Shifting Gears on HCV

Evidence from a few randomized trials and multiple observational studies supports performing a liver ultrasound every six months as part of hepatocellular carcinoma (HCC) surveillance in patients with hepatitis C virus-related cirrhosis (HCVc). Although the possibility of using other technical modalities is tempting, there are concerns regarding radiation exposure and cost. Use of multiphase computed tomography, for example, is associated with an exposure of up to 31 millisieverts per study, which corresponds to 10 times the yearly average natural background radiation. Such exposure over a 10-year period might cause as many cancers as it would prevent. Alpha-fetoprotein has shown an inconsistent performance in most HCC surveillancestudies, and its clinical usefulness has been mostly reduced to predicting advanced HCC stages (i.e., vascular invasion) once diagnosis has been established.

Long-term follow-up studies have shown that sustained virological response (SVR) in patients with HCVc is associated with an up to fivefold reduction in risk for HCC. SVR also stabilizes liver disease and decreases the risk for decompensation and need for transplantation, while reducing overall mortality. However, among available studies, nonviral risk factors that would have confounded the association between viral eradication and HCC risk were not systematically studied, or they were only addressed at baseline. Some of these nonviral factors include the following: HCC family history, alcohol use, smoking, excess weight, diabetes mellitus, staging of cirrhosis and other prescribed drugs. Moreover, regression offibrosis was not evaluated. Therefore, the magnitude of decreased risk related to regressed cirrhosis was not determined.

The profile of patients with HCVc has shifted in the DAA era.

Most studies addressing HCC risk after SVR pertain to the peginterferon era, and less robust evidence is available from the direct-acting antiviral (DAA) era. Based on a few reports finding increased HCC incidence/recurrence after DAA-driven SVR, controversy as to whether DAAs increase HCC risk has been recently published. However, this is likely the result of lead-time and length biases caused by sicker patients with more advanced liver diseases (who would have been excluded from antiviral therapy in the peginterferon era) accessing DAA agents and achieving SVR.

In my practice, I follow international clinical practice guidelines and perform HCC surveillance with an ultrasound every six months in all patients with HCVc (biopsy proven or clinically defined) detected either before or after antiviral therapy. This includes patients with early or “occult” cirrhosis identified solely on the basis of noninvasive markers of fibrosis and with no clinical features suggesting portal hypertension (e.g., liver stiffness from transient elastography 12.5–15 kPa). Although it is conceivable that not all patients with cirrhosis need to continue HCC surveillance after SVR, I continue with the same surveillance protocol after SVR is achieved, given the absence of criteria to identify subpopulation(s) with such a low incidence that surveillance would no longer be cost-effective (predicted HCC incidence less than 1.5 percent per year). As an example, it is possible that a young, lean female with stage 1 cirrhosis, no family history of HCC, and no personal history of smoking, substance abuse, or diabetes would no longer be eligible for continued surveillance after SVR. Similarly, a patient found to have a drop in liver stiffness to less than 12.5 kPa at SVR and no features of advanced liver disease or other associated risk factors could also have a very low risk for incidental HCC. Some might even doubt cirrhosis was present to start with. Unfortunately, there is a gap in the knowledge necessary to safely predict the lack of HCC surveillance’s costeffectiveness after SVR. Therefore, universal HCC surveillance for all HCVc is advised.

My view of SVR in HCVc is that it is an intermediate end point and only the beginning of a healing process aiming to prevent liver transplantation, HCC and liver-related death. Thus, particularly after completion of the DAA regimen, I focus clinic visits on addressing cofactors of liver carcinogenesis that can potentially be modified. The following are some recommendations I give to HCVc patients:
• Remain abstinent from alcohol.
• Keep as lean as possible (aim for a BMI of less than 28).
• Increase physical activity and exercise.
• Avoid smoking tobacco or marijuana.
• Increase coffee consumption.
• Properly control diabetes and othermetabolic diseases.

When applicable, I document the safety of statins in HCVc so patients can be restarted on them.

One last thing needs to be considered: the population of patients who received treatment with peginterferon is likely very different from the one receiving treatment in the DAA era. Consequently, HCC risk will likely differ as well. Although it is widely reported that we are treating patients with more advanced liver disease in the DAA era, I have also found patients to have more (or more severe) extrahepatic comorbidities, to be more reluctant to stop recreational drugs and alcohol use, to be less compliant with medical recommendations or follow-up visits, and to be more frequently medically illiterate. Efforts to improve access to health care and DAA, to speed up staging of liver disease through noninvasive assessment, and to facilitate medication approval, along with a massive advertising campaign from drug companies, have yielded a more heterogeneous population of HCVc being treated with antivirals. Thus, the profile of patients with HCVc has shifted in the DAA era, and the only way to truly know the magnitude of reduced HCC risk after SVR in the years to come will be through performing prospective and long-term followup studies with DAA-based therapy, while taking nonviral factors and regression of fibrosis into account. In the meantime, we should follow international clinical practice guidelines and continue long-term HCC surveillance with ultrasounds every six months in patients with HCVc.

Dr. Duarte-Rojo served on a Gilead Advisory Board and received FibroScan® 530 on loan from Echosens.

1.Gonzalez, H.C., Duarte-Rojo, A. Virologic Cure of Hepatitis C: Impact on Hepatic Fibrosis and Patient Outcomes. Curr Gastroenterol Rep. 2016;18(7): 32.
2.van der Meer, A.J., Veldt, B.J., Feld, J.J., et al, Association Between Sustained Virological Response and All- Cause Mortality Among Patients With Chronic Hepatitis C and Advanced Hepatic Fibrosis. JAMA. 2012;308(24): 2584–2593.
3.ANRS Collaborative Study Group on Hepatocellular Carcinoma. Lack of Evidence of an Effect of Direct-Acting Antivirals on the Recurrence of Hepatocellular Carcinoma: Data From Three ANRS Cohorts. J Hepatol. 2016;65(4): 734–40.

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