RECOMBINANT INTERFERON-ALPHA AND URSODEOXYCHOLIC ACID VERSUS INTERFERON-ALPHA ALONE IN THE TREATMENT OF CHRONIC HEPATITIS-C - A RANDOMIZED CLINICAL-TRIAL WITH LONG-TERM FOLLOW-UP

Objectives: The purpose of this study was to compare, within a randomi zed controlled trial, the efficacy of recombinant interferon-alpha in combination with ursodeoxycholic acid versus interferon-alpha alone in the treatment of chronic HCV hepatitis. Methods: Forty anti-HCV posit ive chronic hepatitis patients with ALT levels persistently greater th an 3 times the upper normal level were randomized to receive either in terferon-alpha (6 million units three times/wk for 6 months) plus urso deoxycholic acid (10 mg/kg/day for 9 months) (n = 20) or interferon-al pha (6 million units three times/wk for 6 months) alone (n = 20). Dise ase activity was monitored monthly by ALT measurement until 18 months after interferon-alpha cessation. Serum HCV-RNA was measured at baseli ne and after 6, 9, and 24 months. Liver biopsies (basal and at the 9th month) were evaluated blindly and scored by Knodell's criteria. Resul ts: The probability of full or partial response during interferon-alph a treatment was similar in the two groups. The probability of biochemi cal relapse (i.e, any persistent return of ALT above normal) after 18- month of posttreatment follow-up was 75% in both the combination and t he monotherapy group. Relapse, however, occurred significantly later i n the combination than in the monotherapy group (6.6 +/- 5.4 [SD] mont hs and 1.8 +/- 1.6 months after IFN-alpha cessation, respectively, p < 0.02). Severe biochemical relapse (i.e., a persistent ALT elevation g reater than 3 times normal) occurred more frequently and earlier (p = 0.05) in patients treated with interferon-alpha (58.3%) than in those receiving the combination therapy (27.3%). The cumulative duration of normalized ALT periods during and after treatment was significantly gr eater (p = 0.005, chi 2) in patients treated with IFN-alpha+UDCA than with monotherapy (189/354 months vs 136/323 months. Lobular necrosis i mproved in both groups (p = 0.056 and p = 0.001, respectively), wherea s portal inflammation improved (p = 0.009) only in the combination the rapy group. Among the 30 patients who were viremic at entry, plasma HC V-RNA was no longer detectable after 6 months in four from the combina tion group and in five from the monotherapy group, yet all patients bu t one returned HCV-RNA positive 3 months after interferon-cr cessation and were still viremic after 18 months. Cox's multiple regression ide ntified the histological degree of posttreatment portal inflammation a s the sole positive indicator of relapse. Conclusions: The combination of interferon-cm and ursodeoxycholic acid prolongs the efficacy of in terferon-a alone in chronic hepatitic C by delaying the probability of biochemical relapse and/or by reducing its severity, without affectin g HCV viremia.