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PubMed1993

A novel interferon-inducible domain: structural and functional analysis of the human interferon regulatory factor 1 gene promoter.

We have cloned and functionally characterized the human interferon regulatory factor 1 (IRF-1) gene promoter. The promoter contains a CpG island, with several GC boxes, a CAAT box, but no TATA box. IRF-1 mRNA is strongly induced by gamma interferon (IFN-gamma) but more weakly and transiently by IFN-alpha. There are several putative kappa B motifs and numerous AA(G/A)G(G/T)A and GAAANN motifs throughout the promoter. The IRF-1 promoter is not autoregulated by the IRF-1 gene product. IFN inducibility of the promoter was studied with 5' deletion mutants linked to a heterologous reporter gene. Gel mobility shift assays were used to show IFN-inducible factor binding to the IRF-1 promoter. These studies showed that IFN inducibility is conferred by a novel imperfect inverted-repeat arrangement of two GAAANN motifs within a domain, 130 nucleotides upstream of transcription initiation. This inverted repeat binds a factor upon induction with IFN and can confer IFN inducibility on a heterologous promoter. Conversely, point mutations of the inverted repeat are not IFN inducible when linked to the same heterologous promoter.

Base Sequence↗
PubMed1999

Two distinct gamma interferon-inducible promoters of the major histocompatibility complex class II transactivator gene are differentially regulated by STAT1, interferon regulatory factor 1, and transforming growth factor beta.

The major histocompatibility complex (MHC) class II transactivator (CIITA) is the master regulatory factor required for appropriate expression of class II MHC genes. Understanding the expression of CIITA is key to understanding the regulation of class II MHC genes. This report describes the independent regulation of two distinct CIITA promoters by cytokines with opposing functions, gamma interferon (IFN-gamma) and transforming growth factor beta (TGF-beta). A functional analysis of deletion mutations of the upstream promoter (promoter III) identified an IFN-gamma-responsive region located approximately 5 kb from the transcriptional start site. An in vivo DNase I hypersensitivity analysis detected a hypersensitive site in this area which supports the relevance of this region. When the downstream promoter (promoter IV) was studied by in vivo genomic footprinting, IFN-gamma-induced changes at putative binding sites for STAT1, interferon regulatory factor 1 (IRF-1), and E-box proteins were seen. Gel shift and supershift analyses for IRF-1 confirmed the in vivo footprint results. The role of the IFN-gamma-inducible transcription factor STAT1 was examined functionally. Although both promoters were controlled by STAT1, promoter-specific regulation was exhibited. The IFN-gamma response of promoter III was completely dependent on STAT1 and not IRF-1, while promoter IV was partially activated by IRF-1 in the total absence of STAT1 expression. While both promoters were affected by TGF-beta, activation of promoter III by IFN-gamma was more severely diminished by TGF-beta treatment. The differential control of CIITA promoters by TGF-beta, IRF-1, and STAT1 may be important in refining regulation of class II MHC genes in different cell types and under different stimulatory conditions.

Base Sequence↗
PubMed1991

Spontaneous release of interferon gamma by intestinal lamina propria lymphocytes in Crohn's disease. Kinetics of in vitro response to interferon gamma inducers.

The spontaneous induced release of interferon gamma (IFN gamma) by cultured intestinal lamina propria lymphocytes was investigated in patients with Crohn's disease. In contrast to normal lymphocytes, intestinal lymphocytes from these patients spontaneously released IFN gamma and seemed to contain IFN gamma in their cytoplasm. Autologous peripheral lymphocytes did not release IFN gamma. When stimulated with interferon inducers lamina propria lymphocytes from Crohn's disease tissue showed an increase in IFN gamma release 24 hours after induction with no appreciable further increase over the next two days of culture, while in control cells, either peripheral or intestinal, IFN gamma release progressively increased, peaking 72 hours after induction. These findings indicate that in Crohn's disease the intestinal lymphocytes are stimulated in vivo to produce IFN gamma and that the spontaneous IFN gamma production is compartmentalised to the gut lymphocytes. These data support the concept that locally released IFN gamma has a crucial role in cell interactions in the lamina propria and contribute to the locally occurring immune phenomena in Crohn's disease, including the increased epithelial expression of major histocompatibility complex class II antigens.

Cell Membrane↗
PubMed1998

Interferon therapy for chronic hepatitis C in hemodialysis patients: increased serum levels of interferon.

BACKGROUND/AIMS: The efficacy and side effects of interferon (IFN) therapy have not been well clarified in hemodialysis patients with chronic hepatitis C. METHODS: In 6 of 9 hemodialysis patients with chronic hepatitis C, 3 million units (MU) or 6 MU of recombinant IFN-alpha2b or natural IFN-alpha were administered intramuscularly daily for the first 2 weeks, followed by three times a week for 22 weeks. In the remaining 3 patients, 3 MU of IFN-alpha2b were given three times a week for 24 weeks. Serum concentrations of IFN-alpha2b were measured sequentially after the injection of interferon. Responders were defined as the patients with normal serum aminotransferase and negative serum HCV RNA 6 months after the cessation of IFN therapy. RESULTS: Three of the 6 patients who were administered IFN daily in the first 2 weeks were responders, while the other 3 withdrew from the therapy due to serious adverse events such as depression, loss of consciousness and persistence of high-grade fever. Serious adverse events were not observed in the 3 patients without daily administration. Half-lives of IFN-alpha2b in hemodialysis patients were significantly longer than those in nonuremic patients (10.0 vs. 6.0 h, p < 0.05). Moreover, the areas under the serum concentration curve of the hemodialysis patients were significantly larger than those of nonuremic patients (756 +/- 223 vs. 324 +/- 223 IU.h/ml, p < 0.05), despite the fact that the dose of IFN-alpha administered to hemodialysis patients was half that administered to nonuremic patients. CONCLUSIONS: In hemodialysis patients with chronic hepatitis C, pharmacokinetic parameters of IFN may be different from those in nonuremic patients, and daily or high-dose administration of IFN may lead to serious adverse events in those patients.

Adult↗
PubMed1985

Leukocyte adherence inhibition, natural killer cell activity, gamma-interferon production capacity and phytohemagglutinin response in patients treated with recombinant leukocyte A interferon.

10 patients with disseminated colorectal cancer were treated either chronically or cyclically with human recombinant leukocyte A interferon (IFl-rA) for 3 months. During this period, leukocyte adherence inhibition (LAI), natural killer (NK) cell activity, concanavalin A-induced gamma-interferon production capacity (GIPCA) and phytohemagglutinin response were sequentially monitored. In both chronically and cyclically treated patients, IFl-rA therapy led to a 'short-lived' augmentation of NK cell activity. In the chronically treated patients, there was a further depression in the NK cell activity during the course of therapy. The outcome of LAI remained unaltered irrespective of the mode of IFl-rA therapy. There was an inverse correlation between GIPCA and phytohemagglutinin response.

Aged↗
PubMed2000

Interferon-gamma induces AT(2) receptor expression in fibroblasts by Jak/STAT pathway and interferon regulatory factor-1.

The expression of angiotensin II type 2 (AT(2)) receptor is closely associated with cell growth, differentiation, and/or injury. We examined the effect of interferon (IFN)-gamma on AT(2) receptor expression in mouse fibroblast R3T3 cells and demonstrated that IFN-gamma treatment increased the expression of AT(2) receptor mRNA as well as its binding. Interferon regulatory factor (IRF)-1 was induced in mouse fibroblast R3T3 cells after IFN-gamma stimulation, and electrophoretic mobility shift assay showed an increase in IRF-1 binding with the IRF-specific binding sequence in the AT(2) receptor gene promoter region after IFN-gamma stimulation. The IRF-1 gene promoter contains an IFN-gamma-activated sequence (GAS) motif for possible binding of signal transducer(s) and activator(s) of transcription (STAT). Indeed, in R3T3 cells, IFN-gamma treatment resulted in rapid activation of Janus kinase (Jak) 1, Jak2, and STAT1 via tyrosine phosphorylation. Electrophoretic mobility shift assay with the GAS probe revealed increased STAT1 binding to the IRF-1 gene promoter in response to IFN-gamma stimulation. Transfection of GAS-binding oligonucleotides inhibited the effect of IFN-gamma on IRF-1 production, resulting in the AT(2) receptor trans-activation. Taken together, our data show that IFN-gamma upregulates AT(2) receptor expression in R3T3 cells via the activation of the intracellular Jak/STAT pathway and production of IRF-1.

3T3 Cells↗
PubMedDate not supplied

Clinical study with recombinant interferon gamma versus interferon alpha-2c in patients with condylomata acuminata.

A multi-centre, randomized, open-label trial was conducted to evaluate the safety and efficacy of recombinant interferon (rIFN) alpha-2c versus rIFN gamma in patients with recurrent or persistent condylomata acuminata (CA). Thirty-three such patients were treated either with 6 micrograms rIFN alpha-2c or with 0.1 mg rIFN gamma (both equivalent to 2 x 10E6 IU), single dose, subcutaneously 3 times a week for 6 weeks. In case of no complete clearance at week 10, a second course of treatment with the other type of rIFN was given. There was no significant difference in the complete clearance proportions at week 10 between the two treatment groups (3/16 vs 6/17). No relapses occurred in these patients during the 16 weeks' follow-up. Further clearances during the follow-up resulted in a total complete clearance proportion of 14/33 at the end of study. The treatment was well tolerated. Repeated interferon therapy has its place in treating persistent or recurrent condylomas.

Adolescent↗
PubMed2004

Interferons and interferon inhibitory activity in disease and therapy.

Interferon (IFN) resistance is an important factor in the pathophysiology of neoplastic disorders, certain viral infections (e.g., AIDS), and autoimmune diseases (e.g., lupus erythematosus and Wegner's granulomatosis). In addition, in some of these disorders, there is also decreased ability to produce IFNs. The capacity of viruses and neoplastic processes to interfere with the IFN system are thought to represent a "virus-against-host" or "cancer-against-host" defense mechanism. Four resistance factors have been identified: 1) release of free IFN-alpha/beta type 1 receptors into the circulation that, at appropriate concentrations, capture and inactivate IFNs; 2) a new IFN inhibitory protein has been isolated and its chemical structure is under study; 3) prostaglandin E2, which is produced by certain tumor cells, inhibits IFN production; and 4) high levels of cAMP phosphodiesterases present, for example in certain tumor cells, reduces cAMP, an important second messenger in IFN synthesis. Studies are under way to reverse these inhibitory effects and to increase endogenous interferon production.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Bone mineral density and cytokine levels during interferon therapy in children with chronic hepatitis B: does interferon therapy prevent from osteoporosis?

BACKGROUND: Our aim was to determinate bone mineral density (BMD), levels of biochemical markers and cytokines in children with chronic hepatitis B treated with interferon (IFN)-alpha and to investigate effect of IFN-alpha therapy on these variables. To the best of our knowledge, this is first study carried out about BMD and cytokine levels in pediatric patients with chronic hepatitis B treated with IFN-alpha. METHODS: BMD, levels of parathyroid hormone (PTH), osteocalcin, C-terminal cross-linking telopeptide of type I collagen (CTX), calcium, alkaline phosphates (ALP), cytokines as TNF-alpha, interleukin (IL)-1beta, IL-2r, IL-6, and IL-8 were studied in 54 children with chronic hepatitis B (4-15 years old) treated with interferon alone (n = 19) or in combination with lamivudine (n = 35) for six months and as controls in 50 age-matched healthy children. RESULTS: There was no significant difference in respect to serum IL-1beta, TNF-alpha and osteocalcin levels while serum IL-2r (p = 0.002), IL-6 (p = 0.001), IL-8 (p = 0.013), PTH (p = 0.029), and CTX (p = 0.021) levels were higher in children with chronic hepatitis B than in healthy controls. BMD of femur neck (p = 0.012) and trochanter (p = 0.046) in patients were higher than in healthy controls. There was a statistically significant correlation between serum IL-1beta and osteocalcin (r = -0.355, p < 0.01); between serum IL-8 and CTX levels (r = 0.372, p = 0.01), and ALP (r = 0.361, p = 0.01); between serum ALP and femur neck BMD (r = 0.303, p = 0.05), and trochanter BMD (r = 0.365, p = 0.01); between spine BMD and IL-2R (r = -0.330, p < 0.05). CONCLUSION: In conclusion, our study suggest that BMD of femur, serum IL-2r, IL-6, IL-8, PTH, and CTX levels were higher in children with chronic hepatitis B treated with IFN-alpha alone or combination with lamivudine than in healthy children. High femur BMD measurements found in patients may suggest that IFN-alpha therapy in children with chronic hepatitis B could contribute indirectly to prevent from hip osteoporosis. Additionally, further investigations on effects of IFN-alpha for bone structure in children should be performed in the future.

Adolescent↗
PubMed2002

Low interferon gamma producers are better treatment responders: a two-year follow-up of interferon beta-treated multiple sclerosis patients.

As response to interferon beta (IFNB) treatment, a 50% reduction of the mean relapse rate compared to pretreatment values has been reported. However, individual responses vary considerably, ranging from no reduction in exacerbation frequency to complete suppression of relapses for at least two years. At the moment, valid predictors for IFNB response are lacking. Here we present a prospective evaluation of 33 patients with primary relapsing multiple sclerosis who were followed for two years of IFNB treatment A low interferon gamma (IFG) production before treatment predicted a two-year term without exacerbations in 68.8% of cases correctly, whereas a high pretreatment IFG production implied the risk of at least one relapse in the first two years in 70.6%. These preliminary results encourage further evaluation of IFG as predictor of an IFNB treatment response.

Adjuvants, Immunologic↗
PubMed1998

Phase III trial of modulation of cisplatin/fluorouracil chemotherapy by interferon alfa-2b in patients with recurrent or metastatic head and neck cancer. Head and Neck Interferon Cooperative Study Group.

PURPOSE: In preclinical experiments, interferon alfa modulates the anticancer activity of fluorouracil (5-FU) and cisplatin (CDDP). To test this effect clinically in patients with recurrent or metastatic head and neck cancer (RMHNC), a multicenter randomized controlled trial with CDDP and 5-FU with or without interferon alfa-2b (IFNalpha) was performed. PATIENTS AND METHODS: Eligible patients had histologically confirmed RMHNC; a good performance status; measurable disease; adequate bone marrow, hepatic, and renal function; no prior chemotherapy for recurrent or metastatic disease; only one chemotherapy regimen administered with previous local therapy; and a treatment-free interval of at least 3 months following previous local therapy. Patients were randomized and stratified according to treatment center, and prior radiotherapy and chemotherapy. The treatment regimen consisted of CDDP 100 mg/m2 on day 1 and 5-FU 1,000 mg/m2/d by continuous infusion for 96 hours (days 1 to 4), without (arm A) or with (arm B) IFNg alpha 3 x 10(6) U/d subcutaneously on days 1 to 5. Cycles were repeated every 21 days. RESULTS: One hundred twenty-two patients were entered on each arm. The response rate (RR) was similar in both arms (arm A: complete response [CR] 10.7%, partial response [PR] 36.4%; arm B: CR 6.8%, PR 31.6%) (.70 < P < .50). There was no difference in median survival between the two arms (arm A 6.3 months v arm B 6.0 months; P = .49). Anorexia, fever, leukopenia, and thrombocytopenia grade III to IV were significantly more frequent in the IFNalpha arm. CONCLUSION: Modulation of CDDP and 5-FU with IFNalpha as used in this study does not improve the RR or the median survival in patients with RMHNC. Patients on both study arms had a poor prognosis, which indicates the need for novel therapies.

Adult↗
PubMed1995

Biphasic transcriptional regulation of the interferon regulatory factor-1 gene by prolactin: involvement of gamma-interferon-activated sequence and Stat-related proteins.

Stimulation of quiescent Nb2 T cells by PRL leads to the rapid transcriptional activation of a T cell activation gene, interferon regulatory factor-1 (IRF-1). IRF-1 is induced twice by PRL in a single cell cycle, first during G1 at 30-60 min and again over early S phase at 10-12 h. By nuclear run-on transcription analysis of IRF-1 promoter-chloramphenicol acetyl transferase (CAT) constructs, the -1.7 kilobase (kb) 5'-flanking IRF-1 DNA was shown to contain elements that mediate both G1 and S phase expression. The -200 bp IRF-1 promoter DNA contains elements that respond to G1 PRL stimulation in a protein synthesis independent manner, suggesting the involvement of pre-existing factors. Further promoter deletion analysis delineated a minimal PRL responsive region between -112 and -205 bp. Within this region is a Gamma Interferon Activated Sequence or GAS, consisting of two inverted GAAA motifs (-123/-113), which confers PRL-inducible expression to a reporter gene, suggesting that GAS can function as a PRL responsive element. Further, GAS exhibits binding with nuclear proteins in a PRL-inducible, cell cycle-dependent manner. One of these proteins appears to be related to the emerging family of Signal Transducer and Activator of Transcription or Stat factors. These studies suggest that the GAS site and Stat-like proteins participate in PRL receptor signal transduction to regulate the biphasic expression of the IRF-1 gene in PRL-stimulated T cells.

Animals↗
PubMed2004

Interleukin-2 plus ribavirin versus interferon-alpha-2b plus ribavirin in patients with chronic hepatitis C who did not respond to previous interferon-alpha-2b treatment.

BACKGROUND: Interferon (IFN)-alpha-2b therapy has been shown to improve clinical conditions of patients with chronic hepatitis C. Several studies showed that the addition of ribavirin to IFNalpha-2b greatly improved the biochemical as well as the virologic and histological response rate in patients with chronic hepatitis C. The aim of this study was to evaluate biochemical, virologic, and histological responses as well as adherence to a treatment employing ribavirin plus low doses of recombinant interleukin (IL-2) or IFNalpha-2b in subjects with chronic active hepatitis C, which relapsed or did not respond to previous treatment with interferon alone. PATIENTS AND METHODS: We evaluated all 75 consecutive adult patients with chronic hepatitis C admitted to our department, who were previously treated with one course of recombinant or lymphoblastoid IFNalpha-2b (3 million to 6 million IU three times a week for at least 4 months), and either relapsed or did not respond to this treatment. Sixty patients met the inclusion criteria for enrollment in our study. Randomization was performed on the basis of a computer-generated list. The treatment schedule was based on subcutaneous administration of recombinant IFNalpha-2b (Intron A) at a dosage of 3 million IU every day, or IL-2 (aldesleukin) at a dose of 1 million IU every day, with oral ribavirin administered 400 mg twice daily (morning and night) [for patients weighing <75 kg] or 500 mg twice daily (for those weighing > or = 75 kg). The planned treatment period was 6 months. RESULTS: Both IFN and IL-2 treatment groups achieved a significant biochemical response with respect to baseline values at the end of the treatment (p < 0.0001 for both) and at the end of the follow up (p < 0.001 for both). The differences between the two groups at the end of treatment and at the end of the follow up were significant (p < 0.04 and p < 0.003 respectively) in favor of IL-2-treatment. The virologic response rate for IL-2-treated patients was significantly higher than for IFN-treated patients at months 3 (p < 0.05) and 6 (p < 0.05) of the treatment. Both groups showed significant improvement in histological activity index with respect to baseline values, but the difference between the groups was not significant. No withdrawals have been registered. CONCLUSION: The combination of IL-2 and ribavirin seems to increase the probability of a sustained biochemical and virologic response in patients with chronic hepatitis C that is unresponsive to IFN. Our study showed that IL-2 plus ribavirin may provide a clinically important option that appears to be well tolerated and effective in patients with chronic hepatitis C virus infection.

Adult↗
PubMed2001

A patient with chronic hepatitis C who obtained sustained response by retreatment of interferon after decrease of viral load and mutation in interferon sensitivity determining region.

A 44-year-old man with chronic hepatitis C received three courses of interferon (IFN) therapy. HCV genotype was 1b, viral load was 1,200 kcopies/ml and interferon sensitivity determining region (ISDR) was the intermediate type before the 1st IFN therapy. The 1st and 2nd IFN therapies resulted in failure to yield a sustained response. Seven years after from the 1st therapy, viral load had decreased to 15 kcopies/ml and ISDR had changed to mutant type. The 3rd IFN therapy yielded sustained response. Thus, we should consider retreatment with IFN when a decrease of the viral load and change of ISDR to mutant type are observed.

Adult↗
PubMed2000

The janus kinase inhibitor, Jab/SOCS-1, is an interferon-gamma inducible gene and determines the sensitivity to interferons.

The Janus family of protein tyrosine kinases (JAKs) and STAT transcription factors regulate cellular processes involved in cell growth, differentiation, and transformation through their association with cytokine receptors. The CIS family of proteins (also referred as the SOCS or SSI family) has been implicated in the regulation of signal transduction by a variety of cytokines. Among them, we have shown that JAB/SOCS-1 is strongly induced by interferon-gamma and forced expression of JAB/SOCS-1I conferred cells interferon resistance. This resistance was caused by inhibition of JAK1 and JAK2 activation in response to IFNgamma. Moreover, recent detailed analysis of JAB/SOCS-1 knockout mice revealed that JAB/SOCS-1 is indeed a "negative feedback regulator" that determine the sensitivity of cells to IFNgamma. Using in vitro mutagensis, we defined a functional structure of JAB/SOCS-1 and proposed a mechanism for how JAB inhibits JAK kinase activity.

3T3 Cells↗
PubMed1996

Efficacy of in vitro treatment of chronic myelogenous leukemia cell line, K562 cells, using 4-hydroperoxycyclophosphamide, alpha-interferon and gamma-interferon.

Alpha-interferon (alpha-IFN) and gamma-interferon (gamma-IFN) are highly effective biologic agents in the treatment of chronic myelogenous leukemia (CML). 4-hydroperoxycyclophosphamide (4-HC) is the most commonly used chemotherapeutic drug when purging bone marrow contaminated with malignant cells. To investigate the efficacy of alpha-IFN, gamma-IFN and 4-HC as purging agents in CML patients, K562 cells, a human CML cell line, were treated in vitro with these drugs singly or in combination. The cytotoxic effect was evaluated by MTT assay. Data were analyzed for synergism by the median effect principle of Chou and Talalay. Using Southern blot analysis, the effect of purging on the suppression of bcr gene rearrangement was also evaluated. Alpha-IFN, gamma-IFN and 4-HC all showed good concentration-dependent cytotoxic effect. Median cytotoxic doses of alpha-IFN gamma-IFN and 4-HC were 0.03 microM 0.20 microM and 1.97 microM respectively, and molar ratios of median doses of alpha-IFN to 4-HC, gamma-IFN to 4-HC and alpha-IFN to gamma-IFN were 1:80, 1:10 and 1:8, respectively. The combination treatment of alpha-IFN and 4-HC, and gamma-IFN and 4-HC showed significant synergistic cytotoxic activities, but combination of alpha-IFN and gamma-IFN was antagonistic. Status of bcr gene rearrangements in K562 cells was not changed after the treatments. Our results appear to provide an efficient method for removing CML cells from the bone marrow of CML patients.

Antineoplastic Agents↗
PubMed2005

Effect of interferon and ribavirin combined with amantadine in interferon and ribavirin non-responder patients with chronic hepatitis C (genotype 1).

AIM: To evaluate the efficacy of amantadine plus interferon-alpha and ribavirin in non-responder patients with chronic hepatitis C. METHODS: Twenty-six non-responder patients received the regimen of IFN-alpha-2a at a dose of 6 million units three times a week, 1 000-1 200 mg of ribavirin daily, and 200 mg of amantadine daily in divided doses over 48 wk. After the end of treatment, at the 72nd wk, a sustained viral response rate was determined. RESULTS: An early (after 12 wk of therapy) response was seen in 34.6% (9/26) of patients. Response rate at the 24th wk was 42.3% (11/26). End of treatment response (ETR) was 53.8% (14/26). Sustained viral response (SVR) was 42.3% (11/26). There was a statistically significant difference between 0 and 12 wk (P = 0.04), 0 and 24 wk (P = 0.01), 0 and 48 wk (P = 0.00), and 0 and 72 wk (P = 0.001). No patient had severe adverse effects during the treatment. CONCLUSION: Combination regimen of interferon-alpha, ribavirin and amantadine can enhance sustained viral response on IFN-alpha and ribavirin non-responder patients with HCV. Triple therapy with amantadine should be evaluated in further studies.

Adult↗
PubMed2006

Different doses of consensus interferon plus ribavirin in patients with hepatitis C virus genotype 1 relapsed after interferon monotherapy: a randomized controlled trial.

AIM: To assess the efficacy of different schedules of consensus interferon (CIFN) plus ribavirin in retreating chronic hepatitis C patients who relapsed after recombinant interferon (rIFN) monotherapy. METHODS: Forty-five patients (34 males and 11 females) with chronic hepatitis due to hepatitis C virus (HCV) genotype 1 who relapsed after a previous course of rIFN monotherapy were randomized to receive 9 mug CIFN three times per week for 52 wk (group A, n = 22) or 18 mug CIFN three times per week for 52 wk (group B, n = 23) in combination with ribavirin 800 to 1200 mg daily for 52 wk (according to body weight). Virological response was evaluated at week 24 (EVR), at the end of treatment (ETR) and at 76 wk (SVR). RESULTS: By intention-to-treat analysis, subjects in group A had an EVR in 35% of cases, an ETR in 35% and a SVR in 27.3% of cases. Subjects in group B had an EVR in 32% of cases, an ETR in 35% and a SVR in 26.1% of cases. Treatment was stopped because of adverse effects (mostly intolerance) in 15 patients (6 in group A and 9 in group B). IFN dose reduction was needed in 2 patients (1 in group A and 1 in group B). Ribavirin dose was reduced in 2 patients in group A and 1 in group B respectively. Among the 15 subjects who received at least 80% of the intended schedule, the rate of SVR was 80% (6 in group A and 6 in group B). CONCLUSION: CIFN in combination with ribavirin when given to HCV genotype 1 relapsers after rIFN monotherapy obtains an unsatisfactory rate of sustained viral clearance independently of dosage of the drug. This may be due to its scarce tolerability.

Adult↗