Low Incidence of Hyperbilirubinemia Events With ABT-450/r-Ombitasvir and Dasabuvir With or Without Ribavirin in HCV Genotype-1 Infected Patients

Abstract

Introduction: Ribavirin (RBV) is known to cause hemolytic anemia that can lead to hyperbilirubinemia. In addition, the NS3/NS4A protease inhibitor ABT-450 can increase unconjugated bilirubin levels due to transporter inhibition. We report the rate of hyperbilirubinemia in HCV genotype 1-infected patients treated with ABT-450/r-ombitasvir (formerly ABT-267) and dasabuvir (formerly ABT-333) (3D regimen) with or without RBV. Methods: Data from 910 patients randomized in 3 phase 3 trials (PEARL-II, PEARL-III, and PEARLIV), which examined the contribution of RBV to the safety and efficacy of the 3D regimen, were used to evaluate the incidence and severity of clinical events related to bilirubin (hyperbilirubinemia, jaundice) during 12 weeks of treatment. Total, direct, and indirect bilirubin were assessed at baseline and every 1-2 weeks per protocol. Results: Total bilirubin elevations of >3X ULN occurred in 23/401 (5.7%) 3D+RBV patients and in 2/509 (0.4%) patients receiving the RBV-free 3D regimen. The majority of patients in each group (>90%) had normal total bilirubin levels at the end of treatment. Mean total bilirubin levels were significantly higher at each treatment visit in the RBV-containing treatment groups. Mean total bilirubin peaked at week 1 in both treatment groups (predominantly indirect), and declined to baseline by week 2 in the RBV-free group. Events of hyperbilirubinemia and jaundice were mostly mild, occurred within the first 2 weeks of treatment and did not result in study drug discontinuation. One patient underwent RBV dose modification and one interrupted study drug due to hyperbilirubinemia; both patients achieved sustained virologic response 12 weeks post-treatment. Two patients receiving 3D+RBV experienced ALT ≥3X ULN and total bilirubin ≥2X ULN, however, the timing and predominance of indirect bilirubin were not consistent with drug induced liver injury. No serious adverse events related to hyperbilirubinemia were reported. Conclusion: Low rates of hyperbilirubinemia were observed with both 3D regiments but were less frequent in the RBV-free 3D regimens, suggesting that increases in bilirubin associated with ABT-450-containing regimens are enhanced by RBV-induced hemolysis. Bilirubin-related adverse events were infrequent with both regimens and did not affect treatment response. Disclosure - D Bernstein - Grant/Research Support: AbbVie, BMS, Gilead, Janssen, Vertex, Merck, Genentech; Consultant/Speaker’s Bureau: AbbVie, Gilead, Janssen, Vertex, Merck. N Tsai - Consultant/Advisory Board: AbbVie, Gilead, Janssen; Grant/Research Support: AbbVie, Janssen, Genentech-Roche, Vertex, BMS; Speaker’s Bureau: Gilead, Genentech-Roche, BMS, Vertex, Merck, Janssen. T Hassanein - Grant/Research Support: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Gilead Sciences, Janssen, Idenix, Ikaria, Mochida, Roche, Ocera, Taigen, Takeda, Salix, Sundise, Vertex. Speaker’s Bureau: Baxter, Bristol-Myers Squibb, Gilead, Salix; Advisory Board: AbbVie, Bristol-Myers Squibb. F Rodriguez-Perez - Advisory Board: AbbVie, Gilead, Janssen, Merck; Speaker’s Bureau: BMS, Merck. M Romero-Gomez - Advisory Board/Speaker’s Bureau: AbbVie, Roche, Gilead Sciences, MSD, Janssen, Merz, BMS, Boehringer Ingelheim, GSK. R Marinho - Advisory Board/Speaker’s Bureau: AbbVie, Gilead, BMS, Roche, Merck, Janssen. R Planas Vila - Advisory Board: Roche, MSD, BMS, Gilead, Janssen; Speaker’s Bureau: Roche, MSD, BMS, Gilead, Janssen, Boehringer Ingelheim; Grant/Research Support: Roche, MSD, BMS, Gilead, Janssen. M Colombo - Grant/Research Support: Merck, Roche, BMS, Gilead; Advisory committee; AbbVie, Merck, Roche, Novartis, Bayer, BMS, Gilead Sciences, Tibotec, Vertex, Janssen Cilag, Achillion, Lundbeck, Abbott, Boehringer Ingelheim, GSK, GenSpera; Speaker’s Bureau: Tibotec, Roche, Novartis, Bayer, BMS, Gilead Sciences, Vertex. M Pedrosa - Employee/Stockholder: AbbVie. S Lovell - Employee/Stockholder: AbbVie. J Enejosa - Employee/Stockholder: AbbVie. Y Luo - Employee/Stockholder: AbbVie. D Cohen - Employee/Stockholder: AbbVie. KR Reddy - Ad-Hoc Advisory Board: AbbVie, BMS, Gilead, Vertex, Janssen, Merck, Genentech-Roche, Idenix; Grant/Research Support: AbbVie, BMS, Gilead, Vertex, Janssen, Merck, Genentech-Roche, Genfit. This research was supported by an industry grant from AbbVie.Table 1