The Era of Direct-acting Antivirals Has Begun

The Beginning of the End for HCV?

Marie-Louise Vachon, M.D., M.Sc.; Douglas T. Dieterich, M.D.


Semin Liver Dis. 2011;31(4):399-409. 

In This Article

GS-9451 and GS-9256

GS-9451 is a potent macrocyclic HCV NS3 PI that achieved a median maximal change in HCV RNA of 3.6 log10 IU/mL (range, -4.7 log10 to -3.1 log10 IU/mL) following 3-day monotherapy in treatment-naïve patients with HCV genotype 1 infection during phase I.[28] It is currently being evaluated in phase II studies in combination with other DAAs. A phase IIb study with RGT will evaluate the efficacy and safety of 16 and 24 weeks of a four-drug regimen with GS-9451 and tegobuvir (a nonnucleoside HCV polymerase inhibitor) and 24 weeks of a three-drug regimen of GS-9451 without tegobuvir, all with pegIFN and RBV. Other phase II studies evaluating different DAA combinations that include the NS5A inhibitor GS-5885 are ongoing.

GS-9451 has additive to synergistic antiviral activity when combined with pegIFN, RBV, NS5A inhibitors, or polymerase inhibitors. Although a PI, GS-9451 retains activity against V36M and T54S, two NS3 mutations. However, R155K, A156T, and D168V are cross-resistant to GS-9451. The NS3 resistance mutations selected during treatment with GS-9451 are fully susceptible to other HCV inhibitor classes.[29] This supports its use in combination with other DAAs of the company's pipeline. A new study evaluating a four all-oral drug regimen is currently recruiting patients. In this study, GS-9451 is administered with GS-5885 (a NS5A inhibitor given at two different dosages), tegobuvir, and RBV for 12 or 24 weeks in patients with chronic HCV genotype 1 infection. This type of combination could completely revolutionize HCV treatment if found potent and well tolerated.

GS-9256 is also a potent PI that was being evaluated until recently. Preliminary results of the phase II study evaluating GS-9256 in combination with tegobuvir ± RBV and ± pegIFN for 28 days have been presented.[28] With the three oral drugs, 38% achieved RVR, 100% then achieved complete early virologic response (cEVR; undetectable HCV RNA at week 12) and maintained undetectability at week 24. With four drugs, 100% achieved RVR and were still undetectable at week 24. Without RBV and pegIFN, GS-9256 and tegobuvir led to RVR in only 7% of patients (1/15). Of these 15 patients, 12 achieved cEVR following the addition of pegIFN/RBV. All combinations were well tolerated. It was decided that GS-9256 would not be further developed, in part due to its higher potential to inhibit the transport and metabolism of bilirubin compared with GS-9451.[30]


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: