Anti-HBe-positive chronic hepatitis B with HBV-DNA in the serum response to a 6-month course of lymphoblastoid interferon

doi:10.1016/0168-8278(92)90161-H

Journal of Hepatology

Volume 14, Issues 2–3, March 1992, Pages 221-225

https://doi.org/10.1016/0168-8278(92)90161-H Get rights and content

Abstract

Eighteen heterosexual HBsAg carriers with anti-HBe- and HBV-DNA-positive chronic hepatitis B (CHB) were randomly assigned to receive human lymphoblastoid interferon (ly-IFN) at a dose of 5 MU/m² i.m. three times a week for 6 months (ten cases) or no treatment (eight cases). All patients were followed for 24 months after IFN discontinuation and received a second liver biopsy. During the 6 months of treatment all patients had a progressive reduction of serum HBV-DNA levels, and at the end of therapy nine out of ten were HBV-DNA-negative and had normal ALT values. None of the untreated patients became persistently HBV-DNA-negative or showed significant variations of ALT levels. During the post-treatment follow-up, from 1 to 17 months after ly-IFN discontinuation, eight of the nine responders (89%) had recurrent or persistent reappearance of HBV-DNA in the serum and reactivation of the liver disease activity, with an ALT peak in four of them. On the post-trial liver biopsy seven of the eight relapsed patients showed persistence of HBcAg reactivity with no significant difference in the percentage of positive cells with respect to the pre-treatment liver specimen. Histological features improved in four treated patients, worsened in one untreated case and were unchanged in the remaining patients. These results indicate that ly-IFN shows a transient antiviral effect in the therapy of anti-HBe- and HBV-DNA-positive CHB. The 6-month treatment regimen employed in this study seems insufficient for eradicating the replicating virus from the liver cells in the majority of patients and consequently does not appear to prevent HBV reactivation after IFN discontinuation.

References (22)

F Bonino et al.
Chronic hepatitis in HBsAg carriers with serum HBV-DNA and anti-HBe
Gastroenterology
(1986)
S Hadziyannis et al.
Interferon alfa-2b treatment of HBeAg-negative/serum HBV-DNA-positive chronic active hepatitis type B
J Hepatol
(1990)
LJ Scully et al.
Lymphoblastoid interferon therapy of chronic HBV infection
J Hepatol
(1987)
MR Brunetto et al.
A new hepatitis B vims strain in patients with severe anti-HBe-positive chronic hepatitis B
J Hepatol
(1990)
WF Carman et al.
Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection
Lancet
(1989)
T Santantonio et al.
Prevalence and type of pre-C HBV mutants in anti-HBe-positive carriers with chronic liver disease in a highly endemic area
Virology
(1991)
F Bonino et al.
HBV-DNA in the sera of HBsAg carriers: a marker of active hepatitis B virus replication in the liver
Hepatology
(1981)
MJ Tong et al.
Spontaneous reactivation of hepatitis B in Chinese patients with HBsAg-positive chronic hepatitis
Hepatology
(1987)
SJ Hadziyannis et al.
Analysis of liver disease, nuclear HBcAg, viral replication and hepatitis B virus DNA in liver and serum HBeAg vs anti-HBe-positive carriers of hepatitis B virus
Hepatology
(1983)
ASF Lok et al.
Contribution of low level HBV replication to continuing inflammatory activity in patients with anti-HBe-positive chronic hepatitis B virus infection
Gut
(1984)

T Santantonio et al.

Prognostic value of serum HBV-DNA in anti-HBe-positive hepatitis B surface antigen chronic carriers

Ital J Gastroenterol

(1986)

Cited by (126)

Meta-analyses on Viral Hepatitis
2009, Infectious Disease Clinics of North America
Citation Excerpt :
No meta-analyses or systematic reviews of the use of interferon for patients who have HBeAg-negative chronic hepatitis B have been published. Four randomized trials with a total of 170 patients have reported the proportion of patients who achieve a 12-month sustained response (defined as loss of HBV DNA and normalization of ALT) with interferon compared with no intervention.43–46 The response rates in the individual trials vary considerably.
This article summarizes meta-analyses on interventions for acute and chronic viral hepatitis. The primary focus is on interventions assessed in systematic reviews and meta-analyses of randomized trials. The interventions assessed include active and passive immunization for hepatitis A and B and treatments for hepatitis B and C. The results of meta-analyses on conventional interferon-alpha, pegylated interferon alpha, lamivudine, adefovir, and interferon plus ribavirin are summarized.
Peginterferon for the treatment of chronic hepatitis B in the era of nucleos(t)ide analogues
2008, Best Practice and Research: Clinical Gastroenterology
Citation Excerpt :
Response was sustained in the majority of patients after therapy, reactivation occurred in 10–20%.11,22,23 Standard IFN-induced responses were less durable in HBeAg-negative chronic HBV, with sustained response in 10–47% (average 24%) at 12 months after cessation of therapy.24–28 Long-term follow-up studies showed better overall survival and lower incidence of hepatic decompensation and HCC in responders to standard IFN than in non-responders.11,23,29,30
The practising clinician is currently faced with a number of effective treatment options for chronic hepatitis B, including two formulations of interferon (standard IFN and pegylated IFN) and five nucleos(t)ide analogues (lamivudine, adefovir, entecavir, telbivudine and tenofovir). Treatment strategies can be divided into those aiming for sustained response after discontinuation of therapy and those that need to be maintained by prolonged antiviral therapy. Sustained response is particularly achieved with interferon-based therapy, while treatment-maintained response can be achieved with long-term nucleos(t)ide analogue therapy in the majority of patients. Of currently available drugs for the treatment of chronic hepatitis B, PEG-IFN seems to result in the highest rate of off-treatment sustained response after a 1-year course of therapy. Sustained transition to the immune-control phase (inactive HBsAg carrier state) can be achieved in 30–35% of HBeAg-positive patients and 20–25% of HBeAg-negative patients. Loss of HBsAg has been observed in 11% of both HBeAg-positive and HBeAg-negative patients after 3–4 years. Since hepatitis B virus (HBV) genotype is an important predictor of response to PEG-IFN, determination of HBV genotype is essential in patients in whom sustained off-treatment response is pursued. Aiming for sustained response is of particular interest because many HBV-infected patients are in need of antiviral therapy at a young age and may otherwise require indefinite antiviral therapy.
Treatment of chronic hepatitis B
2008, Gastroenterologie Clinique et Biologique
Le traitement de l’hépatite chronique B a nettement progressé au cours des dernières années. Plusieurs molécules sont actuellement disponibles pour le traitement de cette infection : les interférons α2a et 2b (IFN), l’interféron pégylé α2a (IFN-PEG α2a), la lamivudine, l’adéfovir, l’entécavir, la telbivudine et le ténofovir. Chaque traitement a des avantages et des inconvénients. L’IFN et l’IFN-PEG α2a peuvent induire une réponse virologique après une durée d’administration limitée. Cependant, ces traitements sont efficaces chez une minorité de patients et entraînent de nombreux effets secondaires. Les analogues nucléosidiques ou nucléotidiques ont l’avantage d’être administrés par voie orale avec une bonne tolérance, de présenter une forte efficacité antivirale et un bon profil de résistance. Cependant, ces thérapies antivirales nécessitent une administration à long terme. En effet, l’interruption du traitement est associée à une réactivation virale. L’efficacité de la lamivudine est limitée par l’émergence de virus résistants. L’incidence de la résistance à l’adéfovir est faible, mais son efficacité antivirale n’est pas optimale. L’entécavir présente une efficacité antivirale accrue, avec un profil de tolérance favorable et un taux d’incidence de la résistance très faible. La telbivudine semble avoir une efficacité antivirale supérieure et un taux de résistance inférieure à la lamivudine, mais son taux de résistance reste sensiblement supérieur aux autres thérapies disponibles. Le ténofovir possède un profil de résistance et une efficacité antivirale supérieurs à l’adéfovir. Avec la puissante efficacité antivirale et un taux d’incidence de la résistance très faible des nouvelles molécules, il n’est pas certain que l’avenir du traitement de l’hépatite chronique B repose sur l’utilisation de combinaison de différents antiviraux. Les avantages éventuels des combinaisons thérapeutiques par rapport à la monothérapie devraient être des effets antiviraux additifs ou synergiques et une réduction de la survenue des résistances virales. Malheureusement, nous ne disposons actuellement que de très peu de données cliniques sur l’utilisation des combinaisons thérapeutiques. La seule combinaison ayant montré sa supériorité est l’association de l’interféron pégylé à la lamivudine. Les combinaisons associant l’interféron pégylé et un puissant analogue comme l’entécavir ou le ténofovir sont en cours d’évaluation. Elles devraient permettre d’améliorer l’efficacité, diminuer le risque de résistance et augmenter le taux de séroconversion HBs. La séroconversion HBs est l’objectif ultime du traitement puisqu’elle reflète une rémission complète et définitive. La quantification de l’antigène HBs devrait devenir un test très utile pour prédire la séroconversion HBs et faire donc partie du suivi du traitement. Il convient de définir le rôle et la place de l’interféron pégylé au sein des combinaisons thérapeutiques. D’avantage d’études visant à évaluer l’efficacité des combinaisons de nouveaux antiviraux plus puissants sont à réaliser, afin d’améliorer l’efficacité du traitement et de mieux comprendre les mécanismes entraînant une résistance.
In recent years, marked progress has been made in the treatment of chronic hepatitis B. Several agents have been approved: interferon α-(IFN), pegylated interferon α2a (PEG-IFN α2a), lamivudine, adefovir, entecavir, telbivudine and recently, tenofovir. Each drug has advantages and limitations. IFN and PEG-IFN α2a have the advantage of inducing a sustained virologic response after a defined, limited course of treatment. However, these drugs are only effective in a minority of patients and have frequent side effects. Analogues have the advantage of being administered orally, with good safety profiles and a potent antiviral effect. However, these drugs need to be administered indefinitely since withdrawal of therapy is generally associated with reactivation, and a sustained response is uncommon except in HBeAg positive patients who develop HBe seroconversion. In case of HBe seroconversion, therapy should usually be continued for at least another 24 weeks. The efficacy of lamivudine is limited by the emergence of lamivudine-resistant HBV. Adefovir is associated with a moderate incidence of resistance but its antiviral effect is not optimal. Entecavir has shown to be more effective with a favourable safety profile and a low incidence of resistance. Telbivudine is more potent and has a lower rate of resistance than lamivudine but the resistance rate is significantly higher than other approved drugs. Tenofovir has a potent antiviral effect with a good resistance profile. The future of chronic hepatitis B therapy appears to be different drug combinations. Normally the advantage of drug combinations versus monotherapy should be additive or synergistic antiviral effects and a decrease in viral resistance. Unfortunately, there are few data available and none of the evaluated analogue combinations have been shown to be better than monotherapy. The only combination which has shown a synergistic effect is of pegylated interferon α2a with lamivudine. Therefore, combinations of pegylated interferon with the most potent analogues need to be evaluated. The ultimate goal of therapy is HBsAg seroconversion which is more often observed with interferon. Indeed, quantification of serum HBsAg will be a useful tool to predict the treatment outcome. More potent drugs and new combinations as well as understanding the mechanisms of viral resistance should be evaluated to improve the efficacy of treatment.
Treatment options in HBV
2006, Journal of Hepatology
The available evidence on interferon-alpha (IFN) treatment for chronic hepatitis B is sufficient to conclude that in patients with HBeAg positive chronic hepatitis, standard IFN therapy significantly improves clearance of HBeAg (number needed to treat [NNT]=4), loss of HBV-DNA (NNT=4) and clearance of HBsAg (NNT=18). HBeAg positive patients with normal or slightly raised ALT should be treated only if there is histological evidence of progressive disease. In patients with HBeAg negative chronic hepatitis, less than 20% of subjects who have achieved an end-of-treatment virological response after a course of standard IFN mantain a sustained virological response in the long-term. IFN treatment could help to delay or prevent disease decompensation and liver-related deaths but further large studies are needed. Lamivudine is effective at reducing, and sometimes clearing, HBV replication in heavily immunosuppressed patients and can be safely administered to patients with advanced liver disease. Lamivudine should be continued over an undefined extended period of time, with a switch from lamivudine to adefovir if there is an HBV-DNA breakthrough under therapy. Adefovir, excluding cost, is preferable to lamivudine as a first-choice because there is less chance of inducing resistance. The long-term benefit of lamivudine and adefovir and the role of combinations is under investigation.
Hepatitis B Virus e antigen activates the suppressor of cytokine signaling 2 to repress interferon action
2017, Scientific Reports
Influence of hepatitis B virus genetic heterogeneity on treatment response against lamivudine and interferon in Pakistani isolates
2016, Anti-Infective Agents

View all citing articles on Scopus

View full text

Regular paperAnti-HBe-positive chronic hepatitis B with HBV-DNA in the serum response to a 6-month course of lymphoblastoid interferon

Abstract

Gastroenterology

J Hepatol

J Hepatol

J Hepatol

Lancet

Virology

HBV-DNA in the sera of HBsAg carriers: a marker of active hepatitis B virus replication in the liver

Hepatology

Spontaneous reactivation of hepatitis B in Chinese patients with HBsAg-positive chronic hepatitis

Hepatology

Analysis of liver disease, nuclear HBcAg, viral replication and hepatitis B virus DNA in liver and serum HBeAg vs anti-HBe-positive carriers of hepatitis B virus

Hepatology

Contribution of low level HBV replication to continuing inflammatory activity in patients with anti-HBe-positive chronic hepatitis B virus infection

Gut

Prognostic value of serum HBV-DNA in anti-HBe-positive hepatitis B surface antigen chronic carriers

Ital J Gastroenterol

Regular paper
Anti-HBe-positive chronic hepatitis B with HBV-DNA in the serum response to a 6-month course of lymphoblastoid interferon