Antiviral therapy after curative treatment of hepatocellular carcinoma in patients with chronic hepatitis B infection: Is tenofovir or entecavir preferred?

Abstract

Hepatitis B remains a major health problem. Globally, approximately 240 million persons are chronically infected (HBsAg positive). Prevalence is decreasing in highly endemic countries due to better socioeconomic circumstances and vaccination programs. However, prevalence and incidence in several low-endemic European countries are changing, owing to higher HBsAg prevalence rates in migrants and refugees from outside Europe compared with the indigenous population. Hepatocellular carcinoma (HCC) is one of the major and most deadly consequences of chronic hepatitis B. Globally, deaths from HCC are estimated at 340,000 per year [[1]Lozano R Naghavi M Foreman K Lim S Shibuya K Aboyans V et al.Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010.Lancet. 2012; 380: 2095-2128https://doi.org/10.1016/S0140-6736(12)61728-0Abstract Full Text Full Text PDF PubMed Scopus (9090) Google Scholar]. Although several new treatment options such as transarterial chemo- or radioembolization and systemic therapies have been introduced in the last decades with promising results, these treatments are generally used in a palliative setting. Only a minority of patients are elegible for curative treatment (liver transplantation, surgical resection and -sometimes- radiofrequency ablation). In a nationwide cohort study conducted in the Netherlands between 2009-and 2016, these curative treatment options were applied in only 6%, 15% and 14% of patients [[2]Reinders MTM van Meer S Burgmans MC de Jong KP Klümpen HJ de Man RA et al.Trends in incidence, diagnosis, treatment and survival of hepatocellular carcinoma in a low-incidence country: data from the Netherlands in the period 2009–2016.Eur J Cancer. 2020; 137: 214-223https://doi.org/10.1016/j.ejca.2020.07.008Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. Unfortunately, even in case of resection or radiofrequency ablation, risk of recurrent intrahepatic HCC is high due to persistence of the underlying liver disease. High levels of hepatitis B virus (HBV) viremia are associated with higher rates of HCC recurrence after surgical resection [[3]Wang M Li C Liang L Xing H Sun L Quan B et al.Early and late recurrence of hepatitis B virus-associated hepatocellular carcinoma.Oncologist. 2020; 25https://doi.org/10.1634/theoncologist.2019-0944Crossref Scopus (10) Google Scholar] and suppressing HBV DNA levels with nucleos(t)ide analogues (NUCs) may lower the risk of HCC recurrence with improved survival [4Chan ACY Chok KSH Yuen WK Chan SC Poon RTP Lo CM et al.Impact of antiviral therapy on the survival of patients after major hepatectomy for hepatitis B virus-related hepatocellular carcinoma.Arch Surg. 2011; 146: 675-681https://doi.org/10.1001/archsurg.2011.125Crossref PubMed Scopus (89) Google Scholar, 5Wu CY Chen YJ Ho HJ Hsu YC Kuo KN Wu MS et al.Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection.JAMA - J Am Med Assoc. 2012; 308: 1906-1913https://doi.org/10.1001/2012.jama.11975Crossref PubMed Scopus (621) Google Scholar, 6Yin J Li N Han Y Xue J Deng Y Shi J et al.Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study.J Clin Oncol. 2013; 31: 3647-3655https://doi.org/10.1200/JCO.2012.48.5896Crossref PubMed Scopus (190) Google Scholar, 7Huang G Lau WY Wang ZG Pan ZY Yuan SX Shen F et al.Antiviral therapy improves postoperative survival in patients with hepatocellular carcinoma.Ann Surg. 2015; 261: 56-66https://doi.org/10.1097/SLA.0000000000000858Crossref PubMed Scopus (130) Google Scholar]. The persistent risk of HCC recurrence despite NUC therapy-mediated HBV DNA suppression may be partially attributed to persistent intrahepatic replication, as illustrated by the observation that higher serum viral antigen levels are associated with reduced recurrence-free survival independent from HBV DNA load [[8]Beudeker BJB Groothuismink ZMA de Man RA Witjes CDM van der Eijk AA Boonstra A et al.Hepatitis B core-related antigen levels predict recurrence-free survival in patients with HBV-associated early-stage hepatocellular carcinoma: results from a Dutch long-term follow-up study.J Viral Hepat. 2021; 28: 205-208https://doi.org/10.1111/jvh.13394Crossref PubMed Scopus (3) Google Scholar]. Pending the availability of novel antiviral agents that specifically target other aspects of the viral life-cycle, optimizing NUC therapy remains the primary focus. Entecavir (ETV) and Tenofovir disoproxil fumarate (TDF) are currently recommended as first-line antiviral therapy for hepatitis B in treatment-naïve patients because of their similarly high antiviral efficacy and low rates of resistance. In case of previous lamivudine treatment, there is a significant risk of resistance with subsequent ETV, but not with TDF. On the other hand, TDF can decrease renal function and may increase the risk of osteoporosis, which is not the case with ETV. An alternative to TDF (albeit at significantly increased costs) in case of compromised renal function or osteoporosis may be tenofovir alafenamide (a novel tenofovir prodrug). Although antiviral efficacy in treatment-naïve patients is probably comparable between ETV and TDF, there is some data suggesting higher serum interferon (IFN)-λ3 levels and a more pro-inflammatory cytokine profile in TDF treated patients [[9]Murata K Asano M Matsumoto A Sugiyama M Nishida N Tanaka E et al.Induction of IFN-λ 3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection.Gut. 2018; 67: 362-371https://doi.org/10.1136/gutjnl-2016-312653Crossref PubMed Scopus (89) Google Scholar,[10]Murata K Tsukuda S Suizu F Kimura A Sugiyama M Watashi K et al.Immunomodulatory mechanism of acyclic nucleoside phosphates in treatment of hepatitis B virus infection.Hepatology. 2020; 71: 1533-1545https://doi.org/10.1002/hep.30956Crossref PubMed Scopus (17) Google Scholar]. This concept of immune induction by TDF has however been challenged by the observation that patients who discontinued TDF had a lower probability of sustained virological response when compared to patients who discontinued ETV [[11]Sonneveld MJ Park JY Kaewdech A Seto W-K Tanaka Y Carey I et al.Prediction of sustained response after nucleo(s)tide analogue cessation using HBsAg and HBcrAg levels: a multicenter study (CREATE).Clin Gastroenterol Hepatol. 2020; https://doi.org/10.1016/j.cgh.2020.12.005Abstract Full Text Full Text PDF Scopus (7) Google Scholar]. Similarly, while early reports suggested a reduction in the risk of de novo HCC in TDF-treated patients compared to ETV-treated patients, this was not confirmed in a recent meta-analysis [[12]Tseng CH Hsu YC Chen TH Ji F Chen IS Tsai YN et al.Hepatocellular carcinoma incidence with tenofovir versus entecavir in chronic hepatitis B: a systematic review and meta-analysis.Lancet Gastroenterol Hepatol. 2020; 5: 1039-1052https://doi.org/10.1016/S2468-1253(20)30249-1Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. Nevertheless, these findings have sparked controversy with regard to the optimal choice of antiviral therapy in patients who have undergone potentially curative treatment of HBV-associated HCC. This discussion was fueled by several small studies that suggested improved outcomes with TDF when compared to other antivirals, but these studies had important limitations including small sample size, suboptimal adjustment for potential confounders and use of comparator arms that included patients treated with older antivirals [13Zhang X Li C Wen T Yan L Yang J Tang H et al.The different effects of nucleotide and nucleoside analogues on the prognosis of HBV-related HCC after curative resection.J Gastrointest Surg. 2020; https://doi.org/10.1007/s11605-020-04633-3Crossref Scopus (2) Google Scholar, 14Zhang M Wang D Liu H Li H. Tenofovir decrease hepatocellular carcinoma recurrence in chronic hepatitis B patients after liver resection.Infect Agent Cancer. 2018; 13https://doi.org/10.1186/s13027-018-0191-8Crossref Scopus (10) Google Scholar, 15Ge Z Ma J Qiao B Wang Y Zhang H Gou W. Impact of tenofovir antiviral treatment on survival of chronic hepatitis B related hepatocellular carcinoma after hepatectomy in Chinese individuals from Qingdao municipality.Medicine (Baltimore). 2020; 99: e21454https://doi.org/10.1097/MD.0000000000021454Crossref PubMed Scopus (3) Google Scholar]. The issue therefore remained unresolved pending the availability of more data. In the current Issue of the Journal, Lee et al.[[16]Lee JH Kim BK Park SY Tak WY Park JY Kim DY et al.The efficacies of entecavir and tenofovir in terms of enhancing prognosis after curative treatment of hepatitis B virus-related hepatocellular carcinoma.Eur J Intern Med. 2021; https://doi.org/10.1016/j.ejim.2021.02.019Abstract Full Text Full Text PDF Scopus (5) Google Scholar] report the results of a large retrospective cohort study on the efficacy of TDF versus ETV after curative treatment of HCC in South Korean patients with chronic hepatitis B. They found no differences in the risk of HCC recurrence and/or mortality rates between the two antivirals after adjustment for potential confounders. Importantly, these data contradict another publication from South Korea by Choi et al. which was published almost simultaneously [[17]Choi J Jo C Lim YS. Tenofovir versus entecavir on recurrence of hepatitis B virus–related hepatocellular carcinoma after surgical resection.Hepatology. 2021; 73: 661-673https://doi.org/10.1002/hep.31289Crossref PubMed Scopus (24) Google Scholar]. Some relevant details of the recent studies by Lee et al. [[16]Lee JH Kim BK Park SY Tak WY Park JY Kim DY et al.The efficacies of entecavir and tenofovir in terms of enhancing prognosis after curative treatment of hepatitis B virus-related hepatocellular carcinoma.Eur J Intern Med. 2021; https://doi.org/10.1016/j.ejim.2021.02.019Abstract Full Text Full Text PDF Scopus (5) Google Scholar] and Choi et al. [[17]Choi J Jo C Lim YS. Tenofovir versus entecavir on recurrence of hepatitis B virus–related hepatocellular carcinoma after surgical resection.Hepatology. 2021; 73: 661-673https://doi.org/10.1002/hep.31289Crossref PubMed Scopus (24) Google Scholar] are given in Table 1. Both are retrospective cohort studies with a large number of patients included. In both studies, TDF-treated patients were younger, more frequently HBeAg positive, and with higher ALT values and HBV DNA loads than the ETV-treated patients. In the study by Choi et al [[17]Choi J Jo C Lim YS. Tenofovir versus entecavir on recurrence of hepatitis B virus–related hepatocellular carcinoma after surgical resection.Hepatology. 2021; 73: 661-673https://doi.org/10.1002/hep.31289Crossref PubMed Scopus (24) Google Scholar]. The TDF group exhibited more unfavourable tumor characteristics: larger tumor sizes, more advanced tumor stages and more frequent microvascular invasion. On the other hand, the percentage of cirrhotics was less in the TDF group. The authors of both papers subsequently balanced differences for key variables between both treatment groups with the aid of inverse probability of treatment weighting (IPTW) and propensity score–matched analyses. These are innovative approaches to adjust for confounding: with IPTW, patients with a higher probability of receiving a certain treatment (based on different distribution of key variables between both groups) are assigned a smaller weight and patients with a lower probability of receiving this treatment have a larger weight in the final analysis. With propensity score–matched analyses a similar approach is used.Table 1Main baseline clinical and tumour characteristics and outcome parameters.Lee et al.[16]Lee JH Kim BK Park SY Tak WY Park JY Kim DY et al.The efficacies of entecavir and tenofovir in terms of enhancing prognosis after curative treatment of hepatitis B virus-related hepatocellular carcinoma.Eur J Intern Med. 2021; https://doi.org/10.1016/j.ejim.2021.02.019Abstract Full Text Full Text PDF Scopus (5) Google ScholarChoi et al[17]Nr (%: TDF/ETV)726 (44%/56%)1895 (52%/47%)Age (yrs: TDF/ETV)55/57 *Significantly different between tenofovir and entecavir groups. ALT, alanine amino transferase.55/55Male (%)76/7476/76Cirrhosis (%: TDF/ETV)46/4554/64*Significantly different between tenofovir and entecavir groups. ALT, alanine amino transferase.Main inclusion criteriaResection or RFABCLC⁎⁎⁎BCLC, Barcelona Clinic Liver Cancer stage. stage 0 or A. Curative resectionInclusion period2013-20172010-2018Maximal tumor size (cm: TDF/ETV)2.9 ± 2.2cm/2.7 ± 1.9 cm2.8 cm/2.7 cm*Significantly different between tenofovir and entecavir groups. ALT, alanine amino transferase.ALT (IU/mL: TDF/ETV)35/27*Significantly different between tenofovir and entecavir groups. ALT, alanine amino transferase.33/28*Significantly different between tenofovir and entecavir groups. ALT, alanine amino transferase.HBeAg pos (%:TDF/ETV)39%/27%*Significantly different between tenofovir and entecavir groups. ALT, alanine amino transferase.28%/23%*Significantly different between tenofovir and entecavir groups. ALT, alanine amino transferase.HBV DNA⁎⁎Log10IU/mL. (Log10IU/mL: TDF/ETV)3.28 ± 2.06/ 2.44 ± 1.80*Significantly different between tenofovir and entecavir groups. ALT, alanine amino transferase.Significantly higher in TDFAFP (ng/mL:TDF/ETV))15.2/10.215.8/16.6Postoperative start medication (%:TDF/ETV)65/514% (entire groupFollow up (median: TDF/ETV)44/47 months2.6/4.4 yrs*Significantly different between tenofovir and entecavir groups. ALT, alanine amino transferase.Recurrence (%: TDF/ETV))1, 3 and 5 yr recurrence rate 16%, 30% and 36%/13%, 30%, and 38%#inverse probability of treatment weighting (IPTW) analyses.propensity score–matched patients5 yr intrahepatic recurrence 34% / 44%*Significantly different between tenofovir and entecavir groups. ALT, alanine amino transferase.Mortality (%: TDF/ETV)1, 3 and 5 yr mortality rate 2.3%, 6.1%, and 7.3%/2.6%, 7.5%, and 8.7%#inverse probability of treatment weighting (IPTW) analyses.propensity score–matched patients3-yr overall survival 93.3%/90.0%*Significantly different between tenofovir and entecavir groups. ALT, alanine amino transferase. Significantly different between tenofovir and entecavir groups. ALT, alanine amino transferase. Log10IU/mL. BCLC, Barcelona Clinic Liver Cancer stage.# inverse probability of treatment weighting (IPTW) analyses.## propensity score–matched patients Open table in a new tab In the IPTW analysis by Lee et al. [[16]Lee JH Kim BK Park SY Tak WY Park JY Kim DY et al.The efficacies of entecavir and tenofovir in terms of enhancing prognosis after curative treatment of hepatitis B virus-related hepatocellular carcinoma.Eur J Intern Med. 2021; https://doi.org/10.1016/j.ejim.2021.02.019Abstract Full Text Full Text PDF Scopus (5) Google Scholar], cumulative probabilities of HCC recurrence at 1, 3, and 5 years were 16%, 30% and 36%, in the TDF group and 13%, 30%, and 38% in the ETV group (P=0.896). Cumulative probabilities of death at 1, 3, and 5 years were 2.3%, 6.1%, and 7.3% in the TDF group and 2.6%, 7.5%, and 8.7% in the ETV group (P=0.309). On the contrary, in the study by Choi et al. [[17]Choi J Jo C Lim YS. Tenofovir versus entecavir on recurrence of hepatitis B virus–related hepatocellular carcinoma after surgical resection.Hepatology. 2021; 73: 661-673https://doi.org/10.1002/hep.31289Crossref PubMed Scopus (24) Google Scholar], the estimated 3-year recurrence-free survival rates were significantly better in the TDF group (73% versus 64%). Also overall survival rate was significantly higher in the TDF group (estimated 3-year overall survival rates 93% vs 90%). Of note, the advantage of TDF was limited to intrahepatic recurrence and was not observed for extrahepatic metastases. What could be potential explanations of these contradictory results? There are important differences in inclusion criteria: Lee et al. [[16]Lee JH Kim BK Park SY Tak WY Park JY Kim DY et al.The efficacies of entecavir and tenofovir in terms of enhancing prognosis after curative treatment of hepatitis B virus-related hepatocellular carcinoma.Eur J Intern Med. 2021; https://doi.org/10.1016/j.ejim.2021.02.019Abstract Full Text Full Text PDF Scopus (5) Google Scholar] appear to have selected patients with a more unfavorable prognosis by including patients after resection as well as after radiofrequency ablation. In contrast, Choi et al. [[17]Choi J Jo C Lim YS. Tenofovir versus entecavir on recurrence of hepatitis B virus–related hepatocellular carcinoma after surgical resection.Hepatology. 2021; 73: 661-673https://doi.org/10.1002/hep.31289Crossref PubMed Scopus (24) Google Scholar] included only patients after curative resection of hepatocellular carcinoma BCLC (Barcelona Clinic Liver Cancer) stage 0 or A (i.e. very early and early stage). Although radiofrequency ablation can have a curative outcome, local recurrence is more frequent than with surgical resection (especially for tumors larger than 2.5 cm). It should be noted in this respect, that Lee et al. [[16]Lee JH Kim BK Park SY Tak WY Park JY Kim DY et al.The efficacies of entecavir and tenofovir in terms of enhancing prognosis after curative treatment of hepatitis B virus-related hepatocellular carcinoma.Eur J Intern Med. 2021; https://doi.org/10.1016/j.ejim.2021.02.019Abstract Full Text Full Text PDF Scopus (5) Google Scholar] did not find different recurrence or survival rates between TDF and ETV therapy when the subgroups of resection and radiofrequency ablation were analyzed separately. Another difference of potential relevance is the time point of initiation of antiviral therapy. In the study by Choi et al. [[17]Choi J Jo C Lim YS. Tenofovir versus entecavir on recurrence of hepatitis B virus–related hepatocellular carcinoma after surgical resection.Hepatology. 2021; 73: 661-673https://doi.org/10.1002/hep.31289Crossref PubMed Scopus (24) Google Scholar], 96% were already on maintenance NUC therapy at the time of resection. In contrast, in the study by Lee et al. [[16]Lee JH Kim BK Park SY Tak WY Park JY Kim DY et al.The efficacies of entecavir and tenofovir in terms of enhancing prognosis after curative treatment of hepatitis B virus-related hepatocellular carcinoma.Eur J Intern Med. 2021; https://doi.org/10.1016/j.ejim.2021.02.019Abstract Full Text Full Text PDF Scopus (5) Google Scholar], this was the case only in a minority of patients (35% in the TDF group and 49% in the ETV group. Furthermore, the duration of antiviral therapy in those with pre-operative NUC therapy was much shorter in the TDF group: 7 months versus 25 months with ETV (p<0.001). Therefore the duration of TDF therapy could have been too short to reveal superiority. Indeed, in the study by Choi et al. [[17]Choi J Jo C Lim YS. Tenofovir versus entecavir on recurrence of hepatitis B virus–related hepatocellular carcinoma after surgical resection.Hepatology. 2021; 73: 661-673https://doi.org/10.1002/hep.31289Crossref PubMed Scopus (24) Google Scholar], the reduction in HCC recurrence risk observed with TDF was much more pronounced for late recurrence (> 2 years postoperatively) than for early recurrence. Finally, an important aspect that remains unreported is the degree of HBV DNA suppression achieved during antiviral therapy in these studies. Persistent low level viremia during antiviral therapy has been associated with increased HCC risk, and it is conceivable that differences in the degree of viral suppression, rather than the type of NUC, explains the heterogeneity across studies [[18]Kim JH Sinn DH Kang W Gwak GY Paik YH Choi MS et al.Low-level viremia and the increased risk of hepatocellular carcinoma in patients receiving entecavir treatment.Hepatology. 2017; 66: 335-343https://doi.org/10.1002/hep.28916Crossref PubMed Scopus (92) Google Scholar]. Finally, it should be appreciated that both studies are retrospective and at serious risk of bias. This applies especially to the study of Choi et al. [[17]Choi J Jo C Lim YS. Tenofovir versus entecavir on recurrence of hepatitis B virus–related hepatocellular carcinoma after surgical resection.Hepatology. 2021; 73: 661-673https://doi.org/10.1002/hep.31289Crossref PubMed Scopus (24) Google Scholar], because their inclusion started in 2010, three years before TDF became available in South Korea (patients in that study were only treated with ETV during the first 3 years). Also, physicians may have preferred entecavir in case of frail, elderly patients with a worse prognosis, because tenofovir has some risk of renal deterioration and osteoporosis. The results of the two studies may also not be generalizable to other regions: South Korean hepatitis B patients are generally generally infected through vertical transmission and often have genotype C hepatitis B virus (which is infrequent in the western world). What should be our recommendations to the clinician caring for patients with HBV-associated HCC, in absence of data from blinded placebo-controlled trials in the next years? Based on the existing body of evidence, one could consider TDF after resection or radiofrequency ablation in patients without contraindications. However, in case of any contraindication to TDF (especially compromised renal function, which is very prevalent in cirrhotics) ETV is a good choice in treatment-naïve patients. In lamivudine-experienced patients with a concomitant increased risk of renal and/or bone disease, tenofovir alafenamide may be an option, although its role in HCC prevention remains to be determined. KJvE declares no conflict of interest. MJS has received speaker's fees and research support from Roche, BMS, Gilead and Fujirebio.