Long-term Studies Show Tenofovir (Viread) Safety and Efficacy Is Sustained at 3 Years in HBeAg Positive and Negative Hepatitis B Patients

SUMMARY: Long-term follow-up data from 2 clinical trials show that tenofovir (Viread) remained active against hepatitis B virus (HBV) and was generally well-tolerated for up to 3 years, researchers reported this past weekend at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston.

By Liz Highleyman

Tenofovir is a nucleotide analog produced by Gilead Sciences that has been approved for HIV treatment since 2001 and for hepatitis B treatment since August 2008. The latter indication was based in part on results from 2 Phase 3 clinical trials, Study 102 and Study 103.

Both studies were randomized, double-blind trials comparing tenofovir versus Gilead's earlier approved drug adefovir (Hepsera) in patients with chronic hepatitis B. Study 102 included 375 hepatitis B "e" antigen (HBeAg) negative patients -- a group that responds better to treatment -- and Study 103 included 266 HBeAg positive patients.

Most participants (nearly 80% in Study 102 and about 70% in Study 103) were men. The mean age was about 44 years in Study 102 and about 35 years in Study 103. Most patients were treatment-naive, though some had previously used lamivudine (Epivir-HBV).

The main studies continued for 48 weeks. At that point, 389 participants in the 2 trials who were originally randomized to the tenofovir arm began receiving the drug on an open-label basis, while 196 patients originally assigned to receive adefovir switched to open-label tenofovir. After 72 weeks, patients who still had HBV viral load of 400 copies/mL or more on 2 consecutive tests had the option to add emtricitabine (Emtriva), using the Truvada (tenofovir/emtricitabine) combination pill.

Study 102 Results

	At Week 144, 328 patients (87%) were still undergoing follow-up.
	In an intent-to-treat analysis, 87% of HBeAg negative patients had sustained HBV DNA suppression < 400 copies/mL at Week 144.
	Efficacy was similar in patients who received tenofovir monotherapy for the entire study and those who started on adefovir and later switched to tenofovir (87% vs 88%, respectively).
	In an as-treated analysis, 99% of participants in the ongoing tenofovir arm and 100% in the adefovir-to-tenofovir arm achieved undetectable HBV viral load by Week 144.
	3 patients with continued HBV viremia added emtricitabine at or after Week 72, and all achieved undetectable viral load by Week 144.
	3 other participants still had viral load of 400 copies/mL or more at week 144.
	Alanine aminotransferase (ALT) levels remained normal through Week 144 (overall mean 33 U/L).
	No participants experienced hepatitis B surface antigen (HBsAg) loss by Week 144.
	Overall, tenofovir was well-tolerated through Week 144.
	1 drug-related serious adverse event (mild kidney impairment) was reported in the ongoing tenofovir arm and none in the adefovir-to-tenofovir arm.
	The rate of serious (grade 3-4) laboratory abnormalities was similar in the ongoing tenofovir and adefovir-to-tenofovir arms (14% vs 15%, respectively).
	3 participants (1.3%) in the ongoing tenofovir arm discontinued treatment due to adverse events (hepatocellular carcinoma, dizziness/fatigue/lack of concentration, and septic shock).
	No participants experienced a confirmed 0.5 mg/dL increase in serum creatinine or a decrease in creatinine clearance to less than 50 mL/min (indicators of kidney function impairment).
	3 deaths occurred during the open-label phase, none of them considered attributable to tenofovir (nasopharyngeal cancer, metastatic liver cancer, and cervical cancer).
	No evidence of drug resistance mutations was observed through 144 weeks.

Study 103 Results

	At Week 144, 214 patients (80%) were still undergoing follow-up.
	In an intent-to-treat analysis, 71% of HBeAg positive patients had sustained HBV DNA < 400 copies/mL at Week 144.
	Again, efficacy was similar in patients who received ongoing tenofovir and those who switched from adefovir to tenofovir (72% vs 71%, respectively).
	In an as-treated analysis, 95% of patients in the ongoing tenofovir arm and 91% in the adefovir-to-tenofovir arm achieved undetectable HBV DNA by Week 144.
	31 participants with confirmed viremia added emtricitabine between 72 and 144 weeks, and 17 achieved undetectable viral load by Week 144.
	5 patients still had HBV viral load of 400 copies/mL or more at Week 144.
	34% of participants achieved HBeAg loss and 26% experienced HBeAg seroconversion.
	8% experienced HBsAg loss.
	ALT levels were near normal by week 144 (mean 39 U/L).
	Again, tenofovir was generally well-tolerated through Week 144.
	2 drug-related serious adverse events were reported in the ongoing tenofovir arm (increased ALT and facial spasm) and 2 in the adefovir-to-tenofovir arm.
	12% of patients in the ongoing tenofovir arm and 16% in the adefovir-to-tenofovir arm experienced grade 3-4 laboratory abnormalities.
	1 patient discontinued tenofovir due to a 0.5 mg/dL increase in creatinine, and 2 participants in the adefovir-to-tenofovir arm had confirmed 0.5 mg/dL creatinine increases, but none experienced a decrease in creatinine clearance to less than 50 mL/min.
	No drug resistance mutations were observed through 144 weeks.

In the 2 studies combined, continued follow-up did not reveal any new or unexpected adverse events or tolerability problems beyond those observed during the first 48 weeks of treatment. The most common adverse event overall was nausea, occurring in 9% of patients at Week 48. Other adverse events reported by more than 5% of participants included abdominal pain, diarrhea, headache, dizziness, fatigue, sore throat, back pain, and skin rash.

"[Tenofovir] was well tolerated and produced potent, continuous viral suppression and no mutations associated with [tenofovir] resistance were detected through 3 years of [tenofovir] treatment," concluded the Study 102 investigators.

The Study 103 team confirmed this conclusion, adding that tenofovir produced "increasing HBeAg and HBsAg loss through 3 years of treatment in HBeAg positive patients."

"The development of resistance is a significant challenge for practitioners treating patients with chronic hepatitis B," said Study 102 principal investigator Patrick Marcellin in a press release issued by Gilead. "The robust and comprehensive resistance surveillance in these studies provides important information for the medical community and shows that Viread offers a high barrier to resistance."

Study 102 team: Hopital Beaujon, University of Paris, Clichy, France; Hospital General Universitari Vall d'Hebron and Ciberehd, Barcelona, Spain; University Hospital St Ivan Rilsky, Sofia, Bulgaria; Papageorgiou Peripheral General Hospital of Thessaloniki, Thessaloniki, Greece; University of Manitoba, Winnipeg, Manitoba, Canada; University Hospital Sveta Marina, Varna, Bulgaria; Medizinische Universitatsklinik Eppendorf, Hamburg, Germany; Waikato Hospital, Hamilton, New Zealand; San Jose Gastroenterology, San Jose, CA; University of Uludag, Bursa, Turkey; University of Toronto, Toronto, Ontario, Canada; Gilead Sciences, Durham, NC.

Study 103 team: University of Toronto, Toronto, Ontario, Canada; Middlemore Hospital, Auckland, New Zealand; Erasmus MC, University Medical Center, Rotterdam, Netherlands; University of Calgary, Calgary, Alberta, Canada; Medical University of Bialystok, Bialystok, Poland; Medical School of Hannover, Hannover, Germany; Medical University, Sofia, Bulgaria; Haydarpapa Numune Hospital, Istanbul, Turkey; Virginia Commonwealth University, Richmond, VA; Hopital Beaujon, University of Paris, Clichy, France; Gilead Sciences, Durham, NC.

11/3/09

References

Three Years of Tenofovir Disoproxil Fumarate (TDF) Treatment in HBeAg-Negative Patients with Chronic Hepatitis B (Study 102); Preliminary Analysis
P Marcellin, M Buti, Z Krastev, and others. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 481.

E Heathcote, EJ Gane, RA De Man, and others. Three Years of Tenofovir Disoproxil (TDF) Treatment in HBeAg-Positive Patients (HBeAg+) with Chronic Hepatitis B (Study 103), Preliminary Analysis. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 483.

Other source

Gilead Sciences. Gilead Announces Long-Term Data from Two Pivotal Phase III Studies Evaluating Viread For Chronic Hepatitis B. Press release . October 31, 2009.