Therapeutic Strategies for Hepatitis C

In most areas of the country, the treatment of hepatitis C generally falls within the purview of specialists in gastroenterology, hepatology, or infectious diseases, although primary care physicians who treat a large number of patients with hepatitis C may also choose to administer treatment. We recommend that only clinicians who are thoroughly familiar with the disease and its management undertake the care of these patients, unless there is no alternative.

In this article, we discuss current therapeutic strategies. In a companion piece (page 955), we review diagnostic guidelines.

FIRST-LINE TREATMENT

The current standard of treatment for chronic hepatitis C is a combination of pegylated interferon (PEG-IFN) alfa-2a or alfa-2b and ribavirin (RBV). The rationale for binding IFN to a polyethylene glycol (PEG) molecule is that this process delays clearance of the drug, which results in higher peak drug levels and a prolonged half-life, with a much greater pharmacokinetic area under the curve. As a result, PEG-IFN can be given once weekly, with more constant exposure to drug than is possible with the traditional regimens of standard IFN 3 times weekly. PEG-IFN alfa-2a is formulated as a fixed dosage of 180 µg/wk; PEG-IFN alfa-2b is formulated as a weight-based dosage of 1.5 µg/kg/wk.

In multicenter trials, the rate of sustained virologic response (SVR) (defined as an absence of detectable virus in the serum 6 months after completion of antiviral therapy)was 54% to 56% for patients treated with PEG-IFN alfa-2b or alfa-2a plus RBV.^1,2 SVR occurred in 42% to 46% of patients with genotype 1 and 76% to 82% of patients with genotype 2 or 3. In the PEG-IFN alfa-2a study, PEG-IFN was dosed at 180 mg/wk and RBV at 1000 to 1200 mg/d (depending on whether body weight was more or less than 75 kg).² The PEG-IFN alfa-2b was dosed at 1.5 mg/kg/wk and RBV at 800 mg/d.¹ The different study designs, drug doses, and patient populations in these trials preclude a direct comparison of the results. In both studies, however, higher body weight was associated with a weaker response, possibly because of the fixed dose of PEG-IFN in one study and of RBV in the other.

A third pivotal study with PEG-IFN alfa-2a showed that patients infected with hepatitis C virus (HCV) genotype 1 had superior results if RBV was dosed at 1000 to 1200 mg/d rather than 800 mg/d and if treatment was given for 48 weeks rather than 24 weeks.³ In contrast, patients with genotype 2 or 3 fared equally well at either dose of RBV and with 24 or 48 weeks of therapy.

Hepatitis C therapy has significant adverse effects; these are listed in the Table. Discontinuation because of side effects occurred in 13% of patients in the pivotal trials; dose reductions occurred more frequently, usually because of hematologic adverse effects. Patients require close monitoring for neuropsychiatric effects, especially depression, and hematologic and other toxicities. Because of the teratogenicity of RBV, strict birth control must be used regardless of which partner is undergoing treatment, both throughout the treatment period and for 6 months afterwards.

Contraindications to treatment include major depression, autoimmune disease, severe cardiac or pulmonary disease, and moderate to severe cytopenia. Important predictors of a favorable response include non-genotype 1 disease, low viral load (less than 800,000 IU/mL), younger age, and mild or no fibrosis.

EARLY VIROLOGIC RESPONSE

There has long been interest in identification of early time points at which patients destined not to have an SVR can discontinue therapy, confident that they are not being deprived of a meaningful opportunity for cure. The best time point that has been identified in this context is 12 weeks, at which time failure to have achieved at least a 2-log (100-fold) reduction in viral load is associated with a virtually negligible chance of subsequent SVR.^4,5 Thus, a greater than 2-log reduction at week 12 has come to be termed an early virologic response. If the patient is a responder, therapy is continued and a viral-load measurement is repeated at 24 weeks. Persistent viremia at that point generally leads to treatment discontinuation, because it, too, is associated with a very low subsequent chance of SVR.

In certain settings, however--such as near-complete clearance and a steady decline in viral load from the 12-week point--a clinician might choose to continue therapy despite the small chance of success. At completion of therapy, the viral load is measured again. If it is undetectable, the patient is considered to have had an end-of-treatment response. A viral-load measurement is repeated 6 months after the completion of therapy. If results of a polymerase chain reaction test are still negative, the patient is considered to have had an SVR.

Not all patients who achieve early virologic response go on to SVR. About 15% to 20% of patients may clear the virus completely but relapse after the completion of therapy. Others may have a "breakthrough relapse" during treatment, and still others may have a 2-log reduction by week 12 but never entirely clear HCV RNA. A recent study of patients who had achieved SVR showed that some may continue to harbor small quantities of HCV RNA in the liver; this challenges our current notion of "cure," but for practical purposes, relapse beyond 6 months after cessation of therapy is virtually never seen.⁶

RECENT FINDINGS AND EMERGING TRENDS

Extended therapy. The recommended duration of PEG-IFN and RBV therapy is 48 weeks for genotype 1 infection when there has been at least a 2-log reduction in viral levels by 12 weeks. However, a recent study has shown that prolongation of therapy to 72 weeks in patients who do not achieve complete viral clearance by week 4 results in a significantly higher rate of SVR than that achieved with cessation of therapy at week 48 (48% vs 32%).⁷ In another study of patients with genotype 1 disease who were treated for 48 weeks versus 72 weeks, 72 weeks of treatment in patients still viremic at week 12 significantly reduced the relapse rate compared with 48 weeks of treatment.⁸ Thus, some experts favor an extended course of treatment in patients with "slow virologic response" (ie, delayed clearance of HCV RNA).

HIV and HCV coinfection. This is a major problem because one third of HIV-infected persons in the United States have HCV infection, and these patients are at risk for more rapidly progressive liver disease than monoinfected patients. Recent studies have demonstrated that in coinfected patients, as in monoinfected patients, combination therapy with PEG-IFN and RBV is superior to that with standard IFN and RBV.^9,10 Although SVR rates are lower in coinfected than in monoinfected patients, HCV-HIV coinfection mandates serious consideration of HCV therapy.

Ethnicity. Studies have shown that significant differences in treatment response exist among various ethnic groups. For example, in one study involving African Americans and non-Hispanic whites infected with HCV genotype 1, the responses to treatment were 19% and 52%, respectively.¹¹ More recently, it was reported that weight-based RBV (800 to 1400 mg) combined with PEG-IFN alfa-2b doubles the rate of SVR in African Americans, compared with a fixed dose of RBV (800 mg). However, even with weight-based dosing, the rate of SVR was lower (21%) than that seen in many studies of non- African American patients.¹²

A large NIH-sponsored study is currently evaluating HCV therapy in 200 African American and 200 white patients. It is also assessing the scientific mechanisms that underlie an impaired response, such as the possibility of inadequate activation by IFN of IFN-response genes.

References:

REFERENCES:

1.

Manns MP, McHutchison 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 randomised trial.

Lancet.

2001;358:958-965.

2.

Fried MW, Shiffman ML, Reddy KR, et al. Pegin-terferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.

N Engl J Med.

2002;347:975-982.

3.

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;346-355.

4.

Davis GL, Wong JB, McHutchison JG, et al. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C.

Hepatology.

2003;38:645-652.

5.

Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.

N Engl J Med.

2002;347:975-982.

6.

Radkowski M, Gallegos-Orozco JF, Jablonska J, et al. Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C.

Hepatology.

2005;41:23-25.

7.

Sanchez-Tapias JM, Diago M, Escartin P, et al. Longer treatment duration with peginterferon alfa-2a (40KD) (PEGASYS) and Ribavirin (COPEGUS) in naïve patients with chronic hepatitis C and detectable HCV RNA by week 4 of therapy: final results of the randomized, multicenter TERVIC-4 study.

Hepatology.

2004;40(4 suppl 1):218A.

8.

Berg T, von Wagner M, Hinrichsen H, et al. Reduction of the relative relapse rate by prolongation of the duration of a therapy with peginterferon alfa-2a plus ribavirin in patients with genotype 1 infection up to 72 weeks.

Hepatology.

2004;40(4 suppl 1): 238A.

9.

Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients.

N Engl J Med.

2004;351:438-450.

10.

Laguno M, Murillas J, Blanco JL, et al. Peginterferon alfa-2b plus ribavirin compared with inter-feron alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients.

AIDS.

2004;18:F27-F36.

11.

Muir AJ, Bornstein JD, Killenberg PG; Atlantic Coast Hepatitis Treatment Group. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites.

N Engl J Med.

2004;350:2265-2271.

12.

Jacobson I, Brown R, McCone J, et al. Weight-based ribavirin dosing improves virologic response in HCV-infected genotype 1 African Americans compared to flat-dose combination therapy.

Hepatology.

2004;40(4 suppl 1):217A.