Approximately one third of hepatitis C virus (HCV) genotype 1 patients achieved a sustained virological response (SVR) after 24 weeks of treatment with peginterferon ␣-2a (40 kd) plus ribavirin in a randomized, multinational trial. We aimed to identify factors associated with a rapid virological response (RVR) at week 4 (HCV RNA <50 IU/mL) and a SVR (HCV RNA <50 IU/mL at the end of follow-up) in these patients. Stepwise multiple logistic regression analysis was used to explore the prognostic factors for a RVR and SVR in genotype 1 patients treated for 24 weeks. Fifty-one of 216 (24%) genotype 1 patients in the 24-week treatment groups had a RVR. SVR rates were considerably higher in patients with than without a RVR (89% vs. 19%, respectively). Patients with a baseline HCV RNA of less than 200,000 IU/mL (OR 9.7, 95% CI 4.2-22.5; P < .0001) or 200,000-600,000 IU/mL (OR 3.6, 95% CI 1.5-9.1; P ‫؍‬ .0057) were more likely to achieve a RVR than those with HCV RNA greater than 600,000 IU/mL. HCV subtype (1b vs. 1a) was also independently associated with RVR (OR 1.8, 95% CI 0.9-3.7; P ‫؍‬ .0954). RVR (OR 23.7 vs. no RVR, 95% CI 9.1-61.7) and baseline HCV RNA less than 200,000 IU/mL (OR 2.7 vs. >600,000 IU/mL, 95% CI 1.1-6.3; P < .026) were significant and independent predictors of SVR in patients treated for 24 weeks. T he treatment of choice for chronic hepatitis C is the combination of a pegylated interferon plus ribavirin. Overall sustained virological response (SVR) rates of up to 63% have been achieved with optimal regimens of peginterferon ␣-2a (40 kd) plus ribavirin in randomized phase III trials, 1,2 although SVR rates are heterogenous and vary significantly by hepatitis C virus (HCV) genotype. Current guidelines for the management of chronic hepatitis C recommend the combination of a pegylated interferon plus ribavirin 1,000 or 1,200 mg/d for 48 weeks as initial treatment for patients infected with HCV genotype 1. 3 Treatment for a shorter duration (24 weeks), with a lower dose of ribavirin (800 mg/d), or both, is associated with markedly reduced SVR rates in this frequently encountered but difficult-to-treat subpopulation. These recommendations are based on the results of a large, multinational, phase III trial in which patients were randomized to 1 of 4 combination regimens of peginterferon ␣-2a (40 kd) plus ribavirin. 2 The timing and magnitude of the virological response to antiviral therapy in patients infected with HCV genoAbbreviations: SVR, sustained virological response; HCV, hepatitis C virus; RVR, rapid virological response; LD, low dose; SD, standard dose. From the

No abstract

Expression of the E1A oncogene of adenovirus type 5 inhibits the response of interferon (IFN)-inducible constructs to Type I (alpha,beta) and II (gamma) IFNs in transient transfection assays. In human cell lines stably expressing E1A mRNA and protein acquisition of an antiviral state and the induction of a number of genes in response to alpha- and gamma-IFNs is inhibited. A short IFN-stimulable response element (ISRE) present in the 5' flanking region of a number of genes mediates induction by alpha- and gamma-IFNs. In cells expressing E1A there is a substantial reduction in the levels of the ISRE-binding factors E and M, inducible by alpha-IFN, and of factor G, inducible by gamma-IFN. In E1A-expressing cells the E alpha subunit of factor E is activated normally in response to alpha-IFN; the defect is in the production or activation of the E gamma subunit. The inhibitory activity of E1A is lost upon deletion of the CR1 domain. The induction of HLA class II genes by gamma-IFN, which involves a different DNA response element(s), and of beta-IFN mRNA in response to double-stranded RNA are also inhibited by E1A. An essential component(s) of a number of signalling pathways must, therefore, be subject, directly or indirectly, to inhibition by E1A.

Constructs expressing the core, surface, X, or polymerase proteins of hepatitis B virus were transfected into human cells. In transient assays, only the polymerase inhibited the responses to interferons a and y (IFN-a and -y). Stable expression of the polymerase was achieved in the cell line 2fTGH, which carries an IFN-inducible marker gene, by growth under conditions that select for inhibition of the response to IFN-a, but the clones grew poorly. When expressed alone, the terminal protein domain of the polymerase gene inhibited the response to IFN-a and the reverse transcriptase plus RNase H domains appeared to be toxic. Clones of cells expressing terminal protein alone, selected for the loss of response to IFN-a, grew normally and had no detectable response to IFN-a, IFN-y, or double-stranded RNA. Binding of IFN-a to these cells was not impaired but did not lead to activation of the Ea subunit of the IFN-induced transcription factor E. These observations are of potential importance in relation to the pathogenesis of chronic hepatitis B virus infection and the resistance of such infection to IFN-a therapy.

No abstract