Gary Davis, Univ of Florida Coll of Medicine, Gainesville, FL; J McHutchison, Scripps Clin and Res Fdn, La Jolla, CA; T Poynard, Hospitalier Pitie-Salpetriere, Paris France; R Esteban-Mur, Hospital Valle Hebrou, Barcelona Spain; J Albrecht, S Cort, M H Ling, Schering-Plough, Kenilworth, NJ; J J Garaud, for the Intl Hepatitis Interventional Therapy Group
Several studies have now confirmed that viral response to interferon (IFN) monotherapy usually persist if they are maintained for at least 6 months after treatment is stopped. Thus, patients who are HCV-RNA negative 6 months after treatment are labeled as sustained responders. The combination of IFN and oral ribavirin (I/R; Rebetron“, Schering-Plough) results in higher end-of-treatment and early sustained response rates, but there remains little long-term follow-up to insure that responses persist.
Aim: To assess the durability of the 6-month post-treatment (“sustained”) virologic response to IFN or Rebetron in patients with chronic hepatitis C. Methods: 2089 patients with chronic hepatitis C were enrolled in 4-randomized controlled trials of 24 to 48 months of IFN ± ribavirin for either treatment naive or IFN relapsers (NEJM 1998; 339:1485 & 1493; Lancet 1998; 352:1426). 558 (26.7%) subjects were HCV-RNA negative at the end of treatment and 6 months later (sustained virologic response (SR); 455/1183 (38.5%) treated with I/R; 103/906 (11.4%) treated with IFN alone). 393 of these SR (70.4%) agreed to participate in long-term follow-up; 316 (81%) have completed at least 6 more months of follow-up (total 12 months post-treatment) and form the basis of this report. 272 (86%)now have 18 months post-treatment follow-up and 16 (5%) have 30 months. Relapse rates for SR are reported beginning 6 months after treatment was stopped, i.e. when subjects were labeled as SR. Serum HCV-RNA was measured by quantitative PCR (NGI); a value < 100 copies per mL was considered to be negative.
Results: A total of 9/316 (2.8%) SR relapsed more than 6 months after treatment was discontinued. The actuarial rate of relapse among SR during the first year of follow-up (6 thru 18 months post-treatment) was 9.1% for IFN alone for 6 months, 4.2% for IFN alone ¥ 12 months, 2.8% for I/R ¥ 6 months, and 1.8% for I/R ¥ 12 months (differences NS). Late relapses were equally likely to occur in the 6-12 month (5/316 at risk) as compared to the 12-18 month post-treatment period (4/310 at risk). Late relapse rates were similar for subjects who had been treatment naive or IFN relapsed prior to study participation (8/259 (3.1%) vs 1/57 (1.7%)). Compared to durable responders, late relapsers were only slightly more likely to have genotype 1 (6/9 vs 125/307; p=0.17), although pre-treatment HCV-RNA levels were not different (3.6±0.9 vs 3.3±0.2 million copies).
Conclusions: Few patients with chronic hepatitis C who remain HCV-RNA negative for 6 months following completion of treatment with either IFN or combination therapy will subsequently relapse. Late relapse is slightly less common after treatment with combination therapy than after IFN alone. Longer follow-up of these viral negative responders is necessary to ensure that virologic response persists.
Disclosure: Drs. Davis, McHutchison, Poynard, Esteban-Mur are lead investigators. All other authors are employees of Schering-Plough Research Institute of New Jersey.