In Vitro and In Vivo Antiviral Activity and Resistance Profile of Ombitasvir, an Inhibitor of Hepatitis C Virus NS5A

Abstract

Ombitasvir (ABT-267) is a hepatitis C virus (HCV) NS5A inhibitor with picomolar potency, pan-genotypic activity, and 50% effective concentrations (EC 50 s) of 0.82 to 19.3 pM against HCV genotypes 1 to 5 and 366 pM against genotype 6a. Ombitasvir retained these levels of potency against a panel of 69 genotype 1 to 6 chimeric replicons containing the NS5A gene derived from HCV-infected patients, despite the existence of natural sequence diversity within NS5A. In vitro resistance selection identified variants that conferred resistance to ombitasvir in the HCV NS5A gene at amino acid positions 28, 30, 31, 58, and 93 in genotypes 1 to 6. Ombitasvir was evaluated in vivo in a 3-day monotherapy study in 12 HCV genotype 1-infected patients at 5, 25, 50, or 200 mg dosed once daily. All patients in the study were HCV genotype 1a infected and were without preexisting resistant variants at baseline as determined by clonal sequencing. Decreases in HCV RNA up to 3.1 log 10 IU/ml were observed. Resistance-associated variants at position 28, 30, or 93 in NS5A were detected in patient samples 48 hours after the first dose. Clonal sequencing analysis indicated that wild-type virus was largely suppressed by ombitasvir during 3-day monotherapy, and at doses higher than 5 mg, resistant variant M28V was also suppressed. Ombitasvir was well tolerated at all doses, and there were no serious or severe adverse events. HCV genotype 1, predominant in North America, Europe, and Japan, accounts for 60% of the global infections (4-6). Genotype 2 infections are most prevalent in North America, Europe, and Japan, while genotype 3, 6, and 7 infections are predominant within various parts of Southeast Asia (3, 7-9). In Egypt, HCV infections are almost exclusively genotype 4, while genotype 5 is common in South Africa (10, 11). The levels of nucleotide sequence diversity between genotypes and between subtypes are 30 to 35% and 20 to 25%, respectively (12). The viral dynamics are rapid for HCV, with 10 12 virions being produced daily with a half-life of 45 min (13). Moreover, the RNA-dependent RNA polymerase of HCV is intrinsically error prone, and its lack of a proofreading function allows for introduction of approximately one nucleotide change per genome per replication cycle, which under drug pressure results in the expansion of preexisting drug resistant variants (13). These factors have created challenges in developing pan-genotypic HCV inhibitors with high genetic barriers to the development of resistance.HCV replication can be inhibited at various points in the replication cycle by targeting viral or host cell functions (14,15). For the treatment of HCV genotype 1, three HCV NS3/4A protease inhibitors (telaprevir, boceprevir, and simeprevir) and one nucleoside NS5B polymerase inhibitor (sofosbuvir), each in combination with pegylated interferon (pegIFN) and ribavirin (RBV), have received marketing approval in the United States and Europe. The sustained virologic response (SVR) rate increased from 40 to 52% with pegIFN and RBV regimens to 67...

Combination Therapy with Ombitasvir/Paritaprevir/Ritonavir for Dialysis Patients Infected with Hepatitis C Virus: A Prospective Multi-Institutional Study

“…In our detailed RAV analysis, L28F and L31M concerning HCV/2b-NS5A RAVs were detected before the combination therapy, although no RAVs were found in the NS3 or NS5A regions of the co-infected HCV/1b. These combination mutations confer 247-fold-reduced susceptibility to OBV in HCV/2b (Krishnan et al 2015). In addition to these mutations, A160T/A and D168D/V mixed mutations concerning HCV/2b-NS3 RAVs developed after viral breakthrough.…”

“…V170I is not known to be associated with resistance to NS3/4A protease inhibitors (Romano et al 2010;Halfon and Locarnini 2011). In addition, there were no mutations at aa 155, 156, or 168 in the NS3 region or at aa 28, 31, or 93 in the NS5A region, which are known to be associated with resistance to PTV and OBV, respectively (Krishnan et al 2015;; Interview form of VIEKIRAX ® ver. 4 [http://www.abbvie.co.jp/content/dam/ abbviecorp/japan/docs/if_Viekirax_j.pdf]) (Table 3).…”

“…He had not received interferon-based therapy. He had no RAVs known to be associated with resistance to NS3/4A protease inhibitors, including linear ketoamids and macrocyclic compounds (Romano et al 2010;Halfon and Locarnini 2011), or NS5A inhibitors, including DCV (Fridell et al 2011) and OBV (Krishnan et al 2015) (Table 3). He had several comorbidities, such as atrial septal defect, atrial fibrillation, hypertension, upper gastrointestinal disease, and liver cysts with calcification.…”

“…He had HCV with a mutation in the non-structural region 5A (NS5A) (Q54H), which is known as a RAV against BMS-790052 (DCV); however, without Y93H or L31V-Y93H, this mutation could not confer reduced susceptibility to DCV (Fridell et al 2011). This mutation is unlikely to be associated with resistance to OBV (Krishnan et al 2015; Interview form of VIEKIRAX ® ver. 4 [http://www.abbvie.…”

Population Pharmacokinetics of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin in Patients with Hepatitis C Virus Genotype 1 Infection: Combined Analysis from 9 Phase 1b/2 Studies

“…a large number of both treatment-naive and treatmentexperienced patients and patients representing a range of demographic and clinically important subgroups (10)(11)(12)(13). This varied cross section allows for the assessment of parameters that influence drug exposures, which could ultimately affect the efficacy and safety profile of the regimen.…”