Claudio Avila

Randomized clinical trial: efficacy and safety of telbivudine and lamivudine in treatment-naïve patients with HBV-related decompensated cirrhosis

Summary.  Patients with decompensated cirrhosis owing to chronic hepatitis B viral (HBV) infection have a high morbidity/mortality rate, and the treatment remains a challenge. We studied the safety and efficacy of telbivudine and lamivudine in such patients. This noninferiority, double‐blind trial randomized 232 treatment‐naive patients with decompensated HBV (1:1) in 80 academic hospitals to receive once‐daily telbivudine 600 mg or lamivudine 100 mg for 104 weeks. Primary composite endpoint was proportion of patients with HBV DNA <10 000 copies/mL, normal alanine aminotransferase (ALT) and Child‐Turcotte‐Pugh score improvement/stabilization at week 52. Response rates using a post hoc modified endpoint (HBV DNA <300 copies/mL [57 IU/mL] and ALT normalization) in intent‐to‐treat analysis (missing = failure) were 56.3%vs 38.0% after 76 weeks (P = 0.018) and 45.6%vs 32.9% after 104 weeks (P = 0.093) for telbivudine vs lamivudine. Telbivudine treatment was an independent predictive factor for HBV DNA <300 copies/mL and ALT normalization (P = 0.037). Response rates with protocol‐defined composite endpoint in intent‐to‐treat analysis (M = F) were 56.2 vs 54.0% (noninferiority not achieved) and 39.1%vs 36.4% (noninferiority achieved) in telbivudine and lamivudine groups at 52 and 104 weeks. Telbivudine treatment was associated with a significant improvement in glomerular filtration rate compared to lamivudine treatment and was also associated with a trend for improvement in survival (87%vs 79%). No cases of lactic acidosis were reported. Telbivudine compared to lamivudine was associated with a higher rate of patients with both viral suppression and ALT normalization, a trend towards a higher rate of survival and significant improvement in glomerular filtration.

Efficacy and safety of prolonged 3-year telbivudine treatment in patients with chronic hepatitis B

Background: In the GLOBE trial, telbivudine demonstrated superior efficacy to lamivudine at 2 years in patients with chronic hepatitis B (CHB).

Telbivudine plus pegylated interferon alfa-2a in a randomized study in chronic hepatitis B is associated with an unexpected high rate of peripheral neuropathy

BACKGROUND & AIMS This study investigated the antiviral efficacy and safety of telbivudine in combination with pegylated interferon (PegIFN) alpha-2a in chronic hepatitis B (CHB) patients. METHODS This was a randomized, open-label, multicentre study, in treatment-naïve patients with HBeAg-positive CHB, comparing the efficacy and safety of telbivudine in combination with PegIFN alpha-2a with telbivudine monotherapy and PegIFN alpha-2a monotherapy. The study was terminated early due to increased rates of peripheral neuropathy in the combination-therapy group. RESULTS Of the 159 patients randomized (from 300 planned) 50 were assigned to combination therapy, 55 to telbivudine, 54 to PegIFN, and 110 (18, 49, and 43, respectively) reached week 24. Peripheral neuropathy occurred in 7/50, 1/54, and 0/54 patients in the three groups of safety populations, respectively. No relationship between the occurrence of peripheral neuropathy and other variables (e.g., pharmacokinetic data, treatment efficacy, ALT levels, creatine kinase elevations) were observed. At week 24, undetectable HBV DNA (<300 copies/ml) was achieved by 71% (12/17), 35% (17/48), and 7% (3/42) of patients, with available data receiving combination therapy, telbivudine monotherapy and PegIFN monotherapy, respectively (p = 0.022 for combination therapy vs. telbivudine; p<0.0001 for combination therapy vs. PegIFN). CONCLUSIONS Combination therapy carried an increased risk of peripheral neuropathy. Despite the rapid and profound reductions in HBV DNA levels, combination therapy with telbivudine and PegIFN should not be used.

Alisporivir plus ribavirin, interferon free or in combination with pegylated interferon, for hepatitis C virus genotype 2 or 3 infection

Alisporivir is a cyclophilin inhibitor with pan‐genotypic anti–hepatitis C virus (HCV) activity and a high barrier to viral resistance. The VITAL‐1 study assessed alisporivir as interferon (IFN)‐free therapy in treatment‐naïve patients infected with HCV genotype 2 or 3. Three hundred forty patients without cirrhosis were randomized to: arm 1, alisporivir (ALV) 1,000 mg once‐daily (QD); arm 2, ALV 600 mg QD and ribavirin (RBV); arm 3, ALV 800 mg QD and RBV; arm 4, ALV 600 mg QD and pegylated IFN (Peg‐IFN); or arm 5, Peg‐IFN and RBV. Patients receiving IFN‐free ALV regimens who achieved rapid virological response (RVR) continued the same treatment throughout, whereas those with detectable HCV RNA at week 4 received ALV, RBV, and Peg‐IFN from weeks 6 to 24. Overall, 300 patients received ALV‐based regimens. In arm 1 to arm 4, the intent‐to‐treat rates of sustained virological response (SVR) 24 weeks after treatment (SVR24) were from 80% to 85%, compared with 58% (n = 23 of 40) with Peg‐IFN/RBV. Per‐protocol analysis showed higher SVR24 rates in patients who received ALV/RBV, IFN‐free after RVR (92%; n = 56 of 61) than with ALV alone after RVR (72%; n = 13 of 18) or with Peg‐IFN/RBV (70%; n = 23 of 33). Both RVRs and SVRs to ALV IFN‐free regimens were numerically higher in genotype 3– than in genotype 2–infected patients. Viral breakthrough was infrequent (3%; n = 7 of 258). IFN‐free ALV treatment showed markedly better safety/tolerability than IFN‐containing regimens. Conclusions: ALV plus RBV represents an effective IFN‐free option for a proportion of patients with HCV genotype 2 or 3 infections, with high SVR rates for patients with early viral clearance. Further investigations of ALV in IFN‐free combination regimens with direct‐acting antiviral drugs deserve exploration in future trials. (Hepatology 2015;62:1013‐1023)

Early Viral Kinetics of Telbivudine and Entecavir: Results of a 12-Week Randomized Exploratory Study with Patients with HBeAg-Positive Chronic Hepatitis B

ABSTRACT We characterized the early viral kinetic profiles of telbivudine and entecavir and the effects of these potent nucleoside analogs on hepatitis B virus (HBV) DNA and alanine aminotransferase levels in adults with hepatitis B e antigen-positive compensated chronic hepatitis B. Forty-four patients were enrolled in this open-label, parallel-group, multicenter study and randomized to receive telbivudine or entecavir for 12 weeks. Reductions in hepatitis B virus DNA and alanine aminotransferase levels from baseline to weeks 2, 4, 8, and 12 were assessed. Viral kinetic parameters, including viral clearance per day, loss of infected cells per day, and efficiency of inhibition of viral production, were estimated by using a biphasic mathematical model. Statistical analyses were limited to descriptive analyses. The 2 treatment groups achieved similar reductions in HBV DNA and alanine aminotransferase levels. Mean reductions in levels of hepatitis B virus DNA at week 12 were 6.6 ± 1.6 and 6.5 ± 1.5 log10 copies/ml for the telbivudine- and entecavir-treated patients, respectively. There were no significant differences between groups in values for mean viral clearance per day, mean loss of infected cells per day, or efficiency of blocking viral production. The safety profiles for both medications were favorable. During the first 12 weeks of treatment, telbivudine and entecavir demonstrated similar antiviral potencies, resulting in a rapid and profound suppression of serum hepatitis B virus DNA and reduction of alanine aminotransferase levels. No differences in the effects of these 2 agents on early viral kinetics were observed. Both medications were well tolerated.

1214 MULTIPLE MUTATIONS IN DOMAIN II OF NS5A IDENTIFIED IN GENOTYPE 2/3 VITAL-1 STUDY BREAKTHROUGH PATIENTS ARE REQUIRED TO REDUCE SUSCEPTIBILITY TO ALISPORIVIR IN VITRO

the ribavirin-sparing arm were excluded because of their high virological failure rates. Separate logistic regression models were obtained for FDV and BI207127 for plasma concentrations obtained during different time windows in the first month of therapy. Results: Patients with GT1b (any IL28B genotype) had flat or shallow relationships between trough concentrations of FDV and BI207127 and predicted SVR12. The predicted SVR12 was high throughout the concentration ranges examined. For both drugs there was a significantly greater effect of trough concentration on SVR12 in GT1a-CC patients compared with GT1b patients; GT1a-CC patients had predicted SVR12 >70% only at higher concentrations. Conclusions: GT1b-infected patients carrying any IL28B genotype are predicted to achieve high SVR rates across broad plasma concentration ranges of FDV and BI207127 given in combination. The results suggest that the daily doses tested in SOUND-C2 give adequate plasma concentrations in GT1b-infected patients. GT1aCC patients are predicted to require higher levels of FDV and BI207127. Further investigations of plasma concentration-response relationships in various patient subgroups, factors contributing to low plasma levels, and potential confounders, should be performed. Phase III trials of FDV 120mg QD plus BI207127 600mg BID plus RBV for 16 or 24 weeks are ongoing in GT1b-infected patients.

Sa1033 Interferon-Free Alisporivir Treatment Down-Regulates Interferon-Stimulated Genes Suggesting a Unique Antiviral Mechanism of Action for the Cyclophilin Inhibitor Alisporivir

BACKGROUND: VITAL-1 study assessed safety, tolerability and antiviral activity of the cyclophilin inhibitor alisporivir (ALV) as monotherapy or combination with ribavirin (RBV) compared to IFN/RBV and ALV/IFN in treatment-naive GT2/3 HCV patients. We describe genotypic and phenotypic changes in patients from this study who experienced a viral breakthrough (VB). METHODS: VITAL-1 study patients on IFN-free regimens that did not achieve RVR (, 25 U/ml) at week 4 were administered IFN/RBV/600 mg QD ALV starting at week 6 (IFN-add-on). VB defined as an increase of HCV RNA .1 log10 above nadir. The HCV NS5A gene was analyzed by population sequencing. The entire NS5A region isolated at baseline and at VB was cloned into a JFH1subgenomic shuttle vector for phenotypic analyses. Selected mutations were engineered into a wild type replicon and their impact on replication fitness and susceptibility to ALV and direct acting antiviral drugs were determined. RESULTS: The VB rate with IFN-free or IFN-add-on regimens was 2.7% (7/ 260). Low ALV drug level (Cmin , 20% of group mean; , 100 ng/mL) was observed (5/ 7 VB patients). Genotypic analysis of the NS5A gene revealed amino acid changes in these patients at the time of VB compared to baseline. Replicons bearing NS5A from patients at breakthrough conferred 1.2-16.9-fold shift over baseline EC50 values; 5/7 had impaired replication fitness. No cross-resistance to other classes of HCV inhibitors was observed. Most frequently identified mutations were D320E (D316E in G2), R347W and A349V in Domain II of NS5A, which by themselves decreased ALV susceptibility by 5-, 4, and 8-fold, respectively, in vitro when engineered into wild-type replicon. Combination of multiple mutations decreased susceptibility further, but generally at the cost of replication fitness. CONCLUSION: In treatment-naive G2/3 patients with viral breakthrough, mutations in NS5A domain II were selected, which individually conferred ≤ 8-fold reduced susceptibility to ALV in vitro. The combination of multiple mutations was required to further reduce susceptibility which is consistent with the high barrier to resistance for host-targeting ALV. Observed genotypic changes did not confer cross-resistance to other classes of HCV inhibitors, supporting the use of ALV in future drug combination therapies.

Sa1030 Alisporivir Interferon-Free G2/3 Vital-1 Study: Low Rate of Viral Breakthrough and Combination of Multiple NS5A Domain II Mutations Required to Reduce Susceptibility to Alisporivir In Vitro

BACKGROUND: VITAL-1 study assessed safety, tolerability and antiviral activity of the cyclophilin inhibitor alisporivir (ALV) as monotherapy or combination with ribavirin (RBV) compared to IFN/RBV and ALV/IFN in treatment-naive GT2/3 HCV patients. We describe genotypic and phenotypic changes in patients from this study who experienced a viral breakthrough (VB). METHODS: VITAL-1 study patients on IFN-free regimens that did not achieve RVR (, 25 U/ml) at week 4 were administered IFN/RBV/600 mg QD ALV starting at week 6 (IFN-add-on). VB defined as an increase of HCV RNA .1 log10 above nadir. The HCV NS5A gene was analyzed by population sequencing. The entire NS5A region isolated at baseline and at VB was cloned into a JFH1subgenomic shuttle vector for phenotypic analyses. Selected mutations were engineered into a wild type replicon and their impact on replication fitness and susceptibility to ALV and direct acting antiviral drugs were determined. RESULTS: The VB rate with IFN-free or IFN-add-on regimens was 2.7% (7/ 260). Low ALV drug level (Cmin , 20% of group mean; , 100 ng/mL) was observed (5/ 7 VB patients). Genotypic analysis of the NS5A gene revealed amino acid changes in these patients at the time of VB compared to baseline. Replicons bearing NS5A from patients at breakthrough conferred 1.2-16.9-fold shift over baseline EC50 values; 5/7 had impaired replication fitness. No cross-resistance to other classes of HCV inhibitors was observed. Most frequently identified mutations were D320E (D316E in G2), R347W and A349V in Domain II of NS5A, which by themselves decreased ALV susceptibility by 5-, 4, and 8-fold, respectively, in vitro when engineered into wild-type replicon. Combination of multiple mutations decreased susceptibility further, but generally at the cost of replication fitness. CONCLUSION: In treatment-naive G2/3 patients with viral breakthrough, mutations in NS5A domain II were selected, which individually conferred ≤ 8-fold reduced susceptibility to ALV in vitro. The combination of multiple mutations was required to further reduce susceptibility which is consistent with the high barrier to resistance for host-targeting ALV. Observed genotypic changes did not confer cross-resistance to other classes of HCV inhibitors, supporting the use of ALV in future drug combination therapies.