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VIRAL HEPATITIS

HCV therapy and risk of liver cancer recurrence: who to treat?

Recurrence of hepatocellular carcinoma after resection or ablation with curative intent is common and not prevented by direct-acting antiviral agent (DAA) therapy for hepatitis C. Owing to multiple methodological inconsistencies, available studies fail to answer whether DAA therapy anticipated risk of severe tumour recurrence: a prospective randomized study might serve the purpose.

Refers to Huang, A. C. et al. Direct-acting antivirals do not increase the risk of hepatocellular carcinoma recurrence after local-regional therapy or liver transplant waitlist dropout. Hepatology https://doi.org/10.1002/hep.29855 (2018).

The advent of potent and user-friendly direct-acting antiviral agents (DAAs) to treat HCV infection has inflated the expectations that the control of such a potentially lethal disease is now possible. The scrutiny of the huge database of the Veterans Affairs practice has provided unequivocal proof that eradication of HCV with DAAs is attainable in almost all patients with any stage of infection, even in the presence of multiple comorbidities (such as obesity, alcohol abuse and diabetes), resulting in a substantial decline of short-term mortality and de novo hepatocellular carcinoma (HCC) development1,2. Yet, an area of uncertainty remains regarding the safety and efficacy of these innovative therapies in patients with liver cancer who have already received anticancer therapy. In a new study, Huang and colleagues retrospectively inspected a small cohort of liver transplantation candidates with HCV infection and HCC who were patients at the University of California, San Francisco, USA, with the intent to assess whether DAA therapy had any influence on the outcome of tumour treatment with local ablative techniques (LTR)3. In an adjusted competing risk analysis using weighted propensity score modelling, risk of recurrence seemed to be unaffected by DAA therapy (HR 0.91, 95% CI 0.58–1.42, P = 0.67); whereas in an adjusted weighted analysis, DAA-treated patients had a lower risk of waitlist dropout due to tumour progression or death than untreated patients (HR 0.30, 95% CI 0.13–0.69, P = 0.005)3. This finding led the authors to conclude that, not only was DAA therapy for liver transplantation candidates with HCV infection and HCC with an initial complete response to LRT not associated with an increased risk of HCC recurrence, but rather it was clinically beneficial3. Although aligning with previous reports in the liver transplantation setting4, the main finding and message of the study by Huang and colleagues is also coherent with the updated guidelines of the International Liver Transplantation Society, which recommends DAA therapy in patients with HCC and HCV infection within Milan criteria who are listed to liver transplantation5.

The debate surrounding HCC recurrence and DAA use is controversial. Analysis of data from a Veterans Affairs cohort has highlighted that responses to DAAs in HCV-infected patients with a previous history of HCC and no radiological evidence of persistent viable tumour are suboptimal when compared with similarly treated patients with no tumour history1. While waiting for these findings to be confirmed with third-wave DAA regimens, surveillance of patients with a history of HCC and HCV infection has been refined to identify those patients at greater risk of HCC recurrence in whom proliferation of hidden cancer cells can be boosted by DAAs6. This proliferative process has been interpreted as the possible cause for the unusual rates of early and severe tumour recurrence observed in HCV-infected patients who were successfully treated with DAAs after a curative resection or ablation of a small tumour7,8.

“The debate surrounding HCC recurrence and DAA use is controversial”

Within the conundrum of DAA therapy and skyrocketing rates of HCV infection eradication being burdened by potentially lethal exacerbation of tumour recurrence, the debate on safety of DAAs was further fuelled by the observation of HBV and herpes virus reactivation occurring in patients co-infected with HCV who received anti-HCV DAAs6. This finding associated a swift eradication of HCV, as is observed in DAA-treated patients, with impaired immune surveillance and risk of enhanced proliferation of sparse liver cancer cells in patients with a cured liver tumour6. Supporting this immunological interpretation is a preliminary report from a multicentre study in the USA, which highlighted a faster liver tumour recurrence in DAA-treated patients compared with patients who had not received DAAs (223 versus 554 days); however, without any apparent implication on incidence (42% versus 53%) and clinical aggressiveness of the recurrences (27% in both groups)9.

All these issues notwithstanding, antiviral therapy of HCV infection in patients undergoing invasive treatment of HCC is recommended by both the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver owing to the fact that the majority of patients with HCC have underlying advanced hepatitis C that poses a substantial risk of lethal clinical decompensation if treatment of HCV infection is deferred10. Having said that, it must be mentioned that reports of DAA therapy associated with enhanced risk of HCC recurrence are outnumbered by studies worldwide that disputed any link between DAAs and exacerbation of tumour recurrence6,8. Moreover, it should be emphasized that all positive and negative reports were biased by relevant methodological weaknesses, particularly the heterogeneity of patient selection and HCC treatment coupled with the lack of prospective surveillance for HCC6,8. Ultimately, after repeated statistical scrutinization of the data sets, patient age, liver disease severity, response to DAAs and possibly timing and modality of cancer treatment have all emerged as independent predictors of tumour recurrence, therefore making it difficult to form meaningful recommendations for optimizing DAA therapy of this patient population.

A common perception is that the deliberation on DAAs and risk of HCC recurrence is still ongoing and that a prospective study is deemed necessary to identify an ideal time point to start DAA therapy and determine which patients with HCV infection can be safely treated with DAAs after experiencing a cure of HCC (Box 1). One possible design is to randomly assign patients with compensated liver disease to receive DAAs either upfront after radiological confirmation of HCC cure or 6–12 months after tumour eradication. This strategy is based on the assumption that an aggressive surveillance of HCC with sensitive imaging techniques such as MRI might help identification and treatment of small nodules of HCC maturing during the ‘window phase’, thus preventing recurrence of invasive cancer under DAA pressure. As the research and clinical community wait for meaningful insights from such a study, deferral of antiviral therapy after tumour cure has become a consolidated practice in several centres, as it offers the opportunity for aggressive tumour surveillance with MRI during the phase preceding DAA administration. Although perfectly compensated patients might well tolerate such a short-lasting deferral of antiviral therapy after HCC cure without experiencing a substantial risk of early decompensation, recruiting patients with viraemia and compensated cirrhosis and HCC for such a study might be unrealistic in most European countries where DAA therapy has been prioritized in the population with advanced HCV infection, that is the patients at greatest risk of developing HCC. Rather, a similar study could more realistically be performed in geographical areas with high HCV infection burden (such as Central Asia, Middle East and Far East) where multiple barriers have so far prevented a scale-up of DAA therapy, and patient access to low-priced generic DAAs might substantially contain the cost of such a large-scale study.

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Correspondence to Massimo Colombo.

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M.C. has served on the advisory committees for AbbVie, Achillion, AlfaWasserman, Bayer, Bristol–Myers Squibb, GenSpera, Gilead Science, GlaxoSmithKline, Janssen, Jennerex, Lundbeck, MSD, Novartis, Roche, Tibotec and Vertex, and received speaking and teaching fees from AbbVie, Bayer, Bristol–Myers Squibb, Gilead, Janssen, MSD, Novartis, Roche, Sanofi, Tibotec and Vertex. V.B. is on advisory boards for AbbVie and Gilead.

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Colombo, M., Boccaccio, V. HCV therapy and risk of liver cancer recurrence: who to treat?. Nat Rev Gastroenterol Hepatol 15, 392–393 (2018). https://doi.org/10.1038/s41575-018-0018-5

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