Sunday, July 16, 2017

Hepatitis C virus eradication with direct antiviral agents and liver cancer recurrence: Is the best the enemy of the good?

Liver International
Volume 37, Issue 8
August 2017
Pages 1110–1112

Hepatitis C virus eradication with direct antiviral agents and liver cancer recurrence: Is the best the enemy of the good?
Authors Massimo Colombo, Savino Bruno, Ana Lleo
First published: 14 July 2017
Full publication history DOI: 10.1111/liv.13479 

See Article on Page 1122

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Antiviral therapy has long been perceived as an adjuvant treatment modality worth to be offered to patients with chronic hepatitis C virus (HCV) infection after successful removal of a hepatocellular carcinoma (HCC), an approach dating more than two decades since interferon was first employed to treat non-A, non-B hepatitis.[1, 2] The rationale for using antivirals in this context is two-fold, on one hand to halt progression of hepatitis C towards liver failure and, on the other hand, to prevent the onset of second primary tumours resulting from both direct and indirect carcinogenic damage of hepatocellular DNA fuelled by unrested HCV replication.[3] While tumour recurrence caused by ongoing hepatitis C usually takes place 1 or 2 years after a cure of a primary HCC, a significant number of patients may experience earlier recurrence caused by proliferation of pre-existing cancer cells that survived removal of the primary tumour, a tumour size dependent complication which results from cancer cells invading the tumour vessels and/or tumour satellites emerging far from parental HCC.[4] The understanding that survival benefits provided by either curative resection or local ablation of a HCC are challenged by a lifelong risk of tumour recurrence (ie estimated to be in the range of 70%) prompted investigations on secondary prevention of HCC based on delivery of adjuvant therapies.[5] While early tumour recurrence could not be prevented by chemotherapy, pro-apoptotic regimens or sophisticated immunotherapeutic interventions,[6] the selection of the appropriate treatment modality guided by tumour size clearly emerged as the only pragmatic approach to efficiently serve the purpose. Thus, while patients with a small tumour (less than 3 cm in size) have experienced similar survival benefits following either limited hepatic resection or radiofrequency ablation, hepatic resection ultimately emerged as the treatment of choice for patients with larger than 3 cm tumours, as it efficiently removes distant satellites compared to radiofrequency ablation.[7] On top of this, patients with an eradicated tumour may gain additional survival benefits following control of HCV, as suggested by studies with interferon reporting histological regression of cirrhosis, prevention of HCC and control of clinically significant portal hypertension, whereas direct antiviral agents (DAA) regimens can lead to recompensation of Child Pugh C patients and delisting from liver transplant of HCC-free patients.[8-11]

It was therefore alarming to read that in a significant number of patients with a cured HCC the clinical benefits provided by HCV eradication with interferon-free regimens were jeopardised by accelerated and, in some instances, clinically aggressive recurrence of HCC. This was in fact, the unequivocal message released by the BCLC team in Barcelona during the 2016 International Liver Conference of EASL [12] where they reported a surprisingly high rate (28%) of earlier than expected HCC recurrences in patients with a small HCC cured by resection or local ablation, a finding that was echoed by a group in Bologna, Italy, who reported early HCC recurrence in 17 out of 59 (29%) similar patients after completing a DAA treatment (Table 1).[13] Worryingly, the BCLC group was able to confirm their findings in a larger multicentre study that was presented this year at the EASL meeting in Amsterdam,[14] thus reinforcing the suspicion that a rapid removal of HCV with interferon-free regimens may affect immune surveillance mechanisms that keep under control or favour the clearance of invisible liver cancer cells like those surviving removal of a nodule of HCC.[15, 16] Alarmingly enough, early recurrence of HCC was observed also in real life cohorts of cirrhotics after exposure to anti-HCV therapy with DAA, a complication that was not investigated in registration trials and unlikely to have occurred in the past with the administration of anti-HCV regimens based on interferon only.[17] Mitigating the concern raised by these reports, however, was the perception of a potential referral bias stemming from the retrospective design of studies and the parallel publication of more than one study from different geographical regions, including a large multicenter ARNS study in France, that provided opposite interpretation regarding the risk of HCC occurrence and recurrence after DAA therapy. In more than one study, a relationship was demonstrated between HCC occurrence following DAA therapy, duration of the post-treatment surveillance period, patient age and severity of the liver impairment [18-24] (Table 1).
Table 1. Recent data summarised in this table suggest a relationship between hepatocellular carcinoma (HCC) occurrence following direct antiviral agents (DAA) therapy, duration of the post-treatment surveillance period and severity of the liver impairment

AuthorHCC CRaPt #Mos. from CR to DAARecurrence×100 pp/month
  1. Mos., months.
  2. a Complete response (CR) to resection or radiofrequency.
Reig[12]+580.85-3.4216 (27.6%)-
Conti [13]+591.5-9017 (28.8%)-
Pol[18]+1891.424 (13%)0.73
Kozbial[19]+13-1 (7.7%)1.11
Zavaglia[20]+311.71 (3.2%)-
Virlogeux[25]+230.3-71.411 (4.8%)1.7

Along this line, this issue of Liver International, reports a single centre retrospective analysis of 68 HCV cirrhotic patients with a first diagnosis of HCC, who after successful tumour eradication, were subsequently treated (n=23) or not (n=45) with a DAA combination.[25] The finding of 11 recurrences of HCC among treated patients vs 33 recurrences among untreated patient, led Virlogeux and associates to speculate on the potential chemopreventive effect of interferon-free regimens used as an adjuvant therapy in this patient population. Softening, however, the authors’ conclusions are certain methodological inconsistencies of the study. Firstly, the time elapsed between demonstration of HCC cure and DAA therapy initiation that in fact was extremely wide, especially considering the small sample size of the study. While the time lag ranged between 0.3 and 71.4 months when tumour eradication and initiation of antiviral treatment were considered, the same time period was between 8 and 15 months when DAA start and HCC recurrence were analysed. In addition to the wide confidence interval reflecting the small sample size of this study, data interpretation could have been clouded also by the inclusion of patients with a less than 6-month surveillance time between HCC removal and last imaging of complete response, and the use of a propensity score analysis to compensate for the lack of randomisation. However, the authors did not provide details on the exclusion criteria for DAA treatment in the untreated group. Finally, owing to the small number (n=11) of DAA-treated patients showing HCC recurrence, it should be acknowledged that models including too few outcomes per each independent variable fall into an overfitting bias, making the usual test of statistical significance invalid.

In conclusion, the clinical benefits of HCV eradication in cirrhotic patients are undisputed and acknowledged by all international liver societies that strongly recommend anti-HCV treatment of this patient population. In the face of the current controversy regarding safety of DAAs in HCC patients, the last meeting of EASL in Amsterdam offered the opportunity to a panel of HCV experts chaired by Professor Jean-Michel Pawlotsky to recommend the institution of a prospective randomised study in order to clearly define the safety of DAA therapy in this patient population. Meanwhile, we all are eagerly waiting for robust data to be generated on the clinical impact that HCV eradication with DAA may have on late recurrence of HCC and, most important, on liver-related mortality.

Massimo Colombo: grant and research support (BMS, Gilead Science), advisory committees (Merck, Roche, Novartis, Bayer, BMS, Gilead Science, Tibotec, Vertex, Janssen Cilag, Achillion, Lundbeck, GSK, GenSpera, AbbVie, Alfa Wasserman), speaking and teaching (Tibotec, Roche, Novartis, Bayer, BMS, Gilead Science, Vertex, Merck, Janssen, AbbVie); Savino Bruno: advisory committees (Abbvie, Merck), speaking and teaching (Abbie, Gilead, Merck); Ana Lleo: speaking and teaching (Intercept, Merck).

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