Nucleos(t)ide analogues to treat hepatitis B virus-related hepatocellular carcinoma after radical resection

Significant advances have been made in nucleos(t)ideanalogue(NA) therapy to treat chronic hepatitis B,and this therapy reduces the risk of hepatitis B virus(HBV)-related hepatocellular carcinoma(HCC) in somepatients.However,whether NAs can also prevent recurrence after radical resection of HBV-related HCC remains controversial and is an important question,giventhat most patients will experience recurrence within afew years of curative surgery.Here we systematicallyreviewed the literature since 2004 on outcomes afteradministering NAs to patients with HBV-related HCCfollowing radical resection.We focused on treatmentindications,duration,effects on recurrence-free survivaland overall survival,and the management of NA resistance.We find that patients with HCC should stronglyconsider NA therapy if they are positive for HBV-DNA,and that the available evidence suggests that postoperative NA therapy can increase both recurrence-free andoverall survival.To minimize drug resistance,cliniciansshould opt for potent analogues with higher resistancebarriers,and they should monitor the patient carefully for emergence of NA-resistant HBV.

Nucleos(t)ide analogs in the prevention of hepatitis B virus related hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is among the most common cancer types and causes of cancer related mortality worldwide.Almost 50% of all HCC cases globally are attributable to chronic hepatitis B virus(HBV) infection.The incidence rates of HCC in untreated Asian subjects with HBV infection was estimated to be 0.2% in inactive carriers,0.6% for those with chronic hepatitis without cirrhosis,and 3.7% for those with compensated cirrhosis.In Western populations,HCC incidences are reported to be 0.02% in inactive carriers,0.3% in subjects with chronic hepatitis without cirrhosis,and 2.2% in subjects with compensated cirrhosis.Despite effective antiviral treatment options which are able to transform chronic hepatitis into an inactive carrier state,the risk of HCC cannot be fully ruled out to exclude those patients from surveillance.Newer nucleos(t)ide analogues(NAs) as entecavir and tenofovir are very potent in terms of sustained virological suppression which leads to improved liver histology.However,they do not have any influence on the ccc DNA or integrated DNA of HBV in the liver.Nonetheless,viral replication is the only modifiable component among the established risk factors for HBV-related HCC with the current treatment options.In this review,it was aimed to summarize cumulative evidence behind the concept of prevention of HBV related HCC by NAs,and to discuss remaining obstacles to eliminate the risk of HCC.

Antiviral treatment to prevent chronic hepatitis B or C-related hepatocellular carcinoma

Antiviral treatment is the only option to prevent or defer the occurrence of hepatocellular carcinoma(HCC) in patients chronically infected with hepatitis B virus(HBV) or hepatitis C virus(HCV). The approved medication for the treatment of chronic HBV infection is interferon-α(IFNα) and nucleos(t)ide analogues(NAs), including lamivudine, adefovir dipivoxil, telbivudine, entecavir and tenofovir disoproxil fumarate. IFNα is the most suitable for young patients with less advanced liver diseases and those infected with HBV genotype A. IFNα treatment significantly decreases the overall incidence of HBV-related HCC in sustained responders. However, side effects may limit its long-term clinical application. Orally administered NAs are typically implemented for patients with more advanced liver diseases. NA treatment significantly reduces disease progression of cirrhosis and therefore HCC incidence, especially in HBV e antigen-positive patients. NA-resistance due to the mutations in HBV polymerase is a major limiting factor. Of the NA resistance-associated mutants, A181 T mutant significantly increases the risk of HCC development during the subsequent course of NA therapy. It is important to initiate treatment with NAs that have a high genetic barrier to resistance, to counsel patients on medication adherence and to monitor virological breakthroughs. The recommended treatment for patients with chronic HCV infection is peg-IFN plus ribavirin that can decrease the occurrence of HCC in those who achieve a sustained virological response and have not yet progressed to cirrhosis. IFN-based treatment is reserved for patients with decompensated cirrhosis who are under evaluation of liver transplantation to reduce post-transplant recurrence of HCV. More effective therapeutic options such as direct acting antiviral agents will hopefully increase the response rate in difficult-totreat patients with HCV genotype 1. However, the risk of HCC remains in cirrhotic patients(both chronic HBV and HCV infection) if treatment is initiated after cirrhosis is established. Future research should focus on investigating new agents, especially for those patients with hepatic decompensation or post-transplantation.

Effectiveness of entecavir in preventing hepatocellular carcinoma development is genotype-dependent in hepatitis B virus-associated liver cirrhosis

BACKGROUND The oral nucleos(t)ide analogue,entecavir(ETV)was demonstrated to reduce the rate of hepatocellular carcinoma(HCC)in patients with hepatitis B virus(HBV)-associated liver cirrhosis.However,the reduction of HCC differs in various regions of the world.AIM To investigate the reduction of HCC development due to ETV therapy by metaanalysis.METHODS We surveyed the differences in HCC development following ETV treatment based on published articles using PubMed(2004-2019).RESULTS The regions with the most marked reduction in HCC development due to ETV therapy were Spain(1.0%/year)and Canada(Southern part,1.3%/year),and the most ineffective areas were South Korea(3.6%-3.8%/year),China(3.3%/year),Taiwan(2.4%-3.1%/year),and Hong Kong(2.8%/year).Following ETV administration,the incidence of HCC in genotype D regions(1.89%±0.28%/year,mean±SE)was significantly lower than that in genotype C regions(2.91%±0.24%/year,P<0.01).With regard to the initial HBV-DNA level,in genotype C patients(average:5.61 Log10IU/mL)this was almost the same as that in genotype D patients(average:5.46 Log10IU/mL).Moreover,there was no association between the prevalence ratio of HBV and the incidence of HCC on ETV treatment.CONCLUSION The effectiveness of ETV in preventing HCC development in HBV-associated liver cirrhosis is genotype-dependent.

Antiviral drug resistance increases hepatocellular carcinoma:A prospective decompensated cirrhosis cohort study

AIM:To study the clinical outcome of antiviral therapy in hepatitis B-related decompensated cirrhotic patients.METHODS:Three hundred and twelve patients with decompensated hepatitis B cirrhosis were evaluated in a prospective cohort.With two years of follow-up,198patients in the group receiving antiviral therapy with nucleos(t)ide analogues and 39 patients in the control group without antiviral treatment were analysed.RESULTS:Among the antiviral treatment patients,162had a complete virological response(CVR),and 36 were drug-resistant(DR).The two-year cumulative incidence of hepatocellular carcinoma(HCC)in the DR patients(30.6%)was significantly higher than that in both the CVR patients(4.3%)and the control group(10.3%)(P<0.001).Among the DR patients in particular,the incidence of HCC was 55.6%(5/9)in those who failed rescue therapy,which was extremely high.The rtA181T mutation was closely associated with rescue therapy failure(P=0.006).The Child-Pugh scores of the CVR group were significantly decreased compared with the baseline(8.9±2.3 vs 6.0±1.3,P=0.043).CONCLUSION:This study showed that antiviral drug resistance increased the risk of HCC in decompensated hepatitis B-related cirrhotic patients,especially in those who failed rescue therapy.

Overview of methodologies and statistical strategies in observational studies and meta-analyses on the risk of hepatocellular carcinoma in patients with chronic hepatitis B on entecavir or tenofovir therapy

Entecavir(ETV)and tenofovir disoproxil fumarate(TDF)are first-line antiviral therapies for patients with chronic hepatitis B(CHB)and reduce the risk of disease progression and liver-related complications,as well as improve survival by effectively suppressing viral replication.Nevertheless,since the first publication in 2019 on a lower risk of hepatocellular carcinoma(HCC)in Korean patients receiving TDF than those receiving ETV,the topic has remained a hot and unsettled debate.Multiple studies and meta-analyses have yielded conflicting results.As HCC takes time to develop,studies are mainly observational to benefit from a larger sample size and longer follow-up that provides a higher statistical power to compare the two treatments.However,TDF was available to CHB patients a few years later than ETV in most countries,thus leading to a difference in follow-up duration.Moreover,despite studying the same topic,the difference in data sources and available parameters,inclusion and exclusion criteria,and use of statistical methods complicated the interpretation and comparison of the findings and contributed to between-study heterogeneity in meta-analyses.This review describes some caveats in interpreting and comparing the results from these observational studies and meta-analyses.Future studies should explore better designed observational studies with high-quality data sources,and aggregation of patient data in metaanalysis to tackle between-study heterogeneity.

Role of antiviral therapy in patients with chronic hepatitis B or C virus in preventing the development of hepatocellular carcinoma

Patients with chronic hepatitis B virus(HBV)and hepatitis C virus(HCV)infection are at significant risk for hepatocellular carcinoma(HCC).The most important risk factor associated with HCC is liver cirrhosis,which is again predominantly caused by chronic HBV or HCV infection.The most effective approach to avoid HCC development is to prevent HBV and HCV infection through vaccination.Indeed,HBV vaccine is the first vaccine demonstrated to prevent cancers.However,a vaccine for HCV is not available.Thus,the prevention of HCV-related HCC and to a large extent HBV-related HCC(among persons who are already chronically infected)will rely on antiviral therapy to prevent progressive liver disease.The evidence that these patients can effectively be protected against HCC risk by the treatment with antiviral therapy is rather controversial,due to the lack of randomized controlled trials(RCTs)that are ideally needed to establish the effi cacy,but are logistically and ethically challenging.Although the strongest evidence to support that antiviral therapy can prevent HCC should be derived from RCTs with HCC as an endpoint,it should be emphasized that clinical trials showing the efficacy of antiviral therapy on virus suppression or eradication,and/or improvement in liver histology can be considered indirect evidence that antiviral therapy can prevent HCC because high virus levels(in the case of HBV infection)and cirrhosis(in both HBV and HCV infection)are the most important risk factors for HCC.

核苷(酸)类似物在经肝动脉介入治疗乙型肝炎病毒相关性肝细胞癌中的作用

目的 探讨核苷（酸）类似物在乙型肝炎病毒（HBV）相关肝细胞癌（HCC）经肝动脉介入治疗（TAIT）中的应用价值。方法 入组60例HBsAg阳性且不能手术切除的HCC患者,配对分为核苷（酸）类似物治疗组（A组）和常规保肝降酶组（B组）,每组30例。对两组进行常规TAIT同时,给予常规保肝降酶治疗,A组同时联合核苷（酸）类药物行抗病毒治疗。比较两组的生存率,分析预后影响因素。结果 A组核苷（酸）类似物抗病毒初始治疗药物选择：恩替卡韦14例,拉米夫定8例,阿德福韦酯8例,其中4例患者出现病毒学突破,经加用另一核苷（酸）类似物后实现病毒持续抑制。B组中,13例（13/30,43.33%）患者分别在第1～9次TAIT后发生病毒学突破,中位突破时间为5.52个月（4次TAIT后）。两组共死亡48例,其中A组20例,B组28例,中位生存期分别为29.63、14.77个月（χ2=7.51,P=0.01）。A组和B组中BCLC分期C期患者中位生存期分别为23.63、8.07个月（2χ=7.11,P=0.01）。Cox回归模型分析显示：患者是否行核苷（酸）类似物抗病毒治疗、肝功能分级、肝癌BCLC分期影响患者预后。未发生核苷（酸）类药物相关严重不良反应。结论 采用TAIT治疗HBV相关HCC时联合应用核苷（酸）类药物安全、有效。

经α-干扰素和核苷(酸)类似物治疗的慢性乙型肝炎患者原发性肝癌发生率比较研究

目的分析比较应用干扰素α(IFN-α)和核苷(酸)类似物(NAs)治疗对慢性乙型肝炎患者肝细胞癌(HCC)发生率的影响差异。方法 2007年1月~2010年12月收治的30岁~60岁慢性乙型肝炎(CHB)患者,接受IFN-α2b治疗210例,治疗48~72 w,接受NAs治疗222例,长期应用和未抗病毒组136例。随访6年,观察疗效和HCC发生情况。应用SPSS 19.0统计软件分析。结果在治疗72周末,IFN-α2b治疗组HBe Ag阳性患者比率显著低于NAs治疗组或未抗病毒组(P均<0.05),但NAs治疗患者血清HBV DNA和ALT水平显著低于IFN-α2b治疗组或未抗病毒组(P均<0.05);IFN-α2b治疗组与NAs治疗组血清肝纤维化标志物变化无显著性差异(P均>0.05),但均比未抗病毒组低(P均<0.05);随访6年,未抗病毒组HCC发生率为16.91%(23/136),显著高于NAs治疗组的9.46%(21/222,x^2=4.345,P=0.037)或IFN-α2b治疗组的0.0%(0/210,x^2=38.044,P=0.000),NAs治疗组HCC发生率显著高于IFN-α2b治疗组,具有统计学差异(x^2=20.880,P=0.000)。结论 IFN-α2b和NAs抗病毒治疗均具有阻断HCC发生的作用,但IFN-α2b治疗在阻断HCC发生方面作用更强。

慢性乙型肝炎的评估和治疗进展

应用无创性生物标志物和肝脏瞬时弹性成像技术,可以更加精准地评估慢性乙型肝炎(chronic hepatitis B,CHB)患者的疾病严重度,有助于确定抗病毒治疗的时机,通过核苷(酸)类似物[nucleos(t)ide analogues,NA]长期抗病毒治疗,可以使患者临床获益,选择合适的患者,通过优化治疗方案,诸如应用NA和聚乙二醇干扰素联合或序贯治疗,可以提高HBeAg血清学转换率和HBsAg清除率,应用患者年龄、性别、肝硬化状态、病毒学因素、治疗应答情况和肝脏瞬时弹性成像检测,可以预测CHB患者发生肝细胞癌(hepatocellularcarcinoma,HCC)的风险,然而,如何进一步降低HCC的发生风险,仍然是CHB临床管理的重大挑战.