Long-term Outcome of Chronic Hepatitis C After Sustained Virological Response to Interferon-based Therapy

C. Koh; T. Heller; V. Haynes-Williams; K. Hara, X. Zhao; J. J. Feld; D. E. Kleiner; Y. Rotman; M. G. Ghany; T. J. Liang; J. H. Hoofnagle

Disclosures

Aliment Pharmacol Ther. 2013;37(9):887-894. 

In This Article

Materials and Methods

Patients

All patients who achieved a 6-month post-treatment SVR in clinical research protocols conducted by the Liver Diseases Branch, NIDDK between 1984 and 2003 were included in this analysis. Of the 262 patients enrolled, 103 achieved an SVR. Thereafter, many patients were followed on a regular basis. Starting in 2007, patients who had not returned in the previous 2 years were asked to return for a medical evaluation, blood tests, abdominal ultrasound and ultrasound transient elastography. The initial protocols included studies of interferon alfa-2b alone for 6 or 12 months,[26–29] escalating doses of interferon alfa-2b for 12 months, and the combination of standard interferon alfa-2b or peginterferon alfa-2a with ribavirin for 6–12 months.[29–31] All patients gave written informed consent for the initial trials as well as for long-term follow-up and transient elastography in a protocol, which was approved by the NIDDK Institutional Review Board and registered in ClinicalTrials.gov (#NCT00001971). All authors had access to the study data and had reviewed and approved the final manuscript.

Laboratory Tests

At the time of last follow-up, patients were tested for liver biomarkers including alanine and aspartate aminotransferase (ALT, AST), alkaline phosphatase, gamma glutamyl-transpeptidase (GGT), immunoglobulin levels (IgG, IgA, IgM), rheumatoid factor, alpha-fetoprotein and platelet counts. Results of these markers before therapy were available from most patients. Serum HCV RNA was tested by quantitative and qualitative reverse transcriptase polymerase chain reaction (Amplicor; Roche Molecular Systems, Pleasanton, CA, USA) with a lower limit of sensitivity of 100 viral copies/mL (50 IU/mL). HCV genotyping was done using reverse hybridisation (INNO-LiPA; Innogenetics, Ghent, Belgium). HCV RNA testing before, during and immediately after therapy was performed using assays that were available at the time and were not always of similar specificity and sensitivity. Virological testing from the initial studies (done between 1984 and 1992) was done on serum samples, stored at −80 °C.[29] In patients who relapsed, stored serum samples (−80 °C) were retrieved and retested for HCV RNA at the time of SVR using the Amplicor system to confirm the absence of HCV RNA.

All except three patients underwent a pre-treatment liver biopsy with interpretation by one hepatopathologist (DEK) using the Ishak modification of the HAI scoring system for activity and fibrosis.[32]

Transient Elastography

Patients evaluated after 2007 underwent ultrasound transient elastography (TE) performed via FibroScan (Echosens, Paris) after informed consent.[33] Elastography was done by individuals specifically trained in the technique. At least 10 determinations were made and median results were expressed in kilopascals (kPA). Values range from 2.5 to 75 kPA with values of <7.0 being normal and suggesting no or mild hepatic fibrosis, values of 7.1–13.7 suggesting moderate to advanced fibrosis and values of >13.8 suggesting cirrhosis.

Statistical Analysis

Continuous variables were reported as mean (±standard deviation), and categorical variables as percentages. Mean and proportion of abnormal values, differences of baseline ALT, AST, GGT, alkaline phosphatase, total and direct bilirubin, IgG, albumin, alpha-fetoprotein, rheumatoid factor and platelets and the most recent follow-up values were compared via paired student's t-test for continuous variables or McNemar's test for categorical variables. As a sensitivity analysis, regression analysis was used to explore the effect in time between baseline to follow-up and mean differences between baseline and follow-up values. Cumulative incidence of relapse was plotted using the Kaplan–Meier method. In comparing pre-treatment liver biopsy scores with follow-up TE, the McNemar's exact test for association was used. Significance was accepted at a P-value of less than 0.05. Data analysis was performed using sas, Version 9.1.3 (SAS Institute Inc., Cary, NC, USA) software.

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