Severe acute exacerbation of chronic hepatitis B: A unique presentation of a common disease
Declaration of conflict of interest: H. L. Y. C. is an advisory board member of Bristol-Myers Squibb, Novartis Pharmaceutical, Pharmasset and Schering-Plough.
Professor Henry LY Chan, Department of Medicine and Therapeutics, 9/F Prince of Wales Hospital, Shatin, Hong Kong, China. Email: firstname.lastname@example.org
Severe acute exacerbation is a unique presentation of chronic hepatitis B characterized by very high alanine aminotransferase level accompanied by jaundice and hepatic decompensation. The underlying pathogenesis is likely related to excessive immune clearance, which may be related to the genotype of hepatitis B virus. The mortality is very high once hepatic encephalopathy develops, but some patients can recover to almost normal liver function in contrast to patients with end-stage liver cirrhosis. This condition should be differentiated from acute hepatitis B and other causes of acute hepatitis must be excluded. Conventional prognostic systems may not be applicable to severe acute exacerbation of chronic hepatitis B. In general, patients who have thrombocytopenia, hyperbilirubinemia and coagulopathy have a higher risk of mortality regardless of the serum alanine aminotransferase levels. There is no evidence that lamivudine treatment can reduce the short-term mortality of severe acute exacerbation. However, patients with severe acute exacerbation tend to have a higher rate of maintained virological response, higher rate of hepatitis B e antigen seroconversion and low rate of drug resistance on extended lamivudine treatment as compared to other chronic hepatitis B patients. Virological relapse and severe hepatitis reactivation is common after treatment cessation and therefore long-term antiviral treatment is recommended. Liver transplantation, particularly living donor liver transplantation, should be considered for patients who develop hepatic failure secondary to severe acute exacerbation.
Chronic hepatitis B virus (HBV) infection affects more than 350 million people worldwide. It is the commonest cause of liver cirrhosis and hepatocellular carcinoma in Southeast Asia.1 In the late stage of liver cirrhosis, development of jaundice is the hallmark of hepatic decompensation. Most patients with decompensated liver cirrhosis have relatively silent disease or mild necroinflammation as reflected by normal or mildly elevated alanine aminotransferase (ALT) levels.2 However, some chronic hepatitis B patients may have spontaneous severe acute exacerbation of the disease presented with very high ALT levels, jaundice and sometimes liver failure.3 This condition should be defined as acute-on-chronic liver failure according to a recent Asia–Pacific consensus recommendation.4 It is very different from the acute liver failure, in which the individual has no underlying liver disease, as commonly seen in the West.5 This presentation is somewhat similar to chemotherapy-induced hepatitis reactivation of chronic hepatitis B, which will not be discussed in this review as it has been covered extensively in the published work.6 Spontaneous severe acute exacerbation is a unique clinical presentation of chronic hepatitis B and is rarely observed in chronic hepatitis C. On the other hand, it may be easily confused with acute viral hepatitis. As patients suffering from severe acute exacerbation of chronic hepatitis B may not have underlying liver cirrhosis, they may recover to a relatively normal liver function in contrast to those suffering from end-stage liver cirrhosis. It is therefore important to recognize this important clinical presentation of chronic hepatitis B and understand the prognosis and management strategy of this condition.
Most Asian patients acquire HBV infection through the perinatal route or at infancy. In the initial few decades of life, owing to the relative lack of immune pressure on the virus, Asian patients are characterized by an immune tolerance phase in which viral replication is very high but hepatic damage is minimal.7,8 At the age of 20–40 years, due to an as yet uncertain immune trigger, the majority of chronic hepatitis B patients undergo immune clearance of the virus accompanied by reactivation of hepatitis. Immune clearance is characterized by an increase in ALT and reduction in HBV DNA level. Successful immune clearance is associated with hepatitis B e antigen (HBeAg) seroconversion to anti-hepatitis B e antibodies (anti-HBe), suppression of HBV DNA and resolution of hepatitis. Patients who have prolonged but unsuccessful immune clearance may eventually develop progressive liver fibrosis and liver cirrhosis.9 Up to 30% of chronic hepatitis B patients experience spontaneous reactivation of hepatitis every year.10 Hepatitis reactivation can occur in both HBeAg-positive and -negative patients.11,12 A proportion of patients develop jaundice and hepatic decompensation during the hepatitis reactivation, namely, severe acute exacerbation, and may progress into acute-on-chronic hepatic failure.13–15 In Hong Kong and Taiwan, 23–38% of patients have been reported to develop jaundice and hepatic decompensation during biochemical exacerbation of chronic hepatitis B,16,17 and these exacerbations are associated with significant mortality.18,19 The pathogenesis of severe acute exacerbation is believed to associate with too vigorous immune pressure leading to excessive hepatic necroinflammation and decompensation.
Eight different HBV genotypes (A–H) have been described based on their genomic heterogeneity.20 In Asia–Pacific countries, genotype B and C HBV are predominant. Genotype C HBV is associated with delayed HBeAg seroconversion and more aggressive disease activity as compared to other HBV genotypes (with most data vs genotype B HBV).21–23 It can be extrapolated to a higher risk of hepatocellular carcinoma among genotype C HBV infected patients.24–26 In two case–control studies conducted in Hong Kong, genotype B HBV was found to be the predominant HBV strain among patients suffering from severe acute exacerbation as compared to control patients with various severities of liver diseases (Table 1).27,28 However, this association cannot be reproduced among patients in Taiwan where genotype B HBV is more prevalent than genotype C HBV in general.30 In a study in Japan, a high prevalence of genotype B HBV was found among patients suffering from acute fulminant hepatitis, which may partly be composed of patients with severe acute exacerbation of chronic hepatitis B, as the diagnosis of acute hepatitis was based only on the presence of immunoglobulin (Ig)M against hepatitis B core antigen (anti-HBc).29 Nonetheless, these controversies suggest a possibility that the immunogenicity of the two HBV genotypes is different. Genotype B HBV may associate with more vigorous immune response that leads to a higher chance of successful immune clearance but also a higher risk of hepatic decompensation during the hepatitis flare. On the contrary, genotype C HBV is associated with less vigorous and prolonged, abortive immune clearance, which is more likely to cause progressive liver damage and eventually liver cirrhosis and hepatocellular carcinoma. The underlying pathogenic mechanism, however, warrants further investigations.
Table 1. Proportion of genotype B (vs genotype C) hepatitis B virus among patients with severe acute exacerbation of chronic hepatitis B versus different control populations
|Chan et al.27|| ||Inactive disease||Early cirrhosis||Decompensated cirrhosis|| |
|n = 21||n = 31||n = 49||n = 31|
|Yuen et al.28|| ||Inactive disease||Mild hepatitis||Moderate hepatitis||Severe hepatitis without decompensation|
|n = 30||n = 110||n = 67||n = 41|
| || || || ||n = 43|
|Imamura et al.29|| ||Other chronic hepatitis B patients||Acute hepatitis||Fulminant hepatitis|| |
|n = 17||n = 521||n = 40||n = 15|| |
|Tsai et al.30|| ||Severe hepatitis without decompensation|| || || |
|n = 19||n = 31|| || || |
|74%||65%|| || || |
The typical presentation of severe acute exacerbation is a short onset of jaundice and very high ALT level, sometimes preceded by prodromal constitutional symptoms, in a patient with chronic hepatitis B. However, some patients presenting with severe acute exacerbation of chronic hepatitis B may not know their carrier status. In other words, the severe acute exacerbation may be the first presenting feature of their chronic hepatitis B.31 The symptoms of severe acute exacerbation of chronic hepatitis B can be very similar to those of acute hepatitis B.32 Hence, severe acute exacerbation of chronic hepatitis B might be misdiagnosed as acute hepatitis B in some cases.
Patients with severe acute exacerbation of chronic hepatitis B can have positive IgM anti-HBc, which may again be confused with the diagnosis of acute hepatitis B.33 An Indian study suggests that a low titer of IgM anti-HBc (< 1:1000) and high HBV DNA level (> 0.5 pg/mL, which equals ∼141 500 copies/mL)34 are useful to identify severe acute exacerbation of chronic hepatitis B from acute hepatitis B.32 However, HBV DNA may sometimes become undetectable at the peak of the biochemical exacerbation due to vigorous immune clearance, a phenomenon commonly observed in chemotherapy-induced hepatitis reactivation.35 The presence of basal core promoter mutation and precore stop codon mutations have been suggested to differentiate severe acute exacerbation of chronic hepatitis B from acute hepatitis B in Japanese series, but its use in clinical practice needs further validation.29,36
A detailed history on the potential risk of exposure to acute HBV infection is therefore important. A previous history of chronic hepatitis B or a positive family history of chronic hepatitis B helps to suggest chronic carrier status. Liver biopsy showing evidence of chronicity may suggest chronic infection, but this procedure may not be feasible in a patient with hepatic decompensation due to the risk of bleeding. In uncertain cases of acute hepatitis B versus severe acute exacerbation of chronic hepatitis B, one can manage these patients as severe acute exacerbation and repeat hepatitis B surface antigen testing (HBsAg) 6 months later. In over 95% of acute hepatitis B acquired in adulthood, HBsAg will be cleared on the follow-up testing.8 As chronic hepatitis B infected patients still can acquire other viral infection that causes acute hepatitis, other viral hepatitis (A, C, D and E) must be excluded by serological assays. If suspected, drug-induced hepatitis (particularly paracetamol overdose), autoimmune hepatitis and Wilson's disease should also be excluded before a diagnosis of severe acute exacerbation of chronic hepatitis B is made. The factors that may help to differentiate severe acute exacerbation of chronic hepatitis B from acute hepatitis B are summarized in Table 2.
Table 2. Factors to differentiate severe acute exacerbation of chronic hepatitis B from acute hepatitis B
|Useful history||Past history of chronic hepatitis B||Recent at risk blood, percutaneous or sexual exposure to HBV|
|Family history of chronic hepatitis B|
|IgM anti-HBc titer||Negative or low (< 1:1000)||High (≥ 1:1000)|
|HBV DNA level||High (≥ 100 000 copies/mL)||Low (< 100 000 copies/mL)|
|Histology||Evidence of chronicity||No evidence of chronicity|
|Follow-up HBsAg after 6 months||Positive||Negative in over 95% of patients|
|Basal core promoter mutation||Present||Absent|
|Precore stop codon mutation||Present||Absent|
|Symptoms and signs||Prodromal symptoms||Prodromal symptoms|
|Jaundice and itching||Jaundice and itching|
|Abdominal discomfort||Abdominal discomfort|
|Alanine aminotransferase||Very high||Very high|
As in other liver diseases, the prognosis of patients with acute-on-chronic hepatic failure (with hepatic encephalopathy) is extremely poor with a mortality of 65–93% unless timely orthotopic liver transplantation can be arranged.37 King's College criteria have been used widely for prognostication of acute hepatic failure, but its role in severe acute exacerbation of chronic hepatitis B has not been validated.38 In chronic hepatitis B-related liver cirrhosis, Child–Pugh score and Model for End-Stage Liver Disease (MELD) score can been used for prognostication and organ allocation for liver transplantation.39 Recently, serum sodium has been found to be important prognostically and addition of serum sodium to MELD to generate a formula of MELD-sodium has been proposed.40,41 All these prognostic models are developed and validated based on patients with end-staged liver cirrhosis and may not be applicable in patients with severe acute exacerbation of chronic hepatitis B.
In a small series of acute-on-chronic hepatic failure secondary to severe acute exacerbation of chronic hepatitis B in Hong Kong, the only prognostic indicator for survival was the presence of comorbid complications.19 Patients who died or received liver transplantation tend to develop either sepsis (e.g. urinary tract infection, pneumonia and spontaneous bacterial peritonitis) or renal failure. Serum bilirubin, prothrombin time, ALT, creatinine and viral factors at presentation could not predict transplant-free survival.
In a Hong Kong series reporting 46 chronic hepatitis B patients who developed severe acute exacerbation but without hepatic encephalopathy at presentation, 24% patients died or received liver transplantation during hospital admission.31 The only independent factors that could predict in-hospital mortality were low platelet count (≤ 143 × 109/L) and high serum bilirubin (> 172 µmol/L). The mortality of patients who had both risk factors (low platelet and high bilirubin) was 69%. On the other hand, the mortality of patients who had either thrombocytopenia or elevated bilirubin alone was much lower (11% and 13%, respectively), and the mortality of patients who had none of the two risk factors was zero in this series. Thrombocytopenia might reflect underlying liver cirrhosis and portal hypertension, while hyperbilirubinemia might reflect the severity of hepatic impairment. Owing to their limited hepatic reserve, cirrhotic patients are expected to recover slower from the hepatic insult and are more prone to complications including sepsis, gastrointestinal bleeding and acute renal failure. These findings are echoed by other series in Hong Kong, Taiwan and Japan, in which patients with pre-existing liver cirrhosis and more serious hepatic dysfunction (prolonged prothrombin time, elevated serum bilirubin and high Child–Pugh score) have a higher risk of mortality (Table 3).18,42,44 In all studies, the level of serum ALT has no prognostic value. Therefore, liver transplantation should be considered among patients who have severe hepatic dysfunction regardless of the serum ALT level even before the development of hepatic encephalopathy.
Table 3. Independent prognostic factors for mortality (and liver transplantation) in severe acute exacerbation of chronic hepatitis B
|Bilirubin||High (> 172 µmol/L)||High||High (marginal effect)||High|
|Platelet count||Low (≤ 143 × 109/L)||Low||–||–|
|HBV DNA||Not studied||–||–||–|
|Serum creatinine||–||–||–||Not studied|
|Liver cirrhosis||Not studied||Present||–||Present|
|Ascites||Not studied||Not studied||Present||–|
|Child–Pugh score||Not studied||High||High||Not studied|
In severe acute exacerbation of chronic hepatitis B when immune clearance is already excessive, interferon-based treatment may be dangerous in further aggravating the hepatic decompensation and is thus contraindicated. Oral nucleos(t)ide analogs are the treatment of choice. The rationale behind oral anti-viral agent is direct suppression of HBV DNA, which hopefully can calm down the immune activity and buy time for the hepatitis to settle. Most data in the published work involves the use of lamivudine to treat severe acute exacerbation of chronic hepatitis B.
Short-term therapeutic effect
It is controversial if antiviral therapy improves short-term mortality in patients with severe acute exacerbation of chronic hepatitis B. In a small preliminary study in Japan, three cirrhotic patients presented with severe acute exacerbation and grade 2 hepatic encephalopathy responded dramatically to lamivudine treatment.45 However, in a larger prospective cohort from Hong Kong, among 24 patients with severe acute exacerbation and hepatic encephalopathy treated with lamivudine, 13 of them died and three received liver transplantation.19 Even among patients with severe acute exacerbation received lamivudine before the onset of hepatic encephalopathy, and case–control studies from Hong Kong and Japan cannot demonstrate any survival benefit from lamivudine treatment.31,44 In the Hong Kong series, the mortality rate was similar between lamivudine users (6/28, 21%) and historical controls who did not receive any antiviral therapy (5/18, 28%).31 In the Japanese study including 25 patients with severe acute exacerbation treated with lamivudine and 25 untreated historical controls, lamivudine again did not reduce the short-term mortality (12% vs 20%, respectively) or risk of hepatic failure (24% vs 28%, respectively).44
The high mortality rate of these patients despite lamivudine treatment was likely related to the delayed commencement of lamivudine and viral suppression. In patients with liver failure, their livers have already undergone massive or submassive hepatic necrosis. Suppressing viral replication with lamivudine at this late stage is unlikely to be effective, because the main determinant for recovery is liver regeneration and rapid cessation of ongoing necroinflammation. Both factors are not directly dependent on the replication of HBV and both events take time. The liver regeneration is further impaired among patients who have pre-existing liver cirrhosis related to telemore shortening.46 During this vulnerable period, these patients may develop complications including sepsis and renal failure and many of the non-survivors died of multi-organ failure.
In support of this hypothesis, a study from Taiwan suggests that the beneficial effect of antiviral therapy on short-term survival depends on the timing of treatment.18 Among consecutive chronic hepatitis B patients with severe acute exacerbation treated with lamivudine, all 25 patients who had baseline bilirubin below 342 µmol/L (20 mg/dL) survived. Among patients with low (< 20 mg/dL) baseline serum bilirubin level, lamivudine treatment has definite survival benefit as compared to historic controls who did not receive lamivudine (5/20 patients died, 20%, P = 0.013). On the other hand, the mortality rate of the patients who received lamivudine when bilirubin was above 342 µmol/L (23/35, 67%) was similar to that of the untreated historical controls (9/11, 82%). Hence, for antiviral treatment to be effective, it should be administered early, preferably before serum bilirubin has gone up too high to ‘the point of no return’.
Long-term therapeutic benefit
Although antiviral therapy is unlikely to have impact on the short-term survival, its administration is still recommended with the aim of preventing further hepatitis exacerbations and liver injury.47,48 Among patients who develop hepatic failure and require liver transplantation, suppression of HBV DNA can reduce the risk of viral recurrence after liver transplantation, particularly when lamivudine is used as the only prophylactic agent as in many southeast Asian countries.49,50 Antiviral therapy may reduce the long-term risk of hepatocellular carcinoma and cirrhotic complications.51 In patients with history of severe acute exacerbation, antiviral therapy normalizes liver function tests and prevents progression to cirrhosis.44
Several important questions arise when one uses antiviral drugs in patients with severe acute exacerbation. Drug resistance is common when an antiviral agent which has a low genetic barrier for resistance such as lamivudine is used. The cumulative risk of lamivudine resistance is up to 70% after 4 years of therapy.52,53 The incidence of lamivudine resistance and subsequent outcome in patients with severe acute exacerbation should be evaluated. The durability and off treatment response are also important. Finally, whether newer and more potent antiviral drugs such as entecavir and tenofovir can improve the long-term outcome should be studied. At present, there is limited experience in the use of more potent antiviral drugs in the setting of severe acute exacerbation, but this would likely become the future trend as these drugs become more widely available and affordable.
Three studies have provided long-term data on lamivudine treatment for severe acute exacerbation of chronic hepatitis B (Table 4). In a study among HBeAg-negative patients in Hong Kong, 32 patients received lamivudine treatment for up to 4 years.54 Maintained virological response (HBV DNA < 10 000 copies/mL) was achieved in 94%, 94%, and 71% at years 1, 2 and 3, respectively. At the end of follow up, 56% patients had undetectable HBV DNA by polymerase chain reaction and another 41% patients had HBV DNA between 100 and 10 000 copies/mL. Cumulative risk of genotypic lamivudine resistance was 3%, 6%, 11% and 25% at years 1, 2, 3 and 4, respectively. Although there was no control group in this study, the virological responses and drug resistance rate were numerically much better than that reported in patients suffering from HBeAg-negative chronic hepatitis B (Fig. 1).56
Table 4. Long-term treatment response to lamivudine in severe acute exacerbation of chronic hepatitis B
|Location||Hong Kong||Hong Kong||Japan|
|Follow-up duration (years)||2.5 ± 1.1 (0.9–4.2)||Median 2.8 (range 1.0–7.1)||Median 2.9 (range 1.8–4.4)|
|Bilirubin (µmol/L)||176 ± 146||106 (51–534)||80 (36–527)†|
|Alanine aminotransferase (IU/L)||1758 ± 1097||1325 (580–3041)||816 (86–2928)†|
|Clotting profile||International normalized ratio 1.63 ± 0.37||Prothrombin time 14.3 (10.0–23.8)||Prothrombin time 57% (27–73)†|
|HBeAg positive (%)||0||100||79†|
|HBV DNA (log copies/mL)||6.76 ± 1.94||8.08 (2.96–9.92)||8.69 (7.90–> 9.58)†|
|Maintained virological response‡||Twenty-one of 26 patients on maintenance therapy||Twenty-one of 29 patients on maintenance therapy||Eighteen of 21 patients|
|Virological breakthrough||Five of 32 patients (4 had rtM204I)||Eight of 45 patients (all had rtM204V/I and 7 had rtL180M)||Three of 21 patients (all had rtM204I)|
|Virological relapse alter stopping treatment||Four of six patients||Eleven of 15 patients after hepatitis B e antigen seroconversion||One patient had relapse immediately after stopping treatment|
Among HBeAg-positive patients with severe acute exacerbation of chronic hepatitis B, 45 patients were reported from Hong Kong receiving lamivudine for up to 7 years.55 In this study, HBeAg-positive patients who were treated with lamivudine in the same time period but did not have severe acute exacerbation were used as controls. HBeAg seroconversion occurred more frequently in patients with severe acute exacerbation (78%) as compared to the controls (52%) (P = 0.02). Cumulative risk of genotypic lamivudine resistance was 4%, 14%, 22%, 22% and 33% at year 1, 2, 3, 4 and 5, respectively, among patients with severe acute exacerbation, which again was lower than that among other HBeAg-positive chronic hepatitis B patients (Fig. 2). In the same vain, a Japanese study with predominantly HBeAg-positive patients also revealed a low rate of lamivudine resistance with a cumulative rate of 14% at year 3 among 21 patients receiving long-term lamivudine.43
The good virological response and the relative low incidence of lamivudine resistance among patients with severe acuteexacerbation reflect more potent immune viral clearance.58 However, the durability of lamivudine treatment is still poor. In the Hong Kong series, among six HBeAg-negative patients who stopped lamivudine after 1 year of treatment, four (67%) had virological relapse and two of them had severe acute exacerbation.54 Similarly, 11 of 15 (73%) HBeAg-positive patients who stopped lamivudine after HBeAg seroconversion developed virological relapse and two of them had severe acute exacerbation.55 This means that despite more potent immune response among patients with severe acute exacerbation, the durability of treatment is not better than that in other chronic hepatitis B patients.59,60 Furthermore, the high rate of severe acute exacerbation among the relapsers (18–50%) poses great risk to patients upon treatment cessation. Long-term antiviral therapy should be advocated to prevent further hepatitis exacerbations.
Management of lamivudine resistance
Data on the use of adefovir dipivoxil in severe acute exacerbation are scarce. In two case reports, adefovir dipivoxil failed to salvage cases of lamivudine resistance after jaundice and liver failure set in.61,62 One case died and the other required liver transplantation despite adefovir administration. Adefovir has relatively weak antiviral activity and the onset of action is slow.63 This also suggests that it may not be advisable to use adefovir as first-line treatment in severe acute exacerbation.
On the other hand, adefovir salvage therapy is possible if it is started early. In our experience, the majority of patients with lamivudine resistance respond to adefovir even though they had severe acute exacerbation prior to lamivudine treatment.55 This highlights the importance of vigilant HBV DNA monitoring and early salvage therapy in patients on antiviral therapy. Adefovir add-on therapy is most successful when the viral load remains low, before biochemical breakthrough occurs.64,65
High-dose entecavir and tenofovir are alternative agents for lamivudine resistance.66,67 Owing to the partial cross-resistance, entecavir resistance is common in lamivudine-refractory patients and may not be a good choice as salvage. Telbivudine shares cross-resistance with lamivudine and is therefore not recommended in lamivudine refractory patients.67
Supportive treatment for acute liver failure has been extensively reviewed elsewhere.5,68 In essence, close monitoring and aggressive treatment of complications are required. In patients with grade III–IV hepatic encephalopathy, airway protection by tracheal intubation should be considered. The head of the bed should be elevated, and insertion of an intracranial pressure monitoring device may be considered. Infection and coagulopathy are treated with antibiotics and transfusion support, respectively. Terlipressin and albumin infusion are useful in type 1 hepatorenal syndrome.69 Electrolytes, fluid status, glucose and nutrition should also be monitored closely.
Liver support systems have been tested in patients with acute liver failure. Albumin dialysis, such as by Molecular Adsorbents Recirculation System (MARS), attempts to achieve detoxification by artificial means. Lately, bioartificial devices are introduced to mimic hepatic function by the addition of human or mammalian hepatocytes.70 However, the reported studies included few patients and the beneficial effects were usually transient and not reproducible. At present, liver support systems cannot be recommended outside clinical trial settings.5
The outcome of acute liver failure after liver transplantation is good. In a multicenter prospective study of 308 consecutive patients with acute liver failure in the USA, the short-term survival was 84% among those who received liver transplantation.71 In our small series, three of four patients undergoing transplantion for severe acute exacerbation and acute-on-chronic hepatic failure did not develop resistance on lamivudine monoprophylaxis and two of them survived in a follow up of 61 to 166 weeks.72 Owing to the shortage of organs in Asia, living donor liver transplantation has become increasingly important to improve the survival of acute-on-chronic hepatic failure related to severe acute exacerbation of chronic hepatitis B.73
Severe acute exacerbation of chronic hepatitis B is a unique presentation that may progress to liver failure and death. The diagnosis requires careful history taking and ruling out other causes of acute liver failure. Serum ALT may fall during massive hepatic necrosis and does not predict outcome. Patients with underlying cirrhosis are at highest risk of developing liver failure and death. Hyperbilirubinemia, thrombocytopenia and coagulopathy are important prognostic factors. Antiviral therapy has no obvious impact on short-term survival, but may prevent future exacerbations and ongoing liver injury. The majority of patients with severe acute exacerbation are likely to achieve maintained virological response even with weaker antiviral drugs such as lamivudine, but drug resistance and virological breakthrough remain major challenges. Long-term antiviral therapy is recommended as virological relapse resulting in another severe acute exacerbation is common after cessation of the antiviral agent. Outcome data on the use of newer antiviral drugs for this condition is urgently needed. Liver transplantation, particularly living donor liver transplantation, is the last resort of treatment for patients who develop acute-on-chronic hepatic failure secondary to severe acute exacerbation.