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Background/Aims: Viral decline during lamivudine therapy in chronic hepatitis B patients is bi-phasic. We studied the influence of lamivudine dose and baseline characteristics on parameters obtained from a mathematical model. Methods: Chronic hepatitis B patients were randomized to receive 150 mg (group 1; n = 11) or 600 mg (group 2; n = 10) lamivudine daily for 4 weeks. Hepatitis B virus DNA was measured frequently with the Digene Hybrid Capture II test and the Roche PCR assay. Results: The description of viral decline in our closely monitored patients by means of the mixed-effects approach with both the bi-phasic model and a piecewise linear regression model resulted in a good fit. Baseline alanine aminotransferase (ALT) was significantly related to the slope of the second phase of viral decline. Previous lamivudine-treated patients showed a significant slower first phase than patients naive to lamivudine treatment. Conclusions: The initial observed difference in viral decline between 150 and 600 mg of lamivudine disappeared when baseline ALT was taken into account. This strengthens the hypothesis that the level of intrinsic activity is related to the turnover of infected hepatocytes. Moreover, reintroduction of lamivudine in previously lamivudine-treated patients should be considered carefully.

Background/Aims Albinterferon alfa-2b is a novel, long-acting, fusion polypeptide that is dosed q2wk or q4wk. The predictive value of early virologic response during albinterferon alfa-2b or peginterferon alfa-2a treatment was investigated in interferon-naive patients with genotype 1, chronic hepatitis C. Methods Four hundred and fifty-eight patients were randomized to: albinterferon 900 or 1200μg q2wk, or 1200μg q4wk, or peginterferon 180μg qwk. HCV RNA was measured by real-time PCR. A linear exhaustive search algorithm was used to determine the best SVR prediction algorithm in the per-protocol population ( n =368), with inclusion of key ITT analyses to assess impact. Results SVR rate: 54–67% ( P =NS between arms). Rapid initial virologic response rate at week 2 (RIVR; viral decline >2log 10 IU/mL) was 32–50% and gave rise to positive predictive value of 88–97% for SVR. No initial virologic response at week 4 (NIVR; viral decline 10 IU/mL; viral load >5.5log 10 IU/mL) demonstrated a 100% negative predictive value for SVR. A sequential prediction algorithm based on viral kinetics at weeks 2 and 4 identified four prediction groups that reliably predicted SVR, positively or negatively, in 65–72% of patients. Conclusions Improved SVR prediction was obtained by integrating absolute levels and reduction of HCV RNA at treatment week 2 and 4. Patients with RIVR had a high likelihood of achieving SVR.

BACKGROUND/AIMS: Analysis of hepatitis C virus (HCV) RNA kinetics in compartments other than plasma may help in understanding HCV replication and identifying clinically significant patterns of treatment response. METHODS: After 6 weeks of pegylated interferon-alpha2a/ribavirin therapy, 74 chronic hepatitis C patients were randomized to individualized or standard treatments for another 42 weeks. HCV RNA was quantified in peripheral blood mononuclear cells (PBMCs) by TaqMan-based real-time PCR and compared to plasma HCV RNA. RESULTS: HCV RNA declines in PBMCs and plasma were comparable during the initial 12 weeks of therapy (Spearman's rank correlation range over different time points, 0.73-0.97). However, a delay of HCV RNA decay in PBMCs, expected if kinetics in PBMCs only reflected kinetics in plasma, was rarely observed. For many patients, HCV RNA decline in PBMCs started as early as in plasma and for some of them the kinetics strongly differed in the two compartments, hinting at a compartment-specific HCV replication and treatment effect. Fast viral decay in PBMCs was associated with sustained virological response, but viral kinetics in PBMCs added only minor predictive information compared with kinetics in plasma. CONCLUSIONS: Future kinetics studies of HCV RNA during therapy with new antivirals should take into account their compartment-specific effect.

Background/Aims : Recombinant human albumin-interferon alfa (alb-IFN) is a novel 85.7-kD recombinant protein consisting of interferon alfa-2b genetically fused to human serum albumin. Methods : A phase 2, open-label, dose-ranging study was conducted in IFN-alfa-naive patients with genotype 1 chronic hepatitis C to evaluate the antiviral activity, safety, and pharmacokinetics of alb-IFN. Fifty-six patients were enrolled to receive two subcutaneous injections of alb-IFN 14 days apart in five dose cohorts of 200, 450, 670, 900, and 1200μg. Results : A 2 log 10 IU/mL or greater reduction in hepatitis C virus (HCV) RNA at Week 4 was observed in 69% (18/26) of patients who received the higher alb-IFN doses of 900 and 1200μg. The mean HCV RNA reduction at Week 4 in these two higher-dose cohorts was 3.2 log 10 IU/mL. Modeling of viral kinetics demonstrated a biphasic response that was dose dependent. Adverse events were mostly mild to moderate in severity. The most common adverse events were headache (73%), chills (63%), fatigue (61%), and arthralgia (55%). The median terminal half-life was 141h consistent with previous alb-IFN data from IFN-alfa-experienced patients. Conclusions : Alb-IFN demonstrated significant antiviral activity and was well tolerated in patients with HCV genotype 1 infection.

Background/Aims The existence of an extrahepatic hepatitis C virus replication compartment is an important question for optimizing therapy and preventing the infection of liver grafts. An extraheptic replication compartment could be indicated if viral decline during the anhepatic phase is not a single exponential. However, the duration of the anhepatic phase is too short (0.5–2h) to allow such analysis. Here we mathematically analyze viral decline during liver transplantation beyond the period of the anhepatic phase and examine the possibility of viral compartmentalization. Methods Viral load of 30 patients undergoing liver transplantation was frequently measured. Simulation and non-linear fitting of differential equation models were used to test different compartmentalization hypotheses. Results In 16 of the patients (56%), a bi-phasic viral decline was observed which is explained by the existence of a second replication compartment. This extrahepatic compartment is responsible for about 3.1% of virus in circulation and the mean half-life of its infected cells is 2.6 days. The remaining patients, with a single exponential decline, have either a second compartment with relatively low contribution or no second compartment. Conclusions These results provide a first quantitative picture of the extrahepatic hepatitis C viral contribution and may suggest new approaches for viral clearance.

Methods: Results from two Phase 1 studies were pooled for the analysis. Study 1 investigated the antiviral activity of oral filibuvir doses of 100, 300 and 450mg BID and 300mg TID or placebo, for 8 days in treatment naive patients. In the second study, the antiviral activity of filibuvir 450mg BID in treatment experienced patients dosed for 10 days and 700mg BID in treatment naive patients dosed for 3 days was evaluated. Filibuvir exposures achieved over 24 hours (AUC24) were utilized to inform the ER analysis of the maximum log change in viral load from baseline. The relationship was described by an inhibitory Emax model using a non-linear mixed effects model. Effects of food, baseline viral load (BVL) and genotype (1a/1b) on relevant model parameters were also evaluated. The antiviral response for a range of doses was simulated from the model. Results: The ER data from 52 subjects were adequately described by the Emax model with Emax (95%CI) = −2.14 (−2.54, −2.02) IU/ml and AUC2450 (95%CI) = 54,176 (44,606, 102,006) ng·hr/ml. BVL was the only influential covariate which described the maximal response (Emax). The analysis indicated that doses in excess of 300mg BID were expected to achieve atleast 70% of Emax. Furthermore, filibuvir exposures resulting from doses greater than 600mg BID produced responses close to Emax indicating that higher doses (>600mg BID) are unlikely to provide additional efficacy. Conclusions: Filibuvir exposures adequately described the maximum log change in viral load relative to baseline. The above analysis in conjunction with results from a Phase 2a study (200/300/500mg BID+SOC, rapid viral response rates of 60–75%) suggests that filibuvir doses of 300 and 600mg BID are expected to be efficacious when combined with SOC and will be further investigated in Phase 2b studies.

regression model TGF-b HP genotype was confirmed as an independent positive predictor for SVR in interferon-alpha therapy (Odds ratio:4.4; 95CI: 1.5−13.4; p = 0.009). Conclusions: Response rates to interferon-alpha therapy are enhanced in acute HCV-infected HIV-positive patients carrying the TGF-b “high producer” genotype. This finding may indicate that a TGF-b “highproducer” state can partially compensate HCV NS5A-induced inhibition of TGF-b signaling.