the development of IFN-neutralizing antibodies. [12][13][14] TheoretTo compare the long-term effectiveness and tolerabilically, these risks might be enhanced by long-term adminity of lymphoblastoid interferon (IFN-aN1) and recombiistration of a single type of IFN and mitigated by the adminnant interferon alfa 2a (IFN-a2a) in patients with istration of different types of IFN. Lymphoblastoid IFN chronic hepatitis caused by hepatitis C virus (HCV), 234 (IFN-aN1), a mixture of 22 interferons, 15 was shown to induce consecutive patients with HCV-related chronic hepatitis a response in 40% of nonresponders to recombinant IFN 16,17 were randomized prospectively to receive titrated doses and resulted in a complete response in all patients with hepa-(starting dose Å 6 million units [MU]) of IFN-a2a (n Å titis C who relapsed during treatment with recombinant 118) or IFN-aN1 (n Å 116) for 12 months. HCV RNA was IFN. 14 To assess whether treatment of hepatitis C can be detected by reverse-transcription polymerase chain reimproved by using lymphoblastoid IFN, we have conducted action (RT-PCR), quantified by branched-DNA (bDNA) a prospective randomized comparative trial in which patients assay, and genotyped by reverse hybridization assay.with chronic hepatitis caused by HCV were randomized to Thirty-one patients in the IFN-a2a group and 28 in the either recombinant IFN-a2a or lymphoblastoid IFN-aN1. IFN-aN1 group (total, 59 [25%] had normal transami-To avoid potential bias caused by insufficient dose or duranases and undetectable HCV RNA by RT-PCR after 12 tion of therapy, we elected to treat patients for 12 months months of therapy, but only 19 in the first group and 20and modify the dose according to the alanine transaminase in the second group (total, 39 [17%]) had biochemical (ALT) response. The initial dose was 6 MU. To gain insight and virological responses 12 months after treatment was on the cost-effectiveness of treatment regimens, we analyzed discontinued. The two treatment groups differed in the tolerability and cost of the two treatments, as well as terms of prevalence of major drug-related adverse reacclinical and virological predictors of treatment outcome that tions (23% vs. 37%, P Å .025). The mean total dose per could be used for refining therapy duration or dosage. size made it possible to perform an interim analysis when 50% of the patients had been enrolled. It was planned that the trial would Less than 25% of the patients with chronic hepatitis C be discontinued at that time if the difference in response rates beachieve sustained biochemical responses with undetectable se-tween the two treatments was outside the confidence interval (CI) related to a type I error equal to 0.025 (3.8%-36.2%). and longer duration of therapy have been attempted to in-ies, and abnormal serum transaminase levels. Enrollment was crease the response rates, but the data are inconclusive. [4][5][6][7][8][9] stopped in November 1992 when 258 patients had been recruited, Nonresponse or loss of response during IFN therapy could and...

No abstract

We compared two commercial assays for quantification of serum hepatitis C virus (HCV) RNA to investigate whether pretreatment levels of serum HCV RNA could predict the outcome of interferon (IFN) therapy. The Amplicor HCV Monitor test is based on a single, combined reverse transcription and amplification reaction carried out by the Tth DNA polymerase using specific primers for the 5' untranslated (UTR) region. The Quantiplex HCV RNA 2.0 assay is based on specific hybridization of viral RNA by synthetic oligonucleotides complementary to the 5'-UTR and core regions of the genome, allowing equal quantification of the six major genotypes. Receiver-operating characteristic (ROC) analysis was employed to identify the best cut-off value (predicting patients who were non-responsive to treatment) with corresponding sensitivity and specificity values. Logistic regression analysis was performed using these cut-off values. We studied 133 consecutive patients with chronic hepatitis C enrolled in a prospecsustained responders was 5322 copies ml-1 by the Monitor test and less than 0.2 million equivalents ml-1 (MEq ml-1) by the Quantiplex assay; for the 115 non-responders/relapsers, the median viraemia was 83,125 copies ml-1 and 1.128 MEq ml-1 for the Monitor test and Quantiplex assay, respectively. Spearman's rank test gave a correlation of 0.63 between assays. The best predicting cut-off values were 22,134 copies ml-1 for the Monitor test and 0.330 MEq ml-1 for the Quantiplex assay; their respective sensitivities and specificities were 72% and 75% for Monitor and 67% and 83% for Quantiplex. By logistic regression analysis, the age and gender-adjusted odds ratios of high vs low HCV RNA levels, defining the risk of non-response, were 10.6 (CI 3.1-35.7) for Monitor and 14.3 (CI 4.3-47.3) for Quantiplex. The two assays had comparable sensitivity for serum HCV RNA but they identified different predictive cut-offs for non-response to therapy.

The efficacy and tolerability of 12-month treatment with titrated doses of recombinant interferon-alpha 2a (IFN-alpha 2a) in chronic hepatitis C were studied in 67 consecutively recruited patients randomly assigned either to a starting dose of IFN-alpha 2a 6 MU, subsequently adjusted to the serum alanine aminotransferase (ALT) response (n = 35), or to no therapy (n = 32; controls). End-of-treatment ALT levels were normal and hepatitis C virus (HCV) RNA was negative by nested polymerase chain reaction (PCR) in 17 (49%) treated patients compared to none of the controls (P < 0.001). During the 12 months after stopping treatment the number of patients who remained in remission was eight (23%) and one respectively (4%) (P = 0.031). Follow-up liver biopsy showed reduced hepatic inflammation in 80% of treated patients and in 29% of controls (P < 0.001). The eight sustained responders and 27 non-responders or relapsers received similar mean total doses of IFN (565 MU vs 545 MU) and had a similar incidence of anti-IFN neutralizing antibodys (13% vs 19%). Absence of cirrhosis was the only independent pretreatment parameter that predicted a sustained response. In conclusion, a mean cumulative dose of IFN 549 MU, titrated over 12 months, was well tolerated, and resulted in the long-term clearance of HCV RNA and normal ALT levels in 23% of patients.