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Hepatitis B seldom needs to be treated immediately. However, there are clinical situations in which prompt or even urgent therapy is required to forestall disease progression, decrease morbidity, or clinically stabilize the patient. These indications are reviewed here, beginning with those areas where the evidence for treatment benefit is strongest. The reader is referred to current American Association for the Study of Liver Diseases (AASLD) Practice Guidelines for less urgent indications.1

Advanced Fibrosis and Compensated Cirrhosis

  1. Top of page
  2. Abstract
  3. Advanced Fibrosis and Compensated Cirrhosis
  4. Decompensated Cirrhosis
  5. Acute Reactivation Superimposed on Chronic Hepatitis B
  6. Severe or Protracted Acute Viral Hepatitis
  7. Discussion
  8. References

Immediate initiation of nucleoside analogue therapy is indicated for all patients with active disease and advanced fibrosis (defined as ≥Ishak stage 4) (Table 1). Between 10% and 15% of patients in the registration trials for currently licensed nucleoside analogues had cirrhosis on baseline biopsy. In the pivotal tenofovir studies, an additional 20% had Ishak stage 4 disease.2 Improvement in fibrosis was seen in all of these studies after a relatively short treatment duration (48-52 weeks).

Table 1. Indications for Prompt or Urgent Treatment of Hepatitis B
 Major Supportive DataKey Indications for Urgent TreatmentPreferred Treatment
  • *

    It has been the author's practice to use maintenance antiviral therapy for all HBsAg-positive patients with cirrhosis even if initially HBV DNA–negative to prevent future reactivation.

  • Dosing should be according to renal status as indicated in drug brochure.

  • Rarely, such patients may present with <2,000 IU of HBV DNA following extensive hepatocytolysis. Maintenance antiviral therapy is strongly recommended, however, to prevent future reactivation episodes or ready the patient for transplantation. See the text for further details.

  • §

    Either agent can be used if the anticipated duration of therapy is ≤6 months.

Cirrhosis*   
 DecompensatedOpen label; multiple large case seriesClinical stabilization; minimize risk for recurrence posttransplantationEntecavir (0.5 mg) or tenofovir (300 mg)
 BorderlineUndefinedForestall disease progression; avoidance of transplantationAs above
 Well compensatedRandomized, controlled trialsAs aboveAs above
Acute liver failure   
 HBV reactivationOpen label with comparison to historical controlsMinimize further liver injury; reduce risk for recurrence after transplantation if neededEntecavir (0.5 mg) or tenofovir (300 mg),
 Severe acute hepatitisAs above, but smaller case seriesMinimize further liver injury and enhance full recoveryConsider lamivudine or telbivudine§

Recently, the degree of histological improvement associated with long-term tenofovir or entecavir has been extensively analyzed. Paired biopsies were available in 328 (51%) of patients who received tenofovir for 4 to 5 years.1 Histological improvement (≥2 point improvement in Knodell necroinflammatory score without increase of fibrosis) was observed in 95% of 235 noncirrhotic patients. Liver biopsies were also available in 93 patients with cirrhosis (Ishak 5 or 6) at baseline, and 72% had a ≥2 point decrease in fibrosis stage by week 240 of treatment. Although the data are less striking, reversal of cirrhosis has also been reported after ≥3 years of entecavir.3

Clinical disease also has been shown to improve with continuous viral suppression of patients with advanced fibrosis. In a multinational placebo-controlled trial of Asian hepatitis B surface antigen (HBsAg) carriers with Ishak fibrosis score ≥4 (including 400 with cirrhosis), the number of patients with a ≥2 point increase in Child-Turcotte-Pugh (CTP) score and newly diagnosed hepatocellular carcinoma were significantly less in lamivudine-treated patients after a median period of 32 months.4

Taken together, these results are extremely encouraging. It remains to be determined whether reversal of the histologic features of cirrhosis independently contributes to a declining risk for hepatocellular carcinoma or whether this reduces clinical complications associated with established portal hypertension.

Decompensated Cirrhosis

  1. Top of page
  2. Abstract
  3. Advanced Fibrosis and Compensated Cirrhosis
  4. Decompensated Cirrhosis
  5. Acute Reactivation Superimposed on Chronic Hepatitis B
  6. Severe or Protracted Acute Viral Hepatitis
  7. Discussion
  8. References

Decompensated cirrhosis needs to be treated immediately. Decompensation is clinically definable by hyperbilirubinemia, hypoalbuminemia, elevated international normalized ratio (INR), or disease complications such as ascites, portal hypertensive bleeding, or encephalopathy. Clinical trials of nucleoside analogue therapy have largely focused on patients who are wait-listed for transplantation. However, years of declining liver function often can be observed prior to overt decompensation, and such individuals may have bilirubin and albumin values that still fall within the normal reference range when first seen. Individuals with declining values should be treated with the same sense of urgency as patients with obvious features of decompensation (Table 1).

The availability of lamivudine was hailed as the first major therapeutic breakthrough for patients with decompensated cirrhosis because interferon-α therapy had been shown to be dangerous. Clinical stabilization occurred in a subset of lamivudine-treated patients, but the rate of drug resistance was unacceptably high, and this was often associated with clinical progression and high rates of recurrence posttransplantation.4, 5 Of some importance, an open label study of 154 patients with decompensated cirrhosis demonstrated that hyperbilirubinemia, renal dysfunction, and detectable hepatitis B virus (HBV) DNA were predictive of mortality during the first 6 months of treatment, thus emphasizing that therapeutic benefit required earlier treatment.6

The therapeutic landscape changed again when adefovir became available. The low resistance rate (2%) in the first few years of treatment led to clinical stabilization and good outcomes posttransplantation. In one study involving 226 wait-listed patients, clinical improvement led to delisting in 20% of cases.7

Entecavir and tenofovir are currently preferred for the treatment of decompensated cirrhosis because of greater antiviral potency and a high genetic barrier to resistance. In a multinational study, 191 patients with decompensated cirrhosis (mean CTP score 8.8, Model for End-Stage Liver Disease [MELD] score 17.1) were treated with entecavir or adefovir for up to 96 weeks.8 Although entecavir was more effective in viral suppression, both drugs caused improvement or stabilization in both scores.

There are few direct comparisons between entecavir and tenofovir in decompensated cirrhosis. In a randomized, controlled study of 112 patients with mildly decompensated cirrhosis (average MELD score 11, CTP score 7), HBV DNA at week 48 was undetectable in 71% of tenofovir-treated patients, 88% treated with emtricitabine plus tenofovir (FTC/TDF), and 73% treated with entecavir.9 Hepatitis B e antigen seroconversion occurred significantly less frequently with entecavir, but this may have been influenced by inclusion of lamivudine-pretreated patients and switching to open-label FTC/TDF if viremia persisted at week 24.

Acute Reactivation Superimposed on Chronic Hepatitis B

  1. Top of page
  2. Abstract
  3. Advanced Fibrosis and Compensated Cirrhosis
  4. Decompensated Cirrhosis
  5. Acute Reactivation Superimposed on Chronic Hepatitis B
  6. Severe or Protracted Acute Viral Hepatitis
  7. Discussion
  8. References

Hepatic decompensation can also result from an acute episode of severe reactivation (alanine aminotransferase >10 times the upper limit of normal with hyperbilirubinemia and/or increased INR) superimposed on chronic hepatitis B. This may occur spontaneously, as a result of coinfection with human immunodeficiency virus, as a result of drug-resistant HBV, or as a complication of immunosuppressive drug therapy. In some instances the associated hepatitis flare heralds a sustained suppression of HBV replication, whereas in other cases viral suppression is only transient. These patients may or may not have underlying cirrhosis, and serum HBV DNA is usually 2 to 8 log10 IU when first seen.

The goal of antiviral therapy in reactivated hepatitis B is to suppress viral replication, prevent further liver damage, and minimize the chances for recurrent hepatitis B if transplantation is necessary. Severe reactivation should always be treated emergently, because mortality rates in excess of 50% have been reported in untreated patients. When jaundice or encephalopathy is evident, the situation requires urgent consideration for transplantation.

A few case series have reported biochemical and clinical improvement and increased survival compared with historical or untreated controls.10, 11 A controlled clinical trial of reactivated hepatitis B has recently been reported from India in which 27 patients were either randomized to placebo or active treatment with tenofovir (median baseline HBV DNA 9 × 105 log10 IU).11 At 3 months, the probability of survival was higher in the treated versus nontreated group (8/14 versus 2/13).

Many patients with severe reactivation will require long-term therapy or consideration for transplantation. Thus, high genetic barrier drugs are always preferable. Entecavir should not be used if the patient has been heavily pretreated with lamivudine or telbivudine. Due to the urgency of the situation and need for a prompt reduction in viral replication, the author does not advocate adefovir monotherapy or adding adefovir to lamivudine if YMDD mutant HBV is a possibility.

Severe or Protracted Acute Viral Hepatitis

  1. Top of page
  2. Abstract
  3. Advanced Fibrosis and Compensated Cirrhosis
  4. Decompensated Cirrhosis
  5. Acute Reactivation Superimposed on Chronic Hepatitis B
  6. Severe or Protracted Acute Viral Hepatitis
  7. Discussion
  8. References

Very limited data are available on nucleoside analogue therapy for severe or fulminant acute hepatitis B. In a prospective study of lamivudine therapy in 17 patients with severe or fulminant hepatitis B, treatment was associated with a significantly lower rate of encephalopathy and need for transplantation when compared with historical controls.12 In a randomized controlled trial of lamivudine versus placebo in 71 patients with acute hepatitis and jaundice (bilirubin >5 mg/dL), serum HBV DNA levels decreased more rapidly in the lamivudine group, but higher rates of clinical and biochemical improvement were not observed.13 Recently, data on 61 patients with fulminant liver failure due to acute hepatitis B was reported from the US Acute Liver Failure Study Group.14 A difference in survival was not noted in 27 patients treated with nucleoside analogue therapy compared with untreated patients (67% and 71%, respectively). However, treatment was started more than 3 weeks after the onset of symptoms in 75% of cases, which could have potentially affected the results. Baseline enrollment values for serum HBV DNA were <4 log10 IU in both groups, and nearly 20% were already HBsAg-negative.

The AASLD Practice Guidelines recommend that antiviral therapy be initiated in patients with acute hepatitis B if liver failure or protracted, severe acute hepatitis is present.1 A reasonable working definition of protracted, severe hepatitis is detection of a prolonged prothrombin time (≥1.6) and deep jaundice (bilirubin ≥10 mg/dL) that is persistent for more than 4 weeks. The authors of the guidelines point out that such recommendations are empiric and are based on the potential for benefit and lack of evidence for harm from antiviral therapy. Although not specifically mentioned, the use of antiviral therapy presupposes the patient still has detectable HBV DNA or HBsAg. The choice of a high versus low genetic barrier drug may be less important in such severe cases of acute hepatitis B unless the patient becomes persistently infected or is being considered for transplantation.

Discussion

  1. Top of page
  2. Abstract
  3. Advanced Fibrosis and Compensated Cirrhosis
  4. Decompensated Cirrhosis
  5. Acute Reactivation Superimposed on Chronic Hepatitis B
  6. Severe or Protracted Acute Viral Hepatitis
  7. Discussion
  8. References

Antiviral therapy for hepatitis B should be started as soon as possible whenever a patient with active disease has severe fibrosis or potentially life-threatening disease. The strongest evidence for antiviral treatment benefit exists for advanced fibrosis, cirrhosis, and decompensated chronic hepatitis B. The data are less clear for reactivation of chronic hepatitis B and acute fulminant hepatitis, because studies have been small and mostly retrospective in nature. The treatment of severe acute hepatitis B associated with liver failure remains particularly problematic, because disparate results have been reported. Based on the expectation that antiviral therapy will be beneficial, a controlled, clinical trial can no longer be ethically justified.

The provider should be aware that a rapid decline in serum HBV DNA often occurs in severe acute infection or reactivating chronic hepatitis B because of a robust cell-mediated immunologic response. This explains why some patients present with borderline or nondetectable HBV DNA, a situation that may be anticipated more often when a prolonged delay exists between the onset of symptoms and first assessment.12, 14 It can be argued that complete clinical recovery in these instances may depend more on the adequacy of hepatocellular regeneration rather than the rate or degree to which viral replication is suppressed by antiviral therapy.

These theoretical considerations aside, the author strongly recommends prompt initiation of antiviral treatment in all cases of fulminant hepatitis B, or clinically apparent reactivation. Determination of HBV DNA and HBsAg, however, should either be available shortly before or after treatment is initiated, because it can be helpful in distinguishing acute hepatitis B from reactivation (Fig. 1). If the diagnosis remains unclear, testing for immunoglobulin M (IgM) anti-HBc may have value, because the combination of high IgM anti-HBc and low HBV DNA (≤104 IU) are more supportive of acute hepatitis B.15 Provided transplantation is not thought to be needed, treatment can be discontinued in acute cases after HBsAg disappears or HBsAg seroconversion occurs. By contrast, it should be continued long-term in patients with severe reactivation (Fig. 1).

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Figure 1. Proposed management algorithm for liver failure due to acute severe hepatitis B or clinically apparent reactivation. Antiviral therapy should be immediately initiated for both disorders. If HBV testing has not been done recently (e.g., 1 week prior), HBsAg and HBV DNA testing should be done soon after treatment is started. The results of these tests can help to distinguish between acute versus reactivating hepatitis B and influence the choice of drug. Testing for IgM anti-HBc (assessing signal-to-noise ratio) can be additionally helpful if separation remains unclear (see text and Dao et al.15 for details). The author recommends use of a high genetic barrier drug in patients who appear to be in need of transplantation or those in whom reactivation is strongly suspected or ultimately proven.

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In conclusion, antiviral therapy should be given when the patient is first seen if there is active disease with advanced fibrosis, severe acute hepatitis B, or HBV reactivation superimposed on chronic hepatitis B. Antiviral therapy forestalls disease progression in advanced fibrosis and cirrhosis, and reversal of the histological features of cirrhosis can be anticipated with long-term use of high genetic barrier drugs. In decompensated cirrhosis, antiviral therapy can lead to clinical stabilization, reduced need for transplantation, and improved posttransplantation outcomes. Although the data on treatment benefit are less clear in protracted, severe acute hepatitis B, fulminant hepatitis B, or HBV reactivation, immediate treatment is always justifiable when a patient presents with acute liver failure because of the maxim of reasonable expectation of benefit and the absence of major adverse events from therapy. Further laboratory testing may lead to modifying the choice of drug and length of therapy.

References

  1. Top of page
  2. Abstract
  3. Advanced Fibrosis and Compensated Cirrhosis
  4. Decompensated Cirrhosis
  5. Acute Reactivation Superimposed on Chronic Hepatitis B
  6. Severe or Protracted Acute Viral Hepatitis
  7. Discussion
  8. References
  • 1
    Lok ASF, McMahon BJ. Practice guidelines. Chronic hepatitis B: update. Hepatology 2009; 50: 136.
  • 2
    Afdhal N, Buti M, Fung S, Gane E, Martins E, Bekele N, et al. Factors associated with regression of cirrhosis in patients with chronic hepatitis B infection treated with tenofovir disoproxil fumarate. Presented at the 47th Annual Meeting of the European Association for the Study of the Liver, April 18–22, 2012. Poster Number 497.
  • 3
    Chang T-T, Liaw Y-F, Wu S-S, Schiff E, Han K-H, Lai C-L, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 2010; 52: 886893.
  • 4
    Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351: 15211531.
  • 5
    Perrillo RP, Wright T, Rakela J, Levy G, Schiff E, Gish R, et al. A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology 2001; 33: 424432.
  • 6
    Fontana Rj, Hann HW, Perrillo RP, Vierling JM, Wright T, Rakela J, et al. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy. Gastroenterology 2002; 123: 719727.
  • 7
    Schiff E, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, et al. Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results. Liver Transpl 2007; 13: 349360.
  • 8
    Liaw YF, Raptopoulou-Gigi M, Cehinquer H, Sarin SK, Tanwandee T, Leung N, et al. Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with hepatic decompensation: a randomized, open-label study. Hepatol 2011; 54: 91100.
  • 9
    Liaw YF, Sheen IS, Lee CM, Akarca US, Papatheodoridis GV, Suet-Hing W, et al. Tenofovir disoproxil fumurate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology 2011; 53: 6272.
  • 10
    Huang K, Hu J-H, Wang H-F, He W-P, Chen J, Duan X-Z, et al. Survival and prognostic factors in hepatitis B virus-related acute on chronic liver failure. World J Gastroenterol 2011; 17: 34483452.
  • 11
    Garg H, Sarin SK, Kumar M, Garg V, Sharma BC, Kumar A. Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure. Hepatology 2011; 53: 774780.
  • 12
    Tillmann HL, Hadem J, Leifeld L, Zachou K, Canbay A, Eisenbach C, et al. Safety and efficacy of lamivudine in patients with severe acute or fulminant hepatitis B, a multicenter experience. J Viral Hepat 2006; 13: 256263.
  • 13
    Kumar M, Satapathy S, Mnga RE, Das K, Hissar S, Pande C, et al. A randomized controlled trial of lamivudine to treat acute hepatitis B. Hepatology 2007; 45: 9710.
  • 14
    Dao DY, Seremba E, Ajmera V, Sanders C, Hynan LS, Lee WM. Use of nucleoside (tide) analogues in patients with hepatitis B-related acute liver failure. Dig Dis Sci 2012; 57: 13491357.
  • 15
    Dao DY,HynanLS Sanders C, Balko J, Attar N, Lok ASF, et al. Two distinct subtypes of hepatitis B virus-related acute liver failure are separable by quantitative serum immunoglobulin M anti-hepatitis B core antibody and hepatitis B virus DNA levels. Hepatol 2012; 55: 676684.