Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b–infected null responders

Abstract

Patients with chronic hepatitis C virus (HCV) infection and previous null response to pegylated interferon (Peg-IFN) and ribavirin (RBV) have limited therapeutic options. HCV genotype 1 is the most common worldwide and the most difficult to treat; genotype 1b is the most common subtype of genotype 1 outside North America. The enhanced antiviral activity achieved by combining two direct-acting antiviral (DAA) agents may improve clinical outcomes. This open-label, phase IIa study included 10 patients with chronic HCV genotype 1b infection and previous null response (<2 log10 reduction in HCV RNA after 12 weeks) to Peg-IFN and RBV. Patients received dual DAA treatment for 24 weeks with the nonstructural protein 5A replication complex inhibitor, daclatasvir (60 mg once-daily), and the nonstructural protein 3 protease inhibitor, asunaprevir (initially 600 mg twice-daily, then subsequently reduced to 200 mg twice-daily). The primary efficacy endpoint was the proportion of patients with sustained virologic response (SVR) at 12 weeks post-treatment (SVR12). Nine patients completed 24 weeks of treatment; 1 patient discontinued treatment after 2 weeks. In the 9 patients who completed the full course of treatment, HCV RNA was undetectable at week 8 and remained undetectable through the end of treatment; all 9 patients achieved SVR12 and SVR24. HCV RNA also remained undetectable post-treatment in the patient who discontinued after 2 weeks. There was no viral breakthrough. Diarrhea and headache, generally mild, were the most common adverse events; transaminase elevations were reported in 3 patients, but did not result in discontinuation. Conclusions : Dual therapy with daclatasvir and asunaprevir, without Peg-IFN and RBV, can achieve high SVR rates in difficult-to-treat patients with HCV genotype 1b infection and previous null response to Peg-IFN and RBV.

Comparison of improved prognosis between hepatitis B‐ and hepatitis C‐related hepatocellular carcinoma

“…Safer and more effective HCV regimens may improve the prognosis of C-HCC. [34][35][36] A previous study also revealed the improved prognosis of B-HCC over time. However, that study included patients treated with surgery, ablation therapies and TACE.…”

Interferon-Free Strategies without a Nucleoside/Nucleotide Analogue

“…40,41 Response rates in prior null responders, as reported in one of the trials, were 100%; in the other trial, response rates of 63.6% and 90.5% were reported in PegIFN intolerant/ineligible (n ¼ 22) and null-responder (n ¼ 10) patients, respectively. 40,41 Of note, in these Japanese phase 2 trials asunaprevir dose was adjusted from 600 mg twice daily to 200 mg twice daily due to observed hepatotoxicity at higher doses. 43 The U.S. study investigated different dosing regimens of asunaprevir (200 mg twice daily vs. 200 mg once daily) in HCV genotype1b null-responders without cirrhosis: SVR rates ranged from 65 to 78%.…”

“…Therapeutic efficacy of this dual DAA regimen administered for 24 weeks was further investigated in several phase 2 trials conducted in Japan and in the United States. [40][41][42] Two Japanese studies enrolled HCV genotype 1b patients without cirrhosis who were intolerant/ineligible and/or nullresponder patients. 40,41 Response rates in prior null responders, as reported in one of the trials, were 100%; in the other trial, response rates of 63.6% and 90.5% were reported in PegIFN intolerant/ineligible (n ¼ 22) and null-responder (n ¼ 10) patients, respectively.…”

“…[40][41][42] Two Japanese studies enrolled HCV genotype 1b patients without cirrhosis who were intolerant/ineligible and/or nullresponder patients. 40,41 Response rates in prior null responders, as reported in one of the trials, were 100%; in the other trial, response rates of 63.6% and 90.5% were reported in PegIFN intolerant/ineligible (n ¼ 22) and null-responder (n ¼ 10) patients, respectively. 40,41 Of note, in these Japanese phase 2 trials asunaprevir dose was adjusted from 600 mg twice daily to 200 mg twice daily due to observed hepatotoxicity at higher doses.…”

Viral Factors Associated with Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection

“…Many NS5A inhibitors are now undergoing clinical trials. A trial of combination therapy with NS5A inhibitor (BMS-790052) and NS3/4A PI (BMS-650032) in Japanese HCV G1b patients with prior null response to PEG-IFN plus RVB therapy revealed extremely high SVR rates [58]. In contrast, the efficacy of this combination is discouraged in American HCV G1a patients that were previously null responders.…”