Reinforced interferon alpha-2b and ribavirin is more effective than standard combination therapy in the retreatment of chronic hepatitis C previously nonresponsive to interferon: a randomized trial.

Interferon-alpha (IFN) monotherapy results in sustained virological clearance in a minority of patients with chronic hepatitis C. The aim of this study was to assess the effect of a reinforced regimen combining ribavirin and high-dose IFN for 48 weeks compared with a nonreinforced regimen combining a standard IFN regimen and ribavirin for 24 weeks in nonresponders with chronic hepatitis C. A total of 231 patients with chronic hepatitis C and previous nonresponse to IFN monotherapy were randomized. The reinforced group (n = 114) received IFN-2b 6 million units (MU) thrice weekly (TIW) and ribavirin for 48 weeks, and the nonreinforced group (n = 117) received IFN-2b 3 MU TIW and ribavirin for 24 weeks. The main outcome measure was a sustained virological response, defined as negative serum hepatitis C virus (HCV)-RNA 24 weeks following the end of treatment. This endpoint was determined in 98 patients of the reinforced group and 105 patients of the nonreinforced group. At the end of follow-up, a sustained virological response was observed in 29 of the 98 patients (29.6%) in the reinforced group vs 16 of the 105 patients (15.2%) in the nonreinforced group (P = 0.014). In multivariate analysis, factors associated with a sustained virological response were treated with a reinforced regimen [odds ratio (OR) 2.9; P = 0.06] and genotype 2 or 3 (OR 8.8; P < 0.0002). A total of 160 patients had paired biopsies before and after treatment. Histological activity improvement was observed in 32 of 80 patients (40%) and fibrosis worsening in 26 of 80 patients (33%) in the reinforced group vs 13 of 80 (16%) and 19 of 80 (24%) in the nonreinforced group (P = 0.30 and 0.20, respectively). Hence in nonresponders, a high-dose 48-week regimen of IFN and ribavirin combination was more effective than a regimen with interferon at lower dose and ribavirin for 24 weeks only.

A short induction regimen of interferon-alpha is not effective for treatment of relapse in chronic hepatitis C: a randomized trial. For the multicentre GER-CYT-01 group.

The aim of this work was to assess the effect of a high-dose (10 million units, MU) short-duration (14 weeks) interferon-alpha2b (IFN-alpha2b) regimen in relapsers compared with the standard IFN regimen of 3 MU three times weekly (t.i.w.) for 6 months. Fifty-eight non-cirrhotic patients (who had relapsed after previous treatment with IFN) with chronic hepatitis were randomized: 29 to the high-dose, short-duration regimen and 29 to the standard regimen. By the end of IFN therapy, in the high-dose, short-duration group alanine aminotransferase (ALT) normalization was observed in 23 (79%) of 29 patients, and undetectable hepatitis C virus (HCV) RNA in eight (28%) vs 25 (86%) and 11 (38%) of the 29 patients in the standard group, respectively (P = NS). At the end of the 72-week follow-up, in the high-dose, short-duration group a sustained ALT normalization was observed in two (7%) patients, and undetectable HCV RNA in 0 (0%) vs five (17%) and four (14%) patients in the standard group (P = NS). There was less fibrosis improvement in the high-dose, short-duration group (two of 26 patients, 8%) than in the standard group (eight of 25 patients, 32%) (P = 0.04). Tolerance to IFN was good and similar in the two groups. In conclusion, in IFN relapsers, high-dose, short-duration treatment with IFN-alpha has no advantage when compared to a 6-month treatment with 3 MU IFN t.i.w.

Prognostic value of the soluble interleukin-2 receptor in chronic hepatitis C treated with interferon-alfa. Multicenter GER-CYT 04 Group.

BACKGROUND/AIMS: High serum levels of the soluble interleukin 2 receptor (sIL-2R) have been reported in patients with chronic hepatitis C. The aims of this study were to determine the evolution of sIL-2R considered as an indicator of activation of T cells in patients with hepatitis C virus (HCV) treated with IFN-alpha and to correlate sIL-2R serum levels with parameters reflecting ongoing liver disease and with outcome of interferon treatment. METHODS: In a case-control study, we studied patients enrolled in a multicenter randomized clinical trial which had demonstrated the benefit of a reinforced regimen of interferon alpha. Each of the 26 sustained virological responders (SVR) was paired for treatment regimen with two non-responders (NR). RESULTS: Prior to treatment, higher levels of sIL-2R were found in the sera of 78 patients compared with healthy controls (3791+/-210 pg/ml versus 956+/-88 pg/ml (p<0.001)). In the 78 patients after 4 weeks of treatment, the levels of sIL-2R were higher than pretreatment levels (4308+/-206 pg/ml (p<0.01)). In the NR, levels of sIL-2R increased significantly after 4 weeks of treatment compared with pretreatment levels (p<0.01), and levels of sIL-2R at week 72 were not significantly different from those at pretreatment. Conversely, in the SVR, levels of sIL-2R at week 4 did not significantly increase compared to pretreatment values, and thereafter gradually decreased. At week 72, levels of sIL-2R were significantly lower than before treatment (p<0.001). The difference between levels of sIL-2R at week 4 and before initiation of treatment (delta s IL-2R) was smaller in the SVR than in the NR (142+/-219 pg/ml versus 704+/-107 pg/ml (p<0.02). The disappearance of HCV RNA from the serum at week 4 showed a sensitivity of 92% (95% confidence interval 86-98) and a specificity of 60% (95% confidence interval 49-71), delta sIL-2R had a sensitivity of 42% (95% confidence interval 31-53) and a specificity of 81% (95% confidence interval 79-90) for the prediction of a sustained virological response 6 months after stopping treatment. The disappearance of HCV RNA from serum at week 4 and delta sIL-2R were independent and early predictive factors for a sustained virological response 6 months after stopping treatment. CONCLUSIONS: At week 4, delta sIL-2R may be a more specific parameter than the disappearance of HCV RNA for assessing total, and hence more sustained, elimination of HCV infection 6 months after stopping treatment.

A study of the relative bioavailability of cysteamine hydrochloride, cysteamine bitartrate and phosphocysteamine in healthy adult male volunteers.

AIMS: Cysteamine, the only drug available for the treatment of cystinosis in paediatric patients, is available as the hydrochloride, the bitartrate and as sodium phosphocysteamine salts. It has been suggested that cysteamine bitartrate and phosphocysteamine are better tolerated and may have a better bioavailability than cysteamine hydrochloride. This has, however, never been demonstrated. METHODS: We compared the pharmacokinetics and tolerance of these three formulations of cysteamine in 18 healthy adult male volunteers in a double-blind, latin-square, three-period, single oral dose cross-over relative bioavailability study. RESULTS: No statistical difference was found between relative bioavailabilities, AUC (0, infinity) (geometric mean and s.d. in micromol l(-1) h: 169+/-51, 158+/-46, 173+/-49 with cysteamine hydrochloride, phosphocysteamine and cysteamine bitartrate respectively), Cmax (geometric mean and s.d. in micromol l(-1); 66+/-25.5, 59+/-12, 63+/-20) and tmax (median and range in h: 0.88 (0.25-2), 1.25 (0.25-2), 0.88 (0.25-2)) with each of the three forms of cysteamine tested. Bioequivalence statistics (90% confidence intervals) showed non equivalence of Cmax of cysteamine base as the only non equivalence of pharmacokinetics between the three formulations: 90% CI for Cmax relative ratios to cysteamine hydrochloride were [75.6-105.81 for phosphocysteamine and [74.2-124.2] for cysteamine bitartrate. The only significant adverse event was vomiting whose frequency was inversely correlated with body weight (Spearman's r=-0.76, P<0.001). The nature of the salt tested did not influence vomiting. CONCLUSIONS: While none of the three forms of cysteamine tested has a clear advantage over the others in terms of pharmacokinetics and tolerance profile, this should now however be addressed in patients treated for cystinosis during repeat administrations.

Reinforced regimen of interferon alfa-2a reduces the incidence of cirrhosis in patients with chronic hepatitis C: a multicentre randomised trial. Multicentre GER-CYT-04 Group.

BACKGROUND/AIMS: Our aim was to assess and compare the long-term effect of interferon at standard (6 months) and reinforced dose and duration regimens in chronic hepatitis C. METHODS: A multicentre institutional trial included 244 previously untreated patients with chronic hepatitis C, without cirrhosis, who were randomly allocated to either standard (3 MU thrice a week for 24 weeks; n=120) or reinforced (6 MU daily for 12 days, 6 MU thrice a week for 22 weeks, 3 MU thrice a week for 24 weeks; n=124) regimens. The main endpoint was sustained ALT response at 72 weeks (18 months); secondary end-points were virological (branched DNA and PCR) and histological responses (incidence of cirrhosis) at month 18. RESULTS: Sustained ALT response was observed in five patients (4%, 95% confidence interval 0-8%) in the standard group and in 21 patients (18%, 95% confidence interval 11-25%), from the reinforced group (p=0.002), in agreement with virological response in 21 (81%) patients. Cirrhosis at month 18 was observed in ten (10%) patients in the standard group and one (1%) in the reinforced group (p=0.004). CONCLUSIONS: The standard regimen of interferon, in chronic hepatitis C, confers a minimal sustained response rate at 18 months and may not prevent the occurrence of cirrhosis. Reinforced regimens allow sustained response to be reached in a limited number of patients and reduce the risk of cirrhosis during 18 months of follow-up.

Determination of total cysteamine in human serum by a high-performance liquid chromatography with fluorescence detection.

A convenient, reliable and rapid method for determination of total cysteamine in human plasma by high-performance liquid chromatography with fluorescence detection is reported. This assay involves reduction of samples with dithiothreitol, derivatization of total cysteamine by addition of monobromobimane and protein precipitation by perchloric acid. The calibration curve was linear in the range 2-150 nmol ml-1 and the detection limit was 0.5 nmol ml-1. This method was successfully applied for a pharmacokinetic study of three cysteamine derivatives in healthy volunteers without any interference from coexisting substances.

Immunomodulatory activity of low doses of interferon alpha,beta in mice.

We evaluated the immunomodulatory effects of mouse interferon (IFN) alpha, beta on the specific humoral response of mice (OF1) to sheep erythrocytes and on cell-mediated immunity by studying the cytotoxic activity of allospecific T-cells (CTL) and natural killer (NK) cells. Four injections of 2 IU of IFN before administration of the antigen did not have an effect on the humoral response, whereas 4 injections of 2 x 10(-10) IU of IFN caused a significant increase in the number of antibody-secreting cells. When C57BL/6 mice were treated with 5 injections of 2 IU or 2 x 10(-10) IU of IFN before the second immunization with allogeneic cells, the CTL activity was not modified; but when the mice were also treated with 2 x 10(-10) IU 3 times after immunization, this activity was strongly stimulated. IFN caused a decrease in the activity of CTL from NZB at both doses. The cytotoxic response of NK cells was stimulated by 5 injections of 2 IU of IFN in both strains of mice. The results of our study suggest that very low doses of IFN alpha,beta have immunopharmacologic activity.