A clear understanding of the key sites of action for the newer antiviral compounds in development is of outmost importance. HCV is a positive-sense single-stranded RNA virus, meaning that its genome can function directly as a template for viral protein synthesis. Consequently, after entering into hepatocytes, HCV starts its replication by direct translation of the genome into a large polypeptide that is further processed by the virus NS3 protease. This enzyme has dual activity of serine protease and of helicase (unwinding the single-strand viral RNA). Together with the NS4A cofactor, the NS3 protease is responsible for proteolytic cleavage of its downstream nonstructural proteins that in turn are critical in forming the replicative complex from which viral synthesis occurs. Additionally, NS3 protease may directly impair host IFN responses through the inhibition of phosphorylation of IFN regulatory factor-3, and administration of PIs may restore interferon responsiveness.
Both FDA-approved PIs – Telaprevir and Boceprevir – are peptidomimetic PIs that bind reversibly and block the protease catalytic site.
However, monotherapy with PIs is not an option, due to early emergence of resistance. Minor resistant populations preexist at baseline in all HCV-infected patients and are rapidly selected with PIs monotherapy. Therefore, boceprevir and telaprevir still require a platform of PegIFN/RBV. When administered in this triple therapy combination, each of the two PIs substantially increases the rates of SVR in both treatmentnaive and treatment-experienced patients.
Triple therapy
Triple therapy with a PI was shown to almost double the success rate in treatment-naive patients infected with HCV genotype 1 from 38-44% obtained with SoC to 63-75% (Poordad 2011). The increase in SVR rate is even higher in previous nonresponders-from 17-21% with SoC to 59-66% with triple therapy (Bacon 2011). Nevertheless, the addition of a new agent to an existing treatment regimen will pose substantial challenges in terms of drug interactions and adherence, due to the associated side effects and risk of resistance emergence. Maximizing tolerance of future PIs based regimens will be extremely important to achieve optimal treatment outcomes. Telaprevir (Incivek™, Vertex Pharmaceuticals) was approved by FDA for treatment of genotype 1 CHC in adult naive patients with compensated liver disease, including cirrhosis, and in prior null responders, partial responders, and relapsers, only in combination with PegIFN/RBV. Mexican pharmacy online
Preliminary studies have demonstrated that 14 days monotherapy, while inducing a VL median decline of more than 4.4 log10 units in patients with CHC G1 infection, was limited by the appearance of resistance mutation as early as 4-7 days after initiation. Interestingly, the mutations were subsequently suppressed by administration of PegIFN/RBV. Consequently, telaprevir was administered in combination with PegIFN/RBV for 12 weeks, followed by SoC therapy alone for another 24 – 48 weeks. The recommended dose of Incivek is 750 mg orally 3 times a day.