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Prolonged Entecavir for Slow Responders

SUMMARY
Treatment-naive hepatitis B patients who stay on entecavir (Baraclude) monotherapy despite suboptimal response at 48 weeks are likely to go on to achieve undetectable viral load.

Several FDA-approved nucleotide/nucleoside analogs demonstrate good activity against hepatitis B virus (HBV), but drug resistance can emerge over time and compromise the effectiveness of long-term therapy, especially if the virus continues to replicate.

Entecavir (Baraclude) Tablet

Entecavir is among the more potent nucleoside analogs approved to treat chronic hepatitis B. Current European Association for the Study of the Liver (EASL) treatment guidelines recommend that patients who do not experience compete virological response, or undetectable HBV DNA, by 48 weeks should modify therapy by switching or adding additional drugs.

As described in the May 11, 2011, advance online edition of Hepatology, Roeland Zoutendijk from Erasmus University Medical Center in Rotterdam and colleagues investigated the long-term safety and efficacy of entecavir in chronic hepatitis B patients who still had detectable HBV DNA after 48 weeks on treatment.

This cohort study included 333 participants treated with entecavir monotherapy between 2005 and 2010 at 10 large hepatitis referral centers in Europe. Of these, 243 were nucleoside/nucleotide-naive at the start of therapy, while 90 had previously used this class of drugs. All participants included in the analysis took entecavir for at least 3 months.

Three-quarters of participants were men, about half were white, about 30% were Asian, and the average age was 43 years. The mean baseline HBV viral load was 6.2 log IU/ml, 43% were hepatitis B "e" antigen (HBeAg) positive, and 27% had liver cirrhosis. People with HIV and hepatitis C coinfection were excluded.

Results

At 48 weeks, 48% of HBeAg positive and 89% of HBeAg negative nucleoside/nucleotide-naive participants achieved virological response (HBV DNA < 80 IU/mL).
Virological response rates for nucleoside/nucleotide-naive patients continued to increase with further time on entecavir monotherapy:
 
96 weeks: 76% of HBeAg positive and 98% of HBeAg negative patients;
144 weeks: 90% of HBeAg positive and 99% of HBeAg negative patients.
Among nucleoside/nucleotide-naive patients with at least 48 weeks of follow-up, 21% had partial virological response, or continued detectable HBV viral load.
81% of people with partial response achieved compete virological response during prolonged entecavir monotherapy.
No participants developed entecavir resistance despite ongoing viral replication after week 48.
Among 22 patients with viral load < 1000 IU/mL at 48 weeks, all but 1 (95%) achieved complete virological response with longer treatment, compared to 57% of participants with >1000 IU/mL at week 48.
Continuous HBV DNA decline was observed among most participants without complete virological response during follow-up.
However, 7 patients with partial response -- including 3 with suboptimal adherence according to treating physicians -- never achieved full viral suppression with longer therapy.
Prolonged entecavir monotherapy was safe and well-tolerated, and did not lead to kidney-related adverse events or cause lactic acidosis (a sign of mitochondrial toxicity).

Based on these findings, the study authors concluded, "Entecavir monotherapy can be continued in [nucleoside/nucleotide analog]-naive patients with a detectable HBV DNA at week 48, particularly in those with a low viral load at week 48, as long-term entecavir leads to a virological response in the vast majority of patients."

"The current multicenter study showed that entecavir is effective up to 3 years in [nucleoside/nucleotide analog]-naive patients, irrespective of having a virological response at week 48," they elaborated in their discussion.

They added that most people with partial virological response went on to achieve undetectable HBV DNA with prolonged entecavir monotherapy therapy without treatment modification, suggesting they should be considered slow responders rather than non-responders.

No participants -- including 2 with viral breakthrough -- developed entecavir resistance, the researchers noted. In contrast, previous studies of adefovir (Hepsera) and telbivudine (Tyzeka) plus lamivudine (Epivir-HBV) found that persistent viral replication at weeks 24 and 48 predicted emergence of resistance.

"In conclusion, in contrast to what is suggested in recently published EASL guidelines on the management of chronic hepatitis B, adjustment of entecavir monotherapy in [nucleoside/nucleotide analog]-naive patients with a partial virological response at week 48 is not necessary," they wrote.

"This highlights that treatment paradigms based on data from studies investigating agents with a low barrier to resistance cannot be translated to newer and more potent drugs [such] as entecavir and [tenofovir (Viread)]," they advised.

Investigator affiliations: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Netherlands; Department of Hepatology and Gastroenterology, Imperial College London, UK; Department of Hepatology, Hotel Dieu Hospital Lyon, France; Department of Hepatology and Gastroenterology, Queen Elizabeth Hospital, Birmingham, UK; Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Germany; Liver Unit, IFI Institute, Asklepios Klinik St. Georg, Hamburg, Germany; Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany; Department of Hepatology, Hospital Vall de Hebron, Barcelona, Spain; Clinic of Infectious Diseases, University of Foggia, Italy; Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Leipzig, Germany; Department for Internal Medicine, University Medical Center, Hamburg-Eppendorf, Germany.

6/3/11

Reference
R Zoutendijk, JG Reijnders, A Brown, et al. Entecavir treatment for chronic hepatitis B: Adaptation is not needed for the majority of naive patients with a partial virological response. Hepatology (abstract). May 11, 2011 (Epub ahead of print).


 

 

 

 

 

 

 

 

 

 

 

 

 

 


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