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Abstract
Nineteen Chinese patients with chronic hepatitis B virus (HBV) infection, seropositive for HBV e antigen (HBeAg) and HBV DNA on at least three occasions in 6 months, were randomised to receive either recombinant human interferon-gamma (rIFN gamma) 0.1 mg/m2 intramuscularly thrice weekly for 16 weeks (n = 11) or no anti-viral therapy (controls, n = 8). Five patients in the treatment group and four patients in the control group had persistently elevated serum alanine aminotransferases (ALT) of over two times the upper limit of normal before entering into the trial. rIFN gamma had no or minimal inhibitory effect on serum HBV DNA during treatment and no patient developed e-seroconversion or sustained loss of serum HBV DNA. Hepatitic flare, which occurred in a proportion of patients responding successfully to interferon-alpha (IFN alpha) therapy, was not observed with rIFN gamma treatment. Side-effects included pyrexia and mild headache that showed tachyphylaxis and were well tolerated by all patients. In the control group, one patient with elevated pre-entry serum ALT lost serum HBV DNA and seroconverted to anti-HBe. Another patient with elevated ALT lost serum HBV DNA transiently during therapy. In the dose given, rIFN gamma was safe but had no apparent anti-viral effects in Chinese patients with chronic HBV infection.
... Many studies have considered the use of IFN-γ as treatment of CHB patients in combination with type-I IFN (76)(77)(78)(79)(80)(81). However, the therapeutic benefit of IFN-γ has not been clearly proven. ...
... However, the therapeutic benefit of IFN-γ has not been clearly proven. Whilst, it has been shown to be effective in suppressing HBV replication in CHB Caucasian patients (79,82), in contrast, a study in Chinese patients showed no effect of an intramuscular injection of recombinant IFN-γ on serum HBV-DNA levels and seroconversion to anti-HBeAg (81). Two other studies observed an inhibitory effect but administration of IFN-γ appeared less effective against HBV compared to IFN-α treatment (77,78). ...
... In the case of chronic infection, current treatments are not yet efficient enough to eliminate the virus due to the persistence of cccDNA in the nucleus of hepatocytes. With regards to the use of IFN-γ as treatment, the therapeutic benefit of IFN-γ has not been clearly proven (79,81,82). HBV persistence leads to liver injury and the development of hepatocellular carcinoma. ...
About 0.8 million people die because of hepatitis B virus (HBV) infection each year. In around 5% of infected adults, the immune system is ineffective in countering HBV infection, leading to chronic hepatitis B (CHB). CHB is associated with hepatocellular carcinoma, which can lead to patient death. Unfortunately, although current treatments against CHB allow control of HBV infection, they are unable to achieve complete eradication of the virus. Cytokines of the IFN family represent part of the innate immune system and are key players in virus elimination. IFN secretion induces the expression of interferon stimulated genes, producing proteins that have antiviral properties and that are essential to cell-autonomous immunity. IFN-α is commonly used as a therapeutic approach for CHB. In addition, IFN-γ has been identified as the main IFN family member responsible for HBV eradication during acute infection. In this review, we summarize the key evidence gained from cellular or animal models of HBV replication or infection concerning the potential anti-HBV roles of IFN-γ with a particular focus on some IFN-γ-inducible genes.
... Other common side effects include rash, injection site erythema or tenderness, diarrhea and nausea, and leukopenia. [3][4][5][6][7][8] IFN-γ clinical trials have been conducted using recombinant derived protein (IFN-γ1b, Actimmune), adenovirus vectors which express IFN-γ cDNA (TG-1041, TG-1042), and neutralizing antibodies against IFN-γ (HuZaf and AMG811). Actimmune has been used to treat a wide variety of diseases, including cancer, tuberculosis, hepatitis, chronic granulamotous disease, osteopetrosis, scleroderma, among others. ...
... In chronic HBV trials, IFN-γ1b alone was not found to have any significant impact on viral infection but did modulate the immune system. 7 Treatment of HCV with IFN-γ1b has also proven generally unsuccessful 8,39 but pretreatment with IFN-γ prior to IFN-α treatment resulted in enhanced immunologic activity in HCV patients. The enhanced immunological activity is speculated to enhance IFN-α-mediated viral clearance. ...
Interferon gamma (IFN-), a pleotropic cytokine, has been shown to be important to the function of virtually all immune cells and both innate and adaptive immune responses. In 1986, early clinical trials of this cytokine began to evaluate its therapeutic potential. The initial studies focused on the tolerability and pharmacology of IFN- and systematically determined its antitumor and anti-infection activities. In the 20-plus years since those first trials, IFN- has been used in a wide variety of clinical indications, which are reviewed in this article.
... Other common side effects include rash, injection site erythema or tenderness, diarrhea and nausea, and leukopenia. [3][4][5][6][7][8] IFN-γ clinical trials have been conducted using recombinant derived protein (IFN-γ1b, Actimmune), adenovirus vectors which express IFN-γ cDNA (TG-1041, TG-1042), and neutralizing antibodies against IFN-γ (HuZaf and AMG811). Actimmune has been used to treat a wide variety of diseases, including cancer, tuberculosis, hepatitis, chronic granulamotous disease, osteopetrosis, scleroderma, among others. ...
... In chronic HBV trials, IFN-γ1b alone was not found to have any significant impact on viral infection but did modulate the immune system. 7 Treatment of HCV with IFN-γ1b has also proven generally unsuccessful 8,39 but pretreatment with IFN-γ prior to IFN-α treatment resulted in enhanced immunologic activity in HCV patients. The enhanced immunological activity is speculated to enhance IFN-α-mediated viral clearance. ...
Interferon-gamma (IFN-gamma) is a key immunoregulatory protein that plays a major role in the host innate and adaptive immune response. Also known as type II interferon, IFN-gamma is a single-copy gene whose expression is regulated at multiple levels by the host. Transcription control is regulated through epigenetic mechanisms as well as the accessibility of chromatin and the binding of activating and inhibitory proteins to promoter and enhancer elements. Post-transcriptional control is mediated through mRNA localization and mRNA stability while post-translational control occurs through the activation of protein kinase R by the 5' portion of the mRNA, protein folding within the endoplasmic reticulum and the possible interaction of the mRNA with microRNAs. The biological effects of IFN-gamma are widespread, as almost every cell type is altered upon interaction with this protein. Thus it has become very apparent that IFN-gamma is a multipotent cytokine whose regulation and effects are complex and essential to host survival.
... IFN-γ based adjunctive therapy has shown to activate the signal transduction and gene expression in alveolar macrophages and improve the disease related clinical outcomes (Condos et al., 1997;Suarez-Mendez et al., 2004). In chronic HBV infection, IFN-γ1b alone has no impact on viral infection but exerts an immunomodulatory effect (Lau et al., 1991). Similar findings were reported for HCV infection (Muir et al., 2006), but the pre-treatment with IFN-γ prior to IFN-α treatment significantly enhanced immunological responsiveness in HCV cases which could be attributed to the interferon mediated enhanced viral clearance (Saez-Royuela et al., 1991;Katayama et al., 2001). ...
Modern Biotechnology in Healthcare: Advances and Applications covers some of the most important and latest research trends and applications in modern biotechnology, with special attention on how modern biotechnology advances human healthcare. These ground-breaking technologies hold tremendous potential in the development of new tools and techniques that can in turn be used in the synthesis and production of novel biological entities with a potential to improve disease diagnostics in general and healthcare facilities in particular.
... Analysis of chimpanzees and transgenic mice demonstrated that IFN-g produced by CD8 + T cells activates ISGs in the liver and suppresses HBV replication [22,23]. Despite its crucial role in HBV control, clinical trials that tested therapeutic IFN-g intervention failed to demonstrate efficacy against chronic HBV infection [24]. Although not effective as a standalone therapy, IFN-g remains an important marker of T cell functionality for other HBV immunotherapies due to its essential role in viral clearance. ...
Hepatitis B virus (HBV) causes chronic infections that are associated with immune dysfunction. Though T cell impairment is perhaps the most prominent immune change contributing to viral persistence, HBV interaction with the innate immune system is also likely key, as the lack of effective innate immunity has functional consequences that promote chronic infection. In addition to an intrinsic ability to fight viral infections, the innate immune system also impacts T cell responses and other adaptive immune mechanisms critical for HBV control. Therefore, it is essential to understand the relationships between HBV and innate immunity, as these interactions may be useful immunotherapeutic targets to manage the infection.
... The most common adverse therapeutic events occurring with IFNγtherapy are flu-like symptoms and signs such as fever, headache, chills, myalgia, or fatigue [21]. Other common side effects include rash, erythema or tenderness at the injection site, diarrhoea and nausea, and leukopenia [22][23][24][25][26][27]. ...
IFN- is a type II IFN known as immune IFN that differs from virus-induced type I and III IFNs. IFN- has been clinically used to treat a wide variety of diseases. The original function of IFN- is its natural antiviral activity, and this molecule may be effective in viral infection and consequent disseminated multi-organ invasion. Despite its role as an inflammatory cytokine, IFN- induces regulatory T cells and antigen-specific regulatory B cells, which play a counter-regulatory role in the immune reaction, possibly preventing or controlling excessive immune responses such as cytokine storms that can result in death.
The advantages of IFN- are as follows: 1) IFN- is a non-virus-specific antiviral therapeutic and can be used in new virus infections and epidemics; 2) IFN- is strongly predicted to be effective in viral infection; 3) adequate clinical data for the clinical protocols of IFN- including dosage and period of use, are available; 4) IFN- is a relatively safe drug with few side effects and no rare severe side effects; 5) IFN- is available immediately; and 6) IFN- is not expensive.
New viruses have appeared every several years, causing serious epidemics to pandemic circumstances. Researchers must develop antiviral strategies against viral diseases, especially for critically serious viral epidemics. Among the IFNs, IFN- is regarded as suitable and strongly recommended as a major antiviral agent, at least in high-risk patients who are infected by viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), when no vaccines or virus-specific antiviral therapeutics are available.
... It has been approved by FDA to treat chronic granulomatous disease and osteopetrosis, and is experimentally used for the treatment of idiopathic pulmonary fibrosis and Friedreich's ataxia [113]. However, IFN-g has not been successful in treating viral infections [114,115]. IFN-l has shown specific antiviral activity in both chronic HBV and HCV patients; although its efficacy was not superior compared to IFN-a therapy, IFN-l had more limited side effects [116,117]. This is because IFNlR1 has a more restricted tissue-specific pattern of expression. ...
Interferon-stimulated genes (ISGs) are a group of gene products that coordinately combat pathogen invasions, in particular viral infections. Transcription of ISGs occurs rapidly upon pathogen invasion, and this is classically provoked via activation of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway, mainly by interferons (IFNs). However, a plethora of recent studies have reported a variety of non-canonical mechanisms regulating ISG transcription. These new studies are extremely important for understanding the quantitative and temporal differences in ISG transcription under specific circumstances. Because these canonical and non-canonical regulatory mechanisms are essential for defining the nature of host defense and associated detrimental proinflammatory effects, we comprehensively review the state of this rapidly evolving field and the clinical implications of recently acquired knowledge in this respect.
... A large RCT in pulmonary fibrosis was stopped early with lack of benefit (117) . In Chinese patients with chronic hepatitis B, rIFNγ showed no benefit (118) . Aerosolized rIFNγ was ineffective in mild to moderate cystic fibrosis (119) . ...
Interferon gamma (IFNγ) is an integral and critical molecule of the immune system, with multiple functions, mostly related to Th1 response to infection. It is critical to defence against mycobacterial infection and of increasing interest in defence against fungi. In this article, we review the genetic and epigenetic variants affecting IFNγ expression and investigate it's role in disease, with an emphasis on fungal diseases such as invasive and chronic pulmonary aspergillosis. Over 347 IFNγ gene variants have been described, in multiple ethnic populations. Many appear to confer a susceptibility to disease, especially tuberculosis and hepatitis, but also some non-infectious conditions such as aplastic anaemia, cervical cancer and psoriasis. Several epigenetic modifications are also described, increasing IFNγ expression in Th1 lymphocytes and reducing IFNγ expression in Th2 lymphocytes. Recombinant IFNγ administration is licensed for the prophylaxis of infection (bacterial and fungal) in patients with the phagocyte functional deficiency syndrome chronic granulomatous disease, although the benefits appear limited. IFNγ therapy is given to patients with profound defects in IFNγ and IL-12 production and appears to be beneficial for patients with invasive aspergillosis and cryptococcal meningitis, but the studies are not definitive. A high proportion of patients with chronic pulmonary aspergillosis are poor producers of IFNγ in response to multiple stimuli and could also benefit from IFNγ administration. The investigation and management of patients with possible or demonstrated IFNγ deficiency in adulthood is poorly studied and could be greatly enhanced with the integration of genetic data.This article is protected by copyright. All rights reserved.
... Each infection, although the treatment effect on HBV viral load is smaller compared to HCV and only about 30% of treated individuals respond to treatment (Leung 2002; Lau and others 2005; Lai and others 2006). Clinical trials of IFN-γ for chronic HBV infection failed to show a signifi cant anti-HBV effect (Marcellin and others 1990; Kakumu and others 1991; Lau and others 1991). Previous studies have shown that IFN-α and IFN-γ share a broad range of signal transduction pathways (Stark and others 1998; Samuel 2001; Sanda and others 2006). ...
Interferon (IFN) plays a central role in the innate and adaptive antiviral immune responses. While IFN-alpha is currently approved for treating chronic hepatitis B and hepatitis C, in limited studies, IFN-gamma has not been shown to be effective for chronic hepatitis B or C. To identify the potential mechanism underlying the differential antiviral effects of IFN-alpha and IFN-gamma, we used cDNA microarray to profile the global transcriptional response to IFN-alpha and IFN-gamma in primary human hepatocytes, the target cell population of hepatitis viruses. Our results reveal distinct patterns of gene expression induced by these 2 cytokines. Overall, IFN-alpha induces more genes than IFN-gamma at the transcriptional level. Distinct sets of genes were induced by IFN-alpha and IFN-gamma with limited overlaps. IFN-alpha induces gene transcription at an early time point (6 h) but not at a later time point (18 h), while the effects of IFN-gamma are more prominent at 18 h than at 6 h, suggesting a delayed transcriptional response to IFN-gamma in the hepatocytes. These findings indicate differential actions of IFN-alpha and IFN-gamma in the context of therapeutic intervention for chronic viral infections in the liver.
... In controlled clinical trials, treatment with recom-binant IFN-␥ or interleukin-2 in chronic hepatitis B had no antiviral effect, and there were no ALT flares. 36,37 In vitro treatment of chronically infected woodchuck hepatocytes with IFN-␥, or in vivo IFN-␥ expression in liver, did not suppress woodchuck hepatitis virus replication in chronically infected animals. 38,39 The treatment strategy in chronic hepatitis B aims to suppress HBV replication and to restore HBV-specific T-cell responses to achieve sustained remission. ...
Interleukin-12 (IL-12) is an immunomodulatory cytokine that promotes cellular immunity. Pre-clinical data suggest that IL-12 inhibits hepatitis B virus (HBV) replication by stimulating interferon-gamma (IFN-gamma) production. We investigated whether a combination treatment with lamivudine plus recombinant human interleukin-12 (rhIL-12) will result in a greater and prolonged suppression of HBV replication in comparison with lamivudine monotherapy. Fifteen patients with HBeAg-positive chronic hepatitis B were randomized to receive either lamivudine alone for 24 weeks (group 1); combination of lamivudine for 16 weeks and rhIL-12 (200 ng/kg twice weekly), starting 4 weeks after initiation of lamivudine, for 20 weeks (group 2), or the same schedule as for group 2, with lamivudine and a higher dose of rhIL-12 (500 ng/kg, group 3). Serum HBV DNA levels, T-cell proliferation, frequency of virus-specific T-cells, and IFN-gamma production were evaluated serially during and 24 weeks posttreatment. Lamivudine plus rhIL-12/500 showed greater antiviral activity than lamivudine monotherapy. However, after stopping lamivudine in groups 2 and 3, serum HBV DNA increased significantly despite continuing rhIL-12 administration. Lamivudine plus rhIL-12 treatment was associated with a greater increase in virus-specific T-cell reactivity, IFN-gamma production, and an inverse correlation between the frequency of IFN-gamma-producing CD4+ T-cells and viremia. The T-cell proliferative response to HBcAg did not differ between the three groups. In conclusion, the addition of IL-12 to lamivudine enhances T-cell reactivity to HBV and IFN-gamma production. However, IL-12 does not abolish HBV replication in HBeAg-positive patients and does not maintain inhibition of HBV replication after lamivudine withdrawal.
As a cytokine, gamma-interferon (IFN-γ) is considered a key player in the fine-tuned orchestration of immune responses. The extreme cellular sensitivity to cytokines is attested by the fact that very few of these bioactive molecules per cell are enough to trigger cellular functions. These findings can, at least partially, explain how/why homeopathically-prepared cytokines, and especially micro-immunotherapy (MI) medicines, are able to drive cellular responses. We focused our fundamental research on a unitary MI preparation of IFN-γ, specifically employed at 4 CH, manufactured and impregnated onto sucrose-lactose pillules as all other MI medicines. We assessed the IFN-γ concentration in the medium after dilution of the IFN-γ (4 CH)-bearing pillules and we evaluated in vitro drug responses in a wide range of immune cells, and in endothelial cells. Our results showed that IFN-γ (4 CH) stimulated the proliferation, the activation and the phagocytic capabilities of primary immune cells, as well as modulated their cytokine-secretion and immunity-related markers’ expression in a trend that is quite comparable with the well-recognized biological effects induced by IFN-γ. Altogether, these data provide novel and additional evidences on MI medicines, and specifically when active substances are prepared at 4 CH, thus suggesting the need for more investigations.
Chronic hepatitis B viral infection remains one of the major medical problems in the world and is a leading cause of morbidity and mortality. Advances in the treatment and prevention of hepatitis B virus (HBV) infection represent among the most dramatic achievements of modern medicine and have resulted from fully exploiting discoveries in molecular immunology and virology as well as rational drug design. The first major breakthrough in the therapy of HBV was the development of regimens of interferon-alfa that give 30–40% long term remission rates in chronically infected patients. Despite this advance, the glass has also remained half empty. The more recent development of nucleoside analog agents with potent antiviral activity have now provided additional armamentarium in the care of HBV infected patients. The initial part of this chapter will address, in a practical manner, the therapy of appropriate patients with interferon and the anticipated effects and benefits of this therapy. The chapter will then discuss the evolving role of nucleoside analogs and even more experimental agents in the management of patients who are either refractory to or are poor candidates for interferon-alfa therapy.
Die chronische Virushepatitis ist eine heterogene Erkrankung, die entweder durch das Hepatitis-B-Virus, das Hepatitis-Delta-Virus oder durch Non-A-non-B-Viren hervorgerufen werden kann. Die beiden ersten Formen sind aufgrund serologischer und molekularbiologischer Methoden eindeutig definiert, die Diagnose der Non-A-non-B-Hepatitis stellt bislang noch eine Ausschlußdiagnose dar und basiert hauptsächlich auf anamnestischen Angaben (Transfusionen, Gerinnungspräparate, Drogenabusus, epidemisches Auftreten), auch wenn sich hier möglicherweise ein Durchbruch in der serologischen Diagnostik durch den kürzlich gelungenen Nachweis von 2 der Non-A-non-B-Viren abzeichnet [8, 44]. Eine spezifische kausale Therapie der verschiedenen Formen der Virushepatitis gibt es bisher leider noch nicht. In den letzten Jahren ist aber etwas mehr Klarheit in die Therapiekonzepte dieser Erkran-kungen eingekehrt, und es zeichnen sich geringe Fortschritte ab. Diese sind eng mit den Fortschritten auf dem Gebiet der Virologie und der Aufklärung der Pathogenese der Hepatititen verknüpft, wie man besonders deutlich am Beispiel der Hepatitis-B-Infektion sehen kann.
The Gastrointestinal Tumor Study Group performed a two-stage trial of alpha-2B interferon in 30 hepatocellular carcinoma patients. Two patients did not receive the treatment and are not considered in the analysis. Only two (7%) short-lived objective responses were observed and the median survival time was 22 weeks. Toxicity was, in general, acceptable. Fourteen severe toxic reactions were observed with fever, chills, malaise, and myalgia accounting for the majority. Our experience indicates that recombinant alpha-2B interferon does not have significant antitumor activity against hepatocellular carcinoma.
IntroductionIFN-γ – The MoleculeFDA-approved Indications: Established Benefit and Risks Chronic Granulomatous Disease (CGD)OsteopetrosisAdverse ReactionsInfectious Diseases Mycobacterial Infection LeprosyMycobacterium avium InfectionTuberculosis (TB)LeishmaniasisOpportunistic Infections in HIV DiseaseInfection Following Serious TraumaAtopic Dermatitis (AD)Idiopathic Pulmonary Fibrosis (IPF)Systemic Sclerosis (SSc)Radiation-induced FibrosisChronic HepatitisOncology Indications: Ovarian CancerConclusions Chronic Granulomatous Disease (CGD)OsteopetrosisAdverse Reactions Mycobacterial Infection LeprosyMycobacterium avium InfectionTuberculosis (TB)LeishmaniasisOpportunistic Infections in HIV Disease LeprosyMycobacterium avium InfectionTuberculosis (TB)
Fifty-nine patients with prior hepatitis B virus infection underwent orthotopic liver transplantation. During the first 2 mo, mortality was not significantly different in the hepatitis B virus–infected group (25.5%) vs. a hepatitis B virus–immune control group (21%). Beyond 2 mo, the mortality, rate of graft loss, need for retransplantation and incidence of abnormal liver function were significantly higher in the hepatitis B virus–infected group. Treatment of the hepatitis B virus infection was attempted with passive immunization, combined active and passive immunization, -interferon or nothing. The clinical outcome was not significantly influenced by any of these therapies. However, of the patients who lived more than 60 days, 6 of 22 treated with active plus passive immunization were cleared of HBsAg, something achieved once in 16 patients treated with -interferon, never in 3 patients with passive immunization only and once in 4 patients with no therapy. In patients with recurrent hepatitis B virus infection, the pace of hepatitis development in the graft appeared to be accelerated, and this was particularly striking in patients who underwent multiple retransplantations at progressively shorter intervals. None of the patients who became HBsAg-negative had HBeAg preoperatively. (HEPATOLOGY 1991;13:619–626.)
The first priority in treating fibrosis is to eliminate the causes that result in liver injury, e.g., hepatitis B and C virus. However, in many liver diseases the cause is either unknown or untreatable. The present study was designed to investigate the long-term antifibrotic effect of interferon-gamma (IFN-gamma) treatment in patients chronically infected with hepatitis B virus.
A total of 42 patients, 30 treated with IFN-gamma and 12 controls, were enrolled from an original clinical trial (Clin Gastroenterol Hepatol 2005;3:819.). Three serial liver biopsies that were obtained at the initiation and end of IFN-gamma treatment as well as 4 to 6 years after treatment discontinuation were assessed according to the modified Chevallier scoring system.
Twenty-five out of 30 IFN-gamma-treated patients were followed up until 4 to 6 years after the treatment was stopped. However, all controls were excluded from follow-up due to death, loss and elevated virus level within 2 years. Twenty-five IFN-gamma-treated patients had stable serum liver function and liver fibrosis indices without any further anti-viral or anti-fibrotic treatment. Improved inflammatory and fibrotic scores were found after nine months of IFN-gamma treatment according to the modified Chevallier scoring system (inflammation: 11.8+/-6.5 at the beginning of IFN-gamma treatment vs. 9.2+/-4.1 after 9 months, P<0.05; fibrosis: 15.0+/-7.3 at baseline vs. 12.6+/-6.8 after 9 months, P<0.05). Among them, 14 patients accepted a third serial liver biopsy 4 to 6 years after treatment discontinuation, and the fibrotic score was increased (14.2+/-8.3 vs. 11.9+/-7.6 after 9 months, P<0.05).
Nine-month IFN-gamma treatment significantly improves the fibrosis score in patients with chronic HBV infection. The majority of patients demonstrate stable serum biochemical indices and quality of life. However, they do not show a long-term benefit according to histological criteria. Given the limited sample size, long-term IFN-gamma treatment regimens should be assessed in further clinical trials.
Interferon alpha is the only available therapy for patients with chronic hepatitis B. With interferon alpha 3-15 MU thrice weekly or 5 MU daily during 3-6 months one-third of the patients achieve seroconversion of HBeAg and HBV-DNA together with normalization of aminotransferases and slight improvement of histology. Loss of HBsAg is reported in a minority of responders during treatment, but increases during follow-up. Patients with baseline alanine aminotransferase of at least twice the upper limit of normal and low HBV-DNA concentration achieve the best response rates. HIV-positive patients with low CD4 counts and Asians are poor responders. As side-effects influenza-like symptoms are experienced by almost all patients. Mild leukopenia, thrombocytopenia and decreased hairgrowth are frequently reported. Severe depression, depersonalization and psychosis are reported in a small number of patients but tend to be poorly recognized in some studies. The decision whether dose reduction is indicated seems strongly related to the opinion of the investigator. Although long-term effects on the occurrence of cirrhosis and the development of hepatocellular carcinoma are not available yet, the achieved results are promising.
Interferon-α has been shown recently to selectively enhance hepatocyte expression of HBsAg/pre-S2 in chronic hepatitis B virus infection in a way that may enhance immune recognition. To determine the effect of interferon-γ on hepatitis B virus antigen expression, hepatocytes isolated from patients with chronic hepatitis B virus infection were incubated in the absence or presence of interferon-γ and viral antigen expression was assessed by both radioimmunoassay and immunocytochemistry using appropriate monoclonal antibodies.
Interferon-γ inhibited the expression of all hepatitis B virus antigens tested. Intracellular HBsAg measured by radioimmunoassay of sonicated hepatocytes fell by 29% with 1 U/ml (p < 0.01) and 36% with 10 U/ml of interferon-γ (p < 0.001) compared with control treatment. Secreted HBsAg was reduced by 19% with 10 U/ml of interferon-γ (p < 0.01). Intracellular HBeAg was also decreased by 29% with 1 U/ml (p < 0.05) and 42% with 10 U/ml of interferon-γ (p < 0.05), but no significant change was found in the amount of secreted HBeAg. The proportion of hepatocytes containing various hepatitis B virus antigens and the intracellular viral antigen staining densities also fell significantly with interferon-γ incubation. Interestingly, the addition of interferon-γ abolished the augmenting effect of interferon-α on intracellular HBsAg.
These data indicate that interferon-γ, in contrast to interferon-α, has an inhibitory effect on hepatocyte expression of all hepatitis B virus antigens including HBsAg/pre-S2, suggesting that this may be one factor that accounts for their difference in clinical activity in patients with chronic hepatitis B virus infection. (HEPATOLOGY 1991;14:975–979.)
Fifty-nine patients with prior hepatitis B virus infection underwent orthotopic liver transplantation. During the first 2 mo, mortality was not significantly different in the hepatitis B virus-infected group (25.5%) vs. a hepatitis B virus-immune control group (21%). Beyond 2 mo, the mortality, rate of graft loss, need for retransplantation and incidence of abnormal liver function were significantly higher in the hepatitis B virus-infected group. Treatment of the hepatitis B virus infection was attempted with passive immunization, combined active and passive immunization, alpha-interferon or nothing. The clinical outcome was not significantly influenced by any of these therapies. However, of the patients who lived more than 60 days, 6 of 22 treated with active plus passive immunization were cleared of HBsAg, something achieved once in 16 patients treated with alpha-interferon, never in 3 patients with passive immunization only and once in 4 patients with no therapy. In patients with recurrent hepatitis B virus infection, the pace of hepatitis development in the graft appeared to be accelerated, and this was particularly striking in patients who underwent multiple retransplantations at progressively shorter intervals. None of the patients who became HBsAg-negative had HBeAg preoperatively.
Forty patients with compensated chronic active hepatitis B and elevated aminotransferases who were HBsAg and HBeAg positive were randomised to a treatment group receiving recombinant interferon alpha-2b (rIFN alpha-2b) or no treatment as a control group. The treated patients were divided into 2 groups, group I (n = 12) received IFN in a dose of 5 MU/m2 thrice weekly by subcutaneous injection for 16 weeks, and group II (n = 8) received the same dose daily for the same duration. Patients were followed up for 12 months after therapy ended. Initiation of IFN therapy was associated with an increase in aminotransferases, reaching a peak at 4-6 weeks in most patients, associated with clearance of HBeAg. At end of follow-up, 81% of the treated patients had cleared HBeAg vs 33% of the control group (p less than 0.01). Changes in other HBV markers were more frequent in the treated patients, though insignificantly. The type of response to therapy was significantly related to the duration of illness, being shortest in those who cleared HBsAg. A complete response to therapy with loss of HBsAg was associated with marked reduction in biochemical and histological activity. A partial response with clearance of HBeAg was associated with moderate improvement in biochemical parameters and ongoing activity in liver histology; whereas persistence of HBeAg was associated with elevated aminotransferases and histological deterioration in most cases. The rise in aminotransferases during seroconversion was associated with hepatic decompensation and death on 3 occasions: one during spontaneous seroconversion, and the other 2 during IFN therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Of all the hepatotropic viruses, HBV is associated with the greatest worldwide morbidity and mortality. This is because of the ease of transmission and the potential for progression to a chronic infective carrier state, with the complications of cirrhosis and hepatocellular carcinoma. The use of PCR has shown that some of the earlier concepts concerning the interpretation of serological data were inaccurate. Many patients with anti-HBe and anti-HBs have viral DNA detectable by PCR, and some hepatocellular carcinoma patients have detectable HBV DNA in their livers in the absence of all serological markers of HBV disease. The clearance of HBV infected cells from the liver is dependent on the interplay between the interferon system and the cellular limb of the host immune response. The importance of the nucleocapsid proteins as targets for sensitized cytotoxic T cells has been established for chronic HBV infection. The importance of pre-S sequences as inducers and targets of the virus-neutralizing humoral immune response is becoming established, but their precise role must await the development of in vitro models of hepadnavirus infection and a greater understanding of the mechanisms of viral uptake. The epidemiology and clinical course of the disease can be modified by immunization, immune stimulation and antiviral chemotherapy. For the developing world, a programme of immunization at birth would be the most effective way of eliminating this disease, but at present the cost is prohibitive. For the developed world, immunization is realistic for the at-risk population, and anti-viral and immunostimulatory therapy available for those already infected. In adult acquired chronic HBV infection alpha-interferon produces HBe antigen clearance in 40-60% of cases and is followed by resolution of the hepatic inflammation. Results in neonatally acquired infection are less impressive and prednisolone priming followed by interferon may be needed. The presence of a mutation in the pre-core region of some virus isolates has recently been described. Hepatocytes infected with this virus cannot produce HBe antigen and the course of the liver disease is fairly rapid. Whether this mutant causes liver damage in the same way as the wild virus or is directly cytopathic remains unclear, and its relationship to fulminant hepatitis is under investigation.
Chronic viral hepatitis caused by hepatitis B, C or D may lead to cirrhosis, hepatocellular failure and hepatocellular carcinoma. The morbidity of these diseases has necessitated a prolonged search for effective therapy. Interferon-alpha has been studied widely, and remains the mainstay of treatment. Therapy for hepatitis B has now become possible with the demonstration that alpha-interferons inhibit hepatitis B virus (HBV) replication and that prolonged therapy can lead to a remission in disease. A number of other cytokines, including thymosin, are being evaluated. Currently used nucleoside analogues and anti-retroviral therapies used in human immunodeficiency virus infection have not proven useful in chronic hepatitis B. There are a number of new experimental nucleoside analogues with activity against HBV. Unfortunately, fialuridine has been associated with severe mitochondrial damage and hepatotoxicity. Other stereoisomers may be more active and less toxic, but the potential danger of these drugs indicates that large scale clinical trials should proceed cautiously. Experimental test systems for the preliminary investigation of antiviral compounds in hepatitis B and C will be required. Antisense oligodeoxyribonucleotides may inhibit the expression of the HBV genes. The natural history of hepatitis C is uncertain. Therapeutic trials of interferon-alpha indicated that a proportion of patients may respond to treatment with this agent. There is most information about 3 mU t.i.w. administered for 6 months. It is not yet clear whether this dose is optimal. Multivariate analysis of several pretreatment parameters indicate that patients without cirrhosis are more responsive to interferon. The influence of genotypes of hepatitis C is the subject of considerable interest at present. Patients with diverse circulating quasispecies may be less responsive to therapy than those with a single major species. Improved responses have been observed in patients with lower levels of circulating hepatitis C virus RNA.
The effects of tumor necrosis factor-alpha and/or interferon-gamma on the replication of hepatitis B virus were examined using HB611 cells. These cells were derived from human hepatoblastoma cells, Huh6, by integrating hepatitis B virus DNA, and produce hepatitis B virus continuously. Each of the cytokines inhibited hepatitis B virus replication in the cells assessed as the amount of episomal hepatitis B virus DNA, without a decrease in cell viability. When the two cytokines were administered together, the inhibitory effect became greater. Incubation of the cells with 1,000 U/ml tumor necrosis factor-alpha decreased HBV DNA replicative intermediates by 55%, and that with 1,000 U/ml interferon-gamma decreased these by 51%. Furthermore, incubation with 1,000 U/ml tumor necrosis factor-alpha and 1,000 U/ml interferon-gamma in combination decreased HBV DNA replicative intermediates by 71%. In contrast, the amount of hepatitis B virus RNA and secretion of hepatitis B e antigen were not apparently reduced by the cytokines, and 2',5'-oligoadenylate synthetase activity was not detected in the supernatant. These results suggest that tumor necrosis factor-alpha and interferon-gamma inhibit hepatitis B virus replication by blocking some step in reverse transcription and that the 2',5'-oligoadenylate synthetase is not involved in the mechanism underlying the inhibition by these two cytokines.
Interferon-alpha is currently the only therapy approved for treatment of chronic HBV in the United States and Europe. Interferon-alpha therapy causes loss of HBeAg and HBV DNA in approximately a third of treated patients, and the loss of these markers of active viral replication is associated with improvements in hepatic histology and ALT levels. However, the long-term effects of interferon-alpha on morbidity and mortality, and especially on the incidence of the complications of chronic HBV infection, remain to be defined. The currently available treatment for chronic HBV is far from perfect. Interferon therapy is usually associated with significant side effects and requires subcutaneous administration. Additionally, there are a large number of patients who either fail to meet criteria for treatment, or who, with therapy, fail to respond (at least 60% of all patients). Moreover, interferon treatment is expensive (approximately $5,000 for a 16 week course of 5MU daily). Hence the search continues for effective, orally-available and cost-efficacious therapy. Of the agents available, the nucleoside analogues appear to have the greatest promise. The availability of cell culture systems and animal models for studying potential anti-HBV drugs will aid in the future development of these agents. Therapeutic vaccines, and combination therapies (given either concurrently or sequentially) may also play a future role in the management of chronic HBV infection. While prevention of disease must be a primary goal in the war against this common infection, a continued focus must be maintained on the treatment of the approximately 300 million individuals world-wide with established chronic HBV infection.
Treatment of chronic replicative hepatitis B virus (HBV) infection is aimed at stopping viral replication and preventing the development of chronic liver disease. beta-Interferon treatment has been less well studied than alpha-interferon.
The efficacy and tolerability of a 6-month course of subcutaneously administered human recombinant beta-interferon (rINF-beta ser) was studied and the results of a low-dose regime compared with a high-dose regime. Twenty patients (17 men and three women), aged 24-54 years, with chronic hepatitis B virus infection (all hepatitis B surface antigen-positive with detectable HBV-DNA in their sera for at least 3 months prior to therapy) were randomized into two treatment groups of 10 patients each. The low-dose group received 6 x 10(6) U/dose and the high-dose group received 30 x 10(6) U/dose, both groups receiving their respective doses three times a week initially for 1 month and continuing for a total of 6 months.
The treatment was well tolerated in both groups. None of the patients required dosage reduction or cessation of treatment because of side-effects. HBV-DNA decreased in all patients during treatment, demonstrating the anti-viral efficacy of rINF-beta ser, and was undetectable in 20 and 40% of patients receiving low-dose and high-dose regimes, respectively, at the end of 6 months treatment (P = N.S.). One year after completion of treatment, HBV-DNA was undetectable in 50 and 30% of patients in the low-dose and high-dose groups, respectively (P = N.S.). However, only one patient achieved seroconversion with loss of the hepatitis B surface antigen and appearance of an antihepatitis B 'e' antigen at the end of 18 months.
This study shows that subcutaneously administered rINF-beta ser is well tolerated, but the optimal dose and duration of treatment still needs to be defined by further studies.
Currently, the only therapy of proven benefit in chronic hepatitis B is interferon-alpha which leads to a long-term benefit in only one-third of patients. New therapies for hepatitis B fall into three categories; antiviral chemotherapy, immunomodulation with cell-based therapies, vaccines or cytokines, and gene therapy such as with antisense oligonucleotides, ribozymes or viral mutants. The most promising immediate approach to therapy is with the new nucleoside antivirals--lamivudine and famciclovir. These drugs are well absorbed orally, result in profound inhibition of circulating hepatitis B virus, and, in some cases, loss of hepatitis B e antigen and improvement in serum aminotransferases. Controlled trials of long-term famciclovir and lamivudine therapy currently underway aim to show whether these drugs are safe and can provide sustained inhibition of viral replication and attentant improvement in liver disease.
Background/Aims: Interferon-alpha is used widely to treat viral hepatitis. Interferon-gamma modulates a system attacking infected cells and also has an anti-fibrotic effect. A treatment with interferon-alpha and -gamma has undergone trials in eliminating hepatitis C virus. We investigated effects of cotreatment in a liver fibrosis model to explore anti-fibrotic effects. Methods: Rats were assigned to groups including normal controls (NC), CCl(4) controls, rat interferon-alpha treatment, rat interferon-gamma treatment, and cotreatment. All groups except normal controls received CCl(4) orally for 8 weeks. At the beginning of the third week of exposure, 6 weeks of treatment were initiated according to interferon group. Digitally analyzed immunohistochemistry, biochemical assays, and Northern analysis were performed. Results: Pixels (x10(5)) per field containing immunoreactive type III collagen (fibrotic density) in CCl(4) controls, interferon-alpha, interferon-gamma, and cotreatment groups respectively were [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text]. Liver hydroxyproline content correlated with fibrotic density, and was significantly low in the cotreatment group. Plasma hyaluronate and transaminase were significantly low in cotreatment and interferon-alpha groups. Northern blotting showed lowest mRNA expression for type I collagen, desmin, transforming growth factor (TGF)-beta1, and matrix metalloproteinase-2 mRNA in the cotreatment group; tissue inhibitor of metalloproteinase-1 and -2 mRNAs were significantly low in the interferon-gamma group. Conclusions: Cotreatment can suppress collagen and transforming growth factor-beta1 and has an overall anti-fibrotic effect without exacerbating inflammation.
Currently, there are no effective therapies available for patients with chronic hepatitis C who have failed to respond to optimal interferon alfa-based regimens. The aims of this pilot study were to assess the antiviral activity and safety of interferon gamma in chronic hepatitis C.
Patients with chronic hepatitis C, genotype 1, who had not responded to or who had relapsed after therapy with interferon alfa and ribavirin were enrolled in a trial of interferon gamma 1b given in doses of 100, 200 or 400 microg subcutaneously three times weekly for 4 weeks. Frequent blood samples were obtained for HCV RNA levels.
Fourteen patients were enrolled. Geometric mean HCV RNA levels remained unchanged. Serum aminotransferase levels also did not change, while there were significant decreases in neutrophil counts (-41% from baseline) and hematocrit (-5%). Low grade fever and malaise were common with the first injection of interferon gamma, but no serious side effects were encountered.
Although relatively well tolerated, interferon gamma in doses of 100-400 microg thrice weekly had no effect on HCV RNA levels in patients with chronic hepatitis C who had failed to achieve a sustained response to interferon alfa-based therapies.
Hepatic fibrosis due to chronic HBV infection has enormous socioeconomic impact. Besides strategies targeting virus elimination, prevention or reversal of liver fibrosis is amenable. Given the antifibrotic activity of interferon-gamma (IFN-gamma), a randomized open-labeled multicenter trial was initiated to test IFN-gamma in HBV infection.
HBsAg-positive patients with biopsy proven hepatic fibrosis (n = 99, stages 2-4, Scheuer criterion) were treated with diammone-glycyrrhizinate and potassium-magnesium aspartate. Sixty-six randomly assigned patients were treated with 50 mug IFN-gamma intramuscularly on a daily basis for 3 months and on alternate days the subsequent 6 months. Efficacy was evaluated by liver biopsy and serologic markers.
Fifty-four patients in the IFN-gamma group and 29 patients in the control group completed the study. The hepatic fibrosis score was significantly reduced in 63% of IFN-gamma treated patients compared with 24.1% in the control group by using a semiquantitative scoring system evaluating both liver architecture and fibrotic deposits. Mean values for the total fibrosis score decreased from 13.8 +/- 5.8 to 10.1 +/- 5.1 in the IFN-gamma group (P = .0001), whereas they were unchanged in control subjects (13.2 +/- 6.8 vs 12.6 +/- 4.8, P = .937). The Scheuer system showed 12 out of 54 patients improved >or=1 stage(s) in the IFN-gamma group compared with 1 of 29 in the control group. Antifibrotic activity might be attributed to decreased transforming growth factor-beta signaling via phosphorylated Smad2 and reduced number of activated, alpha-smooth muscle actin positive hepatic stellate cells.
IFN-gamma treatment for 9 months improves fibrosis scores in patients with chronic HBV infection most likely by antagonizing profibrogenic transforming growth factor-beta effects.
Given that the complications of hepatitis C are due to fibrosis, we hypothesized that the antifibrotic effects of interferon gamma on stellate cells would lead to beneficial effects in patients with hepatitis C. Thus, we evaluated the safety and efficacy of interferon gamma-1b in patients with hepatitis C. A cohort of 20 patients with chronic hepatitis C who failed or were intolerant to previous interferon-alpha-based regimens received 200 mug of interferon gamma-1b subcutaneously three times weekly for 24 weeks. Liver biopsy was performed prior to and at the end of treatment. Biopsies were evaluated by a single blinded pathologist using the Knodell system modified by Ishak, and fibrosis was also quantitated by morphometric analysis. The study population was 75% male and 70% Caucasian. Mean age was 47.9 +/- 7.5 years. Eighteen of 20 patients completed therapy. One patient discontinued therapy because of constitutional symptoms. One patient discontinued therapy because of elevated aminotransferases greater than twice baseline. No serious adverse events occurred. Morphometric analysis revealed that six patients (30%) had >1% absolute reduction in fibrosis score. Four of 20 (20%) patients had improvement in Ishak fibrosis scores after treatment. In conclusion, interferon gamma therapy is safe and well tolerated in patients with chronic hepatitis C. Although we did not detect an overall reduction in fibrosis, interferon gamma-1b treatment led to a reduction in fibrosis in selected patients. These data provide a basis for further study of interferon gamma-1b in patients with chronic fibrosing liver disease.
Chronic hepatitis C virus infection is common in the United States with an estimated prevalence of 2.7 million persons. Fortunately, the incidence of new infections has markedly declined in recent years and the natural history of chronic hepatitis usually only results in significant progression after several decades of infection. However, the majority of chronically infected patients acquired their infections more than 20 years ago; these patients with long-standing chronic hepatitis are now presenting in increasing numbers with decompensated cirrhosis and the need for liver transplantation. Cirrhosis caused by chronic hepatitis C is now the most common indication for liver transplantation. Interferon monotherapy became clinically available 10 years ago but resulted in sustained improvement in liver disease and durable loss of detectable virus in fewer than 10% of treated patients. The recent use of the combination of interferon with the nucleoside analogue ribavirin for 6–12 months results in a sustained virological response in 30%–40% of previously untreated patients. The response to this combination therapy is also excellent in patients who had initially responded to interferon monotherapy and later relapsed. Furthermore, some recent studies suggest that a small proportion of patients who failed to respond to a prior course of interferon (primarily noncirrhotic patients with low levels of virus and genotypes other than 1) may also benefit from retreatment with this combination.
Chronic hepatitis B is a common and often progressive liver disorder for which there is no accepted therapy. To assess the efficacy of treatment with interferon, we randomly assigned patients with chronic hepatitis B to one of the following regimens: prednisone for 6 weeks followed by 5 million units of recombinant interferon alfa-2b daily for 16 weeks; placebo followed by 5 million units of interferon daily for 16 weeks; placebo followed by 1 million units of interferon daily for 16 weeks; or observation with no treatment.
Hepatitis B e antigen and hepatitis B viral DNA disappeared from serum significantly more often in the patients given prednisone plus interferon (16 of 44 patients, or 36 percent) or 5 million units of interferon alone (15 of 41; 37 percent) than in the untreated controls (3 of 43; 7 percent; P less than 0.001); the difference between those given 1 million units of interferon (7 of 41; 17 percent) and the controls was not significant. The strongest independent predictor of a response to treatment was the amount of hepatitis B viral DNA in serum at entry (P less than 0.0001). Of the 38 patients who responded to interferon, 33 (87 percent) had normal serum aminotransferase levels after therapy; 11 patients who responded (29 percent), but no controls, lost the hepatitis B surface antigen. Blinded histologic assessment revealed a significant improvement in periportal necrosis in the treated patients (P = 0.03).
In chronic hepatitis B, treatment with interferon alfa-2b (5 million units per day for 16 weeks) was effective in inducing a sustained loss of viral replication and achieving remission, assessed biochemically and histologically, in over a third of patients. Moreover, in about 10 percent of the patients treated with interferon, hepatitis B surface antigen disappeared from serum.
Interferons (IFNs) are a class of proteins, secreted by animal cells in response to various inducers1, which confer resistance to viral infections and are designated according to their cellular origin or to the inducing agent. Viruses induce type I Interferon, subdivided into alpha-interferon, produced by leukocytes (Le) or lymphoblastoid (Ly) cells, and beta-interferon, produced by fibroblasts1. Mitogens and antigenic stimuli induce in lymphocytes type II immune IFN-gamma. Interferons seem to bind to specific receptors2 to elicit a variety of cellular responses3; several early studies provided indirect evidence for such binding4-6. Direct evidence for specific interferon receptors was presented by Aguet7, who showed that biologically active 125I-labelled mouse (Mu)IFN binds to sensitive L1210-S cells, but not to interferon-resistant L1210-R cells8. The main obstacle in carrying out such studies is the availability of pure interferon. Recently, Maeda et al.9 constructed plasmids containing human interferon sequences. The plasmid p104 was used as a probe to isolate the coding region of a human interferon (IFLrA), which was expressed in Escherichia coli10 and purified with monoclonal antibodies11. This interferon, designated HuIFN-alphaA, was labelled with 125I for binding assays on human cells. We have determined the specificity of different HuIFNs for the cellular sites which bind HuIFN-alphaA and show here that HuIFN-gamma does not compete for binding, whereas all type I HuIFNs do.
Pharmacokinetics, tolerance and biological effects of human recombinant γ-interferon were studied in 12 patients with chronic active hepatitis B. Serum concentrations of γ-interferon were measured by radioimmunoassay in four patients after a subcutaneous injection of 10 million U (0.5 mg); the peak serum concentration of γ-interferon (29 ± 7 U/ml) was reached after 5 to 8 hr and γ-interferon remained detectable for 24 to 36 hr. Twelve patients received recombinant γ-interferon, 2.5 to 10 million U daily, for 4 mo. All suffered from a dose-dependent, flulike syndrome similar to that induced by α-interferon. Recombinant γ-interferon induced a marked increase of serum ALT and a significant decrease of serum hepatitis B virus-DNA. Serum hepatitis B virus-DNA disappeared in one patient during administration of recombinant γ-interferon. Serum hepatitis B virus-DNA disappeared in four additional patients, and HBeAg disappeared in two patients during the 12 mo after administration of recombinant γ-interferon. These results indicate that subcutaneous injection is suitable for administration of recombinant γ-interferon and that recombinant γ-interferon has an antiviral effect in patients with chronic active hepatitis B. (HEPATOLOGY 1990;12:155–158).
Chronic hepatitis C is often a progressive liver disease for which there is no satisfactory treatment. We studied the efficacy of recombinant alpha-interferon or gamma-interferon in the treatment of this disease in comparison with a control group. Thirty patients were randomly assigned to three groups. Ten patients received 7.5 MU alpha-interferon/m2 body surface three times weekly for 3 mo, then 5 MU/m2 for 3 mo and 2.5 MU/m2 for 6 mo. Ten patients were treated with gamma-interferon at a dose of 2 MU/m2 for 6 mo and the other 10 served as controls without treatment. The mean serum ALT levels and liver histological findings improved significantly only in the patients treated with alpha-interferon. No changes were observed in patients treated with gamma-interferon or in controls. Five of 10 patients treated with alpha-interferon had complete responses (mean ALT normal during therapy). After treatment ALT returned to pretreatment levels in two of 5 patients. The long-term response rate after alpha-interferon therapy was 30% at 18 mo. We conclude that alpha-interferon is effective in controlling disease activity in a portion of patients with chronic hepatitis C. High doses of alpha-interferon do not appear to add further benefit in the response rate or relapse rate. gamma-Interferon therapy is ineffective.
Pretrial and posttrial liver biopsy samples from 124 adult patients who participated in two randomized, controlled trials of interferon alfa therapy for chronic hepatitis B virus (HBV) infection were analyzed to determine the effects of interferon on the replication of HBV in the liver. Replicative forms of HBV DNA were detected in the pretrial biopsy samples from all and posttrial biopsy samples from 74% treated patients and 86% controls. Replicative forms of HBV DNA were detected in the posttrial biopsy samples from all patients who remained positive for hepatitis B e antigen and HBV DNA in the serum, in 77% treated patients and 80% controls who cleared HBV DNA in the serum but who remained positive for hepatitis B e antigen, but in only 19% treated patients and 40% controls who cleared HBV DNA as well as hepatitis B e antigen in the serum. Serum alanine aminotransferase levels were significantly lower in patients whose posttrial biopsies did not contain replicative forms of HBV DNA. In summary, we demonstrated that in most patients with chronic HBV infection treated with interferon alfa, serological response was associated with the disappearance of replicative forms of HBV DNA in the liver.
Ninety Chinese hepatitis B surface antigen (HBsAg) carrier children, aged 2-17 years, positive for hepatitis B e antigen (HBeAg) and hepatitis B virus DNA on at least three occasions in 6 months, were randomized into 3 groups. Thirty children received syrup vitamin B complex as control, 29 received 6 weeks of placebo syrup followed by 16 weeks of recombinant alpha 2b-interferon [intron A (rIFN2b)], 5 x 10(6) u/m2 subcutaneously thrice weekly; and 31 received 6 weeks of syrup prednisone (0.6 mg/kg tailed to 0.2 mg/kg) followed by 16 weeks of recombinant alpha 2b-interferon as above. The placebo/prednisone syrup was given on a double-blind basis. At 24 months of follow-up, persistent loss of hepatitis B virus DNA occurred in none of the children in the control group, in one child receiving recombinant alpha 2b-interferon alone, who also seroconverted to anti-HBe and anti-HBs and in five children receiving interferon with steroid priming (p = 0.0571 compared with controls), with four seroconverting to anti-HBe and one also seroconverting to anti-HBs. A rise of transaminases to above twice the upper limit of normal levels during the first 7 months of follow-up occurred in one subject in the control group, four in the group receiving alpha 2b-interferon alone and nine in the group receiving recombinant alpha 2b-interferon with steroid priming (p = 0.0144 compared with controls). Side effects of the steroid were negligible; those of recombinant alpha 2b-interferon were transient and acceptable. We conclude that 6 weeks of prednisone followed by 16 weeks of recombinant alpha 2b-interferon is of use in inducing persistent loss of hepatitis B virus DNA (16.1 per cent) and e-seroconversion (12.9 per cent) in a proportion of Chinese HBsAg carrier children: the prednisone probably enhances the immunomodulatory effect of recombinant alpha 2b-interferon.
Eight patients with chronic hepatitis B entered a pilot study of gamma interferon and alpha interferon in combination. Gamma interferon alone had minimal inhibitory effects on serum levels of hepatitis B virus as monitored by serum HBV DNA and DNA-polymerase activity. The drug also gave troublesome side effects. In contrast, alpha interferon had more potent inhibitory effects on serum HBV levels and fewer side effects. When combined, the two interferons showed no additive or synergistic effects in inhibiting serum levels of HBV DNA or DNA polymerase. These findings indicate that the addition of gamma interferon to alpha interferon provides no additional antiviral effects but contributes significantly to side effects.
A previous randomized controlled study has shown a 30% rate of HBe antigen/antibody seroconversion within 1 year of a month course of adenine arabinoside-5'-monophosphate; no seroconversion occurred in the control group. In this study of patients derived from the same population, 45 hepatitis B virus carriers with chronic liver disease were randomized to receive either a short (4-week) course of adenine arabinoside-5'-monophosphate, a long (7 to 8-week) course of adenine arabinoside-5'-monophosphate or a 12-week course of lymphoblastoid interferon. Long-lasting suppression of hepatitis B virus replication with disappearance of serum hepatitis B virus DNA and clearance of HBeAg occurred within 12 months of treatment in four patients who received the short course of adenine arabinoside-5'-monophosphate and in five who received interferon. Of the nine responders, four also lost HBsAg. A response to antiviral therapy was accompanied by clinical and biochemical evidence of improvement in liver disease. None of the patients who received a long course of adenine arabinoside-5'-monophosphate responded. Peripheral neuropathy and myalgia were the most serious adverse effect affecting three recipients of the short course of adenine arabinoside-5'-monophosphate and eight recipients of the long course. Thrice weekly administration of interferon was well-tolerated. Further studies to identify the characteristics of the "responder patients" and large-scale controlled trials of antiviral therapy in these subgroups are indicated.
To characterize receptors for alpha interferon (IFN-alpha) on human cells, we studied the binding of radioiodinated recombinant DNA-derived human IFN-alpha to human peripheral blood mononuclear cells (PBMCs) from normal individuals and from patients with chronic type B hepatitis. At 1 degree C, binding reached equilibrium after 2 to 3 hours of incubation, and saturation of specific binding occurred at a concentration of approximately 4000 fmol/ml. Binding of labeled IFN-alpha was specific; it was inhibited by an excess of unlabeled IFN-alpha or IFN-beta but not by cholera toxin or IFN-gamma. Scatchard analysis of binding data yielded for normal PBMCs an apparent dissociation constant (Kd) of 1.54 +/- 0.49 x 10(-9) mol/L (mean +/- SD) and an apparent maximum binding capacity (Bmax) of 7.35 +/- 1.22 x 10(-11) mol/L. Corresponding values for patients with chronic type B hepatitis who had not received treatment were similar, suggesting that such patients should respond normally to endogenous interferon. Analysis of data on the binding of labeled IFN-alpha to normal PBMCs from experiments in which a high specific activity ligand or subpopulations of PBMCs had been used revealed that receptors for IFN-alpha on PBMCs are heterogenous. In patients with chronic type B hepatitis who were receiving IFN-alpha therapy, the apparent Kd was increased (3.02 +/- 0.91 x 10(-9) mol/L) without any appreciable change in the apparent Bmax or any appreciable changes in the proportions of subpopulations of PBMCs. This decreased affinity induced by IFN-alpha treatment does not necessarily reflect an effect on a single binding site.(ABSTRACT TRUNCATED AT 250 WORDS)
We have used molecular hybridization techniques to show that hepatitis B virus (HBV) DNA from different individuals may have
substantial differences in sequence homology. Seven specimens of HBV DNA were isolated from plasma of different blood donors.
Samples were applied as dots to membranes and nick-translated to form probes. Densitometry of the radioautograms showed that
hybridization was most extensive with probe prepared from the same specimen. The hybridization bias was statistically significant
(P < .02) and visible to the naked eye.Hybridization to probes that were digested with nuclease SI before nick translation did
not eliminate the bias. Nor was the bias related to the d/y subdeterminants; on the average, 15 other specimens hybridized equally well to probes prepared from HBV with the same or
different subdeterminant. Many specimens among 37 other serum samples showed greater or lesser degrees of homology to different
probes, as demonstrated by repro bing of samples fixed to nylon membranes.
In Southeast Asia, 15 to 20 percent of the population are hepatitis B surface antigen carriers. The majority of these carriers have chronic hepatitis and would progress to cirrhosis or hepatocellular carcinoma at an annual incidence of 2 percent and 1 percent, respectively. Previous studies from Southeast Asia suggested that immunosuppressive therapy could be harmful, or at best of no value, and antiviral treatment with vidarabine, picibanil, or even interferon was also unsatisfactory. Currently, a randomized controlled trial of human lymphoblastoid interferon, with or without prednisolone pretreatment, versus placebo in patients with hepatitis B core antigen in the liver and hepatitis B e antigen in the serum is being conducted. Forty-five patients (29 receiving interferon, 16 receiving placebo) have been entered in the trial for at least two months. Actuarial analysis shows that the response to interferon therapy was better than that to placebo. Although flu-like symptoms, hair loss, and body weight loss were seen, no side effect requiring specific treatment has been encountered. These preliminary results suggest that human lymphoblastoid interferon is effective and safe in Oriental patients.
Chronic infection with hepatitis B virus (HBV) continues to represent a major public health problem. Our group has been studying antiviral therapy for chronic HBV hepatitis since 1975. Several interferon preparations have been used in pilot studies and controlled trials in the treatment of hepatitis B, including human α interferon and human fibroblast β interferon. The goals of this phase I/II study were as follows: (1) to investigate the safety of recombinant-derived β(ser) interferon and recombinant-derived γ interferon in human subjects with chronic HBV infection and the patients' tolerance of the agents; (2) to compare the efficacies of γ interferon and β(ser) interferon in the same patient in achieving DNAP suppression; and (3) to see if combinations of β(ser) interferon and γ interferon had additive, synergistic, or antagonistic effects in achieving DNAP suppression.
We have investigated the efficacy of a relatively prolonged course of recombinant leukocyte interferon treatment in 14 chronic HBsAg-, HBeAg-, hepatitis B virus DNA- and DNA polymerase-positive carriers. alpha-Interferon was administered for 9 weeks. Six of 14 treated carriers have a sustained loss of HBeAg, hepatitis B virus DNA and DNA polymerase. Four subsequently lost HBsAg (28.5%). Elevated pretreatment SGPT concentrations, histologic chronic active hepatitis, an exacerbation of chronic hepatitis with an increase in SGPT concentrations in the last weeks of treatment and possibly recent onset of the carrier state was associated with complete inhibition of viral replication. None of 11 matched, untreated HBsAg-, HBeAg-, hepatitis B virus DNA- and DNA polymerase-positive carriers monitored during the same period lost HBsAg. The effect of recombinant leukocyte interferon may require an appropriate host-immune response. The efficacy of recombinant leukocyte interferon therapy is restricted, but it may be of benefit in a proportion of carriers, if these carriers can be precisely identified.