Ombitasvir/paritaprevir/ritonavir & dasabuvir ± ribavirin following protease inhibitors failure - a prospective multi-centre trial

Abstract

Background: Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma. Treatment with first generation protease inhibitors (PI) + peg-interferon (pegIFN) and ribavirin (RBV) achieved sustained virologic response (SVR) rates of 65-75% but was associated with multiple side effects. The aim of this study was to evaluate safety and efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir (3D) ± RBV in HCV genotype 1 patients that failed previous treatment with first generation PIs.

Methods: An investigator-initiated, open-label, multi-centre clinical trial. HCV Genotype 1 patients who were previously null/partial responders or relapsers to telaprevir, boceprevir or simepravir+pegIFN/RBV and met eligibility criteria were included. 3D ± RBV were administrated for 12 or 24 weeks according to label. The primary outcome was antiviral response (SVR12); Secondary outcomes were patient reported outcomes, adverse events and resistance associated variants.

Results: Thirty-nine patients initiated treatment according to study protocol (59% men, age 54.0 ± 8.7 years, BMI 28.7 ± 4.5 kg/m²). Thirty-seven (94.9%) completed the study. Thirty-five patients had genotype 1b (9 cirrhotics) and 4 had genotype 1a (2 cirrhotics). Intention-to-treat SVR12 was 92.3% and per-protocol SVR12 was 97.3%. The rate of advanced fibrosis (FibroScan® score F3-4) declined from 46.2 to 25.7% (P = 0.045). Abnormal ALT levels declined from 84.6 to 8.6% (P < 0.001). Seven patients (17.9%) experienced serious adverse events (3 Psychiatric admissions, 1 pneumonia, 1 ankle fracture, 2 palpitations), and 12 patients (30.8%) experienced self-reported adverse events, mostly weakness.

Conclusion: 3D ± RBV is safe and effective in achieving SVR among patients with HCV genotype 1 who failed previous first-generation PI treatment.

Trial registration: NCT02646111 (submitted to ClinicalTrials.gov, December 28, 2015).

Keywords: AbbVie 3D; Direct acting anti-viral agents; HCV; Protease inhibitors failure.

Fig. 1

Hepatitis C Viral load. Per-protocol scatter plot of entire cohort’s patient’s viral load according to study period. * One patient had a breakthrough after 12 weeks of treatment. Non-c, non-cirrhotic

Fig. 2

The rate of SVR12 according to HCV genotype and the presence of cirrhosis. White columns - no cirrhosis; Black columns - cirrhosis. (a) Intention-to treat analysis; (b) Per-protocol analysis

Fig. 3

FibroScan® scores before treatment and at the end of the study. FibroScan® scores were divided to three categories: black- F0–1 - absent or mild fibrosis (< 7 kPa); white – F2 - moderate fibrosis (7 < and < 9.5 kPa); grey – F3–4 - severe fibrosis/cirrhosis (> 9.5 kPa). Baseline scores disparity was compared to end of study scores disparity (12 weeks after last treatment) (p = 0.045, Pearson Chi-Square test). Data is presented as number (%)

Fig. 4

Alanine transferase (ALT) before treatment and at the end of the study. ALT blood level was divided to three categories: black-within normal range-(ALT < 35 U/L); white – elevated but less than twice the upper normal limit (35 ≤ ALT< 70 U/L); grey – more than twice the upper normal limit (ALT≥70 U/L). baseline dispersion was compared to end of study dispersion (12 weeks after last treatment) (p < 0.001, Pearson Chi-Square test). Data is presented as number (%)