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 HIV and Coverage of the
th Annual Meeting of the American Association
for the Study of Liver Diseases
(AASLD 2009)

October 30 - November 3, 2009, Boston, MA

Tenofovir (Viread) Regimens Are Effective and Well-tolerated in Chronic Hepatitis B Patients with Decompensated Liver Disease

SUMMARY: The nucleotide analog tenofovir (Viread), especially when combined with emtricitabine (Emtriva) -- the 2 drugs in the Truvada coformulation -- was well-tolerated and produced good hepatitis B virus (HBV) suppression and hepatitis B "e" antigen (HBeAg) loss and seroconversion in patients with decompensated liver disease, according to data presented this past weekend at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston.

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. Patients with advanced disease are considered difficult to treat, but have an urgent need for effective therapy to inhibit viral replication and slow further progression of liver damage.

An international team of researchers undertook a study to assess the safety and tolerability of tenofovir, tenofovir + emtricitabine, and entecavir (Baraclude) in 112 patients with decompensated liver disease (current or past Child-Pugh-Turcotte [CPT] score > 7, but currently < 12) due to chronic hepatitis B. Participants were randomly assigned to the 3 arms in a 2:2:1 manner.

Most participants (84%) were men, the median age was 52 years, a majority (54%) were Asian, and 65% were initially HBeAg negative. The mean CPT score was 7 and the mean MELD score was 9.5. At baseline, one-third had creatinine clearance < 80 mL/min (a sign of impaired kidney function). None had previously used tenofovir or entecavir.

The primary study end-point was safety, specifically "tolerability failure," defined as adverse events resulting in permanent treatment discontinuation. The researchers also assessed kidney impairment, defined as a creatinine increase > 0.5 mg/dL from baseline or a phosphorus level < 2 mg/dL. Decompensated liver disease is a risk factor for kidney dysfunction, and studies of people with HIV indicate that tenofovir can cause kidney problems in a small proportion of at-risk individuals.

Preliminary analysis of efficacy was a secondary objective. Patients with insufficient viral suppression at week 8 or continued detectable HBV DNA at week 24 or later could start open-label tenofovir/emtricitabine, but were considered "failures" in the efficacy analysis.

The overall study was designed to last for 168 weeks; preliminary 48-week data were presented at AASLD.


71% of participants taking tenofovir, 89% taking tenofovir/emtricitabine, and 73% taking entecavir remained on their original randomized treatment assignment at week 48.
Tolerability failure occurred infrequently across all 3 arms: 7% with tenofovir, 4% with tenofovir/emtricitabine, and 9% with entecavir (not a statistically significant difference).
Rates of confirmed kidney impairment were 9%, 7%, and 5%, respectively (also non-significant).
24%, 42%, and 23%, respectively, experienced serious adverse events of any kind, but these were mostly considered not study drug related.
6 patients discontinued therapy due to an adverse event, only 1 of which was considered study drug related.
Adverse event and laboratory profiles were consistent with advanced liver disease.
The researchers identified no unexpected "safety signals" for any of the study drugs.
6 participants received liver transplants, and none experienced HBV recurrence.
Mortality rates in the 3 arms were 4%, 4%, and 9%, respectively, and none of the deaths were considered study drug related.
In an intent-to-treat analysis, statistically similar proportions of patients in the 3 arms achieved HBV DNA < 400 copies/mL:

- Week 12: 51% taking tenofovir, 47% taking tenofovir/emtricitabine, and 50% taking entecavir;
- Week 24: 66%, 74%, and 68%, respectively;
- Week 48: 71%, 88%, and 73%, respectively.

Among participants with baseline lamivudine (Epivir-HBV) resistance, 50%, 89%, 33%, respectively had HBV DNA < 400 copies/mL at week 48.
57% of patients taking tenofovir, 76% taking tenofovir/emtricitabine, and 55% taking entecavir had normal ALT at week 48.
CPT (median change -1 in all arms) and MELD scores (median change -2 in all arms) generally improved.
21% of patients in the tenofovir arm and 27% in the tenofovir/emtricitabine arm experienced HBeAg loss, while 21% and 13%, respectively, had HBeAg seroconversion.
No entecavir recipients experienced HBeAg loss or seroconversion.
No patients in any arm achieved hepatitis B surface antigen (HBsAg) loss.
No tenofovir recipients developed mutations associated wit tenofovir resistance.

Through week 48, "all treatments were well-tolerated and had comparable safety and tolerability" in patients with decompensated liver disease due to chronic hepatitis B, the investigators concluded.

"The overall incidence of renal [kidney] events was low and no significant renal safety difference was observed between groups in this vulnerable population," they continued. "HBeAg loss or seroconversion was only observed in the [tenofovir] containing regimens."

Chang-Gung Memorial Hospital - LinKou, Taoyuan Hsien, Taiwan; Gilead Sciences, Durham, NC; Chang-Gung Memorial Hospital - Kaohsiung, Kaoshiung Hsien, Taiwan; Ege Universitesi Tip Fakultesi Hastanesi, Izmir, Turkey; 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; Servicio de Medicina Interna Hepatologia, Barcelona, Spain; Hospital La Fe, Valencia, Spain; Medizinische Klinik mit Schwerpunkt Hepatologie & Gastroenterology, Berlin, Germany; University of Miami, Miami, FL.


Y Liaw, C Lee, US Akarca, and others. Interim Results of a Double-Blind, Randomized Phase 2 Study of the Safety of Tenofovir Disoproxil Fumarate, Emtricitabine plus Tenofovir Disoproxil Fumarate, and Entecavir in the Treatment of Chronic Hepatitis B Subjects with Decompensated Liver Disease. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 122.


























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