Treatment of hepatitis B: the next five years

The natural history of individuals chronically infected with hepatitis B typically fluctuates, with periods of active viral replication with or without an associated hepatitis and sometimes prolonged periods of spontaneous viral suppression and inactive liver disease. In the majority, this chronic infection is clinically silent unless either liver failure and/or hepatocellular carcinoma (HCC) supervenes. Thus proactive steps are needed to first identify those with hepatitis B infection and to then serially monitor those found to be chronically infected for both level of alanine aminotransferase (ALT) and hepatitis B virus DNA (HBV-DNA) (using sensitive polymerase chain reaction techniques. Antiviral therapy significantly reduces the risk of liver disease progression and HCC in those with ongoing viral replication > 10(5) c/mL and advanced hepatic fibrosis. The decision of when to initiate (possibly lifelong) treatment has to be made judiciously. Before introducing therapy both patient and physician must recognise the need for compliance with both treatment and viral surveillance so as to minimise the development of drug resistance. Drug resistance needs to be identified prior to recurrence of hepatitis (rise in ALT) to prevent hepatic decompensation, this necessitates serial HBV-DNA testing.     

Peginterferon alpha/ribavirin combination therapy for the treatment of hepatitis C infection.

Chronic infection with the hepatitis C virus is widespread in the United States. This disease is associated with a progression of fibrosis of the liver leading to liver cirrhosis in as many as 20% of cases. The current standard of care for the treatment of chronic hepatitis C infection is combination therapy with pegylated interferon alpha plus ribavirin. In more than 50% of patients, this regimen has been shown to induce a sustained viral response, defined as undetectable hepatitis C viral ribonucleic acid (RNA) for 6 months after the end of treatment. Typically, patients are treated for 24 or 48 weeks. A number of possible adverse events are associated with combination therapy, and patient empowerment through supportive nursing care is critical to facilitating patient adherence to treatment. This article provides an update on information concerning the diagnosis and treatment of chronic hepatitis C infection. This information can be tailored to provide patient-focused assessment, education, and treatment.     

Molecular methods of hepatitis C genotyping

Hepatitis C virus is an RNA virus that is associated with chronic infection in the majority of people infected. Chronic infection with hepatitis C virus is the cause of significant morbidity and mortality worldwide and is associated with a large spectrum of liver disease including cirrhosis and hepatocellular carcinoma. End-stage liver disease due to chronic hepatitis C virus infection is currently the leading indication for liver transplantation in the USA. Hepatitis C virus genotyping of viral isolates circulating in the blood during chronic infection has become an important part of hepatitis C virus monitoring in chronically infected patients, and is useful as a prognostic indicator and to direct duration of therapy. This review will summarize information on hepatitis C genotyping, describe the limitations of current commercially available methods, give information on more recently developed methods, and provide a look to the future in terms of where advances in hepatitis C virus genotyping assays need to be made.     

Clinical management of patients with recurrent viral hepatitis after liver transplantation

Liver transplantation is indicated in end-stage chronic viral liver disease, but unless adequate prophylaxis is administered, the patient will in most cases develop recurrent hepatitis B (HBV) and C (HCV) virus infection. Today, patients receiving prophylaxis using nucleoside analogue drugs with or without specific immune globulin drugs in connection with orthotopic liver transplantation for HBV related cirrhosis, present low risk of relapse and high 5–10 year survival rates. Lamivudine was the first drug used in the prophylactic treatment, but this drug has increasingly been combined with or replaced by adefovir due to the low genetic barrier, which causes viral resistance. Most patients develop viral recurrence after orthotopic liver transplantation for HCV related cirrhosis, and in an elevated number of cases, cirrhosis and hepatic insufficiency set in after a few years. Prophylaxis before transplantation and pre-emptive treatment using interferon and ribavirin present numerous side effects resulting in reduction of doses and suspension of therapy, with consequently low sustained virological remission rates and risk of rejection.The treatment is better tolerated by patients with histologically confirmed chronic disease, but also in these patients virological remission rates are low. This pathology requires new therapeutic protocols and/or new drugs in order to obtain better compliance and better responses.     

Peginterferon-alpha(2b) and ribavirin

Hepatitis C virus infection is among the leading causes of chronic liver disease in the USA and has a worldwide prevalence of approximately 300 million people. Chronic hepatitis C virus is the most common indication for liver transplantation in the USA. Due to the chronic nature of hepatitis C virus infection, these numbers are expected to grow fourfold in the next decade. Interferon-alpha(2b) monotherapy followed by combination therapy with ribavirin have been used to treat chronic hepatitis C virus with limited success. The development of pegylated interferon-alpha(2b), (Peg-intron, Schering-Plough) instituted the next chapter in hepatitis C virus therapy. The demonstration of its safety and efficacy led to a major trial studying coadministration with ribavirin for compensated chronic hepatitis C virus infection. Pegylated interferon combination therapy has improved efficacy over standard interferon combination therapy without an increase in adverse effects. This article reviews the data regarding pegylated interferon-alpha(2b) with ribavirin therapy. The pharmacokinetics and pharmacodynamics of combination therapy will be presented along with clinical trial data. The efficacy and ease of usage of Pegintron and ribavirin support its use for chronic hepatitis C virus infection.     

Long-term outcome of chronic hepatitis C virus infection in primary hypogammaglobulinaemia

The clinical course of HCV infection in patients with primary hypogammaglobulinaemia appears to be more severe than in immunocompetent patients. We studied the long-term course of chronic HCV infection in 20 Norwegian hypogammaglobulinaemia patients with a 13-15 year known history of HCV infection. Twelve of 20 patients developed cirrhosis during the observation period (1984-1999), and the remaining eight also had chronic liver disease verified by liver biopsy in the majority of the cases. Eleven of the 20 patients are dead. Two died following liver transplantation for HCV cirrhosis. Five died due to terminal liver failure without receiving a liver allograft. Two patients died from other causes, but with advanced liver disease contributing to the outcome, while two deaths were unrelated to the HCV infection. Among patients with common variable immunodeficiency (CVI), five out of six are dead. Two patients cleared the hepatitis C virus 3 years following interferon monotherapy, while three patients achieved a sustained response to combination therapy with interferon and ribavirin. Viral load did not seem to have a major impact on disease progression. Our results emphasize the severity of hepatitis C virus infection in patients with hypogammaglobulinaemia. Patients with CVI appear to have the poorest prognosis.     

Autoimmunity induced by interferon-alpha therapy for chronic viral hepatitis.

Type I interferons, which are mostly alpha-interferons (either as single agents or in combination with antiviral drugs), are currently the standard therapy for chronic viral hepatitis B, B/D, and C. Side-effects are not uncommon and include exacerbation of pre-existing autoimmune disorders or the de novo induction of autoimmunity. These adverse effects are attributed to the immunomodulatory properties of type I interferons, and should be distinguished from autoimmunity associated with chronic viral hepatitis in which interferon treatment may indeed be beneficial. The major autoimmune side-effects of interferon therapy for chronic viral hepatitis are thyroid or liver disease. Therefore, screening for thyroid antibodies and auto-antibodies indicative of autoimmune hepatitis both before, during, and after interferon therapy is strongly recommended. The presence of high concentrations of thyroid auto-antibodies or antibodies associated with autoimmune hepatitis can be contraindicative to interferon therapy. However, treatment is not contraindicated in viral hepatitis (in particular chronic hepatitis C) associated with autoimmune phenomena--including low-titer thyroid antibodies or other non-organ specific auto-antibodies. If interferon-induced autoimmunity occurs, the necessity of therapy has to be balanced carefully against the risks of autoimmune disease. Further research is needed to identify the factors which determine susceptibility to interferon-associated autoimmunity in individual patients.     

Adefovir dipivoxil in the treatment of chronic hepatitis B virus infection

Adefovir dipivoxil (Hepsera^®, Gilead Sciences) is a prodrug of adefovir, with potent antiviral activity against hepatitis B virus. Adefovir dipivoxil therapy, 10 mg daily for 48 weeks, is effective in hepatitis B e antigen-positive and -negative chronic hepatitis B. In hepatitis B e antigen-negative chronic hepatitis B, adefovir dipivoxil was recently found to maintain its efficacy even after 3 years of therapy. Adefovir dipivoxil is effective in patients with compensated or decompensated chronic viral B liver disease, and in pre- and post-transplant hepatitis B virus patients who develop resistance to lamivudine (Epivir^®, GlaxoSmithKline). It is well-tolerated and safe even after the third year of long-term therapy, and is associated with low rates of viral resistance. All these characteristics make adefovir dipivoxil an important drug for the treatment of hepatitis B virus infection and an excellent candidate for long-term maintenance therapy in chronic viral B liver disease.     

Optimal duration of therapy in HBV-related cirrhosis

It is estimated that one-third of the world's population has been exposed to hepatitis B virus and that 300-400 million people have chronic hepatitis B. In areas of the world where hepatitis B infection is endemic, this chronic viral infection is a major cause of premature morbidity and mortality related to hepatocellular carcinoma (HCC) and complications of end-stage liver disease. Recent data from population-based studies suggest that the level of viral replication in chronic hepatitis B is an independent predictor of the future complications of the disease; patients with hepatitis B viral DNA titres >10(4) copies/mL (especially those with titres >10(5) copies) have a significantly greater risk of developing HCC and cirrhosis. There is also recent evidence that treatment with antiviral therapy in patients with chronic hepatitis B who have advanced hepatic fibrosis is associated with a reduction in the risk of decompensation of liver disease and HCC. Several new antiviral medications have been recently approved for the treatment of chronic hepatitis B. Several recent position statements and practice guidelines have recommended treatment of patients with chronic hepatitis B with oral antiviral medications. However, there remains some disagreement as to the threshold of viral load before treatment should be initiated and the optimal duration of therapy in patients with cirrhosis due to hepatitis B. This article describes the current recommendations regarding therapy in this group of patients and suggests some criteria for treatment of patients with chronic hepatitis B-related cirrhosis or advanced hepatic fibrosis.     

Peginterferon-α2b and ribavirin

Hepatitis C virus infection is among the leading causes of chronic liver disease in the USA and has a worldwide prevalence of approximately 300 million people. Chronic hepatitis C virus is the most common indication for liver transplantation in the USA. Due to the chronic nature of hepatitis C virus infection, these numbers are expected to grow fourfold in the next decade. Interferon-α_2b monotherapy followed by combination therapy with ribavirin have been used to treat chronic hepatitis C virus with limited success. The development of pegylated interferon-α_2b, (Peg-intron^®, Schering-Plough) instituted the next chapter in hepatitis C virus therapy. The demonstration of its safety and efficacy led to a major trial studying coadministration with ribavirin for compensated chronic hepatitis C virus infection. Pegylated interferon combination therapy has improved efficacy over standard interferon combination therapy without an increase in adverse effects. This article reviews the data regarding pegylated interferon-α_2b with ribavirin therapy. The pharmacokinetics and pharmacodynamics of combination therapy will be presented along with clinical trial data. The efficacy and ease of usage of Pegintron and ribavirin support its use for chronic hepatitis C virus infection.     

Adefovir dipivoxil in the treatment of chronic hepatitis B virus infection

Adefovir dipivoxil (Hepsera, Gilead Sciences) is a prodrug of adefovir, with potent antiviral activity against hepatitis B virus. Adefovir dipivoxil therapy, 10 mg daily for 48 weeks, is effective in hepatitis B e antigen-positive and -negative chronic hepatitis B. In hepatitis B e antigen-negative chronic hepatitis B, adefovir dipivoxil was recently found to maintain its efficacy even after 3 years of therapy. Adefovir dipivoxil is effective in patients with compensated or decompensated chronic viral B liver disease, and in pre- and post-transplant hepatitis B virus patients who develop resistance to lamivudine (Epivir, GlaxoSmithKline). It is well-tolerated and safe even after the third year of long-term therapy, and is associated with low rates of viral resistance. All these characteristics make adefovir dipivoxil an important drug for the treatment of hepatitis B virus infection and an excellent candidate for long-term maintenance therapy in chronic viral B liver disease.     

Therapeutic antibodies against viral hepatitis

Antibodies have the potential to be immunotherapeutic agents, used either as stand-alone therapy or as an adjunct for managing chronic viral infection. In addition, antibodies may be used prophylactically in individuals who have been accidentally exposed to hepatitis B virus (HBV) or hepatitis C virus (HCV), or to prevent re-infection of the liver in patients who have undergone liver transplantation. Human monoclonal antibodies to HBV and HCV were generated and their ability to reduce viral load was tested in different animal model systems, the Trimera mouse model and HBV-carrier chimpanzees. These antibodies were further developed and are currently being studied in clinical trials for chronic HBV or HCV and in liver transplant patients. The antibodies were shown to be safe, tolerable and could significantly reduce viral load. Their ability to inhibit HCV re-infection in the transplanted liver is being evaluated.     

Early detection of hepatitis B drug resistance: implications for patient management

Despite the availability of safe and effective prophylactic vaccines, hepatitis B viral disease has remained a tenacious scourge, ranking ninth globally among all causes of mortality (up to 1 million deaths annually). Approximately 6% of the global population--more than 350 million people--have failed to resolve viral infection and become chronic carriers, eventually placing between 15 and 25% of such individuals at risk for end-stage liver disease. Until recently, the immunomodulator interferon-alpha and especially the nucleoside analog lamivudine (Epivir) have been the treatments of choice for chronic hepatitis B viral infection. However, the inexorable development of drug resistance to lamivudine has been a major clinical impediment to the long-term use of such treatment. Herein, the current and future diagnostic methods for early detection of emerging drug resistance to the hepatitis B virus is reviewed. Given the recent approval of adefovir dipivoxil (Hepsera) and the possibility that other nucleoside and nucleotide analogs could soon become part of the hepatitis B virus therapeutic arsenal, the clinical ramifications for co-ordinated use of diagnostic tests together with new antihepadenaviral agents for optimal patient management is also discussed.     

Effects of alcohol consumption on viral hepatitis B and C

The liver is the main target organ for hepatitis viruses and the vital organ for alcohol metabolism. These two factors of viral hepatitis and alcohol abuse in combination can exert dual harmful actions, leading to enhanced damage to the liver. Epidemiological studies have revealed a higher prevalence of hepatitis C virus (HCV) infection among alcoholics than the general population. The interaction of alcohol with viral hepatitis [e.g., hepatitis B virus (HBV), HCV] and the underlying mechanisms are not fully understood. The effects of alcohol on viral hepatitis include promoted viral replication, weakened immune response, and increased oxidative stress. Clinically, alcohol abuse is correlated with an increased risk of developing end-stage liver cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B and C, suggesting that the combination of alcohol and HBV/HCV lead to more severe liver damage. The influence of mild to moderate alcohol drinking on the HBV-induced liver fibrosis, cirrhosis, and hepatocellular carcinoma among patients infected with HBV remains unclear. Unlike HBV infected patients, no safe level of alcohol intake has been established for patients with HCV. Even light to moderate alcohol use can exert a synergistic effect with viral hepatitis, leading to the rapid progression of liver disease. Furthermore, interferon-based therapy is less effective in alcohol drinkers than in control patients, even after abstinence from alcohol for a period of time. Therefore, abstaining from alcohol is highly recommended to protect the liver, especially in individuals with HBV/HCV infection, to improve the clinical efficacy of antiviral treatment and prevent the rapid progression of chronic viral hepatitis.     

乙型肝炎病毒感染者肾移植前肝穿刺活检与预后分析

背景：乙肝病毒感染者肾移植手术国内有较多报道,但乙肝病毒感染者肾移植前肝穿刺活检观察有限。目的：对慢性肾功能衰竭合并不同程度慢性乙型病毒性肝炎患者进行肾移植前肝穿刺活检,移植后2年随访观察转归情况。方法：对接受肾移植的21例乙型肝炎病毒感染的尿毒症患者进行肝穿刺活检。根据肝活检组织病理学改变,分为轻度（n=9）、中度（n=7）、重度（n=5）3组。肾移植后随访观察2年。3组中各有2例进行重复肝活检组织病理学检查。结果与结论：轻度慢性乙型肝炎组在随访2年中各项观察指标均无明显变化。中度慢性乙型肝炎组从移植后3个月开始谷氨酰转肽酶活性明显高于正常水平,随访至终点时,2例重复肝活检病理显示已处于重度病变。重度慢性乙型肝炎组从移植后3个月开始谷氨酰转肽酶活性持续高于正常水平;18个月开始,血清白蛋白水平低于正常值,球蛋白水平高于正常值;随访至终点时,有4例呈肝硬化改变。提示不同程度的慢性乙型病毒性肝炎患者肾移植后预后不同,肝活检是评价肝脏病变程度的重要手段,具有指导肾移植选择的作用。     

乙型肝炎病毒感染者肾移植前肝穿刺活检与预后分析

背景:乙肝病毒感染者肾移植手术国内有较多报道,但乙肝病毒感染者肾移植前肝穿刺活检观察有限.目的:对慢性肾功能衰竭合并不同程度慢性乙型病毒性肝炎患者进行肾移植前肝穿刺活检,移植后2年随访观察转归情况.方法:对接受肾移植的21例乙型肝炎病毒感染的尿毒症患者进行肝穿刺活检.根据肝活检组织病理学改变,分为轻度(n=9)、中度(n=7)、重度(n=5)3组.肾移植后随访观察2年.3组中各有2例进行重复肝活检组织病理学检查.结果与结论:轻度慢性乙型肝炎组在随访2年中各项观察指标均无明显变化.中度慢性乙型肝炎组从移植后3个月开始谷氨酰转肽酶活性明显高于正常水平,随访至终点时,2例重复肝活检病理显示已处于重度病变.重度慢性乙型肝炎组从移植后3个月开始谷氨酰转肽酶活性持续高于正常水平;18个月开始,血清白蛋白水平低于正常值,球蛋白水平高于正常值;随访至终点时,有4例呈肝硬化改变.提示不同程度的慢性乙型病毒性肝炎患者肾移植后预后不同,肝活检是评价肝脏病变程度的重要手段,具有指导肾移植选择的作用.     

Living donor liver transplantation in a patient with HIV

Highly active anti-retroviral therapy(HAART) for human immunodeficiency virus(HIV) has delayed the disease progression. The advances prompted us to undertake liver transplantation in a 41-year-old man with hemophilia B, HIV infection, and hepatitis C(HCV) end-stage liver disease. The donor was the patient's elderly brother. His right liver was implanted by the standard method. Two months after the operation, interferon alfa and ribavirin were administered for HCV infection. HCV was eradicated two weeks after the treatment. The HIV viral load is persistently negative and HAART has not been started so far. Utilizing a organ from living relatives should be one of the options to resolve the concern around the utilization of a scarce public source from cadavers for patients who may not have an equivalent survival to HIV negative patients.     

HCV-HBV infection

Chronic infection of hepatitis C (HCV) and B virus (HBV) frequently causes viral hepatitis. Patients with chronic viral hepatitis are at risk for liver cirrhosis and even hepatocellular carcinoma. In patients with chronic hepatitis C, the most effective therapy is elimination of HCV with interferon (IFN). The most effective initial IFN therapy is the combination of pegylated IFN alpha-2b plus ribavirin. Forty-eight weeks of this combination therapy produces sustained viral response rates of approximately 50%. Moreover, several reports showed that long-term IFN therapy also reduced the risk of liver carcinogenesis. In patients with chronic hepatitis B, seroconversion from HBeAg to anti-HBe antibodies suppresses viral replication and attenuates the hepatitis. Twenty-four weeks of IFN therapy produces HBeAg seroconversion rates approximately 30%.     

Interferon alfa-2a treatment for chronic hepatitis C without cirrhosis and its effects on the incidence of hepatocellular carcinoma

The aim of interferon treatment for chronic hepatitis C is eradication of the hepatitis C virus during the early stages of the disease to prevent progression to liver cirrhosis or hepatocellular carcinoma. However, the effects of interferon on preventing the development of hepatocellular carcinoma for chronic hepatitis C without cirrhosis remain obscure. We wished to study these effects. In this retrospective study, we followed up 66 patients with chronic hepatitis C who were treated with interferon alfa-2a (total dose 324 to 792 MIU) for an average period of 3 years after treatment. Of these 66 patients, 3 patients developed hepatocellular carcinoma during the follow-up period (range, 0.3 to 2.8 years; yearly incidence 1.5%). All 3 patients were among 27 patients who did not respond to interferon treatment. Of these 3 patients, 1 patient developed liver cirrhosis after interferon treatment, and the histologic staging of the remaining 2 patients before interferon treatment was F3, according to the new Inuyama classification. None of the 18 patients who were complete responders to interferon treatment or the 21 patients with incomplete responses developed hepatocellular carcinoma. Our results suggest that patients with chronic hepatitis C who have no response to interferon treatment and histologically advanced disease should be closely followed up after interferon treatment, although the mechanism of malignant transformation to hepatocellular carcinoma in patients with chronic hepatitis C virus infection is still obscure.     

Achievement of sustained viral response after switching treatment from pegylated interferon α-2b to α-2a and ribavirin in patients with recurrence of hepatitis C virus genotype 1 infection after liver transplantation: a case report

We report a case in which sustained viral response was achieved after switching treatment from pegylated interferon (PEG-IFN) α-2b to α-2a and ribavirin (RBV) in patients with recurrence of hepatitis C virus (HCV) infection after living donor liver transplantation. The patient was a 62-year-old man with liver cirrhosis due to HCV genotype 1b infection. The patient had 8 amino acid (aa) substitutions in the interferon sensitivity-determining region, and had substitutions for mutant and wild-type at aa70 and aa91, respectively, in the core region. The patient had minor genotype (GG) IL28B single nucleotide polymorphisms (rs8099917). He had initially received interferon α-2b and RBV for 2 years, and later developed hepatocellular carcinoma (HCC). After surgical resection of HCC, he subsequently received PEG-IFN α-2b and RBV for 1.5 years, without undetectable viremia during the treatment course. Due to recurrence of HCC, the patient received a living donor liver transplantation. Later on, hepatitis C relapsed. For the management of relapse, he received another course of PEG-IFN α-2b and RBV. However, breakthrough viremia occurred. PEG-IFN was thus switched from α-2b to α-2a and RBV for another 17 months. The patient eventually achieved a sustained viral response.