Michael W. Fried, MD

NIH Consensus Development Conference on
Management of Hepatitis C: 2002 

Bethesda, Maryland
June 10-12, 2002

Introduction

The side effect profile of combination therapy of standard interferon plus ribavirin is well known. In the registration trials of these agents, significant side effects were noted that resulted in discontinuation of treatment in approximately 20 percent of subjects. (1,2) The major types of side effects of combination therapy include influenza-like symptoms, hematologic abnormalities, and neuropsychiatric symptoms.

Pegylated interferons (pegylated interferon alfa-2a and pegylated interferon alfa-2b) have significantly improved pharmacokinetics, (3–5) resulting in  improved antiviral efficacy, that also has the potential to alter the side effect profile. This review will focus on the prevalence and management of side effects reported with the use of pegylated interferon plus ribavirin for the treatment of chronic hepatitis C.

Peginterferon Alfa-2a Plus Ribavirin

The results of a large, phase III clinical trial of peginterferon alfa-2a plus ribavirin have recently been reported in preliminary form. (6) Over 1,100 subjects were randomized to therapy with peginterferon alfa-2a plus ribavirin, peginterferon alfa-2a plus placebo, or standard interferon alfa-2b plus ribavirin. Premature withdrawal from therapy due to laboratory abnormalities or adverse events in the combination arms with either pegylated interferon alfa-2a (10 percent) or standard interferon alfa-2b (11 percent) was comparable. The most common reason for withdrawal was depression, although the rate of depression in subjects treated with peginterferon alfa-2a was lower than those treated with standard combination therapy (22 percent vs. 30 percent). Influenza-like symptoms were also lower in the peginterferon treatment groups.

Dose reductions of peginterferon alfa-2a for any adverse event were required in 32 percent in the combination arm. Laboratory abnormalities such as anemia, neutropenia, and thrombocytopenia were the most frequent indications for dose reductions. Thus, approximately 25 percent of participants required at least one dose reduction (temporary or permanent) for laboratory abnormalities during therapy. The frequency of ribavirin dose reduction for anemia was similar in the combination arms of the study. The frequency of dose reduction for neutropenia was greater in the peginterferon combination arm compared to standard interferon (20 percent vs. 5 percent). Thrombocytopenia was also more common in the peginterferon arms.

However, only a minority of patients discontinued therapy due to laboratory abnormalities in the two combination arms (peginterferon + ribavirin = 3 percent vs. standard interferon plus ribavirin = 1 percent).

Peginterferon Alfa-2b Plus Ribavirin

In a large, phase III study that compared the antiviral efficacy of two different regimens of peginterferon alfa-2b plus ribavirin to standard interferon alfa-2b plus ribavirin, (7) premature  withdrawal from therapy due to an adverse event occurred in 14 percent of participants treated with the higher dose of peginterferon. Discontinuation of therapy due to neutropenia (~1 percent) or anemia was very uncommon. Dose reductions for any adverse event occurred in 42 percent of patients treated with the higher dose peginterferon alfa-2b plus ribavirin compared to 34 percent treated with standard interferon and ribavirin. Dose reduction due to neutropenia was also more common in the higher dose combination (18 percent) than in the low dose pegylated (10 percent) or the standard interferon combination arms (8 percent).

Few differences were noted in the side effect profile in the pegylated combination arms compared to those seen with standard interferon plus ribavirin. The incidence of depression was similar in all treatment arms (~30 percent). The increase of several flu-like symptoms over standard therapy was attributed to the higher dose of interferon provided by the pegylated preparation. Injection site reaction, generally mild, was also noted to be more common in those receiving peginterferon alfa-2b (58 percent) compared to the standard interferon alfa-2b(36 percent).

Management of Side Effects

General strategies for management of side effects of combination therapy have been previously reviewed and are applicable to the newer agents. (8) Before starting treatment, patient education about expectations and self-management techniques are most beneficial. Regular followup visits during therapy and a supportive environment will permit early detection and intervention for developing adverse events and will also encourage patient adherence to the medication regimen.

Depression is a frequent and often dose-limiting side effect of combination therapy with pegylated interferon and ribavirin. The mechanism of interferon-associated depression remains largely speculative. Directed questioning of the patient and significant others, when available, about the presence and severity of depression is warranted. Treatment should be discontinued immediately in patients with suicidal ideation and, for patients judged to be in potential danger, immediate referral should be made to a mental health professional. Antidepressants, particularly selective serotonin-reuptake inhibitors, are prescribed frequently for less severe depression associated with antiviral therapy. Prophylactic paroxetine, evaluated in patients treated with high-dose interferon alfa-2b for melanoma, was shown to minimize depressive symptoms and decrease the rate of interferon discontinuation compared to placebo. (9) However, prophylactic strategies could result in inappropriate use of these agents in the 70–80 percent of patients that do not develop significant depression while on combination therapy for hepatitis C. Thus, additional information is needed concerning the mechanisms of interferon-associated depression and the optimal treatment regimen that will minimize disruptions to antiviral therapy.

Anemia, thrombocytopenia, and especially, neutropenia occur regularly in patients treated with peginterferon and ribavirin. To date, management of hematologic abnormalities in all phase III clinical trials has relied upon dose reductions of study medications according to predetermined criteria. This has proven to be a safe and effective approach to management; hemoglobin, absolute neutrophil and platelet counts improve quickly so that discontinuation of therapy is rarely necessary. Nevertheless, the possibility that adherence to study medications may affect sustained virological response has encouraged evaluation of erythropoietin and granulocyte stimulating factors as adjunctive therapies to minimize dose reductions of interferon and ribavirin. Preliminary data suggest that the dose of ribavirin may be maintained with epoietin alfa. (10) However, no study thus far has demonstrated that the use of stimulating factors to maintain full doses of interferon and ribavirin will improve sustained virological response.

Furthermore, the incidence of serious sequelae associated with hematologic abnormalities appears to be low. Thus, these adjunctive agents cannot be routinely recommended as treatment for the hematologic abnormalities induced by combination therapy for hepatitis C. Additional studies are required to better understand the consequences of neutropenia in the patient with chronic hepatitis C and to determine whether lower levels of neutropenia can be safely tolerated. Detailed investigations of the relationship between dose reduction on outcome and prospective trials of alternative methods for managing hematologic abnormalities with growth factors are necessary.

In summary, no unique or unexpected side effects have been noted with the administration of pegylated interferons plus ribavirin in two large phase III trials of these agents. Hematologic abnormalities requiring dose reductions may be more common with the newer agents. Additional emphasis on improving patient management strategies is warranted.

References

1. Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, Bain V, et al. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998;352:1426–32.

2. McHutchison JG, Poynard T. Combination therapy with interferon plus ribavirin for the initial treatment of chronic hepatitis C. Semin Liver Dis 1999;19 Suppl 1:57–65.

3. Glue P, Fang JW, Rouzier-Panis R, Raffanel C, Sabo R, Gupta SK, Salfi M, et al. Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin Pharmacol Ther 2000;68:556–67.

4. Zeuzem S, Heathcote JE, Martin N, Nieforth K, Modi M. Peginterferon alfa-2a (40 kDa) monotherapy: a novel agent for chronic hepatitis C therapy. Expert Opin Investig Drugs 2001;10:2201–13.

5. Reddy KR, Wright TL, Pockros PJ, Shiffman M, Everson G, Reindollar R, Fried MW, et al. Efficacy and safety of pegylated (40-kd) interferon alpha-2a compared with interferon alpha-2a in noncirrhotic patients with chronic hepatitis C. Hepatology 2001;33:433–8.

6. Fried MW, Shiffman ML, Reddy KR, Sulkowski M, Smith C, al.  Pegylated (40kDa) interferon alfa-2a in combination with ribavirin: efficacy and safety results from a phase III, randomized, actively controlled multicenter study. Gastroenterology 2001. 

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

8. Afdhal NH, Geahigan T: Supporting the patient with chronic hepatitis during treatment. In: Koff RS, Wu GY, eds. Clinical Gastroeneterology: Diagnosis and Therapeutics. Totowa, NJ: Humana Press.

9. Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS, Greiner K, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 2001;344:961–6.

10. Talal AH, Weisz K, Hau T, Kreiswirth S, Dieterich DT. A preliminary study of erythropoietin for anemia associated with ribavirin and interferon-alpha. Am J Gastroenterol 2001;96:2802–4.