thymosin and Hepatitis-C--Chronic

Thymosin α 1 (Tα1) is a peptidic biological response modifier, which plays a significant role in activating and regulating various cells of the immune system. For the above-mentioned activities it is expected to exert a clinical benefit in the treatment of diseases where the immune system is altered.. Several clinical trials have been carried out with Tα1 for treatment or prevention of many different infectious diseases such as hepatitis B and C, sepsis and Aspergillosis in bone marrow-transplanted patients. Data available on the use of Tα1 in infectious disease as well as a vaccine enhancer will be reviewed to possibly generate new working hypothesis.. Tα1 has been widely used in thousands of patients. Nevertheless, there are some issues that have not yet been properly addressed (i.e., dose, schedule, combination treatments, end-points to be evaluated in clinical trials). In the most recent clinical trials Tα1 has been used at higher doses than those commonly used in the past showing a direct proportionality between the dose and the effect. The safety profile of Tα1 is excellent and it is virtually devoid of toxicity.

Topics: Amino Acid Sequence; Communicable Diseases; Hepatitis B, Chronic; Hepatitis C, Chronic; History, 20th Century; History, 21st Century; Humans; Molecular Sequence Data; Sepsis; Thymalfasin; Thymosin; Treatment Outcome

Thymalfasin exhibited an immunomodulatory and a direct antiviral mechanism of action. The low rate of sustained response of chronic hepatitis with current therapies, underscores the need for new therapeutic options. It has been suggested that thymalfasin may have efficacy in the treatment of chronic hepatitis B and C. Pilots studies in patients with chronic hepatitis B treated with thymalfasin in combination with interferon or nucleoside analogue, showed a 70% complete sustained response rate. Studies in chronic hepatitis C patients, would indicate that thymalfasin in combination with standard or pegylated interferon with ribavirin may improve response rate in hepatitis C virus (HCV) naïve and nonresponder patients. However, a large phase-III randomized study conducted in Europe in HCV patients nonresponder to Peg-interferon with ribavirin, demonstrated that thymalfasin did not improve the rate of sustained virologic responses, but, in patients who completed therapy, thymalfasin significantly diminished the relapse rate. In conclusion, thymalfasin, in combination with the standard of care, may be helpful as an adjuvant in the treatment of patients with chronic hepatitis B and C.

Topics: Adjuvants, Immunologic; Antiviral Agents; Europe; Hepacivirus; Hepatitis B; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Interferons; Polyethylene Glycols; Polymerase Chain Reaction; Ribavirin; Thymalfasin; Thymosin; Viral Vaccines

Thymosin alpha(1) (Talpha(1)), a synthetic version of a thymic-derived biological response modifier was the first of the thymosins in clinical use. Talpha(1) is approved in over 35 countries for the treatment of hepatitis B and C, and as an immune stimulant and adjuvant. Talpha(1) is also in late-stage clinical testing in the United States and Europe for hepatitis C and stage IV melanoma.. Novel applications and other recently completed trials point to much broader clinical applications of Talpha(1) in the treatment of life-threatening and chronic diseases, and are the subject of this review.. The most recent reports of clinical trials with Talpha(1) are pointing to important, hitherto unrecognized, applications in a number of diseases and disorders, including septic shock, acute respiratory distress syndrome, peritonitis, acute cytomegalovirus infection, TB, severe acute respiratory syndrome, and lung infections in critically ill patients. It is also emerging as a promising chemoprotection agent in patients undergoing chemotherapy.

Topics: Animals; Hepatitis B; Hepatitis C, Chronic; Humans; Immune System Diseases; Point-of-Care Systems; Technology, Pharmaceutical; Thymalfasin; Thymosin

Approximately 50% of treatment-naive hepatitis C patients fail to achieve a sustained virologic response with standard peginterferon and ribavirin therapy. Patients who are infected with genotype 1 have high viral loads and are nonresponders to previous therapy, and are even more difficult to treat, underscoring the need for new therapeutic options. Thymalfasin (thymosin-alpha1), in combination with peginterferon-alpha2a, has demonstrated efficacy among difficult-to-treat patients with hepatitis C. The addition of ribavirin to thymalfasin and peginterferon-alpha2a has also exhibited promising results among patients who have genotype 1 hepatitis C, high viral loads and are nonresponders to previous therapy.

Topics: Adjuvants, Immunologic; Amino Acid Sequence; Animals; Antiviral Agents; Hepacivirus; Hepatitis C, Chronic; Humans; Molecular Sequence Data; Thymalfasin; Thymosin

Topics: Adjuvants, Immunologic; Amantadine; Animals; Antiviral Agents; Cysteine Endopeptidases; DNA-Directed RNA Polymerases; Drug Therapy, Combination; Enzyme Inhibitors; Hepacivirus; Hepatitis C, Chronic; Humans; Immunization, Passive; IMP Dehydrogenase; Interferons; Nucleosides; Oligonucleotides, Antisense; RNA Helicases; Thymalfasin; Thymosin; Viral Hepatitis Vaccines; Viral Nonstructural Proteins

Despite improvements in the treatment of chronic hepatitis C virus (HCV) infection, nearly half of all patients do not respond to initial therapy. Retreatment of these patients with pegylated interferon and ribavirin has been successful in only a limited percentage of cases. Factors associated with sustained virologic response (SVR) following retreatment include prior treatment with interferon monotherapy, HCV genotype 2 or 3, a low serum HCV RNA level, and the absence of cirrhosis. Fewer than 6% of nonresponders who were previously treated with interferon and ribavirin and who have cirrhosis, genotype 1, and a high viral load achieve SVR following retreatment with pegylated interferon and ribavirin. No therapy has been shown to yield SVR in patients who do not respond to pegylated interferon and ribavirin. Long-term maintenance therapy with pegylated interferon is currently being evaluated in nonresponders with advanced fibrosis and cirrhosis. Its use should be considered investigational at this time.

Topics: Adjuvants, Immunologic; Alcoholism; Amantadine; Antiviral Agents; Black or African American; Clinical Trials as Topic; Counseling; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Infusions, Intravenous; Injections, Subcutaneous; Interferons; Liver Cirrhosis; Meta-Analysis as Topic; Oligonucleotides, Antisense; Patient Compliance; Ribavirin; RNA, Viral; Thymalfasin; Thymosin; Time Factors; White People

Treatment of chronic hepatitis B and C viruses (HBV and HCV) is still disappointing, and both are the major causes of liver cirrhosis and hepatocarcinoma. Interferon and lamivudine are the registered drugs for chronic HBV but are scarcely effective on HBeAg-negative patients, and resistance due to virus mutation is the rule with lamivudine. Interferon and ribavirine represent the standard treatment for chronic HCV but less than the half of the infected population is eligible for this treatment and less of the half of treated patients will experience a sustained response. No single new drug to date has shown the potential to overcome this dismal picture. Combined strategies are thus the currently most available approach to improve the response rate of chronic HBV and HCV infection, with a subsequent decrease in the number of patients developing hepatocellular carcinoma (HCC). Combination of thymosin alpha 1 with interferon or antiviral agents is currently the most promising option, but nontoxic immunomodulants, such as oral MIMP, should be explored. This review focuses on the difficulties with current therapy and the rationale for use of combination therapy with thymosin alpha 1 for both HBV and HCV therapies.

Topics: Adjuvants, Immunologic; Antiviral Agents; Carcinoma, Hepatocellular; Clinical Trials as Topic; Drug Therapy, Combination; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis, Viral, Human; Humans; Liver Neoplasms; Thymalfasin; Thymosin

Antiviral therapy is generally indicated in patients who have histologic evidence of chronic hepatitis and ongoing viral replication. The aim of treatment is to normalize alanine aminotransferase levels and to eliminate virus replication. Interferon-alfa (IFN-alpha) is the most used agent. The standard treatment regimen for hepatitis B e antigen (HBeAg)-positive cirrhosis is based on IFN-alpha given alone, but the efficacy of new antivirals (famciclovir, lamivudine) with or without IFN-alpha is currently under investigation. Conversely, the therapy of antiHBe-positive cirrhosis is far from being satisfactory. The results of treatment of patients affected by type C cirrhosis with IFN-alpha alone have been disappointing, as 10-15% of treated patients shows a sustained virologic response. Although current evidence suggests that the combination of ribavirin and IFN-alpha might be more efficacious than IFN alone in increasing the response rate in patients in the advanced fibrotic stage, the efficacy of this regimen for patients with well-compensated HCV-related cirrhosis is still unknown and prospective well-designed studies are urgently needed. Patients with decompensated cirrhosis are not generally treated unless they are included in liver transplantation programs. Prospective long-term trials with large sample sizes are needed to determine if responders to IFN-alpha have a low incidence of liver-related complications and hepatocellular carcinoma.

Topics: 2-Aminopurine; Antiviral Agents; Clinical Trials as Topic; Famciclovir; Female; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Interferon-alpha; Lamivudine; Liver Cirrhosis; Male; Prognosis; Reverse Transcriptase Inhibitors; Survival Rate; Thymalfasin; Thymosin; Treatment Outcome

This study was conducted to determine whether the adding thymosin alpha-1 to standard of care for re-treatment of nonresponding hepatitis C infections can improve sustained viral response (SVR) rates. Patients (n = 552) with hepatitis C infections not responding to the combination of Peginterferon alfa-2a or 2b with ribavirin (RBV)were randomized to receive peginterferon alfa-2a 180 mg/week with RBV 800-1200 mg/daily plus either thymosin alpha-1 1.6 mg SC twice weekly (n = 275) or placebo (n = 277) for 48 weeks. Eighty-eight per cent of patients had HCV genotype 1, 6.6% type 4, 2.2% type 2 and 3.6% type 3. SVR rates in the intention to treat population were similar between thymosin alpha-1 and placebo (12.7%vs 10.5%; P = 0.407). Among patients who completed all 48 weeks of therapy, the SVR rate was significantly higher in the thymosin alpha-1 group at 41.0% (34/83) compared with 26.3% (26/99) in the placebo group (P = 0.048). No significant difference was observed between treatment groups in the incidence of adverse events. The addition of thymosin alpha-1 to the standard of care did not increase the on-treatment HCV viral response. Thymosin alpha-1 seems to play no role in the primary therapy of the disease. This study raises the hypothesis that thymosin alpha-1 may have a secondary therapeutic role as an adjuvant in the prevention of relapses in patients achieving a virologic response during therapy.

Topics: Adjuvants, Immunologic; Adult; Aged; Double-Blind Method; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thymalfasin; Thymosin; Treatment Outcome; Viral Load; Young Adult

In this pilot study, we evaluated the efficacy of interferon-alpha (IFN) plus Thymosin-alpha 1 (TA1) to that of IFN alone in naive patients with chronic hepatitis C. Twenty-two patients were randomized to receive interferon-alpha 2b (3 million units three times a week) plus thymosin-alpha l (900 microg/m2 body surface area) and 19 received interferon-alpha 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.

Topics: Adjuvants, Immunologic; Adult; Aged; Alanine Transaminase; Antiviral Agents; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C Antibodies; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Liver; Male; Middle Aged; Pilot Projects; Recombinant Proteins; RNA, Viral; Thymalfasin; Thymosin

The worldwide spread of hepatitis C virus is enormous; chronic hepatitis C virus infection is a leading cause of liver cirrhosis and hepatocellular carcinoma. While treatment options have improved substantially over the last decade, responses are still disappointing, particularly in certain difficult-to-treat groups such as patients who are immunosuppressed or have decompensated disease. Preliminary studies have indicated that combined treatment strategies may provide effective approaches for the future. The combination of thymalfasin with pegylated interferon is currently a promising option for the treatment of patients with chronic hepatitis C virus infection. An ongoing phase 3 study in the USA should provide much needed data to improve the outcome for these patients.

Topics: Adult; Antiviral Agents; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Pilot Projects; Polyethylene Glycols; Recombinant Proteins; Research Design; RNA, Viral; Thymalfasin; Thymosin; Time Factors; Treatment Failure; Treatment Outcome; United States; Viral Load; Virus Replication

Despite steady progress in antiviral treatment for patients with chronic hepatitis C virus (HCV), many patients still have detectable serum HCV RNA levels by the end of interferon-based treatment and are known as virological non-responders. Re-treatment of these patients not responding to previous therapy remains challenging. Studies of the dynamics of the HCV population show a marked decline in new cases since 1996; however, the relative proportion of non-responders is expected to increase over time and, similarly, the number of patients eligible for first-line treatment is expected to decrease. The current standard of care for treatment involves the use of pegylated interferons in combination with ribavirin. However, many difficult-to-treat groups still have low response rates. Newer combinations are being investigated to optimize chances of attaining a sustained response in these groups: one such triple therapy regimen is peginterferon alfa-2a, ribavirin and thymalfasin, which was given to 23 previously non-responder patients. Viral response was 60.8% at week 12 and 47.8% at week 24. These preliminary results encourage further evaluation of this promising combination.

Topics: Adult; Antiviral Agents; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Male; Mexico; Middle Aged; Pilot Projects; Polyethylene Glycols; Recombinant Proteins; Ribavirin; RNA, Viral; Thymalfasin; Thymosin; Time Factors; Treatment Failure; Treatment Outcome; Viral Load; Virus Replication

The worldwide spread of hepatitis C virus is enormous; chronic hepatitis C virus infection is a leading cause of liver cirrhosis and hepatocellular carcinoma. While treatment options have improved substantially over the last decade, responses are still disappointing, particularly in certain difficult-to-treat groups such as patients who are immunosuppressed or have decompensated disease. Preliminary studies have indicated that combined treatment strategies may provide effective approaches for the future. The combination of thymalfasin with pegylated interferon is currently a promising option for the treatment of patients with chronic hepatitis C virus infection. An ongoing phase 3 study in the USA should provide much needed data to improve the outcome for these patients.

Topics: Adjuvants, Immunologic; Adult; Antiviral Agents; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Pilot Projects; Polyethylene Glycols; Recombinant Proteins; Thymalfasin; Thymosin

The efficacy and safety of IFN alpha 2a and Thymosin alpha1 combination therapy in patients with chronic hepatitis C were determined. Twelve chronic hepatitis C patients (9 M, 3F), with positive HCV-RNA and histology compatible with chronic hepatitis C were included in this open, prospective study. Each patient received a combination therapy of IFN alpha 2a 3 mU s.c. TIW and Thymosin alpha1 1.6 mg s.c. twice a week for 52 weeks. Up to the present, 11 patients are still being followed-up after the end of 52 weeks' treatment. One patient dropped out after 32 weeks of follow-up due to noncompliance. Responses to treatment were evaluated by measuring serum HCV-RNA levels determined by RT-PCR. and serum amino transferases at the end of 48 weeks of treatment (end of treatment response: ETR). There were 8 naive and 4 previously IFN treated patients with partial response with a mean age of 45.0 +/- 10.1 (mean +/- SD). The mean duration from diagnosis until treatment was 25.1 +/- 22.9 months. The mean AST, ALT, and HCV-RNA levels before treatment were 79.5 +/- 36.8 U/L, 128.3 +/- 68.5 U/L, and 3.9+1.9 x 10(5) copies/ml respectively. Serum AST, ALT, and HCV-RNA levels were significantly lower at week 24 and 48 after treatment compared to before treatment (p<0.05). Of 11 cases, complete HCV-RNA clearance at week 24 was noted in 33.3 per cent, whereas, normal alanine aminotransferase values (ALT < 40 U/L) were observed in 41.7 per cent of patients. Complete HCV-RNA clearance and normal alanine aminotransferase at week 48 were seen in 45.5 per cent of the patients. At the end of week 48, complete response occurred in 4 of 5 naive patients. Minor side effects were observed during treatment with this combination therapy and these included myalgia (33.3%), mild form of alopecia (33.3%), and weight loss (8.3%). In patients with chronic hepatitis C, Interferon alpha 2a and Thymosin alpha1 combination therapy produced a good response rate especially in naive patients with acceptable safety profile. The sustained response will be determined after the completion of follow-up for another 6 months.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Hepatitis C, Chronic; Humans; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Recombinant Proteins; Severity of Illness Index; Thailand; Thymalfasin; Thymosin; Time Factors; Treatment Outcome

Hepatitis C is a major cause of liver disease leading to cirrhosis. Although interferon (IFN) is the only approved therapy, treatment is characterized by low response rates and dose-limiting side effects. We evaluated the addition of thymosin alpha1 (TA1), an immunomodulatory peptide, to the standard treatment regimen for hepatitis C to determine if combination therapy shows biological activity using outcome measures including normalization of alanine aminotransferase levels, histological activity, and viral load during treatment. We performed a randomized, double-blind, placebo-controlled trial to compare the biological activity of a combination TA1 and IFN with that seen for IFN alone in patients with chronic hepatitis C infection. One hundred nine patients were randomized for intention to treat and received 1.6 mg of TA1 subcutaneously twice weekly and 3 MU of IFN three times weekly; 3 MU of IFN three times weekly and placebo TA1; or placebo for both agents. All patients had chronic HCV infection with confirmation of chronic hepatitis on liver biopsy. Biochemical responders were followed up until alanine aminotransferase (ALT) levels became abnormal or for 26 weeks, and relapsers were retreated for 26 weeks in the same treatment arm. One hundred three patients completed treatment for 26 weeks, and six patients dropped out. The groups were similar with regard to sex, gender distribution, baseline histological activity index (HAI) score, risk factors, and viral titers. End-of-treatment biochemical response was seen in 37.1% of patients treated with combination therapy, 16.2% of patients treated with IFN alone, and 2.7% of untreated controls by intent-to-treat analysis (IFN/TA1 vs. IFN, chi2 = 4.05, P = .04). HCV RNA clearance was seen in 37.1% of IFN/TA1-treated patients and 18.9% of IFN-treated subjects. Mean HCV RNA titers were significantly lower than baseline at weeks 8, 16, and 24 after drug initiation among patients treated with IFN/TA1 but not in the other treatment arms. Histological improvement, as evidenced by a decrease in HAI of more than two points, occurred in the combination therapy arm more frequently than in comparison groups. Cumulative sustained biochemical responses were 14.2% and 8.1% in the IFN/TA1 and IFN arms, respectively, based on an intention-to-treat model. The combination of TA1 and standard IFN treatment for chronic hepatitis C showed evidence of biological activity at the completion of treatment by biochemical, histological

Topics: Adult; Antiviral Agents; Double-Blind Method; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Recombinant Proteins; RNA, Viral; Thymalfasin; Thymosin

This randomized study was performed to compare the efficacy of interferon-alpha (IFN-alpha) + thymosin alpha 1 (Talpha1) treatment to that of IFN-alpha alone in light of biochemical and virological response of naive patients with chronic hepatitis C.. Seventeen patients were treated with IFN alpha-2b (3 million units MU three times a week) + Talpha1 (1 mg twice weekly); the other 17 patients received only IFN alpha-2b at the same dose. All patients were treated for 6 months and followed up for 12 months. Biochemical (ALT values) and virological (HCV-RNA) responses to treatment were determined.. Combination therapy showed significantly higher efficacy than monotherapy in achieving biochemical and virologic end-of-treatment response (p<0.05). At 12 month follow-up, the sustained biochemical response was slightly greater in patients treated with combination therapy than in those treated with monotherapy. No significant difference in response by HCV-1b subtype was observed between the two treatment groups; however, HCV-2c subtype showed a trend to responding better to IFN-alpha+Talpha1 than to IFN-alpha alone.. These data suggest that the immune modulator Talpha1 may be additive or synergistic with IFN-alpha in normalizing end-treatment biochemical and virological responses in patients with chronic hepatitis C. Higher doses and/or more prolonged courses may improve the sustained response rates to this treatment.

Topics: Adult; Aged; Alanine Transaminase; Drug Synergism; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Thymalfasin; Thymosin; Treatment Outcome

The current standard therapy for the treatment of chronic hepatitis C virus (HCV) is the combination of peginterferon and ribavirin, although many patients fail to clear the virus and their retreatment options are still unsatisfactory. Thymosin alpha1 (Talpha1) is an immunomodulating agent that has been proposed as complementary therapy for chronic HCV, especially in the setting of difficult-to-treat patients. The aim of this study was to evaluate, in patients nonresponsive to previous Peg-based therapy, the effect of standard antiviral therapy with or without Talpha1 on peripheral lymphocyte subsets. Twenty-four patients, 12 receiving Talpha1 and 12 standard therapy, were enrolled. Peripheral subpopulations were analyzed by flow cytometry. Although the addition of Talpha1 did not seem to significantly modify the T-lymphocyte subpopulations, as comparable behaviors were observed in the CD4 and CD8 longitudinal evaluation, Talpha1 produced an earlier increase of natural killer cells. An accurate selection of HCV patients who can benefit from immunomodulation is needed.

Topics: Adult; Aged; Antiviral Agents; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Immunomodulation; Male; Middle Aged; Polyethylene Glycols; Retreatment; Ribavirin; Thymalfasin; Thymosin

Despite the use of combination therapy with pegylated interferon alpha2a (peg-IFN-alpha2a) + Ribavirin, a large proportion of patients with chronic hepatitis C (CHC) remain unresponsive to treatment. Thymosin alpha 1 (Talpha1) is an immunomodulator, which displays immunological and antiviral activities against hepatitis C virus (HCV) in preclinical clinical settings. The purpose of this study was to evaluate the efficacy and safety of a triple combination therapy with peg-IFN-alpha2a + Ribavirin + Talpha1 in CHC patients who were nonresponders to a previous course with peg-IFN-alpha2a + Ribavarin. The primary endpoint is the rate of sustained virological response (SVR). We designed a phase 3, randomized, double-blind, multicenter, prospective, placebo controlled study. Patients meeting selection criteria were randomized centrally (through IVR system) to receive either peg-IFN-alpha2a 180 mcg s.c. once weekly + Ribavirin 1000-1200 mg p.o. daily + Talpha1 1.6 mg s.c. twice weekly for 24 weeks. Patients who remained HCV-RNA positive after 24 weeks stopped treatment and were considered nonresponders. HCV-RNA negative patients continued treatment up to week 48. All patients were followed up for 24 additional weeks after the end of treatment for the evaluation of the SVR. From December 2004 to November 2006, 638 patients were screened in 52 European sites. Preliminary blinded safety analysis suggests that both regimens are well tolerated. Efficacy evaluation will be available after the opening of this blinded phase 3 trial, planned for May 2008.

Topics: Antiviral Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thymalfasin; Thymosin

The purpose of this review article is to examine previous and ongoing studies of thymalfasin in combination with peginterferon-alpha2a and peginterferon-alpha2a plus ribavirin in difficult-to-treat hepatitis C virus (HCV) patients. The following studies will be reviewed in detail: (1) Sherman and colleagues conducted a study in 109 HCV RNA positive HVC patients comparing the combination of thymalfasin + IFN versus IFN alone versus placebo. (2) Rustgi et al. evaluated the efficacy and safety of thymalfasin and peg-IFN-alpha2a in 31 genotype 1, high viral load, HCV nonresponders in a 12-week viral kinetic study. (3) Di Bisceglie, Sherman et al. performed a study of previous HCV nonresponders being retreated with either peginterferon-alpha2a plus thymalfasin or peginterferon-alpha2a plus placebo. (4) Poo and colleagues in Mexico evaluated triple combination therapy using thymalfasin, peginterferon-alpha2a, and ribavirin for the treatment of Hispanic HCV nonresponders.

Topics: Adjuvants, Immunologic; Antiviral Agents; Drug Therapy, Combination; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thymalfasin; Thymosin

SciClone Pharmaceuticals licensed the commercial and patent rights to thymosin alpha1, for geographical regions of the world excluding the United States and Europe, in the early 1990s. With this license, SciClone embarked on global drug development, and the issues encountered for thymosin alpha1 are reflective of the roller coaster of modern approval of pharmaceuticals. Most of the required toxicology studies had been completed prior to licensure, but some newer studies had to be conducted to obtain approvals in certain countries. The recent development of the "International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use" (ICH) guidelines allows for a clearer definition of the required battery of toxicology studies, although some countries still have not adopted these guidelines, and the local regulations have had to be understood and followed. Other hurdles include the complications that manufacturing requirements can differ between countries, and certain countries require local clinical experience trials in addition to SciClone's cumulative clinical data. A further obstacle was the pleiotropic nature of the mechanism of action of thymosin alpha1, with the resulting difficulty in the unraveling of its pharmacologic effects. With close attention to these regulatory details, SciClone has obtained approvals in more than 30 countries and has successfully begun commercial sales.

Topics: Adjuvants, Immunologic; Drug Industry; Europe; Hepatitis B, Chronic; Hepatitis C, Chronic; Marketing; Patents as Topic; Pharmaceutical Preparations; Thymalfasin; Thymosin; United States

More than one million individuals in Mexico are infected with hepatitis C virus (HCV), and 80% are at risk for developing a chronic infection that could lead to hepatic cirrhosis and other complications that impact quality of life and institutional costs. The objective of the study was to determine the most cost-effective treatment against HCV among the following: peginterferon, peginterferon plus ribavirin, peginterferon plus ribavirin plus thymosin, and no treatment.. We carried out cost-effectiveness analysis using the institutional perspective, including a 45-year time frame and a 3% discount rate for costs and effectiveness. We employed a Bayesian-focused decision tree and a Markov model. One- and two-way sensitivity analyses were performed, as well as threshold-oriented and probabilistic analyses, and we obtained acceptability curves and net health benefits.. Triple therapy (peginterferon plus ribavirin plus thymosin alpha-1) was dominant with lower cost and higher utility in relationship with peginterferon + ribavirin option, peginterferon alone and no-treatment option. In triple therapy the cost per unit of success was of 1,908 [USD/quality-adjusted life years (QALY)] compared with peginterferon plus ribavirin 2,277/QALY, peginterferon alone 2,929/QALY, and no treatment 4,204/QALY. Sensitivity analyses confirmed the robustness of the base case.. Peginterferon plus ribavirin plus thymosin alpha-1 option was dominant (lowest cost and highest effectiveness). Using no drug was the most expensive and least effective option.

Topics: Adjuvants, Immunologic; Antiviral Agents; Costs and Cost Analysis; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Liver Cirrhosis; Male; Mexico; Polyethylene Glycols; Prospective Studies; Quality of Life; Quality-Adjusted Life Years; Recombinant Proteins; Ribavirin; Thymalfasin; Thymosin

Interferon alpha (IFN-alpha) with or without ribavirin is an approved therapy for patients with chronic hepatitis C. However, a sustained response is achieved in less than 40% of all treated cases. Retreatment of relapsers or non-responders usually fails. Thymosin alpha 1 (Ta-1) is a polypeptide with immunomodulatory properties that has been suggested to increase response rates in patients with chronic hepatitis C. The aim of present study was to evaluate the efficacy of a novel triple regimen which includes Ta-1 for relapsers and non-responders to the combination of TA-1 and ribavirin.. In the present study, 11 patients who relapsed (n=5) or did not respond (n=6) to previous INF-alpha-based therapy were retreated with combination Ta-1, INF-alpha and ribavirin for 12 months, and followed up for a further six months.. Four out of five relapsers had a sustained response. One of the non-responders cleared the HCV RNA during the post-treatment follow-up. Minor adverse effects were observed during treatment with this combination therapy and no dose reduction or discontinuations were needed.. This data suggests that thymosin alpha 1 may add to the efficacy of INF-alpha plus ribavirin in the retreatment of relapsers or non-responders to previous INF-alpha-based hepatitis C therapy.

Topics: Adjuvants, Immunologic; Adult; Antiviral Agents; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Retreatment; Ribavirin; Thymalfasin; Thymosin

Despite steady progress in antiviral treatment for patients with chronic hepatitis C virus(HCV), many patients still have detectable serum HCV RNA levels by the end of interferon-based treatment and are known as virological non-responders. Re-treatment of these patients not responding to previous therapy remains challenging. Studies of the dynamics of the HCV population show a marked decline in new cases since 1996; however, the relative proportion of non-responders is expected to increase over time and, similarly, the number of patients eligible for first-line treatment is expected to decrease. The current standard of care for treatment involves the use of pegylated interferons in combination with ribavirin. However, many difficult-to-treat groups still have low response rates. Newer combinations are being investigated to optimize chances of attaining a sustained response in these groups: one such triple therapy regimen is peginterferon alfa-2a, ribavirin and thymalfasin, which was given to 23 previously non-responder patients. Viral response was 60.8% at week 12 and 47.8% at week 24. These preliminary results encourage further evaluation of this promising combination.

Topics: Adjuvants, Immunologic; Antiviral Agents; Drug Therapy, Combination; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Interferons; Pilot Projects; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thymalfasin; Thymosin; Time Factors; Treatment Failure

Current evidence suggests that increased expression of Th1-associated cytokines is important for immune-mediated eradication of hepatitis C infection, while an increase in Th2-associated cytokines is associated with persistence of infection. In this study we evaluated the effects of thymosin-alpha1 (TA1), a naturally occurring thymic peptide, and interferon-alpha (IFN-alpha) on cytokine production in peripheral blood mononuclear cells from untreated patients with chronic hepatitis C. We examined the effect of incubation with TA1, IFN-alpha, or both, on production of Th1-associated cytokines (IL-2, IFN-gamma), Th2-associated cytokines (IL-4, IL-10), and synthesis of the antiviral protein 2',5'-oligoadenylate synthetase. TA1 treatment induced a significant increase in production of IL-2 and 2',5'-oligoadenylate synthetase. Smaller increases were also seen after treatment with IFN-alpha, while incubation with TA1 and IFN-alpha together led to an additive or synergistic effect. Incubation with TA1 resulted in a decrease in IL-4 and IL-10, whereas IFN-alpha increased these cytokines. The addition of TA1 to IFN-alpha significantly reversed this IFN-alpha-induced increase. Hence, TA1 treatment could benefit patients with hepatitis C infection by increasing the Th1-type response, fundamental for sustained clearance of hepatitis C; and by decreasing the Th2-type response, associated with persistence of viraemia.

Topics: 2',5'-Oligoadenylate Synthetase; Adjuvants, Immunologic; Adult; Antiviral Agents; Cells, Cultured; Concanavalin A; Cytokines; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon-alpha; Leukocytes, Mononuclear; Male; Middle Aged; Th1 Cells; Th2 Cells; Thymalfasin; Thymosin

Hepatitis C (HCV) can cause liver damage or liver cancer, and it is doubtful that antiviral drugs alone will be able to cure HCV. Because of the limitations of antiviral drugs, researchers are studying ways to enhance the immune system's ability to fight HCV. The current standard therapy for treating HCV is to use Interferon-alpha, although this may change to a combination of Interferon-alpha and Ribavirin. However, Ribavirin can have detrimental effects on bone marrow and may not be tolerated by some patients. Results of a study are presented.

Topics: Antiviral Agents; Clinical Trials as Topic; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Male; Recombinant Proteins; Thymosin