Lamivudine treatment failure in preventing fatal outcome of de novo severe acute hepatitis B in patients with haematological diseases

doi:10.1016/S0168-8278(01)00220-3

Journal of Hepatology

Volume 35, Issue 6, December 2001, Pages 823-826

https://doi.org/10.1016/S0168-8278(01)00220-3 Get rights and content

Abstract

Background: Patients with malignant haematological diseases administered or no longer receiving immunosuppressive therapy are at high risk of reactivation or de novo hepatitis B infection and fulminant hepatitis. Despite promising results in the treatment of chronic hepatitis and its use in selected patients with acute hepatitis B, there is no consensus on lamivudine treatment in severe acute hepatitis portending a fatal clinical outcome.

Case reports: Of the ten patients with malignant haematological disorders who became infected with the same strain of hepatitis B virus during hospitalisation in a haematology ward, five received lamivudine (and in some cases, ganciclovir and famciclovir). The other patients received only supportive therapy, since deteriorating clinical conditions hampered specific treatment efforts. Eight patients died from acute liver failure and one from a fatal course of the haematological disease; one had a favourable outcome from the therapy. There was no significant difference in terms of survival between the treated and untreated patients.

Conclusions: Although lamivudine has proved promising in the therapy of chronic hepatitis B and of recurrent hepatitis after liver transplantation, its use in de novo severe acute hepatitis should be investigated further, particularly in immunocompromised patients.

Introduction

Infection with hepatitis B virus (HBV) leads to fulminant hepatitis (FH) in approximately 1% of patients, but carries a high mortality rate [1]. Fulminant HBV infection determines a rapid destruction of the hepatic parenchyma, leading to liver failure, death, or needing liver transplantation in more than 80% of these patients. The pathogenesis of FH is still unclear, though both viral factors and the host's immune response may play an important role [2], [3]. In particular, patients undergoing or following withdrawal of immunosuppressive therapy for oncological and haematological diseases, and patients undergoing liver transplantation for viral-related diseases are at high risk of reactivation or de novo HBV infection, often leading to a fatal clinical outcome [4], [5].

Lamivudine, a nucleoside analogue, has been approved for the treatment of chronic hepatitis B; extensive clinical studies have suggested that early treatment with the drug improves hepatic histology in patients with chronic hepatitis B, and can prevent recurrence of hepatitis B after liver transplantation [6], [7], [8]. Lamivudine has also been considered to treat selected patients with severe, acute hepatitis B [9], [10], [11].

We have recently described a nosocomial outbreak of hepatitis B, which occurred among the inpatients of a haematology unit, accounting for a fatal outcome in most infected patients [12]. Extensive epidemiological and molecular analysis showed that transmission of the same viral strain occurred from an HBsAg-positive patient with acute reactivation of the infection to all case-patients. We report here the clinical course of ten of the 11 patients with de novo acute hepatitis B involved in the outbreak, and the therapeutic approach used in all cases.

Section snippets

Patients

Ten patients (three males, mean age 49.5 years, range 12–68 years) were admitted between December 1997 and March 1998 in the Infectious Disease (ID) Department of San Salvatore Hospital, Pesaro, Italy; all had haematological diseases and became infected with HBV during their stay in the haematology ward of the same hospital; all patients tested positive for HBsAg, IgM anti-HBc, and serum HBV-DNA at admission. Details of the epidemiological and virological investigations are reported elsewhere

Discussion

Eight out of ten patients with acute hepatitis B who were referred to the Infectious Diseases Department of San Salvatore Hospital, Pesaro, Italy, between December 1997 and March 1998, died from acute liver failure; one probably had a fatal course of the haematological disease with a plurivisceral involvement of the lymphoma; finally, one HBV-infected patient had a favourable outcome of the hepatitis and survived. All patients had haematological disorders and had been infected with the same

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Citation Excerpt :
Twelve % of patients developed reactivation after 1 year of stopping CT. Reactivation most frequently follows cessation of CT but may occur during CT.2,38,39 The reported interval usually ranges from 1 to 12 months from initiation of CT but has also been upto 39 months as seen in some of our patients.40–43 We observed that 20.7% of patients needed to interrupt CT because of HBVR.
Hepatitis B virus reactivation (HBVR) is common in patients withcancer. The aim of the present study was to find out clinical profile of patients with cancer receiving chemotherapy with HBVR and to study the efficacy of entecavir (ETV) and tenofovir in the treatment of HBVR.
This is a prospective study in which all consecutive patients with cancer with evidence of HBVR were included. HBVR was defined as: New onset transaminitis with alanine aminotransferase (ALT) >3 times upper limit of normal and >10 fold increase in HBV DNA levels from baseline levels or detection of HBV DNA ≥100,000 IU/ml in patients with no baseline HBV DNA. Patients with HBVR were put on ETV or tenofovir and were closely monitored for efficacy and safety for minimum of 1 year.
Of 204 Hepatitis B surface antigen (HBsAg)-positive patients with different cancers, 92 met the inclusion criteria. Of 92, 46 received ETV 0.5 mg/day and 46 received tenofovir disoproxil fumarate (TDF) 300 mg/day. At 6 months, there was 4.7 log reduction in HBV DNA level in the ETV group and 5.2 log reduction in the TDF group (P = 0.029). Proportion of patients with undetectable HBV DNA (75.7% vs 87.5%), ALT normalization (89.2% Vs 87.5%), HBsAg negativity (25% vs 28.1%), and seroconversion (2.8% vs 3.1%) at 1 year were almost similar in both groups with P value > 0.05 for all efficacy end points. There was no HBVR-related mortality in any group.
Both ETV and tenofovir are very effective in the treatment of HBVR and reduce the liver-related mortality and morbidity in such patients.
Treatment with lamivudine and entecavir in severe acute hepatitis B
2016, Indian Journal of Medical Microbiology
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.
Extended lamivudine therapy against hepatitis B virus infection in hematopoietic stem cell transplant recipients
2006, Biology of Blood and Marrow Transplantation
Lamivudine has demonstrated efficacy in the treatment and prevention of hepatitis B virus (HBV) reactivation after hematopoietic stem cell transplantation (HSCT). However, most of these studies involved short durations of prophylaxis, so there is significant concern regarding lamivudine resistance in these patients. Between March 1984 and November 2002, 71 HBV surface antigen–positive HSCT recipients, including a subgroup of 16 who received pretransplantation lamivudine therapy, which was continued into the posttransplantation period to prevent reactivation hepatitis, were enrolled onto our study. The efficacy of lamivudine therapy was first evaluated for the subgroup of 16 patients in terms of treatment response, lamivudine resistance, and viral recurrence after discontinuation by using virologic assays. Efficacy was then evaluated for all patients in terms of the hazards of lamivudine therapy for reactivation hepatitis after transplantation. During a median lamivudine therapy period of 73 weeks (range, 19-153 weeks), the initial response showed a median reduction of 2.54 log₁₀ in serum HBV DNA (−0.28 to 6.72 range). Lamivudine-resistant mutations were detected in 10 (63%) of 16 patients during therapy, and 1 (12%) of 16 patients finally developed a viral breakthrough. At a median follow-up of 30 months after discontinuation, 3 (27%) of 11 cases had recurrence of HBV infection. Despite the emergence of the mutations, no deaths were due to HBV reactivation or severe cases of hepatitis. In the Cox proportion regression model regarding reactivation hepatitis after transplantation of all enrolled patients, lamivudine therapy was found to be the only favorable factor for the event, with a hazard ratio of 0.122 (95% confidence interval, 0.016-0.908; P = .040). In conclusion, extended lamivudine therapy is safe and effective for the prevention of HBV reactivation in an HSCT setting and significantly decreases reactivation hepatitis after transplantation.
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Hepatitis B virus (HBV) is a serious cause of morbidity and mortality in hepatitis B surface (HBsAg) antigen–positive patients treated with chemotherapy. Because the hepatitis is related to HBV virological reactivation, application of effective antiviral therapy, such as Lamivudine, has been attempted. Despite the use of these antiviral agents at the time of clinical hepatitis, some HBsAg-positive patients still develop hepatic failure and die. We used the Molecular Adsorbent Recirculating System (MARS) (MARS Monitor; Teraklin AG, Rostock, Germany) to treat 5 HBsAg-positive lymphoma patients with acute hepatic failure due to chemotherapy despite lamivudine treatment. Before and after each treatment we monitored the parameters of neurological status (EEG, cerebral CT and Glasgow coma score), hemodynamic parameters, acid-base equilibrium and blood gases as well as hepatic and renal function. The inclusion criteria were these of the King’s College Hospital. Statistical analysis by Student t method showed significant results (P < .01). Three of 5 patients are alive without signs of reactivation of viral or hematological diseases at 1 year follow-up. The 2 patients died because MARS treatment was started too late, with Glascow coma score grade IV, hemodynamic instability, and mechanical ventilator assistance. Despite the limited number of cases, we believe that MARS can be applied to patients with a high tolerance and yield good results, but the treatment has to start at the first signs of hepatic failure.
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Case reportLamivudine treatment failure in preventing fatal outcome of de novo severe acute hepatitis B in patients with haematological diseases

Abstract

Introduction

Section snippets

Patients

Discussion

Hepatology

Eur J Cancer

Hepatology

Lancet

J Hepatol

Am J Gastroenterol

Hepatology

Acute liver failure

N Engl J Med

Case report
Lamivudine treatment failure in preventing fatal outcome of de novo severe acute hepatitis B in patients with haematological diseases