What is the impact of HCV therapy on HCC development?

Chronic hepatitis C is the most common cause of hepatocellular carcinoma (HCC) in the United States and Europe. Antiviral therapy against hepatitis C virus (HCV) has long been regarded as one of the most effective chemopreventive strategies for HCC. Sustained viral response (SVR) in patients without cirrhosis can halt disease progression, thereby decreasing the risk of HCC to near zero. In patients with cirrhosis, interferon (IFN)-based SVR was associated with an 81 percent reduction in the incidence of HCC and related mortality.1 Similarly, SVR was associated with a 67 percent reduction in HCC recurrence after complete response in the IFN era.2 However, whether a reduction in HCC risk was related to clearance of HCV or a direct IFN-mediated antitumor effect remains unclear. This debate over the impact of antiviral therapy for HCV infection on hepatocarcinogenesis became particularly relevant after the introduction of IFN-free direct-acting antiviral (DAA) regimens, which have replaced IFN-based therapy.

The results of early studies reported a higher-than-expected HCC incidence and recurrence after DAA therapy, raising concern that DAA therapies may not decrease a person’s risk of HCC. Conti et al and Cardoso et al reported incident HCC in 3.2 percent of patients within six months and 7.4 percent within 12 months of DAA therapy, respectively.3,4 Similarly, Reig et al reported that, of 58 patients with complete response to HCC-directed therapy, HCC recurred in 16 (27.6 percent) patients after a median follow-up period of 5.7 months.5 It is unlikely the DAAs have a direct oncogenic effect, so this association is hypothesized to be related to decreased immunosurveillance of microscopic HCC tumor clones in the setting of a rapid decrease in HCV viral load and related hepatic inflammation.

Recently, the results from several large studies with longer follow-up times demonstrated significant reductions in HCC incidence after DAA therapy. A study that enrolled 62,354 patients from the U.S. Veterans Affairs Health Care System who initiated antiviral therapy found that SVR was associated with significantly decreased HCC risk in multivariable models, irrespective as to whether the antiviral treatment was IFN-based (hazard ratio [HR] 0.32; 95 percent confidence interval [CI], 0.28 to 0.37) or IFN-free (HR 0.29; 95 percent CI, 0.23 to 0.37).6 Being treated with IFN-free therapy was not associated with an increased HCC risk when compared with receiving an IFN-containing regimen (HR 0.97; 95 percent CI, 0.77 to 1.22) after adjusting for baseline differences in patient characteristics. Similarly, a study from Scotland comparing patients who achieved SVR after IFN-based and IFN-free therapies found that the increased HCC risk observed with IFN-free therapy disappeared after adjusting for baseline differences in patient characteristics, such as patient age, Child-Pugh class and degree of portal hypertension (HR 1.15; 95 percent CI, 0.49 to 2.71).7 In light of these recent data, we recommend treatment for patients with HCV infection without the need to alter HCC surveillance frequency during therapy. Patients with cirrhosis should undergo surveillance ultrasonography and alpha-fetoprotein testing every six months, including before initiating DAA therapy, to exclude the presence of HCC.8,9

Although these data have alleviated concerns about increased incident HCC risk, debate continues about the impact of DAA therapy on risk of HCC recurrence in patients with a complete response to HCC-directed therapy. Whereas some studies have shown high recurrence rates, such as Conti et al (28.8 percent recurrence after a median followup period of 5.5 months), others have found substantially lower recurrence rates, such as Ogawa et al (17.5 percent during a 17-month follow-up period) and Cabibbo et al (20.3 percent during an 8.7-month follow-up period).3,10,11 In comparison, historic, actuarial HCC recurrence rates after curative treatments in patients naïve to HCV therapy were 7.4 percent at six months and 47.0 percent at two years.12 We recently completed a systematic review and found a pooled estimate of 24.4 percent for HCC recurrence after DAA therapy, although significant clinical heterogeneity was present within and between studies, including tumor burden, HCC treatments leading to complete response, and followup periods.13 Further, we noted most studies had significant methodologic limitations, including high potential for misclassification and ascertainment biases, potentially leading to overestimates and underestimates of HCC recurrence, respectively. The few existing comparative studies between patients treated with DAA and IFN or those naïve to treatment suggest that those receiving DAA therapy have similar, if not lower, recurrence rates than their counterparts; however, these studies were limited by potential selection bias and residual confounding. Finally, all studies have reported intermediate outcomes, such as early recurrence, but no studies have sufficient followup to examine longer-term outcomes such as overall survival. Ongoing prospective studies have addressed several of these limitations and should provide higher quality data in the near future.

Given the known benefits of HCV therapy, such as improvement in liver dysfunction and quality of life, current data are not sufficiently strong to withhold DAA therapy from patients with a history of HCC.

Given the known benefits of HCV therapy, such as improvement in liver dysfunction and quality of life, current data are not sufficiently strong to withhold DAA therapy from patients with a history of HCC. However, delaying DAA therapy has been associated with a lower risk of recurrence in several studies.5,13 This may allow for a longer duration of immunosurveillance for microscopic tumor clones as well as to verify HCC complete response, thereby minimizing the likelihood of misclassification bias. Given the unclear benefit of HCV treatment in patients with active HCC and lack of urgency for HCV therapy, we recommend confirming durable complete response of HCC by multiphase computed tomography (CT) or magnetic resonance imaging (MRI) for four to six months prior to initiating DAA therapy. We often perform more intensive surveillance monitoring for patients with recurrent HCC using multiphase CT or MRI every three months while the patient is on DAA therapy and during the subsequent six-month period. If patients remain recurrence free at that time, they can then return to multiphase CT or MRI every six months. However, this institutional practice is based primarily on theoretical concerns, with limited high-quality data to inform optimal surveillance algorithms in these patients.

In summary, recent data have demonstrated that IFN-free DAA therapy significantly decreases the risk of incident HCC, highlighting the safety of treating patients with HCV infection and no prior history of HCC. However, uncertainty still exists about the risk of HCC recurrence following DAA therapy, with large variations in reported HCC recurrence rates between studies and notable methodological limitations that make the studies difficult to interpret. Ongoing prospective studies should provide higher-quality data in the near future to better address the optimal timing and potential impact of HCV therapy on HCC recurrence risk. While awaiting those data, DAA therapy does not need to be withheld from patients with a history of HCC, but it can be delayed four to six months to ensure complete response and mitigate any potential risk of HCC recurrence.

Key takeaways

  • IFN-free DAA therapy for chronic HCV infection significantly decreases the risk of incident HCC in HCV-infected patients with or without cirrhosis, highlighting the benefit of treating these patients.
  • There are conflicting data, with methodological limitations, about a potential increased risk of HCC recurrence after DAA therapy. Ongoing prospective studies should provide higher quality data to address this issue in the near future.
  • While awaiting these data, we recommend confirming durable HCC complete response for four to six months by multi-phase CT or MRI scans before initiating DAA therapy.

Dr. Singal is a consultant and on the advisory board for Bayer, is on the speakers’ bureau for Gilead and has received a research grant from Abbvie. He is on AASLD’s Practice Guidelines and Research Committees and the ACG Research Committee. Dr. Parikh is a consultant for Bristol -Myers Squibb and has served on advisory boards for Bayer and Eisai. He was awarded a research grant from Target Pharmaceuticals.

1. 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;308:2548-2593.
2. Miyake Y, Takaki A, Iwasaki Y, Yamamoto K. Metaanalysis: interferon-alpha prevents the recurrence after curative treatment of hepatitis C virus-related hepatocellular carcinoma. J Viral Hepatitis. 2010;17:287-92.
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4. Cardoso, H., Vale, AM., Rodriguez, S., et al, High incidence of hepatocellular carcinoma following successful interferon-free antiviral therapy for hepatitis C associated cirrhosis. J Hepatol. 2016;65:1070-1071.
5. Reig, M., Boix, L., Bruix, J. The impact of direct antiviral agents on the development and recurrence of hepatocellular carcinoma. Liver Int. 2017;3(suppl 1):136-139.
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8. Tzartzeva, K., Obi, J., Rich, N.E., et al, Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis. Gastroenterology. 2018;154:1706-1718.e1.
9. Singal, A.G., Pillai, A., Tiro, J.A. Early detection, curative treatment, and survival rates for HCC surveillance in patients with cirrhosis: a meta-analysis. PLOS Med. 2014;11:e1001624
10. Ogawa, E., Furusyo, N., Nomura, H., et al, Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment. Aliment Pharmacol Ther. 2018;47:104-113.
11. Cabibbo, G., Petta, S., Calvaruso, V., et al, Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by treatment with direct-acting antivirals? A prospective multicentre study. Aliment Pharmacol Ther. 2017;46:688-695.
12. Cabibbo, G., Petta, S., Barbara, M., et al, on behalf of the ITA.LI.CA Study Group. A meta-analysis of single HCV-untreated arm of studies evaluating outcomes after curative treatments of HCV-related hepatocellular carcinoma. Liver Intl. 2017;37:1157-1166.
13. Saraiya, N., Yopp, A.C., Rich, N.E., et al, Systematic review with meta-analysis: recurrence of hepatocellular carcinoma following direct-acting antiviral therapy. Aliment Pharmacol Ther. 2018. [Epub ahead of print].

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