Recombinant Interferon Alpha-2b Research Articles

HCV-associated thrombocytopenia: clinical characteristics and platelet response after recombinant alpha2b-interferon therapy.

Hepatitis C virus (HCV) has been proposed as a possible causative agent of chronic thrombocytopenia. We investigated HCV infection in a series of 51 unselected Spanish patients with chronic acquired thrombocytopenia. Anti-HCV and HCV viraemia were detected in 13/51 (22.5%) of cases; this prevalence was particularly significant when compared with HCV seropositivity in age-matched controls (0.4%). Anti-HCV-positive patients, four men and nine women with a median age of 59.3 years (range 36-72), had a mean platelet count of 55.8 x 109/l (range 12-96). Only one of our HCV-positive thrombocytopenic patients had hypersplenism. Platelet-associated IgG (PAIgG) was negative, as measured by immunofluorescent flow cytometric analysis in 11/13 HCV-positive thrombocytopenic patients. Thus, thrombocytopenia in our HCV-positive patients appeared to be non-autoimmune mediated. In six patients, a trial of recombinant alpha2b-interferon (IFN-alpha) given at a dose of 3 MU three times per week for 6-24 months gave a durable (> 1 year) and significant increase in platelet count in all six patients. The maximum increase occurred after 6 months of IFN-alpha therapy. In conclusion, the ability of IFN-alpha to increase platelet counts in HCV-positive thrombocytopenic patients supports mechanisms involving a direct role for HCV inhibiting platelet production.

Interferon alpha-2b at low doses as long-term antiangiogenic treatment of a metastatic intracranial hemangioendothelioma: a case report.

We describe a case of intracranial haemangioendothelioma in a 20-year old female patient who presented severe neurological symptoms and relapsed after two surgical interventions. The patient was treated with low doses of recombinant interferon alpha-2b (1 MUI three times a week) after surgical resection which led to recovery of daily function and work activity. To our knowledge, this is the ninth patient reported with intracranial hemangioendothelioma, but the only one having diffuse and painful bone metastases resolved by treatment with interferon. After 30 months the patient is free from symptoms and recurrence. The effectiveness shown by recombinant interferon alpha-2b against vascular neoplasms prompted us to look for the possible biological basis of such a property.

Identification of a linear epitope of interferon-alpha2b recognized by neutralizing monoclonal antibodies.

Four monoclonal antibodies (mAbs) directed against the recombinant human interferon-alpha2b (IFN-alpha2b) were used as probes to study the interaction of the IFN molecule to its receptors. The [125I]IFN-alpha2b binding to immobilized mAbs was completely inhibited by IFN-alpha2b and IFN-alpha2a but neither IFNbeta nor IFNgamma showed any effect. Gel-filtration HPLC of the immune complexes formed by incubating [125I]IFN-alpha2b with paired mAbs revealed the lack of simultaneous binding of two different antibodies to the tracer, suggesting that all mAbs recognize the same IFN antigenic domain. Furthermore, the mAbs were also able to neutralize the IFN-alpha2b anti-viral and anti-proliferative activities as well as [125I]IFN-alpha2b binding to WISH cell-membranes. As [125I]mAbs did not recognize IFN exposed epitopes in the IFN:receptor complexes, mAb induction of a conformational change in the IFN binding domain impairing its binding to receptors was considered unlikely. In order to identify the IFN region recognized by mAbs, IFN-alpha2b was digested with different proteolytic enzymes. Immunoreactivity of the resulting peptides was examined by Western blot and their sequences were established by Edman degradation after blotting to poly(vinylidene difluoride) membranes. Data obtained indicated that the smallest immunoreactive region recognized by mAbs consisted of residues 107-132 or 107-146. As this zone includes the sequence 123-140, which has been involved in the binding to receptors, and our mAbs did not show an allosteric behaviour, it is concluded that they are directed to overlapping epitopes located close to or even included in the IFN binding domain.

Low virological response to interferon in children with chronic hepatitis C

Background/Aims: Children with chronic hepatitis C were recently found to have higher rates of sustained response to interferon compared to adults. The aim of this study was to verify the response to interferon using frequent viremia measurements.Methods: Sera from 25 children (13 males; mean age 7.9 years) with chronic hepatitis C, treated with recombinant alpha-2b interferon for 12 months, were tested for liverfunction tests and viremia levels for a median of 27.5 months. Autoantibodies were evaluated during and after interferon.Results: Fifteen patients completed 12 months of interferon; treatment was stopped in 10 other patients. In 11 (44%) patients viremia was undetectable already at the second administration of interferon; one of them remained viremia-free up to the end of follow-up and had persistently normal alanine-amino-transferase levels (complete sustained responder). A complete sustained response was observed only in one other patient, who normalized alanine amino-transferase and cleared viremia from the 3rd month of therapy. Three patients with persistent viremia normalized alanine-aminotransferase from the 3rd week of therapy up to the end of follow-up (biochemical sustained responders). Viremia was undetectable during treatment in four patients, who stopped interferon because of worsening in hypertransaminasemia. Three of these four patients were anti-liver-kidney microsomal type 1-positive.Conclusions: In this study the response rate to interferon was very low and viremia and transaminase findings were often discordant.

Interferon alpha-2b and ribavirin in combination for patients with chronic hepatitis C who failed to respond to, or relapsed after, interferon alpha therapy: a randomized trial

PURPOSE: To assess the efficacy of interferon alpha-2b and ribavirin in combination in the treatment of patients with chronic hepatitis C who had either failed to respond to therapy with interferon alpha (nonresponders), or who had relapsed after interferon therapy (relapsers). SUBJECTS AND METHODS: Four hundred patients with chronic hepatitis C (200 nonresponders and 200 relapsers) were randomly assigned in equal numbers to receive either subcutaneous administration of recombinant interferon alpha-2b (3 million units three times per week) and ribavirin (1,000 to 1,200 mg/daily orally) or interferon alpha-2b alone (6 million units three times per week). Both ribavirin and interferon alpha-2b were given for 24 weeks. The patients were then followed for an additional 24 weeks. RESULTS: At the end of the treatment period, normalization of serum alanine aminotransferase levels and absence of hepatitis C virus RNA were seen in 21% of nonresponders and in 39% of relapsers who were treated with interferon alpha-2b and ribavirin, compared with 5% of nonresponders ( P = 0.001) and 9% of relapsers treated with interferon alpha-2b alone ( P <0.001). At the end of follow-up, 14% of nonresponders and 30% of relapsers treated with the combination therapy had a sustained response, compared with 1% of nonresponders ( P = 0.001) and 5% of relapsers treated with interferon alpha alone ( P <0.001). CONCLUSIONS: A 24-week course of treatment with interferon alpha-2b and ribavirin offers a chance of sustained response, whereas retreatment with interferon alpha-2b alone does not give satisfactory results. The role of long-term therapy in inducing prolonged remission remains to be explored.

Durable Clinical and Pathologic Response of Hepatocellular Carcinoma to Systemic and Hepatic Arterial Administration of Platinol, Recombinant Interferon α 2B, Doxorubicin, and 5-Fluorouracil

The case described here illustrates the antitumor activity of a four-drug systemic combination chemobiotherapy with platinol, recombinant interferon alpha 2b, doxorubicin (Adriamycin), and 5-fluorouracil (5-FU) (PIAF) in a patient with diffuse hepatocellular carcinoma involving the liver and lungs.

Comparative Evaluation of Chemoimmunoradiotherapy and Chemoradiotherapy in the Management of Advanced Head and Neck Cancer

50 patients of advanced squamous cell carcinoma of the head and neck were randomised cither to receive chemotherapy followed by radiation therapy or chemoimmunotherapy followed by radiotherapy. In the chemoimmunotherapy arm, the patients received recombinant interferon alpha 2b 3 M.U. subcutaneously, thrice a week on alterante days for 5 weeks from Day 1, Cisplatinum 70 mg/ m(2) on Day 1 and 21, and 5 - flurouracil 1000mg/m(2) on Day 1, 2, 3 and Day 21, 22, 23, followed by from Dav 36, radiotherapy'by Co bait 60 to a tumour dose of 65 Gy in 30 # over 6 weeks. In the control arm, patiens received Cisplatitnum 70 mg/ m(2) on Day 1 and Day 21, 5 flurouracil 1000 mg/ m(2) on Dav 1, 2, 3 and Day 21, 22, 23 followed by radiotherapy by Cobalt 60 to a tumour dose of 65 Gy in 30 # over 6 weeks from Day 36. Only Grade II and III toxicity was observed in the two arms which were manageable Patients treated with chemoimmunotherapy followed by radiotherapy showed 60% complete response, 20% partial response and 12% no change/ progressive disease; while the patients on the control arm treated with chemotherapy and radiotherapy showed 12% complete response 44% Partial response and 32% no change" progressive disease. This trial concludes that chemoimmunotherapy followed by radiotherapy is an excellent alternative therapeutic strategy for the management of advanced head and neck cancers with manageable toxicity.

Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. Osaka Hepatocellular Carcinoma Prevention Study Group.

The effect of interferon therapy on the incidence of hepatocellular carcinoma in chronic hepatitis C is poorly defined. To compare the incidence of hepatocellular carcinoma in interferon-treated patients with chronic hepatitis C to that of historical controls and to examine whether response to therapy is related to incidence of hepatocellular carcinoma in patients with chronic hepatitis C. Retrospective cohort study. One university hospital and seven university-affiliated hospitals. 419 consecutive patients with chronic hepatitis C who started interferon therapy between January 1992 and December 1993 (interferon group) and 144 patients with chronic hepatitis C who had liver biopsy between January 1986 and December 1989 and did not receive interferon (controls). Patients in the interferon group received human lymphoblastoid interferon, recombinant interferon-alpha2a, or recombinant interferon-alpha2b for 6 months. The end point was development of hepatocellular carcinoma on abdominal ultrasonography or computed tomography. Sustained response was defined as persistent normalization of alanine aminotransferase (ALT) levels during interferon therapy and follow-up. Relapse was defined as a normal serum ALT level at the end of treatment with an increase to an abnormal level after cessation of treatment. Nonresponse included all other ALT patterns. Median follow-up in the interferon and control groups was 47.6 and 46.8 months, respectively. During follow-up, hepatocellular carcinoma was found in 28 interferon-treated patients and 19 controls. Cox proportional hazards regression analysis that included all patients revealed that interferon therapy (P=0.041), older age (P=0.003), greater histologic activity (P=0.029), and higher histologic stage (P=0.049) were independent factors associated with the development of hepatocellular carcinoma. The risk ratios for development of hepatocellular carcinoma in patients with sustained response, relapse, and nonresponse were 0.06 (95% CI, 0.01 to 0.46), 0.51 (CI, 0.20 to 1.27), and 0.95 (CI, 0.48 to 1.84), respectively, compared with controls. The incidence of hepatocellular carcinoma was lower in patients with sustained response to interferon therapy than historical controls and nonresponders. Interferon therapy may decrease the risk for hepatocellular carcinoma in patients with chronic hepatitis C.

Treatment of chronic hepatitis D with interferon alpha-2b in patients with human immunodeficiency virus infection

Background/Aims: Hepatitis delta virus (HDV) coinfection is frequent in patients infected with human immunodeficiency virus (HIV), and it may cause death independently of the development of full-blown AIDS. In order to evaluate the efficacy and tolerability of interferon alpha in the treatment of hepatitis delta in HIV-infected patients, and to compare them with those observed in anti-HIV-seronegative patients,we carried out an open uncontrolled trial on 21 HIV-uninfected and 16 HIV-infected patients without severe immunodeficiency. Methods: All patients were treated with recombinant interferon alpha 2b (IFN) at doses of 10 million units thrice weekly for 6 months, and 6 million units thrice weekly for an additional 6 months. Patients showing alanine transaminase activity values persistently reduced by at least 50% from basal values received an additional 1-year course of 3 million units thrice weekly. Results: Alanine aminotransferase normalization was observed in 19% of HIV-infected and 14% of HIV-uninfected subjects during the first year; in 12% of HIV-infected and in 9% of HIV-uninfected patients during the second year. Twenty-five percent of HIV-infected and 14% of HIV-uninfected patients stopped IFN because of poor compliance or side effects. Two years after stopping interferon treatment, one anti-HIV-seropositive and two anti-HIV-seronegative patients showed complete persistent biochemical, virological and histologic remission. Conclusion: Long-term efficacy and toxicity of IFN treatment seem not to be different in HIV-infected and -uninfected patients with delta hepatitis; given the overall poor rate of long-term response, IFN treatment could be considered only in immunocompetent HIV-HDV-coinfected patients, strictly selected because of rapidly evolving liver disease.

Changes in liver fibrosis at the end of alpha interferon therapy and 6 to 18 months later in patients with chronic hepatitis C: quantitative assessment by a morphometric method

Background/Aims: The aims of the study were to determine, in patients with chronic hepatitis C treated with alpha interferon: (i) changes in the morphometric evaluation of liver fibrosis at the end of treatment and 6, 12 and 18 months after treatment; (ii) the predictive value of histologic lesions for the response to treatment, in particular the predictive value of morphometric evaluation of liver fibrosis. Methods: Seventy patients with chronic hepatitis C who participated in two trials of recombinant interferon alpha 2b treatment were studied. Liver specimens were obtained before and at the end of treatment and 6, 12 or 18 months later. Histologic lesions were assessed according to the Knodell system. Quantitative study of total fibrosis and of Disse space collagen was done by the computerized automated morphometric method. Results: A significant decrease in morphometric Disse space collagen was observed at the end of treatment and 6 months later. This decrease was also observed, although it was not significant, 12 and 18 months after treatment. There was no relationship between this decrease and the biochemical and virological responses or the dose of interferon. The pretreatment Knodell activity score, but not the morphometric evaluation of fibrosis, was a significant predictor of sustained response. Conclusion: A decrease in Disse space collagen, as assessed by the sensitive morphometric method, was observed at the end of and 6 months after treatment. This observation is consistent with an anti-fibrogenetic effect of alpha interferon. Mild or moderate histologic activity was associated with a sustained response to therapy.

Reversible cardiomyopathy in a patient with hairy cell leukaemia.

A 64-year-old man presented with severe congestive heart failure. He was diagnosed to have hairy cell leukaemia a year ago and was receiving recombinant interferon alpha-2b injections of 5x10 6...

Intracavitary Bleomycin vs Interferon in the Management of Malignant Pleural Effusions

We read with great interest the article by Wilkins and colleagues (June 1997), 1 Wilkins HE Connolly MM Grays P et al. Recombinant interferon alpha-2b in the management of malignant pleural effusions. Chest. 1997; 111: 1597-1599 Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar reporting a 100% success rate in 15 patients treated with intrapleural interferon (IFN) alpha-2b for symptomatic malignant pleural effusion. Such a percentage of success is surprising and encouraging, as intrapleural IFN has been reported to achieve remarkably lower rates of response, ranging from 38% 2 Rosso R Rimoldi R Salvati F et al. Intrapleural natural beta interferon in the treatment of malignant pleural effusions. Oncology. 1988; 45: 253-256 Crossref PubMed Scopus (61) Google Scholar to 70%. 3 Goldman CA Skinnider LF Maksymiuk AW. Interferon instillation for malignant pleural effusions. Ann Oncol. 1993; 4: 141-145 PubMed Scopus (25) Google Scholar As suggested by Wilkins and colleagues, the technique utilized (closed chest tube thoracostomy drainage until complete resolution of the effusion, before instilling IFN) has probably played an important role in obtaining the promising results. However, criteria for assessment of response are different from those adopted in most studies investigating the palliative treatment of malignant pleural effusion, 2 Rosso R Rimoldi R Salvati F et al. Intrapleural natural beta interferon in the treatment of malignant pleural effusions. Oncology. 1988; 45: 253-256 Crossref PubMed Scopus (61) Google Scholar , 3 Goldman CA Skinnider LF Maksymiuk AW. Interferon instillation for malignant pleural effusions. Ann Oncol. 1993; 4: 141-145 PubMed Scopus (25) Google Scholar , 4 Paladine W Cunningham TJ Sponzo R et al. Intracavitary bleomycin in the management of malignant effusions. Cancer. 1976; 38: 1903-1908 Crossref PubMed Scopus (139) Google Scholar and we agree with the authors that further controlled trials are necessary to clarify the role of IFN in the treatment of this condition.

A comparison of four types of interferon alpha in the treatment of chronic hepatitis C

Several clinical trials and meta-analyses have shown that the efficacy of interferon (IFN)-alpha in the treatment of chronic hepatitis C is variable, depending on the type of IFN-alpha used. We randomly assigned 220 patients with hepatitis C to receive a 6-month treatment (3 megaunits three times per week) with lymphoblastoid IFN-alpha (group A), recombinant IFN alpha-2a (group B), leukocyte IFN-alpha (group C), or recombinant IFN alpha-2b (group D). The groups were homogeneous with reference to histologic severity of the disease (chronic persistent hepatitis, 21.4%; mild chronic active hepatitis, 28.2%; moderate chronic active hepatitis, 28.6%; and severe chronic active hepatitis, 21.8%). We used common laboratory techniques to detect and assess all serum variables. Liver biopsy was conducted according to Menghini's modified technique, and administration of IFN alpha was conducted according to a double-masked method. A total of 220 patients were enrolled in the study. Ninety-two patients dropped out because of side effects, comorbidity unrelated to the baseline disease, or voluntary termination and 128 patients (32 patients in each group) completed the treatment course and the follow-up period. At the 6-month end point, 14 of 32 patients were completed responders in group A, 13 of 32 in group B, 14 of 32 in group C, and 8 of 32 in group D. After completion of the follow-up period, 10 of 32 patients had a sustained response in group A, 9 of 32 in group B, 10 of 32 in group C, and 8 of 32 in group D. Treatment failure and relapse rates were higher in the patients treated with recombinant alpha IFNs than in patients treated with leukocyte or lymphoblastoid IFN alpha. We observed no relation between the relapse rate and baseline severity of the disease. Among the recombinant IFNs, a major rate of clinical response was observed in patients treated with recombinant IFN alpha-2a. Although leukocyte IFN-alpha and lymphoblastoid IFN-alpha treatments showed an overlapping efficacy in terms of complete or sustained response, the former achieved a lower rate of treatment failure or relapse.

Estimates of the cost-effectiveness of a single course of interferon-alpha 2b in patients with histologically mild chronic hepatitis C.

Chronic hepatitis C is a major cause of illness and death in the United States. Interferon-alpha 2b can induce clinical, biochemical, and virologic remission in some patients with chronic hepatitis C, but the long-term cost-effectiveness of this treatment, particularly in patients with histologically mild disease, is unknown. To estimate the cost-effectiveness of interferon-alpha 2b in mild chronic hepatitis C. Meta-analysis of five prospective trials and cost-effectiveness analysis. Projection of the clinical and economic outcomes expected from loss of hepatitis C virus was done by using a Markov simulation. The potential effect of uncertainty in the model assumptions was tested by using sensitivity analyses. Search of the MEDLINE database, opinions of expert panels, hospital cost data, and adjusted physician charges. Hypothetical cohorts with histologically mild chronic hepatitis C. The model assumed a single 6-month course of recombinant interferon-alpha 2b. Life expectancy, quality-adjusted life expectancy, costs, and marginal cost-effectiveness ratios from a managed care perspective. In 27% of patients with mild chronic hepatitis C treated with interferon-alpha 2b for 6 months, serum alanine aminotransferase levels permanently returned to normal and viral status remained negative. The model estimated that interferon-alpha 2b treatment in this population should increase life expectancy by 3.1 years if given at 20 years of age, by 1.5 years at 35 years of age, and by 22 days at 70 years of age; discounted marginal cost-effectiveness ratios are $500, $1900, and $62,000 per year of life gained, respectively. Varying the long-term response rates and progression rates for mild and moderate chronic hepatitis to near zero in sensitivity analyses substantially affected the results: Ratios ranged from $31,000 for a 20-year-old patient to $640,000 for a 70-year-old patient. On the basis of estimations in this mathematical model of the natural history of chronic hepatitis C, treating mild chronic hepatitis with interferon-alpha 2b should prolong life expectancy at a reasonable marginal cost per year of life gained, particularly in younger patients.

Immunochemotherapy with recombinant interferon-alpha 2b plus dacarbazine in the treatment of advanced malignant melanoma.

In order to estimate the therapeutic activity and tolerability of immunochemotherapy with recombinant interferon-alpha 2b (rIFN-alpha 2b) plus dacarbazine (DTIC), a study was carried out in 61 patients with cytologically and/or histologically confirmed metastatic malignant melanoma. The treatment regimen was as follows: rIFN-alpha 2b 2 x 10(6) IU intramuscularly on days 1 to 4, and DTIC 800 mg/m2 intravenously on day 5, repeated at 3-week intervals until the progression of the disease or, in the case of a complete response, for up to 6 months. The overall response rate was 28%-12% complete response (CR) and 16% partial response (PR). The median response duration was 10.9 months (CR 11.5 months, PR 9.3 months; P > 0.05). Responses occurred in soft tissue and lung metastases only. The median times to treatment failure for responding and non-responding patients were 10.9 and 3 months, respectively (P < 0.0001), and the median survival durations were 16.5 and 5.8 months, respectively (P < 0.0001). The stratification of the patients into a low-risk group (World Health Organization performance status [WHO PS] < or = 1 and soft tissue or lung metastases) and a high-risk group (WHO PS = 2 or disease localization other than skin, lymph nodes or lung) showed a significant advantage for the first group with respect to the response rate, median time to treatment failure and survival duration. A flu-like syndrome was recorded in 72% of patients, nausea and vomiting in 34%, haematological toxicity in 26%, hepatic toxicity in 5%, and neurotoxicity in 5%. In view of the results obtained in our study and those reported in the literature, IFN plus DTIC immunochemotherapy represents a reasonable treatment option, particularly for patients with soft tissue and lung metastases.

The incidence and clinical significance of antibodies to interferon-a in patients with solid tumors.

It is well known that natural and recombinant proteins can cause antibody formation in the host. We have studied the incidence of binding and neutralizing antibodies in carcinoid patients (n = 327). All together 204 patients received interferon-alpha 2b (Intron-A), median does 15 MU range 9-35 MU/week subcutaneously and 51% of the patients developed binding antibodies by immunoassay and 17% showed positive neutralization assay but high titer antibodies (> 800 NU/ml) were only found in 4% of the patients. The median time until the development of binding antibodies was 26 months and neutralizing antibodies 25 months. Twenty-nine patients received interferon-alpha 2a (Roferon), median does 18 MU/week subcutaneously and 45% developed binding antibodies, 38% had positive neutralization assay and 28% presented high titer antibodies. Binding and neutralizing antibodies occurred at the same time after median six months of treatment. Patients treated with Wellferon (n = 45) and leukocyte interferon (n = 48), median dose of 15 MU/week subcutaneously did not develop any neutralizing antibodies. The majority of the interferon-alpha 2 antibodies were of the IgG isotype. The clinical relevance of the development of high titer neutralizing antibodies was evaluated in the patients. All together 17 patients developed high titer neutralizing antibodies and of these 12 patients showed loss of antitumor response measured as increased level of tumor markers and of tumor progression. In nine of these patients a switch to human leukocyte interferon reinstituted an antitumor response. Neutralizing antibodies against recombinant interferon-alpha 2a and 2b might occur in patients with carcinoid tumors. The incidence of high titer neutralizing antibodies is significantly higher in patients treated with interferon-alpha 2a compared to interferon-alpha 2b. A significant number of patients lost the antitumor effect during development of neutralizing antibodies at high titers, but human leukocyte interferon can be used as rescue treatment.

Recombinant Interferon Alpha-2b in the Management of Malignant Pleural Effusions

Twenty-one patients with malignant pleural effusion (MPE) were prospectively entered into a nonrandomized, single-armed study to evaluate the efficacy and safety of recombinant interferon (IFN) alpha-2b (INTRON A; Schering-Plough; Kenilworth, NJ) as an intrapleural palliative agent. From March 1989 through February 1993 (48 months), 21 patients were entered into the study. No symptomatic effusion recurred and no substantial side effects were associated with treatment. This suggests recombinant IFN alpha-2b represents a safe and effective intrapleural agent for the palliation of MPE.

Pre-treatment levels of anti-HCV core IgM antibodies are closely associated with response to alpha interferon therapy in chronic hepatitis C patients.

To investigate the relationship between pre-treatment levels of anti-hepatitis C virus (HCV) immunoglobulin M (IgM) antibodies and the outcome of interferon therapy, and also the relationship with genotypes and quantitative viraemia. One hundred and four patients with biopsy-proven chronic hepatitis C without cirrhosis, consecutively enrolled in three general hospitals in Turin, Italy, and treated according to the same interferon schedule (3 MU of recombinant alpha-2b interferon three times a week for 6 months). Anti-HCV IgM were measured by a second-generation enzyme-linked immunoassay and results expressed as sample-cutoff ratio. In 30 patients, determination of viraemia by branched DNA (bDNA) and genotyping were performed and the correlation with anti-HCV IgM ratios was assessed. According to univariate analysis, anti-HCV IgM ratios, age, serum gamma-glutamyltranspeptidase (gamma-GT) and ferritin levels were significantly associated with sustained response to therapy. A log-linear model, testing the effect of these variables on response to therapy, showed that anti-HCV IgM ratio was the only independently associated variable (P=0.00057). Anti-HCV IgM were associated with viraemia levels (r=0.57), but not with genotype distribution. Patients with anti-HCV IgM ratio less than 1 were sustained responders to the 'standard therapy' in 65% of cases. By contrast, among patients with a ratio greater than 3, sustained response was achieved in only one patient (3%), while 73% were non-responders; the majority of relapsers were found among patients with a ratio between 1 and 3. Anti-HCV IgM antibodies provide an easily accessible and cheap serological marker of active viral replication, and are significantly related to the outcome of interferon therapy in patients with chronic hepatitis C.

Determination of Interferon-alpha Receptors in Urothelial Cancer and in Normal Urothelium

We determined and compared the presence and frequency of interferon-alpha 2b receptors in urothelial neoplasms and normal urothelium, since the biological activity of interferons becomes apparent only after they bind to specific receptors. With our method detection of interferon-alpha 2b receptors required a large number of cells, that is more than 1 x 10(6) cells per ml. We studied 14 patients with relatively large tumors of all stages and grades. Three patients had grade I, 4 grade II and 7 grade III disease. As controls we used biopsies of normal urothelium from 14 patients who underwent transvesical prostatectomy. Interferon-alpha 2b receptors were detected quantitatively through the binding of radiolabeled 125iodine human recombinant interferon-alpha 2b in normal and malignant urothelial tissue samples. The interferon-alpha 2b receptors are expressed as receptor sites per cell, and the results were evaluated with Scatchard analysis. The number of interferon-alpha 2b receptor sites per cell ranged from 43 to 100 (mean plus or minus standard deviation 62 +/- 18) in normal urothelium and from 110 to 210 (mean 174 +/- 25) in malignant epithelium. This difference was statistically significant (p < 0.001), Student's t test 13.75). The difference in the number of interferon-alpha 2b receptors in grades I plus II and grade III tumors is suggestive but not statistically significant (p < 0.10, Student's t test 2.075). High grade tumors expressed greater numbers of interferon-alpha 2b receptors than low grade tumors. The method used needs refining so that it will require fewer cells to determine interferon-alpha 2b receptors. Interferon-alpha 2b receptors are detected in bladder urothelium and are abundant in malignant tissue with increasing frequency as tumor grade increases. If we can establish, in the future, a correlation of the number of interferon-alpha 2b receptors with the potential response of patients to intravesical instillation therapy with interferon, we might have an important prognostic method for selecting subgroups of patients with transitional cell carcinomas who will benefit from interferon-alpha 2b instillation.

Interleukin-2 and interferon alpha 2 combination

We have studied activity and toxicity of subcutaneous recombinant interleukin-2 and interferon alpha 2b in a series of 14 patients with advanced renal cell carcinoma. No objective response was observed, and the median survival was 16 months (range 3-19); toxicity was acceptable. All the patients had poor prognostic factors and were pretreated with interferon.