|Year : 2016 | Volume
| Issue : 2 | Page : 166-172
Treatment with lamivudine and entecavir in severe acute hepatitis B
A Streinu-Cercel1, O Sandulescu1, M Stefan2, A Streinu-Cercel1
1 Department of Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest 050474,; Department of Adults II, National Institute for Infectious Diseases, Bucharest 021105, Romania
2 Department of Applied Sciences, Polytechnic University of Bucharest, Bucharest 060042, Romania
|Date of Submission||29-Jul-2013|
|Date of Acceptance||14-Dec-2015|
|Date of Web Publication||14-Apr-2016|
Department of Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest 050474,; Department of Adults II, National Institute for Infectious Diseases, Bucharest 021105
Source of Support: None, Conflict of Interest: None
Background: Severe acute hepatitis B (SAHB) is an insufficiently described clinical entity, with relatively scarce data on anti-viral therapy available in field literature. Methods: We performed an open-label study to evaluate specific anti-viral therapy in SAHB in Bucharest, Romania, during 2005-2009. Patients were allocated to two treatment groups and one control group: Group 1 - lamivudine 100 mg/day, Group 2 - entecavir 0.5 mg/day and Group 3 - standard of care, without anti-viral therapy. The primary endpoint was hepatitis B surface antigen (HBsAg) to hepatitis B surface antibody (anti-HBs) seroconversion by 24 weeks. Additional analyses included assessment of HBsAg clearance and hepatitis B e antigen (HBeAg) to hepatitis B e antibody (anti-HBe) seroconversion. Results: In Group 1, 7/69 patients (10.14%, P = 0.032) reached HBsAg/Ab seroconversion by 24 weeks, compared with 9/21 (42.85%, P = 0.053) in Group 2 and 25/110 (22.72%) in Group 3. HBsAg clearance by 24 weeks: 16/69 patients (23.18%, P = 0.027) in Group 1, 11/21 (52.38%, P = 0.256) in Group 2 and 43/110 (39.09%) in Group 3. HBeAg/Ab seroconversion: 46/61 (75.40%, P = 0.399) in Group 1, 9/19 (47.36%, P = 0.001) in Group 2 and 74/100 (74.00%) in Group 3. Conclusion: Anti-viral therapy can be considered for managing selected cases of SAHB. Biochemical as well as virological parameters need to orient the choice of the anti-viral agent. Lamivudine displayed a greater decrease in viral load compared to controls, but it was associated with lower levels of HBsAg to anti-HBs seroconversion. Patients treated with entecavir showed a better response in terms of HBs seroconversion by 24 weeks.
Keywords: Acute hepatitis B, antiviral, hepatitis B surface antigen, hepatitis B virus, virologic response
|How to cite this article:|
Streinu-Cercel A, Sandulescu O, Stefan M, Streinu-Cercel A. Treatment with lamivudine and entecavir in severe acute hepatitis B. Indian J Med Microbiol 2016;34:166-72
|How to cite this URL:|
Streinu-Cercel A, Sandulescu O, Stefan M, Streinu-Cercel A. Treatment with lamivudine and entecavir in severe acute hepatitis B. Indian J Med Microbiol [serial online] 2016 [cited 2019 Sep 22];34:166-72. Available from: http://www.ijmm.org/text.asp?2016/34/2/166/176837
| ~ Introduction|| |
Hepatitis B virus (HBV) chronically infects roughly 350 million people worldwide. Chronic hepatitis B is the well-known outcome of the disease , whereas severe acute hepatitis B (SAHB) is an insufficiently described clinical entity.  The transition between mild outcomes of disease and fulminant hepatitis, and criteria for diagnosis are somewhat equivocal. Patients with recently acquired HBV infection who are likely to progress to acute liver failure are said to have SAHB.  Hepatitis guidelines do not present enough clinical data to indicate whether anti-viral therapy for SAHB increases the rate of seroconversion; for this reason, we performed a study to assess the impact of lamivudine or entecavir on the evolution of SAHB. Nowadays, given the current knowledge, designing future randomised placebo-controlled trials for SAHB could be considered unethical, and comparative efficacy trials would rather be more adequate. However, this was not the case when this particular study was designed: it was conducted at a time when the options available were limited and when data were mainly derived from sporadic case presentations.
| ~ Methods|| |
As described by other authors, diagnosis of SAHB should include two of the following three criteria: (1) hepatic encephalopathy; (2) serum bilirubin above 10 mg/dL and (3) International Normalised Ratio (INR) above 1.6. , Another definition is closer to that used for the study we are reporting: prothrombin ≤36%, INR >2.0, absolute prothrombin time ≥23 s.  These are all definitions provided by other authors, in their respective studies, in the attempt to better describe SAHB.
The definition used for the study we are reporting was based on the clinical and biochemical characterisation of the outline of disease seen in Romanian patients: "A marked deterioration of hepatic function in patients with recently acquired HBV infection, translated into an alanine aminotransferase (ALT) >5 times the upper normal limit plus a prothrombin concentration of ≤36% or an INR >2.0." Recently acquired infection was considered as positive immunoglobulin M (IgM) hepatitis B core antibodies (anti-HBc).
At the time when the study was designed, field literature was scarce in data regarding anti-viral therapy in SAHB. ,,,, Recent updates in hepatitis B guidelines  do mention the possible use of anti-virals in protracted SAHB and that treatment should be continued until hepatitis B surface antigen (HBsAg) clearance is confirmed  or for at least 3 months after seroconversion to hepatitis B surface antibodies (anti-HBs). However, to date, there is still no precise indication as to which patients would benefit from anti-viral therapy in SAHB, field literature presenting isolated clinical cases , rather than complex, randomised studies, on representative patient groups. ,
The hypotheses of our study were: (1) Does HBV-specific anti-viral therapy correlate with recovery from SAHB? and (2) Does it limit the progression to chronic hepatitis B?
This was a prospective, open-label study conducted in Romania, evaluating the efficacy of anti-viral treatment in patients with SAHB. The study was performed at the Institute over the course of 4 years (May 2005 to May 2009), and it included 200 patients with SAHB. The main viral genotype circulating in Romania during the time span of the study was genotype D, as shown by the Romanian epidemiology data for HBV infection. The initial study design stipulated random allocation of patients into two study groups: a lamivudine treatment group and a control group. Over the course of the study, in the beginning of 2007, entecavir became available as specific anti-viral therapy for hepatitis B in Romania, so we amended the protocol to include a second treatment group, for entecavir, based on an algorithm for continuing randomisation.
For a statistical power of 90%, the initial sample size was calculated at 160 using Altman's nomogram  and a standardised difference calculated at 0.4. To our knowledge, no standard deviation is available for the primary outcome, and since a literature review revealed no similar studies in comparable populations, we calculated it based on estimated proportions, as indicated by Whitley and Ball. 
A computer-generated list of random numbers was used. We initially applied simple, 1:1 randomisation, followed by an algorithm for continuing randomisation once the second treatment group was included. Given the different formulation and appearance of the administered drugs (lamivudine comes as oval-shaped, white tablets and entecavir as triangular, blue tablets) and the individualised nature of the usual care administered in the control group, masking could not be performed and patients and physicians were aware of the allocated groups. However, our data analysts were blinded to the allocation.
Eligible participants were adults diagnosed with SAHB as described above, by: positive serum HBsAg, IgM anti-HBc, active viral replication (detectable HBV-DNA), hepatic cytolysis (five times the upper normal limit of ALT); prothrombin concentration ≤36% or INR >2.0; a negative serum pregnancy test was required for female subjects of fertile age. To exclude reactivations of chronic HBV infection and ascertain the acute status of infection, subjects were also required to present a previous negative screening test (HBsAg) not older than 6 months.
Exclusion criteria were: superinfection or co-infection with hepatitis D virus, hepatitis C virus, Epstein-Barr virus, cytomegalovirus or HIV;  other causes of acute hepatitis; ,, history of prior exposure to study drugs; hepatic diseases such as: Wilson's disease, alcoholic steatohepatitis, autoimmune hepatitis; signs of chronic liver disease; obstructive or haemolytic malignant jaundice; systemic causes of prolonged prothrombin time; intravenous drug use; history of drug hypersensitivity; any other condition (including alcohol or substance abuse) or prior therapy that could make the subject unsuitable for the study or unable to comply with dosing requirements.
Prior to inclusion, all patients gave their written informed consent to participate in the study. The study protocol was in line with the ethical prerogatives of the 1975 declaration of Helsinki and respected the Good Clinical Practice standards. The study included one clinical site and received approval of the Review Board and the Ethics Committee of the Institute for the study protocol and the informed consent forms.
Group 1 received the standard of care (SOC) for SAHB + lamivudine (GlaxoSmithKline, UK), 1 tablet of 100 mg orally once daily, at the same time of day.
Group 2 received SOC for SAHB + entecavir (Bristol-Myers Squibb, USA), 0.5 mg orally once daily, at the same time of day.
For both treatment groups, in case of HBsAg to anti-HBs seroconversion or occurrence of serious adverse events (SAE), anti-viral therapy was to be stopped earlier than intended. The maximum intended duration of administration was 24 weeks; however, patients who did not clear HBsAg by 24 weeks continued into our chronic hepatitis B program and received the appropriate care, as recommended by the respective guidelines.
We did not use a placebo, Group 3 receiving SOC for SAHB which would include any of the following, according to the individual needs of the patients: hospitalisation, endovenous perfusions with arginine, ursodeoxycholic acid and/or, in case of coagulation issues, fresh frozen plasma.
The primary endpoint was HBsAg to anti-HBs seroconversion by 24 weeks. Additional analyses included assessment of HBsAg clearance and hepatitis B e antigen (HBeAg) to hepatitis B e antibody (anti-HBe) seroconversion.
Outcomes were assessed at several time points after randomisation: at baseline, weekly during the first 4 weeks, at 8, 12 and 24 weeks, with a follow-up visit at 48 weeks. The prespecified time point of primary interest was 24 weeks.
HBsAg to anti-HBs seroconversion was considered an equivalent of recovery from hepatitis B (with the obvious limitation of using this concept in relation to HBV, a virus known to integrate in hepatocytes' genomes).  An improvement in the evolution of disease was defined as HBeAg to anti-HBe seroconversion, , improvement of coagulation (prothrombin concentration over 60%, normalisation of INR).
We used the S-Plus 6 software (TIBCO, Palo Alto, CA, USA) and applied the independent samples Z test for comparing two proportions. In interpreting results, we considered P < 0.05 to be statistically significant. We report the P values for comparisons of treatment groups versus control.
HBV-DNA was assessed with Abbott HBV-DNA PCR kit, real-time polymerase chain reaction assay, Princeton, New Jersey, USA: detection limit - 27 IU/mL and analytical sensitivity - 12 IU/mL. For hepatic markers, we used VITROS 3602 Immunodiagnostic Systems (Ortho Clinical Diagnostics, Johnson and Johnson, Raritan, New Jersey, USA). For ALT, the reference range was 9-52 U/L and for AST, 14-36 U/L (VITROS_1, Ortho Clinical Diagnostics, Johnson and Johnson, Raritan, New Jersey, USA).
| ~ Results|| |
We assessed 249 patients with symptomatic acute hepatitis B for eligibility: 36 were found to be not eligible (not meeting the criteria for SAHB) and 13 met at least one of the exclusion criteria [Figure 1]. A total of 200 patients were randomised into three groups.
|Figure 1: Patient flow diagram. HCV: hepatitis C virus, CMV: cytomegalovirus, ASH: alcoholic steatohepatitis, ITT: intention-to-treat analysis|
Click here to view
The sizes for G1 and G2 were determined by the available quantity of anti-viral drugs that we were able to provide for the study. Local availability and the introduction of entecavir in 2007 were the sole reasons for selecting a smaller group of patients to be treated with entecavir.
Over the course of the study, 6 patients were lost to follow-up. We performed an intention-to-treat analysis that included 69 patients in G1, 21 in G2 and 110 in G3.
We recorded no cases of hypersensitivity to therapy. Nausea and vomiting were recorded in 6 and 4 patients, respectively, in G1, 5 and 3 in G2 and 3 and 2 in G3. These events were mild and did not require stopping therapy. There were no SAEs.
The age distribution was similar in the three groups, with a median age of 37.9 in Group 1, 34.8 in Group 2 and 35.2 in Group 3. The two treatment groups displayed a slight predominance of the male gender whereas the control group displayed a slight predominance of the female gender. The baseline characteristics of the study population are presented in [Table 1].
In G1, 7/69 patients (10.14%, [Figure 2]) displayed HBsAg/Ab seroconversion by 24 weeks (Z test P = 0.032), compared with 9/21 patients (42.85%) in G2 (Z test P = 0.053) and 25/110 (22.72%) in G3.
|Figure 2: Hepatitis B surface antigen to antibody seroconversion in the three groups|
Click here to view
Clearance of hepatitis B surface antigen
We assessed HBsAg clearance by 24 weeks, as an indicator for preventing progression to chronic hepatitis B.  Initially, HBsAg clearance appeared similar but gradually, the three groups displayed different evolutions with different therapeutic implications. We recorded HBs antigen clearance in 16/69 patients (23.18%) in G1 (Z test P = 0.027), 11/21 (52.38%) in G2 (Z test P = 0.256) and 43/110 (39.09%) in G3 [Figure 3].
|Figure 3: Percentage of patients that cleared hepatitis B surface antigen in the 3 study groups|
Click here to view
Hepatitis B e antigen to hepatitis B e antibody seroconversion
HBeAg/Ab seroconversion was recorded in 46/61 (75.40%) in G1 (Z test P = 0.399), 9/19 (47.36%) in G2 (Z test P = 0.001) and 74/100 (74.00%) in G3 [Figure 4].
|Figure 4: Hepatitis B e antigen to antibody seroconversion in the three groups|
Click here to view
The logarithmic evolution of HBV-DNA in the three groups showed that at 24 weeks, 56/69 (81.15%) of the patients in G1 displayed a decrease with more than 2log at 24 weeks, compared to 14/21 (66.66%) in G2 and 102/110 (92.72%) in G3.
Clinical and paraclinical parameters
The overall clinical evolution was favourable in all groups. In G1, 59 patients (85.50%) displayed normal prothrombin concentrations by 24 weeks, compared with 18 patients (85.71%) in G2 and 101 patients (91.81%) in G3. The differences between groups were not statistically significant (Z test P = 0.09 for G1 and Z test P = 0.42 for G2).
Total bilirubin returned to normal by 24 weeks in 19 patients in G1 (27.53%, Z test P = 0.0001) and 4 patients in G2 (19.04%, Z test P = 0.0005), compared to 25 patients (22.72%) in G3.
AST returned to normal by 24 weeks in 19 patients in G1 (27.53%, Z test P = 0.0002) and 14 patients in G2 (66.66%, Z test P = 0.0024) compared with 55 patients (50.00%) in G3 [Figure 5]. Similarly, ALT values returned to normal in 16 patients in G1 (23.18%, Z test P = 0.0075) and in 10 patients in G2 (47.61%, Z test P = 0.004), compared to 38 in G3 (34.54%).
|Figure 5: Normalisation of aspartate aminotransferase in the three groups|
Click here to view
We recorded evolution towards chronic hepatitis B in 62/69 patients (89.86%) in G1, 12/21 (57.15%) in G2 and 85/110 (77.28%) in G3. Follow-up data at 1 year showed 5.79% mortality (4/69) in G1, 4.76% (1/21) in G2 and 4.54% (5/110) in G3.
| ~ Discussion|| |
A more consistent HBs seroconversion was registered in G2 - entecavir treatment - (42.85% vs. 10.14% in G1 and 22.72% in G3), despite the fact that viral load decrease appeared to be less prominent in this group. When analysing the primary endpoint in Groups 1 and 3, we noticed a selective inflexion pressure at week 4 (possibly explained by precore mutations). This data [Figure 2] appears to correlate with the study of Kumar et al.  who reported a statistically significant decrease in HBV-DNA levels in the lamivudine treatment group at week 4 compared with the control group, advantage subsequently lost after week 4.
Based on this data, we can infer that entecavir might bring a certain therapeutic benefit in SAHB, with a rate of HBsAg clearance of 52.38% in G2 compared with 39.09% in G3, P = 0.256. Lamivudine displayed an initially beneficial effect on HBsAg clearance during weeks 3-8 [Figure 3]. After week 8, however, the curve of HBsAg loss for G1 passed under that of G3 (the natural history of infection). Thus, lamivudine therapy might be beneficial only within a narrow timeframe, up to week 8, subsequently recording an opposite effect - hindering the clearance of HBsAg (P = 0.027).
Viral load dynamics appear to corroborate the idea that the current HBV-specific therapy may not be efficient in this stage of disease (clinically and biologically manifest SAHB). However, there are certain notable differences between groups. A first milestone was week 4 when all groups displayed a decrease of HBV-DNA with more than 2log. A second milestone was week 24, when a 2log decrease was recorded in 81.15% in G1, 66.66% in G2 and 92.72% in G3.
The baseline percentage of HBeAg-positive patients was similar for the three groups: 61/69 (88.40%) in G1, 19/21 (90.47%) in G2 and 100/110 (90.90%) in G3.
Based on the study observation that positive anti-HBe at week 4 correlated with a globally unfavourable response (patients tending to remain HBV positive), it appears that HBV sacrificed HBeAg, permitting induction of anti-HBe [Figure 4], possibly in favour of viral integration; thus, we may hypothesise that HBeAg can play a role as distracting factor to the host immune system. In the light of these findings, we theorise that the evolutionary graph of acute HBV infection could be restructured to include a virologic and an immune component, based on the dynamics of HBs and HBe seroconversions. To provide a maximal practical utility, we also compared the standard and the surrogate parameters cited in field literature. As a result, we redefine the evolutionary stages of SAHB as:
- Extremely early acute virologic response - week 4
- Early acute virologic response - week 8
- Distracting virologic response - week 12 positive anti-HBe
- Acute virologic response - week 12 negative anti-HBe
Interpreting the reported data, we consider that entecavir could be a suitable option as HBV-specific anti-viral therapy in selected cases of SAHB, as it improved the evolution of patients included in the study, compared to the natural evolution of severe acute infection.
We were only able to perform an evaluation for precore mutations at baseline, not upon each evaluation. A certain amount of bias cannot be ruled out, given the small number of participants and the relatively short time of follow-up.
Given the large percentage of HBeAg-positive patients in the three study groups (88.40%, 90.47% and 90.90%), a stratified analysis according to baseline HBeAg status did not yield significant results. Further studies are necessary to determine possible differences regarding the response to anti-viral treatment according to baseline HBeAg.
To determine whether specific anti-viral treatment in SAHB prevented viral integration in the patients who displayed HBs seroconversion, it would be necessary to perform liver biopsy for evaluating the presence of covalently closed circular DNA (cccDNA). Unfortunately, we were unable to perform this test and therefore, at this moment, we have no data regarding viral integration.
A longer surveillance for the patients included in the study, for at least 5 years, could provide important information regarding the evolution of chronic liver disease or the sustainability of HBs seroconversion. We aim to reevaluate the patients included in the study at a future time and further analyse the follow-up results.
Another limitation is the small number of patients included in G2, this being subject to the timeline of the availability of entecavir in Romania during the study period and to the limited resources, once it did become available. To clearly define the role of entecavir in SAHB, there is a need for further studies, with larger numbers of patients. In 2012, Tillmann et al.  mentioned that given the current knowledge, designing future randomised placebo-controlled trials for SAHB would be unethical and rather recommends the design of comparative trials for the efficacy of different antivirals, such as lamivudine, entecavir or tenofovir. Lisotti et al.  also warranted further placebo-controlled trials to be unethical in the context of the good evolution of patients with SAHB under specific anti-viral therapy.
National and international current information
Baseline presence of precore mutations, as well as infection with viral genotype D, have both been shown to associate a high risk for fulminant acute hepatitis.  This viral genotype can also be partly responsible for the surprisingly low rate of HBs seroconversion that we have recorded in the control group.  Another possible explanation for this low seroconversion resides in the nature of the study per se - this was not a population-based screening study and, therefore, the results, unfortunately, cannot closely mimic the natural history of infection.
To put the results of our reported study into perspective, we reviewed the data available in field literature, on the topic of anti-viral therapy in SAHB. No centralised national data are available regarding anti-viral treatment in SAHB; therefore, we turned to international data. Most international clinical reports on lamivudine communicated good results, ,,,,,, but the interpretation of data was mostly based on the analysis of biochemical parameters rather than the virological evolution of disease. In 2012, Tillmann et al. recommended lamivudine or other potent antivirals such as entecavir or tenofovir in the treatment of SAHB.  One study that strongly advised against the use of lamivudine in AHB was that of Kumar et al.  that did not report a significant biochemical and clinical improvement, although lamivudine was correlated with a greater decrease in HBV-DNA. This data corroborates our results, with a greater decrease in viral load in G1 that was not correlated with a higher percentage of HBs seroconversion. Given the conclusions of the only two controlled trials reported so far , and in the light of our study's findings, we would rather support the conclusion of Kumar et al. to choose entecavir over lamivudine in the treatment of SAHB.
For the use of entecavir in SAHB, our results confirm the positive findings from other studies ,,,, although for the time being, we do not have a reasonable explanation for the slow viral load decrease recorded in G2 compared with the other two groups, apart from the inherent limitation of the small number of patients included in G2. This data seems to suggest that HBV-DNA alone may not be suitable to predict clearance of HBsAg and that it should probably be correlated with other parameters when monitoring the evolution of hepatitis B. ,, All these elements need to be taken into account in order to make informed decisions for the management of SAHB. 
| ~ Conclusion|| |
HBV-specific anti-viral therapy should be considered an option for managing selected cases of SAHB. Biochemical and virological parameters need to orient the choice of the anti-viral agent. Lamivudine displayed a greater decrease in viral load compared to controls, but it was associated with lower levels of HBsAg to anti-HBs seroconversion. Patients treated with entecavir, on the other hand, showed a better response in terms of HBs seroconversion by 24 weeks.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| ~ References|| |
Pitigoi D, Rafila A, Pistol A, Arama V, Molagic V, Streinu-Cercel A. Trends in hepatitis B incidence in Romania, 1989-2005. Euro Surveill 2008;13:pii: 8012.
Solomons HD. Carbohydrate deficient transferrin and alcoholism. Germs 2012;2:75-8.
Beniwal M, Kumar A, Kar P, Jilani N, Sharma JB. Prevalence and severity of acute viral hepatitis and fulminant hepatitis during pregnancy: A prospective study from North India. Indian J Med Microbiol 2003;21:184-5.
Khanna S, Tandon R. Management of severe acute hepatitis B. Hepat B Annu 2007;4:107-17.
Schmilovitz-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.
Kumar 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.
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;13:256-63.
Reshef R, Sbeit W, Tur-Kaspa R. Lamivudine in the treatment of acute hepatitis B. N Engl J Med 2000;343:1123-4.
Petrelli E, Balducci M, Pieretti C, Rocchi MB, Clementi M, Manzin A. Lamivudine treatment failure in preventing fatal outcome of de novo severe acute hepatitis B in patients with haematological diseases. J Hepatol 2001;35:823-6.
Torii N, Hasegawa K, Ogawa M, Hashimo E, Hayashi N. Effectiveness and long-term outcome of lamivudine therapy for acute hepatitis B. Hepatol Res 2002;24:34.
Kondili LA, Osman H, Mutimer D. The use of lamivudine for patients with acute hepatitis B (a series of cases). J Viral Hepat 2004;11:427-31.
European Association for the Study of the Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012;57:167-85.
Lok AS, McMahon BJ. Chronic hepatitis B: Update 2009. Hepatology 2009;50:661-2.
Girke J, Wedemeyer H, Wiegand J, Manns MP, Tillmann HL. Acute hepatitis B: Is antiviral therapy indicated? Two case reports. Dtsch Med Wochenschr 2008;133:1178-82.
Lisotti A, Azzaroli F, Buonfiglioli F, Montagnani M, Alessandrelli F, Mazzella G. Lamivudine treatment for severe acute HBV hepatitis. Int J Med Sci 2008;5:309-12.
Yu JW, Sun LJ, Zhao YH, Kang P, Li SC. The study of efficacy of lamivudine in patients with severe acute hepatitis B. Dig Dis Sci 2010;55:775-83.
Altman D. How large a sample? London, UK: British Medical Association; 1982.
Whitley E, Ball J. Statistics review 4: Sample size calculations. Crit Care 2002;6:335-41.
Guaraldi G. Evolving approaches and resources for clinical practice in the management of HIV infection in the HAART era. Germs 2011;1:6-8.
Hristea A, Neacsu A, Ion DA, Streinu-Cercel A, Staniceanu F. BCG-related granulomatous hepatitis. Pneumologia 2007; 56:32-4.
Palmela C, Badura R, Valadas E. Acute Q fever in portugal. epidemiological and clinical features of 32 hospitalized patients. Germs 2012;2:43-59.
Alnuaimi O, Lazar M, Apostolescu C, Scheau C, Adriana Ion D. Hepato-porto-biliary changes following a high energy electrical shock. Germs 2011;1:22-6.
Shafritz DA, Shouval D, Sherman HI, Hadziyannis SJ, Kew MC. Integration of hepatitis B virus DNA into the genome of liver cells in chronic liver disease and hepatocellular carcinoma. Studies in percutaneous liver biopsies and post-mortem tissue specimens. N Engl J Med 1981;305:1067-73.
Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, et al.
Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002;347:168-74.
Caruntu FA, Streinu-Cercel A, Gheorghe LS, Grigorescu M, Sporea I, Stanciu C, et al.
Efficacy and safety of peginterferon alpha-2a (40KD) in HBeAg-positive chronic hepatitis B patients. J Gastrointestin Liver Dis 2009;18:425-31.
Alavian SM, Miri SM. Dilemma of HBsAg seroconversion in chronic hepatitis B infection: Dilemma of HBsAg in chronic HBV. Hepat Mon 2011;11:67-8.
Tillmann HL, Zachou K, Dalekos GN. Management of severe acute to fulminant hepatitis B: To treat or not to treat or when to treat? Liver Int 2012;32:544-53.
Panassié L, Borentain P, Nafati C, Bernardin G, Doudier B, Thibault V, et al.
Fatal fulminant primary hepatitis B virus infections with G1896A precore viral mutants in southeastern France. Clin Res Hepatol Gastroenterol 2012;36:e1-8.
Sánchez-Tapias JM, Costa J, Mas A, Bruguera M, Rodés J. Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients. Gastroenterology 2002;123:1848-56.
Roussos A, Koilakou S, Kalafatas I, Kalantzis C, Apostolou N, Grivas E, et al.
Lamivudine treatment for acute severe hepatitis B: Report of a case and review of the literature. Acta Gastroenterol Belg 2008;71:30-2.
Roznovský L, Orságová I, Kloudová A, Mrázek J. Lamivudine therapy in patients with severe acute hepatitis B. Klin Mikrobiol Infekc Lek 2007;13:59-65.
Begini P, Cox MC, Angeletti S, Gigante E, Baccini F, Di Fonzo M, et al.
Effectiveness of entecavir in the management of acute hepatitis B developing in a patient with Hodgkin's lymphoma: A case report. Scand J Infect Dis 2011;43:750-2.
De Socio GV, Mercuri A, Di Candilo F, Baldelli F. Entecavir to treat severe acute hepatitis B. Scand J Infect Dis 2009;41:703-4.
De Socio GV, Sgrelli A, Tosti A, Baldelli F. Severe acute hepatitis B treated with entecavir. Mediterr J Hematol Infect Dis 2011;3:e2011010.
Jochum C, Gieseler RK, Gawlista I, Fiedler A, Manka P, Saner FH, et al
. Hepatitis B-associated acute liver failure: Immediate treatment with entecavir inhibits hepatitis B virus replication and potentially its sequelae. Digestion 2009;80:235-40.
Streinu-Cercel O, Streinu-Cercel A, Preotescu LL, Streinu-Cercel A. Entecavir as specific antiviral therapy in selected cases of severe acute hepatitis B. Germs 2012;2:18-22.
Gupta E, Kumar A, Choudhary A, Kumar M, Sarin SK. Serum hepatitis B surface antigen levels correlate with high serum HBV DNA levels in patients with chronic hepatitis B: A cross-sectional study. Indian J Med Microbiol 2012;30:150-4.
Changotra H, Dwivedi A, Nayyar AK, Sehajpal PK. Diagnosing different stages of hepatitis B infection using a competitive polymerase chain reaction assay. Indian J Med Microbiol 2008;26:138-42.
Rodrigues C, Deshmukh M, Jacob T, Nukala R, Menon S, Mehta A. Significance of HBV DNA by PCR over serological markers of HBV in acute and chronic patients. Indian J Med Microbiol 2001;19:141-4.
Streinu-Cercel A. Hepatitis B in the spotlight. Germs 2011;1:5.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]