JAC Advance Access originally published online on April 4, 2006
Journal of Antimicrobial Chemotherapy 2006 57(6):1030-1034; doi:10.1093/jac/dkl123
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Leading articles |
Antiviral options for the treatment of chronic hepatitis B
1 Division of Infectious Diseases, Emory University School of Medicine Atlanta, GA, USA 2 Division of Gastroenterology, University of Michigan Medical Center 1500 E. Medical Center Drive, 3912 Taubman Center, Ann Arbor, MI 48109-0362, USA
*Corresponding author. Tel: +1-734-615-4628; Fax: +1-734-936-7392; E-mail: aslok{at}med.umich.edu
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Abstract |
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 Top Abstract IntroductionGoals of treatmentSelection of patients for...Choice of treatmentConclusionsTransparency declarationsReferences |
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Hepatitis B virus (HBV) is an important cause of end-stage liver disease and hepatocellular carcinoma. Effective treatment can delay or prevent these outcomes. The decision to treat is based on the activity of liver disease and HBV replication status, and the likelihood of a long-term benefit. Approved therapies include standard and pegylated interferon-alfa and nucleoside analogues: lamivudine, adefovir and entecavir. Current therapies do not eradicate HBV so long-term treatment is usually required. Development of drug resistance is a major concern with long-term treatment. Even with successful therapy, patients remain at risk for reactivation of viral replication and require lifelong monitoring.
Keywords: interferon , lamivudine , adefovir , entecavir , natural history
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Introduction |
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Chronic hepatitis B virus (HBV) infection is a worldwide problem, affecting over 350 million people and accounting for 0.5–1 million deaths each year.
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Goals of treatment |
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The goals of treatment of chronic hepatitis B are 3-fold: (i) to slow the progression of fibrosis to cirrhosis; (ii) to prevent hepatic failure; and (iii) to prevent the development of hepatocellular carcinoma (HCC). There is no cure for hepatitis B. HBV is maintained in a replicative form in the hepatocyte nuclei termed covalently closed circular DNA (cccDNA) which serves as a template for viral transcription. Current therapies have little or no direct effect on cccDNA. Hence, viral relapse occurs once antiviral medications are discontinued.
Because HBV cannot be eradicated, the efficacy of antiviral therapy of chronic hepatitis B is measured using surrogate markers. These include suppression of HBV DNA, normalization of alanine aminotransferase (ALT), and loss of hepatitis B e antigen (HBeAg) or hepatitis B surface antigen (HBsAg). The course of chronic HBV infection is characterized by periods of activity and quiescence. Thus, all HBV carriers should be regularly monitored.
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Selection of patients for treatment |
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The persistence of HBV despite treatment often necessitates long (perhaps indefinite) durations of therapy. Therefore, the decision to treat must balance the risk of liver-related morbidity and mortality in the future with the likelihood of sustained response to treatment. The development of antiviral resistance is a major obstacle in long-term viral suppression; hence, therapy should be initiated only when the benefits outweigh the risks.
Initial evaluation of HBV carriers should include assessment of HBV replication: HBeAg and HBe antibody (anti-HBe), and quantitative HBV DNA level; and activity/stage of liver disease: ALT, indicators of liver synthetic function (albumin, bilirubin and prothrombin time), and evidence of portal hypertension (platelets and ultrasound). A liver biopsy is the only reliable method to assess histological damage, but is not necessary in all cases. High risk carriers should also be screened for HCC.
The American Association for the Study of Liver Diseases has devised guidelines for the treatment of hepatitis B (Figure 1).1,2 Patients who acquire hepatitis B perinatally often progress through a period known as the ‘immune-tolerant phase’. During this time, HBeAg is positive and HBV DNA level is high (>7 log10 IU/mL), but ALT levels are normal and histological damage is mild. Whereas antiviral therapy at this point is effective in suppressing HBV replication, treatment does not increase the rate of HBeAg loss and is therefore not recommended. These patients develop elevation in ALT later in life and may benefit from treatment at that stage. The immune-tolerant phase in adult-acquired infections is generally short, and may have passed by the time of diagnosis.
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Patients who are HBeAg-positive with elevated ALT are considered to be in the ‘immune clearance phase’. Patients with effective immune clearance may undergo spontaneous HBeAg clearance with very little liver injury. Thus, it is recommended to observe patients with ‘HBeAg-positive chronic hepatitis B’ for 3–6 months and to initiate treatment only if there is no spontaneous HBeAg seroconversion, unless the patient presents with jaundice or decompensation. Some patients have recurrent hepatitis flares and transiently undetectable HBV DNA. These patients have increased risk of cirrhosis and HCC. Therefore, treatment should be initiated in patients who have had two or more hepatitis flares. The endpoint of treatment is HBeAg seroconversion (loss of HBeAg and detection of anti-HBe), which is associated with sustained viral suppression in 60–90%. Viral suppression without HBeAg seroconversion is invariably associated with viral rebound when treatment is discontinued. Interferon is administered for a finite duration, whereas nucleoside analogues (NA) are usually administered for an additional 6 months (consolidation therapy) after HBeAg seroconversion.
Approximately two-thirds of patients enter an ‘inactive phase’ after HBeAg seroconversion. These patients are HBeAg-negative, with normal ALT levels and serum HBV DNA undetectable or <3 log10 IU/mL. Liver biopsy usually shows minimal or no necroinflammation but inactive cirrhosis may be present if hepatitis activity was severe or prolonged during the preceding phase. Antiviral therapy will not provide any benefit to inactive carriers, but monitoring should continue because up to 20% will have reactivation of HBV replication later in life.
Patients who are HBeAg-negative but have elevated ALT and high levels of HBV DNA (>4 log10 IU/mL) are considered to have ‘HBeAg-negative chronic hepatitis B’. Many of these patients have HBV variants with mutations in the core promoter or precore region that decrease or abolish HBeAg synthesis. HBeAg-negative chronic hepatitis B is present worldwide. In the United States, it has been estimated that one-third of patients with chronic hepatitis B presenting to tertiary care liver units are HBeAg-negative. Compared with those with HBeAg-positive disease, patients with HBeAg-negative chronic hepatitis B are older, have more advanced liver disease and are more likely to have a fluctuating course. The goals of treatment are sustained suppression of HBV DNA and normalization of liver enzymes. On-treatment viral suppression is achieved in 60–90% of patients but relapse after discontinuation of therapy is virtually universal. The endpoint of treatment is unclear. Most patients receive indefinite treatment.
Areas of controversy in HBV treatment include management of patients with borderline abnormal ALT or high HBV DNA with normal ALT. A liver biopsy is particularly useful in older patients (>40 years) and those with borderline normal or intermittently normal ALT to determine the need for antiviral therapy.
HBV carriers who do not meet criteria for treatment on initial evaluation require continued monitoring. Those in the immune-tolerant phase should be followed with ALT every 3–6 months, and more often as ALT levels increase, so that treatment can be initiated if spontaneous HBeAg seroconversion does not ensue. Inactive carriers should be monitored with ALT every 3 months for the first year (to rule out HBeAg-negative chronic hepatitis B), and every 6–12 months thereafter. Increases in ALT should prompt HBV DNA testing and consideration of treatment if there is progression to HBeAg-negative chronic hepatitis B.
Screening for HCC (with abdominal ultrasound and serum 
-fetoprotein) is indicated for patients who have cirrhosis, men over the age of 40 and women over the age of 50, and those with a family history of HCC.3
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Choice of treatment |
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There are five approved treatments for hepatitis B in the United States. Responses to these treatments are summarized in Table 1.
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Interferon-alfa and pegylated interferon-alfa
In addition to being antivirals, the interferons are also immunomodulators, which enhance the natural immune response to HBV. Both standard interferon-alfa-2b (Intron A, Schering) and pegylated interferon-alfa-2a (Pegasys, Roche Pharmaceuticals) are administered as subcutaneous injections. For HBeAg-positive patients, the duration of treatment is 4–6 months for standard interferon and 12 months for pegylated interferon. Approximately 80–90% of patients with HBeAg loss have sustained response during long-term follow-up. For HBeAg-negative patients, the duration of treatment is 12 months with both types of interferon. Approximately 15–20% of patients have sustained response after treatment is stopped. Sustained response has been shown to be associated with improved clinical outcome and increasing likelihood of HBsAg loss.
The major drawback of interferon is the frequent occurrence of side effects.5,12,13 Interferon is contraindicated in patients with clinical evidence of cirrhosis. Its main advantages include higher rates of HBsAg loss, more durable response, a finite duration of treatment, and the absence of drug-resistant mutations.
Lamivudine
Lamivudine (2,3-dideoxy-3-thiacytidine, Epivir HBV, GlaxoSmithKline) is an oral NA that inhibits HBV DNA synthesis. Lamivudine is not recommended as first-line therapy unless cost is a concern because of the high rate of drug-resistant mutations. The most common mutations involve the YMDD motif of the HBV polymerase (rtM204V/I). The rate of genotypic resistance increases from 14% to 32% at 1 year,7,8 to 70% at 5 years. Antiviral resistance is manifested as virological breakthrough (1 log10 increase in HBV DNA level from nadir in a medication compliant patient). This is usually followed by biochemical breakthrough (elevated ALT), and in some instances acute hepatitis flare and hepatic failure. Lamivudine had been shown to prevent disease progression in patients with high HBV DNA levels and cirrhosis.17 New antiviral therapies with lower rates of drug resistance are likely to have similar if not better results.
Adefovir
Adefovir dipivoxil (Hepsera, Gilead Sciences) is an NA of adenosine monophosphate. It has antiviral activity against wild-type as well as lamivudine- and entecavir-resistant HBV mutants.18 Adefovir can be used as initial therapy in patients with HBeAg-positive or HBeAg-negative chronic hepatitis B or as additional therapy in those with lamivudine-resistant HBV.9,16,18 At the approved dose of 10 mg daily, nephrotoxicity is rare, but 25–50% of patients have suboptimal viral response.19 Resistance to adefovir occurs later and is less frequent compared with lamivudine. Genotypic resistance (rtA181V/T and rtN236T) was not detected after 1 year of therapy in Phase III clinical trials,20 but was present in 29% of patients after 5 years of therapy.21 Continuation of lamivudine after the addition of adefovir in patients with lamivudine-resistant HBV decreases the risk of adefovir resistance.
Entecavir
The newest addition to the HBV treatment armamentarium is entecavir (Baraclude, Bristol-Myers Squibb), an NA of guanosine. Phase III clinical trials showed that entecavir is more potent than lamivudine in suppressing HBV replication, with significantly higher rates of biochemical and histological responses in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B.22,23 HBeAg seroconversion rates were similar. Entecavir is also effective in suppressing lamivudine-resistant HBV but the activity is lower compared with wild-type HBV, even at the higher approved dose (1.0 mg versus 0.5 mg for patients with no prior NA treatment). Furthermore, the presence of lamivudine-resistant HBV mutations increases the likelihood of entecavir resistance.10,24 Thus, while entecavir resistance has not been observed after 2 years of treatment in patients with no prior NA therapy, entecavir-resistant HBV mutants have been reported in patients with lamivudine-resistant HBV after 1 year of treatment. Entecavir is best used as a first-line treatment because of its potency and the high genetic barrier to resistance in patients with no prior NA treatment. Entecavir's safety profile is similar to lamivudine's.
Combination therapy
Theoretically, combination therapy should have additive or synergistic antiviral activity, and prevent or reduce drug resistance. Combination of pegylated interferon and lamivudine resulted in greater on-treatment viral suppression, but sustained response rates after discontinuation of treatment were similar to that of pegylated interferon monotherapy in both HBeAg-positive and in HBeAg-negative patients.5,13 Combination of lamivudine and adefovir did not result in a greater degree of viral suppression or HBeAg seroconversion. While the rate of lamivudine resistance was lower compared with lamivudine monotherapy, the drug-resistance rate was higher than treatment with adefovir alone. A Phase II trial of telbivudine and lamivudine found that combination therapy was inferior to telbivudine alone suggesting an antagonistic effect.25 Thus, the promise of combination therapy remains elusive for hepatitis B.
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Conclusions |
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TopAbstractIntroductionGoals of treatmentSelection of patients for...Choice of treatmentConclusionsTransparency declarationsReferences |
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The treatment of chronic hepatitis B is an art that requires careful evaluation of the likelihood of liver-related morbidity and mortality and the likelihood that treatment will prevent or decrease adverse clinical outcomes. Because viral eradication is not possible, long-term treatment is necessary in most patients. While currently approved treatments have been shown to be safe in licensing clinical trials, the safety of these medications over years and decades remains to be proven. Additionally, the long-term risk of drug resistance can negate initial improvement, lead to worsening of liver disease, and limit future treatment options. Thus, treatment is only recommended for patients with active or advanced liver disease and high levels of HBV DNA. All approved treatments can be used as initial therapy, with avoidance of lamivudine unless cost is a limiting factor. Interferon is contraindicated in patients with clinical cirrhosis. The ultimate choice of therapy should take into account the patient's age, comorbid medical conditions, severity of liver disease, preference and anticipated duration of treatment.
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Transparency declarations |
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M. K. O.: nothing to declare. A. S. F. L.: supported in part by the National Institutes of Health contract N01 DK-9-2323 and grants U01 DK57577, U01 DK62498, U01 CA084986 and R01 DK066840. Receives research support from Roche, GlaxoSmithKline, Bristol-Myers Squibb, Gilead, Idenix, Innogenetics and Valeant. Serves as advisor for Idenix, Gilead, GlaxoSmithKline, Bristol-Myers Squibb, Innogenetics, Anadys, PowderMed, Roche and Pharmasset.
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Footnotes |
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Present address. University of Michigan Medical Center, Division of Gastroenterology, 1500 E. Medical Center Drive, 3912 Taubman Center, Ann Arbor, MI 48109-0362, USA 
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References |
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