Navigating the Hep C Treatment and Cancer Risk Minefield

Damian McNamara

June 02, 2017




AMSTERDAM — Contradictory findings are driving disagreement over whether patients cured of hepatitis C after treatment with direct-acting antivirals should be monitored for hepatocellular carcinoma.


A flashpoint in the controversy was a Spanish study that revealed a 28% rate of radiologic tumor recurrence in 103 people with a history of liver cancer who were treated with direct-acting antivirals (J Hepatol. 2016;65:719-726). In that study, the investigators noted that the "high rate of cancer recurrence" after patients with a history of hepatocellular carcinoma were treated with direct-acting antivirals should prompt larger trials.


And it did.


"The original observations made by these researchers from the Barcelona Clinic Liver Cancer Group have sparked a huge number of studies aimed at verifying the potential association between direct-acting antiviral treatment and increased hepatocellular carcinoma recurrence after cure," said Francesco Negro, MD, from the University of Geneva, who is a governing board member of the European Association for the Study of the Liver.


"There is no reason to alter treatment guidelines until the issue is clarified," he pointed out. "We cannot exclude, however, that we may have to revise post-SVR surveillance in specific patient subgroups."


Evidence Pointing to a Heightened Cancer Risk
           Follow-up data from the Barcelona Clinic Liver Cancer Group were presented at the recent International Liver Congress. At a median of 12 months, the rate of recurrence for liver cancer was 31% in 77 patients with hepatitis C and a history of hepatocellular carcinoma who were treated with direct-acting antivirals. And the findings suggest that recurrence can be aggressive: 30% of patients treated for recurrent disease experienced cancer progression in the subsequent 6 months.


"Our study supports previous findings of an unexpected high recurrence rate of hepatocellular carcinoma associated with direct-acting antivirals, and this association may result in a more aggressive pattern of recurrence and faster tumor progression," said lead investigator Maria Reig, MD, from Hospital Clinic Barcelona.


An Israeli study also points to an increased risk for malignancy in hepatitis C patients treated with direct-acting antivirals. Findings from the retrospective assessment of 273 consecutive patients infected with hepatitis C, some with a history of liver cancer and others without, were also presented at the International Liver Congress.


A sustained viral response at 12 weeks was achieved by 95% of the patients. However, over the next 15 months, 14 patients, or 5% of all participants, developed malignancy. Specifically, there were six cases of de novo hepatocellular carcinoma, three cases of recurrent hepatocellular carcinoma, four cases of extrahepatic cancer, and one case of intrahepatic cholangiocarcinoma.

It is concerning; you can't ignore it.

"When we observed the efficacy of direct-acting antivirals, we started to see some cases of malignancies," said study investigator Assaf Issachar, MD, from the Rabin Medical Center in Petah Tikva, Israel.


The higher risk did not surprise him, he explained, because the findings support those from the Barcelona group.


But "it is concerning; you can't ignore it," Dr Issachar told Medscape Medical News.


Although the mechanism of the association, if any, remains unknown, Dr Issachar and his colleagues note that their findings of increased risk after direct-acting antiviral treatment "may support the theory of a sudden impairment of the immune system, allowing existing preclinical cancer clones to grow."


Studies Finding No Elevated Cancer Risk
           In contrast, investigators saw no increased risk for hepatocellular carcinoma in patients treated with direct-acting antivirals in a retrospective study of 178 patients with hepatitis C infection and hepatocellular carcinoma who were candidates for liver transplantation.


The research, presented during a late-breaking poster session at the International Liver Congress, showed the cumulative incidence of recurrence over 1 year was lower in patients treated with direct-acting antivirals before a diagnosis of hepatocellular carcinoma than in a control group of patients never treated with direct-acting antivirals.


Dr Annsa Huang


However, when the antivirals were administered after a diagnosis of liver cancer, the risk for recurrence was similar in the antiviral and control groups, which suggests that prediagnosis antiviral therapy could be protective, reported Annsa Huang, MD, a resident at the University of California, San Francisco Medical Center.


"Our study contributes to the literature in a different population — liver transplant patients on a wait list," Dr Huang told Medscape Medical News. "When patients took direct-acting antivirals before a hepatocellular carcinoma diagnosis, there was a statistically significant decrease in recurrence" (P = .04).


When patients had a complete initial response to cancer therapy, direct-acting antiviral use did not significantly increase the transplantation wait-list dropout rate, Dr Huang explained. "Our results support the use of direct-acting antiviral therapy in patients on the transplant waiting list with hepatocellular carcinoma who have achieved initial response to locoregional treatment."


A systemic review, meta-analyses, and meta-regression revealed no difference in risk for hepatocellular carcinoma in patients treated with direct-acting antivirals and those treated with interferon-based therapy. The Australian study, also presented during a late-breaker presentation at the International Liver Congress, involved 13,875 people from 26 studies on hepatocellular carcinoma occurrence and 15 studies on disease recurrence.


In fact, the investigators note, other factors could explain the higher incidence of cancer.


Other Culprits
           "These data show that the higher incidence of hepatocellular carcinoma observed following direct-acting antiviral therapy can be explained by the shorter duration of follow-up and older age of participants, rather than the treatment regimen," said lead investigator Gregory Dore, PhD, from the Kirby Institute at the University of New South Wales in Sydney, Australia. On meta-regression, direct-acting antiviral therapy was not significantly associated with hepatocellular carcinoma occurrence (relative risk [RR], 0.7; P = .6) or recurrence (RR, 1.4; P = .49).


In a Scottish study, risk for liver cancer after sustained virologic response was not significantly different between patients treated with interferon-free therapy and those treated with interferon-based therapy. The findings of Hamish Innes, MD, from the School of Health and Life Sciences at Glasgow Caledonian University, and his colleagues were reported during a late-breaker presentation at the International Liver Congress.


Of the 857 cirrhotic patients treated at one of 12 clinics in Scotland, 32% were treated with a direct-acting antiviral regimen. The patients were typically middle age, white, and male, and had well-compensated cirrhosis.


During a median follow-up of 1.8 years, fewer patients in the interferon-free group than in the interferon group developed hepatocellular carcinoma (12 vs 34). Even so, the risk was significantly higher in the interferon-free group (incidence rate ratio [IRR], 2.18; P = .03).


As in the Australian study, other factors implicated in risk were identified on univariate analysis. Patients in the interferon-free group tended to be older, to have presented with more advanced liver disease (illustrated by the higher rate of thrombocytopenia), and to have a higher prevalence of decompensated cirrhosis.


However, on multivariate analysis, the risk for hepatocellular carcinoma was equivalent in the interferon-free and interferon groups (IRR, 0.96; P = .929), Dr Innes explained.


Vetting the Risk in Veterans
           And risk for hepatocellular carcinoma was not elevated in a study of 22,500 veterans with no evidence of the disease who were treated with direct-acting antiviral therapy. A sustained viral response was achieved by 19,518 (86.7%) patients.


"Overall, SVR was associated with a substantially lower risk of hepatocellular carcinoma," Fasiha Kanwal, MD, from the Baylor College of Medicine in Houston, said during a standing-room-only session at Digestive Disease Week.


In fact, the annual risk for hepatocellular carcinoma was only 0.90% in patients who achieved a sustained viral response, whereas it was 3.45% in those who did not.


Over an average of 15 months, 183 responders developed hepatocellular carcinoma, as did 88 nonresponders (0.01% vs 0.03%).


"Because many of our patients in clinical practice now achieve SVR, we wanted to look at factors associated with risk of hepatocellular carcinoma in this growing patient population," Dr Kanwal explained. So the team did an analysis limited to patients who achieved a sustained viral response.


"In a multivariate analysis, cirrhosis was the most important factor associated with elevated risk of hepatocellular carcinoma, with an overall sevenfold higher risk, compared with patients who did not have documented cirrhosis at the time of direct-acting antiviral initiation," she reported. The incidence rate was lower in black patients than in patients with diabetes and in those with alcohol use disorders (0.56 vs 1.28 vs 1.56).


"Among patients treated with direct-acting antivirals, SVR resulted in a considerable reduction in the risk of hepatocellular carcinoma," Dr Kanwal said. "We did not find any evidence to suggest that direct-acting antivirals promote hepatocellular carcinoma, either during or after treatment."


However, the absolute risk for hepatocellular carcinoma was high in several subgroups of patients who achieved sustained viral response, including the 40% who had already progressed to cirrhosis at baseline. "We think clinicians should take this risk into account when conducting hepatocellular carcinoma surveillance," she said.


Dr Negro, Dr Issachar, Dr Huang, Dr Innes, and Dr Kanwal have disclosed no relevant financial relationships. Dr Reig reports financial relationships with Bayer, BTG, and Gilead. Dr Dore reports financial relationships with Gilead, Merck, AbbVie, Bristol-Myers Squibb, and Janssen.


Follow Medscape Gastroenterology on Twitter @MedscapeGastro and Damian McNamara @MedReporter



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