From
Medscape Gastroenterology
Hepatology Focus
Update on Hepatitis C Treatment
Series Editor:
Paul Martin, MD, Cedars-Sinai Medical Center, and UCLA School of Medicine, Los Angeles, California
Sammy Saab, MD, Clinical Instructor, UCLA School of Medicine, Los Angeles, California, and Paul Martin, MD, Medical Director, Liver Transplantation, Cedars-Sinai Medical Center, Associate Professor of Medicine, UCLA School of Medicine, Los Angeles, California
[Medscape Gastroenterology, 3(1) 2001. © 2001 Medscape, Inc.]
 Background
Although screening of blood products and other interventions such as clean-needle exchange programs have significantly reduced the incidence of acute hepatitis C in the United States and elsewhere, there remains a large reservoir of chronically infected individuals, many of whom are unaware of their infection. Current estimates suggest a seroprevalence of 1.8% among Americans, most of whom are viremic.[1] The clinical burden of chronic hepatitis C virus (HCV) infection is expected to increase over the next 2-3 decades as a large cohort of patients infected between the 1960s and 1980s, primarily as a result of recreational drug use, develops progressive liver disease. Between 8000 and 10,000 deaths each year in the United States are believed to be caused by infection with HCV -- which is now the most frequent indication for liver transplantation.[2]
Even before identification of HCV, interferon-alfa (IFN-alfa) had been evaluated as a potential therapy for what had been called chronic non-A, non-B hepatitis.[3]
Further studies using normalization of serum alanine aminotransferase (ALT) levels and improvement in liver histology as endpoints demonstrated the efficacy of IFN-alfa as therapy for the causative agent of chronic non-A, non-B hepatitis (HCV).[4,5] Subsequent advances in molecular diagnosis have now increasingly allowed establishment of virologic criteria to evaluate efficacy of treatment in patients with chronic hepatitis C (see Table).
Definition of Virologic Response in Patients Receiving Therapy for Chronic Hepatitis C
End-of-treatment response (ETR) refers to absence of viremia (ie, serum HCV RNA below level of detection) at completion of therapy. Sustained response (SR) indicates persistent absence of serum HCV RNA 6 months or more after cessation of therapy. A study by Marcellin and coworkers[6] on the long-term clinical outcome in 80 patients with chronic HCV followed for a mean of 4 years following therapy highlighted the clinical implications of a virologic SR. Persistent absence of HCV RNA from serum was observed in 96% of patients with a lack of histologic progression on serial liver biopsy. In addition, ALT levels were persistently normal in over 90%. The most recent follow-up biopsy showed normal or near normal histologic findings in 62% of these patients. Thus, virologic SR was shown to be associated with both an absence of detectable serum HCV RNA and marked histologic improvement.
Relapsers are defined as patients who have undetectable serum HCV RNA at completion of therapy but who subsequently redevelop viremia. Nonresponders (NRs) are patients who fail to clear HCV RNA from serum during therapy.
A recent paper by Everson and associates[7] underscores the importance of HCV RNA testing in defining treatment response. In patients with marked fibrosis and cirrhosis, they found a major discrepancy between biochemical (ALT) and virologic (HCV RNA) responses to therapy. Two of 7 (29%) patients with marked fibrosis and 2 of 6 (33%) patients with cirrhosis cleared HCV RNA without normalizing ALT. In contrast, only 3 patients (10%) without significant fibrosis had an HCV RNA response without normalization of ALT. Thus, clinical trials for chronic HCV are now typically reported using virologic response rates.
What then are the current goals of antiviral therapy in patients with chronic hepatitis C? Immediate goals are eradication of viral replication and improvement in hepatic inflammation and fibrosis. Long-term potential goals include prevention of cirrhosis, hepatocellular carcinoma, and liver failure.
Interferon Monotherapy
IFN-alfa 2 was the first agent approved for the treatment of chronic HCV. Since the initial trials establishing its efficacy, data regarding treatment duration and dose have evolved. Currently, 2 forms of IFN-alfa that differ by a single amino acid residue are approved for treatment of chronic HCV infection: IFN-alfa 2b (Schering-Plough, Kenilworth, New Jersey) and IFN-alfa 2a (Hoffmann-La Roche, Basel, Switzerland). The recommended dose is 3 million units 3 times each week for up to 12 months.
When used alone in monotherapy, the alfa interferons have similar efficacies, with SRs of only 10% to 20%, with the modestly higher response rates associated with more prolonged therapy. Higher-dose IFN-alfa (ie, > 9 million units per week) results in SRs between 8% and 20% in treatment-naive patients. High-dose IFN-alfa has also been studied in NRs and relapsers, but with mixed results. With prior NR, SRs achieved with higher doses are only between 0% and 4%. In relapsers, SRs range from 20% to 40%. However, side effects are more troublesome with higher doses.[8]
Because of the low overall response rate to standard IFN-alfa, more recent studies have focused on newer regimens, including synthetic IFN (IFN alfacon-1), "combination" therapy (IFN-alfa 2b + ribavirin), and longer-acting IFNs (pegylated IFNs). A number of major pretherapy predictors of NR have been identified, notably HCV genotype 1, the presence of cirrhosis, and higher viral load.[9] In addition, patient's race appears to affect response to IFN, with African Americans having an overall low SR to therapy.[10]
Combination Therapy
A significant improvement in SR resulted from the addition of ribavirin to standard IFN-alfa. Ribavirin, a guanosine analogue, was initially evaluated as monotherapy for chronic HCV because of its antiviral activity against other RNA viruses.[11-13] Although as monotherapy it reduces ALT levels, it does not appear to have a direct antiviral effect and fails to lower serum HCV RNA levels. Moreover, results of most studies with ribavirin have found no improvement in hepatic histology, although a longer 2-year treatment regimen was shown to reduce necroinflammatory activity.[13]
However, in combination with IFN-alfa 2b, ribavirin leads to a significant increase in SR in treatment-naive patients.[14] SRs of 31% with 24 weeks and 38% with 48 weeks of combination therapy were achieved vs 6% with 24 weeks and 13% with 48 weeks of IFN monotherapy.[14] In relapsers, enhanced SR rates also occur on retreatment using combination therapy, from 30% to 49%; in prior NRs, SR of 14% has been reported with 6 months of combination therapy.[15,16]
Histologic improvement was more common among treatment-naive patients treated with combination therapy.[14] Similar improvement was found in a randomized controlled trial of treatment-relapse patients.[15]
However, the improved SR rates observed with combination therapy are also associated with more expense and an increased frequency of adverse effects compared with IFN-alfa monotherapy.[14] Dose-related hemolytic anemia is a particular concern with ribavirin[11,13] as is teratogenicity, based on animal studies.[16] The mean drop in hemoglobin in patients treated with combination therapy is between 2 and 3 g/dL, although a fall of more than 4 g/dL has been observed in about 10% of patients. The anemia may be poorly tolerated in patients with ischemic heart disease in particular as treatment is extended to older patients.[17] Accumulation of ribavirin metabolites that are not cleared by dialysis occurs in end-stage renal disease.(18)
Consensus Interferon
Consensus IFN (CIFN; IFN alfacon-1, Amgen, Thousand Oaks, California) is a genetically engineered compound synthesized by combining the most common amino acid sequences from naturally occurring IFNs.[19,20] CIFN shares 88% homology with IFN-alfa and 30% with IFN-beta. Although it has greater cytokine induction, antiviral, antiproliferative, natural killer cell, and gene-induction activities than both IFN-alfa 2a and IFN-alfa 2b on an equal mass basis, initial studies with the recommended CIFN dose of 9 mcg in IFN-naive patients with chronic hepatitis C resulted in viral response rates similar to those achieved with standard IFN-alfa monotherapy.[19,20]
More recently, higher-dosage CIFN regimens of 15 mcg thrice weekly were reported to result in virologic SRs of 13% in prior NRs and 58% in relapsers treated for 48 weeks.[21]
Pegylated Interferon
Pharmacokinetic studies have provided a rationale for enhanced IFN dosing. The initial decline in serum HCV RNA levels seen after a single dose of IFN therapy is believed to reflect a direct antiviral effect, whereas the subsequent and more delayed decline in HCV RNA levels is due to destruction of infected hepatocytes.[22] An important limitation of the antiviral effect of standard IFN dosing is the rapid decline in circulating drug level with thrice-weekly administration. The short half-life of the drug and the rapid production of HCV virions diminish the efficacy of standard IFN therapy. In an effort to achieve more stable and efficacious IFN activity, pegylated formulations have been developed.
The production of a pegylated IFN involves the addition of a nontoxic long-acting formulation of interferon using the drug delivery system of pegylation. Polyethylene glycol molecules are added to IFN-alfa 2a (Pegasys, Hoffmann-La Roche) and IFN-alfa 2b (PEG-Intron, Schering-Plough). Pegylation is already used in the delivery of other drugs. Its attachment to IFN-alfa permits once-weekly dosing.
In a recent report, Zeuzem and colleagues[23] indicate that at week 72, the SR was 39% after 48 weeks of therapy at a dose of 180 mcg with pegylated IFN alfa-2a compared with a 19% SR in control patients. Drug discontinuation in these treatment-naive patients and frequency of dose reduction were similar in the 2 treatment arms. Heathcote and colleagues[24] have also reported on the use of pegylated IFN alfa-2a in a controlled trial in cirrhotic patients. SR was 30% following 48 weeks of therapy with 180 mcg, compared with 8% for patients treated with standard alfa IFN, again without a significant increase in side effects with the pegylated product.
Trepo and colleagues[25] have also reported, in abstract form, initial studies with pegylated IFN-alfa 2b. Virologic SR for the unmodified IFN-alfa 2b (3 million units, thrice weekly for 48 weeks) was 12%, whereas the SR for the pegylated IFN-alfa 2b was 18%, 25%, and 23% with 0.5 mcg/kg, 1.0 mcg/kg, and 1.5 mcg/kg, respectively, administered weekly in treatment-naive patients.
As with standard IFN-alfa monotherapy, ribavirin may augment response rates when combined with the pegylated IFNs.[26,27] Recent trials will help evaluate further the role of ribavirin in augmenting the efficacy of pegylated IFN (see Figure).
 |
Figure. (click image to zoom) Initial antiviral therapy against hepatitis C virus.*
* Abbreviations: IFN = interferon; CSN = consensus interferon; IFN/RIB = interferon + ribavirin; PEG = pegylated interferon; PEG/RIB = pegylated interferon + ribavirin. |
Future Trends
There has been continued interest in developing non-IFN-based therapies for HCV despite the promise of the pegylated IFNs. A recent study examined the role of human interleukin-10 in treating prior NRs with chronic HCV.[28] Although, HCV RNA remained detectable in all patients at the end of treatment,[25] 5 (23%) of the 22 treated patients had persistent ALT normalization at the end of follow-up. Future studies should determine whether combining interleukin-10 with other antiviral agents will increase efficacy in this setting. Interleukin-12 has also been evaluated as monotherapy, again without clear antiviral benefit.[29]
There is also increasing enthusiasm for targeting HCV molecular products. For example, ribozyme gene therapy has the potential to accurately degrade HCV RNA.[30] Human studies are anticipated.
Conclusion
Treatment options for HCV infection continue to expand. Whereas SRs of 10% were achieved with IFN monotherapy only several years ago, it may soon be possible to achieve SR rates greater than 50% with combination pegylated IFN and ribavirin. Molecular-based, specific therapeutic strategies are also likely to become a reality in the future, although therapy will remain interferon-based the next several years.
References
- Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556-562.
- Centers for Disease Control and Prevention Web site. Available at www.cdc.gov. Accessed February 1, 2000.
- Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon. A preliminary report. N Engl J Med. 1986;315:1575-1578.
- Di Bisceglie AM, Martin P, Kassianides C, et al. Recombinant interferon alfa therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. N Engl J Med. 1989;321:1506-1510.
- Davis GL, Balart LA, Schiff ER, et al. Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial. Hepatitis Interventional Therapy Group. N Engl J Med. 1989;321:1501-1506.
- Marcellin P, Boyer N, Gervais A, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med. 1997;127:875-881.
- Everson GT, Jensen DM, Craig JR, et al. Efficacy of interferon treatment for patients with chronic hepatitis C: comparison of response in cirrhotics, fibrotics, or nonfibrotics. Hepatology. 1999;30:271-276.
- Iino S. High dose interferon treatment in chronic hepatitis C. Gut. 1993;34:114S-118S.
- Davis GL, Lau JY. Factors predictive of a beneficial response to therapy of hepatitis C. Hepatology. 1997;26:122S-127S.
- Reddy KR, Hoofnagle JH, Tong MJ, et al. Racial differences in responses to therapy with interferon in chronic hepatitis C. Consensus Interferon Study Group. Hepatology. 1999;30:787-793.
- Dusheiko G, Main J, Thomas H, et al. Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study. J Hepatol. 1996;25:591-598.
- Bodenheimer HC Jr, Lindsay KL, Davis GL, et al. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial. Hepatology. 1997;26:473-477.
- 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.
- McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1485-1492.
- Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1493-1499.
- Barbaro G, Di Lorenzo G, Belloni G, 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;107:112-118.
- Lyons M, Coddou A, Varon C, et al. Side effect profile of combination with interferon alpha-2b and ribavirin in a community-based clinical trial. Gastroenterology. 1999;116:A77.
- Glue P, Tan Y, Sacks M, et al. Use of ribavirin in patients with renal and hepatic dysfunction -- pharmacokinetic data and recommendations. Hepatology. 1999;30:309A.
- Ozes ON, Reiter Z, Klein S, et al. A comparison of interferon-Con1 with natural recombinant interferons-alpha: antiviral, antiproliferative, and natural killer-inducing activities. J Interferon Res. 1992;12:55-59.
- Klein SB, Blatt LM, Taylor MW. Consensus interferon induces peak mRNA accumulation at lower concentrations than interferon-alpha 2a. J Interferon Res. 1993;13:341-347.
- Heathcote EJ, Keeffe EB, Lee SS, et al. Re-treatment of chronic hepatitis C with consensus interferon. Hepatology. 1998;27:1136-1143.
- Zeuzem S. Clinical implications of hepatitis C viral kinetics. J Hepatol. 1999;31:61S-64S.
- Zeuzem S, Feinman SV, Raseneck J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med. 2000;343:1666-1672.
- Heathcote EJ, Shiffman ML, Cooksley WG, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med. 2000;343:1673-1680.
- Trepo C, Lindsay K, Niederau C, et al. Pegylated interferon alfa-2B (PEG-Intron) monotherapy is superior to interferon alfa-2B (Intron A) for the treatment of chronic hepatitis C. J Hepatol. 2000;32:29.
- Sulkowski MS, Reindollar R, Yu J. Pegylated interferon alfa-2A (PEGASYS) and ribavirin combination therapy for chronic hepatitis C: a phase II open-label study. Gastroenterology. 2000;118:A950.
- Manns MP, McHutchinson JG, Gordan S, et al. Peginterferon alfa-2b plus ribavirin compared to interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C: 24 week treatment analysis of a multicenter, multinational phase III randomized controlled trial. Hepatology. 2000;32:297A.
- Nelson DR, Lauwers GY, Lau JY, et al. Interleukin 10 treatment reduces fibrosis in patients with chronic hepatitis C: a pilot trial of interferon nonresponders. Gastroenterology. 2000;118:655-660.
- Zeuzem S, Hopf U, Carreno V, et al. A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis C. Hepatology. 1999;29:1280-1287.
- Welch PJ, Yei S, Barber JR. Ribozyme gene therapy for hepatitis C virus infection. Clin Diagn Virol. 1998;10:163-171.
Paul Martin, MD, has disclosed that he holds source of funding for clinical grants from Schering-Plough and Hoffmann-La Roche. He is on the Speakers' Bureau for Schering-Plough and Hoffmann-La Roche and is a consultant for Hoffmann-La Roche. Sammy Saab, MD, has no significant financial interests to disclose.
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