The protease inhibitor, GS-9256, and non-nucleoside polymerase inhibitor tegobuvir alone, with ribavirin, or pegylated interferon plus ribavirin in hepatitis C

Abstract

Tegobuvir (GS-9190), a non-nucleoside nonstructural protein (NS)5B polymerase inhibitor, and GS-9256, an NS3 serine protease inhibitor, individually have activity against hepatitis C virus (HCV) genotype 1. The antiviral activity of tegobuvir and GS-9256 as oral combination therapy, or together with ribavirin (RBV) or pegylated interferon (Peg-IFN) alpha-2a and RBV, was assessed in a phase II, randomized, open-label trial. Treatmentnaïve patients with genotype 1 HCV were assigned 28 days of tegobuvir 40 mg twice-daily (BID) and GS-9256 75 mg BID (n 5 16), tegobuvir and GS-9256 plus RBV 1,000-1,200 mg daily (n 5 15), or tegobuvir and GS-9256 plus Peg-IFN alpha-2a (180 lg onceweekly)/RBV (n 5 15). The primary efficacy endpoint was rapid virologic response (RVR), with HCV RNA <25 IU/mL at day 28. After 28 days, all patients received Peg-IFN/RBV. All patients with viral rebound or nonresponse, defined as >0.5-log 10 increase in HCV RNA from nadir or <2-log decrease at day 5, initiated Peg-IFN/RBV immediately. Median maximal reductions in HCV RNA were 24.1 log 10 IU/mL for tegobuvir/GS-9256, 25.1 log 10 IU/mL for tegobuvir/GS-9256/RBV, and 25.7 log 10 IU/mL for tegobuvir/ 9256/Peg-IFN/RBV. RVR was observed in 7% (1 of 15) of patients receiving tegobuvir/ GS-9256, 38% (5 of 13) receiving tegobuvir/GS-9256/RBV, and 100% (14 of 14) receiving tegobuvir/9256/PEG-IFN/RBV. The addition of Peg-IFN/RBV at day 28 or earlier resulted in HCV RNA <25 IU/mL at week 24 in 67% (10 of 15), 100% (13 of 13), and 94% (13 of 14) of patients in the three treatment groups. Transient elevations in serum bilirubin occurred in all treatment groups. Conclusion: In genotype 1 HCV, adding RBV or RBV with Peg-IFN provides additive antiviral activity to combination therapy with tegobuvir and GS-9256. (HEPATOLOGY 2012;55:749-758) F or the past decade, the standard of care for patients with chronic infection with genotype 1 hepatitis C virus (HCV) has been 48 weeks of pegylated interferon (Peg-IFN) alpha and ribavirin (RBV). Observed rates of sustained virologic response (SVR) with Peg-IFN and RBV therapy are 40%-52%. [1][2][3][4] However, the addition of the HCV nonstructural protein (NS)3 serine protease inhibitors, telaprevir or

Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

“…The results of phase 1 and 2 studies involving patients with HCV genotype 1 infection have been encouraging and provide support for further development of combination therapies. [8][9][10][11][12][13] In the phase 1b Safety and Antiviral Effect of Oral Combinations without Interferon in Patients Diagnosed with Hepatitis C (SOUND-C1) study, patients who had not previously been treated for HCV infection received 4 weeks of treatment with faldaprevir (an NS3/4A protease inhibitor) and deleobuvir (formerly known as BI207127; a nonnucleoside inhibitor of nonstructural protein 5B [NS5B] polymerase) plus ribavirin. At week 4, 100% and 73% of patients who received faldaprevir plus ribavirin with 600 mg or 400 mg of deleobuvir, respectively, had HCV RNA levels that were lower than 25 IU per milliliter.…”

“…Enrollment in the TID28W-NR group was discontinued on February 3, 2011, at the request of the Food and Drug Administration after other studies showed that virologic breakthrough was more common with interferon-free regimens that did not contain ribavirin than with those that did. 13,17 Baseline demographic and clinical characteristics were similar in the five study groups (Table 1).…”

“…This finding is consistent with results from other studies of interferon-free regimens without ribavirin. 13,17 The higher rate of a sustained virologic response 12 weeks after the completion of therapy among patients infected with HCV genotype 1b than among those infected with genotype 1a may be due to the fact that deleobuvir is less active against genotype 1a. 23,24 In addition, there may be a lower barrier to the emergence of re- sistant variants for genotype 1a virus.…”

Response of Hepatitis C Virus to Long-Term Passage in the Presence of Alpha Interferon: Multiple Mutations and a Common Phenotype

“…The molecular and physiological bases of the therapeutic activity of the current combination treatment with IFN-␣ plus ribavirin are poorly understood. It might be possible to establish new treatment protocols based on recently developed directly acting antiviral agents (DAAs), with or without IFN-␣ and ribavirin (22)(23)(24)(25)(26)(27).…”

Causes of treatment failure for hepatitis C in the era of direct-acting antiviral therapy

“…NS5B RAVs conferring resistance to non-nucleoside NS5B inhibitors (such as dasabuvir or tegobuvir) are much more common than those involving nucleotide inhibitors, and are also associated with viral resistance and breakthrough. Overall, they are more common in genotype 1a than in genotype 1b (23), although variant C316N is more often seen in genotype 1b (24). RAV C316N/H/F has been identified at baseline in 6 patients with genotype 1b HCV who failed to respond to sofosbuvir, and in a patient with genotype 1a who later recurred; however, further studies are needed to appropriately establish the role of RAVs as a cause of resistance to sofosbuvir (25).…”