PRETREATMENT VIRUS LOAD AND MULTIPLE AMINO-ACID SUBSTITUTIONS IN THE INTERFERON SENSITIVITY-DETERMINING REGION PREDICT THE OUTCOME OF INTERFERON TREATMENT IN PATIENTS WITH CHRONIC GENOTYPE 1B HEPATITIS-C VIRUS-INFECTION

Hepatitis C virus (HCV) genotype Ib and high pretreatment virus load a re predictive factors of poor response to interferon therapy in patien ts with chronic hepatitis C. To further examine the factors predicting the response to interferon in patients with genotype Ib infection, we analyzed 110 consecutive patients with HCV who were treated with a to tal of 624 million units of lymphoblastoid interferon alfa. Thirty-six patients (33%) were responders, while the remaining 74 patients (67%) were nonresponders. Multivariate analysis showed that a high virus ti ter (assessed by serum core protein level, P = .0021) and the presence of more than two amino acid substitutions in the interferon sensitivi ty-determining region (ISDR) (P = .0036) correlated significantly with the response to interferon therapy. Because mutations analyzed by dir ect sequencing of polymerase chain reaction (PCR) products may reflect artifacts of direct sequencing, we further analyzed quasispecies of H CV in this region by cloning and sequencing. Although PCR-based analys is of responders with multiple amino acid substitutions in the ISDR sh owed the presence of a small amount of wild-type strain in their serum , the results obtained by direct sequencing and cloning were essential ly the same. A longitudinal study of quasispecies in 2 patients who sh owed a dramatic change in the virus titer showed no conversion from wi ld type to mutant or vice versa. Our results indicate that amino acid substitutions and virus load are independent predictors of the respons e to interferon therapy. The ability of some patients with no mutation in the ISDR or high virus load to eliminate the virus suggests the pr esence of other unidentified factors, host or viral, that influence th e response to interferon therapy.