Adrian M. Di Bisceglie, MD, FACP
Tremendous progress has been made in the field of viral hepatitis over the last 2 decades. In addition to having the tools to control hepatitis A and hepatitis B through the application of vaccines, we now have therapies that are effective in many patients with chronic viral hepatitis. For hepatitis C, improvements in treatment have allowed a large proportion of patients with chronic hepatitis C virus (HCV) infection to essentially be cured of their viral infection. The optimal response to therapy is the sustained virologic response, a term that refers to patients becoming seronegative for HCV RNA while on therapy and remaining negative for at least 6 months after stopping treatment. It is recognized that if patients do not achieve an early virologic response (HCV-RNA-negative or reduced by a 2-log drop from baseline at week 12 of therapy), they have little or no chance of going on to achieve a sustained virologic response.
New information presented at this year's Digestive Disease Week (DDW) meeting focused on even greater improvement of these advances in therapy and on expanding clinicians' knowledge regarding patients with hepatitis C who do not "fit" the typical profile (ie, special populations).
Previously, considerable attention has been paid to the interactions between hepatic steatosis and progression of liver disease due to hepatitis C. Many clinicians have found correlations between the presence and degree of hepatic steatosis and the degree of portal fibrosis associated with HCV infection.
A study from the National Institutes of Health (NIH), conducted by Perumalswami and colleagues, questioned whether this is simply an association or a cause and effect. Thus, they reviewed liver biopsies from 494 patients with hepatitis C and assessed the degree of steatosis in these biopsy specimens. On multivariate analysis of viral and host factors associated with this steatosis, only age, body mass index, and serum alanine aminotransferase (ALT) levels correlated with steatosis. Of the 494 patients, 140 underwent follow-up liver biopsy. They found that the presence and degree of hepatic steatosis in the original biopsy did not predict the degree of progression of hepatic fibrosis on follow-up.
Clearly, this finding needs to be confirmed or contradicted in other prospective studies. If steatosis is associated with more rapid progression of fibrosis, then it could be speculated that exercise and weight loss may perhaps ameliorate hepatic injury due to HCV.
There has been growing awareness regarding the existence and clinical significance of infection with HIV among patients with chronic hepatitis C and of infection with HCV among patients infected with HIV. Although the precise magnitude of this problem remains unknown, a report from the 2002 NIH Consensus Conference on Management of Hepatitis C included a recommendation that patients with HCV infection with risk factors for HIV infection should be offered testing for this coinfecting viral agent.
Bini and coworkers reported on a survey they conducted of nearly 5000 patients with chronic hepatitis C being evaluated for antiviral therapy at multiple sites throughout the United States. Two important findings from this survey were that 8.4% of patients were seropositive for HIV, and, perhaps even more disturbing, that a substantial proportion of patients were not offered testing at all. These findings emphasize the importance of testing patients with chronic hepatitis C for HIV coinfection.
Liver Transplantation in Patients With Hepatitis C
Another special population of patients in the setting of HCV infection includes those individuals undergoing liver transplantation. Cirrhosis due to hepatitis C is the leading indication for liver transplantation in the West. Unfortunately, recurrence of hepatitis C post transplantation is nearly universal, and appears to considerably shorten the graft survival when compared with liver transplants performed for autoimmune liver diseases, such as primary biliary cirrhosis and primary sclerosing cholangitis. In this context, liver transplant programs are becoming increasingly reluctant to offer re-transplantation to patients with severe recurrent hepatitis C.
Chalasani and colleagues reported on the results of 2 clinical trials using peginterferon alfa-2a* to treat recurrent hepatitis C. They found that the use of interferon impeded the progression of hepatic fibrosis compared with untreated controls. However, only about 10% of treated patients achieved a sustained virologic response after 48 weeks of treatment.
These study findings contribute to mounting evidence regarding the benefits of treating recurrent hepatitis C in the posttransplant setting, although such therapy is not yet considered standard and neither of the 2 licensed forms of peginterferon have US Food and Drug Administration approval for use in this setting. It is interesting to note that neither of these 2 trials evaluated used ribavirin in combination with peginterferon. Many patients have minor degrees of renal insufficiency after transplantation because of the use of calcineurin inhibitors as immunosuppressive agents. Ribavirin is renally excreted, making its use potentially dangerous in this setting.
Advances in Treatment
Effect of Twice-Weekly Administration of Peginterferon on Sustained Virologic Response
Considerable controversy remains regarding the relative benefits of the 2 forms of peginterferon in treating patients with chronic hepatitis C. In the pivotal trials leading up to the licensing of peginterferon alfa-2a and peginterferon alfa-2b in combination with ribavirin for treatment of hepatitis C, rates of sustained response were found to be similar with both agents [10,11] Nonetheless, it has been suggested that the half-life in serum of peginterferon alfa-2b is the shorter of the 2 forms of peginterferon and, indeed, its drug levels in serum are very low on days 6 and 7 after the typical once-weekly injection.
Therefore, Lodato and colleagues tested the benefits of using peginterferon alfa-2b twice weekly* in a randomized, controlled trial involving 65 patients who received peginterferon either once (1.5 mcg/kg) or twice (mean dose, 2.4 mcg/kg/week ) weekly. The patients who received twice-weekly peginterferon alfa-2b achieved significantly higher rates of sustained virologic response compared with those receiving once-weekly treatment (46% vs 27%, respectively, for genotype 1). Clearly, more studies involving larger numbers of patients will be required to validate this approach, but these preliminary findings are intriguing.
There is an ever-growing number of patients with chronic hepatitis C who have undergone treatment with combination peginterferon and ribavirin, but who either do not respond to therapy or who respond and then relapse. Typically, these patients are either encouraged to remain under observation in the hope that more effective therapies will be developed at some point in the future, or they are enrolled in clinical trials testing new approaches to therapy. There is little information available on simply re-treating patients again with the same or similar therapeutic regimen.
Dalke and colleagues retreated 195 patients with chronic hepatitis C who were nonresponders and relapsers to a previous course of standard therapy. Patients were randomly allocated to receive either 0.5 or 1.5 mcg/kg/week of peginterferon alfa-2b plus ribavirin 800 mg per day, for a total of 48 weeks.* Nonresponders receiving the higher dose of peginterferon achieved higher rates of sustained virologic response than did those patients receiving the lower dose (24% vs 6%). Previous relapsers to therapy similarly had better outcomes when retreated with higher doses of peginterferon (52% vs 29%).
Although these findings appear promising, they are somewhat in conflict with a recent report regarding the use of peginterferon alfa-2a and ribavirin in previous nonresponders to standard interferon and ribavirin-based therapy, in which the rate of sustained virologic response was no more than 11%.
Other approaches to treatment of nonresponders to previous therapy include combining alpha interferon with gamma interferon, as well as the use of consensus interferon, in patients failing therapy with either form of peginterferon. Leevy and colleagues reported on their experience substituting the combination of daily consensus interferon and gamma interferon* for combination peginterferon plus ribavirin therapy in patients who had not achieved an early virologic response by week 12 of therapy. Nearly 50% of patients with HCV genotype 1 who received this re-treatment regimen went on to achieve on-treatment virologic responses; data regarding sustained virologic responses were not yet available.
In another study, Kaiser and coworkers from Germany randomized 60 nonresponders to combination peginterferon and ribavirin therapy to re-treatment with consensus interferon at a high dose (starting at 27 mcg/day and tapering to 9 mcg/day)* and a lower dose (9 mcg/day), in combination with ribavirin. The study cohort included more than 90% HCV genotype 1 patients, with nearly 30% having cirrhosis. The rate of sustained virologic response was 27% with high-dose consensus interferon and 23% with the lower dose. These intriguing results need to be confirmed, and a larger phase 3 trial will be conducted with this agent.
There was considerable excitement at this year's DDW meeting regarding 2 new agents currently undergoing development for treatment of hepatitis C. The first of these agents, viramidine,* is a prodrug of ribavirin. Viramidine is taken up by the liver to a much larger degree than is ribavirin, which tends to accumulate in red blood cells, thus leading to hemolysis (often dose-limiting).
Gish and colleagues presented results of a phase 2 trial of viramidine and ribavirin used in combination with peginterferon alfa-2a to assess the effect of treatment on hemoglobin levels and antiviral activity. This trial involved 180 patients with chronic hepatitis C who had not been treated previously with ribavirin or interferon. All subjects received peginterferon alfa-2a; they were then randomized into 1 of 4 groups, receiving 400 mg, 600 mg, or 800 mg viramidine twice daily, or the standard ribavirin dose of 1000-1200 mg/day. Although all subjects have not yet completed treatment or follow-up, an analysis at week 24 showed that the degree of hemolysis was significantly reduced in all of the groups receiving viramidine compared with patients receiving ribavirin. Furthermore, the degree of reduction in serum HCV RNA level was not different between groups. Thus, viramidine appears to have comparable antiviral activity against HCV, with less associated anemia. The final results of this trial will be critical in allowing assessment of whether rates of sustained virologic response are comparable with ribavirin and viramidine. If they are, the use of viramidine could well replace ribavirin, particularly in those patients with coexistent HIV infection, renal insufficiency, and underlying hemolytic disorders.
Considerable progress has been made in the development of direct antiviral agents against HCV. Potential targets for new antiviral drugs include the HCV protease, helicase, and polymerase. Although several candidate drugs are currently in development, few have reached human trials. Godofsky and colleagues presented their results on the use of a novel HCV RNA polymerase inhibitor, provisionally named NM283.* This small molecule is a valine-ester prodrug of NM107 (2' C-methylcytidine), a ribonucleoside analogue. NM283 has shown activity against bovine viral diarrhea virus (a flavivirus related to HCV) in cell culture, and against HCV in chronically infected chimpanzees. In this phase 1 study, NM283 was administered to humans for the first time. The study included 83 patients with chronic hepatitis C; they received escalating doses of NM283 for a period of 15 days. There appeared to be a dose-dependent reduction in serum HCV RNA level of more than 1 log by the end of treatment. This reduction is similar to that observed during the first 2 weeks of therapy with interferon/ribavirin-based regimens, but is less than what was seen with a novel protease inhibitor, BILN2061*. NM283 appeared to be quite well tolerated except for some initial nausea, but this was not dose-limiting.
It is hoped that the above discussion appropriately reflects the latest developments in the management of patients with hepatitis C, as based on some of the more key presentations from this year's DDW meeting. Clearly, the major trends in therapeutic advancement are primarily 2-fold in focus: improving applications of current regimens and development of new therapeutic targets. Thus, this report aimed to frame this progress within the appropriate context, highlighting potential implications for clinical practice.
* The United States Food and Drug Administration has not approved this medication for this use.
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2. Adinolfi LE, Gambardella M, Andreana A, et al. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology. 2001;33:1358-1364.
3. Perumalswami P, Kleiner D, Lutchman G, et al. Hepatitis C infection and hepatic steatosis; Fibrosis is not forged in the flame of fat. Gastroenterology. 2004;126(suppl 2):A-672. [Abstract 176]
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9. Chalasani N, Manzarbeitia C, Ferenci P, et al. Peginterferon alfa-2a (40kD) as prophylaxis and treatment for recurrent hepatitis C virus (HCV) infection after orthotopic liver transplantation (OLT). Gastroenterology. 2004;126(suppl 2):A-664. [Abstract 44]
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12. Lodato F, Azzaroli F, Tame MR, et al. Superior efficacy of twice a week administration of peginterferon alfa-2b plus ribavirin in obtaining SVR in HCV genotype 1. Gastroenterology. 2004;126(suppl 2):A-667. [Abstract 122]
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15. Leevy CB, Ramaraju G, Chalmers C, Blatt LM. Interim results of a pilot study of the combination of type 1 (IFN alfacon-1) and type 2 (IFN gamma-1b) interferons in chronic hepatitis C patients who have failed to respond to peg-interferon alpha2 plus ribavirin. Gastroenterology. 2004;126(suppl 2):A-667. [Abstract 124]
16. Kaiser S, Hass H, Gregor M. Succesful retreatment of peginterferon nonresponder patients with chronic hepatitis C with high dose consensus interferon induction therapy. Gastroenterology. 2004;126(suppl 2):A-668. [Abstract 125]
17. Gish R, Nelson D, Arora S, Braeckman R, Yu G. Hepatitis C combination therapy with viramidine and peginterferon alfa-2a reduces potential for ribavirin-related hemolytic anemia. Gastroenterology. 2004;126(suppl 2):A-681. [Abstract 406]
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Thank you for an excellent summary.My doctor mentioned the Kaiser study as cause for encouragement in my situation.
Thank you for an excellent summary.My doctor mentioned the Kaiser study as cause for encouragement in my situation.
Bovine viral diarrhea virus--a flavivirus related to HCV? I know there's some kind of conclusion we can draw from this.....