Tenofovir (Viread) Is Similarly Effective in Chronic Hepatitis B Patients Regardless of Liver Cirrhosis Status

By Liz Highleyman

Tenofovir (Viread) is the most recently approved nucleoside/nucleotide drug for the treatment of chronic hepatitis B virus (HBV) infection; it is also approved as a component of antiretroviral therapy for HIV, and is included in the Truvada and Atripla fixed-dose combination pills.

In a presentation at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) last month in Copenhagen, researchers reported that over 96 weeks, tenofovir worked well in people with or without liver cirrhosis.

It is well known that interferon-based therapy for chronic hepatitis B or C works better and is more easily tolerated in people who have not yet developed advanced liver damage, but the influence of cirrhosis on the effectiveness of nucleoside/nucleotide agents is unclear.

The present analysis included cirrhotic patients who received tenofovir for 96 weeks in studies GS-174-0102 (Study 102) and GS-174-0103 (Study 103), two Phase 3 hepatitis B registration trials sponsored by tenofovir manufacturer Gilead Sciences.

Study 102 included hepatitis B "e" antigen (HBeAg) negative chronic hepatitis B patients and Study 103 included HBeAg positive patients. Otherwise, the study protocols were the same. About three-quarters of participants were men, about 60% were white, about 30% were Asian, and the median ages were 47 in the cirrhotic group and 39 years in the non-cirrhotic group.

At baseline, all participants had elevated ALT (median 92 U/L in the cirrhotic group and 108 in the non-cirrhotic group) and HBV DNA >100,000 copies/mL. Of the total 426 participants in both studies combined, 81 (19%) had cirrhosis: 47 in the HBeAg negative group and 34 in the HBeAg positive group.

Participants were randomly assigned (2:1) to receive 300 mg tenofovir or 10 mg adefovir (Hepsera) once-daily for 48 weeks. Patients who underwent liver biopsy at week 48 were eligible to receive open-label tenofovir for an additional 7 years, with an option to add another drug with dual activity against HBV and HIV -- emtricitabine (Emtriva; combined with tenofovir in the Truvada combination pill) -- after week 72 if they still had confirmed HBV DNA > 400 copies/mL.

Results

Similar proportions of cirrhotic and non-cirrhotic patients achieved HBV DNA suppression < 400 c/mL at week 96:

90% vs 85%, respectively, in an intent-to-treat analysis;

97% versus 95%, respectively, in an observed or as-treated analysis.

No cirrhotic patients, but 7 non-cirrhotic patients, experienced viral breakthrough over 96 weeks (> 1 log increase or rising above 400 copies/mL after falling below this level).

Among participants who remained on telbivudine, 83% of cirrhotic patients and 78% of non-cirrhotic patients had normal ALT levels at week 96 (median 34 and 35 U/L, respectively).

Among HBeAg positive participants with 96 week serology results available, 9 of 29 cirrhotic patients (31%) and 25 of 103 non-cirrhotic patients (24%) experienced HBeAg seroconversion to anti-HBe, not a statistically significant difference.

2 HBeAg positive patients with cirrhosis (6%) experienced hepatitis B surface antigen (HBsAg) seroconversion to anti-HBs, compared with none of the HBeAg negative cirrhotic patients.

Treatment was well-tolerated overall, although there was a non-significant trend toward more adverse events (AEs) among patients with cirrhosis:

11% of cirrhotic and 13% of non-cirrhotic patients experienced grade 3 or 4 AEs;

15% and 9%, respectively, experienced serious AEs;

31% and 23%, respectively, experienced grade 3 or 4 laboratory abnormalities.

1 patient with cirrhosis developed hepatocellular carcinoma.

No patients with cirrhosis progressed to clinically evident liver decompensation.

No cirrhotic patients developed kidney toxicity as indicated by confirmed creatinine increase of 0.5 mg/dL, creatinine clearance < 50 mL/min, or phosphorous < 2 mg/dL (a potential concern with both tenofovir and adefovir).

No tenofovir-associated resistance mutations were detected through week 96.

Based on these findings, the researchers concluded, "The efficacy and safety of [tenofovir] at 96 weeks was not influenced by the existence of cirrhosis at onset of therapy and was comparable among cirrhotic and non-cirrhotic patients with good tolerability in both populations."

Hospital General Universitari Vall d'Hebron, Barcelona, Spain; Henry Dunant Hospital, Athens, Greece; Hopital Claude Huriez, CHRU Lille, France; Intern Klinika, UVN Praha, Prague, Czech Republic; Toronto General Hospital, Toronto, Canada; AW Morrow Gastroenterology & Liver Center, Royal Prince Alfred Hospital, Camperdown, Australia; Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA; Klinik & Poliklinik f. Innere Medizin, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany; Toronto Western Hospital, University of Toronto, Toronto, Canada; Hopital Beaujon, Clichy, France; Gilead Sciences, Durham, NC.

5/08/09

Reference
M Buti, S Hadziyannis, P Mathurin, and others. Two years safety and efficacy of tenofovir disoproxil fumarate (TDF) in patients with HBV-induced cirrhosis. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009. Abstract 21.

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15th Conference on Retroviruses and Opportunistic Infections (CROI 2009)
Coverage by HIV and Hepatitis.com - February 8 - 11, 2009, Montreal
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