Interferon-α for Viral Hepatitis

The interferons (IFNs), a family of glycoproteins discovered in the 1950s, are part of the host defense system against viral infection (1). Interferons have been divided into the following three classes: alpha (α), beta (β), and gamma (γ). Each of these types has been further characterized; and cell sources, molecular weights, and inducers of IFN production have been elucidated. IFNs interact with cell surface receptors and induce synthesis of proteins. Antiviral effects of IFN-α and IFN-β include inhibition of (a) viral entry into cells, (b) translation of viral proteins, and (c) assembly of viral particles (2). Immunomodulatory effects of IFN, especially IFN-γ, include increased expression of HLA classes I and II antigens on cell surfaces (3), activation of macrophages (4) and natural killer cells, increased production of cytokines (5) and prostaglandins, and modulation of immunoglobulin synthesis (6,7). IFN-α, which is produced endogenously in response to viral infection and other stimuli, has been studied most intensively as an antiviral agent. This discussion will focus primarily on the use of IFN-α as therapy for hepatitis B, C, and D infections; IFN-β and IFN-γ will be mentioned only for contrast. IFN-β is synthesized by fibroblasts; its primary inducer is double-stranded RNA. There is only one known human IFN-β gene; it is found on the short arm of chromosome 9, closely linked to the multiple genes for IFN-α (8). There is ≈45% homology between the genes for β and α IFN, especially in the 5′ promotor regions. Because of these similarities, α and β IFN are grouped together as Type I IFN. Although they have many sequences and effects in common, α and β IFN have different cell surface receptors (9). IFN-γ, which is believed to have predominantly immunomodulatory rather than antiviral effects, is synthesized by helper T lymphocytes, in response to various antigens and mitogens. There is a single gene for IFN-γ. It is found on the long arm of chromosome 12 (10), and it has no significant sequence homology with genes for α or β IFN. The surface receptor for IFN-γ is different from those of α or β IFN. Thus, IFN-γ is classified as Type II IFN. BIOLOGY OF INTERFERON-α IFN-α is synthesized by monocytes and some activated B lymphocytes. Recently, a specific mononuclear cell with a high rate of IFN-α synthetic potential has been described; it is called the “natural IFN-producing cell,” or NIPC (11). IFN-α is produced in response to viral infection and other antigenic stimulation. In contrast to the single genes each encoding for IFN β and γ, there are 23 genes encoding for IFN-α; the homology among these 23 genes is 85-90%. IFN-α interacts with a specific cell surface receptor, which is present on many different human cells (12). The gene encoding the IFN-α receptor is on chromosome 21. IFN-α binds to the cell surface receptor, undergoes receptor-mediated endocytosis, and is then degraded. The IFN-α receptor is associated with protein kinases of the Jak (Janus kinase) family, which become activated when the ligand binding occurs. The Jak kinases phosphorylate tyrosine resides on latent cytoplasmic proteins called STAT (signal transducers and activators of transcription). These activated STAT are translocated to the nucleus, where they bind to specific sequences and stimulate transcription (13)(Fig. 1). In the case of IFN-α, the specific STAT are termed ISGF-3 (interferon-stimulated gene factor-3), and the DNA sequences stimulated are called ISG, or interferon-stimulated genes. Most ISG have an interferon-stimulated response element, a highly conserved 12-15 base pair sequence, within 200 base pairs of the transcription start site. Interferon-stimulated gene transcripts encode a variety of proteins; the functions of these proteins have not been fully elucidated, but multiple antiviral, antineoplastic, and immunomodulatory effects are postulated (14)(Table 1). IFN-α has antineoplastic effects; it induces a decrease in the rate of cell division, a decrease in oncogene expression, and cytotoxicity against neoplastic cells. Of greater relevance to this discussion are its antiviral effects, which include decreases in viral uncoating, mRNA synthesis, and protein synthesis. Both IFN-α and IFN-γ have immunomodulatory effects, such as stimulation of HLA I and II antigen expression on cell surfaces, and activation of macrophages and natural killer cells, which may potentiate termination of viral infection by causing destruction and clearance of infected cells. The best-studied IFN-stimulated proteins are 2′5′ oligoadenylate synthetase (2′5′ OAS) and a set of protein kinases. These enzymes are particularly active in the presence of double-stranded RNA, which is found only in cells infected with viruses. IFN-α activates 2′5′ OAS expression at the transcriptional level. The single gene for this enzyme is located on chromosome 11. 2′5′ OAS activates RNase L, which preferentially cleaves viral rather than host RNA; the effects of OAS on DNA viruses are not known. The level of 2′5′ OAS correlates with antiviral effects of IFN (15). IFN-stimulated protein kinases are known to catalyze the phosphorylation of numberous cellular proteins. The activity of some of these proteins correlates with viral resistance in vitro (16). In addition to stimulation of the transcription of numerous cellular genes, IFN-α has other effects, such as down-regulation of its receptor synthesis and interaction with other interferons. PHARMACOLOGY OF IFN-α Several forms of IFN-α are available for clinical trials in patients with viral infections. These include purified lymphoblastoid and leukocyte IFN; two recombinant forms, IFN-α 2a and IFN-α 2b; and, more recently, two recombinant forms for which the nucleotide templates have been rearranged into different sequence, consensus IFN and hybrid IFN. IFN administered subcutaneously has an elimination half-life of 4 to 5 h, but its biologic activity lasts for 2-3 days, thus allowing daily or even thrice weekly doses. Liver metabolism and subsequent biliary excretion are minor pathways of IFN-α elimination; IFN clearance is accomplished primarily by catabolism in renal tubular cells. Ordinarily, no intact drug is excreted into the urine. INTERFERON ANTIBODIES Naturally occurring antibodies to natural and recombinant interferons (IFN-Ab) have been found in both healthy subjects and individuals with autoimmune diseases (17). The role of these antibodies is not known; it has been postulated that they participate in normal cytokine physiology. Patients treated with recombinant IFN-α for chronic hepatitis, malignancies, or other disorders may develop IFN-Ab. The clinical significance of this phenomenon is not clear. There may be differences in the frequency of IFN-Ab production, depending on the preparation administered (18). IFN-Ab have been detected in 35-50% of patients treated for chronic viral hepatitis with recombinant IFN-α. No factors that predispose to development of IFN-Ab have been identified. IFN-Ab may interfere with antiviral activity in chronic HBV infection. In one series, IFN-Ab were associated with nonresponse in HBV DNA positive patients (19); in another series, the development of IFN-Ab appeared to reverse the initial antiviral response (20). In the latter study, IFN-Ab were likely to develop in patients treated with low-dose rather than high-dose IFN. The role of IFN-Ab in the therapeutic response to IFN-α in chronic HCV infection is not as clear. In one report, IFN-Ab were detected in 75% of nonresponders, but also in ≈50% of responders (21). In another series, IFN-Ab developed in 32% of treated patients. These antibodies were found in 40% of nonresponders and 14% of responders; however, this difference was not statistically significant (22). Monitoring for the development of IFN-Ab during treatment of viral hepatitis is not clinically available and not currently recommended. IFN-α FOR CHRONIC HEPATITIS B VIRUS INFECTION The hepatic injury associated with hepatitis B virus (HBV) infection is mediated by the host immune response (23). The virus replicates within the hepatocytes, and viral antigens appear on the cell surface. Subsequently, cytotoxic T lymphocytes directed against these antigens infiltrate the liver, causing hepatocyte necrosis (24). HBV also interferes with the production of cytokines, especially interferons; thus, stimulation of MHC class II antigen expression is inhibited and viral clearance is diminished. Individuals who develop chronic infection with HBV have been found to have a decreased endogenous IFN response (25,26). Pharmacologic doses of leukocyte IFN-α was first reported as a treatment for chronic HBV infection in 1976 (27). Since that time, numerous studies have examined the therapeutic effect of leukocyte, lymphoblastoid, or recombinant IFN-α in this disease. Dosages have ranged from 3 million units (MU) weekly to 60 MU daily; studies that utilized a cumulative dose of > 15 MU/m2/week demonstrated greatest effectiveness. In most trials, 5 or 10 MU was given 3 times weekly or daily, for 3, 4, or 6 months. The thrice weekly dosing schedule was generally associated with fewer side effects, and similar response rates, than daily administration. Most patients with chronic HBV infection are asymptomatic. Response to therapy is usually defined as normalization of ALT level, loss of hepatitis B e antigen (HBeAg), and loss of detectable serum HBV DNA. A transient increase in ALT levels to more than twice baseline, called a “flare,” can occur during the 2nd or 3rd month of treatment. This occurrence is thought to represent IFN-induced activation of the host immune response; it is seen more often in individuals who eventually respond to IFN. Patients need to be monitored carefully during this flare because decompensation of borderline hepatic function may occur. In individuals who respond to IFN-α, histologic improvement, with a decrease in necroinflammatory activity, has been documented, although there is little effect on fibrosis (28). When assayed by HBV DNA from the of responders in most but not most responders who become serum HBV DNA and to have detectable hepatic HBV DNA the of The significance of this viral DNA is have to hepatic mRNA for in patients who have become and HBV DNA treatment The single of IFN-α in the treatment of chronic HBV patients. subjects MU or 5 MU IFN-α daily, the latter with or and were to those in (28). with MU daily was no than no treatment. with 5 MU daily, with or was associated with response in of patients. A of patients serum hepatitis B surface antigen as during of and studies have similar A of 15 trials of IFN-α in a of with chronic HBV infection and has demonstrated a statistically significant for loss of and HBV DNA in have demonstrated loss of in only of patients This for the difference in response rate is not clear. factors include and of infection in the and greater frequency of infection. include serum levels more than twice levels of HBV DNA in serum active on and of HBV infection In these factors a more host immune to HBV at and a of infection. recently, no factors been as response to treatment. A specific viral in of HBV are associated with and response to IFN This of the protein has been found to be of as a occurring that can interfere with cytotoxic T Although generally in individuals with or IFN-α has been to be of some when carefully monitored in this When were treated in this in and in three were but three This treatment be only with and of be Although response to IFN is defined in of ALT and loss of HBV DNA within of some have also been In one of 23 responders for the rate was only and of the responders between 6 and 6 the of treatment a similar from a loss of in only of responders at 4 of IFN-α FOR CHRONIC HBV INFECTION are for only a of of HBV infection in the of occur in individuals of and in of factors in and include from infected family and from such as and represent a with a particularly high of HBV infection Although HBV infection is in than the of chronic infection is to at of infection the of viral into the host this IFN may be of associated with HBV infection have been reported in both and these therapy for chronic HBV infection in is of IFN-α, with and have been in with chronic HBV infection In a significant effect has been with loss of HBV DNA and in of treated subjects most of ALT levels therapy was Although loss of was in these the of was of the studies found that who HBV infection rather than were more likely to respond in a only Most of these in HBV infection was high levels of viral or no clinical an of host immune Dosages in trials have been and it is not known there is decreased with of as seen in IFN-α is not in the for the treatment of chronic HBV infection in individuals of a is currently and with chronic HBV infection may be for IFN-α therapy that can be IFN-α FOR CHRONIC HEPATITIS VIRUS INFECTION The of injury to hepatitis virus infection has not been fully elucidated. has been reported for both viral effects and cellular is by the of within the of infected which activated B and T lymphocytes. These T cells MHC II antigens to various of HCV have been demonstrated are found in individuals infected with that may a role The role of host production in the of infection and of infection with this virus has not been IFN has been to and chronic hepatitis HCV was and Since that numerous trials of lymphoblastoid or recombinant IFN-α have been in patients with chronic HCV infection. Dosages have ranged from to 10 MU three times for 3 to 6 months. In of MU have not increased with chronic HBV most individuals with chronic HCV infection are asymptomatic. response is defined not in clinical but by and HCV can be detected in serum by the and can be by other molecular a DNA and molecular were response to therapy was defined as normalization of that HCV can be detected and response can be defined as normalization of or as loss of HCV RNA. of trials be with in Ordinarily, there is between in ALT and decrease in HCV levels it is that a response can occur of HCV the clinical significance of this to be or 3 MU of IFN-α thrice weekly for demonstrated a response rate of ≈50% trials and of A of trials has been patients given a variety of response rate of ≈50% was the rate was of responders within 6 of of therapy This high rate has to further studies of and of treatment. In no significant in response or has been however, one a rate with 60 of therapy A from has that although not associated with a response in an increase in the of patients with trials the of treatment in subjects who respond but histologic have in and necrosis in responders In some was also effect on hepatic fibrosis was have been as of response to IFN-α therapy in chronic HCV infection. The include ALT level, HCV level, and of or significant fibrosis on Although of of response and HCV level has been by there is no specific that and no for of therapy have been as HCV may also be an loss of HCV and decrease in ALT during therapy are also factors associated with of response include of and IFN-α is generally in individuals with disease. of with HCV infection and and a decrease in ALT and clinical with low-dose IFN-α treatment at this time, there are no for such INTERFERON FOR HCV INFECTION The of HCV infection is often or by it is not often in the and treatment of HCV infection are In series, patients with HCV infection were for treatment with IFN-α. Although in ALT and of HCV levels were during the studies in response and the frequency of to chronic hepatitis In the which of treated but of the HCV and normal ALT at at this time, there are no for treatment of HCV infection. INTERFERON FOR CHRONIC HCV INFECTION The and of HCV infection in in the are not known. to has been the most for HCV The of HCV infection has been in some It has been found in of those with to of of and of of of other has not been in the from other that the frequency of HCV infection A of healthy found a of the other of the of in were of known individuals have that increase with of the that of is an In with clinically or detected hepatitis, for HCV infection has been found in a significant even among those who no of HCV has been and defined by HCV and homology between and viral have been In one study, the of of HCV was to with the of HCV in serum In a of studies of HCV the frequency was found to from to when infection was by HCV Although the frequency of infection is not it is that there are with chronic HCV and is not the only will to occur. There are the and of IFN-α in the treatment of chronic HCV infection in in 12 a dose of 3 three times a for 6 found a high response rate but a of the normal ALT levels at In another study, 12 were treated for 12 with a response rate The drug was in These studies are to of response or for treatment of patients. given the response rate in further trials in are INTERFERON FOR CHRONIC HEPATITIS D VIRUS INFECTION D virus is a associated with a antigen and in an of hepatitis B surface thus, infection with infection with The of hepatic injury is for effects is found in histologic and in vitro the of such as and cell immune The levels of are found in HBV with of active HBV DNA and The by which HBV is production has not been studied in infection. IFN-α thus been the only antiviral found to have a effect in infection. in in both and the have that treatment with a high dose MU thrice weekly or 5 MU of IFN-α in normalization of decrease or loss of from and in hepatic in ≈50% of was therapy was in those individuals who A of trials in ALT levels with various IFN-α but was No of IFN-α response have been identified. There has been little of IFN-α treatment of infection in clearance of and development of and and normalization of in one of two treated with 10 IFN-α three times weekly for with HBV and were given IFN-α at 5 thrice weekly for 3 and then 3 for the ALT in patients during therapy but in most treatment. in of the 10 during but 6 was found in of the Although HBV DNA was in of the with initial no significant in hepatic were IFN-α is only and in chronic infection in INTERFERON FOR CHRONIC HEPATITIS Individuals at for chronic viral hepatitis are also at for human virus infection. The treatment of individuals with an drug such as IFN-α Patients with and HBV often have normal or normal most likely this is to a immune response In one series, no to IFN-α, to of subjects HCV infection not in individuals with for HCV infection of were positive When 12 and HCV were treated with IFN-α at response was demonstrated in to of IFN-α in with and HCV are currently have been reported of patients who associated with IFN-α therapy The role of IFN-α in individuals has not been INTERFERON or chronic viral hepatitis is not among patients In the case of chronic viral hepatitis may be the of disease. have to the of IFN-α therapy in these but no from trials are has been the effects of immune on of renal associated with the use of IFN-α have been reported but this in is clear. OF INTERFERON-α Naturally and recombinant α interferons have been in clinical use for these were at high as therapy for various effects were and with and of these have not been with the more for viral however, use of IFN-α in this is associated with a variety of side effects that may to a decrease in or of therapy The side effects of IFN-α are generally divided into the first and the first of side effects are they include the of and and also occur. The the IFN and for to these include of with the IFN and 4 for h, of the IFN at and with a dose of IFN with of days, these are with subsequent IFN dosing and usually by of side effects of IFN-α therapy are divided into and The most associated with IFN-α therapy are those of the and Of is the occurrence of in patients with to occurring of therapy be as for a infection. The has not been fully elucidated, but it the seen with IFN administration. is with IFN-α it is usually and and leukocyte are most and decreases are usually during the month of treatment. decreases are by or two of the IFN of the drug is for of or of Although of the cell is is IFN-α therapy is associated with of autoimmune and the development of autoimmune Individuals with autoimmune hepatitis may have by the these it is to autoimmune hepatitis with treatment with IFN-α to may in hepatic injury In autoimmune hepatitis Type antibodies will be In Type is will not be positive by allowing in these When an for by more available and is can be by rather than Although the frequency of this is in there is a of Type autoimmune hepatitis in an with IFN-α treatment or is in patients treated with IFN-α for chronic hepatitis In most or is associated with antibodies In a of with normal function IFN the of was increased antibodies was present Although no are available for of function is and IFN-α administration. autoimmune disorders with IFN-α treatment of chronic viral hepatitis include autoimmune a chronic I with cell antibodies and of chronic such as and There are no studies of the effect of IFN-α on other autoimmune but of therapy in patients with these is side effects, such as and are not with IFN-α often not other than and such as and are A of is a to the use of IFN-α. of and has been reported in individuals who have or other of system may they are usually with of IFN. patients for a that appeared during IFN and therapy was has been reported with during IFN therapy side effects of IFN-α include increased and loss can be particularly in and may a decrease in side effects have which is common, and OF INTERFERON-α OF HEPATITIS IFN-α is an and it that to the or for IFN-α is million Thus, a for an with chronic HBV infection for chronic HCV the is in the of and during treatment the to for HBV and for Because is by surface for depending The for treatment of chronic HBV and chronic HCV infection have not been These are only they may on frequency of and in drug the of IFN-α therapy is even more to A which a the and of patients with chronic HBV infection and no with and IFN-α treatment. of reported the of IFN-α and the natural of chronic HBV both an increase in and a decrease in of were demonstrated Thus, IFN-α treatment of chronic HBV infection in is associated with and of when to the therapy for chronic Recently, a was for the frequency of a treatment of 10 for and a of the of by and was of HBV in to for and The greatest was from the both because of IFN and of infections. in of therapy were reported in a similar of the use of IFN-α in patients with chronic HCV infection because the were and in of defined effects on natural the of this of IFN-α has as a treatment of chronic viral Although therapeutic response to IFN is from has been and studies IFN-α with other as as trials with of IFN-α, are not represent a part of the with chronic viral by of are more In can be to be associated with greater from chronic viral to therapy with IFN-α of with chronic viral hepatitis be with to specific and of activation of gene transcription by IFN. binding of IFN-α or IFN-γ to its receptor, the receptors The bind two kinases Jak and tyrosine for IFN-α, or Jak and Jak for IFN-γ. The receptors and the become and this is the for phosphorylation of STAT (signal transducers and activators of transcription). IFN-α receptor STAT and STAT The and the STAT with a protein to the active gene ISGF-3 (interferon-stimulated gene The of the activated by this is the or interferon-stimulated response The of the activated by the is called the gamma activation site. of these genes in subsequent translation and synthesis of the proteins that the IFN-stimulated with of