The effect of the first-generation HCV-protease inhibitors boceprevir and telaprevir and the relation to baseline NS3 resistance mutations in genotype 1: experience from a small Swedish cohort

Abstract

BackgroundThe clinical experience with protease-inhibitor (PI) triple regimen appears disappointing regarding effect, side effects, high work load, and costs. This real-world study evaluates baseline and emerging resistance-associated substitutions (RASs) and their significance for treatment outcome.MethodThirty-six genotype 1a/b patients treated according to Swedish recommendations during 2011–2013 with triple therapy including pegylated interferon and ribavirin in combination with a protease-inhibitor, either boceprevir (BOC) or telaprevir (TVR), were retrospectively evaluated. Frozen serum samples from the patients were tested for resistance with pan-genotypic population sequencing.ResultsOverall, 56% (20/36) of the patients achieved sustained viral response (SVR). The SVR was comparable between BOC (64%; 9/14) and TVR (50%; 11/22) (p = 0.07), and the IL28B type non-CC (48%; 12/25) and CC (46%; 6/13) (p = 0.77). The SVR was higher in patients without cirrhosis (89.5%; 17/19) (p < 0.0005), in treatment-naïve patients (70%; 14/20) (p = 0.02), and those with low viral load (<800,000 IU/mL) (66.7%; 8/12) (p < 0.0002), compared to those with cirrhosis (17.6%; 3/17), treatment-experienced (37.5%; 6/16), and high viral load (>800,000 IU/mL) (50%; 12/24).ConclusionPI triple regimes were highly effective in treatment-naïve patients without cirrhosis, but in this real-world cohort an inferior effect was evident in cirrhotic and treatment-experienced patients. Although tested on a limited sample, the baseline resistance testing seems to have no impact on prediction of therapy outcome. The reason could be that the baseline RASs T54S and V55A have relatively low resistance towards BOC and TVR. Emerging RASs, mainly R155K, with known high resistance to BOC and TVR were frequently found in non-responders.

Potential clinical drugs as covalent inhibitors of the priming proteases of the spike protein of SARS-CoV-2

“…As of the identified hits of TMPRSS2, the most attractive drug might be boceprevir, which is a first-generation inhibitor of hepatitis C virus non-structural protease 3 (HCV NS3) [37] . Based on the docking score and the SCAR enriching score ( Table 1 ), ( S )-boceprevir might be better than ( R )-boceprevir.…”

Industrial Applications of Enzymes: Recent Advances, Techniques, and Outlooks

“…Codexis and Merck have also invested heavily in research for scale-up of a monoamine oxidase (MAO)-catalyzed process for enantiomerically pure desymmetrization of a bicyclic proline intermediate, an important precursor in the synthesis of boceprevir, a NS3 protease inhibitor used for treatment of chronic hepatitis C infections [2,34]. Conventional synthesis of bicyclic proline is an intensive process requiring an excess of metal-based oxidant and reductant through 8 reaction steps; the enantioselective, MAO-catalyzed synthesis of the intermediate is an attractive alternative with the potential to greatly reduce operation time and waste generation [30].…”

Peptidomimetics: An Overview of Recent Medicinal Chemistry Efforts toward the Discovery of Novel Small Molecule Inhibitors

“…In 2011, FDA approved first generation DAAs, namely boceprevir ( 18 , Figure ) and telaprevir ( 19 ), which targeted NS3/4A in patients with genotype 1 HCV infection. These DAAs were used in combination with pegylated interferon (peg-IFN) and ribavirin, significantly increasing the cost of the treatment . However, several side effects and limited efficacy soon discouraged their use .…”

“…These DAAs were used in combination with pegylated interferon (peg-IFN) and ribavirin, significantly increasing the cost of the treatment. 70 However, several side effects and limited efficacy soon discouraged their use. 71 The introduction of second generation DAAs daclatasvir (20, Figure 9) and sofosbuvir (21), discovered as NS5A and NS5B inhibitors, respectively, represented a breakthrough in treatment of HCV, improving rates of sustained viral response (SVR) of more than 95%.…”