Recombinant Interferon Alfa-2b Research Articles

Treatment of chronic NANB viral hepatitis with recombinant interferon alfa-2b. Preliminary clinical and immunologic results

■ About 77% of patients treated with interferon alfa-2b had normal serum ALT levels, compared to no patients in the untreated group. ■ The Knodell HAI improved in 6/7 patients treated. ■ Interferon alfa-2b was well tolerated. No patients discontinued treatment due to toxicity. ■ Expression of CD38 and CD14 was increased in patients treated with interferon alfa-2b.

α-Interferon treatment in Chinese patients with chronic hepatitis B

alpha-Interferon has been shown to be the most promising antiviral agent in the treatment of chronic hepatitis B virus infection in Caucasian patients. The experience with recombinant interferon alfa-2a and alfa-2b in four randomized controlled trials in Chinese adults and children is reviewed here. alpha-Interferon alone has little long-term benefit in the treatment of Chinese patients with chronic hepatitis B virus infection, especially in patients who have normal or near normal serum aminotransferase levels. The response in patients with elevated aminotransferase levels appears to be better. The poor antiviral response in patients with normal aminotransferase levels is probably due to immunological tolerance to HBV induced by exposure to the virus in early life. Prednisone pretreatment does not seem to have any additional benefit to using interferon alone in these patients, while the effect in patients with elevated aminotransferase levels remains to be proven.

A randomized, double-blind, placebo-controlled trial of recombinant human α-interferon therapy for chronic non-A, non-B (type C) hepatitis

The effects of alpha-interferon therapy were evaluated in a prospective, randomized, double-blind, controlled trial of recombinant human interferon alfa-2b versus placebo in patients with well-documented chronic non-A, non-B hepatitis (type C). Forty-one patients, of whom 37 (90%) had hepatitis C virus antibodies in their serum, were enrolled in the trial. Twenty-one patients received interferon (2 million units) and 20 received placebo as subcutaneous injections three times weekly for 6 months. Mean serum aminotransferase activities and liver histology improved significantly in interferon-treated patients but not in placebo recipients. Ten interferon-treated patients (48%) had a complete response to therapy as shown by a reduction of mean serum aminotransferase activities into the normal range during therapy; three more patients had a partial response with aminotransferase activities decreasing by more than 50% on average. In follow up, however, serum aminotransferase levels usually returned to pre-treatment levels; at 6 to 12 months after stopping interferon, only two (10%) patients still had normal aminotransferase activity. These results indicate that alpha-interferon therapy is beneficial in reducing the disease activity in chronic hepatitis C. Only a minority of patients, however, appear to have a long-term response. In this study, interferon was generally well tolerated, with only one patient discontinuing therapy because of adverse effects.

Multicenter study on the treatment of chronic NANB hepatitis with recombinant human interferon alfa-2b

Multicenter study on the treatment of chronic NANB hepatitis with recombinant human interferon alfa-2b

Treatment of chronic hepatitis C with recombinant α-interferon. A multicentre randomized, controlled trial

To assess the efficacy of therapy with the antiviral agent interferon in chronic hepatitis C (non-A, non-B hepatitis), we randomly assigned 166 chronic hepatitis C patients to treatment with either 3 million or 1 million units of recombinant interferon alfa-2b three times weekly for 24 weeks, or to no treatment. The probability of normalization or near normalization of the serum alanine aminotransferase levels after 6 months of interferon therapy was 46% in patients treated with 3 million units of interferon (p less than 0.001) and 28% in those treated with 1 million units (p less than 0.02), but only 8% in untreated patients. Serum alanine aminotransferase levels became completely normal in 22 of the 26 patients (85%) who responded to treatment with 3 million units of interferon and 9 of the 16 patients (56%) who responded to treatment with 1 million units. The patients who received 3 million units of interferon had histological improvement because of the regression of lobular and periportal inflammation. Relapse within 6 months after the completion of treatment occurred in 51% of the patients treated with 3 million units of interferon and 44% of those treated with 1 million units. We conclude that a 24-week course of interferon therapy is effective in controlling disease activity in many patients with hepatitis C, although relapse after the cessation of treatment is common.

Prospective trial of recombinant leucocyte interferon in chronic hepatitis B: a long-term follow-up study

Twenty-one adult patients with chronic hepatitis B and active viral replication as indicated by positivity for hepatitis B e antigen and hepatitis B virus DNA, with increased DNA polymerase levels for more than 6 months, were entered into a prospective trial of low-dose recombinant human alpha-interferon therapy. All patients were treated with 5 million units of recombinant interferon alfa-2b given subcutaneously every other day for 12 weeks. During treatment, 18 patients (86%) showed a significant reduction of DNA polymerase levels (p less than or equal to 0.001), which reached normal values in ten (48%). After 10 months' mean follow up, seven patients (33%) were hepatitis B e antigen negative and five (24%) subsequently became positive for antibodies to e antigen. By 27 months, nine patients (43%) were both hepatitis B e antigen negative and e antibody positive. Only one patient became permanently negative for hepatitis B surface antigen. One patient relapsed during the second year of follow up. Side effects necessitated withdrawal of therapy in two patients: one due to worsening thrombocytopenia after two doses of interferon (data omitted from the study results) and one due to a local reaction at the injection sites. Our data indicate that small doses of recombinant interferon alfa-2b given during a 12-week period induce a significant reduction in viral replication and approximately triple the spontaneous seroconversion rate observed in patients with chronic hepatitis B.

Treatment of chronic hepatitis B with interferon alfa-2b

A total of 58 patients with histologically confirmed chronic viral hepatitis B and presence of hepatitis B surface antigen and hepatitis B virus DNA (HBV DNA) in the serum were randomized in a prospectively controlled trial. Thirty patients were treated with 3 megaunits of recombinant interferon alfa-2b (INTRON A, R Schering-Plough, Essex Corporation) subcutaneously thrice weekly for 4 months. Twenty-eight controls received no treatment. The post-treatment follow-up period consisted of 6 months. Twenty-eight treated patients and 27 controls completed the protocol. One female patient of the treatment group showed a complete response, and eight other treated patients (32%) showed a partial response to therapy. Three patients in the control group (11%) lost hepatitis B e antigen and HBV DNA spontaneously. This finding is statistically significant (p less than 0.05). The elimination of hepatitis B virus markers from the serum was associated with a normalization of aminotransferase activities in the serum. Reactivation of hepatitis was not observed after seroconversion.

Recombinant α-interferon treatment of non-A, non-B (type C) hepatitis: review of studies and recommendations for treatment

Non-A, non-B (type C) hepatitis is a serious world problem which typically results in chronic hepatitis and may lead to cirrhosis and hepatocellular carcinoma. alpha-Interferon has recently been studied in a number of randomized controlled trials throughout the world. The results of those studies are reviewed here. ALT levels were normalized by 2-3 MU recombinant interferon alfa-2b, three times per week s.c. for 6 months (p less than 0.001 vs. control) in 36% of patients in five trials. Biopsy tests also demonstrated histological improvement in lobular and periportal inflammation. Unfortunately, relapse is a common problem in these studies, occurring in 49% of patients treated with 3 million units and 57% of those treated with 1 million units. Retreatment usually brings remission once again. In the future, long-term studies will further elucidate the natural history of the disease and documented guidelines for interferon dosage and duration of dosing in a wider range of patient subgroups will become available.

Interferon alfa-2b treatment of HBeAg negative/serum HBV DNA positive chronic active hepatitis type B

A randomized controlled trial of recombinant interferon alfa-2b has been initiated in patients with chronic active hepatitis who were negative for serum hepatitis B e antigen but positive for serum hepatitis B virus DNA and hepatitis B core antigen expression in the liver. Twenty-five patients received interferon alfa-2b 3 million units thrice weekly for 14-16 weeks and 25 served as untreated controls. Seventeen patients in the treatment and 18 in the control group have already completed a 12-month period of observation. Interferon alfa-2b was well tolerated by all patients. At the end of therapy, complete responses, defined as disappearance of hepatitis B virus DNA from serum and return of alanine aminotransferase to normal, were observed in 10 (59%) of the 17 treated patients compared to none in the control group (p less than 0.01). Twelve months after the onset of interferon alfa-2b therapy, 11 (65%) of the 17 treated patients were complete responders compared to 2 (11%) of 18 in the control group (p less than 0.01). Fifty per cent (4/8) of complete responders to interferon alfa-2b therapy, followed for 16-24 months, experienced reactivations of hepatitis B virus replication with reappearance of serum hepatitis B virus DNA and a return of serum alanine aminotransferase activity. The response to interferon alfa-2b therapy appeared to be independent of pre-treatment serum alanine aminotransferase and hepatitis B virus DNA levels.

Randomized controlled trial of recombinant interferon alfa-2b in chronic NANB hepatitis: Dose schedules and results

Abstract •■ Response rate: 50–65% (87.5% within 2 months). •■ Relapse in 80% after down titration, 80% response again on up titration. •■ Relapse after end of treatment: 55%, usually transient.

Effect of alpha interferon on glucose and alanine transport by rat renal brush border membrane vesicles

To investigate the pathogenetic mechanisms of interferon nephrotoxicity, we studied the effect of recombinant interferon alfa-2b on the uptake of 14C-D-glucose and 14C-L-alanine by rat renal brush-border-membrane vesicles. Interferon significantly inhibited 20 sec. sodium-dependent and 5 and 10 min. equilibrium uptake of both glucose and alanine. The inhibitory effect was dose dependent with maximum effect achieved at interferon concentration of 5 × 10 −8M in the uptake media. The half-maximal inhibitory concentrations, IC 50, of interferon on glucose uptake was 1.8 × 10 −8M, and 5.4 × 10 −9M on alanine uptake. Dixon plot analysis of uptake data was consistent with pure non-competitive inhibition. The inhibition constants, K i, 1.5 × 10 −8M for glucose uptake, and 7.3 × 10 −9M for alanine uptake, derived from Dixon plots were in close agreement with the IC 50s calculated from the semilog dose response curves. These observations reveal that direct interactions at the proximal tubule cell membrane are involved in the pathogenesis of interferon nephrotoxicity, and that its mechanism of nephrotoxicity is similar to that of other low molecular weight proteins.

A randomized controlled trial of interferon alfa-2b as therapy for chronic non-A, non-B hepatitis

Eighty patients with chronic non-A, non-B hepatitis completed a randomized controlled trial of the therapeutic efficacy of recombinant interferon alfa-2b. Twenty-nine received 1 million units and 26 received 3 million units of interferon subcutaneously thrice weekly for 6 months, and 25 were controls. Normalization or a significant decrease of alanine aminotransferase values was obtained in 19/29 (66%) patients treated with 1 million units, in 18/26 (69%) patients treated with 3 million units and in one control patient (4%, p less than 0.05). However, when control patients were randomized after the initial 24 weeks to receive 1 or 3 million units of interferon for 48 weeks, 12/14 (86%) patients receiving 3 million units responded to therapy versus 3/11 patients receiving 1 million units (27%, p less than 0.05). After a 1 to 6 months follow-up period post treatment, an alanine aminotransferase relapse was observed in 18/30 (60%) responders to 3 million units and in 17/22 (77%) responders to 1 million units. Cirrhotic patients responded less than patients with non-cirrhotic disease (47 vs. 78%, p less than 0.05). Only responders treated with 3 million units significantly ameliorated their histologic picture (pre-therapy Knodell's index = 8.9, post-therapy = 6.0, p less than 0.05). The data confirm that treatment with interferon is of benefit in patients with chronic non-A, non-B hepatitis.

Cost-Benefit Analysis of Interferon Alfa-2b in Treatment of Hairy Cell Leukemia

The clinical benefits as well as the cost benefits of use of recombinant interferon (IFN) alfa-2b instead of conventional chemotherapy (primarily chlorambucil) for progressive hairy cell leukemia were assessed retrospectively on the basis of 12 months of clinical data from 128 patients treated with IFN alfa-2b. Data from 71 matched historical control patients who had received conventional treatment were used for survival analysis. Hematologic response (reversal of cytopenias) was achieved by 18% of the control patients versus 73% of the IFN-treated patients. This response was associated with virtual elimination of the need for transfusions and splenectomy as well as dramatic decreases in the frequency of fatal infections (22.5% vs. 1.6%) and the 12-month mortality rate (28% vs. 3.1%). Direct costs per patient per year for medical care (transfusions, antibiotic treatment, splenectomy, and chemotherapy) of those receiving IFN alfa-2b were 2.8-fold lower than costs for medical care of control patients ($5,027 vs. $14,046). Indirect costs, which reflect the present value of future earnings lost due to premature death, were 13.3-fold lower for IFN-treated patients than for control patients ($4,771 vs. $63,507). Our analysis demonstrates that IFN alfa-2b offers substantial clinical and cost advantages to patients with hairy cell leukemia and that the introduction of this therapy using novel biotechnology furthers the health care community's commitment to cost containment.

Treatment of Malignant Carcinoid Tumors With Recombinant Interferon alfa-2b: Development of Neutralizing Interferon Antibodies and Possible Loss of Antitumor Activity

Twenty patients with malignant carcinoid tumors were treated for 6 months with recombinant interferon alfa-2b (IFN alpha-2b; Intron-A; Schering Corp., Bloomfield, NJ) at a mean dose of 5.9 megaunits three times per week. Eleven of the 20 patients (55%) had a greater than 50% reduction of tumor markers (urinary 5-hydroxyindoleacetic acid or plasma neuropeptide K), showing objective tumor response. Six patients (30%) had stable disease with no significant change in tumor markers or tumor size, and three (15%) had progressive disease with an increase in tumor markers and size. These results are similar to those reported earlier for treatment with natural leukocyte IFN in patients with carcinoid tumors. Only two patients (35%) had a slight reduction of tumor size after 6 months of treatment. Three patients developed neutralizing antibodies to IFN alpha-2b. Two of these patients initially showed an objective response, which lasted until IFN antibodies developed. In one of these patients, a change to human leukocyte IFN resulted in normalization of antibody titers within 3 months, and the patient had a second objective clinical response. There was no correlation between development of IFN antibodies and development of autoimmune phenomena such as increased titers of antinuclear antibodies or thyroid autoantibodies. IFN alpha-2b seems to be as potent as human leukocyte IFN in the treatment of patients with malignant carcinoid tumors, but it is important to recognize that antibodies neutralizing IFN may develop in some patients, with concomitant loss of antitumor effects. A change to natural leukocyte IFN might be beneficial in these patients.

Decreased Epstein-Barr virus-induced transformation, and elevated 2–5A synthetase and RNase L activity in peripheral blood mononuclear cells from patients treated with recombinant interferon alfa 2b

Patients with cutaneous T-cell lymphoma (CTCL) were treated with recombinant alfa 2b interferon (rIFN alfa 2b) by intramuscular injection. Therapy-induced changes in Epstein-Barr virus (EBV) induced transformation of patient peripheral blood lymphocytes, 2',5' oligoadenylate (2-5A) synthetase levels and RNase L activation in peripheral blood mononuclear cells were monitored. Inhibition of EBV-induced transformation and elevation of 2-5A synthetase levels correlated with increased activation of RNase L, which provides evidence that intramuscular administration of rIFN alfa 2b induces a sustained anti-EBV state in CTCL patient peripheral blood mononuclear cells which can be detected in vitro.

Treatment of Ph′-positive chronic myelogenous leukemia (CML) with recombinant interferon alfa-2b (INTRON A)

The recent use of human alpha-interferon (IFN) in the treatment of Ph’-positive chronic myeloid leukemia (CML), has clearly been shown to be effective in controlling leukocytosis and thrombocytosis, and in determining cytogenetic improvement in a consistent proportion of patients (4, 6, 8, 9). Furthermore, the temporary control of blast phase and the suppression of secondary Ph’-positive clones in some cases, has suggested that this agent might be useful even in more advanced stages of the disease (10). Clinical trials using IFN on CML patients, have employed daily administration of doses ranging from 3 to 15 x lo6 W/m’. In our investigation, we have utilized an intermittent, low-dose administration of 2 and 5 x IO6 IU/m’, three times a week, in 74 Ph’-positive CML patients (65 in the chronic phase, CP, and nine in the accelerated phase, AP), with the aim of testing the hematologic and cytogenetic effectiveness of this approach.

Recombinant interferon alfa-2b (INTRON A) as post-induction therapy for responding multiple myeloma patients. M84 protocol

The cloning of the interferon alfa-2b gene in 1980 made large quantities of human interferons available for both in vitro and in vivo testing. Athymic nude mouse models (1, 10, 16) and human tumor clonogenic assays were used to demonstrate a variety of interferon (IFN) biologic activities on tumor growth and host immune response modulation. Therapeutic activity of recombinant alpha,-IFN (r a,-IFN) has been demonstrated for some malignant diseases (4, 6-8, 11, 15). V arious clinical trials of r a,-IFN for treatment of multiple myeloma (MM) (2, 5, 9, 12-14) h s owed antitumor activity for untreated and refractory patients without, however, any additional benefit on response and/or survival rates as compared with traditional alkylating chemotherapy. In view of the biologic properties of IFN, its capacity to modify the host’s biologic response to malignant cells and its active impact on MM, the role of r cr,-IFN on a reduced tumor mass, i.e. on responding MM patients, could be evaluated. IFN was investigated as post-induction therapy to test its capacity to prolong remission, a phase of the disease where the role of chemotherapy is not yet well established.

Recombinant Interferon Alfa-2b in Plaque-Phase Mycosis Fungoides

A two-part clinical trial was conducted to determine the therapeutic efficacy of recombinant interferon alfa-2b in plaque-phase mycosis fungoides. In an initial randomized double-blind study, each of six patients had two representative plaques injected intralesionally with 1 X 10(6) U of recombinant interferon alfa-2b per site and two control plaques injected with placebo three times weekly for four consecutive weeks. Complete clinical regression of disease was observed at ten of 12 recombinant interferon alfa-2b sites compared with one of 12 placebo-treated sites four weeks after treatment with injections was stopped. Subsequently, in an open-labeled study, five of these patients were treated intramuscularly with 5 X 10(6) U of recombinant interferon alfa-2b three times weekly for four weeks and two patients were treated with a second, more extended course of therapy lasting 12 to 16 weeks. Three of the five patients treated systemically showed some improvement overall, but the responses were judged not to be clinically significant. The differential response observed from intralesional and intramuscular injections may be related to differences in concentration of recombinant interferon alfa-2b achieved in lesional skin by the two methods of administration.

Rationale for and conduct of a phase I clinical trial with interferon alfa-2b plus doxorubicin.

A human tumor cloning system was utilized to screen for the antitumor activity of recombinant interferon alfa-2b (Intron A) alone and in combination with standard antineoplastic agents. These in vitro studies confirmed synergistic effects of alfa-2b plus doxorubicin against primary human tumors. Based on those in vitro findings, a phase I study has been conducted by Sarosy and colleagues that demonstrated that recombinant interferon alpha-2b and doxorubicin could be given together. Myelosuppression was the dose-limiting toxicity. Because responses were noted in the phase I trials with the combination, phase II trials of the combination are warranted. Additional phase I studies that should be pursued include recombinant interferon alpha-2b plus 5-fluorouracil, interferon plus cisplatinum, and interferon plus DTIC.

Interferon alpha in the treatment of hairy cell leukemia.

Fifty-four patients with hairy cell leukemia were treated for 7 months with three types of subcutaneously injected interferon: recombinant interferon alfa-2a from Hoffmann-La Roche (3 X 10(6) U daily); recombinant interferon alfa-2b from Schering (2 X 10(6) U/m2, three times per week); and partially purified human leukocyte interferon alpha from the Finnish Red Cross (3 X 10(6) U daily). After 4 months, in 27 patients hairy cells decreased dramatically (P less than 0.01) while platelets (P less than 0.05), monocytes (P less than 0.01), polymorphonuclear leukocytes (P less than 0.01) and hemoglobin (P less than 0.01) increased (in this order) as treatment progressed. Morphometric parameters were used to estimate the relative volume of hairy and myeloid cells present in bone marrow. Biopsies were performed at the beginning of the study and in the second, fourth, and seventh months thereafter. Bone marrow disorders were slower to improve as compared with blood. Six severe cases of hairy cell leukemia were responsive to treatment, but required special monitoring during the first 2 months. All three interferons studied are efficient. Interferon receptors, oncogene (mRNA levels) expression, and the relationship between PDGF and fibrosis in hairy cell leukemia are under investigation.