The breakthrough phenomenon during alpha-interferon therapy of chronic hepatitis C: incidence, management, and outcome.

Abstract

Some patients treated with alpha-interferon (alpha-IFN) for chronic hepatitis C (CHC) initially respond with normalization of ALT only to encounter a rise in ALT while still on the drug. This phenomenon is called breakthrough (BT). We reviewed our experience with BT to clarify its incidence, pathogenesis, management, and outcome. Charts from 71 consecutive patients with CHC treated with alpha-IFN were reviewed. Forty of these patients were part of a study of 1-yr escalating dose alpha-IFN, initiated at 2 million units (MU) 3 times per week. Endpoints that were evaluated were: reachievement of normal ALT, complete response (CR) (defined as normal ALT at the end of therapy), and sustained CR maintained for 6 months after therapy. Twenty-one (29.5%) patients sustained 28 BT events. Thirteen (46.4%) BT events occurred during the first 6 months of a course of alpha-IFN therapy, and 15 (53.6%) occurred during months 7 through 12. Of patients experiencing BT, six (28.6%) completed their course of therapy with a CR, of which two (9.5%) were sustained. By comparison, of 22 patients who normalized ALT without BT, all completed their course with a CR by definition (p < 0.0001), and nine (40.9%, p < 0.05) had a sustained CR. Of 28 BT events, 13 (46.4%) were followed by reattainment of normal ALT. Of 16 BT events managed with continuation of the same dose of alpha-IFN, normal ALT was reachieved in seven (43.8%). Of 12 BT events managed with an escalation in alpha-IFN dose, six (50%) reachieved normal ALT. A full sequential series of hepatitis C virus RNA PCR from periods of elevated, normal, and again elevated ALT was available for 12 BT events. The pattern was +/+/+ in six, +/-/+ in five, and +/-/- in one. In one additional patient, an apparent BT was attributable to alpha-IFN-induced autoimmune hepatitis. BT is a common event that may occur at any point during alpha-IFN therapy of CHC. This may limit the benefits of maintenance strategies. After a BT event, normal ALT can be reestablished in about 50% of cases, although the chance of a sustained CR falls to less than 10%. No advantage was demonstrated for escalating the alpha-IFN dose after a BT event. Therefore, we recommend continuation of the same dose as the initial approach. We suspect that BT relates to nonspecific ALT fluctuation in some patients and to emergence of resistant hepatitis C virus strains in others. Other causes of ALT elevation must also be considered in patients with apparent BT.