By Liz Highleyman

Over years or decades, chronic hepatitis B can lead to decompensated liver disease, characterized by symptoms such as ascites (abdominal fluid accumulation), portal vein hypertension, and hepatic encephalopathy.

People with advanced liver disease are considered difficult to treat, but this population has an urgent need for effective therapy to control viral replication and slow further progression of liver damage. A growing body of research has looked at antiviral therapy for patients with end-stage liver disease.

Yun-Fan Liaw from Chang Gung Memorial Hospital in Taiwan and colleagues
conducted a study to compare the safety and tolerability of tenofovir, tenofovir plus emtricitabine (the 2 drugs in the Truvada coformulation approved for HIV treatment), and entecavir.

This Phase 2 study included 112 chronic hepatitis B patients with decompensated liver disease. At baseline the median Child-Turcotte-Pugh (CTP) score was 7 and median MELD scores ranged from 10.5 to 13.0. Most participants (84%) were men, the median age was 52 years, just over half were Asian, and 65% were initially hepatitis B "e" antigen (HBeAg) negative. About one-third had creatinine clearance suggesting impaired kidney function at baseline; advanced liver disease is a risk factor for kidney dysfunction and tenofovir can cause kidney problems in at-risk individuals.

Participants were randomly allocated (2:2:1) to the 3 treatment arms. None had previously used the study drugs; entecavir recipients who previously used or were resistant to lamivudine (Epivir-HBV) took a higher dose. The investigators primarily looked at safety, in particular "tolerability failure" -- adverse events that resulted in permanent treatment discontinuation -- and markers of kidney function.

They also assessed response based on HBV viral load suppression, ALT liver enzyme normalization, and HBeAg loss and seroconversion. Patients with insufficient viral suppression (> 400 copies/mL) at weeks 8 or 24 or later could begin open-label tenofovir/emtricitabine, but were considered "failures" for the 48-week efficacy analysis.

Results

	Tolerability failure was infrequent and statistically similar in all study arms: 6.7% with tenofovir monotherapy, 4.4% with tenofovir/emtricitabine, and 9.1% with entecavir.
	Overall, 8 patients taking tenofovir, 3 taking tenofovir/emtricitabine, and 3 taking entecavir discontinued their assigned study drug prior to week 48; 10 switched to open-label tenofovir/emtricitabine.
	Protocol-defined kidney impairment was also uncommon, occurring in 8.9%, 6.7%, and 4.5%, respectively -- not a significant difference.
	Most participants across all study arms reported adverse events, but adverse event profiles and laboratory abnormalities were consistent with advanced liver disease, with no unexpected safety signals.
	6 patients died (no deaths considered related to study drugs) and 6 received liver transplants with no HBV recurrence.
	At week 48, similar proportions of patients taking tenofovir (70.5%) and entecavir (72.7%) had HBV DNA < 400 copies/mL, rising to 87.8% in the tenofovir/emtricitabine combination arm.
	These proportions rose to 76.7%, 87.8%, and 85.7%, respectively, when participants who switched to open-label tenofovir/emtricitabine were included.
	Similarly, 57% taking tenofovir and 55% taking entecavir had normal ALT, rising to 76% in the combination arm.
	21% of tenofovir recipients and 27% of tenofovir/emtricitabine recipients experienced HBeAg loss, compared with none of the entecavir recipients.
	Corresponding rates of HBeAg seroconversion were 21%, 13%, and 0%, respectively.
	CTP and MELD scores improved in all treatment arms.
	No participants developed resistance to any study drug.

Based on these findings, the authors wrote, "All treatments were well tolerated in patients with decompensated liver disease due to chronic hepatitis B with improvement in virologic, biochemical, and clinical parameters."

"Although the study was not designed to detect differences in efficacy among the 3 treatment regimens, standard chronic hepatitis B efficacy assessments (e.g., viral suppression, normalization of ALT, HBeAg/HBsAg loss, and seroconversion) were generally improved at 48 weeks in the majority of patients in each treatment group, as were measures of severity of liver disease and dysfunction (CTP and MELD scores)," they elaborated in their discussion. "As anticipated, each treatment arm produced reductions in serum HBV DNA and normalization of ALT levels consistent with results obtained in chronic hepatitis B patients without decompensation."

"The percentages of patients with confirmed changes in serum creatinine and/or serum phosphorus were not significantly different among patients who received [tenofovir] compared to [entecavir], suggesting similar renal [kidney] safety," they added.

"In summary, both [tenofovir]-containing regimens were well tolerated in these decompensated chronic hepatitis B patients, with no significant differences compared to [entecavir] with respect to tolerability failures or confirmed changes in renal parameters," the researchers concluded. "These data demonstrate the safety of these treatments through 48 weeks in patients with decompensated chronic hepatitis B and evident therapeutic benefit in all groups."

Investigator affiliations: Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan; Ege Universitesi Tip Fakultesi Hastanesi, Izmir, Turkey; Ippokration General Hospital of Athens, Athens, Greece; Toronto General Hospital, Toronto, Ontario, Canada; National Chen Kun University Hospital, Tainan, Taiwan; Hospital of Infectious Diseases, Warsaw, Poland; Virginia Mason Medical Center, Seattle, WA; Gordon and Leslie Diamond Centre, Vancouver, BC, Canada; Hospital General Universitari Vall d'Hebron, Barcelona, Spain; Hospital La Fe, Valencia, Spain; Charite Campus Virchow-Klinikum, Berlin, Germany; Gilead Sciences, Durham, NC; University of Miami School of Medicine, Miami, FL.

1/18/11

Reference
Y-F Liaw, I-S Sheen, C-Mo Lee, and others. Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology 53(1): 62-72 (Abstract). January 2011.