Hepatitis B Annual

: 2007  |  Volume : 4  |  Issue : 1  |  Page : 107--117

Management of severe acute hepatitis B

Sudeep Khanna, Rakesh Tandon 
 Department of Gastroenterology and Metabolic Disorders, Pushpawati Singhania Research Institute for Liver, Renal and Digestive Diseases, Sheikh Sarai, Phase II, Press Enclave Road, New Delhi-110 017, India

Correspondence Address:
Sudeep Khanna
Department of Gastroenterology and Metabolic Disorders, Pushpawati Singhania Research Institute for Liver, Renal and Digestive Diseases, Sheikh Sarai, Phase II, Press Enclave Road, New Delhi-110 017


HBV infection is a major public health problem. Acute viral hepatitis B is successfully cleared in more than 95% of immunocompetent patients. HBV infection can cause severe acute hepatitis which can progress to acute liver failure. The purpose of this review is to discuss the immune response in acute hepatitis B and the possible role of HBV genotypes in development of severe acute HBV related hepatitis, define severe acute hepatitis B and to look at the role of the available antivirals in this clinical setting.

How to cite this article:
Khanna S, Tandon R. Management of severe acute hepatitis B.Hep B Annual 2007;4:107-117

How to cite this URL:
Khanna S, Tandon R. Management of severe acute hepatitis B. Hep B Annual [serial online] 2007 [cited 2021 Oct 24 ];4:107-117
Available from: https://www.hepatitisbannual.org/text.asp?2007/4/1/107/45092

Full Text


There are approximately 400 million people world-over infected with hepatitis B virus (HBV). There are approximately 250,000 deaths each year from complications of liver injury secondary to HBV infection. [1] In India, a conservative estimate of deaths because of complications related to HBV infection would be 100,000 per year. [2] Acute HBV infection is usually self limited. However 5 to 10% of patients do not clear the virus and develop a chronic carrier state that may or may not progress to significant liver disease. [1] HBV infection is responsible for 14 to 30% of cases of acute viral hepatitis (AVH) in India. [3],[4],[5] Occult HBV infection may be the etiology of acute liver failure (ALF) in varying number of patients depending upon the geography. It has been reported in 0-4% from Europe [6],[7] and up to 50% from Japan in patients with ALF. [8],[9] Thus it becomes important to find out if any available therapy can play a role in preventing the progression of AVH-B to severe hepatitis and ALF.

 Immune Response in Acute Hepatits B

Previous studies in acute symptomatic HBV infection have shown vigorous polyclonal class I-restricted cytotoxic T lymphocyte (CTL) and class II-restricted CD4+ T-helper responses to the envelope, nucleocapsid, polymerase and core proteins in the peripheral blood of patients who successfully clear the infection. It has been seen that the activated HBV-specific CTLs can persist for long periods after clinical recovery from an acute HBV infection due to persistent low levels of HBV DNA. This indicates that despite clinical and serologic recovery, HBV infection may persist, controlled by specific CTL activity which in turn is maintained by low levels of persisting virus. [1] These earlier studies had used chromium release assays, which measure the cytolytic effector function of CTLs. It is now known that chromium release assays are of limited sensitivity. Highly activated cells may undergo apoptosis during the multiple rounds of stimulation required for measurement of cytolysis and thus may not be detected in the final analysis. Different effector functions of CTLs have been used to develop more sensitive assays. For example, ELISPOT, which exploits the release of cytokines by CTL upon recognition of antigen, is more sensitive and quantitative than chromium release assays. The more recent generation of assays measures the binding of antigen to T-cell receptors expressed on the surface of the CTL. Biotinylated class I major histocompatibility complex (MHC) molecules are loaded with peptides and linked in tetramer to streptavidin. After incubation of cells with the tetramers, the percentage of cells binding to the complexes can be measured by flow cytometry; these assays can also incorporate measurement of cell surface markers for activation and memory and of intracellular cytokine production. [10] For HBV infection, these synthetic peptides represent epitopes recognized by HBV-specific CTLs. The advantages of the MHC-peptide tetramer assays are their relatively greater speed and sensitivity compared to traditional assays. The assay has revolutionized our understanding of the kinetics and role of CTLs in many viral infections. [11] Its disadvantage is that it is limited to the study of defined HLA types (most typically HLA A201) and to epitopes that bind to the MHC with high affinity.

Circulating natural killer cells are increased in all patients early in the incubation period consistent with their role in early phases of viral infection. [12] The reduction in natural killer cell number goes hand in hand with the reduction in HBV DNA levels. In a study by Webster et al, [13] in the immunocompetent patients, the CTL responses increased with corresponding increase in serum ALT and symptoms and reached a peak corresponding to the onset of jaundice or symptoms. This rise occured after the fall in HBV DNA but was strongly associated with evidence of liver damage. In contrast, in the immunosuppressed patient in this study, there was no significant increase in the number of CTL responses; neither did this patient develop a biochemical hepatitis nor did he clear the HBsAg, which was consistent with the observation that HLA class I-restricted CTLs are responsible for the observed necroinflammatory process and viral eradication. The study also revealed that the number of CTLs decreased before clinical illness and peak ALT. However, this should be interpreted with some caution, because it is possible that even higher frequencies of CTL responses would have been observed if patients had been sampled for CTL frequency and HBV DNA between weeks 11 and 15. Besides, this analysis was based on a small number of epitopes.

Recovery from acute HBV infection is usually associated with a vigorous polyclonal CD4+ T-cell response directed against multiple epitopes and antibody responses directed against the surface envelope proteins. [14] In the study by Webster et al, [13] HBV-specific CD4+ T-cell responses were detected only in one patient early in the incubation period, which is surprising in the view of the strong CTL responses and the development of core antibody. This in fact may reflect sequestration of CD4+ T cells within the liver during this early phase of infection rather than a sensitivity issue of the assay. If the frequency of HBV-specific CTLs were stable or declining before the clinical illness, then what caused the liver damage? The investigators [13] suggested that the initial influx of HBV-specific T cells leads to the subsequent recruitment or local proliferation of nonspecific T cells. This non-specific proliferation of T cells may result either from stimulation by cross-reactive antigens or by cytokine-mediated bystander activation. [15] T-cell receptor occupancy is not a prerequisite for activation of T cells during viral infection and cytokines such as interleukin 2, tumor necrosis factor α and interleukin 6 can activate not only memory T cells but also antigen-naive T cells. [15] Therefore, it is possible that cytokines produced by HBV-specific cells activate other T cells or enhance the recruitment of T cells into the liver. It has been demonstrated in chronic hepatitis B, that the number of HBc18-27 tetramer-positive cells was not different in patients with chronic HBV and normal transaminases compared with those patients with chronic HBV and increased transaminases. However, the number of total CD8+ T cells in the liver was much higher in those with liver damage, suggesting that the continued presence of an incompletely effective immune response led to recruitment of non-specific T cells. [16] Like most of our understanding of CTL, this concept of bystander activation is undergoing re-evaluation with the ability to more specifically measure immune responses using tetramers. Further insight into whether this does or does not occur in acute HBV will depend on advances with small animal models, because it is obviously not feasible to perform multiple liver biopsies in acute hepatitis. However, a limiting step in the woodchuck model will be the expression of class 1 homologues and definition of CTL isotopes that bind with high affinity.

 Role of HBV Genotypes in Acute Severe Hepatits B

Eight genotypes have been detected by a sequence divergence greater than 8% in the entire HBV genome of approximately 3,200 nucleotides (nt) and designated by capital alphabet letters from A (HBV/A) to H in the order of documentation. [17],[18] The geographical distribution of these genotypes is distinct and the genotypes have been found to be associated with severity of liver disease as well as response to antiviral therapies. [17],[18],[19] Furthermore, subgenotypes have been reported for HBV/A, B and C and named Aa/A1 (Asian/African type) and Ae/A2 (European type), Bj/B1 (Japanese type) and Ba/B2 (Asian type), as well as Cs/C1 (Southeast Asian type) and Ce/C2 (East Asian type). [20],[21] Increasing lines of evidence indicate that subgenotypes of HBV/A and B influence the replication of HBV and this is of clinical relevance. [20],[21] Furthermore, genotypes also affect mutations in precore region and core promoter, thereby influencing the expression of hepatitis B e antigen (HBeAg). [20],[21]

In a recently published study from Japan, 301 patients with AVH-B were analyzed. [22] Comparison of various host and virological factors was made between patients with ALF and acute self-limiting hepatitis.There were 40 patients with ALF and 261 with acute self-limited hepatitis. Patients with fulminant hepatitis were significantly older, more often female and less often positive for HBeAg (23% vs. 60%, P0.0001) than those with acute hepatitis. Peak ALT and total bilirubin levels were higher for fulminant than acute hepatitis (P0.0001) indicating severe hepatic injury. It is also noteworthy that the median HBV DNA level was lower in patients with fulminant than acute hepatitis (4.89 vs. 5.19 log copies/mL, PP0.0086). As far as distribution of genotypes is concerned, HBV/Ae was less frequent (0% vs. 13%, P0.0121), whereas Bj was more often (30% vs. 4%, P0.0001) in patients with ALF. Although HBV/Ce genotype was less common in patients with ALF versus AH (55% vs. 65%), the difference fell short of assuming significance. Precore stop-codon mutation (G1896A) and core-promoter double mutation (A1762T/G1764A) were more frequent in patients with ALF than AH (53% vs. 9% and 50% vs. 17%, respectively; p0.0001 for each). Besides, the mutations in core-promoter at nt 1753 or nt 1754 and G1899A mutation were more frequent in patients with fulminant than acute hepatitis (p0.0003 and p0.0001, respectively).

In view of the majority of Japanese patients who were infected with Bj or Ce, mutations in the precore region and core-promoter were compared between those with fulminant and acute self-limiting hepatitis for each subgenotype. G1896A and A1762T/G1764A were significantly more frequent in patients with fulminant than acute hepatitis infected with either HBV/Bj or Ce (56% vs. 0% and 67% vs. 0% for Bj or 44% vs. 11% and 56% vs. 22% for Ce, respectively; p0.01 for all). For the patients infected with HBV/Bj, in particular, precore and core-promoter mutations were highly frequent in those with fulminant hepatitis (56% and 67%, respectively), whereas they occurred in none of those with acute self-limiting hepatitis. G1899A was equally prevalent in both groups - patients with fulminant and acute self-limiting hepatitis infected with HBV/Bj; it was rarely seen in those with Ce. Mutations involving nt 1753 or nt 1754 tended to be more frequent in patients with ALF than acute self-limiting hepatitis. None of the 33 patients with HBV/Ae genotype developed ALF. In contrast, 55% of patients with HBV/Bj developed ALF.

In vitro replication analysis demonstrated that the intracellular HBV DNA level of the wild-type HBV/Bj was comparable with that of the wild-type Ce. The extracellular HBV DNA level of HBV/Bj-clone, however, was much higher than those of the other genotypes, indicating its strong inclination to be secreted from cells. Such a high concentration of HBV/Bj in the circulation of patients would rapidly and extensively promote infection of hepatocytes. [22]

 Defining Severe Acute Hepatitis B

All patients who are likely to progress to ALF are said to have severe acute hepatitis B. The only available study which has attempted to give a definition for severe AVH-B is from India. [23] In this study patients were classified as having severe AVH-B if they fulfilled any 2 of the 3 criteria:

hepatic encephalopathy, serum bilirubin equal to or more than 10mg/dl; and international normalized ratio (INR) more than or equal to 1.6.

 Management of Severe Acute Hepatitis B

The drugs approved for treating chronic HBV infection include Lamivudine, Adefovir, Entecavir, Telvubidne and Interferon. There is no dearth of literature on the role of these drugs in managing chronic hepatitis B - including their side-effects, response rates and resistance. Unfortunately there is not much literature on the role of antiviral therapy in severe acute hepatitis B. Lamivudine has been tried successfully in immunocompromised patients and in patients with liver transplant with AVH-B. [24],[25] The experience with lamivudine treatment of immunocompetent patients with AVH-B is limited. In a case report, a 74-year-old patient with acute hepatitis B and hepatic encephalopathy responded to lamivudine with the disappearance of serum HBsAg. [26] In a small study, 3 patients with acute hepatitis B were treated with lamivudine 150 mg daily. In all the patients, serum HBV DNA became undetectable and HBsAg and HBeAg disappeared. [27] In a study of 46 patients with severe acute hepatitis B (the criteria for severity were unclear), 3 months after lamivudine treatment, serum HBV DNA became undetectable in all the patients and anti-HBe became positive in 87.5% of the patients. [28] In another study, 15 patients with severe acute HBV infection were treated with lamivudine 100 mg daily for 3-6 months; 5 of these patients had grade 1-4 encephalopathy, prior to the onset of treatment. Thirteen (86.6%) patients responded. Encephalopathy disappeared within 3 days of treatment. Serum HBV DNA became undetectable (by PCR) within 4 weeks and liver enzymes normalized within 8 weeks. Anti-HBe developed in 9 of 11 HBeAg-positive patients within 12 weeks. [29] A study by Hasan and colleagues [30] assessed the efficacy and safety of lamivudine in 17 consecutive immune-competent acute HBV patients; treatment with lamivudine 100 mg/day was started within 10-33 days of onset of illness. All patients had an international normalized ratio (INR) >1.5, with mean alanine aminotransferase (ALT) levels of 3223 1405 IU/mL and elevated serum bilirubin. In 16 of 17 patients, HBsAg was lost within 4 weeks of therapy, but 1 patient died of fulminant hepatic failure. The study authors concluded that although larger studies are needed, lamivudine does have a role in preventing progression to fulminant hepatic failure. However, since 95% of immune-competent adults clear HBsAg spontaneously and because there was no control arm in this study, it is difficult to ascertain whether lamivudine really altered the natural course of illness in these patients. However, it would seem reasonable to offer therapy to all patients with either severe acute HBV infection or those with acute decompensation of chronic disease.

Kumar et al, [23] conducted the only published randomized controlled trial to look at the role of lamivudine in severe acute hepatitis B. AVH-B patients with serum bilirubin of more than 5 mg/dL were randomized to receive either 100 mg of lamivudine daily for 3 months (group 1; n = 31) or placebo (group 2; n= 40). Patients were considered to have severe AVH-B if they fulfilled 2 of the 3 criteria: (1) hepatic encephalopathy; (2) serum bilirubin > 10.0 mg/dL; and (3) international normalized ratio (INR)>1.6. At week 4, HBV DNA levels were significantly lower (P 0.037) in group 1 (median: 3.6721 log copies/mL) than group 2 (median: 4.2721 log copies/mL). Thereafter, HBV DNA levels were comparable in the 2 groups. The improvement in serum bilirubin, ALT and INR values was similar in the 2 groups. Twenty-two patients (71%) in group 1 and 25 patients (62.5%) in group 2 had severe AVH-B. Results were similar when patients with severe AVH-B were analyzed separately. After 12 and 18 months, 93.5% and 92.5%, respectively, of patients in the lamivudine group and 96.7% and 97.5%, respectively, of patients in the placebo group lost HBsAg. There were no deaths in either group. After 1 year, 21 patients (67.7%) in group 1 and 34 patients (85%) in group 2 developed protective anti-HBs titers (P 0.096). All HBeAg-positive patients in both groups lost e antigen and anti-HBe developed in 71% and 87.5% of patients in groups 1 and 2 respectively (p 0.132). Thus it was concluded that though lamivudine causes a greater decrease in levels of HBV DNA, it does not cause significantly greater biochemical and clinical improvement as compared to placebo in patients with acute hepatitis B. At present, studies are not available on the utility of other antiviral drugs approved for chronic HBV infection - in the management of severe acute hepatitis B.


HBV infection is a common cause of AVH in India. More studies are required to look at the genotype associated with severe acute hepatitis and the role of antivirals in these cases, so that antivirals may be started in this group of patients early in the course of disease. Till we have the results from such studies, it is probably justified in starting lamivudine for a short duration of time - in the group of patients with severe acute hepatitis B.


1Curry MP, Koziel M. The dynamics of immune response in acute hepatitis B: New lessons using new techniques. Hepatology 2000;32:1177-9.
2Singh SP. Hepatitis B Eradication Day: It's never too late!! Hep B Annual 2006;3:11-3.
3Hussain Z, Das BC, Husain SA, Murthy NS, Kar P. Increasing trend of acute hepatitis A in north India: Need for identification of high-risk population for vaccination. J Gastroenterol Hepatol. 2006;21:689-93.
4Kaur H, John M, Pawar G, Ninan J, Verma V. Spectrum of acute viral hepatitis and its clinical outcome: A study from Ludhiana, Punjab. Indian J Med Sci 2003;57:71-5.
5Khuroo MS, Kamili S. Aetiology and prognostic factors in acute liver failure in India. J Viral Hepat 2003;10:224-31.
6Mutimer D, Shaw J, Neuberger J, Skidmore S, Martin B, Hubscher S, et al. Failure to incriminate hepatitis B, hepatitis C and hepatitis E viruses in the aetiology of fulminant non-A non-B hepatitis. Gut 1995;36:433-6.
7Feray C, Gigou M, Samuel D, Reyes G, Bernuau J, Reynes M, et al. Hepatitis C virus RNA and hepatitis B virus DNA in serum and liver of patients with fulminant hepatitis. Gastroenterology 1993;104:549-55.
8Suzuki C, Yamashita S, Korenaga M, Uchida K, Tanigawa K, Kimura T, et al. Detection of hepatitis B virus DNA in liver by polymerase chain reaction for the diagnosis of fulminant hepatits B. Hepatol Res 1998;12:23-30.
9Fukai K, Yokosuka O, Fujiwara K, Tagawa M, Imazeki F, Saisho H, et al. Etiologic considerations of fulminant non-A, non-B viral hepatitis in Japan: Analyses by nucleic acid amplification method. J Infect Dis 1998;178:325-33.
10Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI, et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 1996;274:94-6.
11Doherty PC, Christensen J. Accessing complexity: The dynamics of virus specific T cells responses. Ann Rev Immunol 2000;18:561-92.
12Biron C, Nguyen K, Pien G, Cousens L, Salazar-Mather T. Natural killer cells in antiviral defence: function and regulation by innate cytokines. Ann Rev Immunol 1999;17:189-220.
13Webster GJ, Reignat S, Maini MK, Whalley SA, Ogg GS, King A, et al. Incubation phase of acute hepatitis B in man: Dynamic of cellular immune mechanisms. Hepatology 2000;32:1117-24.
14Koziel M. The immunopathogenesis of HBV infection. Antivir Ther 1998;3:13-24.
15Abrignani S. Antigen-independent activation of resting T-cells in the liver of patients with chronic hepatitis. Dev Biol Stand 1998;92:191-4.
16Maini M, Boni C, Lee C, Larrbia J, Reignat S, Ogg G, et al. The role of virus-specific CD81 cells in liver damage and viral control during persistent hepatitis B infection. J Exp Med 2000;191:1269-80.
17Chu CJ, Lok AS. Clinical significance of hepatitis B virus genotypes. Hepatology 2002;35:1274-6.
18Miyakawa Y, Mizokami M. Classifying hepatitis B virus genotypes. Intervirology 2003;46:329-38.
19Kramvis A, Kew MC. Relationship of genotypes of hepatitis B virus to mutations, disease progression and response to antiviral therapy. J Viral Hepatol 2005;12:456-64.
20Tanaka Y, Hasegawa I, Kato T, Orito E, Hirashima N, Acharya SK, et al. A case-control study for differences among hepatitis B virus infections of genotypes A (subtypes Aa and Ae) and D. Hepatology 2004;40:747-55.
21Lindh M, Andersson AS, Gusdal A. Genotypes, nt 1858 variants and geographic origin of hepatitis B virus: Large-scale analysis using a new genotyping method. J Infect Dis 1997;175:1285-93.
22Osaza A, Tanaka Y, Orito E, Sugiyama M, Kang J, Hige S, et al. Influence of enotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection. Hepatology 2006;44:326-34.
23Kumar M, Satapathy S, Monga R, Das K, Hissar S, Pande C, et al. A randomized controlled trial of lamivudine to treat acute hepatitis B. Hepatology 2007;45:97-101.
24Andreone P, Caraceni P, Grazi GL, Belli L, Milandri GL, Ercolani G, et al. Lamivudine treatment for acute hepatitis B after liver transplantation. J Hepatol 1998;29:985-9.
25Castells L, Vargas V, Rodriguez F, Allende H, Buti M, Sanchez-Avila JF, et al. Clinical impact and efficacy of lamivudine therapy in de novo hepatitis B infection after liver transplantation. Liver Transpl 2002;8:892-900.
26Reshef R, Sbait W, Tur-Kaspa R. Lamivudine in the treatment of acute hepatitis B. N Engl J Med 2000;343:1123-4.
27Torii N, Hasegawa K, Ogawa M, Hashino E, Hayashi N. Effectiveness and long-term outcome of lamivudine therapy for acute hepatitis B. Hepatol Res 2002;24:34.
28Abagiu AO, Duna FM, Radulescu CA. Lamivudine in severe acute viral B hepatitis. J Hepatol 2003;38:121.
29Schmilovitz-Weiss H, Ben-Ari Z, Sikuler E, Zuckerman E, Sbeit W, Ackerman Z, et al. Lamivudine treatment for acute severe hepatitis B: A pilot study. Liver Int 2004;24:547-51.
30Hasan F, Owaid S, Ali M. Lamivudine monotherapy for severe acute hepatitis B. J Hepatol 2005;42:A493.