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
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).
|Major Supportive Data||Key Indications for Urgent Treatment||Preferred Treatment|
|Decompensated||Open label; multiple large case series||Clinical stabilization; minimize risk for recurrence posttransplantation||Entecavir (0.5 mg) or tenofovir (300 mg)|
|Borderline||Undefined||Forestall disease progression; avoidance of transplantation||As above|
|Well compensated||Randomized, controlled trials||As above||As above|
|Acute liver failure|
|HBV reactivation||Open label with comparison to historical controls||Minimize further liver injury; reduce risk for recurrence after transplantation if needed||Entecavir (0.5 mg) or tenofovir (300 mg)†,‡|
|Severe acute hepatitis||As above, but smaller case series||Minimize further liver injury and enhance full recovery||Consider 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 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
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
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.
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).
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.