strategy would involve 2 steps. First estimating an individual patient's HCC risk using their risk factor profile and appropriate models. Second, using the HCC risk estimation to determine whether to recommend surveillance or not and whether to recommend an appropriate surveillance strategy according to the patient's risk. The principle is that the comparative effectiveness or cost effectiveness of a surveillance strategy depends on the patient's HCC risk. More effective strategies that are also more expensive (such as screening by abbreviated MRI) or more invasive/harmful, could be more cost-effective if they focus on the high-risk groups.16
Conversely, patients at lower risk of HCC, may undergo screening using only serum/plasma biomarker panels without any ultrasonography, while patients at intermediate risk may undergo screening with both ultrasound and biomarkers.
For risk-based surveillance to become a reality, HCC risk calculators and prediction models need to be improved and validated in diverse populations so that we can reliably estimate HCC risk. Furthermore, the performance characteristics of different screening modalities (including novel imaging tests and biomarker panels) need to be described so that they can be applied according to HCC risk, as shown in a hypothetical example in Fig. 6.

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