Therapy of chronic hepatitis B: today and tomorrow

Hepatitis B virus infection represents an important health problem all around the world, with almost 350 million people chronically infected and 1 million death per year. Despite an efficient vaccination program and despite therapeutic progresses, chronic hepatitis B is still a disease with severe evolution and an increased prevalence in many countries, including Romania. Today, we have two groups of drug that are used for chronic hepatitis B treatment: interferon and lamivudine. Unfortunately, long term results for interferon or lamivudine treatment are far from satisfactory, fact that explains the interest for new antiviral agents, which are under evaluation procedures in many clinical trials. A combination of two or more new antiviral action agents it is believed to be the optimum therapy of chronic hepatitis B in the future.     

Liver Transplantation in Bearers of Hepatitis B Associated or Not With Delta Hepatitis in the Age of the New Antiviral Drugs: Is Hyperimmune Globulin Still Necessary?

Hepatitis B (HBV) is a public health problem worldwide; one-third of the population has already been in contact with HBV, and 350 million people are chronic carriers of virus. The appearance of hyperimmune gamma globulin and antiviral drugs has allowed that group to undergone hepatic transplantation, achieving satisfactory results to prevent a relapse. But the use of hyperimmune gamma globulin has an extremely high cost, and combined therapies with new antiviral drugs seem to be a therapeutic alternative. We analyzed 21 patients with hepatitis B associated or not with Delta hepatitis over a mean follow-up period of 19.5 months, concluding that use of only nucleotide analogues has sufficient to achieve satisfactory results.     

乙型肝炎病毒表面抗原清除的相关因素研究进展

血清乙型肝炎病毒表面抗原（HBsAg）阳性是乙型肝炎病毒（HBV）感染的标志,而HBsAg清除是慢性乙型肝炎（CHB）最接近临床治愈的一个指标。HBsAg清除受宿主、病毒及抗病毒药物等因素的影响。该文就近年来关于CHB患者HBsAg清除的相关因素的研究进展作了综述。     

Additional interferon alpha for lamivudine resistant hepatitis B infection after liver transplantation: a preliminary report

Resistance formation is a major problem in antiviral treatment of hepatitis B recurrence after liver transplantation. One possible therapeutic approach is an antiviral combination therapy with synergistic drugs. Four patients who were transplanted for chronic hepatitis B were analyzed retrospectively. All patients had reinfection of the graft and breakthrough of hepatitis B virus (HBV) during consecutive famciclovir and lamivudine monotherapy. Subsequently a combination therapy of lamivudine and interferon alpha 2a (3 times 3 million units weekly) was initiated. Addition of interferon markedly reduced viral replication rate in all patients. Three patients became HBV-DNA negative despite lamivudine resistance, but only two had a sustained response. No patient seroconverted to anti-HBe or lost HBsAg, but all patients showed a normalization of alanine aminotransferase and aspartate aminotransferase levels. No severe complications, and especially no rejection episodes occurred. Therefore lamivudine combined with interferon might be used for the therapy of hepatitis B reinfection after liver transplantation.     

Viral infection in the renal transplant recipient

Viruses are among the most common causes of opportunistic infection after transplantation and the most important. The risk for viral infection is a function of the specific virus encountered, the intensity of immune suppression used to prevent graft rejection, and other host factors governing susceptibility. Viral infection, both symptomatic and asymptomatic, causes the "direct effects" of invasive disease and "indirect effects," including immune suppression predisposing to other opportunistic infections and oncogenesis. Rapid and sensitive microbiologic assays for many of the common viruses after transplantation have replaced, for the most part, serologic testing and in vitro cultures for the diagnosis of infection. Furthermore, quantitative molecular tests allow the individualization of antiviral therapies for prevention and treatment of infection. This advance is most prominent in the management of cytomegalovirus, Epstein-Barr, hepatitis B, and hepatitis C viruses. Diagnostic advances have not been accompanied by the development of specific and nontoxic anti-viral agents or effective antiviral vaccines. Vaccines, where available, should be given to patients as early as possible and well in advance of transplantation to optimize the immune response. Studies of viral latency, reactivation, and the cellular effects of viral infection will provide clues for future strategies in prevention and treatment of viral infections.     

Management of hepatitis B virus infection in liver transplant recipients: prospects and challenges

Although survival of liver transplantation for patients with hepatitis B infection is comparable to uninfected transplant recipients, prevention of hepatitis B virus (HBV) reinfection remains an important goal. In this article, several aspects of the hepatitis B reinfection and its management will be examined. Approximately 50% of the treatment failures that occur with hepatitis B immune globulin (HBIg) prophylaxis are due to mutations in the 'a' determinant of the HBV. In patients without mutations, failure of HBIg therapy may relate to the frequency and dose of HBIg, the type and amount of immunosuppression, and the pre-transplant replication status. Antiviral therapy with lamivudine and famciclovir has been used successfully to treat patients who have failed HBIg treatment and as monotherapies for liver transplant recipients. Combining antiviral and immunomodulatory therapies appears efficacious, at least in the short term. New developments related to immunotherapy predict three potential trends in future use: 1) i.v. formulated HBIg, 2) monoclonal antibodies, or 3) hepatitis B immune plasma. In conclusion, there are an increasing number of therapeutic options for the management of patients undergoing liver transplantation for hepatitis B infection. Continued improvement in patient outcomes requires further understanding of each therapeutic agent and the specific patient characteristics that may influence efficacy.     

Recommendations for postexposure prophylaxis of operating room personnel and patients exposed to bloodborne diseases

The purpose of this collective review is to discuss management of operating room personnel who have had occupational exposure to blood and other body fluids that might contain hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and human T-cell lymphotropic virus type I (HTLV-I). HBV postexposure prophylaxis includes starting hepatitis B vaccine series in any susceptible unvaccinated operating room personnel who sustain an exposure to blood or body fluid during surgery. Postexposure prophylaxis with hepatitis B immune globulin (HBIG) is an important consideration after determining the hepatitis B antigen status of the patient. Ideally, all operating room personnel should be vaccinated with hepatitis B vaccine before they pursue their career in surgery. Immune globulin and antiviral agents (e.g., interferon with or without ribavirin) should not be used for postexposure prophylaxis of operating room personnel exposed to patients with HCV; rather, follow-up HCV testing should be initiated to determine if infection develops. Postexposure prophylaxis for HIV involves a basic four-week regimen of two drugs (zidovudine and lamivudine; lamivudine and stavudine; or didanosine and stavudine) for most exposures. An expanded regimen that includes a third drug must be considered for HIV exposures that pose an increased risk for transmission. When developing a postexposure prophylaxis regimen, it is helpful to contact the National Clinicians' Postexposure Prophylaxis Hotline (1-888-448-4911).     

Hepatitis B treatment: Lessons for the nephrologist

Hepatitis B affects approximately 350 million people worldwide, and an estimated 1.25 million people in the United States. Although most people infected with the virus do not develop significant hepatic disease from hepatitis B, 15-40% will develop serious complications. These complications include cirrhosis, the development of hepatocellular carcinoma , and hepatic decompensation. Patients with renal failure have increased risk of acquiring the virus through blood transfusions and contact with bodily fluids at hemodialysis centers, and of developing complications from hepatitis B virus infection. Renal transplant patients are at increased risk for exacerbations of hepatitis B with immunosuppression. Thus, it is crucial for the nephrologist to have a clear understanding of the natural history and treatment of hepatitis B, both pre- and post-renal transplant.     

乙肝相关性终末期肝病肝移植后乙肝复发的防治

目的探讨乙肝相关性终末期肝病肝移植术后乙肝病毒再感染的防治。方法回顾性分析我院1999年10月到2007年10月肝移植109例乙肝相关性终末期肝病患者，移植后给予抗病毒预防乙型肝炎病毒再感染，拉米夫定治疗组50例、拉米夫定和乙肝免疫球蛋白（乙肝免疫球蛋白）联合治疗组59例，观察临床表现，血清HbsAg、血清HbeAg、血清HBVDNA及必要时肝穿刺免疫组织化学检测HbsAg等指标。结果109例接受了3个月一8年的抗病毒治疗随访。①拉米夫定治疗组50例，10例复发，复发率为20％，复发病例中2例分别于术后5个月、8个月死于乙肝复发爆发性肝炎；余8例给予阿德夫韦和乙肝免疫球蛋白后，肝功能好转，目前在随访中。②拉米夫定和乙肝免疫球蛋白联合治疗59例，2例复发，给予调整免疫抑制药后，肝功能好转。两组比较差异有统计学意义（χ^2=7．622，P〈0．05）。结论用拉米夫定和乙肝免疫球蛋白联合应用可以有效预防肝移植后乙型肝炎病毒的再感染。     

Reactivation of viral replication after liver resection in patients infected with hepatitis B virus

OBJECTIVE: To investigate the mechanisms and risk factors underlying postoperative reactivation of hepatitis after liver resection for hepatitis B virus-related hepatocellular carcinoma. SUMMARY BACKGROUND DATA: Although risk factors for acute hepatic failure after liver resection have been reported in patients with chronic liver disease, the issue of reactivation of hepatitis B virus replication after liver resection is unresolved. METHODS: Fifty-five patients with hepatocellular carcinoma and hepatitis B surface antigen underwent liver resection. In 25 of these 55 patients, serum levels of hepatitis B virus DNA and the type of hepatitis B virus were determined before and after surgery. RESULTS: Postoperative hepatitis occurred in 13 of the 55 patients (24%). Reactivation of viral replication occurred after liver resection in 7 of the 25 patients tested, and alanine aminotransferase activity increased in 6 of these 7 patients. High preoperative alanine aminotransferase activity, high levels of hepatitis B virus DNA, presence of wild-type DNA, and detection of hepatitis B core antigen in hepatocytes, all features of the immune clearance phase in the natural course of hepatitis B virus infection with no surgery, were more likely to be found in patients with reactivation than in patients without reactivation. CONCLUSIONS: During the immune clearance phase of hepatitis B virus infection, especially the period of acute exacerbation, changes in serum hepatitis B virus DNA level should be monitored for early warnings of reactivation of viral replication, likely to cause severe postoperative hepatitis and acute hepatic failure.     

Prevention of hepatitis B virus reinfection after orthotopic liver transplantation

OBJECTIVE: We discuss the prevention of hepatitis B virus reinfection following orthotopic liver transplantation. METHODS: Sixty-eight cases of chronic fulminant hepatitis B, the end stage of liver cirrhosis and liver carcinoma complicated with HBV cirrhosis, were given antiviral drugs pre- and posttransplantation to prevent hepatitis B virus reinfection. Lamivudine was administered to two cases and lamivudine + HBIG to 63 cases. Adefovir + HBIG was administered to three cases. The serum HBV, HBV DNA, liver biopsy immunohistochemistry and clinical examinations were performed. RESULTS: One of two cases given lamivudine developed reinfection with serum HBSAg, HbeAb, HBcAb, HBV DNA, and positive and liver biopsy immunohistochemistry showing HBSAg phenotype. Two of the 63 cases given lamivudine + HBIG developed reinfection with serum HBSAg, HBeAb, HBcAb positive and liver biopsy immunohistochemistry showing HBSAg phenotype. The serum HBV DNA was positive in one of the two cases. Three cases given adefovir developed no reinfection with HBV. CONCLUSION: Orthotopic liver transplantation is an effective treatment for HBV infection; lamivudine + HBIG or adefovir + HBIG prevent hepatitis B virus reinfection.     

A Comparative Study of Antiviral Therapy After Resection of Hepatocellular Carcinoma in the Immune-Active Phase of Hepatitis B Virus Infection

Background  

The role of antiviral therapy for patients in the immune-active phase of hepatitis B virus (HBV) infection who underwent partial hepatectomy for hepatocellular carcinoma (HCC) is unknown.     

Treatment of hepatitis B and C after liver transplantation. Part 1, hepatitis B

The outcome of OLT for HBV-related liver disease is dependent on the prevention of allograft re-infection. Over the past decade, major advances have been made in the management of HBV transplant candidates. The advent of long-term hepatitis B immune globulin (HBIG) administration as a prophylaxis against HBV recurrence, and the introduction of new antiviral agents against HBV infection, such as lamivudine (LAM), were a major breakthrough in the management of these patients. Results of OLT for HBV infection are similar to those achieved with other indications. Pre-OLT antiviral treatment such as LAM can suppress HBV replication before OLT and thus decrease the risk of re-infection of the graft. Combination prophylaxis with LAM and HBIG after transplantation highly effectively reduces the rate of HBV re-infection, even in HBV replicative cirrhotic patients. The optimal HBIG protocol in the LAM era is yet to be defined: dosing of HBIG, routes of administration, and possibility of stopping HBIG. Several antiviral drugs have been developed for the management of HBV infection on the graft, so outcome is currently good.     

Antiviral therapy to prevent and treat hepatitis B virus infection in hepatic allografts

Hepatitis B infection of a liver allograft can have serious consequences including a negative influence on the probability of survival. Therefore, there is a need for very effective antiviral therapy for transplant recipients. In this article the early experience with nucleoside analogue antiviral agents, both to prevent and to treat hepatitis B in liver allografts, is reviewed. There are several important characteristics of these agents that are already apparent. Ganciclovir and famciclovir have limited efficacy in treating infections when they are used alone. These compounds might be beneficial if used after resistance develops to other drugs or when used in combination with other agents. Lamivudine is effective for about two-thirds of patients in preventing and treating hepatitis B infection in allografts. Hepatitis B immune globulin (HBIg) is known to increase the efficacy of lamivudine in preventing infection. A large study to further characterize this combination therapy is being organized. Resistance to famciclovir and lamivudine can occur if they are used alone for a long time. In order to lower the incidence of drug resistance, it may be necessary to utilize combinations of nucleoside analogues.     

Hepatitis B virus associated focal and segmental glomerular sclerosis: report of two cases and review of literature

The hepatitis B virus (HBV) is estimated to have infected about 350 million people worldwide, making it one of the most common human pathogens. Renal involvement is among its most common extra hepatic manifestations and usually manifests in the form of immune complex mediated glomerulopathy, such as membranous glomerulonephritis (MGN), membranoproliferative glomerulonephritis (MPGN), mesangioproliferative glomerulonephritis and immunoglobulin A (IgA) nephropathy. Occurrence of focal and segmental glomerular sclerosis (FSGS) with HBV infection is rare and only five cases have been reported earlier. We report two cases of hepatitis B associated FSGS. In both the cases, HBsAg was demonstrated in the renal tissue and both the cases showed response to treatment with lamivudine, thus indicating a possible causal association between the viral infection and occurrence of nephrotic syndrome.     

Hepatitis B-positive donors in renal transplantation: increasing the deceased donor pool

It is reasonable to transplant HbsAg-positive kidneys into recipients who are themselves hepatitis B surface antigen (HbsAg) positive with appropriate antiviral treatment after transplantation. Although there are limited data regarding the hepatitis B virus (HBV) transmission risk following transplantation of kidneys from HbsAg-positive donors into HBV-immune recipients, current literature suggests that the risk of chronic infection in the recipient can be prevented by using antiviral agents or by boosting protective anti-HBs titers. The risk of chronic HBV infection following transplantation of kidneys from HbsAg-positive donors for HBV-naive recipients is high but can be minimized by administering lifelong antiviral therapy. Such a policy could be considered in an urgent situation. The most cost-effective antiviral prophylaxis strategy is lifelong lamivudine. Kidneys from HBsAg neg/anti-HBcore pos recipients are associated with a low rate of chronic HBV infection in the recipient and therefore can no longer be regarded as marginal donors. Booster vaccination to achieve protective HBV immunity or lifelong lamivudine therapy should prevent posttransplant HBV infection. Hence, we believe that strategies allowing transplantation of kidneys from donors with HBV can be undertaken safely with careful selection and matching of donors and recipients increasing access to kidney transplantation.     

Treatment of hepatitis B and C after liver transplantation. Part 1, hepatitis B

Abstract The outcome of OLT for HBV-related liver disease is dependent on the prevention of allograft re-infection. Over the past decade, major advances have been made in the management of HBV transplant candidates. The advent of long-term hepatitis B immune globulin (HBIG) administration as a prophylaxis against HBV recurrence, and the introduction of new antiviral agents against HBV infection, such as lamivudine (LAM), were a major breakthrough in the management of these patients. Results of OLT for HBV infection are similar to those achieved with other indications. Pre-OLT antiviral treatment such as LAM can suppress HBV replication before OLT and thus decrease the risk of re-infection of the graft. Combination prophylaxis with LAM and HBIG after transplantation highly effectively reduces the rate of HBV re-infection, even in HBV replicative cirrhotic, patients. The optimal HBIG protocol in the LAM era is yet to be defined: dosing of HBIG, routes of administration, and possibility of stopping HBIG. Several antiviral drugs have been developed for the management of HBV infection on the graft, so outcome is currently good.     

Transplantation of human cells in the peritoneal cavity of immunodeficient mice for rapid assays of hepatitis B virus replication

Kumar M, Bandi S, Cheng K, Gupta S. Transplantation of human cells in the peritoneal cavity of immunodeficient mice for rapid assays of hepatitis B virus replication. Xenotransplantation 2011; 18: 380–389. © 2011 John Wiley & Sons A/S. Abstract: Background: Studies of natural hepatitis B virus infection must be restricted to humans or primates due to viral species‐specificity. Alternative hepadnavirus animal models, e.g., woodchuck hepatitis virus in captive woodchucks, are not convenient, while in transgenic mice hepatitis B virus or viral proteins are expressed permanently through integrated genomes. Availability of small animal models that are easily produced and permit rapid assays will be quite helpful. Aims: We examined whether transplantation of human cells in the peritoneal cavity of mice will generate an appropriate mass of cells with hepatitis B virus replication. Methods: HepG2 2.2.15 cells were transplanted intraperitoneally into NOD/SCID mice. Replication of hepatitis B virus and viral gene expression was determined by analysis of blood and transplanted tissues with viral DNA and hepatitis B core antigen expression. Interruption of viral replication was examined. Results: After intraperitoneal transplantation with microcarrier scaffolds, 2.2.15 cells engrafted and proliferated in the peritoneal cavity of NOD/SCID mice. Hepatitis B virus replicated in transplanted 2.2.15 cells as shown by hepatitis B core antigen expression. Moreover, viral particles were secreted into the blood. Hepatitis B virus replication was susceptible to conventional antiviral drug therapy, such as lamivudine, as well as experimental antiviral gene therapy with a synthetic mimic of an antiviral cellular microRNA. Conclusions: Intraperitoneal transplantation of human cells rapidly provided reservoirs of hepatitis B virus in mice. This simple xenotransplantation approach will be effective and convenient for studies of hepatitis B and other human viruses in vivo.     

Liver transplant and chronic hepatitis B virus infection

Hepatitis B immune globulin use for preventing hepatitis B virus recurrence after liver transplant has changed our behavior radically, and it now seems that hepatitis B immune globulin has a vital role in preventing recurrence. New nucleotide or nucleoside analogues have promising results in treating chronic hepatitis and in posttransplant hepatitis B virus-infected patients. Hepatitis B immune globulin and other antivirals act on different pathways, so it is logical to combine these drugs to achieve maximum response in suppressing hepatitis B virus (HBV)-replication.     

Liver transplantation for hepatitis B-related cirrhosis: recent advances

In the absence of preventative therapy, deceased-donor liver transplantation indicated for hepatitis B virus (HBV) cirrhosis results in dismal graft and patient survival due to HBV infection of the liver graft. Major advances in the management of HBV-infected recipients during the past 15 years have reduced the rate of graft infection, resulting in improved outcomes, comparable to those for patients transplanted for non-HBV indications. Long-term use of hepatitis B immunoglobulin for passive immunotherapy is effective in preventing re-infection. Combination therapy with hepatitis B immunoglobulin and lamivudine after liver transplantation reduces HBV recurrence. Adefovir dipoxil is a safe and effective alternative oral antiviral treatment for lamivudine-resistant mutant HBV. The high cost of hepatitis B immunoglobulin remains a problem that must be overcome by the development of HBV vaccines and potent adjuvants.