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PubMed1982

Interferon and natural killer activity in multiple myeloma. Lack of correlation between interferon-induced enhancement of natural killer activity and clinical response to human interferon-alpha.

Natural killer (NK) activity of peripheral lymphocytes was measured in 39 patients with multiple myeloma prior to and during interferon (IFN) therapy. NK activity increased in a majority of patients following the first injection of IFN and remained at an increased level during 1 year of therapy. Lower doses of IFN seemed to induce a greater increase in NK activity than higher doses. No correlations could be observed between the response of the tumors to IFN therapy and pretreatment levels of NK activity, IFN-induced enhancement of NK activity in vitro or IFN-induced enhancement of NK activity in vivo.

Adult↗
PubMed1984

Decreased interferon synthesis and responsiveness to interferon by leukocytes from multiple sclerosis patients given natural alpha interferon.

Despite the use of interferon (IFN) in numerous clinical trials, relatively little is known about how IFN therapy influences leukocyte function. To evaluate some of its effects, leukocytes from multiple sclerosis (MS) patients given daily treatments of natural alpha IFN (IFN-alpha) were evaluated for IFN synthesis and two responses to IFN in vitro: enhancement (priming) of IFN synthesis and suppression of Concanavalin A (Con A)-induced T-cell mitogenesis. The IFN therapy had no effect on the sensitivity of Con A-stimulated leukocytes to the antiproliferative action of IFN-alpha. However, using Newcastle disease virus (NDV), measles virus, or poly I:C to stimulate IFN synthesis, cells from IFN-treated patients produced less IFN in response to all inducers, with titers ranging between 11% and 44% of pretherapy values. Also, unlike cells from these same patients before therapy or from the placebo recipients, cells from the IFN recipients were not primed by either IFN-alpha or -beta even though IFN-beta had not been used for therapy. The loss of these priming reactivities suggests that resistance to IFN had developed in IFN-treated patients.

Adult↗
PubMed1991

An interferon-induced 16-kD protein is present in the membranes of interferon-sensitive but not in interferon-resistant mouse cells.

Human interferon-alpha (IFN-alpha) or IFN-beta has been shown to induce a 17-kD membrane protein in human cells which when eluted from SDS gels inhibited the multiplication of cells of different human cell lines. We show herein that mouse IFN-alpha/beta induces a 16-kD membrane protein in L1210 and Friend erythroleukemia cells sensitive to IFN-alpha/beta, (but not in the derived IFN-alpha/beta-resistant cell lines) as well in primary and monolayer cultures of mouse embryonic fibroblasts and adult mouse hepatocytes, and in suspensions of spleen cells. In addition, IFN-alpha/beta enhanced the expression of an 11-kD membrane protein which could be shown by immunoprecipitation to be beta 2-microglobulin. Anticell proliferation activity was not recovered from the 16-kD fraction of the SDS gels.

Animals↗
PubMed1985

Interferon-induced 2'-5' oligoadenylate synthetase during interferon-alpha therapy in homosexual men with Kaposi's sarcoma: marked deficiency in biochemical response to interferon in patients with acquired immunodeficiency syndrome.

Titers of circulating interferon (IFN) and the activity of 2'-5' oligoadenylate (2-5A) synthetase, an enzyme specifically induced by IFN, were measured in 28 homosexual men with acquired immunodeficiency syndrome (AIDS) who received one- to six-month courses of antineoplastic therapy with IFN-alpha and in homosexual and heterosexual controls. Fifteen of the patients and two of seven healthy homosexual men had high endogenous levels of 2-5A synthetase. IFN therapy induced further increases in this enzyme in only 10 of the 28 patients with AIDS. Furthermore, peripheral blood cells from all but one of the patients with AIDS and homosexual controls tested were markedly deficient in their ability to respond to IFN in vitro, as measured by increased levels of 2-5A synthetase. We did not find a statistical correlation between cytomegalovirus viremia and pretherapy endogenous circulating IFN, nor any apparent correlation between disseminated infection with cytomegalovirus and either basal levels of 2-5A synthetase or changes in enzyme level during therapy. Pretherapy circulating IFN was significantly correlated with progressive Kaposi's sarcoma during therapy, but rises in levels of 2-5A synthetase were not sufficient to predict a good clinical response.

2',5'-Oligoadenylate Synthetase↗
PubMed1983

Cell surface receptor-mediated internalization of interferon: its relation to the antiviral activity of interferon.

The binding of [3H]leucine-labelled pure human interferon alpha from Namalwa cells to human FL and Daudi cells was studied, and evidence obtained to indicate receptor-mediated internalization of interferon. Cell surface-bound and internalized interferons were quantified separately as trypsin-released and unreleased radioactivities, respectively. At 37 degrees C, surface-bound interferon reached a maximum after 1 h and then decreased, while internalized interferon reached a maximum after 2 h. At 21 degrees C, in contrast, surface-bound interferon reached a maximum after 2 h and did not decrease thereafter; no internalization was observed. The same was true at 37 degrees C in the presence of NaF, indicating dependence of internalization on temperature and energy. In control cultures at 37 degrees C, internalized interferon, after reaching a maximum, decreased after prolonged incubation, and concomitantly acid-soluble radioactivity appeared in the culture medium. The decrease in internalized interferon and the emergence of degraded interferon were inhibited by the lysosomotropic agents, ammonium chloride and chloroquine. The fate of labelled interferon, bound to the cell surface of FL cells at 21 degrees C was studied at 37 degrees C, and the results indicated that trypsin-unreleased interferon was derived from the surface-bound interferon, and was secreted in part into the culture fluid in a degraded form upon prolonged incubation. The relation of internalization of interferon to its biological activity was studied in three ways. In FL cells, the antiviral activity was not induced when internalization of interferon was entirely blocked (at 21 degrees C or in the presence of NaF at 37 degrees C). In Daudi cells, both 2'-5'-oligoadenylate (2-5A) synthetase induction by interferon and internalization of interferon were inhibited completely by diethyldithiocarbamate (DDC), whereas in the case of FL cells, DDC inhibited neither 2-5A synthetase induction nor internalization of interferon. Raji cells, which have an interferon-specific binding site on the cell surface but are insensitive to interferon, were found not to internalize interferon, whereas other Burkitt's lymphoma cells, Daudi and Namalwa, which are sensitive to interferon, did internalize it. These findings suggest (but do not prove) that internalization is required for the establishment of interferon activity.

Biological Transport↗
PubMed1990

One interferon gamma receptor binds one interferon gamma dimer.

We investigated the stoichiometry of the interferon gamma and interferon gamma receptor interaction, using recombinant interferon gamma and recombinant soluble interferon gamma receptor, applying chemical cross-linking and chromatographic techniques, and analyzing the resulting products in denaturing polyacrylamide gels. Interferon gamma cross-linked to itself produced a major band of an apparent molecular mass of 34 kDa, which suggests that it exists as a dimer in physiological buffer and which agrees with published data. Soluble interferon gamma receptor cross-linked to itself produced mainly a 28-kDa band, suggesting that the interferon gamma receptor exists as a monomer. Interferon gamma cross-linked to the soluble interferon gamma receptor resulted in the formation of two main products of apparent molecular masses of 60 and 44 kDa. The predominant 60-kDa band resulted from the cross-linking of one interferon gamma dimer (34 kDa) to one interferon gamma receptor molecule (27 kDa). The 44-kDa band was formed by the cross-linking of one interferon gamma molecule to one interferon gamma receptor. Kinetic studies showed that the cross-linking of interferon gamma dimer to the soluble receptor proceeds through the intermediate formed by cross-linking one molecule of the interferon gamma dimer to the receptor. Reducing and dissociating agents inhibited complex formation. When chromatographed on Sephadex G-100, interferon gamma was eluted as a protein of 34-kDa molecular mass, the soluble interferon gamma receptor as a protein of 40 kDa, and their mixture was eluted in one peak corresponding to an apparent molecular mass of 73 kDa. Sodium dodecyl sulfate-polyacrylamide gel analysis of the eluted mixture showed the presence of both interferon gamma and interferon gamma receptor at a ratio of 2:1. The found results suggest that the interferon gamma receptor binds interferon gamma as a dimer.

Cell Line↗
PubMed1995

Combination antiviral therapy with ribavirin and interferon alfa in interferon alfa relapsers and non-responders: Italian experience.

BACKGROUND/AIMS: A sustained biochemical and virologic response to standard interferon therapy for chronic hepatitis C is seen in no more than 25% of patients, and the efficacy of re-treatment or of higher doses in non-responders and relapsers has not been established. A more effective therapy for interferon alfa-resistant hepatitis C is needed. METHODS: A study of ribavirin plus interferon alfa combination therapy was conducted in 30 patients with chronic hepatitis C resistant to a previous standard course of interferon alfa (14 interferon non-responders, 16 interferon relapsers). Patients were randomly assigned to receive either ribavirin, 800 mg daily, and interferon alfa, 3 MU thrice weekly (n = 15), or interferon alfa alone, 3 MU thrice weekly (n = 15), for 6 months. RESULTS: At the end of treatment, normal alanine aminotransferase levels were observed in eight patients in the combination therapy group: one (14%) interferon non-responder and seven (87%) interferon relapsers (p = 0.01). Six months post-therapy, sustained normalization of alanine aminotransferase was achieved in seven (87%) interferon alfa relapsers, but not in any of the interferon alfa non-responders (p = 0.001). In the group of patients treated with interferon alfa alone, sustained normalization of alanine aminotransferase was observed in one interferon relapser only. Serum HCV RNA became negative in eight patients receiving combination therapy--two (28%) interferon non-responders and six (75%) interferon relapsers. Six months later, circulating HCV RNA remained negative in seven patients: one (14%) interferon non-responder and six (75%) interferon relapsers (p = 0.04). Sustained clearance of HCV RNA was not observed in patients re-treated with interferon alone. The sustained response to combination therapy was accompanied by reduced hepatic necroinflammatory activity on liver biopsy. Hepatitis C virus genotype was not significantly associated with response to combination therapy. Side effects were mild and well tolerated. CONCLUSIONS: Our experience indicates that combination therapy of ribavirin plus interferon alfa induces sustained biochemical, virologic, and histologic responses in most patients who are interferon relapsers.

Antiviral Agents↗
PubMed1994

Immunolocalisation of interferon-alpha in hepatitis C patients and its correlation with response to interferon-alpha therapy.

Localised interferon-alpha production was investigated in hepatitis C patients entered into a trial of interferon-alpha-2a therapy. Antibodies capable of reacting specifically with interferon-alpha-2, interferon-alpha-4 or with all interferon-alpha subtypes were used as immunohistochemical and immunofluorescence probes to study interferon-alpha production in liver biopsy tissue, and peripheral blood mononuclear cells prior to and after stimulation with Sendai virus. Measurement of cytoplasmic interferon-alpha, specifically interferon-alpha-2 and interferon-alpha-4, in peripheral blood mononuclear cells isolated from the hepatitis C patients and of total interferon-alpha secreted into culture supernatants by these cells showed interferon-alpha production similar to that of peripheral blood mononuclear cells isolated from normal individuals. Interferon-alpha-positive cells were observed in the infiltrating mononuclear cells of the liver biopsy tissue obtained from 8 of the 14 patients. Lymphocytes, fibroblasts, Kupffer cells, polymorphonuclear cells and monocytes stained positive for interferon-alpha, and specifically interferon-alpha-4, in all of the eight patients. The cytoplasm of hepatocytes also stained weakly positive in three of these patients. Interferon-alpha positive cells showed a good correlation with the degree of histological damage observed in the liver biopsies but not with presence of antibodies towards hepatitis C virus or levels of serum alanine aminotransferase measured prior to interferon-alpha-2a therapy. Interestingly, response to therapy seemed linked to local interferon-alpha production status. Those patients who responded best to therapy displayed no or only low levels of interferon-alpha positive cells in liver biopsy tissue. Thus patients with a lower activation of their endogenous interferon-alpha system may benefit from administration of exogenous interferon-alpha.

Adolescent↗
PubMed2001

Interferon-kappa, a novel type I interferon expressed in human keratinocytes.

High throughput cDNA sequencing has led to the identification of interferon-kappa, a novel subclass of type I interferon that displays approximately 30% homology to other family members. Interferon-kappa consists of 207 amino acids, including a 27-amino acid signal peptide and a series of cysteines conserved in type I interferons. The gene encoding interferon-kappa is located on the short arm of chromosome 9 adjacent to the type I interferon gene cluster and is selectively expressed in epidermal keratinocytes. Expression of interferon-kappa is significantly enhanced in keratinocytes upon viral infection, upon exposure to double-stranded RNA, or upon treatment with either interferon-gamma or interferon-beta. Administration of interferon-kappa recombinant protein imparts cellular protection against viral infection in a species-specific manner. Interferon-kappa activates the interferon-stimulated response element signaling pathway and a panel of genes similar to those regulated by other type I interferons including anti-viral mediators and transcriptional regulators. An antibody that neutralizes the type I interferon receptor completely blocks interferon-kappa signaling, demonstrating that interferon-kappa utilizes the same receptor as other type I interferons. Interferon-kappa therefore defines a novel subclass of type I interferon that is expressed in keratinocytes and expands the repertoire of known proteins mediating host defense.

Amino Acid Sequence↗
PubMed2001

Efficacy of high-dose interferon in combination with ribavirin in patients with chronic hepatitis C resistant to interferon alone.

OBJECTIVE: Interferon combined with ribavirin has efficacy in the treatment of patients with chronic hepatitis C virus (HCV) infection. However, its utility in patients who have not responded to prior interferon therapy is not clear. Furthermore, the effect of using an increased dose of interferon in combination with ribavirin in patients with chronic hepatitis C resistant to conventional doses of interferon is not known. The aim of our study was to evaluate the effect of high-dose interferon in combination with ribavirin on the efficacy of treating patients with chronic hepatitis C resistant to interferon monotherapy in a large multicenter trial. METHODS: We randomized 154 patients with chronic hepatitis C who failed to achieve a sustained response with prior interferon therapy to receive either 3 or 5 MU of interferon alpha-2b and ribavirin (1000-1200 mg/day) for 12 months. There were 119 patients who had not responded and 35 who initially responded but relapsed after prior interferon monotherapy. Serum HCV RNA levels were measured at entry, 6, and 12 months of treatment and at the end of a 6-month follow-up period. RESULTS: The mean age of the subjects was 47 yr (range 28-68 yr), and 110 (71.4%) were men. One hundred thirty-two patients (86%) had HCV genotype 1, whereas 21 (14%) had cirrhosis. Eighty-one subjects (53%) were randomized to receive 3 MU of interferon alpha-2b. Fifteen of 35 relapse subjects (43%) and 12 of 119 prior nonresponder entrants (10%) achieved a sustained virological response to the 12-month course of treatment. Overall, 11 of 81 patients (14%) receiving 3 MU, and 16 of 73 patients (22%) receiving 5 MU of interferon maintained an undetectable HCV RNA level after cessation of therapy. The difference in sustained response rates between the two interferon dosage groups did not reach statistical significance (p = 0.09). However, among the nonresponder patients alone, there was an increased sustained response in the high-dose interferon group compared with the standard interferon dose group (15.5% vs 4.9%, p = 0.055). Twenty-six patients discontinued therapy before 6 months, including 10 patients (12.3%) in the 3-MU and 16 patients (21.9%) in the 5-MU groups (p = 0.17). CONCLUSIONS: Sustained virological response to combined interferon alpha-2b and ribavirin was significantly higher in relapse patients than those who did not respond to prior interferon monotherapy. Although, when all treated patients were analyzed, there was no significant difference in sustained response between subjects receiving 3 and 5 MU of interferon, among the prior nonresponder patients, treatment with 5 MU of interferon with ribavirin resulted in a slightly increased response compared with treatment with the standard interferon dosage. The tolerability of the treatment regimens was comparable.

Adult↗
PubMed1989

Beta and gamma interferons act synergistically to produce an antiviral state in cells resistant to both interferons individually.

We showed previously that the mouse fibroblastoid cell line Ltk-aprt- is resistant to the antiviral effects of beta interferon. This lack of response reflects a partial sensitivity to the interferon that is accompanied by a failure to activate expression of several interferon-regulated genes, although certain other genes respond in a normal manner. We show here that Ltk-aprt- cells were also unable to establish an antiviral state and to activate expression of 2,5-oligo(A) synthetase when treated with gamma interferon. Strikingly, however, treatment with a combination of beta interferon and gamma interferon provided complete protection against viral replication. Although the cells were completely insensitive to up to 250 U of the interferons per ml added singly, essentially complete protection from viral cytopathic effects was achieved when as little as 10 U of each of the interferons per ml were combined. Expression of 2,5-oligo(A) synthetase was also sensitive to this synergistic effect. Activation of an antiviral state could also be achieved by sequential treatment, first with gamma interferon and then with beta interferon. Partial protection against viral replication could be achieved by pretreatment with gamma interferon for as little as 1 h before incubation with beta interferon and could be blocked by the addition of specific antibodies or by cycloheximide, indicating that gamma interferon induces the synthesis of a protein which can act synergistically with a signal produced by the beta-interferon receptor. We suggest that Ltk-aprt- cells suffer from defects in one or more components of the gene activation pathways for both type I and type II interferons. Nonetheless, gamma interferon is able to activate the expression of a gene encoding a protein required for signal transduction. This protein acts synergistically with a transient signal produced in response to beta interferon, thereby activating the expression of a further group of genes.

2',5'-Oligoadenylate Synthetase↗
PubMed1988

Agonist and antagonist effects of interferon alpha and beta on activation of human macrophages. Two classes of interferon gamma receptors and blockade of the high-affinity sites by interferon alpha or beta.

H2O2-releasing capacity and limited antitoxoplasma activity could be induced in human macrophages (derived from monocytes cultured greater than or equal to 5 d) but not in monocytes themselves (cells cultured less than or equal to 4 d) by a further 3-d incubation with pure natural or rIFN-alpha or -beta. More than 3 pM (10 U/ml) of these IFNs was required, with greatest effects at approximately 300 pM (10(3) U/ml). At 300 pM, H2O2-releasing capacity was enhanced 4.4 +/- 1.6-fold over medium control (mean +/- SD for natural INF-alpha, rIFN-alpha A, rIFN-alpha D, and rIFN-beta) compared to an 8.4 +/- 4.8-fold increase with rIFN-gamma (100 pM, 100 U/ml) in the same experiments. Unexpectedly, low concentrations of IFN-alpha or -beta (3 fM-300 pM) blocked induction of H2O2-releasing capacity by rIFN-gamma (10 pM), with a 50% inhibitory dose of approximately 80 fM. However, IFN-alpha or -beta (3 fM-300 pM) could not inhibit the effect of higher concentrations of rIFN-gamma (1 nM). In contrast to results with monocytes or young macrophages, Scatchard plots of binding of 125I-rIFN-gamma to mature macrophages (day 8 of culture) indicated two classes of binding sites: approximately 2,000 high-affinity sites (Kd approximately 0.43 nM) and approximately 23,000 low-affinity sites (Kd approximately 6.4 nM) per cell. Binding of 125I-rIFN-gamma to the high- but not the low-affinity sites was blocked by simultaneously added IFN-alpha or -beta, with a 50% inhibitory dose of approximately 2 U/0.25 ml (approximately 2 pM), or reversed by subsequently added IFN-alpha or -beta. Thus, differentiation of human mononuclear phagocytes in vitro is accompanied by the emergence of (a) an agonist response to submicromolar concentrations of IFN-alpha or -beta, (b) antagonism of the effect of picomolar IFN-gamma by femtomolar IFN-alpha or -beta, (c) two classes of IFN-gamma-Rs, and (d) nonstimulatory binding of IFN-alpha or -beta to the high- but not the low-affinity IFN-gamma-Rs, with higher affinity than rIFN-gamma itself. We speculate that traces of IFN-alpha or -beta derived from stromal cells, parenchymal cells, or resident macrophages may dampen the activation of mature tissue macrophages by the small amounts of IFN-gamma that diffuse from inflammatory sites into normal tissues. Such a mechanism could constrain the potentially destructive phenomenon of macrophage activation to areas where monocytes have recently immigrated and/or the concentration of IFNs is high.

Adult↗
PubMed1989

Interferon and interferon inhibitor levels in patients infected with varicella-zoster virus, acquired immunodeficiency syndrome, acquired immunodeficiency syndrome-related complex, or Kaposi's sarcoma, and in normal individuals.

PURPOSE: Previous studies had reported that normal individuals do not have measurable levels of interferons in their circulation, whereas high levels have been found in patients in the early stages of AIDS (acquired immunodeficiency syndrome) and in those with AIDS-related complex (ARC). This study was undertaken to compare levels of interferon and interferon inhibitors in plasma samples from patients with AIDS, ARC, Kaposi's sarcoma, or varicella-zoster virus infection, and from control subjects. PATIENTS AND METHODS: A total of 206 persons were tested for the presence of interferon and interferon inhibitors in their plasma: 76 with ARC or AIDS, with or without Kaposi's sarcoma or lymphoma; 32 with varicella-zoster infection; 12 with AIDS-unrelated Kaposi's sarcoma; and 86 normal control subjects at high or low risk of AIDS with or without positive antibody levels to human immunodeficiency virus-1. Total interferon activity was measured by bioassay and the subtypes were not separated. RESULTS: Of 86 normal control subjects, 85 had no significant levels of interferon or interferon inhibitor. One disease-free homosexual exhibited measurable interferon levels. Patients acutely infected with varicella-zoster virus showed no measurable interferon or inhibitor levels except if they were in a high-risk group for AIDS. Seventy-six patients with ARC or AIDS exhibited measurable circulating interferon levels. Only patients with AIDS had interferon inhibitors in their circulation. Of 12 patients with Kaposi's sarcoma unrelated to AIDS, none had measurable interferon inhibitor levels, but some exhibited measurable interferon levels. CONCLUSION: It is suggested that levels of interferon inhibitor should be considered when interferon is used therapeutically in viral or neoplastic diseases.

AIDS-Related Complex↗
PubMed1981

Analysis of interferon mRNA in human fibroblast cells induced to produce interferon.

The levels of interferon mRNA as a function of interferon induction by poly(rI) . poly(rC) in human fibroblast cells were determined by RNA hybridization using a cloned beta interferon cDNA and by translation in Xenopus oocytes. Whereas previous studies analyzed mixtures of interferons, the availability of the cloned beta interferon cDNA and the antiserum to purified beta interferon enabled us to focus on the expression of only one class (beta) of interferon genes. The induction of interferon synthesis depends primarily on the accumulation of interferon beta mRNA in the cells, and the interferon beta mRNA rapidly disappears several hours after its appearance in the cytoplasm. No detectable interferon beta mRNA sequences are present in uninduced cells. The degradation of interferon beta mRNA in the induced cells requires ongoing protein synthesis; accumulation of interferon beta mRNA was observed in the continuous presence of cycloheximide. The interferon beta mRNA detected at the early stages of induction is 1100 nucleotides long and its size progressively decreases with time. By both the hybridization and the translational assay in Xenopus oocytes, only one size of interferon beta mRNA and one species of beta interferon could be identified.

Cells, Cultured↗
PubMed2004

In psoriasis lesional skin the type I interferon signaling pathway is activated, whereas interferon-alpha sensitivity is unaltered.

The epidermal phenotype as observed in psoriatic skin results from inflammation and abnormal proliferation and terminal differentiation of keratinocytes. Mice deficient for interferon regulatory factor-2, a repressor of interferon signaling, display psoriasis-like skin inflammation. The development of this phenotype is strictly dependent on type I interferon (interferon-alpha/beta) signaling. The aim of this study was to assess the involvement of interferon-alpha/beta in the pathogenesis of human psoriasis. In psoriatic skin, we measured an increased expression of components that play central and crucial roles in interferon-alpha/beta signal transduction. Culturing keratinocytes or healthy skin biopsies with recombinant interferon-alpha stimulated this signaling pathway; however, this did not induce the expression of markers that are generally used to define the psoriasis phenotype. Furthermore, skin from psoriasis patients responded identically to interferon-alpha stimulation, demonstrating that psoriatic skin does not have an aberrant sensitivity to type I interferon. We conclude that in psoriatic lesional skin the type I interferon signaling pathway is activated, despite an unaltered interferon-alpha sensitivity. Our data furthermore show that type I interferon, in contrast to interferon-gamma, does not act directly on keratinocytes to induce a psoriatic phenotype. Thus, if the observed activated type I interferon signaling is indeed functionally involved in the pathogenesis of psoriasis, its contribution might be indirect, putatively involving other cell types besides keratinocytes.

Adolescent↗
PubMed1997

Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group.

BACKGROUND: Treatment with interferon prolongs survival in chronic myelogenous leukemia. We conducted a clinical trial to assess the efficacy of treatment with a combination of interferon and cytarabine. METHODS: Previously untreated patients with chronic myelogenous leukemia were randomly assigned to receive either hydroxyurea (50 mg per kilogram of body weight per day) and interferon alfa-2b (5 million units per square meter of body-surface area per day), or hydroxyurea and interferon in the same dosages plus monthly courses of cytarabine (20 mg per square meter per day, for 10 days). The end points were overall survival, complete hematologic remission at 6 months, and major cytogenetic response (less than 35 percent Philadelphia chromosome-positive cells in the bone marrow) at 12 months. RESULTS: The trial was stopped when a sequential analysis showed a benefit of interferon and cytarabine. A significant improvement in survival was observed in the interferon-cytarabine group (360 patients) as compared with the interferon group (361 patients) (P=0.02; relative risk of death, 0.64; 95 percent confidence interval, 0.44 to 0.93). After three years, the survival rate was 85.7 percent with interferon and cytarabine and 79.1 percent with interferon alone. The rate of hematologic response was higher in the interferon-cytarabine group than in the interferon group (P=0.003). Major cytogenetic responses were observed 12 months after randomization in 126 of 311 patients treated with interferon and cytarabine (41 percent) and in 75 of 314 patients treated with interferon only (24 percent, P<0.001). CONCLUSIONS: The combination of interferon and cytarabine, as compared with interferon alone, increases the rate of major cytogenetic response and prolongs survival in patients with the chronic phase of chronic myelogenous leukemia.

Adolescent↗
PubMed2003

Triple (interferon, ribavirin, amantadine) versus double (interferon, ribavirin) re-therapy for interferon relapser genotype 1b HCV chronic active hepatitis patients.

BACKGROUND: Retreatment for 6 months with the association ribavirin-interferon of HCV-related chronic active hepatitis relapser patients has high probability of failure, mostly in those with genotype 1b. We evaluated the efficacy of extending the therapy from 6 to 12 months without or with the addition of amantadine. METHODS: Forty-nine genotype 1b relapser patients were treated with 3 MU of IFN-alpha2b three times per week and ribavirin 1000-1200 mg daily (double therapy). Twenty-four patients, who did not respond after 6 months of treatment, were randomized to continue for further 6 months either with the same schedule or with also the addition of amantadine 200 mg daily (triple therapy). RESULTS: A sustained virological response was observed in 15/37 subjects (41%) treated for 12 months of double therapy. In the arm of the study evaluating amantadine, end of treatment virologic response was observed in 0/12 patients of double therapy group and in 4/12 of triple therapy (P=0.09). After 6 months of follow-up, a sustained virologic response (SVR) was observed in two patients treated with the triple therapy. CONCLUSIONS: This study confirms poor results of retreatment (even if 12 months double or triple therapy) in relapser patients with HCV hepatitis, genotype 1b. No gain was obtained in prolonging from 6 to 12 months the standard double therapy, while triple therapy with amantadine as an additional regimen for this difficult subgroup of patients showed some cases of SVRs: amantadine addition deserves to be evaluated in larger trials.

Journal Article↗