Hepatitis B virus/hepatitis D virus epidemiology: Changes over time and possible future influence of the SARS-CoV-2 pandemic

Hepatitis D virus (HDV) is a defective liver-tropic virus that needs the helper function of hepatitis B virus (HBV) to infect humans and replicate. HDV is transmitted sexually or by a parenteral route, in co-infection with HBV or by super-infection in HBV chronic carriers. HDV infection causes acute hepatitis that may progress to a fulminant form (7%-14% by super-infection and 2%-3% by HBV/HDV co-infection) or to chronic hepatitis (90% by HDV super-infection and 2%-5% by HBV/HDV co-infection), frequently and rapidly progressing to cirrhosis or hepatocellular carcinoma (HCC). Peg-interferon alfa the only recommended therapy, clears HDV in only 10%-20% of cases and, consequently, new treatment strategies are being explored. HDV endemicity progressively decreased over the 50 years from the identification of the virus, due to improved population lifestyles and economic levels, to the use of HBV nuclei(t)side analogues to suppress HBV replication and to the application of universal HBV vaccination programs. Further changes are expected during the severe acute respiratory syndrome coronavirus-2 pandemic, unfortunately towards increased endemicity due to the focus of healthcare towards coronavirus disease 2019 and the consequently lower possibility of screening and access to treatments, lower care for patients with severe liver diseases and a reduced impulse to the HBV vaccination policy.     

Hepatitis B virus infection and the risk of hepatocellular carcinoma

Epidemiological studies have provided overwhelming evidence for a causal role of chronic hepatitis B virus(HBV) infection in the development of hepatocellular carcinoma(HCC).However,the pathogenesis of HBV infection and carcinogenesis of HBV-associated HCC are still elusive.This review will summarize the current knowledge on the mechanisms involved in HBV-related liver carcinogenesis.The role of HBV in tumor formation appears to be complex,and may involve both direct and indirect mechanisms.Integration of H...     

Hepatitis B virus and hepatocellular carcinoma at the miRNA level

AIM: To study Hepatitis B virus (HBV) infection and its association with hepatocellular carcinoma (HCC) at the miRNA level.METHODS: Three cellular models were used to investigate miRNA expression changes during HBV infection: human HepG2 hepatoblastoma cell line as a model without HBV infection;HepG2 cell line transfected with a 1.3-fold full-length HBV genome as an acute infection model;and HepG2.2.15 cell line,which is derived from HepG2 and stably transfected with a complete HBV genome,as a chronic infec...     

乙型肝炎病毒X基因突变与肝细胞癌

原发性肝细胞癌是世界上最常见的恶性肿瘤之一,慢性HBV感染是导致肝细胞癌的主要病因。HBV诱发肝细胞癌的确切机制仍不十分清楚。目前在HBV相关肝细胞癌病人血清和肝癌组织中发现了许多HBV X基因突变体,一些与肝细胞癌发生发展密切相关。本文主要就HBV X基因突变与肝细胞癌研究进展进行综述。     

Apolipoprotein E polymorphism influences orthotopic liver transplantation outcomes in patients with hepatitis C virus-induced liver cirrhosis

BACKGROUNDHepatitis C virus (HCV) infection is responsible for a chronic liver inflammation, which may cause end-stage liver disease and hepatocellular carcinoma. Apolipoprotein E (protein: ApoE, gene: APOE), a key player in cholesterol metabolism, is mainly synthesized in the liver and APOE polymorphisms may influence HCV-induced liver damage. AIMTo determine whether APOE alleles affect outcomes in HCV-infected patients with liver cirrhosis following orthotopic liver transplantation (OLT). METHODSThis was a cohort study in which 179 patients, both genders and aged 34-70 years, were included before or after (up to 10 years follow-up) OLT. Liver injury severity was assessed using different criteria, including METAVIR and models for end-stage liver disease. APOE polymorphisms were analyzed by quantitative real-time polymerase chain reaction. RESULTSThe APOE3 allele was the most common (67.3%). In inflammation severity of biopsies from 89 OLT explants and 2 patients in pre-transplant, the degree of severe inflammation (A3F4, 0.0%) was significantly less frequent than in patients with minimal and moderate degree of inflammation (≤ A2F4, 16.2%) P = 0.048, in patients carrying the APOE4 allele when compared to non-APOE4. In addition, a significant difference was also found (≤ A2F4, 64.4% vs A3F4, 0.0%; P = 0.043) and (A1F4, 57.4% vs A3F4, 0.0%; P = 0.024) in APOE4 patients when compared to APOE3 carriers. The fibrosis degree of the liver graft in 8 of 91 patients and the lack of the E4 allele was associated with more moderate fibrosis (F2) (P = 0.006). CONCLUSIONOur results suggest that the E4 allele protects against progression of liver fibrosis and degree of inflammation in HCV-infected patients.     

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.     

Hepatitis C impairs survival following liver transplantation irrespective of concomitant hepatocellular carcinoma

BACKGROUND/AIMS: Liver transplantation (LTX) is the only curative treatment for end-stage liver disease caused by hepatitis C (HCV). Hepatocellular carcinoma (HCC) is common in patients with HCV cirrhosis. METHODS: Two hundred and eighty-two HCV patients listed for LTX in the Nordic countries in a 17-year period were included. For comparison a group of patients with non-viral chronic liver disease (n=1552) was used. RESULTS: Two hundred and fifty-three (90%) patients received a first liver allograft. HCC was found in 38% of the explanted livers. Survival at 1, 3 and 5years was 82%, 69% and 61% vs. 85%, 80% and 76% for the comparison group (p<0.0001), this survival difference was also evident when excluding patients with HCC (p=0.007). HCV patients with HCC had 1, 3 and 5year survival of 73%, 52% and 46% compared with 88%, 80% and 71% for the HCV patients without HCC (p=0.0005). In an intention-to-treat analysis (from time of acceptance to the waiting list) HCV was also associated with an impaired survival. CONCLUSIONS: HCV cirrhosis, which is now also an important indication for LTX in the Nordic countries, and significantly impairs survival following LTX. Concomitant HCC and donor age are the two most important factors contributing to an impaired survival.     

Liver transplantation for hepatitis B virus: Decreasing indication and changing trends

AIM: To evaluate the indication and outcome of hepatitis B virus(HBV)-related liver transplantation(LT) in the era of newer antiviral agents.METHODS: We collected data on all patients who underwent transplantation at King Faisal Specialist Hospital and Research Center.These data included demographic,perioperative and long-term postoperative follow-up data including viral serological markers,HBV DNA,and repeated liver imaging.Between January 1990 and January 2012,133 patients(106 males and 27 females) underwent LT for HBV-related cirrhosis at our center.All patients were followed up frequently during the first year following transplantation,according to our standard protocol; follow-up visits occurred every 3-6 mo thereafter.Breakthrough infection was definedas re-emergence of HBV-DNA or hepatitis B surface antigen(HBs Ag) while on treatment.Five patients transplanted prior to 1992 did not receive immediate posttransplant anti-HBV prophylaxis; all other patients were treated with HBIG and at least one nucleos(t)ide analog.RESULTS: One hundred and thirty-three patients underwent LT for HBV and were followed for a median of 82 mo(range: 1-274).The rates of post-LT survival and HBV recurrence during the follow-up period were 89% and 11%,respectively.The following factors were associated with disease recurrence: younger age(44.3 ± 16.2 years vs 51.4 ± 9.9 years,P = 0.02),positive pretransplant hepatitis B e antigen(HBe Ag)(60% vs 14%,P 0.0001),detectable pretransplant HBV DNA(60% vs 27%,P = 0.03),positive posttransplant HBs Ag(80% vs 4%,P 0.0001) and positive posttransplant HBe Ag(27% vs 1%,P 0.0001).Forty-four(33%) patients had hepatocellular carcinoma(HCC).In the first(pre-2007) group,HBV was the second leading indication for LT after hepatitis C virus infection.A total of 64 transplants were performed,including 46(72%) for decompensated HBV cirrhosis,12(19%) for decompensated cirrhosis complicated by HCC and 6(10%) for compensated cirrhosis complicated by HCC.In the second group,nonalcoholic steatohepatitis surpassed HBV as the second leading indication for LT.A total of 69 HBV related transplants were performed,including 43(62%) for decompensated HBV cirrhosis,7(10%) for decompensated cirrhosis complicated by HCC and 19(27.5%) for compensated cirrhosis complicated by HCC.There was a significant(P = 0.007) increase in the number of transplants for compensated cirrhosis complicated by HCC.CONCLUSION: The use of potent anti-HBV agents has led to a changing trend in the indications for LT.HBV is currently the third leading indication for LT in this hyperendemic area.     

Role of liver transplantation in human immunodeficiency virus positive patients

End-stage liver disease(ESLD) is a leading cause of morbidity and mortality amongst human immunodeficiency virus(HIV)-positive individuals. Chronic hepatitis B and hepatitis C virus(HCV) infection,drug-induced hepatotoxicity related to combined antiretro-viral therapy,alcohol related liver disease and non-alcohol related fatty liver disease appear to be the leading causes. It is therefore,anticipated that more HIV-positive patients with ESLD will present as potential transplant candidates. HIV infection is no longer a contraindication to liver transplantation. Key transplantation outcomes such as rejection and infection rates as well as medium term graft and patient survival match those seen in the non-HIV infected patients in the absence of co-existing HCV infection. HIV disease does not seem to be negatively impacted by transplantation. However,HIV-HCV coinfection transplant outcomes remain suboptimal due to recurrence. In this article,we review the key challenges faced by this patient cohort in the pre- and posttransplant period.     

Hepatitis B virus mutations related to liver disease progression of Korean patients

Hepatitis B virus(HBV)infection is a global health problem and more than 350 million people worldwide are chronic carriers of the virus.Despite the recent dramatic decline in HBV chronic patients through successful programs of hepatitis B surface antigen vaccination,South Korea is still recognized as an endemic area of HBV infection.HBV infections in South Korea exhibit several distinct features in epidemiologic and clinical aspects.In this review paper,we summarize the distinct HBV mutation patterns related to clinical severity and the molecular epidemiologic traits in Korean chronic patients based on previous reports.Generally,several lines of evidence,including our previous results,have led to the conclusion that a combination of the exclusive predominance of genotype C2,which is prone to mutations,the high prevalence of basal core promoter double mutations,and the presence of distinct immune responses against HBV proteins in the Korean population may generate the distinct HBV variants rarely or not encountered in other areas,which results in distinct clinical manifestations in Korean chronic patients.This may provide a novel insight into the relationships between clinical severity,HBV genotype distribution,and HBV naturally occurring variants.     

Living donor liver transplantation does not increase tumor recurrence of hepatocellular carcinoma compared to deceased donor transplantation

AIM: To compare the recurrence-free survival (RFS) and overall survival (OS) of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT).METHODS: We retrospectively collected clinical data from 408 liver cancer patients from February 1999 to September 2012. We used the chi-squared test or Fisher’s exact test to analyze the characteristics of LDLT and DDLT. Kaplan-Meier analysis was used to compare the RFS and OS in HCC.RESULTS: Three hundred sixty HBV-positive patients (276 DDLT and 84 LDLT) were included in this study. The mean follow-up time was 27.1 mo (range 1.1-130.8 mo). One hundred eighty-five (51.2%) patients died during follow-up. The 1-, 3-, and 5-year RFS rates for LDLT were 85.2%, 55.7%, and 52.9%, respectively; for DDLT, the RFS rates were 73.2%, 49.1%, and 45.3% (P = 0.115). The OS rates were similar between the LDLT and DDLT recipients, with 1-, 3-, and 5-year survival rates of 81.8%, 49.5%, and 43.0% vs 69.5%, 43.0%, and 38.3%, respectively (P = 0.30). The outcomes of HCC according to the Milan criteria after LDLT and DDLT were not significantly different (for LDLT: 1-, 3-, and 5-year RFS: 94.7%, 78.7%, and 78.7% vs 89.2%, 77.5%, and 74.5%, P = 0.50; for DDLT: 86.1%, 68.8%, and 68.8% vs 80.5%, 62.2%, and 59.8% P = 0.53).CONCLUSION: The outcomes of LDLT for HCC are not worse compared to the outcomes of DDLT. LDLT does not increase tumor recurrence of HCC compared to DDLT.     

Hepatitis C virus recurrence after liver transplantation:A 10-year evaluation

AIM: To evaluate the predictors of 10-year survival of patients with hepatitis C recurrence. METHODS: Data from 358 patients transplanted between 1989 and 2010 in two Italian transplant centers and with evidence of hepatitis C recurrence were analyzed. A χ2, Fisher's exact test and Kruskal Wallis' test were used for categorical and continuous variables, respectively. Survival analysis was performed at 10 years after transplant using the Kaplan-Meier method, and a log-rank test was used to compare groups. A P level less than 0.05 was considered significant for all tests. Multivariate analysis of the predictive role of different variables on 10-year survival was performed by a stepwise Cox logistic regression.RESULTS: The ten-year survival of the entire population was 61.2%. Five groups of patients were identified according to the virological response or lack of a response to antiviral treatment and, among those who were not treated, according to the clinical status(mild hepatitis C recurrence, "too sick to be treated" and patients with comorbidities contraindicating the treatment). While the 10-year survival of treated and untreated patients was not different(59.1% vs 64.7%, P = 0.192), patients with a sustained virological response had a higher 10-year survival rate than both the "non-responders"(84.7% vs 39.8%, P 0.0001) and too sick to be treated(84.7% vs 0%, P 0.0001). Sustained virological responders had a survival rate comparable to patients untreated with mild recurrence(84.7% vs 89.3%). A sustained virological response and young donor age were independent predictors of 10-year survival. CONCLUSION: Sustained virological response significantly increased long-term survival. Awaiting the interferon-free regimen global availability, antiviral treatment might be questionable in selected subjects with mild hepatitis C recurrence.     

Liver transplantation： Yesterday, today and tomorrow

With the advances in technical skills, management of postoperative complications and improvements in immunosuppressive drugs, liver transplantation is the standard treatment for many patients with chronic liver disease. Today, shortage of donor organs seems to be the major limiting factor for the application of liver transplantation. This review focuses on five issues that are challenging to clinical practice of liver transplantation and relevant to gastroenterologists. These include living donor liver transplantation, recurrent viral hepatitis, non-heart-beating donors, hepatocellular carcinoma, and ABO incompatible liver transplantation. Living donor and non-heart beating donor transplantations were initiated as a solution to increase the donor organ pool and it is expected that there will be an increase in the number of these donors. Recurrent hepatitis C and hepatocellular carcinoma following liver transplantation are among major problems and ongoing research in these diseases may lead to better outcomes in these recipients.     

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.