Faculty Bibliography

This pooled analysis of five Phase IIb and III studies evaluated the safety and tolerability of simeprevir, a once daily, oral hepatitis C virus (HCV) NS3/4A protease inhibitor. Data were summarised for patients who received simeprevir 150 mg once daily (n = 924) or placebo (n = 540) plus pegylated interferon-alpha/ribavirin for 12 weeks. During the first 12 weeks of treatment, few patients discontinued simeprevir or placebo due to adverse events (AEs) (both 2.2%). Pruritus (23.8% vs 17.4%), rash (any; 22.9% vs 16.7%) and photosensitivity (3.2% vs 0.6%) [Correction added on 16 January 2015, after first online publication: In the above sentence, the values in 'Photosensitivity' were previously incorrect and have now been changed to 3.2% vs 0.6%.] were more prevalent in the simeprevir vs the placebo groups. Most AEs were grade 1/2 (72.4% for simeprevir vs 71.3% for placebo). All grade 3/4 AEs occurred in <5.0% of patients, except neutropenia (9.8% vs 7.6%). Overall incidence of neutropenia was similar (17.3% vs 15.7%). Incidence of anaemia was 13.2% for simeprevir vs 10.9% for placebo, and incidence of increased bilirubin was 8.4% vs 2.8%. Bilirubin increases were mild-to-moderate and transient without concurrent transaminase increases or association with hepatic injury. Safety and tolerability did not vary with METAVIR score, although increased bilirubin and anaemia were more frequent in simeprevir-treated patients with METAVIR F4 (increased bilirubin, 13.0% vs 3.3%; anaemia, 19.0% vs 14.8%). Serious AEs were infrequent (2.1% for simeprevir vs 3.0% for placebo). No deaths were reported during the first 12 weeks of treatment. Patient-reported fatigue and other outcomes were comparable for both groups, but were of shorter duration for simeprevir due to the use of response-guided therapy. Simeprevir is well tolerated in HCV genotype 1-infected patients.

Hepatitis C virus (HCV) uniquely requires the liver-specific microRNA-122 for replication, yet global effects on endogenous miRNA targets during infection are unexplored. Here, high-throughput sequencing and crosslinking immunoprecipitation (HITS-CLIP) experiments of human Argonaute (AGO) during HCV infection showed robust AGO binding on the HCV 5'UTR at known and predicted miR-122 sites. On the human transcriptome, we observed reduced AGO binding and functional mRNA de-repression of miR-122 targets during virus infection. This miR-122 "sponge" effect was relieved and redirected to miR-15 targets by swapping the miRNA tropism of the virus. Single-cell expression data from reporters containing miR-122 sites showed significant de-repression during HCV infection depending on expression level and site number. We describe a quantitative mathematical model of HCV-induced miR-122 sequestration and propose that such miR-122 inhibition by HCV RNA may result in global de-repression of host miR-122 targets, providing an environment fertile for the long-term oncogenic potential of HCV.

Introduction: The all-oral combination of daclatasvir (DCV; pangenotypic NS5A inhibitor), asunaprevir (ASV; NS3 protease inhibitor), and beclabuvir (BCV; BMS-791325; non-nucleoside NS5B inhibitor)- DCV-TRIO regimen-was evaluated without ribavirin in HCV genotype (GT) 1-infected treatment-naive and -experienced patients without cirrhosis in a Phase 3, open-label, international clinical trial. Methods: Patients received a fixed-dose combination (FDC) of DCV 30 mg, ASV 200 mg, and BCV 75 mg twice daily for 12 weeks. SVR12 rates in the treatment-naive and -experienced cohorts were evaluated separately as key efficacy outcomes. Results: SVR12 was achieved by 92 % of treatment-naive patients (Table). Among treatment-experienced patients, 89 % achieved SVR12. Virologic failure occurred in 34 (8 %) patients overall. Baseline characteristics were comparable between the treatment-naive (N = 312) and treatment-experienced (N = 103) cohorts. Overall, patients were 58 %male and 26 %IL28B (rs1297860) CC genotype; 73 % were infected with GT 1a and 27 % with GT 1b. One death reported posttreatment was considered not related to study treatment. There were 7 serious adverse events, all considered unrelated to study treatment, and 3 (<1 %) adverse events leading to treatment discontinuation. The most common adverse events (in>10 % of patients) were headache, fatigue, diarrhea, and nausea. Conclusions: In this Phase 3 study of 415 patients, 12 weeks of alloral treatment with DCV/ASV/BCV FDC achieved high SVR12 rates in patients with chronic HCV GT 1 infection and was well tolerated. These findings demonstrate the potent antiviral activity, safety, and tolerability of the DCV-TRIO regimen in treatment-naive and treatment- experienced patients without cirrhosis

BACKGROUND & AIMS: Chronic hepatitis C treatment for prior non-responders to peginterferon (PegIFN)/ribavirin remains suboptimal. The MATTERHORN study evaluated regimens containing ritonavir-boosted danoprevir (danoprevir/r) in prior PegIFN alfa/ribavirin non-responders. METHODS: Prior partial responders (N=152) were randomized to 24 weeks of twice-daily danoprevir/r 100/100mg, mericitabine 1000 mg and ribavirin 1000/1200 mg (IFN-free); danoprevir/r plus PegIFN alfa-2a/ribavirin (triple); or danoprevir/r, mericitabine and PegIFN alfa-2a/ribavirin (Quad). Prior null responders (N=229) were randomized to 24 weeks of IFN-free therapy, or quad alone (Quad 24) or quad plus 24-weeks of PegIFN alfa-2a/ribavirin (Quad 48). The primary endpoint was sustained virological response (HCV RNA <25 IU/ml) 24 weeks after end-of-treatment (SVR24). Due to high relapse rates, genotype (G) 1a patients in IFN-free arms were offered additional PegIFN alfa-2a/ribavirin. RESULTS: Among prior partial responders, SVR24 rates were 46.2%, 51.0%, and 86.0%, in the IFN-free, Triple and Quad arms, respectively; among prior null responders, SVR24 rates were 45.5%, 80.5%, and 83.8% respectively. Relapse rates were lower and SVR24 rates higher in G1b-infected than G1a-infected patients. SVR24 rates in G1a and G1b patients randomized to Quad were 75.0% and 96.2%, respectively, in the partial Quad arm, and 68.1% and 100%, respectively, in the null Quad 24 arm. Treatment failure was associated with resistance to danoprevir, but not to mericitabine, and was more common in G1a infected patients. Treatment was well-tolerated. CONCLUSIONS: Danoprevir/r, mericitabine plus PegIFN alfa-2a/ribavirin was well-tolerated and produced high overall SVR24 rates in prior partial and null responders to PegIFN alfa/ribavirin. In contrast, IFN-free regimens were associated with unacceptably high relapse rates.

BACKGROUND & AIMS: We evaluated the antiviral response of Asian or Pacific Islander (API) patients with chronic hepatitis B (CHB) who had baseline high viral load (HVL), defined as pre-treatment hepatitis B virus (HBV) DNA >/=9 log10 copies/ml, following up to 288 weeks of tenofovir disoproxil fumarate (TDF) treatment. METHODS: A total of 205 HBeAg-negative and HBeAg-positive self-described API patients received 48 weeks of TDF 300 mg (HVL n = 18) or adefovir dipivoxil 10 mg (HVL n = 15) in a blinded fashion, followed by open-label TDF for an additional 240 weeks. The proportions of HVL vs. non-HVL patients with HBV DNA <400 copies/ml were compared. Mean declines in HBV DNA were evaluated in API vs. non-API patients. RESULTS: Throughout the first 72 weeks of treatment, a smaller proportion of HVL API patients reached HBV DNA <400 copies/ml than non-HVL API patients. However, after this timepoint similar proportions of HVL and non-HVL API patients achieved HBV DNA <400 copies/ml (100% vs. 97%, respectively), which was maintained through week 288, where 92% of HVL patients and 99% of non-HVL API patients on treatment had HBV DNA <400 copies/ml. During the 288 weeks of treatment, API patients had similar mean HBV DNA declines as non-API patients, regardless of whether patients were HVL or non-HVL. No API HVL patient had persistent viremia at week 288. No resistance was detected among HVL or non-HVL patients. CONCLUSIONS: API patients with HVL CHB achieve HBV DNA <400 copies/ml with long-term TDF treatment; however, achieving viral suppression may take longer for HVL patients relative to non-HVL API patients.

UNLABELLED: Historically, clinical trials of regimens to treat chronic infection with hepatitis C virus (HCV) have used, as their primary efficacy endpoint, a sustained virological response (SVR)-defined as HCV RNA levels below a designated threshold of quantification-24 weeks after the end of treatment (SVR24). More recently, regulatory authorities have begun to accept SVR at 12 weeks post-treatment (SVR12) as a valid efficacy endpoint because of its high rate of concordance with SVR24. However, the concordance between SVR12 and SVR24 has not been systematically assessed with new regimens of recently approved direct-acting antiviral agents. The aim of this study was to assess the concordance between SVR at various post-treatment time points in phase III clinical trials of sofosbuvir (SOF)-containing regimens. We conducted a retrospective analysis of five trials enrolling 863 patients infected with HCV genotypes 1-6. The concordance between SVR at 4 weeks post-treatment (SVR4) and SVR12, and between SVR12 and SVR24, were determined, as well as positive predictive values (PPVs) and negative predictive values (NPVs). Overall, 779 of 796 patients (98.0%) with an SVR4 also achieved an SVR12, making the PPV of SVR4 for SVR12 98% and the NPV 100%. Of the 779 patients with an SVR12, 777 (99.7%) also achieved an SVR24, making the PPV of SVR12 for SVR24 >99% and the NPV 100%. Of patients who relapsed post-therapy, 77.6% did so within 4 weeks of completing therapy. CONCLUSION: Data from phase III studies demonstrate that with SOF-based regimens, with or without interferon, SVR12 and SVR24 correlate closely. Thus, SVR12 can be used effectively to determine "cure" rates in trials and in clinical practice.

BACKGROUND: GS-9620 is a potent oral agonist of toll-like receptor 7, a key modulator of the innate immune response. In healthy volunteers, low doses of GS-9620 (2, 4 and 6 mg) induced significant expression of peripheral interferon-stimulated-gene (ISG) mRNA in the absence of detectable serum interferon-alpha and systemic adverse events (AEs). We evaluated the safety, pharmacokinetics and pharmacodynamics of GS-9620 in treatment-naive patients chronically infected with HCV genotype 1. METHODS: In this double-blind, placebo-controlled study, 51 patients were randomized 5:1 (active:placebo) to receive either a single dose or two once-weekly doses of GS-9620 at four dose levels (0.3, 1, 2 and 4 mg) or placebo. Pharmacodynamic assessments included peripheral ISG15 mRNA expression, serum interferon-alpha and interferon-gamma-inducible protein (IP)-10 levels and HCV RNA quantification. RESULTS: GS-9620 was well-tolerated at all doses. Most AEs were mild or moderate in severity. GS-9620 exhibited dose-linear pharmacokinetics with a median half-life in plasma of 18 h. Transient, dose-dependent ISG15 induction was observed at 1, 2 and 4 mg, with peak mean fold change within 48 h followed by a decline to baseline levels within 7 days of dosing. Serum interferon-alpha induction post-baseline was detected in 16.7% (8/48) of patients. No clinically significant reductions in HCV RNA were observed. CONCLUSIONS: GS-9620 was safe, well-tolerated and biologically active in patients with HCV infection. Induction of ISG15 occurred in the absence of detectable serum interferon-alpha or systemic AEs in most patients, supporting a pre-systemic mechanism of action. ClinicalTrials.gov identifier: NCT01591668.

BACKGROUND: Sofosbuvir is a chain-terminating nucleotide analogue inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase that is efficacious in subjects with HCV genotype 1-6 infection. Sofosbuvir resistance is primarily conferred by the S282T substitution in NS5B. METHODS: NS5B sequencing and susceptibility testing of HCV from subjects infected with genotypes 1-6 who participated in phase 2 and 3 sofosbuvir clinical trials was performed. RESULTS: No NS5B variants present at baseline among 1645 sofosbuvir-treated subjects were associated with treatment failure; sofosbuvir susceptibility was within 2-fold of reference. Among 282 subjects who did not achieve sustained virologic response, no novel sofosbuvir resistance-associated variants were identified, and the NS5B changes observed did not confer significant reductions in sofosbuvir susceptibility. In 1 subject with S282T observed at relapse 4 weeks after sofosbuvir monotherapy, the resistant variant (13.5-fold reduced sofosbuvir susceptibility, replication capacity <2% of control) became undetectable by deep sequencing 12 weeks after treatment. L159F and V321A were identified as treatment-emergent variants but did not confer resistance to sofosbuvir in the replicon system. CONCLUSIONS: These data demonstrate a uniform susceptibility of subject-derived HCV to sofosbuvir, and also show that selection of sofosbuvir-resistant HCV is exceedingly rare and is associated with a significant reduction in viral fitness.

BACKGROUND & AIMS: Peginterferon lambda-1a (Lambda) is a type-III interferon with similar antiviral activity to alfa interferons but with a diminished extrahepatic receptor distribution, reducing the risk for extrahepatic adverse events. METHODS: This was a randomized, blinded, actively-controlled, multicentre phase 2b dose-ranging study in patients chronically infected with HCV genotypes 1-4. Treatment-naive patients received Lambda (120/180/240 mug) or peginterferon alfa-2a (alfa; 180 mug) once-weekly with ribavirin for 24 (genotypes [GT] 2,3) or 48 (GT1,4) weeks. RESULTS: Rates of undetectable HCV-RNA at week 12 (complete early virologic response [cEVR]; primary end point) were significantly higher in GT1,4 patients receiving Lambda vs. alfa (170/304, 56% vs. 38/103, 37%); with similar cEVR rates for GT2,3 (80/88, 91% vs. 26/30, 87%). Rates of undetectable HCV-RNA at week 4 were significantly higher on 180 mug (15/102, 15% GT1,4; 22/29, 76% GT2,3) and 240 mug (17/104, 16% GT1,4; 20/30, 67% GT2,3) Lambda than alfa (6/103, 6% GT1,4; 9/30, 30% GT2,3). Sustained virologic responses (post-treatment week 24) were comparable between Lambda and alfa for GT1,4 (37-46% Lambda; 37% alfa) and GT2,3 (60-76% Lambda; 53% alfa). Aminotransferase and/or bilirubin elevations were the primary dose-limiting abnormalities for Lambda; a sponsor-mandated 240 to 180 mug dose reduction was therefore implemented. Serious adverse events were comparable (3-13% Lambda; 3-7% alfa). Grade 3-4 haemoglobin, neutrophil, and platelet reductions were lower on Lambda than alfa. Among alfa patients, 28/133 (21%) had peginterferon and 31/133 (23%) had ribavirin dose reductions for haematologic abnormalities vs. 0/392 and 8/392 (2%) on Lambda. Lambda demonstrated fewer musculoskeletal (16-28% vs. 47-63%) and influenza-like events (8-23% vs. 40-46%) than alfa. CONCLUSION: Lambda was associated with improved or similar rates of virologic response with fewer extrahepatic adverse events than alfa in chronic HCV infection.