No abstract

Treatment with a once-daily, single-tablet regimen of ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a sustained virologic response to prior interferon-based treatment. (Funded by Gilead Sciences; ION-2 ClinicalTrials.gov number, NCT01768286.).

No abstract

Treatment options for patients with hepatitis C virus (HCV) genotype 3 infection are limited, with the currently approved all-oral regimens requiring 24-week treatment and the addition of ribavirin (RBV). This phase III study (ALLY-3; http://ClinicalTrials.gov: NCT02032901) evaluated the 12-week regimen of daclatasvir (DCV; pangenotypic nonstructural protein [NS]5A inhibitor) plus sofosbuvir (SOF; pangenotypic NS5B inhibitor) in patients infected with genotype 3. Patients were either treatment naïve (n = 101) or treatment experienced (n = 51) and received DCV 60 mg plus SOF 400 mg once-daily for 12 weeks. Coprimary endpoints were the proportions of treatment-naïve and treatment-experienced patients achieving a sustained virological response (SVR) at post-treatment week 12 (SVR12). SVR12 rates were 90% (91 of 101) and 86% (44 of 51) in treatment-naïve and treatment-experienced patients, respectively; no virological breakthrough was observed, and ≥99% of patients had a virological response (VR) at the end of treatment. SVR12 rates were higher in patients without cirrhosis (96%; 105 of 109) than in those with cirrhosis (63%; 20 of 32). Five of seven patients who previously failed treatment with an SOF-containing regimen and 2 of 2 who previously failed treatment with an alisporivir-containing regimen achieved SVR12. Baseline characteristics, including gender, age, HCV-RNA levels, and interleukin-28B genotype, did not impact virological outcome. DCV plus SOF was well tolerated; there were no adverse events (AEs) leading to discontinuation and only 1 serious AE on-treatment, which was unrelated to study medications. The few treatment-emergent grade 3/4 laboratory abnormalities that were observed were transient. Conclusion: A 12-week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. Additional evaluation to optimize efficacy in genotype 3–infected patients with cirrhosis is underway. (Hepatology 2015;61:1127–1135)

No abstract

Effective antiviral therapy is essential for achieving sustained virological response (SVR) in hepatitis C virus (HCV)‐infected patients. The phase 2 COSMOS study reported high SVR rates in treatment‐naive and prior null‐responder HCV genotype (GT) 1‐infected patients receiving simeprevir+sofosbuvir±ribavirin for 12 or 24 weeks. OPTIMIST‐1 (NCT02114177) was a multicenter, randomized, open‐label study assessing the efficacy and safety of 12 and 8 weeks of simeprevir+sofosbuvir in HCV GT1‐infected treatment‐naive and treatment‐experienced patients without cirrhosis. Patients were randomly assigned (1:1; stratified by HCV GT/subtype and presence or absence of NS3 Q80K polymorphism [GT1b, GT1a with Q80K, GT1a without Q80K]), prior HCV treatment history, and IL28B GT [CC, non‐CC]) to simeprevir 150 mg once daily+sofosbuvir 400 mg once daily for 12 or 8 weeks. The primary efficacy endpoint was SVR rate 12 weeks after end of treatment (SVR12). Superiority in SVR12 was assessed for simeprevir+sofosbuvir at 12 and 8 weeks versus a composite historical control SVR rate. Enrolled were 310 patients, who were randomized and received treatment (n = 155 in each arm). SVR12 with simeprevir+sofosbuvir for 12 weeks (97% [150/155; 95% confidence interval 94%‐100%]) was superior to the historical control (87%). SVR12 with simeprevir+sofosbuvir for 8 weeks (83% [128/155; 95% confidence interval 76‐89%]) was not superior to the historical control (83%). The most frequent adverse events were nausea, headache, and fatigue (12‐week arm: 15% [23/155], 14% [22/155], and 12% [19/155]; 8‐week arm: 9% [14/155], 17% [26/155], and 15% [23/155], respectively). No patients discontinued treatment due to an adverse event. One (1%, 12‐week arm) and three (2%, 8‐week arm) patients experienced a serious adverse event (all unrelated to study treatment). Conclusion: Simeprevir+sofosbuvir for 12 weeks is highly effective in the treatment of HCV GT1‐infected patients without cirrhosis, including those with Q80K. (Hepatology 2016;64:370‐380)

In patients with chronic hepatitis B, brief lamivudine therapy suppresses hepatitis B virus (HBV) DNA but results infrequently in sustained losses of virus replication posttreatment. We evaluated treatment response and its posttreatment durability during up to 18 months of lamivudine therapy (100 mg/d) in 24 patients who had hepatitis B e antigen (HBeAg) despite 1 to 3 months of prior therapy. Therapy was to be stopped after HBeAg loss or seroconversion (acquisition of antibody to HBeAg); posttreatment monitoring continued for 6 months. During therapy, which was well tolerated, HBV DNA became undetectable in all evaluable patients, accompanied by reduced alanine transaminase (ALT) activity. The cumulative 18-month confirmed loss of HBeAg during therapy was 9 of 24 (38%) and seroconversion was 5 of 24 (21%). Therapy was discontinued after HBeAg loss/seroconversion in 7 patients, and Chronic hepatitis B virus (HBV) infection occurs in approximately 5% of the world' s population and is among the top 10 causes of death. Although interferon alfa has been approved as therapy for chronic hepatitis B, such treatment is suboptimal, yielding clinical benefit in a minority of patients. Lamivudine is an oral dideoxynucleoside that inhibits reverse transcription by causing chain termination of nascent viral DNA in human immunodeficiency virus (HIV) and HBV infection. 1 As reported previously, phase-II dose-ranging trials in North American and western European patients with chronic hepatitis B included daily doses of 5 to 600 mg administered for 1 to 6 months. 2-4 Therapy was well tolerated, doses of 100 mg or more suppressed serum HBV DNA levels consistently during therapy, and no significant advantage was identified for doses above 100 mg. 3,4 A sustained response posttreatment, however, defined as the loss of hepatitis B e antigen (HBeAg) and failure of HBV DNA to reappear after discontinuation of therapy, occurred in only 4% to 12% of patients in these dose-ranging studies. In a recently completed placebo-controlled phase-III trial involving 358 Chinese patients, Lai et al. 5 reported that 12 months of lamivudine therapy at a dose of 100 mg/d was associated with histological improvement in 67% of patients and HBeAg seroconversion in 16%, which is significantly better than response rates observed in concurrent placebo controls. This study in Asian patients, however, did not address treatmentstopping criteria; regardless of HBeAg status at the end of 12 months of therapy, all patients were enrolled in a continuingtreatment follow-up study. 5 In the present study, we wished to determine whether prolonged lamivudine therapy in Western patients would be safe and tolerable and result in loss of HBeAg and HBeAg seroconversion in a higher proportion of patients compared with the shorter dosing regimens studied previously. We also sought to determine whether lamivudine therapy could be withdrawn after HBeAg loss or HBeAg seroconversion. Therefore, we undertook an extended-treatment trial in previously Abbreviations: HBV, hepatitis...

CymaBay Therapeutics.