Teresa L. Wright, MD

NIH Consensus Development Conference on
Management of Hepatitis C: 2002 

Bethesda, Maryland
June 10-12, 2002

The majority of patients with HCV infection have mild liver disease, and concern about this virus would be vastly reduced if it were not for the minority that progress to cirrhosis. All of the potentially life-threatening complications of HCV infection such as hepatocellular carcinoma, bleeding esophageal varices, life-threatening infections, hepatic synthetic failure, and intractable ascites occur in patients with advanced liver disease. Unfortunately, it is not possible to reliably identify those patients who are risk for developing cirrhosis. The management of HCV disease is further complicated because, in general, therapeutic interventions are more successful in patients with early disease than in those with advanced liver disease.

With that background, how successful are existing interventions in patients with advanced liver disease? First and foremost, available therapies are currently limited. Many patients with advanced HCV disease are not candidates for interferon plus ribavirin. Contraindications in this population include cytopenias (platelet counts less than 75 k/mm ³ and white cell counts less than 1,500/mm ³ ) and/or co-morbid conditions such as uncontrolled psychiatric disease that preclude therapy.

Data on safety and efficacy of interferon (standard or pegylated) with or without ribavirin in patients with compensated cirrhosis or transition to cirrhosis have often been derived from subgroup analysis of larger trials, ^(1–3) although in some studies, this population has been the sole focus of the trial. ⁽⁴⁾ In patients with sufficient platelets and white blood cells to tolerate therapy, pegylated interferon alfa 2b in combination with ribavirin has been studied at two different dosing regimens and compared to standard interferon plus ribavirin (Table 1). Viral clearance in patients with advanced liver disease was the similar with all three regimens (41–44 percent), but was lower in patients with advanced liver disease than in patients with minimal or no fibrosis (Table 1).

Similar analyses have been performed in patients receiving combination therapy, which includes pegylated interferon alfa 2a (Table 2). In patients with advanced liver disease, viral clearance ranged from 43 percent in patients receiving pegylated interferon alfa 2a in combination with ribavirin to 21 percent in patients receiving pegylated interferon alfa 2a as monotherapy. Response was 33 percent in patients receiving standard interferon alfa 2b plus ribavirin (Table 2). As for the results from other studies, ⁽²⁾ sustained virological response with all three regimens was lower in patients with advanced liver disease than in patients without cirrhosis (Table 2). Comparisons between trials should not be performed without information about distribution of other variables, such as infecting genotype, that could influence response in the different treatment arms.

In patients with advanced liver disease receiving pegylated interferon alfa 2a in combination with ribavirin, the optimal dose of ribavirin appears to be 1,000 mg/1,200 mg, rather than 800 mg, and the optimal duration of treatment appears to be 48 rather than 24 weeks. ⁽⁵⁾ Efficacy of different doses of ribavirin in combination with pegylated interferon alfa 2b is under study. Median reductions in white blood cell count and platelet count are greater in patients receiving pegylated interferon than in those receiving standard interferon. ^(2–4) Thus patients with significant cytopenias in the setting of advanced liver disease who receive antiviral therapy should be monitored closely.

Table 1. Comparison of Treatment With Standard Interferon Alfa 2b Plus Ribavirin vs. Pegylated Interferon Alfa 2b in Combination With Ribavirin for 48 Weeks (Manns et al., Reference 2)

Table 2. Comparison of Treatment With Standard Interferon Alfa 2b vs. Pegylated Interferon Alfa 2a in Combination With Placebo or With Ribavirin (1,000–1,200mg/D) for 48 Weeks (Roche Data on File)

Another end point of therapy that is pertinent to patients with advanced liver disease is delay in histological disease progression. The premise is that therapy, while not clearing virus, achieves a “clinically meaningful end point” usually defined as a reduction by two or more points in the histological activity index. The clinical relevance of achieving such an end point is currently under evaluation in an NIH-sponsored study (the HALT-C trial) of suppressive therapy with pegylated interferon alfa 2a in preventing the development of complications of advanced liver disease in patients who have previously failed pegylated interferon plus ribavirin. Prior to the availability of results from this trial, it will be necessary to rely on analysis of subsets of patients with advanced liver disease included in multicenter trials of ribavirin plus pegylated interferon alfa 2a or alfa 2b combination therapy. Improvement in liver histology (defined as a reduction of two or more points in the histological activity index) is observed in 68 percent of patients receiving pegylated interferon alpha 2b
(1.5 µg//kg SQ q week) plus ribavirin 800mg qd for 48 weeks, compared with 69 percent of patients receiving standard interferon alfa 2b plus ribavirin. ⁽²⁾ Improvement in fibrosis score was seen less frequently (21 and 20 percent, respectively). ⁽²⁾

During the lead-in phase of the HALT-C trial, on-treatment virological response has been observed in 30 percent of patients receiving pegylated interferon alfa 2a plus ribavirin who had previously failed standard interferon plus ribavirin. ⁽⁶⁾ Thirty-nine percent of patients required dose reduction of either interferon or ribavirin, but only 6 percent could not tolerate treatment. ⁽⁶⁾ Thus, pegylated interferon plus ribavirin, appears to be tolerated in the majority of patients with advanced HCV cirrhosis who have not yet developed clinical complications of their liver disease.

Thus, it is likely that hepatitis C therapy can slow histological disease progression in patients with histologically advanced liver disease, and that sustained viral clearance can be achieved in a proportion of patients. Whether this “histological slowing” translates into reduction in development of life-threatening complications remains to be determined.

A more problematic group of patients are those with decompensated cirrhosis. Patients with HCV-related cirrhosis who meet criteria for listing for liver transplantation have a five year survival rate of only 50 percent. (7) There are small case series of treating patients awaiting liver transplantation (8,9) that suggest that viral clearance is achievable in a proportion of patients with advanced liver disease although adverse events, including potentially life-threatening adverse events, have been observed. If viral clearance is achieved, these patients may be virus-free after liver transplantation. ⁽⁸⁾

Until complete data are available on the safety and efficacy of pegylated interferon plus ribavirin in patients with advanced decompensated HCV-disease, such patients should, when possible, be enrolled in clinical trials. Pegylated interferon plus ribavirin is clearly indicated in patients with compensated HCV disease who have pre-treatment platelet and white blood cell counts that are sufficient to accommodate the cytopenias associated with therapy, but treatment is relatively contraindicated in patients with decompensated cirrhosis, particularly in patients with Childs-Pugh-Turcotte scores of greater than 10. ⁽⁶⁾

What of interventions in patients with HCV disease following liver transplantation? Hepatitis C infection of the graft is the rule following liver transplantation, and disease progression is accelerated compared to immune competent patients with HCV disease. ⁽¹⁰⁾ Moreover, once histological cirrhosis of the allograft occurs, the risk of complications of liver disease is even higher than in the immune competent patients with cirrhosis. ⁽¹¹⁾ Variables associated with post-transplantation disease progression include pre-transplantation antiviral therapy, HCV RNA level at the time of transplantation, and advanced age of the organ donor, as well as treatment of rejection in the post-transplantation period. ⁽¹⁰⁾

There has been interest in “pre-emptive” antiviral therapy early in the post-transplantation period as well as treatment of established liver disease of the allograft. Responses to standard interferon plus ribavirin are generally lower following liver transplantation than in immune competent patients. Moreover, since many patients have renal insufficiency secondary to immunosuppressive agents, ribavirin is poorly tolerated, and if used, ribavirin dose should be reduced. Studies of pegylated interferon with or without ribavirin are under way.

References

1. McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. International Hepatitis Interventional Therapy Group. N Engl J Med 1998;339:1485–92.

2. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffmann M, Reindollar R, Goodman ZD, Koury K, Ling M-H, Albrecht JK and the International Hepatitis Interventional Therapy Group. 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.

3. Fried MW, Shiffman ML, Reddy RK, Marino G, Goncales F, Haeussinger D, Diago M, Garosi G, Zarski J-P, Hoffman J, Yu J. Pegylated (40 kDa) (PEGASYS R ) interferon alfa-2a in combination with ribavirin: efficacy and safety results from a phase III, randomized, actively controlled multicenter study. Gastroenterology 2001;120:A55.

4. Heathcote J, Shiffmann M, Cooksley G et al. Peginterferon alfa 2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000;343:1673–80.

5. Roche data on file.

6. Shiffman ML. Hepatitis C and co-morbid conditions. AASLD Single Topic Conference, Chicago April 2002.

7. Lucey MR, Brown KA, Everson GT, Fung JT, Gish R, Keeffe EB, Kneteman NM et al. Minimal listing criteria for placement of adults on the liver transplant waiting list: A report of a national conference organized by the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases. Liver Transplantation and Surgery 1997;3:628–37.

8. Everson GT, Trouillot T, Trotter J, Skilbred J, Halprin A, McKinley C, Fey B, Epp J. Treatment of decompensated cirrhotics with a slow-accelerating dose regimen (LADR) of interferon-alfa-2b plus ribavirin: safety and efficacy. Hepatology 2000;32:308A.

9. Crippen JS, Sheiner P, Terrault NA, McCashland T, Charlkton M. A pilot study of the tolerability and efficacy of antiviral therapy in patients awaiting liver transplantation for hepatitis C. Hepatology 2000;32:308A.

10. Berenguer M, Lopez-Labrador FX, Wright TL. Hepatitis C and liver transplantation. J Hepatology 2001;35:666–78.

11. Berenguer M, Prieto M, Rayon JM et al. Natural history of clinically compensated HCV-related graft cirrhosis following liver transplantation. Hepatology 2000;32:852–8.