August 2008
Section 4
VIII Chronic HepatitisPeter F Malet, MD
10.2310/7900.S04C08
DefinitionChronic hepatitis is a term that encompasses an etiologically diverse group of clinical and pathologic diseases. Chronic hepatitis is characterized by the presence of hepatic inflammation on liver biopsy and elevation of serum liver enzymes, especially aminotransferase transaminases. 1 Chronic hepatitis is generally defined as disease that has lasted for 6 months or longer; in many cases, however, the diagnosis can be established earlier.
EtiologyThe most important diseases that cause chronic hepatitis are (1) autoimmune hepatitis (AIH) (previously called autoimmune chronic active hepatitis); (2) chronic hepatitis B, which is caused by infection with hepatitis B virus (HBV); and (3) chronic hepatitis C, caused by hepatitis C virus (HCV) [ seeTable 1 ].
Chronic overuse of alcohol may result in chronic hepatic inflammation (alcohol-induced liver disease or alcoholic hepatitis). Nonalcoholic steatohepatitis (NASH) is similar histologically to alcohol-induced liver disease and is discussed more fully elsewhere [ see 4:IX Cirrhosis of the Liver ]. Less commonly, chronic hepatitis is cryptogenic or caused by drugs. Wilson disease, a1 -antitrypsin deficiency, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC) are also chronic liver diseases characterized by hepatocellular or bile duct inflammation, but the term chronic hepatitis is not generally used to describe these conditions. Over the past decade, international working groups have substantially modified the terminology of chronic hepatitis to reflect an etiologic basis rather than a pathologic basis. 1 As a result, previously used terms, such as chronic active hepatitis and chronic persistent hepatitis, are no longer used.
Approach to Chronic Hepatitisdiagnosis
Clinical Manifestations
Clinical manifestations of chronic hepatitis are diverse, ranging from asymptomatic disease characterized by mildly elevated aminotransferase levels to severe, rapidly progressive illness and fulminant hepatic failure. The most common symptoms of chronic hepatitis are fatigue, malaise, and mild abdominal discomfort. Patients with mild chronic hepatitis are usually asymptomatic or have minimal symptoms with no stigma of chronic liver disease on physical examination. In more advanced cases, when hepatic synthetic function begins to diminish (a condition referred to as hepatic decompensation), the symptoms and signs may include anorexia, jaundice, spider angiomas, palmar erythema, ascites, edema, and encephalopathy. Pruritus may occur but is unusual; pruritus is more characteristic of PBC or PSC. A small proportion of patients with AIH have an acute fulminant course and are critically ill at initial presentation. Some extrahepatic manifestations of chronic hepatitis include arthralgias, arthritis, glomerulonephritis, and skin rashes.
Standard Laboratory Tests
The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are usually elevated in patients with chronic hepatitis; however, a minority of patients, especially those who have chronic hepatitis B or C, may have either persistently or transiently normal aminotransferase levels. Therefore, even a mild elevation of aminotransferase levels (5 to 10 IU/L higher than the upper limit of normal) should lead physicians to consider the presence of chronic hepatitis. Elevations of more than 400 IU/L are not unusual in cases of AIH and may occasionally be seen with chronic hepatitis B. Aminotransferase levels that are twofold to threefold higher than the upper limit of normal are common with chronic hepatitis C. The serum bilirubin level is usually normal in chronic viral hepatitis, unless hepatic decompensation has occurred. The serum bilirubin level is higher than 3 mg/dL in patients with moderately severe AIH. A characteristic feature of AIH is an increased Y-globulin level (> 1.6 g/dL), which may sometimes be markedly increased (3 to 7 g/dL). In the most severe forms of chronic hepatitis, hepatic synthetic function is impaired; this is manifested by a decreased serum albumin level and a prolonged prothrombin time.
Imaging studies (i.e., ultrasonography and computed tomography) of the abdomen may be normal in early chronic hepatitis or may show variable degrees of hepatomegaly with or without splenomegaly. When more advanced hepatic fibrosis is present, irregularity of liver texture or contour may be seen. Evidence of portal hypertension with portal collateral vessels or ascites may be seen with advanced disease.
Liver Biopsy
The specific etiology of chronic hepatitis can usually be determined by clinical evaluation combined with serologic testing. Liver biopsy can confirm or exclude certain diagnoses and can establish the grade of inflammatory activity and the stage of fibrosis and cirrhosis.
The grade and stage of chronic hepatitis can be assessed with various semiquantitative scoring systems. 1,2 In the histology activity index (HAI) (also known as the Knodell score), the grades of inflammation range from 0 to 18, and the stages of fibrosis range from 0 to 4. The HAI is sometimes used in clinical research studies but is no longer commonly used in clinical practice. 2 The most popular scoring system for chronic hepatitis is the METAVIR system. 3 This system generates two scores from 0 to 4: one for the degree of inflammation and the other for the degree of fibrosis [ seeTable 2 ]. Other scoring systems are available but are not commonly used in clinical practice. In addition to the characterization of the degree of inflammation and fibrosis, the evaluation of a liver biopsy specimen from a patient with chronic hepatitis includes a description of all of the findings present (e.g., steatosis, bile duct changes, granulomas, type of inflammatory cells, presence of iron, and Mallory hyaline) or a notation of their absence.
Differential Diagnosis
Primary Biliary Cirrhosis
On liver biopsy, PBC may have features similar to those of AIH, including mild interface hepatitis, but is differentiated by the presence of bile duct inflammation or ductopenia. Marked elevation of serum alkaline phosphatase and high titers of antimitochondrial antibody (AMA) (> 1:160) are useful in making the diagnosis of PBC.
Primary Sclerosing Cholangitis
PSC can sometimes mimic chronic hepatitis. Prominent elevations of the serum alkaline phosphatase level and accompanying inflammatory bowel disease will, in most cases, distinguish this disorder from other types of chronic hepatitis. The definitive diagnosis is made by endoscopic retrograde or magnetic resonance cholangiography.
Alcoholic Liver Disease
Liver enzyme elevations caused by alcohol overuse are very commonly encountered in clinical practice. When the patient admits to the overuse of alcohol, the diagnosis is straightforward. However, careful and repeated questioning of the patient and family members may sometimes be required to obtain an accurate assessment of the patient's alcohol use.
Fatty Liver and Nonalcoholic Steatohepatitis
Fatty liver and NASH are increasingly common liver diseases that are usually, but not always, associated with obesity or being overweight. Fatty liver is characterized by macrovesicular and, sometimes, microvesicular steatosis without inflammation; serum aminotransferase transaminase levels may be normal or elevated, sometimes severalfold or more. NASH is characterized by hepatocellular inflammation, steatosis, and, usually, elevated serum aminotransferase transaminase levels. NASH may lead to fibrosis or to cirrhosis. Although radiologic studies are useful in the evaluation of suspected fatty liver and NASH, a definitive diagnosis may be made only with liver biopsy.
Drug-Induced Chronic Hepatitis
Drug-induced chronic hepatitis constitutes a small but important category of chronic hepatitis. 4a-Methyldopa, nitrofurantoin, and isoniazid are well-recognized causes. In addition, cases have occasionally been reported after therapy with sulfonamides, propylthiouracil, diclofenac, terbinafine, and dantrolene; a number of other drugs have also been implicated. Thus, it is reasonable to discontinue as many medications as possible when chronic hepatitis is first diagnosed. If a patient's hepatitis is drug related, liver function abnormalities and the clinical course of disease frequently improve after the causative agent has been withdrawn, although improvement may take weeks or even months.
Wilson Disease
When neurologic abnormalities are absent, Wilson disease can present as chronic hepatitis. It is critical to establish the diagnosis of Wilson disease because specific treatment with penicillamine, trientine, or zinc is available. In Wilson disease, the serum ceruloplasmin level is low and the 24-hour urinary copper level is elevated. Slit-lamp examination for Kayser-Fleischer rings should also be performed. Measurement of the hepatic copper content in a needle-biopsy specimen is diagnostic.
a1 -Antitrypsin Deficiency
a1 -Antitrypsin deficiency, which is usually associated with the presence of homozygous ZZ alleles, is associated with progressive liver disease, which evolves into cirrhosis. Liver disease associated with a1 -antitrypsin deficiency can be distinguished from chronic hepatitis by a reduced serum a1 -antitrypsin level and by inclusions in the liver parenchyma that are positive on periodic acid-Schiff staining.
Autoimmune HepatitisAIH is characterized by portal and periportal inflammation and fibrosis, autoantibodies, and hypergammaglobulinemia. 5 The early recognition of AIH is important because the condition generally responds well to treatment; if left untreated, it can progress to cirrhosis and, occasionally, liver failure and death.
diagnosis
The diagnosis of AIH rests on the presence of characteristic findings combined with the exclusion of other causes of chronic liver disease. The presentation may be acute or subacute but is more commonly chronic. Other autoimmune diseases may be present concurrently.
Elevated levels of serum aminotransferase transaminase and Y-globulin are typical in AIH. Aminotransferase levels may be slightly elevated or more than 10 times higher than normal. The presence of antinuclear antibody (ANA) or one of the other autoantibodies is common but not invariably present.
A liver biopsy is always useful to establish histologic grading and staging; it is essential in cases in which the diagnosis is not clear on the basis of clinical and laboratory data. Interface hepatitis (formerly called piecemeal necrosis) is the histologic hallmark of AIH; however, this finding is not specific for AIH. The inflammatory component of AIH consists mainly of mononuclear cells; typically, plasma cells are present, but, occasionally, they may not be a prominent feature.
In addition to its diagnostic use, liver biopsy is also an important prognostic tool. Patients with portal or mild periportal hepatitis (i.e., hepatitis that extends outside the limiting plate of the portal tract) generally respond well to therapy, whereas those with bridging necrosis (hepatitis that extends or bridges from one portal tract to another), multilobular necrosis, or cirrhosis respond less well to therapy and are at greater risk for progressive liver disease.
The International Autoimmune Hepatitis Group (IAIHG) has published a diagnostic scoring system for atypical AIH for use in adults when the diagnosis is uncertain. 6 The pretreatment score is based on 12 features, and the posttreatment score includes the response to therapy. A pretreatment score of 10 to 15 signifies probable AIH, whereas a score greater than 15 indicates definite AIH. A posttreatment score of 12 to 17 signifies probable AIH, whereas a score greater than 17 indicates definite AIH.
Disease Types
The wide spectrum of clinical and serologic manifestations of AIH has led investigators to propose several types of AIH. 5,7 The distinctions in type are based on seropositive findings; however, it should be noted that in some cases of AIH, no serologic markers are present (so-called marker negative AIH). All of the proposed serologic types of AIH respond similarly to immunosuppressive therapy. Type 1, or classic, AIH is the most common form of the disease in the United States. It is characterized by hypergammaglobulinemia and the presence of ANA, anti-smooth muscle antibody (ASMA), or both. Type 2 AIH is characterized by the absence of ANA and ASMA and by the presence of antibody to liver-kidney microsome (anti-LKM1); it is much less common than type 1 and has been observed primarily in Europe. Type 3 is the least well characterized form of AIH and is distinguished by the presence of antibody to a soluble liver antigen (anti-SLA), a recently characterized liver/pancreas antigen (anti-LP), or both.
Overlap Syndromes
Overlap syndromes of AIH and either PBC or PSC have been recognized but are uncommon. 8,9 The term autoimmune cholangitis has been proposed to characterize patients who have biochemical or histologic cholestasis that resembles PBC. These patients test negative for AMA and have a normal IgM level; however, they have high titers of ANA and elevated levels of IgG. The results of cholangiography are normal.
treatment
The standard treatment of AIH is immunosuppressive therapy. Three large randomized, controlled trials evaluated immunosuppressive treatment in patients with severe AIH 10-12 ; however, data regarding treatment of patients with mild to moderate AIH are less extensive. The potential benefit of immunosuppressive therapy has to be balanced against the risks, particularly in cases of mild AIH. Most patients who have the clinical, biochemical, and histologic features of AIH should be treated, 5 but treatment may not be appropriate for some patients; for example, patients with advanced cirrhosis and relatively mild abnormalities of serum aminotransferase levels (less than twice the upper limit of normal) are probably not good candidates for such treatment.
The purpose of treatment is to relieve symptoms, decrease hepatic inflammation, and prevent the progression of hepatic fibrosis. The decision whether to initiate treatment can sometimes be problematic, particularly in cases that are atypical (e.g., when test results are negative for all autoantibodies). In such cases, the IAIHG scoring system can be useful in decision making.
Prednisone and Azathioprine Regimens
The usual regimen for most AIH patients consists of a combination of prednisone and azathioprine [ seeTable 3 ]. 5 The starting doses are usually 30 mg of prednisone daily and 50 mg of azathioprine daily. Maintenance doses (until remission is achieved) are usually 20 mg of prednisone daily and 50 to 150 mg of azathioprine daily. Prednisone alone may be used with equal effectiveness; it is administered at a starting dose of 60 mg daily and is tapered over 4 weeks to a maintenance dose of 20 mg daily. Use of azathioprine may not be appropriate in patients who have severe cytopenia (because of the drug's bone marrow suppressive effect), who are pregnant (because of its potential to cause birth defects), or who have active malignancy (because of its potential to interfere with standard cancer treatment regimens). Azathioprine alone will not induce remission, but long-term azathioprine therapy is effective in maintaining remission. 13
Response to Therapy
Clinical, biochemical, and histologic remission occurs in 65% of patients within 18 months and in 80% of patients within 3 years after starting treatment. In general, symptoms resolve (i.e., clinical remission) within 3 months, serum aminotransferase transaminase levels improve to normal or less than twice normal (i.e., biochemical remission) within 3 to 6 months, and histologic improvement (i.e., histologic remission) occurs within 18 months to 3 years. The presence of serum autoimmune markers, such as ANA, does not influence the initial response to therapy. Failure to achieve remission may represent either an incomplete response to therapy or treatment failure. Patients who have an incomplete response to therapy may experience some improvement in clinical, laboratory, and histologic features when adequate therapy is administered. In cases of treatment failure, patients will experience worsening of disease despite adequate doses and compliance with therapy. Drug toxicities that necessitate the reduction of drug doses may contribute to the failure to achieve remission.
Discontinuance of Therapy
It is not clear-cut when to taper medication doses for the purpose of discontinuance of therapy. One commonly used approach is to begin tapering drugs when clinical and biochemical remissions have been achieved. Some authorities recommend a repeat liver biopsy to determine whether histologic remission has been achieved; however, this approach is not routine practice. When prednisone and azathioprine are used in combination, the dose of prednisone is tapered first, whereas that of azathioprine is kept constant at 50 to 150 mg daily. Gradual tapering should occur over several months; however, there is no agreement on the rapidity of the tapering process. Once prednisone is completely discontinued, gradual tapering of azathioprine may begin.
Management of Relapse
Despite every precaution, relapse occurs within 3 to 6 months in approximately 20 to 90% of patients. Relapse is less likely if the histologic findings before tapering show that the hepatic inflammatory activity has completely resolved. If relapse occurs, medication doses should be increased in an attempt to induce remission. Once a patient has a relapse, however, the risk of future relapses is significant.
When a patient has had two or more relapses, a change in treatment approach is warranted 5 ; with a change of medications, lower doses can be used to induce remission. After relapse, the aim of therapy is to keep disease activity as quiescent as possible. An acceptable therapeutic end point is a reduction in the serum aminotransferase transaminase level to two times normal or less. Such a goal may be achieved with prednisone alone or in combination with azathioprine. Between 80 and 90% of patients can be maintained on a daily dosage of 10 mg of prednisone or less. When both drugs are used, the dose of prednisone can be gradually tapered, whereas that of azathioprine is held constant at approximately 2 mg/kg/day; this combination regimen has a success rate in maintaining disease quiescence that is similar to that of prednisone alone. Limited data are available on the use of drugs such as 6-mercaptopurine and mycophenolate mofetil for the treatment of AIH.
Chronic Hepatitis Bepidemiology
Chronic hepatitis B is a major global health care problem: 5% of the world's population, or approximately 350 million persons, are chronically infected. 14,15 In the United States, it is estimated that 1.25 million persons are chronically infected. 14 Approximately 0.2 to 0.5% of the US population is positive for hepatitis B surface antigen (HBsAg); however, chronic HBV infection rates five to 10 times higher have been identified for certain groups, including Asian Americans, immigrants from endemic areas, persons who have received multiple blood transfusions or hemodialysis, intravenous drug users, men who have sex with men, and persons with HIV infection. Age at the time of initial HBV infection is the major determinant of chronicity. As many as 90% of infected neonates develop chronic infection; however, only 3 to 5% of newly infected adults develop chronic infection. Another important risk factor for chronicity is the presence of intrinsic or iatrogenic immunosuppression. Gender is also a well-established but poorly understood determinant of chronicity; women are more likely than men to clear HBsAg. As a result, men predominate in all populations with chronic HBV infection.
Ongoing HBV infection is an important risk factor for the development of hepatocellular carcinoma (HCC). The relative risk of HCC may be 200 times higher in patients with chronic HBV infection than in the general population. Patients with advanced fibrosis and cirrhosis are at highest risk. Evidence suggests that the use of screening tests, including ultrasonography and serum a-fetoprotein, may be useful in the early diagnosis of HCC. 14,16
diagnosis
Chronic HBV infection can be readily diagnosed with serologic testing [ seeTable 4 ]. The diagnosis of chronic HBV infection is made when HBsAg remains detectable for more than 6 months. In a small percentage of patients with chronic HBV infection, mainly those who are inactive HBsAg carriers (i.e., 1 to 2% of patients a year), HBsAg clears spontaneously.
Categories of Hepatitis Infection
There are two broad categories of chronic HBV infection. The terminology to describe these states varies; the American Association for the Study of Liver Disease (AASLD) practice guidelines refer to these categories as the inactive carrier state and chronic hepatitis B. 14,15 A person who is positive for HBsAg, has normal aminotransferase levels, and has little or no necroinflammatory hepatic activity is an inactive HBsAg carrier. In inactive HBsAg carriers, the serum HBV DNA usually is relatively low (< 2x10 4 IU/mL). However, in some inactive carriers, the serum HBV DNA may be much higher (often in the range of 10 6 to 10 10 IU/mL), and this has been termed the immune-tolerant state. The immune-tolerant state is most characteristic of patients who were infected perinatally, most commonly in southern Asia.
The other broad disease category defined by AASLD practice guidelines is chronic hepatitis B. A person who is positive for HBsAg, has elevated aminotransferase levels, and has significant necroinflammatory hepatic activity is classified as having chronic hepatitis B. In patients with chronic hepatitis B, the serum HBV DNA usually is relatively high (> 10 5 IU/mL, often > 10 6 -10 8 IU/mL). In chronic hepatitis B, the HBeAg is usually positive (and anti-HBe negative); however, there is an increasing prevalence of HBeAg-negative disease. HBeAg is negative in patients with chronic hepatitis B because of a genetic mutation in the HBV DNA genome affecting the production of HBeAg. Chronic hepatitis B is therefore subdivided into HBeAg-positive and HBeAg-negative disease. Typically, HBV DNA levels are somewhat lower in HBeAg-negative disease, and seroconversion from HBeAg to anti-HBe cannot be used as an end point for therapy in these patients.
Treatment
The ultimate goal of treatment of chronic hepatitis B is to eradicate HBV infection and prevent the development of cirrhosis or HCC. Interferon, lamivudine, adefovir dipivoxil, entecavir, and telbivudine [ seeTable 5 ] can all suppress HBV replication and lead to improvement in the clinical, biochemical, and histologic features of chronic hepatitis B. 14,15 The oral agents are well tolerated. Interferon has a number of potential side effects, and careful consideration must be given to its use.
All patients with chronic hepatitis B should be considered for treatment. 17 In the majority of patients who are not considered suitable candidates for therapy, the severity of disease will be deemed too mild to warrant treatment. The most severely decompensated cirrhotic patients should be treated with an oral agent because of their extremely good tolerability. In the past, lamivudine was used commonly in these patients but is now used less and less because of its high rate of resistance development. For those without severely decompensated cirrhosis, the decision whether to use interferon or oral therapy is based on a variety of factors, not the least of which is patient preference. In practice, oral agents are used far more commonly than interferon. Oral therapy is very well tolerated; however, it typically requires several years of treatment to achieve a seroconversion rate comparable to that which can be achieved by interferon therapy in 6 to 9 months. On the other hand, interferon therapy has many more potential side effects and is considerably more expensive. Generally, interferon treatment is appropriate only for those patients able to tolerate its potentially adverse effects. If interferon therapy fails, subsequent oral therapy can be used.
Terminology Used in Describing Response to Treatment
In HBeAg-positive chronic hepatitis B, the term seroconversion indicates the loss of HBeAg and the appearance of anti-HBe. Seroconversion from HBsAg to anti-HBs can also occur, either spontaneously or after interferon treatment. Response to treatment can be (1) biochemical, as evidenced by the normalization of ALT levels; (2) virologic, as evidenced by a marked decrease in HBV DNA levels (< 2x10 4 IU/mL); or (3) histologic, as evidenced by improvement in or resolution of hepatic necroinflammatory activity. Such responses may be seen either during therapy or after therapy has been stopped. The response to treatment is considered a sustained response if remission is maintained for at least 6 months posttreatment.
Interferon Therapy
Therapy with standard interferon has been most extensively studied; however, pegylated interferon (interferon alfa-2a and alfa-2b) is being used increasingly in clinical practice because of its once-weekly administration and seroconversion rates that are as good as or better than those of standard interferon regimens. Having said that, oral agents are used far more commonly for chronic hepatitis B in clinical practice.
A large number of trials have demonstrated the efficacy of interferon alfa in the treatment of HBeAg-positive chronic hepatitis B. 14 Doses of interferon alfa have been in the range of 5 million units daily to 10 million units three times a week. Treatment for 16 to 24 weeks results in seroconversion from HBeAg to anti-HBe, a low HBV DNA replicative state in about 35% of patients, and loss of HBsAg and the appearance of anti-HBs in approximately 8% of patients. 17 Predictors of a response to interferon therapy include lower pretreatment HBV DNA levels, higher ALT levels (optimally greater than five times the upper limit of normal), and short duration of infection; patients with such characteristics are optimal candidates for treatment with interferon. Relapse and reappearance of HBeAg occur in about 20% of patients. Patients who fail to seroconvert on interferon therapy should be treated with oral agents. It should be noted that interferon therapy is not equally effective in Asian patients, particularly in those whose ALT levels are only minimally elevated.
Patients with mildly decompensated cirrhosis can be treated with low, titrated doses of interferon, although the safety and tolerability of the available oral agents make these oral drugs the first choice for treatment. One third of such patients will respond to therapy and have a sustained loss of HBV DNA and HBeAg (if initially HBeAg positive), which may be associated with resolution of cirrhotic symptoms. These patients must be monitored closely, however, because bacterial infections and exacerbation of hepatitis are potentially serious complications.
Interferon treatment of HBeAg-negative chronic hepatitis B is less well studied. After 12 months of treatment, a sustained response (normalization of ALT levels and low levels of HBV DNA) can be achieved in about 15 to 30% of patients. 17,18
The use of pegylated interferon was recently examined in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. 19,20 In one study, 194 HBeAg-positive patients were randomized to receive 24 weeks of therapy with 90, 180, or 270 µg of pegylated interferon alfa-2a once a week or with standard interferon alfa-2a, 4.5 mIU, three times a week. 19 At the 24-weeks follow-up, the HBeAg seroconversion rates were 37%, 35%, and 29%, respectively, for the three pegylated interferon alfa-2a treatment groups and 25% for the standard-interferon group. In another study of HBeAg-negative chronic hepatitis B, 537 patients were randomized to receive 48 weeks of therapy with 180 µg of pegylated interferon alfa-2a; lamivudine, 100 mg daily; or the two regimens combined. 20 At 24 weeks after cessation of therapy, the rates of biochemical and virologic remission were significantly higher in the groups receiving pegylated interferon; the addition of lamivudine did not improve the response rate. The combination of pegylated interferon with lamivudine or other oral agents continues to be studied, but data suggest that such combination therapy does not offer advantages over montherapy. 21
Side effects of interferon therapy Interferon commonly causes side effects, but these are usually manageable. Among these are influenzalike symptoms (i.e., fever, myalgia, arthralgia, and headache), hematologic toxicity (i.e., granulocytopenia, leukopenia, and thrombocytopenia), systemic symptoms (i.e., fatigue and hair thinning), neurologic signs (i.e., decreased concentration, depression, and irritability), and thyroid dysfunction.
Contraindications to interferon therapy Patients with a history of hypersensitivity to interferon, decompensated cirrhosis, immunosuppression associated with organ transplantation, active autoimmune disease, or severe psychiatric disease or patients who are elderly or frail are not good candidates for treatment.
Lamivudine Therapy
Lamivudine is a nucleoside analogue that inhibits HBV DNA synthesis. A dose of 100 mg/day achieves maximal suppression of HBV DNA. Lamivudine is cleared mainly in urine; thus, dose adjustments are required for patients with impaired renal function, and this also applies to the other oral agents. It has few side effects and could be considered for use in virtually any patient with chronic hepatitis B. 14 Lamivudine is being used less commonly because of a high rate of resistance development and the availability of more potent agents, such as entecavir.
Lamivudine and HBeAg-positive chronic hepatitis B In three placebo-controlled studies, improved liver histology occurred in a significantly higher percentage of patients given lamivudine than in patients who received placebo. 22-24 Improvements in liver histology were similar in treatment-naive patients and patients who experienced relapse after interferon therapy or who did not respond to it; the improvements occurred independently of HBeAg seroconversion. 25,26 Serum HBV DNA levels fell rapidly and remained at least 94% below baseline values; serum ALT levels also decreased during therapy, with 50% of patients achieving and maintaining normal ALT levels 2 years posttreatment. Patients receiving lamivudine for 1 year experienced a 17% rate of seroconversion from HBeAg to anti-HBe. The seroconversion rate increased progressively with additional years of lamivudine therapy, resulting in 27% seroconversion after 2 years, 33% after 3 years, 47% after 4 years, and 50% after 5 years. 27-30 The cumulative HBeAg seroconversion rate was higher in patients who had elevated baseline ALT levels before treatment. The responses to lamivudine are similar in Asian and non-Asian patients; however, the durability of HBeAg seroconversion appears to be lower in Asian patients (i.e., 60 to 80%). Patients who achieve HBeAg seroconversion can discontinue lamivudine therapy. However, on the basis of limited data, relapse rates may be lower (i.e., seroconversion is more durable) if lamivudine is continued for 3 to 6 months after the initial HBeAg seroconversion is documented. The serum levels of ALT and HBV DNA return to pretreatment levels if lamivudine is discontinued before HBeAg seroconversion is achieved. After treatment, some patients may experience serum ALT levels that are transiently higher than pretreatment levels. Generally, no adverse effects have been associated with these elevations, although there are rare reports of severe flares of hepatitis B.
Lamivudine and HBeAg-negative chronic hepatitis B Lamivudine is effective in lowering ALT and HBV DNA levels and improving hepatic histology in patients with HBeAg-negative chronic hepatitis B. Several studies have demonstrated a biochemical and virologic response rate of about 70% at 1 year of therapy 14,17 ; however, this response rate decreases to 50% after 2 years and 40% after 3 years. The end point for treatment is unknown, but it is the consensus that treatment beyond 1 year is warranted, provided that the patient continues to exhibit a response. 15 The relapse rate after discontinuance of therapy is much higher in these patients than in patients with HBeAg-positive chronic hepatitis B.
Viral resistance to lamivudine therapy Resistant strains of HBV may appear within the first year of lamivudine therapy. The frequent emergence of resistance and the availability of more potent oral agents such as entecavir are the reasons why lamivudine is being used less often. The most common mutation imparting resistance occurs near the YMDD (the amino acid sequence tyrosine-methionine-aspartate-aspartate) motif of the HBV DNA polymerase. Resistance to lamivudine therapy occurs in 14 to 32% of patients after 1 year of therapy, 38% after 2 years, 49% after 3 years, 66% after 4 years, and 69% after 5 years. 30 The appearance of lamivudine resistance is manifested by rising HBV DNA and serum aminotransferase transaminase levels. A serologic test detecting HBV DNA mutations imparting lamivudine resistance is available. Generally, patients with lamivudine resistance can be switched to another oral agent, such as entecavir or adefovir. Alternatively, a second oral agent, such as those just mentioned, can be added. Which treatment regimen is optimal for patients with lamivudine resistance is being studied extensively. Similarly, for resistance to the other oral agents, whether to add or substitute another oral agent is the subject of ongoing investigation.
Lamivudine and end-stage liver disease Lamivudine and the other oral agents play a role in patients with chronic hepatitis B who have end-stage liver disease. Stabilization of and even improvement in the biochemical and clinical features of cirrhosis may be seen in a majority of patients. Occasionally, improvement in liver function may result in deferral of liver transplantation. 17,31,32 Such therapy may serve as a bridge to transplantation for patients with decompensated cirrhosis who are awaiting a donor liver. Lamivudine is being used less often in this type of patient because of its high rate of resistance development; adefovir and entecavir, although less well studied in this context, are being used more often.
Lamivudine and liver transplantation Liver transplantation can be performed for liver failure associated with chronic hepatitis B, but HBV infects the allograft in 80 to 100% of cases if antiviral prophylaxis is not given, and long-term graft survival is only 45 to 50% (compared with 80 to 85% in liver transplant patients with other types of cirrhosis). 32 The HBV reinfection often is accelerated and progresses to cirrhosis. As a result, most transplant centers now implement prophylactic antiviral strategies to reduce reinfection. Before undergoing transplantation, patients should be treated with either lamivudine or another oral agent to reduce the HBV viral load. Subsequently, two prophylaxis strategies are (1) the intraoperative, immediately postoperative, and long-term administration of high-dose hepatitis B immune globulin (HBIG) to maintain an anti-HBs level at 100 to 200 mIU/mL or greater and (2) the administration of HBIG in combination with an oral agent. 32 A number of trials suggest that these prophylaxis strategies can reduce the HBV reinfection rate to 10 to 20% and improve 1-year and 3-year graft survival rates.
Adefovir Dipivoxil Therapy
Adefovir dipivoxil is a nucleotide analogue of adenosine monophosphate. Adefovir inhibits HBV DNA polymerase and reverse transcriptase. It is effective against both wild-type and lamivudine-resistant HBV and in both HBeAg-positive and HBeAg-negative chronic hepatitis B. 14,15 Typically, adefovir therapy results in a 3 to 4 log 10 drop in serum HBV DNA levels.
In a randomized study involving 515 patients who had HBeAg-positive chronic hepatitis B, treatment with adefovir 10 mg daily for 48 weeks resulted in a 12% HBeAg seroconversion rate. 33 As with lamivudine, the rate of treatment response is higher in patients who have higher pretreatment ALT values. The HBeAg seroconversion rate increases after 2 or more years of therapy. Adefovir may result in a minor rise in serum creatinine; therefore, it is prudent to periodically monitor creatinine in patients receiving adefovir therapy.
Adefovir therapy in patients with HBeAg-negative chronic hepatitis B results in about a 46% biochemical and virologic response rate after 48 weeks and a 51% response rate after 96 weeks. If therapy is stopped after 48 weeks, relapse occurs in more than 90% of patients. 34,35 Development of drug resistance is somewhat less of a problem with adefovir than with lamivudine. Resistance to adefovir is seen in about 29% of patients after 5 years.
Entecavir Therapy
Entecavir was approved by the Food and Drug Administration (FDA) in early 2005 for use in the treatment of chronic hepatitis B. The efficacy of entecavir (at a daily dose of 0.5 mg orally daily) is superior to that of lamivudine in previously untreated HbeAg-positive and -negative patients. After 1 year of treatment, about 67% of HBeAg-positive and 90% of HBeAg-negative patients have undetectable HBV DNA. It is also effective, at a dose of 1 mg orally daily, in patients who develop lamivudine resistance. Resistance to entecavir occurs in about 1% of patients after 3 to 4 years of therapy in patients not previously resistant to lamivudine. Resistance to subsequent entecavir therapy develops in about 39% of lamivudine-resistant patients after 4 years.
Telbivudine Therapy
Telbivudine was approved by the FDA in late 2006. It is used at a dose of 600 mg daily. It is more potent than lamivudine in both HbeAg-positive and -negative patients, with 60% of HBeAg-positive and 88% of HBeAg-negative patients having undetectable HBV DNA after 1 year of therapy. HBeAg seroconversion occurs in about 22% of patients after 1 year of therapy. Drug resistance occurs in about 20% after 2 years.
Tenofovir Therapy under Investigation
Tenofovir has been approved by the FDA for treatment of HIV infection. Its use in the treatment of chronic hepatitis B is being evaluated. Tenofovir has potent activity in serum suppressing HBV DNA levels. It is possible that tenofovir will be approved by the FDA for treatment of hepatitis B in the near future. The combination of tenofovir and emtricitabine in a single pill (Truvada), which is used to treat HIV, is also being studied for chronic hepatitis B and shows promise.
management of hbv reactivation
In some inactive HBsAg carriers (rarely even patients who are anti-HBc positive only), biochemical, clinical, and histologic exacerbations of disease activity have been noted; such exacerbations are characterized by elevated serum aminotransferase transaminase levels, the presence of HBV DNA, and the reversion from anti-HBe to HBeAg. These exacerbations (so-called reactivations) appear spontaneously in about 20% of inactive HBsAg carriers. Repeated reactivations, which are usually asymptomatic, may occur and may lead to progressive fibrosis. Therefore, even inactive HBsAg carriers should be periodically monitored (i.e., every 6 to 12 months) for resurgence of disease activity.
Reactivation may also occur in patients with malignancy during or after cessation of chemotherapy, especially when the chemotherapy regimens include corticosteroids. It is important to be aware of such a possibility because reactivations in these patients, although generally mild, may at times be severe and even fatal. It is prudent to check patients scheduled for chemotherapy for the presence of HBsAg or anti-HBc prior to initiating chemotherapy. Preemptive therapy with lamivudine in patients with malignancy has been found to decrease the incidence and severity of reactivations. 36,37 Lamivudine or another oral therapy should be strongly considered in inactive-HBsAg-carrier patients who are scheduled to have chemotherapy. Patients with chronic hepatitis B who are scheduled to have chemotherapy would presumably already be receiving an oral agent; if not, they should be started on an oral agent before initiation of chemotherapy.
Chronic Hepatitis Cepidemiology
Approximately 30,000 new cases of acute HCV infection are reported annually to the Centers for Disease Control and Prevention. Of these patients, about 80% develop chronic HCV infection. 38 Approximately four million persons in the United States (1.8%) have been infected with HCV, and 74% of these individuals (1.4% of the population) are viremic. The high chronicity rate of HCV infection makes chronic hepatitis C a much more prevalent disease than chronic hepatitis B (0.2 to 0.5% of the general population).
diagnosis
The diagnosis of chronic hepatitis C is typically made by a positive anti-HCV on enzyme-linked immunosorbent assay and detectable HCV RNA. 38 Serum aminotransferase transaminase levels are usually elevated, but about 20% of patients have persistently normal values. Most infected patients are asymptomatic. Liver biopsy may demonstrate the full spectrum of disease severity, ranging from mild portal tract inflammation and no fibrosis to cirrhosis.
natural history
After the onset of acute HCV infection, the infection resolves in 15 to 30% of patients and there is a loss of HCV RNA, although anti-HCV remains detectable. The natural history of chronic hepatitis C typically spans several decades. In general, liver disease progresses insidiously, and cirrhosis may not develop for two or more decades, if ever. The natural history may be more prolonged when HCV infection occurs earlier in life. In a Japanese study, the mean interval from blood transfusion to development of chronic hepatitis was 10 years; to development of cirrhosis, 21 years; and to development of HCC (a late risk), 29 years. 39 Similar results were found in a population of patients seen in a referral liver center in the United States: the mean interval from transfusion to cirrhosis was 21 years, and for progression to HCC, the mean interval was 28 years. 40
In a European study designed to examine the natural progression of hepatic fibrosis in patients with chronic hepatitis C, the median interval from the presumed time of infection to cirrhosis, identified by liver biopsy, was 30 years. 41 The rate of progression to fibrosis and cirrhosis was not normally distributed; findings suggested at least three populations of patients with chronic hepatitis C: those with rapid progression of fibrosis (median time to cirrhosis < 30 years), those with intermediate progression, and those with no or slow progression of fibrosis. Independent factors associated with an increased rate of progression to cirrhosis are age greater than 40 years at the time of infection, daily alcohol consumption of 50 g or more, and male gender. Fibrosis progression is not related to HCV RNA level or HCV genotype.
treatment
The decision whether or not to treat a patient with chronic hepatitis C involves consideration of a variety of factors, especially important is the presence of any comorbid illnesses, and an extensive discussion with the patient regarding the pros and cons of treatment. The goal of therapy is to eradicate the virus and prevent the progression of fibrosis and the development of cirrhotic complications. In many cases, the physician and the patient may mutually decide to monitor the disease rather than to treat it, such as if the stage of fibrosis is mild and the patient elderly. Treatment should be undertaken only if the potential benefits of therapy are thought to outweigh the possible risks. The standard of care for chronic hepatitis C involves the use of pegylated interferon (interferon alfa-2a or alfa-2b) in combination with ribavirin [ seeTable 6 ]. 38 Polyethylene glycol is a water-soluble polymer that is covalently linked to interferon, which markedly increases the half-life, resulting in sustained serum levels and allowing once-weekly administration. Combination therapy with standard (nonpegylated) interferon and ribavirin is still used, but very infrequently. In patients with certain comorbid conditions, monotherapy with interferon (either a pegylated or standard form) is advised because of the risk of severe anemia associated with ribavirin use [ see Side Effects of Combination Therapy, below ], but the expected success rates are significantly lower.
Pegylated Interferon and Ribavirin Therapy
The persistence of undetectable HCV RNA for 6 months or more after cessation of therapy is the definition of a sustained virologic response (SVR). The major pretreatment determinant of response is HCV genotype. 38 Patients infected with HCV genotype 1 virus (the most common genotype in the United States) have lower SVR rates (in the range of 40 to 45%) than patients with HCV genotypes 2 and 3 (in the range of 75 to 85%). There are varying responses to treatment of HCV genotypes 4, 5, and 6.
Varying study designs and ribavirin doses have been used to evaluate the efficacy of pegylated interferon (interferon alfa-2a and alfa-2b) and ribavirin combination therapy. Therefore, results of treatment have been reported that often do not reflect comparable treatment regimens, particularly with regard to ribavirin doses. Some studies have used a fixed dose of ribavirin, whereas others have used doses based on weight. 38,42,43 Despite these differences, SVR rates for patients with HCV genotypes 1, 2, and 3 have been similar using either interferon alfa-2a or interferon alfa-2b, plus ribavirin at varying doses.
One randomized, double-blind trial clearly addressed the issues of length of therapy and ribavirin doses. 44 In that study, 1,284 patients with HCV genotypes 1, 2, and 3 were randomized to receive pegylated interferon alfa-2a (180 µg/wk) in combination with ribavirin in either a low-dose (800 mg/day) or a standard weight-based dose (1,000 or 1,200 mg/day) for 24 or 48 weeks. The SVR for HCV genotype 1 patients was 52% after 48 weeks of treatment using the regimen with 1,000 to 1,200 mg of ribavirin daily versus 41% using the 800 mg ribavirin daily dose; the SVR rates for 24 weeks of treatment were much lower. The SVRs for patients with HCV genotypes 2 and 3 were similar, ranging from 79 to 84%, regardless of which treatment regimen was used. On the basis of the study's findings, 24 weeks of treatment with pegylated interferon and ribavirin at a dosage of 800 mg daily (which resulted in an SVR of 84%) is sufficient to achieve an optimal SVR in patients with HCV genotype 2 or 3. However, patients with HCV genotype 1 must be treated for 48 weeks using pegylated interferon and ribavirin at a dosage of 1,000 to 1,200 mg daily to achieve an optimal SVR. This and other studies have led to the practice of administering treatment for 48 weeks to patients with genotype 1 and for 24 weeks to those with genotype 2 or 3 [ seeTable 6 ]. Among factors shown to lessen the likelihood of successful therapy are high viral load (> 6-8x10 5 IU/mL), male gender, African-American ethnicity, long duration of infection, and advanced fibrosis.
Early virologic response Because pegylated interferon and ribavirin combination therapy has many side effects, strategies (so-called stopping rules) have been studied to determine whether continuation of treatment after an early virologic response (EVR) will likely result in an SVR. 45,46 Such studies have mostly centered on patients with HCV genotype 1 because the standard treatment length is longer and the SVR rates are lower for genotype 1 than for genotypes 2 and 3. The values of HCV RNA at two time points (12 and 24 weeks) have been closely examined. If a patient with HCV genotype 1 does not achieve an undetectable level of HCV RNA after 24 weeks of treatment (generally using an HCV RNA assay with a lower detection limit of 50 IU/mL), the chance of achieving a SVR with another 24 weeks of treatment is extremely low (i.e., in the range of 1% or less). It is strongly recommended that treatment be halted in such patients, unless individual circumstances dictate otherwise.
Another focus is on the 12-week HCV RNA value and the negative predictive value for achieving an SVR based on a decline in HCV RNA, compared with the pretreatment value. For HCV genotype 1 patients, failure to achieve a drop of 2 log 10 or greater in HCV RNA value after 12 weeks of treatment has a negative predictive value of approximately 97 to 100% for achieving SVR after a full course of 48 weeks of treatment. Clinical judgment must be used in deciding whether to discontinue therapy after failure to achieve a 12-week SVR. The value of determining a 12-week EVR in patients who have HCV genotype 2 or 3 is unclear because virtually all of these patients achieve such a response at 12 weeks.
Rapid virologic response More recently, the utility of determination of HCV RNA values after 4 weeks of therapy has been examined. The achievement of an undetectable HCV RNA value in genotype 1 patients after 4 weeks has been termed a rapid viral response (RVR). An RVR has a very high positive predictive value for achieving an SVR, approximately 90%. Only about 10% of patients achieve an RVR, so failure to achieve an RVR cannot be used as a stopping rule for treatment. In genotype 2 and 3 patients, about 90% achieve an RVR by this criterion, so an RVR is not as useful as a predictor.
Side effects of combination therapy Side effects are varied and common with interferon and ribavirin combination therapy 38,47 and may necessitate discontinuance of therapy in 10 to 15% of patients. The major side effect of ribavirin is a dose-dependent hemolytic anemia, which is reversible and usually stabilizes after 6 weeks of treatment. For milder degrees of anemia, the ribavirin dose can be temporarily decreased. If the anemia is not corrected by a reduction in the ribavirin dose, epoetin can be used. If severe anemia develops, ribavirin must be discontinued, either temporarily or permanently, but such discontinuation may adversely affect the likelihood of an SVR, depending on how much of the cumulative goal dose of ribavirin has been taken.
Patients with preexisting moderate to severe anemia usually cannot tolerate the degree of hemolysis that occurs with ribavirin therapy, which can be dangerous. Moreover, patients with cardiovascular disease are particularly at risk should severe anemia develop during therapy, and very careful consideration would have to be given to the decision to initiate interferon monotherapy because of the drug's side effects. Patients with any degree of symptomatic cardiovascular disease are not candidates for therapy. Patients with chronic hepatitis C and comorbid conditions preventing the use of ribavirin can be treated with interferon monotherapy, although this treatment has an SVR rate considerably lower than that of combination therapy. Ribavirin is teratogenic; therefore, patients must be advised against its use during pregnancy. Other side effects attributed to ribavirin are rash and nasal or sinus problems.
Interferon can cause or exacerbate depression and other psychiatric symptoms. Caution is warranted in using interferon therapy for patients with depression; however, these patients can often be managed with antidepressants, with or without a reduction in interferon dosage. Interferon has many other potential side effects, including leukopenia and thrombocytopenia, thyroid dysfunction, insomnia, hair thinning, headaches, weight loss, various neurologic dysfunctions, and irritability. Deaths have occurred, usually because of sepsis, suicide, or cardiovascular disease.
Sustained virologic response In 5- to 10-year follow-up studies of patients who had an initial posttreatment 6-month SVR, relapse occurred in 1 to 2% of patients. 48 Following an SVR, there is usually an improvement in liver histology, including significant regression of hepatic fibrosis in about 25% of patients. Interferon therapy may delay or prevent liver decompensation resulting from cirrhosis, as well as the development of HCC, particularly in patients who show a sustained response. 49
Relapse after Treatment
Relapse after a course of therapy is defined by detectable levels of HCV RNA, which were undetectable during treatment. Relapse, if it is going to occur, almost always occurs within the first 6 months after treatment. No effective treatment is available to patients in whom relapse occurs after the standard regimen of pegylated interferon and ribavirin.
Nonresponse to Therapy
Nonresponse to antiviral therapy is generally defined as a detectable serum HCV RNA level after 24 weeks of therapy. Nonresponse can also be defined as failure to achieve a 2 log 10 or greater drop in HCV RNA after 12 weeks of therapy for genotype 1 patients. A variant of nonresponse, called breakthrough, is characterized by an initial disappearance of HCV RNA, with subsequent reappearance of HCV RNA while the patient is still being treated. No effective treatments are available for patients who experience a nonresponse to current therapy.
Liver Transplantation
Cirrhosis caused by chronic hepatitis C is the most common indication for liver transplantation. Although HCV reinfects the allograft in nearly all cases, the subsequent illness can be mild. However, a small but significant percentage of cases progress to cirrhosis and liver failure. There is no consensus of opinion regarding guidelines for treatment of chronic hepatitis C after liver transplantation. 38 Posttransplant treatment is more difficult because of more severe cytopenia and other issues related to immunosuppression.
The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter. The drugs pegylated interferon alfa-2a, pegylated interferon alfa-2b, and azathioprine have not been approved by the FDA for the uses described in this chapter.
References1.Desmet VJ, Gerber M, Hoofnagle JH: Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 199419:1513, . [PMID 8188183]
2.Brunt EM: Grading and staging the histopathological lesions of chronic hepatitis: the Knodell histology activity index and beyond. Hepatology 200031:241, . [PMID 10613753]
3.Bedossa P, Poynard T: An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 199624:289, . [PMID 8690394]
4.Lee WM: Drug-induced hepatotoxicity. N Engl J Med 2003349:474, . [PMID 12890847]
5.Czaja AJ, Freese DK: Diagnosis and treatment of autoimmune hepatitis. AASLD Practice Guidelines. Hepatology 200236:479, . [PMID 12143059]
6.Alvarez F, Berg PA, Bianchi FB: Review of criteria for diagnosis of autoimmune hepatitis. International Autoimmune Hepatitis Group report. J Hepatol 199931:929, . [PMID 10580593]
7.Czaja AJ, Manns MP: The validity and importance of subtypes of autoimmune hepatitis: a point of view. Am J Gastroenterol 199590:1206, . [PMID 7639216]
8.Czaja AJ: Frequency and nature of the variant syndromes of autoimmune liver disease. Hepatology 199828:360, . [PMID 9695997]
9.Ben-Ari Z, Czaja AJ: Autoimmune hepatitis and its variant syndromes. Gut 200149:589, . [PMID 11559660]
10.Soloway RD, Summerskill WHJ, Baggenstoss AH: Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled trial of treatments and early prognosis. Gastroenterology 197263:820, . [PMID 4538724]
11.Murray-Lyon IM, Stern RB, Williams R: Controlled trial of prednisone and azathioprine in active chronic hepatitis. Lancet 19731:735, . [PMID 4121073]
12.Cook CG, Mulligan R, Sherlock S: Controlled prospective trial of corticosteroid therapy in active chonic hepatitis. Q J Med 197140:159, . [PMID 4933363]
13.Johnson PJ, McFarlane IG, Williams R: Azathioprine for long-term maintenance of remission in autoimmune hepatitis. N Engl J Med 1995333:958, . [PMID 7666914]
14.Lok ASF, McMahon BJ: Chronic hepatitis B. AASLD Practice Guidelines. Hepatology 200134:1225, . [PMID 11732013]
15.Lok ASF, McMahon BJ: Chronic hepatitis B: update of recommendations. AASLD Practice Guidelines. Hepatology 200439:1, . [PMID 14752813]
16.McMahon BJ, Bulkow L, Harpster A: Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study. Hepatology 200032:842, . [PMID 11003632]
17.Keefe EB, Dietrich DT, Han S-HB: A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol 20042:87, [PMID 15017613]
18.Manesis EK, Hadziyannis SJ: Interferon alpha treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B. Gastroenterology 2001121:101, . [PMID 11438498]
19.Cooksley W, Piratvisuth T, Lee SD: Peginterferon alfa-2a (40 Kda): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepatitis 200310:298, .
20.Marcellin P, Lau GK, Bonino F: Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004351:1206, . [PMID 15371578]
21.Chan HL, Leung NW, Hui AY: A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med 2005142:240, . [PMID 15710957]
22.Dienstag JL, Schiff ER, Wright TL: Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999341:1256, . [PMID 10528035]
23.Lai CL, Chien RN, Leung NW: A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med 1998339:61, . [PMID 9654535]
24.Schalm SW, Heathcote J, Cianciara J: Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomized trial. Gut 200046:562, . [PMID 10716688]
25.Honkoop P, de Man RA, Zondervan PE: Histological improvement in patients with chronic hepatitis B virus infection treated with lamivudine. Liver 199717:103, . [PMID 9138281]
26.Suzuki Y, Kumada H, Ikeda K: Histological changes in liver biopsies after one year of lamivudine treatment in patients with chronic hepatitis B infection. J Hepatol 199930:743, . [PMID 10365796]
27.Liaw YF, Leung NWY, Chang TT: Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Gastroenterology 2000119:172, . [PMID 10889166]
28.Leung NWY, Lai CL, Chang TT: Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. Hepatology 200133:1527, . [PMID 11391543]
29.Chang TT, Lai CL, Liaw YF: Incremental increases in HBeAg seroconversion and continued ALT normalization in Asian chronic HBV (CHB) patients treated with lamivudine for four years. Antiviral Ther 200016 Suppl 1:44, .
30.Guan R, Lai CL, Liaw YF: Efficacy and safety of 5-years lamivudune treatment of Chinese patients with chronic hepatitis B. J Gastroenterol Hepatol 200116:A60, .
31.Villeneuve JP, Condreay LD, Willems B: Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B. Hepatology 200031:207, . [PMID 10613747]
32.Keeffe EB: End-stage liver disease and liver transplantation: role of lamivudine therapy in patients with chronic hepatitis B. J Med Virol 200061:403, . [PMID 10861654]
33.Marcellin P, Chang TT, Lim SG: Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003348:808, . [PMID 12606735]
34.Hadziyannis SJ, Tassopoulos N, Heathcote EJ: Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003348:800, . [PMID 12606734]
35.Hadziyannis SJ, Tassopoulos N, Heathcote EJ: Two year results from a double-blind, randomized, placebo-controlled study of adefovir dipivoxil (ADV) for presumed precore mutant chronic hepatitis B. J Hepatol 200338:143, .
36.Lau GKK, He ML, Fong DYT: Preemptive use of lamivudine reduces hepatitis B exacerbation after allogenic hematopoietic cell transplantation. Hepatology 200236:702, . [PMID 12198664]
37.Rossi G, Pelizzari A, Motta M: Primary prophylaxis with lamivudine of hepatitis B reactivation in chronic HBsAg carriers with lymphoid malignancies treated with chemotherapy. Br J Haematol 2001115:58, . [PMID 11722410]
38.Strader DB, Wright T, Thomas DL: Diagnosis, management, and treatment of hepatitis C. AASLD Practice Guideline. Hepatology 200439:1147, . [PMID 15057920]
39.Kiyosawa K, Sodeyama T, Tanaka E: Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology 199012:671, . [PMID 2170265]
40.Tong MJ, El-Farra NS, Reikes AR: Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med 1995332:1463, . [PMID 7739682]
41.Poynard T, Bedossa P, Opolon P: Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet 1997349:825, . [PMID 9121257]
42.Fried MW, Shiffman ML, Reddy KR: Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection. N Engl J Med 2002347:975, . [PMID 12324553]
43.Manns MP, McHutchison JG, Gordon SC: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001358:958, . [PMID 11583749]
44.Hadziyannis SJ, Sette H, Morgan TR: Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004140:346, . [PMID 14996676]
45.Russo MW, Fried MW: Hepatitis C therapy: guidelines for stopping therapy. Curr Gastroenterol Rep 20046:17, . [PMID 14720449]
46.Davis GL, Wong JB, McHutchison JG: Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 200338:645, . [PMID 12939591]
47.Russo MW, Fried MW: Side effects of therapy for chronic hepatitis C. Gastroenterology 2003124:1711, . [PMID 12761728]
48.Lau DTY, Kleiner DE, Ghany MG: 10-Year follow-up after interferon-alpha therapy for chronic hepatitis C. Hepatology 199828:1121, . [PMID 9755252]
49.Yoshida H, Shiratori Y, Moriyama M: Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan: IHIT Study Group: inhibition of hepatocarcinogenesis by interferon therapy. Ann Intern Med 1999131:174, . [PMID 10428733]
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