Entecavir treatment in patients with severe acute exacerbation of chronic hepatitis B

doi:10.1016/j.jhep.2010.06.043

Journal of Hepatology

Volume 54, Issue 2, February 2011, Pages 236-242

https://doi.org/10.1016/j.jhep.2010.06.043 Get rights and content

Background & Aims

Severe acute exacerbation of chronic hepatitis B is a unique clinical presentation with significant morbidity and mortality. Lamivudine was used in most previous studies, but the drug was limited by the development of resistance. Our objective is to study the safety and efficacy of entecavir in patients with severe acute exacerbation.

Methods

Consecutive patients with severe acute exacerbation of chronic hepatitis B were recruited from 1998 to 2009. All patients had serum alanine aminotransferase and bilirubin increased beyond 10 and 3 times the upper limit of normal, respectively. The primary endpoint was overall mortality at week 48. Virological and biochemical responses were also studied.

Results

Thirty-six patients and 117 patients were treated with entecavir and lamivudine, respectively. By week 48, 7 (19%) patients in the entecavir group and 5 (4%) patients in the lamivudine group died (adjusted hazard ratio 5.1, 95% confidence interval 1.5–17.2, p = 0.010). Similarly, the entecavir group had higher liver-related mortality (adjusted hazard ratio 4.0, 95% confidence interval 1.0–15.7, p = 0.044). Despite a lower prevalence of cirrhosis, more patients in the entecavir group developed prolonged jaundice, hepatic encephalopathy, and ascites. Entecavir resulted in more rapid and complete viral suppression, with 71% of patients achieving undetectable hepatitis B virus (HBV) DNA at week 48, compared to 40% in the lamivudine group (p = 0.007). However, rapid HBV DNA reduction at week 4 was associated with prolonged jaundice.

Conclusions

Entecavir treatment is associated with increased short-term mortality in patients with severe acute exacerbation of chronic hepatitis B but achieves better virological response in the long run.

Introduction

It is estimated that over 350 million people worldwide are chronically infected with hepatitis B virus (HBV). Chronic hepatitis B is one of the most important causes of cirrhosis and hepatocellular carcinoma [1]. In some patients, spontaneous acute exacerbation of the disease occurs, which is characterized by very high serum alanine aminotransferase (ALT) level and jaundice. [2] This may progress to acute-on chronic liver failure and death [3].

Owing to the high morbidity and mortality, most guidelines recommend oral nucleoside analogs in patients with severe acute exacerbation of chronic hepatitis B [4], [5]. For historical reasons, most observational studies reported the experience of using lamivudine in this situation [6], [7], [8]. However, lamivudine is associated with a high risk of drug resistance and virological breakthrough [9]. Although drug resistance appears to be less common in patients with severe acute exacerbation of chronic hepatitis B, the cumulative incidence of lamivudine resistance remains substantial at 25% in 4 years, in patients with hepatitis B e antigen (HBeAg)-negative disease and 33% in 5 years, in patients with HBeAg-positive disease [6], [7]. Lamivudine resistance also results in significant biochemical breakthrough and liver decompensation in some cases [7]. A better treatment with a lower risk of virological breakthrough is preferred.

Entecavir is another oral nucleoside analog with potent antiviral activity [10], [11]. In treatment-naïve patients, the incidence of genotypic resistance to entecavir is only 1.2% at 5 years [12]. While there is little doubt that entecavir is associated with a lower rate of resistance in the long run, its safety during severe acute exacerbation of chronic hepatitis B is unknown. In a recent report of 16 decompensated cirrhotic patients treated with entecavir, five developed severe lactic acidosis and one of them died [13]. Safety data in different groups of patients are, therefore, urgently needed.

In this study, we aimed to investigate the safety of entecavir in patients with severe acute exacerbation of chronic hepatitis B. The clinical outcomes were compared to historical controls who received lamivudine.

Section snippets

Patients and methods

Consecutive patients, admitted to the Prince of Wales Hospital, Hong Kong with spontaneous severe acute exacerbation of chronic hepatitis B, were prospectively studied. Severe acute exacerbation of chronic hepatitis B was defined as elevation of ALT to more than 10 times the upper limit of normal (ULN, 58 IU/L) and bilirubin to at least three times ULN (15 μmol/L). All patients had positive hepatitis B surface antigen (HBsAg) for more than 6 months. Coinfection by hepatitis A virus, hepatitis C

Results

Thirty-six patients who fulfilled the inclusion and exclusion criteria received entecavir treatment. One hundred and seventeen patients who received lamivudine served as historical controls. The follow-up duration of the entecavir and lamivudine groups was 74 ± 52 and 316 ± 143 weeks, respectively (p <0.001). Patients in the entecavir group were older but had lower baseline ALT level (Table 1). There were more female patients in the entecavir group. Otherwise, the baseline bilirubin, albumin,

Discussion

In this cohort of severe acute exacerbation of chronic hepatitis B, entecavir treatment, as compared to lamivudine treatment, was independently associated with increased short-term mortality. On the other hand, entecavir was associated with more rapid virological suppression and higher rates of virological and biochemical response at week 48.

The use of entecavir in cirrhotic patients has been evaluated in cohort studies. In one report, 5 out of 16 chronic hepatitis B patients with decompensated

Financial support

The study was partially supported by the Research Fund of the Department of Medicine and Therapeutics, The Chinese University of Hong Kong.

Conflict of interest

Vincent WS Wong received consulting fee from Novartis Pharmaceutical and paid lecture fee from Abbott Diagnostics. Joseph J.Y. Sung received paid lecture fees from AstraZeneca Hong Kong Limited, GSK Pharmaceuticals International and Roche. Henry L.Y. Chan is a member of the advisory boards of Novartis Pharmaceutical, Schering-Plough Corporation, Bristol-Myers Squibb and Pharmasset.

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Distinction of Drug-Induced Liver Injury From Autoimmune Hepatitis in Patients With Acute Liver Injury: Proposal of a Combination of Diagnostic Scores
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Acute liver injury (ALI) due to autoimmune hepatitis (AIH) can be treated by immunosuppression. In contrast, idiosyncratic drug-induced liver injury (DILI) had a poor prognosis. DILI thus needs to be distinguished from non-DILI.
Twenty-nine patients with DILI and 77 with non-DILI (42 of AIH and 35 with undetermined cause) diagnosed during 2005–2017 comprised the derivation cohort. 110 patients with ALI due to either AIH, DILI, or obscure causes at 6 liver centers during 2010–2015 were the validation cohort. Revised international AIH group scores (IAIHGs) and the Roussel-Uclaf Causality Assessment Method (RUCAM) were modified to calculate results using medical interviews and laboratory data without chronological changes. Diagnostic accuracy for the distinction of DILI and non-DILI was evaluated by receiver operating characteristic analysis and results were expressed as the area under the curve (AUC). This study received institutional institutional review board approval (MH2020-205).
The AUCs of modified IAIHGs and RUCAM scores for the diagnosis of DILI were 0.96 and 1.00 when cut-off values were set at 3 for the modified RUCAM and 5 for the modified IAIHGs in the derivation cohort. In the validation cohort, the AUCs of modified IAIHGs and RUCAM scores for the diagnosis of DILI were 0.95 and 0.97, respectively. The accuracy of the combination of the modified scores was 81% (89/110).
Modified diagnostic scores based on detailed medical interviews and routine laboratory data can distinguish DILI from non-DILI in patients with ALI.
Consensus document of the Spanish Association for Study of the Liver on the treatment of hepatitis B virus infection (2020)
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La infección por el virus de la hepatitis B (VHB) continúa siendo un problema global de salud pública. La vacunación frente al VHB, introducida en España en la década de 1990, constituye el método más eficaz para reducir la incidencia de la enfermedad. No obstante, la migración procedente de países donde la prevalencia de la infección es alta contribuye a que en nuestro país la tasa esté aún entre el 0,5 y el 1%. El espectro de la enfermedad crónica ocasionada por el VHB es muy variable y abarca desde el portador inactivo a pacientes con hepatitis crónica, cirrosis y carcinoma hepatocelular. A pesar de que en los últimos años no se han producido grandes avances en el desarrollo clínico de nuevos fármacos para el tratamiento de la hepatitis B crónica, los cambios en la epidemiología, en el conocimiento de la historia natural, métodos diagnósticos e indicaciones de tratamiento aconsejan la actualización del documento de consenso de la Asociación Española para el Estudio del Hígado (AEEH) sobre el tratamiento de la infección por el VHB publicado en el año 2012. El documento de la AEEH revisa el tratamiento de la hepatitis B crónica y establece como mejor pauta la administración prolongada de un análogo de nucleós(t)ido con alta barrera genética a la resistencia (entecavir, tenofovir o tenofovir alafenamida). El interferón-pegilado constituye una alternativa en pacientes con enfermedad hepática poco avanzada, pero su aplicabilidad es limitada por su baja eficacia y efectos adversos frecuentes. En todos los pacientes se debe evaluar el riesgo de progresión a enfermedad hepática avanzada y de desarrollo de carcinoma hepatocelular. Determinados subgrupos de pacientes con infección crónica por VHB deben ser incluidos en programas de vigilancia para el diagnóstico precoz de carcinoma hepatocelular, que constituye en el momento actual la principal complicación de la enfermedad.
Hepatitis B virus (HBV) infection remains a global public health problem. HBV vaccination is the most effective tool to reduce the incidence of HBV disease. Despite there has not been new clinical developments for the treatment of chronic hepatitis B in the last few years, changing epidemiology and current insights on natural history, diagnostic tools and therapy indications make necessary an update of the former version of the consensus document of the Spanish Association for Study of the Liver on the treatment of hepatitis B infection published in 2012. The current document updates the management of chronic hepatitis B. The treatment of choice is the long-term administration of a nucleos(t)ide analogue with high barrier to resistance (entecavir, tenofovir or tenofovir alafenamide). Pegylated interferon may be an option in patients with non-advanced liver disease, but its applicability is limited due to the low efficacy and poor tolerability. All patients must be monitored for the risk of progression to advanced liver disease and development of hepatocellular carcinoma.
Taiwan consensus statement on the management of chronic hepatitis B
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Citation Excerpt :
ETV can also effectively suppress HBV viral load in CHB patients with hepatic decompensation.226 One study from Hong Kong to compare ETV treatment in 36 patients and LAM treatment in 117 patients with severe acute exacerbation of CHB showed that a short-term mortality was higher in ETV group than in LAM group (19% versus 4%).167 However, a recent study from Taiwan compared 215 cases treated with LAM and 107 cases treated with ETV due to severe acute exacerbation of CHB with hepatic decompensation; the findings showed that antiviral drug with either LAM or ETV was not the determinant associated with mortality.231
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Tenofovir, entecavir, and lamivudine in patients with severe acute exacerbation and hepatic decompensation of chronic hepatitis B
2018, Digestive and Liver Disease
Citation Excerpt :
Furthermore, a recent study reported that the selection of ETV or LAM was not a predictive factor associated with liver-related mortality [10]. Such different results in previous large studies may be because of the different baseline characteristics of the included patients, such as the serum AST levels and MELD scores [9,10,17]. In the present study, selection of NA, including LAM, ETV, and TDF, was not a predictive factor associated with liver-related mortality or LT. Although there was no statistically significant difference, the patients treated with LAM tended to have a higher mortality rate or need LT more often than the patients treated with TDF or ETV.
To compare the efficacy of and mortality after lamivudine (LAM), tenofovir (TDF), and entecavir (ETV) treatment in patients with severe acute chronic hepatitis B (CHB) exacerbation.
We analyzed 91 patients with severe acute CHB exacerbation treated with LAM (n = 28), TDF (n = 26), or ETV (n = 37) for 10 years. The primary endpoint was overall mortality or liver transplantation (LT) by 48 weeks. The determined predictors of mortality, virologic and biochemical responses, and drug resistance were also evaluated.
The overall mortality or LT rate was not significantly different among the LAM (14.3%), ETV (10.8%), and TDF (3.8%) groups (P = 0.435). In the multivariate analysis, the occurrence of ascites (hazard ratio [HR] 10.467, 95% confidence interval [CI] 1.596–68.645, P = 0.014) and model for end-stage liver disease (MELD) scores above 25 (HR 28.920, CI 4.719-177.251, P = 0.000) increased the risk of mortality or LT. All groups showed similar biochemical responses (P = 0.134), virologic responses (HBV DNA <116 copies/mL, P = 0.151), and HBeAg seroconversion (P = 0.560). Antiviral resistance emerged in five patients treated with LAM by 48 weeks (17.9%, P = 0.003).
LAM, ETV, and TDF selection is not related with mortality and LT in patients with severe acute CHB exacerbation and hepatic decompensation. To reduce mortality, patients with ascites and MELD scores above 25 should be considered for LT.
Lamivudine versus entecavir in the rescue of chemotherapy-induced hepatitis B flare-up
2017, Journal of the Chinese Medical Association
Lack of nucleos(t)ide analogue (NA) prophylaxis prior to chemotherapy is a common problem worldwide. The efficacy of newer-generation NAs in the rescue for the hepatitis B virus (HBV) reactivation has not been confirmed. We aimed to compare lamivudine (LVD) and entecavir (ETV) in the rescue of chemotherapy-induced HBV flare-up.
In this retrospective cohort study, we screened all HBV carriers who received therapeutic LVD or ETV for hepatitis flare-up after chemotherapy between January 1, 2004 and December 31, 2015. Patients who had other concurrent primary liver diseases such as chronic hepatitis C, who had baseline HBV viral load <2000 IU/ml or data unavailable, or those who had primary or secondary liver cancers were excluded. By means of propensity scores, LVD users were randomly matched 1:1 with ETV users. Cumulative incidences of, and hazard ratios (HRs) for, mortality at 6 months were analyzed, and 1-year virological responses were evaluated.
In total, 32 LVD and 32 ETV users were matched for outcome analysis, and their baseline characteristics were not significantly different. Comparing LVD users to ETV users, the 6-month liver-related mortality rates (6.3% vs. 12.5%, p = 0.47) and overall mortality rates (31.3% vs. 25%, p = 0.54) were not significantly different. In multivariate analysis, prothrombin time prolongation >4 s (HR: 10.78, 95% confidence interval [CI]: 1.55–74.93) and HBV viral load L (HR: 3.40 per 1 log IU/ml, 95% CI: 1.39–8.40) were independent prognostic factors for liver-related mortality. There was no drug resistance to LVD or ETV over the course of 1 year.
Clinical outcomes were not different between LVD and ETV users. Delayed detection of hepatitis flare-up with coagulopathy and a high viral load could result in a poor prognosis.

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Research ArticleEntecavir treatment in patients with severe acute exacerbation of chronic hepatitis B

Background & Aims

Methods

Results

Conclusions

Introduction

Section snippets

Patients and methods

Results

Discussion

Financial support

Conflict of interest

Hepatocellular carcinoma and hepatitis B virus

Semin Liver Dis

Severe acute exacerbation of chronic hepatitis B: a unique presentation of a common disease

J Gastroenterol Hepatol

Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update

Hepatol Int

Chronic hepatitis B

Hepatology

Long-term lamivudine treatment is associated with a good maintained response in severe acute exacerbation of chronic HBeAg-negative hepatitis B

Antivir Ther

Long-term follow-up of lamivudine treatment in patients with severe acute exacerbation of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B

Antivir Ther

Benefit of lamivudine therapy and factors associated with clinical outcome in spontaneous severe acute exacerbation of chronic hepatitis B virus infection

Intervirology

Long-term safety of lamivudine treatment in patients with chronic hepatitis B

Gastroenterology

A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B

N Engl J Med

Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B

N Engl J Med

Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy

Hepatology

Research Article
Entecavir treatment in patients with severe acute exacerbation of chronic hepatitis B