In Vitro and In Vivo Antiviral Activity and Resistance Profile of the Hepatitis C Virus NS3/4A Protease Inhibitor ABT-450

Abstract

bThe development of direct-acting antiviral agents is a promising therapeutic advance in the treatment of hepatitis C virus (HCV) infection. However, rapid emergence of drug resistance can limit efficacy and lead to cross-resistance among members of the same drug class. ABT-450 is an efficacious inhibitor of HCV NS3/4A protease, with 50% effective concentration values of 1.0, 0.21, 5.3, 19, 0.09, and 0.69 nM against stable HCV replicons with NS3 protease from genotypes 1a, 1b, 2a, 3a, 4a, and 6a, respectively. In vitro, the most common amino acid variants selected by ABT-450 in genotype 1 were located in NS3 at positions 155, 156, and 168, with the D168Y variant conferring the highest level of resistance to ABT-450 in both genotype 1a and 1b replicons (219-and 337-fold, respectively). In a 3-day monotherapy study with HCV genotype 1-infected patients, ABT-450 was coadministered with ritonavir, a cytochrome P450 3A4 inhibitor shown previously to markedly increase peak, trough, and overall drug exposures of ABT-450. A mean maximum HCV RNA decline of 4.02 log 10 was observed at the end of the 3-day dosing period across all doses. The most common variants selected in these patients were R155K and D168V in genotype 1a and D168V in genotype 1b. However, selection of resistant variants was significantly reduced at the highest ABT-450 dose compared to lower doses. These findings were informative for the subsequent evaluation of ABT-450 in combination with additional drug classes in clinical trials in HCV-infected patients. (Study M11-602 is registered at ClinicalTrials.gov under registration no. NCT01074008.) H epatitis C virus (HCV) infection is a global health problem, with 160 to 180 million individuals infected worldwide (1, 2). Chronic HCV infection can lead to serious liver disease, including cirrhosis, liver failure, and hepatocellular carcinoma. There are 7 major HCV genotypes, which differ in their geographic distribution, disease progression, and response to therapy (3). In the United States, Europe, and Japan, genotype 1 is the most prevalent genotype, and globally it accounts for approximately 60% of HCV infections (4).Therapy for those infected with HCV genotype 1 improved with the approval of the NS3/4A protease inhibitors (PIs) telaprevir, boceprevir, and, more recently, simeprevir (5-10). Although the addition of a PI to pegylated interferon (pegIFN) and ribavirin (RBV) therapy significantly improved sustained virologic response (SVR) rates compared to those with pegIFN/RBV therapy alone, IFN-based therapies are associated with treatment-limiting toxicities (11). In addition, there are many patients who are ineligible for IFN-based treatment due to comorbidities such as depression (12). Early clinical trials with these PIs also demonstrated that drug resistance developed within days after initiation of treatment (13-15). The rapid selection of resistant variants is facilitated by a high rate of virus production and the infidelity of the HCV RNA polymerase (16). Thus, there is a need for effective treatme...

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

“…Ombitasvir is being developed for use in combination with ABT-450, a macrocyclic noncovalent peptidomimetic inhibitor of HCV NS3/4A protease (described in an accompanying article [29]), and the nonnucleoside NS5B polymerase inhibitor dasabuvir (ABT-333), with or without RBV, for the treatment of HCV (30)(31)(32)(33)(34). The pan-genotypic activity and the in vitro resistance profile of ombitasvir are described in this report.…”

Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir: A Review in Chronic HCV Genotype 1 Infection

“…Potent antiviral activity against HCV genotype 1a and 1b strains was seen with ombitasvir [half-maximal effective concentration (EC 50 ) of 14 and 5 pmol/L] [15], paritaprevir (EC 50 1.0 and 0.21 nmol/L) [16] and dasabuvir (EC 50 7.7 and 1.8 nmol/L) [17] in replicon cell culture assays. Similarly, when HCV replicons containing NS5A, NS3 or NS5B genes from treatment-naïve patients infected with genotype 1a or 1b were assessed, broad antiviral activity was observed with ombitasvir (EC 50 0.35-0.88 and 0.74-1.5 pmol/L) [18], paritaprevir (EC 50 0.43-1.87 and 0.033-0.087 nmol/L) [16] and dasabuvir (EC 50 0.…”

“…Similarly, when HCV replicons containing NS5A, NS3 or NS5B genes from treatment-naïve patients infected with genotype 1a or 1b were assessed, broad antiviral activity was observed with ombitasvir (EC 50 0.35-0.88 and 0.74-1.5 pmol/L) [18], paritaprevir (EC 50 0.43-1.87 and 0.033-0.087 nmol/L) [16] and dasabuvir (EC 50 0. 18-8.57 and 0.…”

“…In similar experiments with paritaprevir, the single amino acid substitutions in NS3 associated with the largest reductions in paritaprevir susceptibility included F43L, R155G/K/S/T/W, A156T and D168A/E/F/H/N/V/Y in genotype 1a replicons (7-to 219-fold reduction) and A156T and D168A/H/T/V/Y in genotype 1b replicons (7-to 337-fold reduction) [12,16]. Paritaprevir activity was further reduced by up to 26-fold when some of these substitutions were present together with other amino acid substitutions (e.g.…”

Metabolism and Disposition of the Hepatitis C Protease Inhibitor Paritaprevir in Humans

“…HCV NS3-4A protease is essential for the viral replication process (Lin, 2006;Moradpour et al, 2007) and is a validated drug target (McHutchison et al, 2009;Poordad et al, 2011). Paritaprevir is a potent macrocyclic noncovalent peptidomimetic inhibitor [identified by AbbVie (North Chicago, IL) and Enanta Pharmaceuticals (Watertown, MA)] of HCV NS3/4A protease, with 50% effective concentration values of 1.0, 0.21, 5.3, 19, 0.09, and 0.69 nM against stable HCV replicons with NS3 protease from genotypes 1a, 1b, 2a, 3a, 4a, and 6a, respectively (Pilot-Matias et al, 2015). Paritaprevir with ritonavir demonstrated robust in vivo responses with mean maximum decreases in HCV RNA from 3.89 to 4.11 log10 IU/ml after 3-day monotherapy in treatment-naive HCV genotype 1-infected subjects among three dose groups (Lawitz et al, 2010).…”