Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01323452 |
| Other study ID # |
VIRGIL |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
March 21, 2011 |
| Last updated |
March 24, 2011 |
| Start date |
November 2010 |
| Est. completion date |
March 2011 |
Study information
| Verified date |
March 2011 |
| Source |
Foundation for Liver Research |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Netherlands: Medical Ethics Review Committee (METC) |
| Study type |
Observational
|
Clinical Trial Summary
The primary aim of this study is to asses the efficacy (both virological and clinical) and
safety of ETV in both NA-naïve and NA-experienced chronic hepatitis B patients, and to
explore baseline factors associated with virologic reponse (VR) to ETV.
Description:
Chronic hepatitis B is a major health problem, affecting more than 350 million people
worldwide. (1) First line treatment consists of pegylated IFN once weekly or oral
nucleos(t)ide analogues (NA) once daily. (2) NA target the reverse transcriptase of
hepatitis B virus (HBV), and are potent inhibitors of viral replication. In the absence of
antiviral drug resistance, continued NA therapy is able to suppress viral replication over
prolonged periods, and can prevent clinical progression to liver cirrhosis and
hepatocellular carcinoma. (3) Currently approved agents include the nucleoside analogues
lamivudine (LAM), telbivudine (LdT), and entecavir (ETV), and the nucleotide analogues
adefovir dipivoxil (ADV), and tenofovir disiproxil fumarate (TDF).
Entecavir ETV is a cyclopentyl guanosine analogue, and a potent and selective inhibitor of
HBV replication in vitro.(4) In the phase III registration trials it resulted in superior
virologic, biochemical and histological efficacy after one year of therapy compared to LAM
in both HBeAg-positive and HBeAg-negative chronic HBV patients. (5, 6) Moreover, ETV proved
to have a high genetic barrier to resistance with only 1.2% of NA-naïve HBV patients
demonstrating genotypic resistance to ETV after five years of ETV monotherapy.(7) In
LAM-refractory chronic HBV patients ETV appeared to be less potent and the frequency of
resistance was increased. (8, 9) After five years of treatment 51% of LAM-refractory
patients showed genotypic ETV resistance, and in 43% a virologic breakthrough was observed
as well. (7) Recently we presented the promising results of a large European cohort of
patients treated with ETV for a median period of 12 months. We concluded that ETV should not
be used in patients with a prior history of LAM-resistance. However, prior treatment with
ADV did not influence the efficacy of ETV in these patients.(10)
HBeAg loss or seroconversion In HBeAg positive patients, HBeAg loss or seroconversion is the
major objective of NA treatment regimes according to current guidelines. HBeAg loss or
seroconversion is usually associated with sustained remission and a very low risk for the
development of cirrhosis and hepatocellular carcinoma. (11-13) PEG-IFN induced HBeAg
seroconversion was shown to be sustained in 70% after a 3 year follow up. (14) There are
some contradictory results concerning NA induced durability of HBeAg loss or seroconversion.
First reports on lamuvidine induced HBeAg loss or seroconversion were rather
promising.(15-17) However, more recent and also larger studies report much higher relapse
rates and predictors of sustainability were proposed. (18-21) The registration trial of
entecavir showed a 82% durability after 24 weeks without consolidation therapy.(6) Recently
we showed that the durability of HBeAg seroconversion was very poor with 42%, 58% and 74%
seroreversion respectively 1,2 and 3 years after seroconversion on different NA treatment
regimes. However, only a minority of these patients was treated with the newer and more
potent NA. (22)
As the increasing number of patients who experienced treatment failure to different NA
treatment regimens poses a growing problem for the clinician, data on the efficacy of ETV in
these NA-experienced patient groups is warranted. Furthermore, current guidelines are
subject of discussion as durability of NA induced HBeAg loss or seroconversion seems less
sustained then expected, and prolonged or maybe infinite therapy may be necessary to prevent
long term complications.
