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HIV and Coverage of the
46th Annual Meeting of the European
Association for the Study of the Liver

March 30 - April 3, 2011, Berlin, Germany

Tegobuvir Works Well in Triple and Quad Regimens for HCV

SUMMARY: Gilead's HCV polymerase inhibitor tegobuvir (GS-9190) improved response rates in treatment-naive genotype 1 patients when used in various combinations with pegylated interferon, ribavirin, and the experimental protease inhibitor GS-9256, researchers reported at EASL 2011.

By Liz Highleyman

Gilead Sciences is currently testing a portfolio of direct-acting antiviral agents for the treatment of chronic hepatitis C virus (HCV) infection. Among these are tegobuvir, a non-nucleoside HCV NS5B polymerase inhibitor, and GS-9256, a macrocyclic HCV NS3 protease inhibitor. Both agents have demonstrated good antiviral activity in preclinical studies.

At the European Association for the Study of the Liver's International Liver Congress (EASL 2011) this month in Berlin, investigators presented posters showing data from a Phase 2b clinical trial of tegobuvir combined with standard therapy, as well as earlier data on tegobuvir in regimens that also include GS-9256.

Tegobuvir + Standard Therapy

In the first study, E. Lawitz and colleagues looked at treatment with tegobuvir plus pegylated interferon and ribavirin for either 24 or 48 weeks. This Phase 2b trial included 252 previously untreated chronic hepatitis C patients with HCV genotype 1 and without liver cirrhosis.

Participants were randomly allocated to 3 treatment arms. Arm 1 received standard therapy consisting of 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-adjusted ribavirin plus placebo for 48 weeks. Arm 2 received pegylated interferon/ribavirin plus 40 mg twice-daily tegobuvir for 48 weeks. Arm 3 took the same triple regimen for 24 weeks then used a response-guided strategy, either stopping therapy if they experienced extended rapid virological response (eRVR) or continuing for the standard duration.

About 60% of participants were men, 85% were white, and the average age was 47 years; about three-quarters were in the U.S. and the rest in Europe. About 55% had HCV genotype 1a, the remainder 1b. Proportions with the favorable CC IL28B gene pattern ranged from 29% to 45%, being higher in the standard therapy arm.


At week 4, participants who received tegobuvir triple therapy for either 48 weeks or using response-guided therapy were significantly more likely to achieve RVR (HCV RNA < 25 IU/mL) compared with standard therapy recipients (53% and 58% vs 20%, respectively).
At week 12, complete early virological response (cEVR) rates remained higher in the tegobuvir arms compared with standard therapy (76%, 81%, and 58%, respectively).
However, virological response rates were similar across study arms by week 24 (76%, 69%, and 72%, respectively) and week 48 (65%, 61%, and 66%, respectively).
Sustained virological response (SVR) rates 24 weeks after completion of treatment were identical in all 3 arms at 56%.
The SVR rate was 96% for patients in the response-guided triple therapy arm who achieved RVR and were treated for 24 weeks.
More tegobuvir recipients who achieved RVR dropped out prematurely due to adverse events, however, resulting in a lower positive predictive value.
Adverse event profiles were similar overall, though fever, itching, and muscle aches were more common among tegobuvir recipients.

Based on these findings, the researchers concluded, "Similar SVR rates of 56% were observed with [tegobuvir/pegylated interferon/ribavirin] and [pegylated interferon/ribavirin], despite a ~30% improvement in RVR and a ~20% improvement in cEVR."

Tegobuvir with GS-9256

In the second poster, G.R. Foster and colleagues presented preliminary results from a study in which participants received tegobuvir plus GS-9256 alone, or with ribavirin only, or with pegylated interferon and ribavirin for 4 weeks prior to continuing on standard therapy.

This trial included 46 participants. About 80% were men, most were white, and the median age ranged from 47 to 56 years in the various treatment arms. Proportions with the favorable CC IL28B gene pattern ranged from 12% to 40%.

As previously reported, 100% of patients achieved RVR at week 4 with the quadruple regimen compared to 38% with tegobuvir/GS-9256/ribavirin and 7% with tegobuvir/GS-9256 alone.
At week 12, response rates were 100%, 100%, and 80%, respectively.
At week 24, the corresponding rates were 100%, 100%, and 67%, respectively.
Tegobuvir and GS-9256 were generally well-tolerated.
There were 2 serious adverse events not considered treatment-related and no grade 4 laboratory abnormalities.

"We observed that the addition of ribavirin to GS-9256 + tegobuvir was associated with greater virologic suppression [and] decreased resistance emergence," the investigators concluded.

"With the 3 drugs, (GS-9256 + tegobuvir + ribavirin) 38% achieved RVR and all subjects then went on to achieve a cEVR and so far have maintained that response through Week 24 on [pegylated interferon + ribavirin]," they continued. "With the 4 drugs (GS-9256 + tegobuvir + [pegylated interferon + ribavirin]) all patients achieved RVR, without breakthroughs, and have maintained this response through Week 24."

Investigator affiliations:

Abstract 252: Alamo Medical Research, San Antonio, TX; Gastroenterology & Hepatology, Cornell University, New York, NY; Back & Godofsky, MD, PA, Sarasota, FL; Centre for Gastroenterology, Barts and London School of Medicine and Dentistry, London, UK; Wojewódzki Szpital Specjalistyczny, Bialystok, Poland; Medical Associates Research Group, San Diego, CA; Digestive and Liver Disease Specialists, Norfolk, VA; Gilead Sciences, Inc, Foster City, CA.

Abstract 232: Barts and London School of Medicine and Dentistry, London, UK; Medizinische Kern- und Poliklinik, Hamburg, Germany; Hospital Beaujon, Paris, France; J.W. Goethe University Hospital, Frankfurt, Germany; Institute of Liver Studies-King's College London School of Medicine at King's College Hospital, London, UK; Medizinische Hochschule Hannover, Hannover, Germany; Hopital Saint-Louis, Paris, France; Universitatsklinikum Wurzburg, Wurzburg, Germany; Hospital Erasme, Bruxelles, Belgium; Hopital Michallon-CHU de Grenoble, La Tronche, France; Universite Catholique de Louvain, Bruxelles, Belgium; Gilead Sciences, Inc, Foster City, CA.



E Lawitz, I Jacobson, E Godofsky, et al. A phase 2b trial comparing 24 to 48 weeks treatment with tegobuvir (GS-9190)/PEG/RBV to 48 weeks treatment with PEG.RBV for chronic genotype 1 HCV infection. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 252.

GR Foster, P Buggisch, P Marcellin, et al. Four-week treatment with GS-9256 and tegobuvir (GS-9190), ± RBV ± PEG, results in enhanced viral suppression on follow-up PEG/RBV therapy, in genotype 1a/1b HCV patients. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 232.
























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