Con: Treating Hepatitis C Virus With Direct-Acting Antivirals: Fear Not the Perceived Threat of Hepatocellular Carcinoma

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1 CONTROVERSIES IN LIVER TRANSPLANTATION Con: Treating Hepatitis C Virus With Direct-Acting Antivirals: Fear Not the Perceived Threat of Hepatocellular Carcinoma Neil Mehta and Francis Y. Yao Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA What s the Alternative? Not Treating Hepatitis C Virus? Direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection achieve sustained virological response (SVR) rates exceeding 90% in clinical trials (1) and in the real-world setting. (2) Although some studies have suggested an increased risk of hepatocellular carcinoma (HCC) with DAA therapy, any discussion about potential dangers of DAAs must also address the risks inherent to the expected progression of liver disease by withholding HCV treatment. The most important benefit of achieving SVR is a reduction in liver-related and overall mortality compared with no treatment or lack of SVR. (3,4) A meta-analysis has suggested that SVR leads to a reduction in all-cause mortality by 50% overall and 74% among patients with cirrhosis. (3) Achieving SVR may result in the reversal of hepatic decompensation. (5) Not surprisingly, the advent of DAA therapy has coincided with a 32% reduction in liver transplantation (LT) wait-list registrations for HCV. (6) DAAs and the Threat of HCC: Where Is the Evidence? In this review, we examine published data involving DAA therapy and HCC risk in 3 scenarios: DAAs and de novo HCC, DAAs and recurrent HCC after resection or local-regional therapy (LRT), and DAA and HCC outcome before and after LT. Abbreviations: ANRS, Agence Nationale de Recherche sur le Sida; CUPILT, Compassionate Use of Protease Inhibitors in viral C Liver Transplantation; DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LRT, local-regional therapy; LT, liver transplantation; NA, not available; RFA, radiofrequency ablation; SVR, sustained virological response; TACE, transarterial chemoembolization. Address reprint requests to Neil Mehta, M.D., University of California, San Francisco, 513 Parnassus Avenue, Room S-357, San Francisco, CA Telephone: ; FAX: ; neil.mehta@ucsf.edu Copyright VC 2017 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /lt Potential conflict of interest: Nothing to report CONTROVERSIES IN LIVER TRANSPLANTATION DAAs AND DE NOVO HCC RISK The annual incidence of HCC in untreated HCV cirrhosis is 3%-7%. (7) A few studies have reported high de novo HCC incidence rates of 7%-9% within approximately 1 year after completion of DAAs in patients with HCV cirrhosis (Table 1). (8-10) These observations have fueled a debate about DAAs contributing to accelerated HCC development by 1 of several postulated mechanisms including diminished immune cancer surveillance with rapid viral clearance. (14) These studies, however, are limited by a small sample size and reliance on historic controls. The perceived higher rates of HCC development after achieving SVR with DAAs could be attributed to a higher baseline HCC risk in DAA-treated patients, who are generally older with

2 LIVER TRANSPLANTATION, Vol. 23, No. 12, 2017 TABLE 1. Summary of Studies Evaluating Risk of De Novo HCC After Initiation of DAA Therapy Receiving DAA, n Liver Disease Severity Incidence of De Novo HCC Studies suggesting increased risk of de novo HCC after DAAs (versus historic controls) Cardoso et al. (8) (2016) % cirrhosis 7.4% after median 12 months from viral suppression Kozbial et al. (9) (2016) 195 NA 6.6% within 13 months of DAA cessation Ravi et al. (10) (2017) % cirrhosis 9.1% within 6 months of DAA cessation Studies suggesting no increased risk of de novo HCC after DAA Kanwal et al. (11) (2017) 22,500 39% cirrhosis SVR: 0.90 per 100 patient-years No SVR: 3.5 per 100 patient-years Calleja et al. (2) (2017) % bridging fibrosis 52% cirrhosis 0.9% within 18 months of DAA Cheung et al. (12) (2016) % decompensated cirrhosis - 73% Child s B cirrhosis 10% Child s C cirrhosis Romano et al. (13) (2016) % bridging fibrosis (F3) 65% Child s A cirrhosis 7% Child s B cirrhosis 4% within 6 months of DAA (same incidence found in the other 261 not receiving DAA over a 6-month period); 2.5% in months 6-15 from DAA F3: 0.2 per 100 patient-years Child s A: 1.6 per 100 patient-years Child s B: 2.9 per 100 patients-years more advanced liver disease, when compared with interferon-treated historical controls. (15,16) A recent analysis by Kanwal et al. (11) of 22,500 DAA-treated HCV patients at 129 Veterans Health Administration sites has provided the strongest evidence to dispel the notion that SVR after DAA promotes de novo HCC development. Patients who achieved SVR had a significantly lower incidence of HCC compared with those without SVR (0.90 versus 3.5 per 100 patient-years, adjusted hazard ratio of 0.28), but the absolute risk for HCC remained high in those with cirrhosis despite SVR. Using a Spanish national database, Calleja et al. (2) found de novo HCC in only 0.9% (30/ 3233) within 18 months of DAA. In a study by Cheung et al. from the United Kingdom (12) of 671 patients with decompensated HCV cirrhosis, the 406 DAA-treated patients had a HCC incidence of 4% within 6 months of starting DAA therapy that was essentially identical to that in untreated patients, but the rates of hepatic decompensation were 18% and 28%, respectively. In a preliminary report involving 3075 HCV patients with advanced fibrosis receiving DAA therapy at 24 Italian centers, (13) the HCC incidence was 1.6 and 2.9 per 100 person-years in Child s A and B patients, respectively. Not only was this observed HCC incidence rate lower than that of untreated historical HCV patients, achieving SVR on adjusted analysis was associated with an 80% reduction in the risk of HCC. A cause for concern was that approximately half of those developing HCC within 6 months of starting DAA therapy had >3 nodules or an infiltrative appearance on imaging. (13) The study by Kanwal et al., (11) however, has alleviated concern about increased tumor aggressiveness following DAA therapy. The largest tumor size at HCC diagnosis was <5 cm in 92% and only 10% had stage T3 or T4 HCC. Judging from the results of these studies (Table 1), we believe that DAAs do not increase the risk of de novo HCC development after SVR. Patients with HCV cirrhosis who achieve SVR with DAAs remain at high risk for HCC (11) and should continue to undergo HCC surveillance. DAAs AND HCC RECURRENCE AFTER RESECTION OR LRT An even more contentious issue is whether DAA treatment increases the risk of HCC recurrence after resection or LRT. Following resection or ablation of HCC, the incidence of HCC recurrence is approximately 20% at 6 months. (17) Two recent studies have claimed higher than expected rates of early HCC recurrence after DAA treatment for HCV (Table 2). In a Spanish multicenter study, Reig et al. (18) reported HCC recurrence in 28% (16/58) who received DAA therapy at a median of 11 months after a complete response with resection, ablation, or transarterial chemoembolization (TACE), with a median time to HCC recurrence of 3.5 months after DAA. CONTROVERSIES IN LIVER TRANSPLANTATION 1597

3 LIVER TRANSPLANTATION, December 2017 TABLE 2. Summary of Studies Evaluating DAA and Risk of HCC Recurrence After Complete Response to Resection or LRT n Receiving DAAs, n (%) Follow-up HCC Recurrence Rate Studies suggesting increased risk of HCC recurrence after DAA Reig et al. (18) (2016) (100%) 6 months (median) from DAA Conti et al. (19) (2016) (100%) 12 months (median) from last HCC treatment to DAA Studies suggesting no increased risk of HCC recurrence after DAA ANRS (3 cohorts) (20) HEPATHER: (71%) DAA treated: 20 months (median) from DAA DAA untreated: 26 months (median) from complete response CirVir: (17%) 21 months (median) from complete response CUPILT*: (100%) 67 months (mean) from LT to DAA Cabibbo et al. (21) (2017) (100%) 2 months (mean) complete response to DAA ; median follow-up 9 months from DAA Calleja et al. (2) (2017) (100%) 20 months (mean) from complete response Minami et al. (22) (2016) (2.9%) DAA treated: 16 months from DAA 28%; median 3.5 months from DAA to HCC recurrence 29%; within 24 weeks of DAA completion DAA treated: 13% 0.73 per 100 person-months DAA untreated: 21% 0.66 per 100 person-months DAA treated: 1.1 per 100 person-months DAA untreated: 1.7 per 100 person-months 2.2%; 7 months (mean) from DAA to HCC recurrence 20% overall; 12% within 6 months of DAA 27% within 12 months of DAA 13% within 6 months of DAA 30% within 12 months of DAA 21% within 1 year of DAA (versus 31% in HCV-untreated patients) *Only LT recipients in this cohort. The subgroup receiving DAAs for less than 4 months after HCC treatment had the highest HCC recurrence risk at 41%. Conti et al. from Bologna, Italy (19) found a similar HCC recurrence rate of 29% (17/59) within 24 weeks of completing DAA therapy. These 2 studies share similar limitations including small sample size, short period of observation, and lack of a proper comparison group. Furthermore, other studies have questioned whether the threat of a higher HCC recurrence risk is real (Table 2). A multicenter French collaboration (Agence Nationale de Recherche sur le Sida [ANRS]) (20) analyzed 3 cohorts of HCV patients receiving curative HCC therapy (resection, ablation, or LT) and found no significant difference in HCC recurrence rates between DAA-treated and DAA-untreated controls. A multicenter Italian study (21) evaluated 143 patients who received DAAs at a median of 11 months after complete response to HCC therapy, and it found HCC recurrence rates of 12% and 27% at 6 and 12 months, respectively, not higher than that reported in the literature in DAAuntreated patients. Calleja et al. from Spain (2) reported a HCC recurrence rate of 13% within 6 months of starting DAAs in 70 patients who achieved complete response to HCC treatment. Minami et al. (22) from Japan evaluated HCV/HCC patients treated with radiofrequency ablation (RFA) and showed a HCC recurrence rate of 21% within 1 year in those who received DAAs after RFA (n 5 27), not significantly different when compared with a HCC recurrence rate of 31% in 861 controls not receiving HCV therapy after RFA. In a meta-analysis of 11 studies, (23) hepatic decompensation and not HCC recurrence has the greatest 1598 CONTROVERSIES IN LIVER TRANSPLANTATION

4 LIVER TRANSPLANTATION, Vol. 23, No. 12, 2017 impact on survival in cirrhotic HCV patients with early stage HCC and complete response after resection or ablation. Consequently, in the current state of rather weak evidence linking DAAs with accelerated HCC recurrence, patients with HCV cirrhosis who underwent resection or LRT for HCC should not be dissuaded from undergoing DAA therapy to prevent liver disease progression and decompensation. DAAs AND HCC OUTCOME BEFORE AND AFTER LT Two studies on HCV/HCC patients awaiting LT have reported no increased risk for dropout from the waiting list due to HCC progression following DAA treatment. Zanetto et al. from Padua, Italy (24) studied 46 wait-listed HCV/HCC patients and found no significant differences between DAA-treated (n 5 23) and untreated controls (n 5 23) in wait-list dropout due to HCC progression, explant pathology, or post- LT HCC recurrence. Huang et al. from our institution (25) evaluated 178 HCV/HCC patients receiving mostly TACE on the LT waiting list. The observed HCC recurrence (pre-lt) within 1 year after initial complete response to LRT was not significantly different when comparing 62 DAA-treated patients with 87 untreated controls (45% versus 49%, respectively). On adjusted analysis, those receiving DAAs after HCC diagnosis had a trend toward lower dropout risk compared with untreated patients (hazard ratio, 0.47; P ). It has been suggested that the SVR rate with DAA therapy is reduced if HCC is present. (26,27) In 1 study, the SVR was 97% if the HCC was treated versus only 58% in the presence of active HCC. (27) In this context, HCC should be controlled with LRT first before treating HCV with DAAs, and this may result in disease stabilization and even reduction in liver-related death on the waiting list. The decision regarding DAA treatment before versus after LT is complex, but it should take into account the degree of hepatic decompensation and availability of regional HCV-positive donor livers. (28) For LT recipients for HCC who received DAAs, data assessing the impact of DAAs on the risk of HCC recurrence after LT are scant. Yang et al. (29) reported a 27% (5/18) HCC recurrence rate after DAA therapy followed by LT versus 9.5% (6/63; P ) in those who did not receive DAAs prior to LT. In the Compassionate Use of Protease Inhibitors in viral C Liver Transplantation (CUPILT) cohort of the ANRS study, (21) 314 LT recipients who received DAAs after LT had HCC recurrence rate of only 2.2%. Nevertheless, DAAs were initiated at a mean of 67 months after LT, well beyond the period when most HCC recurrence would have occurred, and thus many with early post-lt HCC recurrence might have already been excluded from the study. More data on DAAs and the HCC recurrence risk after LT are needed. In the meantime, there is no reason to withhold DAA treatment in LT recipients, given the high efficacy of DAAs (20) and the substantial risk of accelerated liver disease progression and graft failure due to HCV reinfection. Results from large DAA treatment cohorts have dispelled the notion that SVR following DAAs promotes de novo HCC development. For HCV patients with established HCC who achieve complete response with resection or LRT, there is insufficient evidence to justify withholding DAA treatment and more robust data assessing HCC recurrence risk are needed. In HCV/HCC patients awaiting LT, there are additional factors when considering DAA therapy, but it does not appear to increase wait-list dropout or post-lt HCC recurrence. REFERENCES 1) Falade-Nwulia O, Suarez-Cuervo C, Nelson DR, Fried MW, Segal JB, Sulkowski MS. Oral direct-acting agent therapy for hepatitis C virus infection: a systematic review. 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