IFN-alpha Non-responders Research Articles

Pilot study of interferon-alpha high-dose induction therapy in combination with ribavirin plus amantadine for nonresponder patients with chronic hepatitis C.

Ribavirin plus interferon-alpha (IFN alpha) combination has led to a marked advance in the treatment of IFN alpha-naive or relapser patients with chronic hepatitis C but was shown to be only marginally effective in IFN alpha-nonresponders. We therefore conducted a pilot study to see whether an intensified treatment protocol might be more effective in inducing a virological response in patients who had not responded virologically to previous IFN alpha monotherapy. 14 nonresponder patients with histologically proven chronic hepatitis C were included in the study. Patients received 9 MU IFN alpha-2a daily for one week followed by 9 MU IFN alpha every second day for further 5 weeks. With the beginning of the seventh week, patients were treated with 6 MU IFN alpha thrice in week (tiw) for a period of 6 weeks (until week 12). IFN alpha was continued up to 48 weeks at a dose of 3 MU IFN alpha tiw. Ribavirin (1000-1200 mg/day) and amantadine sulphate (200 mg/day) was given orally for 48 weeks. One patient discontinued therapy after first IFN alpha injection and one other patient after 12 weeks of therapy because of side effects. The remaining 12 patients completed treatment according to the protocol. An initial virological response at week 24 was achieved in 2 of the 14 patients (14%) and both patients remained HCV RNA negative at the end of treatment. However, both patients relapsed 4 weeks after completion of therapy, and therefore none of the patients achieved a virological sustained response. Viral dynamics studies showed a marked decline in hepatitis C viremia during the first 6 weeks of high-dose IFN alpha. After IFN alpha dose reduction, however, viremia stabilized or increased in most patients. These data indicate, that even triple therapy with high-dose IFN alpha plus ribavirin and amantadine fails to improve significantly the response rates in IFN alpha-nonresponders.

Antiviral effect of human recombinant interleukin-12 in patients infected with hepatitis C virus

The heterogeneity of hepatitis C virus (HCV) is due to the continuous and high replication rate, the low fidelity of the RNA-dependent RNA polymerase, and the immune surveillance of the host. Interleukin-12 (IL-12) plays a central role in mounting an effective cellular immune response directed towards elimination of intracellular pathogens. The effect of IL-12 on hepatitis C viremia and the HCV quasispecies population is unknown. In this study, 12 patients (9 males, 3 females; mean age: 44 +/- 11 years), all virological non-responders to previous IFN-alpha treatment, received recombinant human IL-12 s.c. once weekly for 10 weeks stratified to three dose schedules (0.03 microg/kg, 0.1 microg/kg, and 0.5 microg/kg body weight, respectively). Fourteen IFN-alpha non-responders and 14 untreated patients served as age- and sex-matched controls. Serum HCV RNA concentrations and HCV quasispecies distribution were measured serially by quantitative reverse transcription - polymerase chain reaction and single strand conformation polymorphism analysis of the hypervariable region of the second envelope gene, respectively. Serum ALT and median HCV RNA levels before treatment (52.7 +/- 21.7 U/L; 2.6 x 10(6) copies/mL) showed no significant changes during IL-12 treatment (57.3 +/- 58.8 U/L and 3.2 x 10(6) copies/mL, 50.3 +/- 46.2 U/L and 3.1 x 10(6) copies/mL, and 46.8 +/- 35.3 U/L and 3.9 x 10(6) copies/mL at weeks 1, 4, and 10, respectively). Similar results were observed in 14 IFN-alpha non-responders and 14 untreated patients. However, changes in HCV quasispecies occurred in 10/12 (83%) and 9/14 (64%) patients treated with interleukin-12 and interferon-alpha, respectively, but only in 3/14 (21%) untreated subjects (P < 0.003 and P < 0.03). These results imply that interleukin-12 exerts only limited antiviral activity against certain HCV quasispecies in vivo.

IFN-ALPHA THERAPY OF RENAL-CELL CARCINOMA - DEFECT OF LYMPHOCYTE SENSITIVITY TO MITOGENIC AND ACTIVATING CYTOKINE SIGNALS IN PATIENTS NOT-RESPONDING TO THERAPY

The present prospective study was designed to assess whether the renal cell carcinoma (RCC) patients treated with recombinant interferon alpha (IFN alpha), whose tumours respond (responders) and do not respond (non-responders) to IFN alpha therapy, differ with regard to in vitro sensitivity of peripheral blood lymphocytes (PBL) to interleukin 2 (IL-2), IFN alpha, and IFN gamma signals prior to therapy. Twenty-one patients with advanced RCC after nephrectomy, 15 responders and 6 non-responders, were entered into a protocol. The protocol involved isolation and freezing of PBL samples followed by IFN alpha treatment of patients, assessment of proliferative and activating PBL responses, and evaluation of the therapeutic results. Freezing of PBL samples allowed us to compare the in vitro reactivity of PBL from individual RCC patients, repeatedly and under standard conditions. Substantial differences in proliferative responses to the mitogenic IL-2 signal of PBL derived from IFN alpha responders and nonresponders were found. Whereas the IL-2-induced proliferative responses of PBL from normal blood donors and IFN alpha responders were comparable, the proliferative responses of PBL from IFN alpha non-responders were significantly decreased, suggesting an immune dysfunction in non-responders. Cultivation of PBL from RCC patients in medium supplemented with IFN alpha increased the lytic activity of PBL from IFN alpha responders directed against RCC targets; no such increase could be observed with non-RCC targets, with PBL from IFN alpha non-responders, or with PBL from normal blood donors. Detection of phytohaemagglutinin (PHA)-stimulated IFN gamma secretion by PBL at the single cell level using enzyme-linked immunospot (ELISpot) assay revealed that the ability to produce IFN gamma was substantially decreased in IFN gamma non-reponders, as compared to IFN alpha responders and to normal blood donors.