THE BREAKTHROUGH PHENOMENON DURING ALPHA-INTERFERON THERAPY OF CHRONIC HEPATITIS-C - INCIDENCE, MANAGEMENT, AND OUTCOME

Objectives: Some patients treated with cu-interferon (alpha-LFN) for c hronic hepatitis C (CHC) initially respond with normalization of ALT o nly to encounter a rise in ALT while still on the drug. This phenomeno n is called breakthrough (BT). We reviewed our experience with BT to c larify its incidence, pathogenesis, management, and outcome. Methods: Charts from 71 consecutive patients with CHC treated with alpha-IFN we re reviewed. Forty of these patients were part of a study of 1-yr esca lating 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. Results: Twen ty-one (29.5%) patients sustained 28 BT events. Thirteen (46.4%) BT ev ents occurred during the first 6 months of a course of alpha-IFN thera py, and 15 (53.6%) occurred during months 7 through 12. Of patients ex periencing BT, six (28.6%) completed their course of therapy with a CR , of which two (9.5%) were sustained. By comparison, of 22 patients wh o normalized ALT without BT, all completed their course with a CR by d efinition (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 A LT. Of 16 BT events managed with continuation of the same dose of alph a-IFN, normal ALT was reachieved in seven (43.8%). Of 12 BT events man aged with an escalation in alpha-IFN dose, six (50%) reachieved normal ALT. A full sequential series of hepatitis C virus RNA PCR from perio ds 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. Conclusions: BT is a common event th at may occur at any point during alpha-IFN therapy of CHC. This may li mit the benefits of maintenance strategies. After a BT event, normal A LT can be reestablished in about 50% of cases, although the chance of a sustained CR falls to less than 10%. No advantage was demonstrated f or escalating the alpha-IFN dose after a BT event. Therefore, we recom mend continuation of the same dose as the initial approach. We suspect that BT relates to nonspecific ALT fluctuation in some patients and t o emergence of resistant hepatitis C virus strains in others. Other ca uses of ALT elevation must also be considered in patients with apparen t BT.