In a head-to-head comparison, entecavir (Baraclude) demonstrated superior virological efficacy compared to adefovir (Hepsera) in hepatitis B patients with decompensated liver disease.
In the July 2011 issue of Hepatology, Yun-Fan Liaw and colleagues described a randomized, open-label Phase 3 study to assess the safety and efficacy of entecavir vs adefovir in people with chronic hepatitis B virus (HBV) infection and decompensated liver disease. Decompensation refers to the liver’s inability to function properly, usually due to severe scarring (advanced fibrosis or cirrhosis).
In various studies, the 5-year survival rate for people with HBV and decompensated cirrhosis is significantly lower than rates reported for people with compensated cirrhosis (14%-35% vs 80%-86%). Interferon is generally considered to be contraindicated in people with decompensated liver disease due to the risk of serious adverse events, and most data on nucleoside/nucleotide analog therapy in patients with decompensation have come from non-comparative or uncontrolled studies of lamivudine (Epivir-HBV) and adefovir.
Entecavir has been shown to have superior virological and biochemical benefits after 48 weeks of treatment compared to lamivudine or adefovir in nucleoside-naive patients, including people with advanced fibrosis or cirrhosis.
A variety of factors led the researchers to conduct the present study: lamivudine’s high resistance rates, adefovir’s suboptimal potency and potential for kidney toxicity, international HBV guidelines that recommend beginning nucleoside/nucleotide treatment as soon as possible in patients with hepatic decompensation, and a lack of comparative studies looking at the safety and efficacy of entecavir in this population.
In this head-to-head study participants with chronic hepatitis B and hepatic decompensationwere randomly assigned to receive 1.0 mg/day entecavir (n=100) or 10 mg/day adefovir (n=91), both taken orally once-daily. The adefovir dose was chosen because the trial included both lamivudine-experienced and nucleoside/nucleotide-naive participants. Although the study continued for up to 96 weeks, the Hepatology article reported efficacy during the study’s first 48 weeks, as well as cumulative safety.
Safety analyses included cumulative rates of on-treatment adverse events, serious adverse events, discontinuations due to adverse events, death, hepatocellular carcinoma (HCC), renal impairment, and hepatic flares (large increases in liver enzymes).
The primary efficacy endpoint was mean reduction in HBV DNA viral load at week 24. Secondary endpoints included mean change from baseline in HBV DNA at week 48; proportion of participants with HBV DNA < 300 copies/mL; alanine aminotransferase (ALT) normalization; improvement in total bilirubin, prothrombin time, albumin, and platelets; improvement in Model for End-Stage Liver Disease (MELD) scores; and improvement in Child-Turcotte-Pugh (CTP) status.
Beginning in 2003, a total of 191 participants were recruited from 52 sites worldwide and followed for 96 weeks. All participants had hepatitis B with hepatic decompensation. Most (74%) were men, 54% were Asian, 33% were white, and 35% had evidence of lamivudine resistance. Participants had detectable hepatitis B surface antigen (HBsAg) for at least 6 months; 54% were hepatitis B "e" antigen (HBeAg) positive.
At baseline, the mean HBV DNA level was 7.83 log copies/mL, ALT was at least 15 times the upper limit of normal (mean 99.6 times), serum creatinine was below 2.5 mg/dL, mean CTP score was 8.6, and they had no liver masses suggesting HCC. People coinfected with HIV, hepatitis C, hepatitis D, or other known liver diseases were excluded.
Participants were nucleoside/nucleotide-naive, with the exception of some who had taken or were taking lamivudine; 35% had genotypic evidence of lamivudine resistance. Participants on lamivudine at the time of screening stopped taking it upon randomization to entecavir or adefovir. Results
Participants taking entecavir had a greater decrease in HBV DNA than those taking adefovir at all time points through week 48.
At weeks 24 and 48, more study participants on entecavir achieved HBV DNA < 300 copies/mL than those on adefovir (49% vs 16% and 57% vs 20%, respectively).
At week 24, entecavir demonstrated superiority to adefovir in terms of decreased HBV DNA.
37 participants met the criteria for resistance testing at week 48 (5 on entecavir and 32 on adefovir), but none showed resistance to their assigned drug.
The same number met the criteria for resistance testing beyond week 48:
3 of 5 entecavir recipients had entecavir resistance detected at week 144 or beyond;
6 of 27 adefovir recipientshad adefovir resistance beyond week 48 (2 between weeks 48 and 96, 2 between weeks 96 and 144, and 2 at or beyond week 144.
The proportion of participants with ALT normalization was significantly higher in the entecavir group at weeks 24 and 48.
HBeAg loss and seroconversion rates were higher among participants on adefovir at week 24, but became comparable to those on entecavir by week 48.
5 participants taking entecavir showed HBsAg loss by week 48, compared with no participants taking adefovir.
Both treatment groups had improved MELD and CTP scores at week 48:
the mean change from baseline in MELD scores at week 48 was -2.6 for the entecavir group and -1.7 for the adefovir group;
the difference was at least partly due to the difference in baseline MELD scores, which were higher in the entecavir group;
about two-thirds of participants in each group had either an improvement or stabilization of CTP scores;
about one-third of participants in each group had a reduction of at least 2 points in their CTP score and/or improvement in CTP class.
Through week 48 both groups experienced improvement in liver function as measured by changes in total bilirubin, prothrombin time, albumin, and platelets; degree of improvement was comparable across both groups.
Frequencies of adverse events, serious adverse events, and grade 3 or 4 adverse events were comparable between the 2 treatment groups:
the most frequently reported serious adverse events were liver failure or complications of decompensated cirrhosis, as expected in this population;
10 entecavir-treated patients (11%) and 1 adefovir-treated patient (1%) required dose reductions due to changes in kidney function while on treatment;
7 entecavir-treated patients (7%) and 5 adefovir-treated patient (6%) discontinued treatment because of adverse events;
ALT flares were not observed in any participants during the first 48 weeks of the study, but 3 participants experienced flares after week 48.
The cumulative rates of HCC were 12% (12 of 102) in the entecavir arm and 20% (18 of 89) in the adefovir arm.
The mean time to development of HCC did not differ between the 2 groups, however.
8 of 12 entecavir recipients (67%) and 4 of 18 adefovir recipients (22%) diagnosed with HCC had HBV DNA < 300 copies/mL at the time of their diagnosis.
Of the 57 deaths reported at the time of this analysis, 52 occurred in treated participants (23% on entecavir and 33% on adefovir; the other 5 deaths occurred prior to randomization).
Most deaths were the result of liver failure.
“The present study differs from other recently reported clinical trials conducted in this population in that the study enrolled patients with more severe liver disease,” the authors wrote. “The results from this week 48 analysis demonstrated that entecavir and adefovir are effective, safe, and well tolerated in this population.”
“Although the virologic superiority of entecavir over adefovir did not translate into a comparable hepatic improvement, this observation might be related to the baseline severity of disease in this study population and the time required to reverse severe fibrosis once it is established.
In conclusion, the researchers wrote, “[T]he current study demonstrates that entecavir is superior to adefovir in suppressing HBV DNA and achieving ALT normalization through week 48.”
Initial data from this study were presented at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in 2009 and in October 2010 led to U.S. Food and Drug Administration (FDA) approval of entecavir for the treatment of chronic hepatitis B patients with decompensated liver disease, a particularly hard-to-treat population. Investigator affiliations: Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan; Second Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece; Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil; Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India; Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China; China Medical University Hospital, Taichung, Taiwan; Liver Unit, University of Calgary, Calgary, Alberta, Canada; Center for Liver Disease and Transplantation, Columbia University Medical Center, New York, NY; Miami Veterans Affairs Medical Center, Miami, FL; John A. Burns School of Medicine, University of Hawaii, Honolulu, HI; Department of Infectious Diseases, Medical University, Lodz, Poland; Research and Development, Bristol-Myers Squibb Co., Wallingford, CT.
7/26/11 References
Y Liaw, M Raptopoulou-Gigi, H Cheinquer, et al. Efficacy and Safety of Entecavir Versus Adefovir in Chronic Hepatitis B Patients With Hepatic Decompensation: A Randomized, Open-Label Study. Hepatology 54(1):91-100 (abstract). July 2011.
Y Liaw, M Raptopoulou-Gigi, H Cheinquer, et al. Efficacy and Safety of Entecavir Versus Adefovir in Chronic Hepatitis B Patients with Evidence of Hepatic Decompensation. 60th Annual Meeting of the American Association for the Study of Liver Diseases. Boston. October 30-November 1, 2009. Abstract 422.
