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PubMed2002

High-dose interferon alfa-2b and ribavirin in patients previously treated with interferon: results of a prospective, randomized, controlled trial.

BACKGROUND: Kinetic studies have demonstrated a more rapid reduction in hepatitis C virus (HCV) RNA levels among patients taking high daily doses of interferon compared with those taking standard-dose interferon. GOALS: To compare the efficacy and safety of high-dose interferon alfa-2b and ribavirin with standard-dose interferon alfa-2b and ribavirin in chronic hepatitis C patients previously treated with interferon. STUDY: One hundred seven patients (30 interferon relapsers and 77 interferon nonresponders) were randomized to take either high-dose interferon alfa-2b in combination with ribavirin (group A) (consisting of 5 MU/d for 4 weeks, 5 MU three times weekly for 8 weeks, and then 3 MU three times weekly for 36 weeks) or standard-dose interferon alfa-2b and ribavirin (group B) for 48 weeks. Serum alanine transaminase (ALT), HCV RNA levels, and safety data were prospectively collected and compared during treatment and at week 24 of follow-up. RESULTS: The mean serum ALT and HCV RNA levels, as well as the proportion of patients with genotype 1 and cirrhosis and who were African American, were similar in the two treatment groups at study entry. The rates of suppression of HCV RNA to undetectable levels at weeks 4, 12, and 48 were similar. In addition, the sustained virologic response rates at week 24 of follow-up were similar in groups A and B (29% vs. 39%, respectively, p = 0.277). Clinical variables that correlated with a sustained virologic response included a history of relapse to previous interferon therapy and non-1 HCV genotype ( p < 0.01). CONCLUSIONS: Short-term, high-dose interferon alfa-2b and ribavirin failed to demonstrate a tangible benefit compared with standard-dose interferon alfa-2b and ribavirin. However, our study results and others suggest that standard-dose interferon and ribavirin for 48 weeks should be considered for selected patients who did not respond to previous interferon therapy.

Adult↗
PubMed1983

Binding of human interferon alpha to cells of different sensitivities: studies with internally radiolabeled interferon retaining full biological activity.

The characteristics of interferon binding to various cells with different interferon sensitivity were studied by using [3H]leucine-labeled, pure human interferon alpha from Namalwa cells. Scatchard analysis of the binding data on cells sensitive to interferon alpha (human FL and fibroblasts and bovine MDBK) indicated the presence of two kinds of binding sites with high and low affinities. The binding constants of the high-affinity sites in these cells were similar (4 X 10(10) to 11 X 10(10) M-1). Cells insensitive to human interferon alpha (human HEC-1 and mouse L cells) were shown to have only low-affinity sites, suggesting that high-affinity binding sites are indispensable for interferon sensitivity and represent interferon receptors. However, the number of sites in three human diploid fibroblast strains and one strain trisomic for chromosome 21 were not proportionally correlated to the interferon sensitivity of the cells. The high-affinity binding to human cells was completely inhibited by both nonradioactive human interferons alpha and beta in a similar manner, but binding to bovine MDBK cells, on which human interferon beta is practically inactive, was inhibited effectively only by interferon alpha and not by beta. These results suggest that the receptor for human interferon alpha is common to human interferon beta in human cells, whereas the receptor on bovine cells binds only human interferon alpha.

Animals↗
PubMed1984

[Prevention of 5-FU induced toxicity in C3 H/HE mice with interferon or with interferon inducers (poly 1: C, OK-432, Lentinan)].

It is well known that all cell lines, normal as well as malignant, have a sensitivity to the growth-inhibitory effect of Interferon, or Interferon inducers. 5-FU is a widely used anticancer drug considered to be a cell cycle-specific agent. We speculated that the antiproliferative effect of Interferon or Interferon inducers might affect the activity of 5-FU and diminish the uncomfortable side-effects of this agent. Initially this experiment, we observed the mortality rate in mice after administration of 5-FU alone, or 5-FU plus Interferon (alpha inducers). We then carried out cytofluorometric observation of bone marrow cells, and finally studied the influence of Interferon (or inducers) on the anticancer effects of 5-FU against MM48 tumors in C3/He mice. Findings were as follow: 1) Administration of beta-type Interferon for 2 days, following the administration of a toxic dose (140 mg/kg/w) of 5-FU, revealed significant protection from mortality in C3H/He mice. This effect was also observed when Interferon inducers (Poly I: C, OK-432, Lentinan) were administered with 5-FU. Body weight loss was 10.4% at nadir in mice treated with 5-FU alone, while there was a body weight gain of 36.3% in mice treated with 5-FU plus Interferon. 2) Cytofluorometry of bone marrow cells obtained from mice femur at timed intervals after the administration of OK-432, or Lentinan indicated that these drugs inhibited the entry of cells into the S-phase, causing then to accumulated in the G0.G1-phase during the first 48 hours. 3) Histological findings of intestinal mucosa in mice showed prominent destruction after bolus injection of 350 mg/kg of 5-FU alone, while these findings were not observed in mice after the bolus injection of 350 mg/kg of 5-FU combined with Interferon. 4) The tumor volume ratio (T/C) was significantly reduced in the group treated with 5-FU alone as well as that treated with 5-FU combined with Interferon (or inducers) in C3H/He mice bearing MM48 tumors. All mice were dead about 2 weeks after administration of 5-FU alone, while all mice treated with 5-FU plus Interferon (or inducers) were alive in the same period. From these results, we speculate that Interferon, or Interferon inducers play an important role in the prevention of side effects of cell cycle-specific cytotoxic drugs like 5-FU, without decreasing their anticancer activity.

Animals↗
PubMed1982

Interaction of interferon with cellular receptors. Internalization and degradation of cell-bound interferon.

Human interferon alpha A, produced in Escherichia coli by recombinant DNA technology, was labeled with 125I to study its binding to receptors on human lymphoblastoid Daudi cells. This binding showed a marked temperature dependency, with maximum binding obtained at 30-37 degrees C. About 60% of the cell-bound radioactivity was released upon subsequent addition of unlabeled interferon, indicating that only part of the cell-bound interferon could be displaced by competitor. Moreover, about 30-50% of cell-bound interferon was not released by treating the cells with 0.2 N acetic acid, a procedure which removes polypeptide hormones on the cell surface, indicating that part of the interferon bound at 37 degrees C was internalized. This interferon was slowly degraded to acid-soluble products, which were released into the culture medium. Treatment of DAudi cells with the lysosomotropic amines chloroquine and methylamine inhibited the degradation of interferon. Methylamine, however, also inhibited the internalization of interferon. Daudi cells treated with interferon in the presence of chloroquine showed an increase in the interferon-induced enzyme 2',5'-oligo(A) polymerase comparable to that of cells treated with interferon alone. This enzyme increased to a similar extent in cells treated with interferon and cytochalasin, a drug which inhibited internalization of interferon by 50%. These results suggest that degradation and possibly internalization of interferon are not required for at least some of its biological activities.

Biological Transport↗
PubMed2002

Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN).

BACKGROUND: The three interferon beta preparations approved for treatment of relapsing-remitting multiple sclerosis (MS) differ in dose and frequency of administration. Interferon beta-1a 30 microg is administered once a week, interferon beta-1a 22 microg or 44 microg is given three times a week, and interferon beta-1b 250 microg is administered on alternate days. No clinical study directly comparing the different regimens has been published. The INCOMIN study was designed to compare the clinical and magnetic resonance imaging (MRI) benefits of on-alternate-day interferon beta-1b 250 microg with once-weekly interferon beta-1a 30 microg. METHODS: INCOMIN was a 2-year, prospective, randomised, multicentre study. 188 patients with relapsing-remitting MS were assigned to interferon beta-1b (n=96) or interferon beta-1a (n=92). Primary outcome measures were the proportion of patients free from relapses and that of patients free from new proton density/T2 lesions at MRI assessment. Several secondary outcome measures were also assessed. Analysis was by intention to treat. FINDINGS: Over 2 years, 49 (51%) individuals administered interferon beta-1b remained relapse-free compared with 33 (36%) given interferon beta-1a relative risk of relapse 0.76; 95% CI 0.59-0.9; p=0.03); and 42 (55%) compared with 19 (26%), respectively, remained free from new T2 lesions at MRI (relative risk of new T2 lesion 0.6; 0.45-0.8; p<0.0003). In both groups, the differences between the two treatments increased during the second year. There were also significant differences in favour of interferon beta-1b in most of the secondary outcome measures, including delay of confirmed disease progression. INTERPRETATION: High-dose interferon beta-1b administered every other day is more effective than interferon beta-1a given once a week.

Adjuvants, Immunologic↗
PubMed1979

Studies on avian infectious bronchitis virus (IBV). III. Interferon induction by and sensitivity to interferon of IBV.

The induction of interferon by avian infectious bronchitis virus (IBV) and the sensitivity of IBV to interferon were studied. The results of experiments with ten IBV strains are summarized as follows. 1. All the IBV strains tested induced interferon in chick embryo (CE) cells, chicken kidney (CK) cells and embryonated eggs. The Iowa-609 strain induced about 1000 units of interferon in CE cells while the Beaudette-42 strain induced about 200 units of interferon in embryonated eggs; the interferon titers induced by other strains usually ranged from 5 to 60 units. No IBV strain induced interferon in HeLa or BHK-21 cells. 2. IBV particles inactivated by ultraviolet irradiation or by heating lost their ability to induce interferon. 3. The properties of the interferon produced in the present study are similar to those of other interferons produced in chicken cells. 4. HeLa or BHK-21 cells did not acquire resistance to virus infection, after incubation with interferon produced in CE cells. On the other hand, CK cells acquired the same degree of resistance to virus infection as CE cells after incubation with interferon produced in CE cells. 5. All the IBV strains tested were sensitive to interferon in CK cells. The sensitivities of Massachusetts-41 and Holte strains to interferon were similar to that of vesicular stomatitis virus.

Animals↗
PubMed1991

Antiviral actions of interferon. Interferon-regulated cellular proteins and their surprisingly selective antiviral activities.

Considerable progress has been made in the understanding of the molecular biology of the human interferon system. The genes encoding the interferons, their receptors, and the proteins that mediate many of their biological effects have been molecularly cloned and characterized. The availability of complete cDNA clones of components of the interferon systems has contributed significantly to our understanding of both the biology and the biochemistry of the antiviral actions of interferons. At the biological level, the antiviral effects of interferon may be viewed to be virus-type nonspecific. That is, treatment of cells with one type or even subspecies of interferon often leads to the generation of an antiviral state effective against a wide array of different RNA and DNA animal viruses. However, at the biochemical level, the antiviral action of interferon is often virus-type selective. That is, the apparent molecular mechanism which is primarily responsible for the inhibition of virus replication may differ considerably between virus types, and even host cells. For example, the IFN-regulated Mx protein selectively inhibits influenza virus but not other viruses when constitutively expressed in mouse cells. The IFN-regulated 2',5'-oligoadenylate synthetase selectively inhibits EMC and mengo viruses, two picornaviruses, but not viruses of other families when constitutively expressed in transfected cells. Some viruses are typically insensitive to the antiviral effects of interferon, both in cell culture and in intact animals. This lack of sensitivity to IFN may result from a virus-mediated direct antagonism of the interferon system. For example, in the case of adenovirus, the activation of the IFN-regulated RNA-dependent P1/elF-2 protein kinase is blocked by the virus-associated VA RNA. The relative sensitivity to interferon of different animal viruses varies appreciably. All three of the basic components required to measure an antiviral response may play a role in determining the relative effectiveness of the antiviral response: the species of interferon administered; the kind of cell treated; and, the type of virus used to challenge the interferon-treated host cell. Thus, the relative sensitivity to interferon observed for a particular interferon-cell-virus combination is likely the result of the equilibrium between the many agonists and antagonists which contribute to the overall response. That is, the relative sensitivity of a virus to the inhibitory action of IFN is governed by the qualitative nature and quantitative amount of the individual IFN-regulated cell proteins that may collectively contribute to the inhibition of virus replication.(ABSTRACT TRUNCATED AT 400 WORDS)

2',5'-Oligoadenylate Synthetase↗
PubMed1995

Comparison of full-length sequences of interferon-sensitive and resistant hepatitis C virus 1b. Sensitivity to interferon is conferred by amino acid substitutions in the NS5A region.

We have previously demonstrated that sensitivity to interferon is different among hepatitis C virus (HCV) quasispecies simultaneously detected in same individuals and that interferon-resistant HCV quasispecies are selected during the treatment. To determine the genetic basis of their resistance to interferon, HCV genotype-1b was obtained from serum of three patients before and during interferon therapy, and their full-length nucleotide and deduced amino acid sequences were determined. Comparison of the pairs of interferon-resistant and interferon-sensitive HCV isolates in respective individuals demonstrated clusters of amino acid differences in the COOH-terminal half of the NS5A region (codon 2154-2383), which contained a common unique amino acid difference at codon 2218. Additional sequence data of the COOH-terminal half of the NS5A region obtained from six interferon-resistant and nine interferon-sensitive HCV confirmed the exclusive existence of missense mutations in a 40 amino acid stretch of the NS5A region around codon 2218 (from codon 2209 to 2248) in interferon-sensitive HCV. On the other hand, this region of interferon-resistant HCV was identical to that of prototype HCV genotype-1b (HCV-J, HCV-JTa, or HC-J4). We designated this region as the interferon sensitivity determining region. Thus, HCV genotype-1b with the prototype interferon sensitivity determining region appears to be interferon-resistant strains. The specific nature of these mutations might make it possible to predict prognostic effects of interferon treatment.

Adult↗
PubMed1975

Circulating interferon in man after administration of exogenous human leukocyte interferon.

Interferon was measured at different intervals after the iv, sc, and im application of exogenous human leukocyte interferon to patients with various virus diseases or neoplasms. Interferon injected iv into patients had a half-life of about 15 minutes in the 1st hour and of about 90 minutes in the next 3 hours. Six hours after iv injection of 30 million U, no serum interferon was detectable. With a continuous iv infusion, a relatively high serum interferon level was reached. By the im administration of 1 million U interferon, a peak level of serum interferon (mean value 107 U/ml serum) occurred after 2 hours and was fairly stable for about 6 hours. Twenty-four hours after im application, a low level of serum interferon was still detectable. Similar results were found after sc interferon injections. In a patient with subacute sclerosing panencephalitis, no interferon was found in the cerebrospinal fluid at the time of the highest serum interferon level and 24 hours after two im interferon injections. Only minimal side reactions resulted from sc and im interferon injections. In one patient, a shock reaction occurred after iv application. For therapeutic trials, about 1 million U exogenous human interferon should be injected twice daily im or sc.

Encephalitis↗
PubMed1992

Interferon-stimulated genes in interferon-sensitive and -resistant chronic myelogenous leukemia patients.

alpha-Interferon induces hematological and cytogenetic remissions in some individuals with newly diagnosed Philadelphia-positive chronic myelogenous leukemia. However, interferon-resistant disease occurs in a consistent patient subset (primary resistance) and develops during therapy in additional patients (secondary resistance). Several alpha-interferon-inducible genes have been characterized. In interferon-resistant cell line variants, defects in these genes have been implicated in the mechanisms mediating resistance. We have, therefore, evaluated mRNA expression of four interferon-stimulated genes (ISGs) following alpha-interferon therapy. Twenty-seven chronic myelogenous leukemia patients (ten interferon-sensitive patients, 17 interferon-resistant patients) were studied. Peripheral blood samples were collected prior to and 1 to 7 days after starting interferon therapy and analyzed for the expression of 2'-5' oligoadenylate synthetase, ISG-15, ISG-54, and 6-16 transcripts. Following therapy with alpha-interferon, 2'-5' oligoadenylate synthetase, ISG-54, and 6-16 transcripts were discerned in all patients regardless of their response to interferon. The ISG-15 message was detected in eight of nine interferon-sensitive and in 15 of 16 interferon-resistant patients, as well. Overall, no consistent defect in the ISG system could be identified. Therefore, lack of induction of these genes cannot explain resistance to alpha-interferon in chronic myelogenous leukemia patients. Other mechanisms such as posttranslational modification, leading to defects in the ISG corresponding proteins, may play a role in the development of resistance.

2',5'-Oligoadenylate Synthetase↗
PubMed1979

Interferon priming. Effects on interferon messenger RNA.

The effects of priming mouse cells with interferon on the production of interferon and its mRNA were investigated. Interferon-treated (primed) mouse L929 cells produce 3 to 10 times more interferon than do nonprimed cells following induction with Newcastle disease virus. Interferon appears 2 to 4 h sooner in the primed cultures than in nonprimed cultures and interferon production by primed cells becomes resistant to inhibition by actinomycin D about 4 h sooner than interferon production in nonprimed cells. Interferon mRNA is detected in primed-induced cells about 2 h earlier than in nonprimed-induced cells. It reaches peak levels about 2 to 4 earlier in primed cells, but it also disappears sooner in primed cells. The total amounts of interferon mRNA isolated from primed-induced cells and nonprimed-induced cells were indistinguishable, by the methods utilized. Therefore, although primed cells can produce significantly more interferon and make interferon mRNA sooner than nonprimed cells, the total amount of interferon mRNA produced is apparently not increased, nor is its half-life prolonged in primed cells. Thus, enhanced interferon production in primed cells may result from enhanced efficiency of translation of interferon mRNA in the primed cells.

Animals↗
PubMed1994

Interferon antibodies in patients with chronic hepatitic C virus infection treated with recombinant interferon alpha-2 alpha.

Patients treated with alpha-2a interferon for chronic hepatitis C may produce anti-interferon antibodies whose effect, if any, on the individual response to therapy has not been fully clarified. The prevalence and kinetics of anti-interferon, including those of neutralizing type, have been studied in 60 patients with chronic hepatitis C enrolled in a randomized controlled trial of recombinant alpha-2a interferon. Thirty patients received interferon while 30 were untreated controls. Two different methods, an enzyme immunoassay and an antiviral neutralization bioassay, were used and serial serum samples from each patient were analyzed. Enzyme immunoassay-positive anti-interferon appeared in 60.7% of treated patients within 6 months of therapy; antiviral neutralization bioassay-positive anti-interferon appeared in 52.9% of these enzyme immunoassay-positive patients, and was associated with high enzyme immunoassay reactivity and long-term persistence. Anti-interferon was detected in 75% of patients showing no response to interferon. Antibodies were also detected in three out of six patients who showed alanine aminotransferase normalization persisting up to the end of treatment and in 8 out of 14 patients who showed an initial marked reduction or even normalization of alanine aminotransferase, followed by reactivation of liver damage during treatment. Interestingly, patients who became anti-interferon positive before complete alanine aminotransferase normalization later showed reactivation of liver damage independently of interferon dose reduction, while patients who became positive for anti-interferon after complete alanine aminotransferase normalization either did not reactivate or did so only after interferon dose reduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1997

Therapy of hepatitis C: consensus interferon trials. Consensus Interferon Study Group.

Chronic hepatitis C is an insidious disease associated with significant morbidity and mortality. Currently, the only approved therapies for chronic hepatitis C are the alpha interferons. Consensus interferon (CIFN) is a nonnatural, synthetic, recombinant type I interferon derived by assigning the most commonly observed amino acid in each position of several alpha interferon nonallelic subtypes to generate a consensus sequence. The efficacy and safety of CIFN in the treatment of chronic hepatitis C were assessed in two large phase 3 trials. The first trial was a multicenter, randomized, double-blind, controlled study of 704 patients who were treated with one of two doses of CIFN (3 microg and 9 microg) or interferon alfa-2b (3 million units [MU]) weekly for 24 weeks and then observed for an additional 24 weeks. Treatment with CIFN at a dose of 9 microg was safe and effective, with serum alanine aminotransferase (ALT) and hepatitis C virus (HCV) RNA sustained response rates of 20% and 12%, respectively. Responses to 3 MU interferon alfa-2b were comparable to 9 microg CIFN. The response rates were lower in the 3-microg CIFN cohort. At the end of the treatment and posttreatment observation periods, an undetectable serum HCV RNA was a better predictor of a normal ALT than the converse. Serum samples from early time points were available for HCV RNA quantitation from 27 of the 28 patients who experienced a sustained response with 9 microg CIFN. Of these, 13 patients (48%) had undetectable HCV RNA at 2 weeks, 21 patients (78%) at 4 weeks, and 26 patients (96%) at 12 weeks. CIFN (9 microg) induced a significantly greater reduction in the mean serum HCV RNA concentration than interferon alfa-2b during treatment (P < .01). In patients with high viral titers (> or = 4.75 x 10(6) copies/mL), the HCV RNA sustained response rate in patients treated with CIFN (9 microg) and interferon alfa-2b was 7% and 0%, respectively (P = .03). In patients infected with HCV genotype 1, the HCV RNA end-of-treatment (24% vs. 15%; P = .04) and sustained (8% vs. 4%; P = not significant) response rates were greater in patients treated with CIFN (9 microg) than with interferon alfa-2b (3 MU). In a subsequent multicenter trial, a higher dose of CIFN (15 microg) was reinstituted in patients who either had relapsed or were nonresponders to prior CIFN or interferon alfa-2b therapy. Patients were randomized to receive 24 or 48 weeks of retreatment followed by 24 weeks of observation. Patients who had relapsed after prior interferon therapy were more likely to have a serum HCV RNA end-of-retreatment and sustained response than patients who were nonresponders to prior interferon therapy. After patients from the 3-microg CIFN cohort were excluded, the HCV RNA sustained response rates were 28% in relapsers and 5% in nonresponders, respectively, in the 24-week retreatment cohort and 58% and 13%, respectively, in the 48-week retreatment cohort. The administration of 9 or 15 microg CIFN was well tolerated, and the adverse effects were similar to those for interferon alfa-2b. These data demonstrate that CIFN at a dose of 9 microg is effective initial therapy for patients with chronic hepatitis C, and that retreatment with a higher CIFN dose of 15 microg for 48 weeks provides meaningful responses in both relapsers and nonresponders.

Antiviral Agents↗
PubMed1994

Effects of interferon-tau and interferon-alpha on proliferation of bovine endometrial cells.

The ruminant conceptus secretes a unique interferon, interferon-tau, that regulates endometrial prostaglandin secretion during early pregnancy. Because one of the pleiotropic effects of interferons is to inhibit cellular proliferation, a series of experiments was conducted to determine whether or not the bovine endometrium is sensitive to the antiproliferative effect of interferon-tau and the related interferon, interferon-alpha. Endometrial epithelial and stromal cells were prepared from the endometrium of cows from Days 11-17 after estrus and incubated with recombinant bovine interferon-tau (rbIFN tau; 1-1000 ng/ml), recombinant bovine interferon-alpha 1 (rbIFN alpha; 1-1000 ng/ml), recombinant human interferon-alpha 2b (rhIFN alpha; 100 ng/ml), or ovine interferon-tau (oIFN tau; 100 ng/ml). Proliferation was determined by monitoring uptake of [3H]thymidine into DNA. Generally, interferons did not inhibit proliferation of endometrial epithelial cells. Exceptions were for 1000 ng/ml rbIFN tau, which inhibited proliferation by 23%; 100 ng/ml rbIFN alpha, which inhibited proliferation by 28% in one of two experiments only; and 100 ng/ml oIFN tau, which inhibited proliferation by 17%. Proliferation of endometrial stromal cells was not inhibited by any concentration of any interferon in two separate experiments. Therefore, unlike other bovine cells tested previously (lymphocytes and oviductal cells), bovine endometrial cells were not consistently inhibited by IFN tau or IFN alpha. Such reduced responsiveness of endometrial cells to the antiproliferative effects of type I interferons could allow for growth of the endometrium during the period of pregnancy when the conceptus produces IFN tau.

Animals↗
PubMedDate not supplied

Phase II clinical trial of combined natural interferon-beta plus recombinant interferon-gamma treatment of chronic hepatitis B.

BACKGROUND/AIMS: Alpha-interferon (IFN-alpha) is an effective treatment for chronic hepatitis B but only 25-40% of patients will profit from a long-term beneficial response to the currently recommended schedule of 3-6 MU given 3 times a week for 6 months. Clinical trials are therefore needed to investigate alternative modifications of interferon therapy, including combinations of different antivirals or immune modulators in order to improve the therapeutic approach to chronic hepatitis B infection. In a phase II trial we evaluated whether a combination of natural interferon-beta (nIFN-beta) with strong antiviral activity plus recombinant interferon-gamma (rIFN-gamma) with a predominantly immunomodulatory activity is able to increase the response rate compared to historical controls treated with IFN-alpha in a conventional regimen. METHODOLOGY: Forty patients with chronic hepatitis B were included in this trial of combined interferon therapy at a dosage of 6 MU nIFN-beta during week 1 followed by 3 MU for weeks 2-4 plus rIFN-gamma at a daily subcutaneous (s.c.) injection of 150 microg during the entire 4 weeks of the treatment period. Patients entered the trial on the basis of the following criteria: hepatitis B surface antigen (HBsAG), HBeAG and HBV-DNA positive for at least 6 months, HDV, EBV, CMV, anti-HIV negative, and chronic hepatitis proven on biopsy taken within 4 weeks of entry as well as 6 and/or 12 months after interferon therapy. The final diagnosis and classification of chronic hepatitis has been based on guidelines according to a revised classification of chronic hepatitis (Desmet 1994). The post-treatment follow-up was 12 months. RESULTS: The combined interferon therapy achieved complete responses with seroconversion from HBeAG to anti-HBe and a negative HBV-DNA (dot blot) test, as well as normalization of ALT activity in 15 patients, and partial response with negativation of HBV-DNA concomitant to a decrease in aminotransferase activity to near normal levels in 6 patients. Nineteen patients showed no response to viral markers but showed relief of clinical symptoms as well as pronounced decrease of serumtransaminase activity. Grading of liver biopsies demonstrated an improvement of histologic parameters after the interferon regimen in half of the evaluable patients (n=22). Histological response has been quantified by a reduction in the score of histological activity (HAI-index) from 12.6 before to 7.6 after interferon therapy, and in the inflammation and cellular degeneration score (ICD) from 9.9 to 5.2. Histological response, however, failed to show a consistent correlation with serologic response. This medium-dose combination of interferon-beta and interferon-gamma was tolerated very well by the patients, this good tolerability being explained by tachyphylaxis in response to daily interferon doses. No serious side effects or decompensation of liver function were observed during the 4-week period of therapy or the follow-up, despite the special clinical situation where 60% of the patients included in the study presented with histologically proven cirrhosis (35% of them with clinical manifestation of mildly decompensated cirrhosis). CONCLUSIONS: This short-term regimen of combined nIFN-beta + rIFN-gamma therapy in patients with chronic hepatitis B proved to be equieffective to long-term treatment with interferon-alpha and combines high clinical tolerability with good practicability, as it can be administered on an in-patient basis, ensuring close patient monitoring.

Adolescent↗
PubMed1994

Interferon gamma administration increases monocyte HLA-DR antigen expression but not endogenous interferon production.

OBJECTIVE: To determine the effect of the adjuvant administration of interferon gamma on monocyte HLA-DR antigen expression and mitogen-stimulated interferon gamma production following injury. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: University Hospital, Newark, NJ, a level I trauma center. PATIENTS: Persons older than 16 years with an Injury Severity Score greater than 20 and documented bacterial contamination at the time of injury (N = 98). INTERVENTIONS: Recombinant human interferon gamma (n = 46; 0.1 mg subcutaneously) or placebo (n = 52) was given for 10 days following injury. OUTCOMES: Incidence of major infection, monocyte and lymphocyte cell surface antigen expression, and interferon gamma production at multiple time points following injury. RESULTS: Peripheral monocyte HLA-DR was measured as percent of cells staining positive and as mean channel fluorescence. Both values were significantly increased in the interferon gamma group compared with the placebo group on days 3, 5, 8, and 11. The incidence of major infection was unaffected by interferon gamma administration. Infection decreased percent of HLA-DR-positive monocytes and mean channel fluorescence as compared with noninfected patients on postinjury days 8 and 11 in the placebo group but not in the interferon gamma group. Interferon gamma production improved from 3 +/- 3 U/mL on day 1 to 15 +/- 10 U/mL by day 30 but was always significantly lower than normal (25 +/- 3 [mean +/- SD] U/mL). Interferon gamma production was unaffected by either infection or interferon gamma administration. CONCLUSIONS: Interferon gamma administration after injury stimulated monocyte HLA-DR antigen expression and density but failed to improve interferon gamma production, a T-cell-mediated function. The incidence of infection was not decreased by the administration of interferon gamma for 10 days. Improvement in monocyte HLA-DR antigen expression did not correlate with a global restoration of immune function, and other interventions will be necessary to decrease infection after injury.

Adult↗
PubMed2002

Interferon for interferon naive patients with chronic hepatitis C.

BACKGROUND: A previous meta-analysis of interferon therapy in naive patients with chronic hepatitis C has documented its efficacy in achieving virologic clearance, and improving liver biochemistry and histology; however, since its publication additional trials have been reported. OBJECTIVES: To evaluate the response to interferon in interferon naive patients with chronic hepatitis C. The effect of treatment dose and duration, and the response in patients with cirrhosis and those with normal aminotransferases was also investigated. SEARCH STRATEGY: The Cochrane Controlled Trials Register (Cochrane Library Issue 1, 1999), MEDLINE (January 1966 to December 1999), and reference lists were searched, and pharmaceutical companies were contacted for unpublished trials. SELECTION CRITERIA: Randomised clinical trials comparing interferon with placebo, no treatment, or different regimens of interferon were selected. Abstracts were excluded. DATA COLLECTION AND ANALYSIS: The primary outcome measure was sustained disappearance of serum HCV RNA (virologic sustained response (SR)). Biochemical and end of treatment responses, liver histology, and adverse events were also recorded. Assessment of drug efficacy used the methods of Peto and Der Simonian and Laird. MAIN RESULTS: Fifty-four trials enrolling 6545 patients were included. Compared with no treatment, interferon 3 MU thrice weekly for 12 months increased the probability of a virologic SR (Peto odds ratio (OR) 4.60; 95% confidence interval (CI) 1.53 to 13.85). At this dosage and duration of therapy, the rate of virologic SR was 17% (95% CI 10 to 28%) in interferon-treated patients versus 3% (95% CI 1 to 10%) in controls. A dose of 6 MU was more effective than 3 MU thrice weekly (OR for 12 months treatment, 2.21; 95% CI 1.10 to 4.45), as were durations of 12 months or greater versus six months (OR 1.87; 95% CI 1.30 to 2.67). Adverse events were more common with higher doses and prolonged durations of treatment. Compared with no therapy, interferon increased the probability of histologic improvement (OR 9.22; 95% CI 5.69 to 14.94). The response to interferon in cirrhotic patients (virologic SR, 17%; 95% CI 11 to 26%) was similar to that in non-cirrhotic patients. However, interferon was no more effective than control in patients with normal aminotransferases. REVIEWER'S CONCLUSIONS: Interferon is effective in achieving viral clearance and improving liver biochemistry and histology in interferon naive patients with chronic hepatitis C. Higher doses and prolonged durations are more effective, but associated with more frequent adverse events. Interferon is associated with similar benefits in patients with cirrhosis, but the efficacy in patients with normal aminotransferases is unproven.

Antiviral Agents↗
PubMed2002

Clinical comparison of high-dose interferon-alpha2b with or without ribavirin for treatment of interferon-relapsed chronic hepatitis C.

BACKGROUND: Interferon a with ribavirin combination therapy is effective but still unsatisfactory in the treatment of patients with interferon-relapsed chronic hepatitis C. AIMS: To compare, in a randomized, double blind, placebo-controlled study, high-dose interferon-alpha2b with or without ribavirin in the treatment for interferon-relapsers. PATIENTS: A total of 52 patients with interferon-relapsed chronic hepatitis C were randomly assigned to receive 24-week treatment with interferon-alpha2b (6 MU three times per week) combined with either ribavirin (1,000 to 1,200 mg per day) or a matched placebo and then followed for an additional 24 weeks. METHODS: Hepatitis C virus RNA was detected by reverse-transcription polymerase chain reaction. For determining viral concentration, the commercial bDNA Quantiplex hepatitis C virus-RNA 2.0 assay was used. Genotyping was performed by reverse hybridization assay RESULTS: At the end of treatment, no detectable hepatitis C virus RNA levels were observed in 92% (24/26) of patients on interferon alpha2b/ribavirin and 81% (21/26) of patients on interferon alpha2b/placebo. At the end of the follow-up, a higher sustained virological response rate was seen in patients treated with interferon alpha2b/ribavirin than those treated with interferon alpha2b/placebo (69% vs 23%, p < 0.001). Patients with either initially high levels of viral concentration or with genotype 1 responded poorly. Patients who received interferon-alpha2b/ribavirin treatment and in whom no hepatitis C virus RNA was detected at 4th week after treatment had 90% chance to achieve sustained virological response. CONCLUSIONS: High-dose interferon-alpha2b plus ribavirin treatment is highly effective in interferon-relapsed patients.

Adult↗