Diagnostic accuracy of two serum markers of liver fibrosis, hyaluronan (HA) and amino-terminal peptide of type III procollagen (P-III-P), was studied in a cohort of 326 untreated patients with chronic viral hepatitis C. Both P-III-P (RIA-gnost P-III-P, Behring Diagnostic) and HA (HA-test, Pharmacia) serum concentrations correlated with the histological grades of liver fibrosis (P < 0.001). Receiver-operating characteristic (ROC) curves showed that serum HA had greater diagnostic performance than P-III-P, both for discriminating patients with extensive liver fibrosis from those with no or mild fibrosis (area under the ROC curves: 0.864 vs 0.691, P <0.001) or for discriminating patients with cirrhosis from those without cirrhosis (area under the ROC curves: 0.924 vs 0.734, P <0.001). At cutoff values of 0.8 kU/L for serum P-III-P and 85 micrograms/L for serum HA, sensitivities were 70.0% and 64.5%, and specificities were 63.4% and 91.2%, respectively, for discriminating patients with extensive liver fibrosis from those with no or mild fibrosis. At the cutoff values of 1.0 kU/L for serum P-III-P and 110 micrograms/L for serum HA, sensitivities were 60.0% and 79.2%, and specificities were 74.0% and 89.4%, respectively, for discriminating patients with liver cirrhosis from those without cirrhosis. We conclude that, because the diagnostic accuracy of serum HA is greater than that of serum P-III-P as a marker of liver fibrosis, serum HA should be preferred when monitoring liver fibrosis in patients with chronic viral hepatitis C.

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A high viral load is associated with a poor response to interferon alfa (IFN-␣) 1 and T-cell hyporesponsiveness in chronic hepatitis B virus (HBV)-infected patients. 2 Lamivudine, a nucleoside analog inhibitor of HBV polymerase, induces early suppression of serum HBV DNA in almost all patients, [3][4][5][6][7] and has been shown to restore a cellular immune response in chronic hepatitis B. 8 In previous studies, the concomitant administration of lamivudine and IFN-␣ failed to induce HBV-DNA clearance or increase T-cell responsiveness in IFN-␣ nonresponders. 9,10 According to the modes of action of IFN-␣ and lamivudine, 8 we speculated that the optimal timing of therapy was a sequential treatment starting with lamivudine monotherapy, followed by IFN-␣ monotherapy (after a short period of concomitant administration of the two drugs). The aim of this study was to assess the efficacy of this sequential treatment with lamivudine and IFN-␣ in HBV chronically infected patients not responding to previous treatment with IFN-␣ alone. PATIENTS AND METHODSPatients. Between 1998 and 1999, 14 patients with liver biopsyproven chronic hepatitis B were enrolled in the study according to the following criteria: 1) at least one previous course of IFN-␣ at the minimal dose of 5 MU 3 times a week for at least 6 months; 2) lack of response to IFN-␣ defined by the persistence of HBV DNA detected by branched DNA (bDNA) assay (Quantiplex HBV DNA Assay, Chiron Diagnostics, Emeryville, CA) and/or lack of hepatitis B e antigen (HBeAg) seroconversion at the end of the last course of IFN-␣; 3) positive hepatitis B surface antigen (HBsAg) with HBV DNA higher than 100 pg/mL (Quantiplex HBV DNA Assay) on two separate samples assayed during the 6 months before sequential treatment; 4) no previous use of nucleoside analogs; 5) absence of antiviral treatment during the 6 months before sequential treatment; 6) absence of coinfection with hepatitis C virus, hepatitis delta virus, or human immunodeficiency virus; 7) an absence of decompensated cirrhosis or hepatocellular carcinoma; 8) absence of excessive alcohol intake (higher than 40 g/d) or intravenous drug use during the past 6 months; 9) no major adverse effects experienced during previous IFN-␣ therapy; and 10) no other causes of chronic liver disease.Study Design. The treatment schedule was comprised of 3 successive phases: 1) lamivudine (Glaxo Wellcome, Marly-le-Roi, France) 100 mg/d, orally, alone for 20 weeks; 2) association of lamivudine and IFN-␣2b (Intron-A, Schering-Plough, Levallois-Perret, France) 5 MU 3 times per week subcutaneously for 4 weeks; and 3) IFN-␣ 5 MU 3 times per week, alone for 24 weeks. All patients were followed after treatment for 24 weeks. Paracetamol was used when necessary to treat flu-like syndromes following IFN-␣ injections. None of the patients received other antiviral agents, corticosteroids, or immunosuppressive drugs. All patients gave their informed consent.Before sequential treatment, HBV DNA was quantified in sera, and the HBV serologic status (HBsAg, HBs...

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