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During the last several decades, the incidence of hepatocellular carcinoma (HCC) has risen sharply in the United States and globally, driven partly by an increase in hepatitis C virus (HCV) infections.1 In the United States, HCV accounts for approximately 20% to 31% of HCC deaths.1,2 The prevalence of HCC is especially high in patients with cirrhosis as a result of their chronic HCV infection, whose annual risk for HCC is estimated at 2% to 4%.3 Long-term eradication of HCV reduces HCC risk, which was discovered initially in patients who achieved sustained viral response (SVR) with interferon-based therapies.3 Direct-acting antiviral agents (DAAs) have replaced interferon-based treatments for HCV and offer several advantages over their predecessors, including SVR rates greater than 90% and a better safety profile.3,4
A few early reports associated first-generation DAAs with an increased risk for de novo and recurrent HCC, and concern grew that DAAs might have hepatocarcinogenic effects.3,4 Multiple studies have since shown that DAAs significantly reduce the risk for de novo HCC in patients with HCV, a benefit that extends even to patients with decompensated cirrhosis.3,5,6 As with interferon-based regimens, HCC risk after DAA therapy appears to depend on achievement of SVR.3,4 A recent review of 11 retrospective studies that examined HCC incidence in a cumulative ~30,000 patients treated with DAA therapy associated SVR with an approximate 70% reduction in HCC risk.3 “Collectively, these data show that successful HCV eradication confers a benefit of reduced HCC incidence in DAA-treated patients,” the authors wrote.3 Experts continue to debate the appropriate role for DAA therapy in patients with a history of HCC. Studies have produced conflicting data regarding recurrence risk, and their methodical limitations prevent firm conclusions.
DAAs and Hepatocellular Carcinoma Recurrence
The American Gastroenterological Association (AGA) recently published a clinical practice update that includes a detailed review of evidence for the interactions among oral DAAs, chronic HCV infection, and HCC.3 Amit Singal, MD, medical director of the Liver Tumor Program, clinical chief of hepatology, and an associate professor with UT Southwestern Medical Center in Dallas, Texas, was lead investigator. One impetus for the review was the team’s concern that controversy regarding the relationship between DAAs and HCC recurrence had caused some providers to stop administering DAA therapy to patients with a history of HCC.
The AGA review included a meta-analysis by Saraiya and colleagues of 24 studies that examined HCC recurrence after treatment with DAAs.3 Patients with HCC were excluded from most of the pivotal clinical trials of the DAAs, and therefore most of data come from real-world studies.4 Several studies included in the meta-analysis lacked a comparator cohort; most failed to describe initial response to HCC therapy, and they had differences in patient selection criteria, timing of DAA therapy, and follow-up schedules.7 The 2-year recurrence rates varied widely among the studies, but the pooled recurrence rate was 25.1% (95% CI, 19.4%-31.2%).3,7 In the 11 studies that considered HCC recurrence within 6 months of DAA therapy, the pooled rate was 10.3% (95% CI, 6.3%-14.4%).3,7 The AGA group noted that reported recurrence rates after curative treatments for HCC, such as surgical resection and local ablation are typically higher, ranging from 25% to 35% within 1 year and 50% to 60% within 2 years.3 In a review of 3 studies that compared DAA exposure vs either interferon-based therapy, Saraiya and associates found no significant difference in HCC recurrence between the study groups.3,7 They also found no significant difference in HCC recurrence between patients treated with DAAs and patients who received no antiviral therapy.
In May 2019, Singal and colleagues published findings from a retrospective cohort study that included 793 patients treated for HCC across 31 institutions in the United States and Canada, which were also included in the AGA review.3,8 After achieving a complete response to HCC treatment, 304 patients received DAA therapy and 489 received no HCV therapy. The study showed no association between DAA therapy and HCC recurrence (hazard ratio, 0.90; 95% CI, 0.70-1.16).3,8 In an interview with Hepatitis Advisor, Dr Singal said the current data “suggest that there is not increased risk of recurrence after DAA therapy, so it now appears to be safe to treat patients with HCC with DAA therapy.”
Timing of Direct-Acting Antiviral Therapy
Limited high-quality evidence is available to guide the timing of DAA administration in patients with HCV-related HCC. For early HCC, Dr Singal said he and his colleagues “typically recommend treating with DAA therapy after confirmed complete response to HCC therapy, such as surgery or ablation.” The reason for this is that “data suggest patients with active HCC have lower response rates to DAA therapy, so waiting to administer DAAs until after HCC treatment and a complete response may allow maximal response to DAAs,” he said. For example, a study in US veterans with HCV observed an SVR rate of 74.4% in patients who received DAA therapy during active HCC versus 91.1% in patients without HCC.9 The SVR rate for patients with early-stage HCC who received DAA therapy after liver transplantation was 94%.9 Because the SVR rate posttransplant is so strong, Dr Singal said he and his colleagues “typically defer DAA therapy for patients awaiting liver transplantation until after transplant so they will be eligible to receive an HCV-infected graft.” He explained that the pool of HCV-positive donors is larger in some regions, so postponing HCV therapy may facilitate earlier transplant for some patients.
However, if the wait time to transplant is long or the patient has a high degree of liver dysfunction, clinicians may want to consider DAA therapy before transplant.3 In a few retrospective studies, a small number of patients treated with DAA therapy who achieved SVR while awaiting liver transplant experienced sufficient improvement in liver function to receive other curative therapies and forego transplant.4 For those continuing on to transplant, data suggest administering DAA therapy before transplant does not increase posttransplant risk for HCC recurrence.4
For clinicians who remain concerned that DAA therapy might increase the risk for early recurrence in patients with HCC, Dr Singal recommends weighing the potential risk for recurrence against the known benefits of DAA therapy, including fibrosis regression and amelioration of portal hypertension and liver function. “One of the leading causes of death in patients with cirrhosis and completely treated HCC is subsequent liver dysfunction; DAA therapy may lead to improved liver function and thereby improve survival,” he said. Singal and colleagues also hypothesize that by decreasing the HCV viral load and slowing or preventing liver deterioration, DAA therapy could reduce the risk for late HCC recurrence.3
Some studies that reported an increased risk for HCC recurrence with use of DAA therapy correlated earlier HCC recurrence with a shorter interval between complete response to HCC treatment and the DAA agent.3 Because the relationship between HCC recurrence risk and DAA therapy remains murky, the AGA team and other experts suggest waiting several months after a complete response before administering DAA therapy.3 Waiting also permits additional imaging to verify the complete response.
Limited data are available regarding use of DAA therapy in patients with untreated advanced HCC.4 “There is no data that DAA therapy would be of benefit, although there is a theoretical benefit if it were able to improve liver dysfunction and allow continued HCC therapy,” Dr Singal said. Factors to consider are tumor burden, extent of liver dysfunction, life expectancy, and patient preference.3 Use of DAA therapy in the setting of advanced HCC would be palliative, and Dr Singal said more studies relative to that patient population are needed.
References
1. Akinyemiju T, Abera S, Ahmed M, et al. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the Global Burden of Disease Study 2015. JAMA Oncol. 2017;3(12):1683-1691.
2. Islami F, Goding Sauer A, Miller KD, et al. Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States. CA Cancer J Clin. 2018;68(1):31-54.
3. Singal AG, Lim JK, Kanwal F. AGA clinical practice update on interaction between oral direct-acting antivirals for chronic hepatitis C infection and hepatocellular carcinoma: expert review. Gastroenterology. 2019;156(8):2149-2157.
4. Cabibbo G, Celsa C, Cammà C, Craxì A. Should we cure hepatitis C virus in patients with hepatocellular carcinoma while treating cancer? Liver Int. 2018;38(12):2108-2116.
5. McGlynn EA, Adams JL, Kramer J, et al. Assessing the safety of direct-acting antiviral agents for hepatitis C. JAMA Netw Open. 2019;2(6):e194765-e194765.
6. Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology. 2017;153(4):996-1005.
7. Saraiya N, Yopp AC, Rich NE, Odewole M, Parikh ND, Singal AG. Systematic review with meta-analysis: recurrence of hepatocellular carcinoma following direct-acting antiviral therapy. Aliment Pharmacol Ther. 2018;48(2):127-137.
8. Singal AG, Rich NE, Mehta N, et al. Direct-acting antiviral therapy not associated with recurrence of hepatocellular carcinoma in a multicenter North American cohort study. Gastroenterology. 2019;156(6):1683-1692.
9. Beste LA, Green PK, Berry K, Kogut MJ, Allison SK, Ioannou GN. Effectiveness of hepatitis C antiviral treatment in a USA cohort of veteran patients with hepatocellular carcinoma. J Hepatol. 2017;67(1):32-39.
