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Thymosin-a + Interferon for HCV Not effective in Study
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"Thymosin-a 1 plus interferon-a for naive patients with chronic hepatitis C: results of a randomized controlled pilot trial"
Journal of Viral Hepatitis
Volume 11 Issue 1 - January 2004
P. Andreone 1 , A. Gramenzi 1 , C. Cursaro 1 , F. Felline 1 , E. Loggi 1 , A. D'Errico 2 , M. Spinosa 3 , S. Lorenzini 1 , M. Biselli 1 and M. Bernardi 1
Summary. In this pilot study, we evaluated the efficacy of interferon-a (IFN) plus Thymosin-a 1 (TA1) to that of IFN alone in naive patients with chronic hepatitis C. Twenty-two patients were randomized to receive interferon-a 2b (3 million units three times a week) plus thymosin-a l (900 ug/m2 body surface area) and 19 received interferon-a 2b alone at the same dose. Patients were treated for 6 months and followed up for another 6 months. Biochemical (alanine aminotransferase values) and virological (hepatitis C virus-RNA) responses to treatment were determined. Combination treatment showed significantly higher efficacy than monotherapy in achieving virological end-of-treatment response (P = 0.03). At 6-month follow up, the sustained biochemical and virological response was not different between the two groups. Our results indicate that the immune modulator TA1 may enhance the end-of-treatment response in naive patients with chronic hepatitis C. Higher doses and/ore more prolonged courses as well as the association with new interferon formulation such as pegylated interferons could improve the sustained response rates to this treatment.
Virological response
At the end of the treatment period, nine (41%) of the 22 patients in the TA1 plus IFN group and two (10.5%) of the 19 patients in the IFN group were negative for serum HCV-RNA. This difference was statistically significant (P = 0.03). However, at the end of the follow-up period only two of the TA1 plus IFN patients (9%) and three of the IFN patients (16%) tested negative for HCV-RNA.
ALT response
At the end of treatment 14 (64%) of the 22 patients in the TA1 plus IFN group and seven (37%) of the 19 patients in the IFN group were ALT responders. A breakthrough was observed in four patients (18%) in the combined therapy group and in three (16%) in the IFN group. After treatment discontinuation, a relapse in serum ALT levels occurred in seven of the 14 responders from the TA1 plus IFN group and in three of the seven responders from the IFN group, so that a sustained response was observed in seven of 22 in the TA1 plus IFN group (32%) and four of 19 patients in the IFN group (21%). These differences were not statistically significant.
Histological response
The histological response was determined in 36 patients, 18 from each of the treatment groups. The remaining cases refused the control biopsy. A histological improvement was observed in six of 18 (33%) of the TA1 plus IFN group compared with three of 18 (17%) of the IFN group. No significant differences were observed in HAI between pre- and post-treatment biopsies in either group. However, in patients treated with the combination TA1 plus IFN, a significant improvement of the fibrosis score was observed (1.9 ± 1 vs 1.4 ± 1; P = 0.0431).
Safety
Treatment was well tolerated. No patients stopped the therapy before completing the treatment period because of side effects. Only four patients receiving TA1 complained of pain at the injection site.
Author Discussion
In this study we failed to demonstrate a therapeutic improvement of the combination TA1 plus IFN over IFN alone. However, we found that the addition of TA1 to IFN significantly increased the proportion of end of treatment virological response (41%vs 10.5%; P = 0.03). Furthermore, the number of patients showing an end of treatment biochemical response was also greater with the combination treatment (64%) than with IFN alone (37%), although this difference did not reach statistical significance. Our results are consonant with those of previous studies which also showed that the combination of TA1 plus standard IFN treatment is more effective than IFN alone only in terms of biochemical and virological response at the completion of treatment period. In our study, a greater number of patients treated with the combination therapy had improved histology (33% compared with 17% with IFN alone), but the difference between the two treatment groups did not reach statistical significance. However, a significant improvement of the fibrosis score after treatment was only observed in patients treated with the combination of TA1 plus IFN. Histological improvement suggests evidence of biological activity, as previously reported by Sherman et al. in a randomized, placebo-controlled double-blind trial. These results are disappointing if compared with those obtained with the combination IFN plus Ribavirin that currently represents the gold standard for treatment of chronic hepatitis C. However, when we planned this study IFN monotherapy was the standard treatment and, even if the advent of Ribavirin has provided a significant therapeutic advance we believe that evaluation of TA1 in combination with IFN still retains a rationale in terms of both mechanism of action and safety profile.
Immune mechanisms are believed to play a role in both HCV replication and HCV mediated hepatocellular damage. In vitro and in vivo studies have demonstrated that in HCV infection early development of vigorous Th1 cytokine responses not only facilitates the clearance of the virus but also delays disease progression. Consequently, strong Th2 polarization decreases clearance rates and is associated with accelerated disease progression.
Thymosin-a 1 has been shown to enhance the differentiation of stem cells to CD4 cells, to augment T-cell function as well as to stimulate the production of Th1 cytokines. Recently we demonstrated that incubation of peripheral blood mononuclear cells of patients with chronic HCV infection with TA1 alone resulted in a significant increase in Th1 cytokine production. In addition, TA1 induced a decrease in the Th2 cytokines interleukin(IL)-4 and IL-10. By contrast, incubation with IFN alone resulted in a smaller increase in Th1 cytokines (compared with TA1) and also an undesirable increase in Th2 cytokine production. Most importantly, the combination of TA1 and IFN resulted in an even greater Th1 increase than either drug alone, and reversed the IFN-based increase in Th2 production. TA1 treatment also resulted in an increase in 2', 5'-oligoadenylate synthetase, a protein with direct antiviral activity.
Our study does not prove that combination TA1 at the dose of 900 g/m2 twice weekly plus 3 MU of IFN three times a week for 6 months is superior to IFN monotherapy. Our results might be improved by utilizing different treatment schedules. However, the apparent nonlinear dose-response relationship of TA1 makes it difficult to choose an optimal dosing schedule. A longer period of treatment has been shown to have a better response: the sustained response rates after 12 months of combination treatment were superior to those obtained in this study with only 6 months of treatment. In addition, a higher dose of IFN might enhance the response rate. However, when this study was planned, we decided to utilize the IFN schedule suggested by the guidelines available at the moment. On the basis of the recent knowledge on viral kinetics, it could be interesting to evaluate TA1 in association with a loading or daily IFN dose, as well as in combination with pegylated interferons.
An important advantage of the combination of TA1 plus IFN is treatment tolerability. In no case was treatment prematurely discontinued or modified because of adverse events. Safety profiles are important as the combination IFN plus Ribavirin leads to treatment discontinuation in 20% of patients.
In conclusion, our data demonstrate the potential utility of immunomodulators such as TA1 in combination with IFN for chronic hepatitis C. The optimal treatment regimen should be determined in future trials.
INTRODUCTION
Current treatment of chronic hepatitis C is centered on the use of interferon- (IFN) in combination with Ribavirin. New interferon preparation such as pegylated-interferon when continued with Ribavirin have recently shown better treatment response that the traditional interferon plus Ribavirin regimen. However, even with the use of pegylated interferon, the sustained virological response rate is only about 50%. Moreover, the combination of both traditional or pegylated interferon with Ribavirin is associated with additional side effects, so that treatment has to be discontinued in about 20% of patients. Dissatisfaction with the efficacy and tolerability of the currently available treatments has led to the search for alternative therapies.
In hepatitis C virus (HCV) infection, the immune response to the virus appears to be critical both in determining viral clearance or persistence and in contributing to liver injury. Patients who become chronic carriers of HCV have a lower virus-specific type 1 helper T (Th1) cell reactivity than those who succeed in clearing the infection. Drugs that stimulate Th1 cells and their associated cytokines might therefore be useful for the treatment of chronic hepatitis C.
Thymosin-a 1 (TA1) is a 28 amino acid peptide, which selectively stimulates the Th1 immune response. Clinically, TA1 has previously demonstrated encouraging results against viral infection, including treatment of chronic hepatitis B and HIV infection. In a double-blind placebo-controlled pilot trial, TA1 alone showed no efficacy against HCV chronic infection. By contrast, encouraging results have been obtained with TA1 in combination treatment with IFN.
The aim of this study was to evaluate the efficacy and safety of the combination treatment of IFN plus TA1 for the treatment of naive patients with chronic hepatitis C.
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