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Christoph Sarrazin,1 Francesco Castelli,2 Pietro Andreone,3 Maria Buti,4 Massimo Colombo,5 Stanislas Pol,6 Filipe Calinas,7 Massimo Puoti,8 Antonio Olveira,9 Mitchell Shiffman,10 Jerry O Stern,11 George Kukolj,12 Michael Roehrle,13 Stella Aslanyan,11 Qiqi Deng,11 Richard Vinisko,11 Federico J Mensa,11 David R Nelson,14 on behalf of the HCVerso1 and 2 study groups 1Department of Internal Medicine 1, JW Goethe University Hospital, Frankfurt, Germany; 2Department of Infectious and Tropical Diseases, University of Brescia, Brescia, 3Department of Medical and Surgical Sciences, Università di Bologna and Azienda Ospedaliero-Universitaria, Policlinico Sant‘Orsola-Malpighi, Bologna, Italy; 4Department of Internal Medicine, Hospital Universitari Vall d’Hebron and CIBERehd del Instituto Carlos III, Barcelona, Spain; 5Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy; 6University Paris Descartes, Department of Hepatology, Hospital Cochin, APHP and INSERM UMS-20, Institut Pasteur, Paris, France; 7Department of Gastroenterology, Centro Hospitalar de Lisboa Central, Lisbon, Portugal; 8Department of Infectious Diseases, AO Ospedale Niguarda Cà Granda, Milan, Italy; 9Liver Unit, Hospital Universitario La Paz, CIBERehd, Madrid, Spain; 10Liver Institute of Virginia, Bon Secours Health System, Richmond, VA, USA; 11Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 12Boehringer Ingelheim Ltd/Ltée, Burlington, ON, Canada; 13Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; 14Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA Abstract:
The interferon-free combination of once-daily faldaprevir 120 mg, twice-daily deleobuvir 600 mg, and weight-based ribavirin was evaluated in two Phase III studies (HCVerso1, HCVerso2) in hepatitis C virus genotype-1b-infected, treatment-naïve patients, including those ineligible for peginterferon (HCVerso2). Patients without cirrhosis were randomized to 16 weeks (Arm 1; n=208 HCVerso1, n=213 HCVerso2) or 24 weeks (Arm 2; n=211 in both studies) of faldaprevir + deleobuvir + ribavirin. Patients with compensated cirrhosis received open-label faldaprevir + deleobuvir + ribavirin for 24 weeks (Arm 3; n=51, n=72). Primary endpoints were comparisons of adjusted sustained virologic response (SVR) rates with historical rates: 71% (HCVerso1) and 68% (HCVerso2). Adjusted SVR12 rates were significantly greater than historical controls for Arms 1 and 2 in HCVerso2 (76%, 95% confidence interval [CI] 71–81, P=0.002; 81%, 95% CI 76–86, P<0.0001) and Arm 2 in HCVerso1 (81%, 95% CI 77–86, P<0.0001), but not for Arm 1 of HCVerso1 (72%, 95% CI 66–77, P=0.3989). Unadjusted SVR12 rates in Arms 1, 2, and 3 were 71.6%, 82.5%, and 72.5%, respectively, in HCVerso1 and 75.6%, 82.0%, and 73.6%, respectively, in HCVerso2. Virologic breakthrough and relapse occurred in 24-week arms in 8%–9% and 1% of patients, respectively, and in 16-week arms in 7%–8% and 9%–11% of patients, respectively. The most common adverse events were nausea (46%–61%) and vomiting (29%–35%). Adverse events resulted in discontinuation of all medications in 6%–8% of patients. In treatment-naïve patients with hepatitis C virus genotype-1b infection, with or without cirrhosis, faldaprevir + deleobuvir + ribavirin treatment for 24 weeks resulted in adjusted SVR12 rates significantly higher than historical controls. Both studies were registered in ClinicalTrials.gov (NCT01732796, NCT01728324).
Long-term effects on cirrhosis and portal hypertension of direct antiviral agent (DAA)-based eradication of hepatitis C virus (HCV) are still under debate. We analysed dynamics of liver and spleen elastography to assess potential regression of cirrhosis and portal hypertension 3 years post-treatment. Fifty-four patients with HCV-associated cirrhosis and DAA-induced SVR were included. Liver and spleen stiffness were measured at baseline (BL), end of treatment (EOT), 24 weeks after EOT (FU24) and 1, 2 and 3 (FU144) years post-treatment by transient liver elastography (L-TE) and point shear wave elastography (pSWE) using acoustic radiation force impulse (ARFI) of the liver (L-ARFI) and spleen (S-ARFI). Biochemical, virological and clinical data were also obtained. Liver stiffness assessed by L-TE decreased between BL [median (range), 32.5(9.1–75) kPa] and EOT [21.3(6.7–73.5) kPa; p < .0001] and EOT and FU144 [16(4.1–75) kPa; p = .006]. L-ARFI values improved between EOT [2.5(1.2–4.1) m/s] and FU144 [1.7(0.9–4.1) m/s; p = .001], while spleen stiffness remained unchanged. Overall, L-TE improved in 38 of 54 (70.4%) patients at EOT and 29 of 38 (76.3%) declined further until FU144, whereas L-ARFI values decreased in 30/54 (55.6%) patients at EOT and continued to decrease in 28/30 (93.3%) patients at FU144. Low bilirubin and high albumin levels at BL were associated with improved L-ARFI values (p = .048) at EOT or regression of cirrhosis (<12.5 kPa) by L-TE at FU144 (p = .005), respectively. Liver stiffness, but not spleen stiffness, continued to decline in a considerable proportion of patients with advanced liver disease after HCV eradication.