Info

Fatty Liver Remedy

Fatty Liver Disease Homeopathic Treatments

Get Instant Access

Genetically fused interferon alpha with serum human albumin Increased dosing interval of two to four weeks

Abbreviations: ALT, alanine aminotransferase; HCV, hepatitis C virus; IFN, interferon; IMPDH, inosine monophosphate dehydrogenase; PEGIFN, peginterferon; RBV, ribavirin.

Abbreviations: ALT, alanine aminotransferase; HCV, hepatitis C virus; IFN, interferon; IMPDH, inosine monophosphate dehydrogenase; PEGIFN, peginterferon; RBV, ribavirin.

clinical trials or be discarded during preclinical testing. Pharmaceutical companies, clinical research organizations, and governmental web sites can help patients and physicians to remain abreast of drug development and emerging clinical trials with new agents for patients with chronic hepatitis C.

Several agents available to physicians are being evaluated in clinical trials as a potential treatment for patients with chronic HCV infection and NR to previous PEGIFN/RBV therapy. Other trials are investigating the efficacy of higher doses of IFN or PEGIFN or a longer duration of therapy with these agents. Several of these strategies are discussed here because they may potentially be used by physicians for their patients with chronic hepatitis C. Only preliminary data are available regarding the use of these agents in this "off-label" manner. Discussing these approaches in this article does not advocate their use or suggest that they may be effective for treatment of patients who have HCV infection and NR to PEGIFN/RBV. Safety and efficacy will be determined when the results of these ongoing trials become available.

Protease inhibitors

Anti-viral therapy with first generation protease inhibitors has been undergoing evaluation for the past few years. Initially, significant results were seen with BILN 2061 used as monotherapy with 3 log reductions in HCV RNA. Studies were halted, however, after the development of cardiac toxicities in animal models [48]. The enthusiasm for this class of agents has been renewed with the development of three new drugs, NM283, VX-950, and SCH 503034. Each of these agents have been shown to significantly suppress HCV RNA when used either alone or in combination with PEGIFN [49-51]. Given prior experience with these agents, and the early phase of their trials, therapy with anti-HCV protease inhibitors should be approached with caution. Further studies of their use in combination therapy with interferon or triple therapy with interferon and ribavirin need to be evaluated.

Consensus interferon and ribavirin

Consensus interferon (CIFN) is a synthetic IFN product with an amino acid sequence that reflects all a-IFNs. CIFN has been shown to be effective in the retreatment of patients who failed to achieve SVR after 24 weeks of treatment with standard IFN monotherapy [52]. In that study, SVR was achieved in 58% of patients with previous relapse and in 13% with previous NR. High-dose daily CIFN using an "induction" approach has recently been evaluated for patients who have NR after treatment with PEGIFN/ RBV in two small, single-center trials [53,54]. In one of these studies, CIFN was administered at doses of 27 or 18 mg daily for 4 weeks followed by 18 or 9 mg daily for 8 weeks, followed by 9 mg daily plus RBV (10001200 mg/d) for an additional 36 weeks. In the other study, CIFN was dosed at 15 mg/d plus RBV (1000-1200 mg/d) for 12 weeks followed by CIFN

15 mg TIW and RBV (1000-1200 mg/d) for 36 weeks. Preliminary data from these studies suggested that 37% to 42% of patients with previous PEGIFN/RVN could achieve SVR with these high-dose daily CIFN treatment regimens. One of these studies has suggested that this approach may be particularly helpful in African Americans [54], a group with a significantly lower SVR to PEGIFN/RBV therapy [55]. Based upon these single-center preliminary studies, a large, multicenter, clinical trial has been initiated in which CIFN (15 or 9 mg/d) plus RBV (1000-1200 mg/d) is being evaluated for the treatment of HCV patients with NR to previous PEGIFN/RBV therapy. Until this trial has been completed and this approach has been shown to have a positive impact, the use of high-dose daily CIFN along with RBV should be considered "off-label" and investigational.

Higher doses and longer duration of peginterferon and ribavirin

Another approach to the retreatment of patients who have NR to PEGIFN/RBV is to use these same agents but at a higher dose. In a preliminary study, patients with previous NR to IFN/RBV were retreated with 180, 270, or 360 mg of PEGIFNa-2a and RBV (1000-1200 mg/d). Although VR at the end of treatment was similar in all three groups, SVR increased stepwise from 21% to 46% in the highest PEGIFN dose group [56]. The increase in SVRs observed with higher doses of PEGIFN/RBV was therefore the result a marked reduction in relapse after discontinuation of this therapy. These data have led to the initiation of multicenter trials in which higher doses of PEGIFN and RBV are being used in patients who have NR to previous treatment with PEGIFN/RBV.

It has been hypothesized that patients who relapse after treatment with PEGIFN/RBV may have not been treated long enough to achieve long-lasting viral suppression. Preliminary results from a treatment trial in which patients were randomized to receive 48 or 72 weeks of therapy has demonstrated that relapse was reduced from 48% to 13% in patients treated for a longer period of time [57]. This study suggested that genotype 1 patients who relapsed after a standard course of PEGIFN/RBV may fare better if retreated for a longer period of time. The duration of retreatment and doses necessary to optimize SVR using this approach remains to be defined. In contrast, current data suggest that retreating patients with genotype 2 or 3 for a longer duration does not affect SVR because 24 and 48 weeks of therapy yield similar rates of SVR [12].

Peginterferon, ribavirin, and amantadine

Amantadine is an antiviral agent initially used for the treatment of influenza A [58]. Over the past several years, studies have investigated the possible role of amantadine for the treatment of chronic HCV infection. Amantadine has been used alone [59], with IFN [60], and as triple therapy with IFN and RBV [61,62] as initial therapy and for retreatment of patients with previous NR. Although most of these studies have yielded conflicting results, a recent meta-analysis has demonstrated that SVR might be about 5% to 7% higher in patients who received amantadine as part of triple therapy compared with IFN/RBV [63]. Preliminary reports evaluating amantadine, PEGIFN, and RBV triple therapy in patients with chronic HCV and previous NR remain inconclusive [64,65]. It is unclear what role amantadine will play in the management of patients who have failed to achieve SVR with PEGIFN/RBV.

Maintenance therapy

It is well established that patients who achieve SVR have an improvement in liver histology, a reduction in hepatic fibrosis [66-68], a reduced risk for developing hepatocellular carcinoma [69,70], and prolonged survival [70,71]. In contrast, it is doubtful that patients with NR achieve such benefit. Although it does seem that some nonresponders can achieve histologic improvement, this is probably limited to patients with partial VR and a marked decline in serum HCV RNA from the pretreatment baseline level [66,67,72]. Furthermore, the improvement in liver histology associated with partial VR seems to be limited to changes in hepatic inflammation. An overall improvement in liver fibrosis has not been convincingly demonstrated to occur in patients with NR after a single course of IFN [66,72]. Although one study implied that marked regression in fibrosis may occur in some patients with NR, this is unlikely because an equal percentage of patients in this study had fibrosis progression, over 60% of patients had no change in fibro-sis, and the mean fibrosis scores from before and after treatment were not significantly different [68]. It is therefore, most likely that sampling variation accounted for the improvement in fibrosis reported to occur in a subset of patients who had NR.

Fibrosis progression in patients who have chronic HCV is mediated by hepatic inflammation [73,74]. As a result, it is possible that a reduction in hepatic inflammation may reduce the rate of fibrosis progression or allow fibrosis to resolve. This hypothesis forms the basis for the concept of maintenance therapy.

Maintenance therapy using interferon

Maintenance therapy using standard IFN was evaluated in a controlled trial of patients who achieved partial VR and a reduction in hepatic inflammation after an initial course of IFN therapy [72]. These patients were randomly assigned to continue IFN for an additional 2 years or to stop treatment and be followed as a control group. Patients who remained on IFN (3 MU tiw) therapy maintained the initial reduction in serum HCV RNA and improvement in hepatic inflammation observed after initial therapy. In contrast, serum HCV RNA and hepatic inflammation returned to the pretreatrnent baseline in patients randomized to stop therapy. Changes in mean fibrosis scores after 2.5 years in these two groups of patients were small and not statistically significant. Nevertheless, these findings were encouraging and led to the initiation of a several large, multicenter clinical trials to investigate the possibility that long-term maintenance therapy using PEGIFN could prevent fibrosis progression, reduce hepatic decompensation, lower the incidence of hepatocellular carcinoma, reduce the need for liver transplantation, and improve survival in patients who have HCV with NR and advanced fibrosis or cirrhosis. The HALT-C trial is the largest and most well publicized of these studies [75].

Preliminary results from another trial of maintenance PEGIFN (CoPilot) have recently been reported [76]. After 2 years of maintenance therapy (PEGIFNa-2b 0.5 mg/kg/wk), a significant reduction in the incidence of var-iceal hemorrhage was observed compared with patients treated with colchi-cine. No reduction in the incidence of liver failure, the development of hepatocellular carcinoma, the need for liver transplantation, or death was observed. This suggests that continuing PEGIFN as maintenance therapy may selectively reduce portal pressure but may not affect the natural progression of chronic hepatitis C in patients who have advanced fibrosis or cirrhosis.

Final results from the various clinical trials evaluating PEGIFN maintenance therapy will not be available for several years. Based upon available data, it is possible to consider maintenance therapy for patients with advanced fibrosis or stable cirrhosis who have relapsed after treatment with PEGIFN/RVN and who can tolerate the side effects of long-term treatment. Initiating PEGIFN at full dose and gradually tapering the dosage every 3 months to the lowest dose that maintains HCV RNA undetectable is a rational approach to patients with chronic HCV infection and advanced fibrosis or cirrhosis. In contrast, maintenance therapy should probably not be considered at this time in patients who have already developed complications of cirrhosis, in patients who do not achieve VR during treatment with PEGIFN and RBV, or in patients who do not remain HCV RNA undetectable with maintenance PEGIFN monotherapy. There are no data to suggest that patients who remain HCV RNA positive while on maintenance therapy achieve significant benefit from ongoing treatment.

Maintenance therapy using ribavirin

One study has evaluated the benefit of continuing RBV as maintenance therapy in patients who have HCV with NR [77]. Although RBV monotherapy does not reduce serum HCV RNA levels, serum alanine aminotransferase (ALT) declines significantly [78]. This implies that RBV may act as an anti-inflammatory agent to reduce hepatic inflammation and serve as a basis for the use of RBV as maintenance therapy. In this pilot trial, 38 patients who had NR to IFN/RBV were randomized to discontinue IFN and remain on RBV (1000-1200 mg/d) or placebo. After discontinuation of IFN, serum HCV RNA levels rose back to the pretreatment baseline levels in both groups. Although mean serum ALT levels also rose after discontinuation of IFN, patients who remained on RBV had a lower mean serum ALT levels compared with placebo-treated patients. After 48 weeks of RBV maintenance therapy, repeat liver biopsy demonstrated that 47% of patients had a significant decline in inflammation, whereas this was not observed in the placebo group. Although no significant improvement in fibrosis was observed with RBV maintenance therapy, the decline in hepatic inflammation suggests that this approach could be useful for the management of patients who have HCV with NR. It remains unknown which subgroup of patients who have NR could benefit from RBV maintenance therapy and if this decline in inflammation could be maintained without suppressing serum HCV RNA levels. As a result, the use of RBV as maintenance therapy should be considered un-proven at this time.

Modifying lifestyle factors associated with fibrosis progression

Many patients with chronic HCV infection and NR to PEGIFN/RBV have no, mild, or moderate fibrosis. Many of these patients are not at risk for developing fibrosis progression to cirrhosis for 5 to 15 years or longer [73,79,80]. It is estimated that 25% to 33% of patients who have chronic HCV infection will never develop fibrosis. It is therefore rational for many patients who have chronic HCV infection to be observed at periodic intervals until definitive improvements in therapy have been established. During this period, a focus on modifying lifestyle factors that seem to enhance fibrosis progression seems rational.

Several studies have demonstrated that patients who have HCV who consume alcohol on a regular basis have an increased rate of fibrosis progression to cirrhosis and a higher percentage of cirrhosis than patients who consume ethanol rarely or not at alt [42,43,79,81,82]. The minimum amount of alcohol that seems to be safe and not associated with an enhanced rate of fibrosis progression in HCV patients remains undefined. It is therefore prudent to counsel HCV patients not to consume alcohol except on rare occasions.

Another factor that seems to be associated with more rapid fibrosis progression to cirrhosis is hepatic steatosis secondary to nonalcoholic fatty liver disease (NAFLD). Several recent studies have suggested that patients who have chronic hepatitis C and NAFLD, or more importantly nonalcoholic steatohepatitis, have more fibrosis and a higher prevalence of cirrhosis than patients who have HCV infection without fatty liver [83,84]. NAFLD is strongly associated with obesity, insulin resistance, and hyperlipidemia and seems to be improved by weight loss, improved control of diabetes mellitus, and lowering of serum lipids [85,86], Such recommendations are strongly encouraged for patients with chronic HCV infection and coexistent NAFLD.

Patients who have chronic HCV infection should be vaccinated to prevent other forms of viral hepatitis [87,88]. A recent study has demonstrated that patients with chronic hepatitis C who acquire acute hepatitis A virus (HAV) are at increased risk for developing fulminant hepatic failure [89]. Although this same study did not find an increased risk of liver failure after acute infection with hepatitis B virus (HBV), patients coinfected with HCV and HBV seem to progress to cirrhosis at a faster rate [90]. Because exposure to HAV is sporadic and cannot be predicted, it is recommended that all patients with chronic HCV infection be vaccinated against HAV [87,88]. In contrast, the great majority of adults with acute hepatitis B acquired this infection by participating in some sort of risk behavior, most commonly sexual activity or illicit drug use. It is not always possible to predict which HCV patients might indulge in these risk behaviors. As a result, vaccination of patients with chronic HCV and NR against HAV and HBV seems prudent.

Summary

The combination of PEGIFN and RBV is the most effective therapy for patients with chronic hepatitis C. Although more than half of all patients are able to achieve SVR, a significant proportion of patients, particularly those with genotype 1, fail to have undetectable HCV RNA during treatment or relapse after completing therapy with return of detectable HCV RNA. An approach in the management of these patients is to identify factors that could have led to the NR or relapse and that could be corrected before or during a second course of therapy. Because fibrosis progression occurs slowly over decades for many patients with chronic hepatitis C, avoiding alcohol or other factors that could lead to fibrosis progression may be sufficient for the vast majority of patients. Other options that could be considered in patients who have more advanced disease include retreating with one of several new antiviral agents; retreating with higher doses of IFN or PEGIFN and RBV; or using IFN, PEGIFN, or RBV monotherapy long-term as maintenance therapy. The safety and efficacy of these approaches is being evaluated in numerous clinical trials.

References

[1] Hoofnagle JH, Mullen KD, Jones B, et al. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon. N Engl J Med 1986;315:1575-8.

[2] Thomson BJ, Doran M, Lever AML, et al. Alpha-interferon therapy for non-A, non-B hepatitis transmitted by gammaglobulin replacement therapy. Lancet 1987;1:539-41.

[3] Poynard T, Bedossa P, Chevallier M, et al. A comparison of three interferon alfa-2b regimens for the long-term treatment of chronic non-A, non-B hepatitis. N Engl J Med 1995; 332:1457-62.

[4] McHutchinson JG, Gordon S, Schiff ER, 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.

[5] Poynard T, Marcellin P, Lee SS, et al. Randomized 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.

[6] Reddy KR, Wright TL, Pockros PJ, et al. Efficacy and safety of pegylated (40-KD) interferon a-2a compared with interferon a-2a in non-cirrhotic patients with chronic hepatitis C. Hepatology 2001;33:433-8.

[7] Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon-alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000;343:1666-72.

[8] Heathcote EJ, Shiffman ML, Cooksley WG, et al. Peginterferon Alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000;343:1673-80.

[9] Lindsay KL, Trepo C, Heintges T, et al. A randomized, double-blind trial comparing pegin-terferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology 2001;34:395-403.

[10] Manns MP, McHutchinson JG, Gordon SC, et al. Peginterferon-alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358:958-65.

[11] Fried MW, Shiffman ML, Reddy KR, et al. Combination of peginterferon alfa-2a (40 kd) plus ribavirin in patients with chronic hepatitis C vims infection. N Engl J Med 2002;347: 975-82.

[12] Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alfa 2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346-55.

[13] Shiffman ML, Di Bisceglie AM, Lindsay KL, etal. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004;126: 1015-23.

[14] Jacobsen IM, Ahmed F, Russo MW, et al. Pegylated interferon alfa-2b plus ribavirin in patients with chronic hepatitis C: a trial in prior nonresponders to interferon monotherapy or combination therapy and in combination therapy relapsers: final results. Gastroenterology 2003;124(Suppl 1):A-714.

[15] Herrine SK, Brown R Jr, Esposito S, et al. Efficacy and safety of peginterferon alfa-2a combination therapies in patients who relapsed on rebetron therapy. Hepatology 2002;36(Suppl 1): 358A.

[16] KrawittEL, Lidofsky SD, FerrentinoN, etal. Efficacy of peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C previously unresponsive to interferon-based therapy. Hepatology 2002;36(Suppl 1):359A.

[17] Ferreira-Gonzalez A, Shiffman ML. Use of diagnostic testing for managing hepatitis C virus infection. Semin Liver Dis 2004;24(Suppl 2):9-18.

[18] Lindsay KL. Therapy of hepatitis C: overview. Hepatology 1997;27(Suppl 1):71S-7S.

[19] Lindsay KL. Introduction to therapy of hepatitis C. Hepatology 2002;36(Suppl 1):S114-20.

[20] 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.

[21] Saldanha J, Lelie N, Heath A. Establishment of the first international standard for nucleic acid amplification technology assays for HCV RNA. WHO collaborative study group. Vox Sang 1999;76:149-58.

[22] Shiffman ML, Ferreira-Gonzalez A, Reddy KR, et al. Comparison of three commercially available assays for HCV RNA using the international unit standard: implications for management of patients with chronic hepatitis C virus infection in clinical practice. Am J Gastroenterol 2003;98:1159-66.

[23] Anderson JC, Simonetti J, Fisher DG, et al. Comparison of different HCV viral load and genotyping assays. J Clin Viral 2003;28:27-37.

[24] Nolte FS, Fried MW, Shiffman ML, et al. Prospective multicenter clinical evaluation of AMPL1COR and COBAS AMPLICOR hepatitis C virus tests. J Clin Microbiol 2001;39: 4005-12.

[25] Morishima C, Gretch DR. Clinical use of hepatitis C virus tests for diagnosis and monitoring during therapy. Clin Liver Dis 1999;3:717-40.

[26] Davis GL. Monitoring of viral levels during therapy of hepatitis C. Hepatology 2002; 36(Suppl 1):S145-51.

[27] Shiffman ML. Side effects of medical therapy for chronic hepatitis C. Ann Hepatol 2004;3: 5-10.

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

[29] Hadziyannis S, Cheinquer H, Morgan T, et al. Peginterferon alfa-2a in combination with ribavirin: efficacy and safety results from a phase III randomized, double-blind, multicenter trial examining effect of duration of treatment and ribavirin dose. J Hepatol 2002; 36(Supp 1):3.

[30] Shiffman ML, Morgan TR, Ghany MG, et al. The impact of peginterferon and ribavirin dosing on sustained virologic response in patients with chronic hepatitis C virus undergoing re-treatmentin the HALT-C trial. HALT-C trial group. Hepatology 2004;40(Suppl 1):314A.

[31] De Franceschi L, Fattovich G, Turrini F, et al. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology 2000;31:997-1004.

[32] Shiffman ML, Hermann CM, Sterling RK, et al. A randomized, controlled trial to determine if continuing ribavirin as monotherapy in patients who responded to interferon/ribavirin combination therapy will enhance sustained virologic response. J Infect Dis 2001;184: 405-9.

[33] Maddrey WC. Safety of combination interferon alfa-2b/ribavirin therapy in chronic hepatitis C-relapsed and treatment-naive patients. Semin Liver Dis 1999;19(Suppl l):67-75.

[34] Nichols M, Kugelmas M. Reasons for discontinuation of treatment of chronic hepatitis C: an interim analysis of the Frontier trial. Gastroenterology 2003;124(Suppl 1):A703.

[35] Dieterich DT, Wasserman R, Brau N, et al. Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa. Am J Gastroenterol 2003;98:2491-9.

[36] Afdhal NH, Dieterich DT, Pockros PJ, et al. Correction of anemia with epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind study. Gastroen-terology 2004;126:1302-11.

[37] Pockros PJ, Shiffman ML, Schiff ER, et al. Epoetin alfa improves quality of life in anemic HCV-infected patients receiving combination therapy. Hepatology 2004;40:1450-8.

[38] Ahmed F, Jacobson IM, Brown RS Jr, et al. Neutropenia and infections in the WIN-R trial. Gastroenterology 2003;124(Suppl 1).

[39] Boks AL, Brommer EJ, Schalm SW, et al. Hemostasis and fibrinolysis in severe liver failure and their relation to hemorrhage. Hepatology 1986;6:79-86.

[40] Hauser P. Neuropsychiatric side effects of HCV therapy and their treatment focus on IFN alpha-induced depression. Gastroenterol Clin North Am 2004;33(Suppl 1):S35-50.

[41] Maddock C, Baita A, Orru MG, et al. Psychopharmacologic treatment of depression, anxiety, irritability and insomnia in patients receiving interferon-alpha: a prospective case series and a discussion of biologic mechanisms. J Psychopharmacol 2004;18:41-6.

[42] Schiff ER, Ozden N. Hepatitis C and alcohol. Alcohol Res Health 2003;27:232-9.

[43] Peters MG, Terrault NA. Alcohol use and hepatitis C. Hepatology 2002;36:S220-5.

[44] Loguercio C, Di Pierro M, Di Marino MP, et al. Drinking habits of subjects with hepatitis C virus-related chronic liver disease: prevalence and effect on clinical, virological and pathological aspects. Alcohol 2000;35:296-301.

[45] Edlin BR. Prevention and treatment of hepatitis C in injection drug users. Hepatology 2002; 36(Suppl 1):S210-9.

[46] Sylvestre DL, Clements BJ. The impact of negative prognostic factors on hepatitis C treatment outcomes in recovering injection drug users. Hepatology 2002;36:223A.

[47] McHutchison JG, Patel K. Future therapy of hepatitis C. Hepatology 2002;36:S245-52.

[48] Hinrichsen H, Benhamou Y, Wedemeyer H, et al. Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. Gastroenterology 2004;127:1347-55.

[49] O'Brien C, Godofsky E, Rodriquez-Torres M, et al. Randomized trial of valopicitabine (NM283) alone or with peg-interferon vs. retreatment with peg-interferon plus ribavirin in hepatitis C patients with previous non-response PEGIFN/RBV: first interim results [abstract #95]. Hepatology 2005;42:234A.

[50] Reesink HW, Zeuzem S, Weegink CJ, et al. Final results of a phase 1b, multiple dose study of VX-950, a hepatitis C virus protease inhibitor [abstract #96]. Hepatology 2005;42:234A-5A.

[51] Zeuzem S, Sarrazin C, Wagner F, et al. Combination therapy with the HCV protease inhibitor, SCH 503034, plus peg-intron in hepatitis C genotype 1 peg-intron non-responders: Phase 1b results [abstract #201]. Hepatology 2005;42:276A.

[52] Heathcote EJ, Keeffe EB, Lee SS, et al. Re-treatment of chronic hepatitis C with consensus interferon. Hepatology 1998;27:1136-43.

[53] Kaiser S, Hass H, Gregor M. Successful retreatment of peginterferon nonresponders with chronic hepatitis C with high dose consensus interferon induction therapy. Gastroenterology 2003;124(Suppl 1):A700.

[54] Leevy C II, Chamers C, Blatt L. Comparison of African American and non-African American patient end of treatment response for PEG1FN alpha-2a and weight based ribavirin nonresponders retreated with 1FN alfacon-1 and weight based ribavirin. Hepatology 2004;40(Suppl 1):240A.

[55] Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-hispanic whites. N Engl J Med 2004;350: 2265-71.

[56] Diago M, Crespo J, Oliveira A, et al. Peginterferon alfa-2a and ribavirin in patients infected with HCV genotype 1 who failed to respond to interferon and ribavirin: final results of the Spanish high dose induction pilot trial. Hepatology 2004;40(Suppl 1):389A.

[57] Sanchez-Tapias JM, Diago M, Escartin P, et al. Hepatology 2004;40(Suppl 1):218A.

[58] Younossi ZM, Perrillo RP. The roles of amantadine, rimantadine, ursodeoxycholic acid and NSAIDs, alone or in combination with alfa interferons in the treatment of chronic hepatitis C. Semin Liver Dis 1999;19:95-102.

[59] Smith JP. Treatment of chronic hepatitis C with amantadine. Dig Dis Sci 1997;42:1681-7.

[60] Helbling B, Stamenic I, Viani F, et al. Interferon and amantadine in naive chronic hepatitis C: a double-blind, randomized, placebo-controlled trial. Hepatology 2002;35:447-54.

[61] Teuber G, Pascu M, Berg T, et al. Randomized, controlled trial with IFN-alpha combined with ribavirin with and without amantadine sulphate in non-responders with chronic hepatitis C. JHepatol 2003;39:606-13.

[62] Thuluvath PJ, Maheshwari A, Mehdi J, et al. Randomized, double blind, placebo controlled trial of interferon, ribavirin, and amantadine versus interferon, ribavirin, and placebo in treatment naive patients with chronic hepatitis C. Gut 2004;53:130-5.

[63] Mangia A, Leandro G, Helbling B, et al. Combination therapy with amantadine and interferon in naive patients with chronic hepatitis C: meta-analysis of individual patient data from six clinical trials. J Hepatol 2004;40:478-83.

[64] Fargion S, Borzio M, Predabissi O, et al. End of treatment and sustained response to pegin-terferon alfa-2a plus ribavirin and amantadine and to induction therapy with interferon alfa-2a plus ribavirin and amantadine in interferon/ribavirin nonresponders with chronic hepatitis C. Hepatology 2003;38(Suppl 1):733A.

[65] Cantu NS, Davis M, Afdahl N, et al. Triple therapy compared to standard pegylated interferon alfa-2b and weight based ribavirin for previous nonresponders and relapsers with chronic hepatitis C. Hepatology 2003;38(Suppl 1):742A.

[66] Shiffman ML, Hermann CM, Thompson EB, et al. Relationship between biochemical, viro-logic and histologic response during interferon treatment of chronic hepatitis C. Hepatology 1997;26:780-5.

[67] Shiffman ML. Histologic improvement in response to interferon therapy in chronic hepatitis C. Viral Hepatitis Rev 1999;5:27-43.

[68] 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.

[69] Imai Y, Kawata S, Tamura S, et al. Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. Ann Intern Med 1998;129:94-9.

[70] Yoshida H, Arakawa Y, Sata M, et al. Interferon therapy prolonged life expectancy among chronic hepatitis C patients. Gastroenterology 2002;123:483-91.

[71] Fattovich G, Giustina G, Degos F, et al. Effectiveness of interferon alfa on incidence of he-patocellular carcinoma and decompensation in cirrhosis type C. European concerted action on viral hepatitis. J Hepatol 1977;27:201-5.

[72] Shiffman ML, Hofmann CM, Contos MJ, et al. A randomized, controlled trial of maintenance interferon for treatment of chronic hepatitis C non-responders. Gastroenterology 1999;117:1164-72.

[73] Yano M, Kumada H, Kage M, et al. The long term pathological evolution of chronic hepatitis C. Hepatology 1996;23:1334-40.

[74] Ghany MG, Kleiner DE, Alter H, et al. Progression of fibrosis in chronic hepatitis C. Gastroenterology 2003;124:97-104.

[75] Lee WM, Dienstag JL, Lindsay KL, et al. Evolution of the HALT-C trial: pegylated interferon as maintenance therapy for chronic hepatitis C in previous interferon nonresponders. Control Clin Trials 2004;25:472-92.

[76] Afdhal N, Freilich B, Levine R, et al. Colchicine versus Peg-Intron long term (CoPilot) trial: interm analysis of clinical outcomes at year 2. Hepatology 2004;40(Suppl 1):239A.

[77] Hoofnagle JH, Ghany MG, Kleiner DE, et al. Maintenance therapy with ribavirin in patients with chronic hepatitis C who fail to respond to combination therapy with interferon alfa and ribavirin. Hepatology 2003;38:66-74.

[78] Di Bisceglie AM, Conjeevaram HS, Fried MW, et al. Ribavirin as therapy for chronic hepatitis C: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123: 897-903.

[79] Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINVIR and DOSVIRC groups. Lancet 1997;349:825-32.

[80] Afdhal NH. The natural history of hepatitis C. Semin Liver Dis 2004;24(Suppl 2):3-8.

[81] Safdar K, Schiff ER. Alcohol and hepatitis C. Semin Liver Dis 2004;24:305-15.

[82] Wiley TE, McCarthy M, Breidi L, et al. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology 1998;28:805-9.

[83] Ramesh S, Sanyal AJ. Hepatitis C and nonalcoholic fatty liver disease. Semin Liver Dis 2004; 24:399-413.

[84] Younossi ZM, McCullough AJ, Ong JP, et al. Obesity and non-alcoholic fatty liver disease in chronic hepatitis C. J Clin Gastroenterol 2004;38:705-9.

[85] Haynes P, Liangpunsakul S, Chalasani N. Nonalcoholic fatty liver disease in individuals with severe obesity. Clin Liver Dis 2004;8:535-47.

[86] Lonardo A, Adinolfi LE, Loria P, et al. Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterol 2004;126:586-97.

[87] Reiss G, Keeffe EB. Review article: hepatitis vaccination in patients with chronic liver disease. Aliment Pharmacol Ther 2004;19:715-27.

[88] Strader DB, Wright T, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004;39:1147-71.

[89] Vento S, Garofano T, Renzini C, et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med 1998;338:286-90.

[90] Sterling RK, Sulkowski MS. Hepatitis C virus in the setting of HIV or hepatitis B virus co-infection. Semin Liver Dis 2004;24(Suppl 2):61-8.

Infect Dis Clin N Am 20 (2006) 137-153

Was this article helpful?

0 0
Weight Loss New Years Resolution Success

Weight Loss New Years Resolution Success

Sure you haven’t tried this program before but you no doubt aren’t a stranger to the dieting merry go-round that has been plaguing your life up to this point.

Get My Free Ebook


Post a comment