REVIEW: Hepatitis B and liver transplantation

Liver transplantation in hepatitis B virus (HBV)-infected patients is very commonly followed by recurrence of infection in the transplanted liver. Most recipients with HBV recurrence will develop chronic hepatitis that follows a more aggressive course than is seen in non-immuno-compromized subjects and this frequently results in graft failure. The presence of hepatitis B e antigen or significant levels of HBV-DNA in the serum is highly predictive of recurrence and this has led to the view that patients, whose serum is positive for these conventional markers of replication, should be excluded from transplantation. The key to improving the results of transplantation in patients with HBV infection lies in the development of effective strategies to prevent reinfection. High dose anti-HBs immunoglobulin is effective in patients who are coinfected with hepatitis D, those transplanted for fulminant hepatitis and cirrhotic patients who have very low levels of viral replication prior to transplantation. Unfortunately, immunoprophylaxis does not seem to influence the outcome in those patients with higher levels of replication. There are several new orally active nucleoside analogues that are potent inhibitors of hepatitis B replication that may be effective for both the prevention and treatment of recurrent disease. The most promising are lamivudine (2',3', dideoxy, 3', thiacytidine) and famciclovir (a guanosine analogue). Both agents have been extensively evaluated in animal models of HBV and have been shown to rapidly suppress viral replication. The initial experience with these agents in liver transplant recipients has been promising and a number of studies are currently underway to determine whether these drugs, used alone or in combination with immunoprophylaxis, are able to prevent recurrence in those patients at highest risk of post-transplant HBV recurrence.     

Hepatitis C and steatosis

Steatosis is a common finding in patients with chronic hepatitis C (CHC) due to a combination of the direct steatogenic effect of hepatitis C virus (HCV) and the prevalence of metabolic risk factors in the HCV population. Steatosis is now established as a risk factor for disease progression in CHC and significantly impacts therapeutic response. Research efforts should continue to focus on defining the complex viral and host interactions involved in the pathogenesis of HCV-related steatosis so that future therapeutic strategies may be accurately and appropriately targeted.     

Hepatitis C and steatosis

Hepatic steatosis is common in patients with chronic hepatitis C virus (HCV) infection. Epidemiologic studies have shown HCV-associated steatosis to correlate with both patient factors, such as obesity and viral factors, such as HCV genotype 3a. Furthermore, the degree of steatosis has been linked to the extent of hepatic fibrosis in several studies, implying that steatosis may be contributing to disease progression in chronic HCV infection. Whether the pathogenesis of HCV-associated steatosis is linked to oxidative damage non-specifically, to HCV viral properties, or to other factors remains unknown. This steatosis may play an important role in the response to HCV therapy, in disease progression after liver transplantation for HCV, or in HIV-HCV coinfection.     

Hepatitis C and steatosis: a reappraisal

The overall prevalence of steatosis in patients with Hepatitis C virus (HCV) chronic infection is 55.5% (range 34.8-81.2%). This is a two to threefold increase compared with the prevalence of steatosis in chronic hepatitides because of other aetiologies and of the figures expected on the grounds of a steatosis-HCV chance association. HCV genotype 3 (HCV-3) has specific epidemiological features; furthermore, as compared with HCV-non-3 genotypes, it is associated with a higher prevalence (74.1%vs 47.9%, P < 0.01) and with more severe grades of steatosis (prevalence of grade 3 steatosis 29.6 vs 5.5 P < 0.01). Host and viral factors play a role, although to a variable extent, in the pathogenesis of HCV-3 and non-3 steatosis. HCV load and body mass index are associated with steatosis in HCV-3 and in HCV-non-3 patients respectively. Serum cholesterol levels and liver steatosis at baseline follow an inverse relationship in HCV infection. As hypocholesterolaemia corrects only in those sustained responders to antiviral treatment both in genotype 3 and in non-3 genotypes, the occurrence of a virally induced, acquired and reversible hypobetalipoproteinaemia seems plausible. Steatosis affects the natural course of HCV infection: it is associated with fibrosis, a possible mediator of increased risk to develop type 2 diabetes, it impairs the response to antiviral treatment in HCV-3 patients and might constitute a risk factor for the development of hepatocellular carcinoma. These observations indicate the need to evaluate the efficacy of combined antiviral and 'metabolic' approaches vs standard antiviral regimes in patients with steatosis and HCV chronic infection.     

Hepatitis C virus-induced hepatocellular steatosis

Two distinct forms of hepatocellular steatosis can be seen in patients with chronic hepatitis C virus (HCV) infection. Classical metabolic risk factors for hepatocellular steatosis account for the vast majority of cases of steatosis in patients infected by non-genotype 3 HCV strains. In contrast, in patients infected by HCV genotype 3, steatosis is generally induced by the virus itself through a direct cytopathic effect, the mechanisms of which remain debated. Mixed forms of steatosis can also be seen in HCV genotype 3-infected patients with metabolic risk factors. Hepatocellular steatosis appears to be associated with more rapid progression of hepatic fibrosis. However, it is unclear whether this association is due to steatosis itself, or rather to metabolic and host factors that promote steatosis and fibrosis concomitantly. This review discusses current knowledge of HCV-induced steatosis and its relation to chronic HCV-associated liver disease.     

Hepatitis B and end-stage liver disease

Hepatitis B virus (HBV) is the most common cause of chronic hepatitis and end-stage liver disease worldwide. Untreated, chronic hepatitis B acquired early in life results in cirrhosis, liver failure, or hepatocellular carcinoma in up to 40% of individuals. Until recently, the options for a patient who had end-stage hepatitis B cirrhosis were severely limited, but during the past 15 years great strides have been made in prevention and treatment of hepatitis B cirrhosis. This article reviews recent advances in the understanding of the natural history, prevention, and medical management of HBV-related end-stage liver disease.     

Hepatitis B vaccination in liver transplant candidates

Liver transplantation has become the treatment of choice for patients with end-stage liver disease. De novo hepatitis B infection after liver transplantation is a rare event and usually runs a mild clinical and histological course. Despite the favourable outcome, a wide spectrum of hepatitis B virus (HBV)-associated liver disease may develop, ranging from asymptomatic carriage to severe chronic active hepatitis or cirrhosis and even fulminant hepatic failure. The achievement of protective titres of anti-HBs through vaccination has been suggested to be protective against the development of de novo HBV infection. The results of vaccination in cirrhotic patients awaiting for liver transplant have been very disappointing. High-dose/short-term schedules have been tried in transplant candidates in order to increase the response rate. New and more immunogenic formulations (containing new adjuvants or additional pre-S1/pre-S2 recombinant antigens), and, more importantly, early vaccination of potential transplant candidates at earlier stages of their liver disease should further prevent de novo hepatitis B in transplant recipients.     

乙型和丙型肝炎病毒感染与慢性肝病

检测天津地区１１９例慢性肝病毒者ＨＢＶ、ＨＣＶ标志，并对其中２８例ＨＣＶＲＮＡ阳性血清进行基因分型。结果，ＨＢＶ感染率明显高于ＨＣＶ感染率（Ｐ〈０．０５），肝癌患者中ＨＢＶ、ＨＣＶ重叠感染率明显高于慢性肝炎（Ｐ〈０．０５）；各组均以ＨＣＶⅡ型为主。提示天津地区慢性肝病上前仍以ＨＢＶ感染为主；ＨＢＶ、ＨＣＶ重叠感染对肝癌的发生似有相加作用；ＨＣＶⅡ型感染在天津地区ＨＣＶ相关性曙性肝病中可以起主要作用     

Outcomes of liver transplantation using Hepatitis B core-positive liver grafts: Implications for prophylaxis

The number of patients listed for liver transplantation has outpaced the number of transplants that can be performed. This disparity between transplant candidates and the availability of donor grafts has led to an increase in mortality for patients waiting for liver transplantation. One strategy used to increase the donor pool has been the utilization of expanded donor grafts, such as those from donors with hepatitis B core antibody (anti-HBc). However, use of anti-HBc-positive grafts can potentially place the recipient at risk of de novo post-transplant hepatitis B virus (HBV) infection. The spectrum of liver disease from de novo hepatitis B ranges from mild hepatitis to graft loss. Fortunately, the risk of de novo HBV infection can be decreased with administration of oral nucleosides or nucleotides and hepatitis B immunoglobulin to the recipient. This review focuses on the epidemiology, natural history, and prophylactic strategies to reduce the risk of de novo hepatitis B in liver transplant recipients who receive anti-HBc-positive grafts.     

Hepatitis B immune globulin in liver transplantation prophylaxis: an update

Context

Liver transplantation is the best treatment option for end-stage liver disease following hepatitis B (HBV) infection. However, the high rate of recurrence of HBV infection following transplantation is a disadvantage of this option.

Evidence Acquisition

Over the past 2 decades, the gold standard of prophylactic treatment for the prevention of HBV re-infection following liver transplantation has been the administration of low- to high-dose hepatitis B immune globulin (HBIg) along with an antiviral agent to induce passive immunity.

Results

The effectiveness of HBIg in preventing the recurrence of HBV depends on the dosage, route of administration, and duration of HBIg treatment, and the viremic status at the time of transplantation. There is currently no consensus on a standardized recommendation for therapeutic options that include HBIg administration.

Conclusion

This review attempts to summarize the available data on the feasibility of such options. Most recent studies support the use of long-term combination therapy of HBIg and antiviral NAs (especially new agents).     

Hepatitis B and circadian rhythm of the liver

The circadian rhythm in humans is determined by the central clock located in the hypothalamus’s suprachiasmatic nucleus, and it synchronizes the peripheral clocks in other tissues. Circadian clock genes and clock-controlled genes exist in almost all cell types. They have an essential role in many physiological processes, including lipid metabolism in the liver, regulation of the immune system, and the severity of infections. In addition, circadian rhythm genes can stimulate the immune response of host cells to virus infection. Hepatitis B virus (HBV) infection is the leading cause of liver disease and liver cancer globally. HBV infection depends on the host cell, and hepatocyte circadian rhythm genes are associated with HBV replication, survival, and spread. The core circadian rhythm proteins, REV-ERB and brain and muscle ARNTL-like protein 1, have a crucial role in HBV replication in hepatocytes. In addition to influencing the virus’s life cycle, the circadian rhythm also affects the pharmacokinetics and efficacy of antiviral vaccines. Therefore, it is vital to apply antiviral therapy at the appropriate time of day to reduce toxicity and improve the effectiveness of antiviral treatment. For these reasons, understanding the role of the circadian rhythm in the regulation of HBV infection and host responses to the virus provides us with a new perspective of the interplay of the circadian rhythm and anti-HBV therapy. Therefore, this review emphasizes the importance of the circadian rhythm in HBV infection and the optimization of antiviral treatment based on the circadian rhythm-dependent immune response.     

Hepatitis B virus and liver transplantation: concepts in antiviral prophylaxis

Summary. Liver transplantation remains problematic in patients with end-stage liver disease secondary to chronic hepatitis B virus (HBV) infection. Recurrent hepatitis is almost universal in those patients who are HBV DNA-positive prior to transplantation. Prophylactic hepatitis B immune globulin can be given to reduce the rate of hepatitis B recurrence in patients who are HBV DNA-negative prior to transplantation. More recently novel antiviral drugs such as lamivudine or famciclovir have been used specifically to inhibit hepatitis B viral replication. However, the development of drug-resistant viral mutants have been observed. Further studies are needed to investigate these drugs more extensively, particularly to assess whether combination therapy may be a more effective means of controlling viral recurrence in patients transplanted for chronic HBV infection.