Management of chronic hepatitis B before and after liver transplantation

Liver transplantation remains the only curative option for eligible patients with complications of chronic hepatitis B (CHB) infection, including severe acute hepatitis flares, decompensated cirrhosis, and hepatocellular carcinoma. In general, all patients with CHB awaiting liver transplantation should be treated with oral nucleos(t)ide analogs (NAs) with high barriers to resistance to prevent potential flares of hepatitis and reduce disease progression. After liver transplantation, lifelong antiviral therapy is also required to prevent graft hepatitis, which may lead to subsequent graft loss. Although combination therapy using NA and hepatitis B immune globulin (HBIG) has been the regimen most widely adopted for over a decade, recent studies have demonstrated that newer NAs with low rates of resistance are effective in preventing graft hepatitis even without the use of HBIG, achieving excellent long term outcome. For patients without pre-existing resistant mutations, monotherapy with a single NA has been shown to be effective. For those with resistant strains, a combination of nucleoside analog and nucleotide analog should be used. To date, clinical trials using therapeutic vaccination have shown suboptimal response, as CHB patients likely have an immune deficit against HBV epitopes. Future strategies include targeting different sites of the hepatitis B replication cycle and restoring the host immunity response to facilitate complete viral eradication.     

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??Abstract??HBV-related end-stage liver disease and hepatocellular carcinoma (HCC) are the major indications for liver transplantation in China.With the introduction of hepatitis B immunoglobulin (HBIG) and oral nucleos(t)ide analogues (NAs)??new antiviral therapy has significantly improved the prognosis of liver transplantation.Pre-transplant antiviral therapy will significantly reduce the recurrence rates of HBV infection.All HBsAg-positive patients awaiting liver transplantation for HBV-related end-stage liver disease or HCC should be administered with a potent NA with high barrier to drug resistance to achieve the viral load as low as possible.Additional HBIG administration during the anhepatic phase will achieve a better control of HBV infection.HBIG should be used in combination with NAs post-transplantation to prevent HBV recurrence.As the fact that liver transplant recipients usually need life-long medication to prevent HBV recurrence??it is currently recommended that HBIG can be discontinued in patients under long-term administration of potent NAs with high barrier to drug resistance in combination with HBIG.     

慢性乙型肝炎患者抗病毒治疗过程中发生肝癌的风险预测模型

HBV感染是肝硬化和肝癌的主要病因之一。抗病毒药物的使用明显降低了慢性乙型肝炎患者肝癌的发生风险,但部分长期服用抗病毒药物患者,最终仍发生肝癌。因此,有必要对此类患者发生肝癌的风险进行早期识别和预测。当前根据肝硬化、年龄、性别、肝硬度、病毒学、血清学指标、饮酒情况、糖尿病病史等危险因素,形成了一些慢性乙型肝炎患者抗病毒治疗过程中发生肝癌的风险预测模型,这些预测模型包括mREACH-B、PAGE-B、mPAGE-B、APA-B、CAMD、AASL、REAL-B等。综述了慢性乙型肝炎患者抗病毒治疗过程中发生肝癌的风险预测模型研究进展。     

Reactivation of hepatitis B after liver transplantation: Current knowledge,molecular mechanisms and implications in management

Chronic hepatitis B(CHB) is a major global health problem affecting an estimated 350 million people with more than 786000 individuals dying annually due to complications, such as cirrhosis, liver failure and hepatocellular carcinoma(HCC). Liver transplantation(LT) is considered gold standard for treatment of hepatitis B virus(HBV)-related liver failure and HCC. However, post-transplant viral reactivation can be detrimental to allograft function, leading to poor survival. Prophylaxis with high-dose hepatitis B immunoglobulin(HBIG) and anti-viral drugs have achieved remarkable progress in LT by suppressingviral replication and improving long-term survival. The combination of lamivudine(LAM) plus HBIG has been for many years the most widely used. However, life-long HBIG use is both cumbersome and costly, whereas long-term use of LAM results in resistant virus. Recently, in an effort to develop HBIG-free protocols, high potency nucleos(t)ide analogues, such as Entecavir or Tenofovir, have been tried either as monotherapy or in combination with low-dose HBIG with excellent results. Current focus is on novel antiviral targets, especially for covalently closed circular DNA(ccc DNA), in an effort to eradicate HBV infection instead of viral suppression. However, there are several other molecular mechanisms through which HBV may reactivate and need equal attention. The purpose of this review is to address post-LT HBV reactivation, its risk factors, underlying molecular mechanisms, and recent advancements and future of anti-viral therapy.     

Management of hepatitis B virus infection after liver transplantation

Chronic hepatitis B virus(HBV) infection is responsible for up to 30% of cases of liver cirrhosis and up to 53% of cases of hepatocellular carcinoma. Liver transplantation(LT) is the best therapeutic option for patients with end-stage liver failure caused by HBV. The success of transplantation, though, depends on receiving prophylactic treatment against post-transplant viral reactivation. In the absence of prophylaxis, liver transplantation due to chronic hepatitis B(CHB) is associated with high rates of viral recurrence and poor survival. The introduction of treatment with hepatitis B immunoglobulins(HBIG) during the 1990 s and later the incorporation of oral antiviral drugs have improved the prognosis of these patients. Thus, LT for CHB is now a universally accepted option, with an estimated 5 years survival of around 85% vs the 45% survival seen prior to the introduction of HBIG. The combination of lamivudine plus HBIG has for many years been the most widely used prophylactic regimen. However, with the appearance of new more potent oral antiviral agents associated with less resistance(e.g., entecavir and tenofovir) for the treatment of CHB, new prophylactic strategies are being designed, either in combination with HBIG or alone as a monotherapy. These advances have allowed for more personalized prophylaxis based on the individual risk profile of a given patient. In addition, the small pool of donors has required the use of anti-HBc-positive donors(with the resulting possibility of transmitting HBV from these organs), which has been made possible by suitable prophylactic regimens.     

肝移植后乙型肝炎复发的危险因素及预后分析

目的探讨乙型肝炎相关性肝移植患者术后在核苷(酸)类似物联合小剂量乙型肝炎免疫球蛋白的预防下乙型肝炎复发的危险因素及预后。方法 253例乙型肝炎相关性肝移植患者术前即开始给予核苷(酸)类似物预防,术中和术后均给予核苷(酸)类似物联合乙型肝炎免疫球蛋白处理。结果在253例肝移植患者中,死亡29例(11.5%);术前基础病为HBV相关性肝癌患者的病死率为21.2%,显著高于非肝癌患者的5.2%(P=0.000);乙型肝炎复发16例(6.3%);复发后均停用乙型肝炎免疫球蛋白,并调整核苷(酸)类似物,结果患者HBV DNA均<500IU/ml,肝功能稳定;Log-rank检验显示乙型肝炎复发后及时治疗对患者生存无明显影响;经Logistic多因素回归分析表明,术前HBeAg阳性、HBV DNA≥105IU/ml、HCC和HBV/YMDD变异是乙型肝炎复发的危险因素。结论肝移植能够有效治疗乙型肝炎相关性终末期肝病,在核苷(酸)类似物联合乙型肝炎免疫球蛋白预防后,仍有乙型肝炎复发,其对生存率的影响有待于观察。     

Managing hepatitis B to prevent liver cancer: recent advances

Chronic hepatitis B (CHB) infection is a major cause of human mortality worldwide. The majority of people with CHB are infected early in life, and 20–40% of men and 15% of women with chronic infection will develop hepatocellular carcinoma (HCC). Antiviral therapy is recommended for patients with CHB who have cirrhosis or active disease with the aims of reducing disease progression to cirrhosis, liver failure and liver cancer, thereby preventing death. Evidence that treatment with interferon or with early nucleos(t)ide analogue therapy reduces HCC has been somewhat conflicting, however evidence is emerging to support a significant role in HCC prevention of the more effective antivirals, entecavir and tenofovir. Older patients, those with cirrhosis, and those undergoing curative treatments for HCC derive the greatest medium-term benefit in terms of HCC reduction, but HCC can still occur and long-term surveillance is recommended.     

Long-term follow-up of cumulative incidence of hepatocellular carcinoma in hepatitis B virus patients without antiviral therapy

BACKGROUNDChina has a high prevalence of hepatitis B virus (HBV), but most chronic hepatitis B (CHB) patients do not receive standardized antiviral therapy. There are few relevant reports addressing the outcomes of the large number of CHB patients who do not receive antiviral therapy.AIMTo observe the outcomes of long-term follow-up of patients with CHB without antiviral treatment.METHODSThis study included 362 patients with CHB and 96 with hepatitis B cirrhosis without antiviral treatment and with only liver protection and anti-inflammatory treatment from 1993 to 1998. The median follow-up times were 10 and 7 years, respectively. A total of 203 CHB and 129 hepatitis B cirrhosis patients receiving antiviral therapy were selected as the control groups. The median follow-up times were 8 and 7 years, respectively. Kaplan-Meier curves were used to analyze the cumulative incidence of hepatocellular carcinoma (HCC), and the Cox regression model was used to analyze the risk factors for HCC.RESULTSAmong the patients in the non-antiviral group, 16.9% had spontaneous decreases in HBV DNA to undetectable levels, and 32.8% showed hepatitis B e antigen (HBeAg) seroconversion. In the antiviral group, 87.2% of patients had undetectable HBV DNA, and 52% showed HBeAg seroconversion. Among CHB and hepatitis B cirrhosis patients, the cumulative incidence rates of HCC were 14.9% and 53.1%, respectively, in the non-antiviral group and were 10.7% and 31.9%, respectively, in the antiviral group. There was no difference between the two groups regarding the CHB patients (P = 0.842), but there was a difference between the groups regarding the hepatitis B cirrhosis patients (P = 0.026). The cumulative incidence rates of HCC were 1.6% and 22.3% (P = 0.022) in the groups with and without spontaneous HBeAg seroconversion, respectively. The incidence rates of HCC among patients with and without spontaneous declines in HBV DNA to undetectable levels were 1.6% and 19.1%, respectively (P = 0.051). There was no difference in the cumulative incidence of HCC between the two groups regarding the patients with drug-resistant CHB (P = 0.119), but there was a significant difference between the two groups regarding the patients with cirrhosis (P = 0.004). The Cox regression model was used for regression of the corrected REACH-B score, which showed that alanine aminotransferase > 400 U/L, history of diabetes, and family history of liver cancer were risk factors for HCC among men aged > 40 years (P < 0.05). Multifactorial analysis showed that a family history of HCC among men was a risk factor for HCC.CONCLUSIONAntiviral therapy and non-antiviral therapy with liver protection and anti-inflammatory therapy can reduce the risk of HCC. Antiviral therapy may mask the spontaneous serological response of some patients during CHB. Therefore, the effect of early antiviral therapy on reducing the incidence of HCC cannot be overestimated.     

Antiviral therapy for hepatitis B virus‐related decompensated cirrhosis

Antiviral therapy is important in patients with hepatitis B virus (HBV)‐related decompensated cirrhosis. This therapy is beneficial in most patients for the stabilization or improvement of liver disease; however, advanced cirrhosis with a high Child–Pugh or model for end‐stage liver disease (MELD) score may have progressed and does not benefit from antiviral therapy. It is important to identify patients with severe decompensated cirrhosis who will not improve under antiviral therapy and who require liver transplantation as early as possible. Entecavir (ETV) or tenofovir disoproxil fumarate (TDF) is the first‐line therapy for nucleos(t)ide analogue (NA)‐naive patients with decompensated cirrhosis due to their potent and prompt HBV suppressive effect and low rate of drug‐resistant mutations. Patients on antiviral therapy should be monitored for virological and clinical response, compliance, drug resistance and adverse effects as well as surveillance for hepatocellular carcinoma (HCC). Additional studies of TDF and ETV are necessary to determine the optimal agent(s) for treating naive patients and those with drug‐resistant decompensated cirrhosis. In order to evaluate the effectiveness of NA for the treatment of decompensated cirrhotic patients in the real world, high quality observational studies such as registration studies of antiviral therapy for HBV‐related cirrhosis and a long‐term follow‐up in China, where a large number of such patients are found, are recommended.     

Aktueller Stand der Lebertransplantation

End-stage liver disease due to viral hepatitis is a frequent indication for liver transplantation as the ultimate treatment option in Germany and worldwide. Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) lead to liver cirrhosis and progressive organ failure requiring patients to be short-listed for liver transplantation. Treatment options for viral hepatitis before and after liver transplantation have improved considerably in recent years. The effective antiviral treatment of chronic HBV infections with up to date nucleos(t)ide analogues featuring high antiviral potency and low rates of resistance has been followed by a considerable decrease in hepatitis B associated liver transplantations. The effective but expensive combination prophylaxis of human hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues after transplantation has reduced the number of HBV reinfections to almost negligible numbers. Hepatitis C virus reinfection occurs regularly after liver transplantation. Factors such as donor age and excessive immunosuppression negatively influence the course of HCV reinfection. The practicability and value of modern triple therapy regimens including interferon, ribavirin and protease inhibitors as well as substances still in clinical development before and after liver transplantation still need to be evaluated.     

Prevention and Treatment of Recurrent Hepatitis B after Liver Transplantation

Chronic hepatitis B is a global health problem that leads to development of various complications, such as cirrhosis, liver cancer, and liver failure requiring liver transplantation. The recurrence of hepatitis B virus (HBV) post-liver transplantation is a major cause of allograft dysfunction, cirrhosis of the allograft, and graft failure. Patients with high viral load at the time of transplantation, hepatitis B e antigen (HBeAg) positivity, or those with a history of anti-viral drug resistance are considered as high-risk for recurrent HBV post-liver transplantation, while patients with low viral load, including HBeAg negative status, acute liver failure, and hepatitis D virus (HDV) co-infection are considered to be at low-risk for recurrent HBV post-liver transplantation. Antivirals for patients awaiting liver transplantation(LT) cause suppression of HBV replication and reduce the risk of recurrent HBV infection of the allograft and, therefore, all HBV patients with decompensated cirrhosis should be treated with potent antivirals with high genetic barrier to resistance (entecavir or tenofovir) prior to liver transplantation. Prevention of post-liver transplantation recurrence should be done using a combination of hepatitis B immunoglobulin (HBIG) and antivirals in patients at high risk of recurrence. Low dose HBIG, HBIG-free protocols, and monoprophylaxis with high potency antivirals can still be considered in patients at low risk of recurrence. Even, marginal grafts from anti-HBc positive donors can be safely used in hepatitis B surface antigen (HBsAg) negative, preferably in anti-hepatitis B core (HBc)/anti-hepatitis B surface (HBs) positive recipients. In this article, we aim to review the mechanisms and risk factors of HBV recurrence post-LT in addition to the various treatment strategies proposed for the prevention of recurrent HBV infection     

Management of chronic hepatitis B virus infection: a new era of disease control

When assessing patients with chronic hepatitis B virus (HBV) infection, consider the state of viral replication, the immune response and whether viral mutations could be present, as well as evidence for liver disease or extrahepatic manifestations. In wild-type infections, loss of hepatitis B e antigen (HBeAg), gain of anti-HBe and disappearance of HBV DNA from serum indicate immunosuppression of viral replication, or 'nonreplicative chronic HBV infection'. This 'healthy carrier' state must be distinguished from HBeAg-negative chronic hepatitis B (CHB) resulting from precore and core promoter mutations. HBeAg-negative CHB is common with genotypes D (Mediterranean region, south Asia) and C (north Asia) infections. Age, disease activity (alanine aminotransferase level) and severity (fibrosis stage, cirrhosis) influence treatment decisions. Following the marginal effectiveness of interferon and often temporary effectiveness of lamivudine due to drug resistance, treatment of CHB is entering a new era. Adefovir, entecavir, tenofovir, telbivudine and clevudine have equal or superior antiviral efficacy to lamivudine, whereas several agents are effective against lamivudine-resistant HBV. Pegylated-interferon (peginterferon) is superior to conventional interferon for obtaining sustained immunosuppression of HBV without drug resistance. Antiviral suppression of HBV replication for 2-5 years reverses hepatic fibrosis, prevents cirrhosis and, when cirrhosis is established, improves liver function, prevents hepatic decompensation and lowers the risk of liver cancer. Before embarking on immunosuppressive chemotherapy or organ transplantation in patients with chronic HBV infection, it is important to start antiviral therapy to prevent hepatitis flares. Antiviral therapy can be effective against membranous glomerulonephritis and polyarteritis nodosa caused by HBV. Further improvements in treatment of CHB are needed to prevent drug resistance and permanently suppress viral replication by eradicating viral templates or stimulating host immune responsiveness to HBV.     

拉米夫定联合小剂量乙型肝炎免疫球蛋白预防肝移植术后乙型肝炎复发

目的比较单用拉米夫定和拉米夫定联合个体化小剂量肌肉注射乙型肝炎免疫球蛋白两种方案,预防乙型肝炎相关良性终末期肝病患者肝移植术后乙型肝炎复发的疗效。方法111例因乙型肝炎相关良性终末期肝病患者在肝移植术前根据乙型肝炎免疫球蛋白的可获得性非随机分为单用组和联用组,单用组32例患者在移植术后接受拉米夫定100mg/d单药治疗,联用组79例患者在移植术后接受拉米夫定100mg/d和个体化小剂量肌肉注射乙型肝炎免疫球蛋白(维持血清抗- HBs滴度>100U/L)联合治疗。研究总体中位随访时间为32(1～88)个月,监测患者HBsAg、HBV DNA、抗-HBs和YMDD变异情况,随访患者生存率及乙型肝炎复发率。结果单用组共有5例患者乙型肝炎复发,其中3例发生HBV YMDD变异;肝移植术后1、2、3年累积乙型肝炎复发率分别为7.1%、14.3%、17.9%,患者生存率分别为87.5%、84.4%、74.6%。联合组共有2例患者乙型肝炎复发,且均发生YMDD变异;肝移植术后1、2、3年累积乙型肝炎复发率分别为0、1.8%、5.7%,患者生存率分别为83.5%、80.9%、77.6%。两组患者乙型肝炎复发率之间差异有统计学意义(P<0.05),单用组肝移植术前HBV DNA活跃复制与肝移植术后乙型肝炎复发相关(P<0.05),而联用组两者之间无相关性(P>0.05)。结论个体化小剂量肌肉注射乙型肝炎免疫球蛋白联合拉米夫定与单用拉米夫定相比,能更有效地降低良性终末期乙型肝炎患者肝移植术后乙型肝炎复发的风险。     

The role of entecavir in preventing hepatitis B recurrence after liver transplantation

OBJECTIVE: Although hepatitis B recurrence after liver transplantation has been reduced to 0%–10% since the application of the combination therapy of hepatitis B immunoglobulin (HBIG) and lamivudine, the viral mutation resistance of lamivudine is still an obstacle to the outcome of liver transplantation. Here we evaluate the role of entecavir in preventing hepatitis B recurrence after liver transplantation.

METHODS:

Patients who received a liver transplantation for hepatitis B virus (HBV)‐related end‐stage liver disease in our center from March 2006 to December 2008 were enrolled in this study. All patients received entecavir (0.5 mg orally, daily) or lamivudine (100 mg orally, daily) together with a long‐term low dosage of HBIG to prevent hepatitis B recurrence after transplantation. Serum viral markers (HBsAg, anti‐HBs, HBeAg, anti‐HBc and anti‐HBe) and HBV‐DNA level were determined. RESULTS: Thirty patients receiving entecavir and 90 patients receiving lamivudine were matched with the same age and sex in both groups. No reinfection of hepatitis B was detected in the entecavir group. The hepatitis B surface antigen of patients in the entecavir group became negative within one week and no patient had any adverse effect relating to entecavir. There was no difference in the cumulative survival rate between the entecavir group and the lamivudine group (P > 0.05). CONCLUSION: This study shows that entecavir combined with low dosages of HBIG is effective and safe in preventing hepatitis B recurrence after liver transplantation, but its long‐term effect is still under investigation and a large‐sample study will be carried out in the future.     

Solitary pulmonary metastasis arising thirteen years after liver transplantation for HBV-related hepatocellular carcinoma

We described a 59-year-old male patient who underwent liver transplantation in 1989 for hepatocellular carcinoma (HCC) complicating hepatitis B virus (HBV) cirrhosis. In 2001 (12 years after liver transplantation), he developed a lung metastasis of HCC without intrahepatic recurrence and the resection was done. In July 2003, he was symptom free without any recurrence. HCC metastasis can develop even after a very long time of liver transplantation. Many HCCs grow slowly, and the growth rate of recurrent tumors in patients receiving immunosuppressive therapy is significantly greater than that of those who do not receive immunosuppressive therapy.     

Risk for hepatocellular carcinoma in the course of chronic hepatitis B virus infection and the protective effect of therapy with nucleos(t)ide analogues

Hepatocellular carcinoma(HCC) is a major health problem worldwide, representing one of the leading causes of death. Chronic hepatitis B virus(HBV) infection(CHB) is the most important etiologic factor of this tumor, accounting for the development of more than50% of the cases in the world. Primary prevention ofHCC is possible by hepatitis B vaccination conferring protection from HBV infection. However, according to the World Health Organization Hepatitis B Fact sheet N° 204(update of July 2014) globally there exists a large pool of 240 million people chronically infected with HBV who are at risk for development of HCC. These individuals represent a target population for secondary prevention both of cirrhosis and of HCC. Since ongoing HBV replication in CHB is linked with the progression of the underlying liver disease to cirrhosis as well as with the development of HCC, effective antiviral treatment in CHB has also been evaluated in terms of secondary prevention of HCC. Currently, most patients with active CHB are subjected to long term treatment with the first line nucleos(t)ide analogues entecavir and tenofovir. These compounds are of high antiviral potency and have a high barrier to HBV resistance compared to lamivudine, adefovir dipivoxil and even telbivudine. Many studies have shown that patients under antiviral treatment, especially those in virological remission, develop less frequently HCC compared to the untreated ones. However, the risk for development of HCC cannot be eliminated. Therefore, surveillance for the development of HCC of patients with chronic hepatitis B must be lifelong or until a time in the future when new treatments will be able to completely eradicate HBV from the liver particularly in the early stages of CHB infection. In this context, the aim of this review is to outline the magnitude of the risk for development of HCC among patients with CHB, in the various phases of the infection and in relation to virus, host and environmental factors as evaluated in the world literature. Moreover, the benefits of antiviral treatment of CHB with nucleos/tide analogs, which have changed the natural history of the disease and have reduced but not eliminated the risk of HCC are also reviewed.     

Recent advances in prevention of hepatitis B recurrence after liver transplantation

Liver transplantation is the only effective treatment for hepatitis B virus(HBV)-related end-stage liver disease.However,without antiviral prophylaxis,the recurrence rate of hepatitis B is as high as 80%-100%,which leads to a 50% mortality rate in the first 2 years after liver transplantation.Combination therapy of hepatitis B immunoglobulin(HBIG) and lamivudine demonstrated a higher efficacy of prophylaxis and further reduced the rate of recurrence to < 10%.The strategy of HBIG combined with lamivudine has been the standard treatment in many centers.However,the high rate of lamivudine resistance and the many disadvantages of HBIG have compelled surgeons to reconsider the longterm efficacy of this strategy for the prevention of HBV reinfection.Recently,new nucleos(t)ide analogues,such as entecavir and tenofovir,have been approved as first-line monotherapies for the treatment of chronic hepatitis B infection.These antiviral medicines have replaced lamivudine as the first choice in the prevention of HBV recurrence after liver transplantation.Various therapies that are composed of entecavir,tenofovir,and lamivudine plus adefovir,with or without HBIG have been adopted in several liver transplant centers.This article reviews the recent advances in prophylaxis for the recurrence of hepatitis B after liver transplantation.     

Long‐term entecavir or tenofovir disoproxil fumarate therapy in treatment‐naïve chronic hepatitis B patients in the real‐world setting

The aim of this study was to determine the long‐term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) on the natural course of disease in chronic hepatitis B patients (CHB) with/without cirrhosis in clinical practice. A total of 355 treatment‐naïve CHB patients were enrolled into the study. The primary outcome measure was viral suppression as defined by serum HBV DNA level <20 IU/mL. A secondary outcome measure was to determine the development of Hepatocellular carcinoma (HCC). Virological and biochemical responses were similar between the two treatment groups over time. The presence of cirrhosis and hepatitis B e antigen (HBeAg) positivity did not appear to impact viral suppression. The cumulative probability of HBeAg loss was 41% at 4 years of therapy. Hepatitis B surface antigen (HBsAg) loss occurred in four patients. Model for End‐Stage Liver Disease score was significantly improved from baseline to week 48 and 96 under antiviral therapy (P = 0.013, P = 0.01). HCC was diagnosed in 17 patients (4.8%). The cumulative probability of the development of HCC was 3.3% at 1 year and 7.3% at 4 years of therapy. The development of HCC was independently associated with older age (P = 0.031) and the presence of cirrhosis (P = 0.004). Serum creatinine levels and creatinine clearance remained stable over time. ETV and TDF effectively maintained virological and biochemical responses in long‐term follow‐up of CHB patients with/without cirrhosis. HCC may still develop, although at a lower rate, and is more likely to develop in patients with cirrhosis, especially in older patients.     

Impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes of liver disease

Chronic infections with the hepatitis B and C viruses have significant worldwide health and economic impacts. Previous treatments for hepatitis C such as interferon and ribavirin therapy were ineffective and poorly tolerated by patients. The introduction of directly acting curative antiviral therapy for hepatitis C and the wider use of nucleos(t)ide analogues for suppression of chronic Hepatitis B infection have resulted in many positive developments. Decreasing the prevalence of hepatitis B and C have concurrently reduced transmission rates and hence, the number of new infections. Antiviral treatments have decreased the rates of liver decompensation and as a result, lowered hospitalisation and mortality rates for both chronic hepatitis B and C infection. The quality of life of chronically infected patients has also been improved significantly by modern treatment. Antiviral therapy has stopped the progression of liver disease to cirrhosis in certain patient cohorts and prevented ongoing hepatocellular damage in patients with existing cirrhosis. Longer term benefits of antiviral therapy include a reduced risk of developing hepatocellular carcinoma and decreased number of patients requiring liver transplantation. This review article assesses the literature and summarises the impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes from liver disease.     

Eliminating viral hepatitis in children after liver transplants: How to reach the goal by 2030

Viral hepatitis infections are a great burden in children who have received liver transplant.Hepatotropic viruses can cause liver inflammation that can develop into liver graft fibrosis and cirrhosis over the long term.Immunological reactions due to viral hepatitis infections are associated with or can mimic graft rejection,rendering the condition difficult to manage.Prevention strategies using vaccinations are agreeable to patients,safe,cost-effective and practical.Hence,strategies to eliminate viral hepatitis A and B focus mainly on immunization programmes for children who have received a liver transplant.Although a vaccine has been developed to prevent hepatitis C and E viruses,its use is not licensed worldwide.Consequently,eliminating hepatitis C and E viruses mainly involves early detection in children with suspected cases and effective treatment with antiviral therapy.Good hygiene and sanitation are also important to prevent hepatitis A and E infections.Donor blood products and liver grafts should be screened for hepatitis B,C and E in children who are undergoing liver transplantation.Future research on early detection of viral hepatitis infections should include molecular techniques for detecting hepatitis B and E.Moreover,novel antiviral drugs for eradicating viral hepatitis that are highly effective and safe are needed for children who have undergone liver transplantation.