Box 1 Predictors of response in prior relapsers

To standard interferon Genotype non-1 Low viral load No or mild fibrosis Age greater than 40 Non-African-American ethnicity Early virologic response to therapy

To standard interferon and ribavirin Genotype non-1 Low viral load

Early virologic response to therapy antiviral theapy [33]. An early virologic response is also a strong predictor of a virologic cure [20,25].

Longer duration of treatment (24 versus 48 weeks) [22,23,31], particularly for genotype 1 patients with a high viral load, is associated with a better chance for SVR [27,29] in IFN mono-therapy relapsers given IFN and RBV. Higher doses of IFN have not been associated with higher response rates in most studies [23,29,32]. Saracco et al found that the cumulative dose of IFN during the initial course of therapy or retreatment did not predict a favorable response to therapy [29]. Increased dose or duration of therapy in patients with genotypes 2 and 3 is not associated with higher SVR rates [27,29,31].

Similar predictors of response have been recently reported in relapsers to combination standard IFN and RBV therapy who are retreated with PEG IFN and RBV. Genotype non-1 and low viral load are predictors of a favorable response [43,44]. In one study, the absence of HCV viremia at week 6, as determined by the transcription-mediated amplification assay, was highly predictive of SVR (80% in the overall study population, 92% in genotype non-1 patients) [44].

Adjunctive therapies for patients who have relapsed after interferon and ribavirin combination therapy

In an effort to improve SVR rates in this population, some investigators have evaluated adjunctive therapies in addition to PEG IFN a2b and RBV. Freilich et al assessed the benefit of adding amantadine to PEG IFN and RBV therapy in treating patients who previously had relapsed to therapy [45]. They compared PEG IFN (1.0 mg/kg per week) and RBV (1000 mg per day) with a regimen of PEG IFN (1.0 mg/kg per week) and RBV (1000 mg per day) plus amantadine (200 mg per day). The overall SVR

rate presented from interim data in 23 patients was 43%. The addition of amantadine was not beneficial in genotype 1 relapsers. The SVR rate in genotype 1 relapsers was 25% (2/8) in patients treated with amantadine and 40% (2/5) in those treated with standard PEG IFN and RBV combination therapy. In contrast, the addition of amantadine may have led to superior treatment efficacy in nongenotype 1 patients. All (4/4) of the genotype non-1 patients treated with amantadine had an SVR, compared with only 33% (two of six) of patients treated with PEG IFN and RBV alone, but final data from this study are not available, and the number of patients is too small to draw any definitive conclusions.

In another study, 37 relapsers (to standard IFN monotherapy or standard IFN and RBV combination therapy) were retreated with an induction dose of standard IFN (18 MU daily) in combination with ribavirin (1000 to 1200 mg daily) and amantadine (100 mg daily) for two weeks and then randomized to 22 weeks of continued ribavirin and amantadine with or without IFN (6 MU three times weekly) [44]. The 10 patients who discontinued interferon after the 2 week induction course all relapsed within two weeks. Of the patients who received 24 weeks of interferon, the end-of-treatment response was 63% (17/27) and the SVR rate was 44% (12/27). Twenty nine percent (5/17) of patients with an end-of-treatment response subsequently relapsed.

Herrine et al assessed the efficacy of mycophenolate mofetil and amantadine in addition to PEG IFN and RBV in a pilot study [43]. They treated 124 patients (106 relapsers, 18 breakthrough relapsers) who were randomized to receive PEG IFN alfa-2a 180 mg once weekly in addition to one of four following treatment arms: (1) RBV at 800 to 1000 mg daily, (2) mycophenolate at 1000 mg twice daily, (3) amantadine at 100 mg twice daily, or (4) amantadine at 100 mg twice daily and RBV at 800 to 1000 mg daily. End-of-treat-ment response rates were highest in patients who were treated with PEG IFN and mycophenolate (72.4%) and PEG IFN, RBV, and amantadine (71%). Patients who received PEG IFN, RBV, and amantadine had the highest SVR rates (45%), followed by those who received PEG IFN and RBV (38%). However, the difference in response rates in the two groups did not reach statistical significance. Treatment with PEG IFN and either amanta-dine or mycophenolate alone resulted in lower SVR rates (10% and 17%, respectively), as in other trials. Thus, RBV appears to exact its benefit by preventing relapse. There was a trend towards higher SVR rates in patients with genotype non-1 and low HCV viral load. Tolerance of the medications was similar in the different treatment groups, except for the more significant decline in hemoglobin seen in patients who received ribavirin.

Approach to the retreatment of patients who relapse after interferon and ribavirin combination therapy

Patients who relapse after standard IFN and RBV should be considered strongly for retreatment with PEG IFN and RBV because of their significant chance of SVR (30% to 70%). The available data are derived from studies in which PEG IFN and RBV were administered for 48 weeks. In these studies, however, relapse even after PEG IFN and RBV occurred in significant numbers of patients. Current viral kinetic models suggest that a gradual second phase of HCV-infected cell death occurs, ultimately leading to viral eradication in patients who achieve an SVR [17]. It is thought that patients who relapse may have a more prolonged period of elimination of infected cells, which may not have been completed when a standard course of IFN and RBV therapy ends. Therefore, in these patients with a previously demonstrated proclivity to relapse, longer courses of therapy than the standard duration of 48 weeks may be worth consideration in the retreatment of selected patients, with a goal of maximizing the chance of eventual eradication of all virally infected cells. Such patients might include those with genotype 1, high viral load, and advanced fibrosis, or those with a delayed response to therapy. However, controlled trials demonstrating the efficacy of such prolonged therapy have not been reported.

Adherence to optimal doses of PEG IFN and RBV during prior therapy also should be considered. The superior efficacy (44% versus 41%, P = 0.02) of weight-based (800 mg to 1400 mg) versus fixed (800 mg) RBV dosing has been recently demonstrated in a multicenter, randomized, community based trial of 4913 patients [46]. In treatment naive patients, dose reductions of either drug, and particularly both drugs, have a significant impact on attainment of early virologic response (EVR) after 12 weeks (80% EVR with full doses versus 60% to 70% and 33% with dose reduction of either or both drugs, respectively) [47]. In patients who attain EVR, the chance of SVR is adversely affected by dose reductions or discontinuation of therapy beyond the 12-week timepoint. Although comparable data do not exist for the relapse population, these same principles may well apply. Accordingly, every effort must be made to maintain optimal dosing during the retreatment of patients who have relapsed to a prior course of therapy. Patients who underwent dose reduction during prior therapy for depression, anemia, or neutropenia may be considered for anti-depressants, granulocyte colony stimulating factor therapy, or erythropoie-tin, respectively, as appropriate during retreatment. It must be recognized, however, that while recent studies on erythropoietin show an effect on successful maintenance of ribavirin dose, improvements in hemoglobin levels and quality of life [48], no prospective trials have demonstrated the use of adjunctive factors to enhance SVR.

Treatment of patients who have relapsed after pegylated interferon and ribavirin combination therapy

Patients who have relapsed after a course of PEG IFN and RBV pose a difficult problem, because more effective therapy is not available. There are no data on the efficacy of higher doses of drugs, leaving a repeat course of more prolonged therapy as the major option. Goncales et al treated naive patients with either 24 or 48 weeks of combination PEG IFN alfa-2a and RBV. Patients who received 24 weeks of therapy and relapsed were eligible to enter a retreatment study consisting of PEG IFN alfa-2a (maximum dose of 180 mg per week) and RBV (1000 to 12000 mg per day) for 48 weeks [49]. PEG IFN and RBV doses were adjusted by the investigators according to the patients' tolerance of the medications during the initial course of therapy. Preliminary data from this study on 59 patients indicate high end of treatment virologic response rates of 90% (88% in genotype 1 patients; 93% in patients with genotype 2 and 3) with retreatment. SVR rates from this study are awaited.

Because most patients who relapse after a course of PEG IFN and RBV will have received 48 weeks of therapy, the only realistic option is to consider a repeat course of treatment for a longer duration (eg, 72 to 96 weeks). In apparent conformity with concepts of the kinetics of viral clearance, patients who clear HCV RNA on their initial course of PEG IFN and RBV have an enhanced risk of post-treatment relapse if clearance of HCV RNA requires longer than 12 weeks of therapy [41]. The concept of modifying the duration of therapy according to a patient's virologic response pattern to PEG IFN and RBV therapy has been evaluated in a preliminary study of nine HCV genotype 1, treatment-naive patients [50]. These nine patients all had delayed virologic clearance; they were positive for HCV RNA by PCR but had a 2 log decline in HCV RNA by week 12 of therapy and had cleared virus by week 24. Patients were treated for 72 weeks, and 88% (7/8, with one lost to follow-up) had an SVR. As in patients with relapse after a course of standard IFN and RBV, this approach to therapy needs to be evaluated further in patients who have relapsed after a prior course of PEG IFN and RBV, particularly patients with genotype 1, high viral load, and cirrhosis, or patients in whom clearance of HCV RNA was delayed beyond 12 weeks.

Preliminary data with consensus interferon, a novel recombinant type 1 interferon, suggests sustained virologic response rates of 23-37% in previous nonresponders to pegylated interferon and ribavirin [51,52]. However, data from large multicenter studies is needed to confirm these findings in prior nonresponders. Studies evaluating the efficacy of consensus interferon in prior relapsers to PEG IFN and RBV are currently in progress, including at our center.

Future directions

In addition to the options of PEG IFN and RBV for relapsers to previous combination therapy, or prolonged courses of PEG IFN and RBV in re-lapsers to previous PEG IFN and RBV therapy, new therapies on the horizon for treatment-naive patients with chronic hepatitis C include genome sequence-based therapies, viral enzyme inhibitors, and immunomodulatory agents may be efficacious in patients who have relapsed to previous therapy also [9,53]. Most promising are the protease and polymerase inhibitors which are currently in Phase I and Phase II trials. Preliminary data from both treatment-nai've HCV-infected patients and previous nonresponders have demonstrated marked declines in HCV viremia with these novel compounds [54-57]. Patients with mild liver disease or those who had great difficulty tolerating interferon-based therapy may wish to defer retreatment as novel therapies are awaited. In the authors' practice, however, it is felt that most patients with relapse after standard IFN and RBV should be offered a course of PEG IFN and RBV.

Summary

Sustained virologic response rates are significantly higher in patients who have relapsed after a previous course of therapy compared with patients who did not respond. A meta-analysis of combination therapy in patients who failed IFN monotherapy reported SVR rates of 52% in relapsers to prior therapy and 16% in nonresponders [12]. Similarly, relapsers after combination standard IFN and RBV therapy have higher SVR rates than combination of therapy nonresponders when treated with pegylated interferon and ribavirin [34,35-39]. For this reason, patients who relapse after a previous course of therapy should be considered potential candidates for retreatment. Factors that have been associated with SVR in these patients include genotype non-1, low viral loads, and lesser degrees of fibrosis. The course of treatment in all patients who have relapsed after prior therapy should be reviewed to identify possible reasons for failure to achieve an SVR. In particular, optimal dosing of PEG IFN and RBV and the occurrence and timing of treatment dose reductions during prior therapy should be reviewed. The reasons for dose reduction should be addressed before initiating another course of therapy in an effort to optimize the chance for a SVR. Patients who had dose reduction for depression, anemia, or neutropenia, should be considered for antide-pressants, erythropoietin, or, if neutropenia is severe, granulocyte colony stimulating factor therapy, respectively, during retreatment. Prolongation of therapy beyond 48 weeks in patients with relapse after a standard course of PEG IFN and RBV may offer a chance of SVR. Novel agents currently in development, including protease and polymerase inhibitors, may prove to be therapeutic options for these patients in the future.

References

[1] Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of interferon a2b plus ribavirin for 48 weeks or for 24 weeks versus interferon a2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998;352: 1426-32.

[2] McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485-92.

[3] Lau JYN, Tam RC, Liang TJ, Hong Z. Mechanisms of action of ribavirin in the combination treatment of chronic HCV infection. Hepatology 2002;35(5):1002-9.

[4] Graci JD, Cameron CE. Quasispecies, error catastrophe, and the antiviral activity of ribavirin. Virology 2002;298:175-80.

[5] Dixit NM, Layden-Almer JE, Layden TJ, et al. Modelling how ribavirin improves interferon response rates in hepatitis C virus infection. Nature 2004;432:922-4.

[6] Dusheiko G, Main J, Thomas H, Reichard O, Lee C, Dhillon A, et al. Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study. J Hepatol 1996; 25:591-8.

[7] Di Bisceglie AM, Shindo M, Fong TL, Fried MW, Swain MG, Bergasa NV, et al. A pilot study of ribavirin therapy for chronic hepatitis C. Hepatology 1992;16:649-54.

[8] Bodenheimer HC Jr, Lindsay KL, Davis GL, Lewis JH, Thung SN, Seef LB. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: A multi-center trial. Hepatology 1997;26:473-7.

[9] Brouwer JT, Nevens F, Bekkering FC, et al. Reduction of relapse rates by 18-month treatment in chronic hepatitis C. A Benelux randomized trial in 300 patients. J Hepatol 2004;40: 689-95.

[10] Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for the initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958-65.

[11] Fried MW, Shiffman ML, Reddy R, Smith C, Marinos G, Goncales FL, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347(13): 975-82.

[12] Poynard T, McHutchison J, Manns M, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002;122: 1303-13.

[13] Coverdale SA, Khan MH, Byth K, et al. Effects of interferon treatment response in liver complications of chronic hepatitis C: 9-year follow-up study. Am J Gastroenterol 2004; 99(4):636-44.

[14] Davis GL, Lau JYN. Factors predictive of a beneficial response to therapy of hepatitis C. Hepatology 1997;26(3):S122-7.

[15] Leroy V, Baud M, de Traversay C, Maynard-Muet M, Lebon P, Zarski JP. Role of antiinterferon antibodies in breakthrough occurrence during alpha 2a and 2b therapy in patients with chronic hepatitis C. J Hepatol 1998;28(3):375-81.

[16] Hoffmann RM, Berg T, Teuber G, Prummer O, Leifeld L, Jung MC, et al. Interferon antibodies and the breakthrough phenomenon during ribavirin/interferon-alpha combination therapy and interferon-alpha monotherapy of patients with chronic hepatitis. Z Gastroenterol 1999;37(8):715-23.

[17] Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-a therapy. Science 1998;282: 103-7.

[18] Sarrazin C, Teuber G, Kokka R, et al. Detection of residual hepatitis C virus RNA by transcription-mediated amplification in patients with complete virologic response according to polymerase chain reaction-based assays. Hepatology 2000;32:818-23.

[19] Chow WC, Boyer N, Pouteau M, Castelnau C, Martinot-Peignoux M, Martins-Amado V, et al. Re-treatment with interferon alfa of patients with chronic hepatitis C. Hepatology 1998;27:1144-8.

[20] Davis GL, Esteban-Mur R, Rustgi V, Hoefs J, Gordon SC, Trepo C, et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998;339:1493-9.

[21] Weiland O, Zhang YY, Widell A. Serum HCV RNA levels in patients with chronic hepatitis C given a second course of interferon alpha-2b treatment after relapse following initial treatment. Scand J Infect Dis 1993;25:25-30.

[22] Picciotto A, Brizzolara R, Campo N, Poggi G, Sinelli N, De Conca V, et al. Two-year interferon retreatment may induce a sustained response in relapsing patients with chronic hepatitis C. Hepatology 1996;24(4):273A.

[23] Payen JL, Izopet J, Galindo-Migeot V, Lauwers-Cances V, Zarski JP, Seigneurin JM, et al. Better efficacy of a 12-month interferon alfa-2b retreatment in patients with chronic hepatitis C relapsing after a 6-month treatment: a multi-center, controlled, randomized trial. Hepatology 1998;28:1680-6.

[24] Bell H, Hellum K, Harthug S, Myrvang B, Ritland S, Maeland A, et al. Treatment with interferon-alpha 2a alone or interferon-alpha 2a plus ribavirin in patients with chronic hepatitis C previously treated with interferon-alpha 2a. Scand J Gastroenterol 1999;34: 194-8.

[25] Barbaro G, Di Lorenzo G, Belloni G, Ferrari L, Paiano A, Del Poggio P, et al. Interferon alpha-2b and ribavirin in combination for patients with chronic hepatitis C who failed to respond to, or relapsed after, interferon alpha therapy: a randomized trial. Am J Med 1999; 107:112-8.

[26] Cavalletto L, Chemello L, Donada C, Casarin P, Belussi F, Bernardinello E, et al. The pattern of response to interferon alpha (a-IFN) predicts sustained response to a 6-month a-IFN and ribavirin retreatment for chronic hepatitis C. J Hepatol 2000;33:128-34.

[27] Enriquez J, Gallego A, Torras X, Perez-Olmeda T, Diago M, Soriano V, et al. Retreatment for 24 vs 48 weeks with interferon-a2b plus ribavirin of chronic hepatitis C patients who relapsed or did not respond to interferon alone. J Viral Hepat 2000;7:403-8.

[28] Cozzolongo R, Cuppone R, Giannuzzi V, Amati L, Caradonna L, Tamborrino V, et al. Combination therapy with ribavirin and alpha interferon for the treatment of chronic hepatitis C refractory to interferon. Alimentary Pharmacology and Therapeutics 2001;15: 129-35.

[29] Saracco G, Olivero A, Ciancio A, Carenzi S, Smedile A, Cariti G, et al. A randomized 4-arm multi-center study of interferon alfa-2b plus ribavirin in the treatment of patients with chronic hepatitis C relapsing after interferon monotherapy. Hepatology 2002;36: 959-66.

[30] Shiffman ML, Hoofmann CM, Sterling RK, Luketic VA, Contos MJ, Sanyal AJ. A randomized, controlled trial to determine whether continued ribavirin monotherapy in hepatitis C virus-infected patients who responded to interferon-ribavirin combination therapy will enhance sustained virologic response. J Infect Dis 2001;184:405-9.

[31] Di Marco V, Almasio P, Vaccaro A, Ferraro A, Parisi P, Cataldo MG, et al. Combined treatment of relapse of chronic hepatitis C with high-dose a2b interferon plus ribavirin for 6 to 12 months. J Hepatol 2000;33:456-62.

[32] Min AD, Jones JL, Esposito S, Lebovics E, Jacobson IM, Klion FM, et al. Efficacy of highdose interferon in combination with ribavirin in patients with chronic hepatitis C resistant to interferon alone. Am J Gastroenterol 2001;96(4):1143-9.

[33] Portal I, Bourliere M, Halfon P, et al. Retreatment with interferon and ribavirin vs interferon alone according to viraemia in interferon responder-relapser hepatitis C patients: a prospective multicentre randomized controlled study. J Viral Hepatitis 2003;10:215-23.

[34] Krawitt EL, Ashikaga T, Gordon SR, et al. Peginterferon alfa-2b and ribavirin for treatment-refractory chronic hepatitis C. J Hepatol 2005;43:243-9.

[35] Jacobson IM, Gonzalez SA, Ahmed F, et al. A randomized trial of pegylated interferon a-2b plus ribavirin in the retreatment of chronic hepatitis C. Am J Gastroenterol 2005;100:1-10.

[36] Gaglio P, Choi J, Zimmerman D, et al. Weight based ribavirin in combination with pegylated interferon alpha 2-b does not improve SVR in HCV infected patients who failed prior therapy: results in 454 patients. Hepatology 2005;42(4, suppl 1):219A.

[37] Poynard T, Schiff E, Terg R, et al. Sustained virologic response (SVR) with PEG-interferon-alfa-2b/ribavirin weight based dosing in previous interferon/ribavirin HCV treatment failures; week 12 virology as a predictor of SVR in the EPIC3 trials. Gastroenterology 2005; 128:A681.

[38] Portal I, Botta-Fridlund D, Bourliere M, Couzigou P, Barange K, Canva V, et al. Treatment with pegylated-interferon alpha-2b (peg-interferon) + ribavirin in relapsers to standard interferon + ribavirin in chronic hepatitis C: efficacy and safety results from a randomized multi-centric French study. Hepatology 2002;36(4):359A.

[39] Lawitz EJ, Bala NS, Becker S, Brown G, Davis M, Dhar R, et al. Pegylated interferon alfa 2b and ribavirin for hepatitis C patients who were nonresponders to previous therapy. Gastroenterology 2003;124(4):A783.

[40] Ferenci P. Predictors of response to therapy for chronic hepatitis C. Seminars in Liver Disease 2004;24(Suppl 2):25-31.

[41] Davis GL, Wong JB, McHutchison JG, Mann MP, Harvey J, Albrecht J, et al. Early viro-logic response to treatment with pegylated interferon a-2b and ribavirin in patients with chronic hepatitis C. Hepatology 2003;38:645-52.

[42] McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, et al. Adherence to combination therapy enhances sustained response in genotype-1 infected patients with chronic hepatitis C. Gastroenterology 2002;123:1061-9.

[43] Herrine SK, Brown RS, Bernstein DE, et al. Peginterferon a-2a combination therapies in chronic hepatitis C patients who relapsed after or had a viral breakthrough on therapy with standard interferon a-2b plus ribavirin: a pilot study of efficacy and safety. Dig Dis Sci 2005;50(4):719-26.

[44] Weegink CJ, Sentjens RE, Beld MG, et al. Chronic hepatitis C patients with a post-treatment virological relapse re-treated with an induction dose of 18 MU interferon-a in combination with ribavirin and amantadine: a two-arm randomized pilot study. J Viral Hepatol 2003;10: 174-82.

[45] Freilich B, Weston A, DeGuzmann LJ, Kissinger J. Triple therapy for interferon/ribavirin failure patients with hepatitis C: interim data. Hepatology 2002;36(4):361A.

[46] Jacobson IM, Brown RS, Freilich B, et al. Weight-based ribavirin dosing (WBD) increases sustained viral response (SVR) in patients with chronic hepatitis C (CHC): final results of the WIN-R study, a US community based trial. Hepatology 2005;42(4, Suppl 1):749A.

[47] Davis GL, Wong JB, McHutchison JG, et al. Early virologic response to treatment with pe-ginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003;38: 645-52.

[48] Afdhal NH, Dieterich DT, Pockros PJ, et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterol-ogy 2004;126:1302-11.

[49] Goncales F, Berstein DE, Berg C, Sette H, Rasenack J, Diago M, et al. Peginterferon alfa-2a (40KD) (Pegasys) plus ribavirin in chronic hepatitis C: retreatment of patients who relapsed virologically after 24 weeks of therapy. Hepatology 2002;36(4):361A.

[50] Buti M, Valdes A, Sanchez-Avila F, Esteban R, Lurie Y. Extending combination therapy with peginterferon alfa-2b plus ribavirin for genotype 1 chronic hepatitis C late responders: a report of 9 cases. Hepatology 2003;37(5):1226-7.

[51] Leevey CB, Chalmers CP, Blatt LM. Comparison of African American and Non-African American patient end of treatment response for Peg-IFN a-2 and weight-based ribavirin nonresponders re-treated with IFN alfacon-1 and weight-based ribavirin. Hepatology 2004;40(4, Suppl 1):240A.

[52] Kaiser S, Hass H, Gregor. Successful retreatment of chronic hepatitis C patients with a non-response to standard interferon/ribavirin using daily consensus interferon and ribavirin. Hepatology 2004;40(4, Suppl 1):240A.

[53] Di Bisceglie AM, McHutchison JG, Rice CM. New therapeutic strategies for hepatitis C. Hepatology 2002;35(1):224-31.

[54] Zeuzem S, Sarrazin C, Rouzier R, Tarral A, Brion N, Forestier N, et al. Anti-viral activity of SCH 503034, a HCV protease inhibitor, administered as monotherapy in hepatitis C geno-type-1 (HCV-1) patients refractory to pegylated interferon (PEG-IFN-a). Hepatology 2005; 42(4, Suppl 1):233A-4A.

[55] Reesink HW, Zeuzem S, Weegink CJ, Forestier N, van VLiet A, ven de Wetering de Rooij J, et al. Final results of a phase 1B, multiple-dose study of VX-950, a hepatitis C virus protease inhibitor. Hepatology 2005;42(4, Suppl 1):234A-5A.

[56] O'Brien C, Godofsky E, Rodriguez-Torres M, Afdhal N, Pappas SC, Pockros P, et al. Randomized trial of valopicitabine (NM283), alone or in with PEG-interferon, vs. retreatment with PEG-interferon plus ribavirin (PEGIFN/RBV) in hepatitis C patients with previous nonresponse to PEGIFN/RBV: first interim results. Hepatology 2005;42(4, Suppl 1):234A.

[57] Sarisky RT. Non-nucleoside inhibitors of the HCV polymerase. Journal of Antimicrobial Chemotherapy 2004;54:14-6.

Was this article helpful?

0 0

Post a comment