Long-term Safety and Efficacy Results in Hepatitis C Virus Genotype 1–infected Patients Receiving Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir ± Ribavirin in the TOPAZ-I and TOPAZ-II Trials

Fred Poordad; RuiSarmento E. Castro; Armen Asatryan; Humberto Aguilar; Patrice Cacoub; Douglas Dieterich; Rui Tato Marinho; Armando Carvalho; Asma Siddique; Yiran Bonnie Hu; Mariem Charafeddine; Mark Bondin; Nader Khan; Daniel E. Cohen; Franco Felizarta

Disclosures

J Viral Hepat. 2020;27(5):497-504. 

In This Article

Abstract and Introduction

Abstract

The 3-DAA regimen consisting of ombitasvir/paritaprevir/ritonavir plus dasabuvir (OBV/PTV/r + DSV) ± ribavirin (RBV) has shown high sustained virologic response rates (~95%) in phase 3 clinical trials including >2300 HCV genotype 1–infected patients. Real-world evidence studies have confirmed the effectiveness of OBV/PTV/r ± DSV ± RBV in patients with chronic HCV genotype 1 infection and are consistent with clinical trial results. TOPAZ-I and TOPAZ-II are ongoing phase 3b trials, assessing safety, efficacy and long-term progression of liver disease and clinical outcomes for up to 5 years post-treatment in patients treated with OBV/PTV/r + DSV ± RBV. High rates of sustained virologic response (SVR) were achieved regardless of presence or absence of cirrhosis. In this report, we assessed the long-term progression of liver disease and incidence of clinical outcomes up to 3 years of post-treatment follow-up in patients with chronic HCV GT1 infection who were treated with (OBV/PTV/r + DSV) ± RBV in the TOPAZ-I and TOPAZ-II studies. Improvements were observed in liver disease markers including FIB-4, METAVIR and Child-Pugh scores as well as platelet counts. Clinical outcomes related to long-term progression of liver disease such as liver decompensation were infrequent (<1%). Hepatocellular carcinoma (HCC) occurred in 1.4% of cirrhotic patients.

Introduction

Hepatitis C virus (HCV) infection is a global public health problem, with 71 million individuals chronically infected worldwide.[1] Patients with chronic HCV infection are at risk of developing cirrhosis that can further progress to hepatic decompensation, which can manifest with ascites, encephalopathy, variceal haemorrhage, hepatorenal syndrome or impairment of hepatic synthetic function. Cirrhosis also dramatically increases the risk of developing HCC. The risk of developing HCC in patients with cirrhosis is 10%-40% per decade.[2–4] Without liver transplantation, the risk of mortality in patients with liver decompensation is high in 5 years.[5,6] HCV remains a major indication for liver transplantation in the United States because of its high prevalence and resultant complications.[7–9] Depending on various risk factors, between 10% and 20% of all patients with chronic HCV infection develop cirrhosis over 20–30 years of HCV infection.[10] The economic and societal burden of advanced liver disease among patients with HCV is substantial.[11–13]

The goal of anti-HCV therapy is to eliminate HCV infection and thereby reduce the risk of liver cirrhosis, decompensation, hepatocellular cancer and liver-related death. Among patients treated with pegylated (peg) interferon (IFN) and ribavirin (RBV) therapy, achieving a sustained virologic response (SVR) was associated with significant reduction in the risk of all-cause death, liver failure and hepatocellular carcinoma compared with patients who did not achieve SVR.[14,15]

Beginning in 2014, the paradigm of antiviral drug treatment has dramatically changed, as combinations of direct-acting antiviral agents (DAAs) targeting different parts of viral replication cycle replaced IFN-containing regimens as the treatment of choice for chronic HCV infection.[16,17] The 3-DAA regimen consisting of the NS5A inhibitor ombitasvir (OBV), the NS3/4A protease inhibitor paritaprevir (PTV) with the pharmacokinetic enhancer ritonavir (r) and the non-nucleoside NS5B polymerase inhibitor dasabuvir (DSV), administered with or without RBV, demonstrated a favourable safety and tolerability profile and high SVR at post-treatment week 12 (SVR12) rates of >95% in over 2300 HCV-infected patients in phase 3 clinical trials across a variety of patient populations with chronic genotype 1 HCV infection, including those with compensated cirrhosis.[18–22]

TOPAZ-I and TOPAZ-II are ongoing phase 3b trials, assessing safety, efficacy and long-term progression of clinical outcomes in treatment-naïve and IFN/RBV treatment-experienced adult patients with chronic HCV genotype 1 infection, with or without compensated cirrhosis treated with OBV/PTV/r + DSV ± RBV. High SVR12 rates of >95% were achieved regardless of presence or absence of cirrhosis at baseline and were reported previously.[23] Here, we report the first interim assessment from these studies for long-term liver disease-associated outcomes, up to 3 years post-treatment.

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