By Liz Highleyman

Several antiviral agents have potent activity against hepatitis B virus (HBV), but the emergence of drug-resistance mutations is a barrier to long-term treatment effectiveness.

At the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) this week in San Francisco, researchers presented 96-week results from 2 Gilead clinical trials assessing tenofovir (Viread) in patients with hepatitis B "e" antigen (HBeAg) negative and HBeAg positive chronic hepatitis B.

Tenofovir is widely used to treat HIV, and was approved in August as a therapy for chronic hepatitis B.

Studies 102 and 103 were multicenter, randomized, double-blind Phase 3 trials comparing tenofovir versus adefovir (Hepsera) in chronic hepatitis B patients with compensated liver disease. Study 102 included 375 HBeAg negative patients, while Study 103 included 266 HBeAg positive participants. About 68% were men and the mean age was 43 years. In Study 102 about two-thirds were Caucasian and one-quarter were Asian; in Study 103, about half were Caucasian, and about one-third were Asian. Most were treatment-naive, though about 15% had previously used lamivudine (Epivir-HBV). The studies did not include patients with HIV-HBV coinfection.

As previously reported, tenofovir produced higher rates of HBV DNA clearance < 400 copies/mL compared with adefovir at 48 weeks (93% vs 63% in Study 102; 76% vs 13% in Study 203..

After the initial 48-week treatment period, patients originally randomized to receive adefovir in both studies switched to open-label tenofovir for another 48 weeks, while those originally assigned to tenofovir continued to take it for the same duration.

After 72 weeks, patients with continued HBV DNA > 400 copies/mL (confirmed on 2 consecutive visits) had the option of adding emtricitabine (Emtriva, also combined with tenofovir in the Truvada fixed-dose coformulation). Emtricitabine is approved for treatment of HIV and is under study for hepatitis B.

96-week data from both studies was presented at the Liver Meeting. The study is scheduled to continue through 384 weeks (more than 7 years).

Combined Results:

• Patients who received tenofovir for up to 96 weeks experienced sustained HBV DNA suppression.

• All patients who had undetectable HBV DNA while on adefovir maintained virological suppression after switching to tenofovir at week 48.

• Patients generally had achieved ALT normalization by week 48, and this was maintained through week 96.

• Tenofovir continued to be well-tolerated, and no new safety issues were identified.

• No mutations associated with tenofovir resistance were identified in either study.

Study 102 Results

• In an intent-to-treat analysis at 96 weeks, 91% of HBeAg negative patients originally randomized to the tenofovir arm and 89% of those who switched from adefovir to tenofovir achieved sustained HBV DNA suppression < 400 copies/mL.

• In an as treated analysis, 96% of patients in the continuous tenofovir arm and all patients in the switch arm achieved undetectable HBV DNA.

• Of the 2 patients who added emtricitabine after 72 weeks, 1 achieved full virological suppression by week 96.

• None of the patients experienced hepatitis B surface antigen (HBsAg) loss.

• 10% of patients in both the continuous tenofovir arm and the adefovir-to-tenofovir switch arm had grade 3-4 laboratory abnormalities.

• No patients experienced a confirmed 0.5 mg/dL increase in serum creatinine or creatinine clearance less than 50 ml/min (markers of kidney damage, a potential side effect of adefovir and tenofovir in susceptible patients).
The investigators concluded that tenofovir "produced potent, continuous viral suppression and was well tolerated through week 96."

"Patients switching to tenofovir after 48 weeks of adefovir treatment benefited with significant additional viral suppression and had a similar response to patients treated with tenofovir for 96 weeks," they added.

"In this study, Viread [tenofovir] produced a significant and sustained effect over two years of treatment with no evidence of resistance, which is a substantial clinical finding," said principle investigator Patrick Marcellin, MD, in a press release issued by Gilead. "Additionally, patients in this study taking Hepsera [adefovir] were rolled over to Viread without new safety signals and without compromising the efficacy of anti-HBV treatment."

Hopital Beaujon, University of Paris, Clichy, France; Hospital Valle Hebron, Barcelona, Spain; University Hospital St Ivan Rilsky, Sofia, Bulgaria; University of Uludag, Bursa, Turkey; Tokuda Hospital, Sofia, Bulgaria; Royal Free Hospital, London, UK; University of Calgary, Calgary, Alberta, Canada; Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada; Gilead Sciences, Durham, NC.

Study 103 Results

• In a 96-week intent-to-treat analysis, 78% of HBeAg positive patients achieved HBV DNA suppression < 400 copies/mL in both the continuous tenofovir arm and the adefovir-to-tenofovir switch arm.

• In an as-treated analysis, 89% and 85%, respectively, had undetectable HBV DNA at 96 weeks.

• 82% of patients with detectable viremia at week 48 on adefovir experienced full viral suppression at 96 weeks after switching to tenofovir.

• 28 patients added emtricitabine after 72 weeks due to continued viremia, 5 of whom achieved viral suppression by week 96.

• 30% of patients in the continuous tenofovir arm and 28% in the switch arm experienced HBeAg loss, while 26% and 24%, respectively, experienced HBeAg seroconversion (appearance of anti-HBe antibodies).

• 6% of patients in both groups experienced HBsAg loss; 4% who received continuous tenofovir and 5% who switched experienced HBsAg seroconversion (considered an indicator of resolved infection).

• 7% of patients in the continuous tenofovir arm and 10% in the switch arm experienced grade 3-4 laboratory abnormalities.

• No patients experienced creatinine clearance less than 50 ml/min, but 2 in the adefovir-to-tenofovir switch arm had a confirmed 0.5 mg/dL increase in serum creatinine.

As with Study 102, the investigators concluded that tenofovir produced potent, continuous viral suppression and was well tolerated through week 96 in HBeAg positive patients, and that switching from adefovir to tenofovir led to significant additional viral suppression.

Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada; Middlemore Hospital, Auckland, New Zealand; Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; Dreamwork Medical Group, Flushing, NY; Monash University, Melbourne, Victoria, Australia; Center for HIV and Gastroenterology, Dusseldorf, Germany; Hopital Beaujon, University of Paris, Clichy, France; Gilead Sciences, Durham, NC.

11/07/08

References

P Marcellin, M Buti, Z Krastev, and others. Two Year Tenofovir Disoproxil Fumarate (TDF) Treatment and Adefovir Dipivoxil (ADV) Switch Data in HBeAg-Negative Patients with Chronic Hepatitis B (Study 102), Preliminary Analysis. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 146.

E Heathcote, EJ Gane, RA deMan, and others. Two Year Tenofovir Disoproxil Fumarate (TDF) Treatment and Adefovir Dipivoxil (ADV) Switch Data in HBeAg-Positive Patients With Chronic Hepatitis B (Study 103), Preliminary Analysis. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 158.

Other source
Gilead Sciences. Gilead Announces Two-Year Data from Pivotal Phase III Studies Evaluating Viread(R) for Chronic Hepatitis B. Press release. November 1, 2008.