| Abstract|| |
Entecavir is the newest and most potent nucleoside analog to be licensed worldwide for the treatment of chronic hepatitis B infection. It has been shown to be more effective than lamivudine and adefovir in direct head-to-head comparison trials. It is also useful in the treatment of lamivudine-refractory patients. Entecavir is safe with no significant difference in adverse effects compared to lamivudine and adefovir. Available data for up to 2 years of continuous therapy showed no development of viral resistance in nucleos(t)ide-naοve patients. Resistance to entecavir occurs only in patients previously exposed to lamivudine and occurs at a rate of 9% after 2 years of continuous therapy with entecavir.
|How to cite this article:|
Tan CK. Entecavir : A review. Hep B Annual 2006;3:35-53
| Introduction|| |
Entecavir (ETV) is the third nucleos(t)ide analogue (NA) to be licensed for the treatment of chronic HBV infection. It is a deoxyguanosine analog. Synthesis of the novel compound was first reported in 1997. It now takes its place amongst the other therapies available for chronic HBV infection, viz. lamivudine (LAM), adefovir (ADF) and interferon (IFN).
| Mechanism of entecavir action|| |
Hepatitis B virus (HBV) DNA polymerase is the key enzyme in the replication of the virus. The NAs (LAM, ADF, ETV) belong to a class of drugs that inhibits the action of HBV DNA polymerase. The active form of this class of drugs is the triphosphate form (TP). Parent ETV is very efficiently phosphorylated within the mammalian cell into ETV-TP.
There are three distinct phases in the HBV DNA replication cycle-priming, reverse transcription and DNA-dependent DNA synthesis. ETV-TP binds to HBV DNA polymerase with very high affinity and is a highly potent inhibitor of all three phases. LAM-TP, on the other hand, does not inhibit the priming process. Studies have demonstrated that the TP form of ETV is a competitive inhibitor of HBV polymerase with regard to dGTP and is preferentially used by HBV DNA polymerase over the natural substrate.
| Preclinical studies|| |
Preclinical in vitro studies of ETV were all very promising. In the duck hepatitis virus model, the EC 50 of ETV was shown to be more than 1,000-fold higher than lamivudine. Studies using human recombinant HBV nucleocapsids showed ETV as from 100 to 300-fold more potent than LAM against LAM-resistant HBV polymerase. More importantly, ETV reduced the covalently close circular (ccc) DNA by at least 4 logs copies/mL in the woodchuck model of chronic hepatitis infection. This is important as cccDNA is the template for viral replication and is responsible for the persistence and chronicity of HBV infection despite antiviral treatment as it is unaffected by most antiviral agents. As the intracellular half-life of ETV is about 15 hours, it can be dosed once daily. In addition, the in vitro therapeutic index is 8,000 signifying that a wide range of doses is possible without toxicity. These promising pre-clinical studies paved the way for human studies.
| Initial human studies|| |
In an early 28-day, randomized, placebo-controlled, dose-escalating study in 42 patients, all doses of ETV used (0.05, 0.1, 0.5 and 1.0 mg) showed significant suppression of HBV replication by more than 2 log copies/mL. Patients treated with 0.5 and 1.0 mg of ETV showed a significantly slower return of HBV DNA to baseline on cessation of treatment compared to those treated with lower doses. ETV was also shown to be well-tolerated with no significant differences in adverse events between ETV and placebo groups. The next study was a 24-week, randomized, double-blind, multicentre, phase II trial (014 study) of 169 patients comparing safety and efficacy of three doses of ETV (0.01, 0.1 and 0.5 mg/day) with LAM (100 mg/day). There was a significant dose-relationship in the ETV treatment groups. Significantly more patients treated with 0.5 mg/day ETV had undetectable HBV DNA by Quantiplex assay (lower detection limit 7x10 5 HBV DNA copies/mL) compared with the LAM group (83.7 vs. 57.5%, P =0.008). Again ETV was shown to be well-tolerated. These results strongly suggested that ETV has superior antiviral activity over LAM.
Unlike LAM the absorption of ETV is significantly affected by food. Hence, ETV should not be ingested within 2 hours of a meal.
| Entecavir vs . lamivudine clinical trials - week 48 (year 1) data|| |
The three pivotal registration trials of ETV were randomized, blinded, direct head-to-head comparison with LAM in patients with replicative chronic hepatitis B infection. These were the first clinical trials ever to be done comparing two NAs. The three trials comprized of patients who were treatment-naοve and HBeAg-positive (022 study, 709 patients), treatment-naοve and HBeAg-negative (027 study, 638 patients) and lamivudine-refractory HBeAg-positive (026 study, 286 patients).,, Refractoriness to LAM was defined as any of the following: persistently detectable HBV DNA by branched DNA (bDNA) assay after at least 36 weeks of LAM; recurrence of detectable HBV DNA by bDNA assay on two determinations after achieving undetectable HBV DNA (by bDNA assay) on LAM; recurrence and persistence of HBV replication after discontinuing LAM provided that LAM had been reintroduced and maintained for at least 12 weeks prior to screening; or documented YMDD mutation and HBV viremia on LAM regardless of duration of therapy. Patients in the two treatment-naοve trials were treated in a blinded fashion with either 0.5 mg/day ETV or 100 mg/day LAM in while those in the LAM-refractory trial were treated with either 1.0 mg/day ETV or 100 mg/day LAM. Treatment period was for up to 96 weeks. Primary efficacy endpoint was histological improvement at 48 weeks. Histological improvement was defined as two or more points reduction in Knodell necroinflammatory score with no worsening in Knodell fibrosis score. Secondary endpoints included reduction in the serum HBV DNA level, HBeAg loss and seroconversion (for the HBeAg-positive trials) and normalization of the alanine aminotransferase (ALT) level. There were no significant differences in baseline demography, HBV DNA titer at entry, ALT level and HBV subtype between the ETV and LAM treatment arms in all three trials. The primary endpoint of histological improvement at 48 weeks was achieved in significantly more patients in the ETV treatment arm across all three trials [Table - 1]. Similarly, at week 48, significantly more patients in the ETV treatment arm across all three trials achieved a HBV DNA titer of <300 copies/mL and normalization of ALT [Table - 1].
Although ETV was significantly better than LAM in terms of histologic improvement, HBV DNA suppression and normalization of ALT, in both HBeAg positive trials. There was no significant difference in the HBeAg to anti-HBeAb seroconversion rate at 48 weeks between ETV and LAM [Table - 1]. Of greater interest is that even in the LAM-refractory study, there was no significant difference in the HBeAg to anti-HBeAb seroconversion rate between patients receiving ETV and LAM despite massive differences between the two groups in the other endpoints. This observation suggests that mere inhibition of HBV DNA polymerase, which is the mode of action of NAs, does not contribute to the sought after endpoint of HBeAg to anti-HBeAb seroconversion.
Durability of response 24 weeks after discontinuation of trial medication was better in the treatment-naοve HBeAg-positive patients (82 and 73% in ETV and LAM groups, respectively) compared to the treatment-naοve HBeAg-negative group (48 and 35% in ETV and LAM groups, respectively) [Table - 1]. This high incidence of relapse after stopping ETV (52%) in HBeAg-negative chronic hepatitis patients does not differ from ADF or IFN therapy. Thus ETV does not offer advantage in this aspect over the other currently available treatments. In the LAM-refractory patients, the incidence of relapse 24 weeks after discontinuation of ETV was also similarly high (62%). Thus one would be enticed to continue with ETV beyond 1 year in these two groups of patients even if they have achieved response to treatment.
Overall combined safety analysis of all these three trials and a dose-ranging study of ETV in LAM-refractory patients (014 study) showed no significant differences between the ETV and LAM groups [Table - 2]. None of the deaths were related to study medications. There was also no significant difference in both ETV and LAM treatment arms with regard to the most common adverse effects [Table - 3].
There was no incidence of resistance to ETV in the two treatment-naοve trials. This is in contrast to 13 and 6% of patients in the HBeAg-positive and HBeAg-negative trials, respectively, developing resistance to LAM., However, in the LAM-refractory trial, two patients (1.4%) developed resistance to ETV. Both had pre-existing lamivudine-resistance substitutions at the time of entry into the study. The subject of resistance to ETV will be discussed in detail later.
For the treatment-naοve patients, further analyses showed that significant histological and virological benefits of ETV were not affected by demographic factors (geographical location, race and gender) and responses to ETV are consistent across baseline ALT strata and HBV genotypes, remaining comparable or superior to LAM throughout., Thus ETV differs from LAM in that in previous studies of the latter, responses were better in patients with higher baseline ALT. In the LAM-refractory trial, patients with baseline ALT level ≥ twice upper limit of normal (ULN) had higher rates of histologic improvement and the majority of ETV-treated patients showed histologic improvement and substantial mean HBV DNA change at week 48 regardless of baseline disease and demographic characteristics.
ETV was shown to be safe in compensated, cirrhotic patients in all the three studies. In the important subgroup of patients with biopsy-proven advanced liver fibrosis (Ishak score of 4-6), 57 and 59% of HBeAg-positive and HBeAg-negative patients, respectively, showed histologic improvement of a decrease of ≥1 point in the Knodell fibrosis score at 48 weeks. Also of note is that 43% of LAM-refractory patients with advanced fibrosis/cirrhosis as defined above showed improvement in Ishak fibrosis score after 48 weeks of treatment with ETV.
| Entecavir vs . lamivudine clinical trials -week 96 (year 2) data|| |
Patients with partial response to treatment in all the three pivotal registration trials continued on the same-blinded medication for a maximum of 96 weeks, thus providing important data on 2 years of continuous usage of ETV. Unfortunately, as liver biopsy was not mandatory at week 96, important data on continued improvement of histology or otherwise were not available.
In the HBeAg-positive treatment-naοve trial (022 study), 243 patients in the ETV arm (out of an original 354 patients) who did not achieve loss of HbeAg, but whose HBV DNA was <0.7 MEq/mL by bDNA assay at week 48 (i.e, partial/virologic responders) were continued on ETV. Of these, 198 patients received continuous ETV for 96 weeks. About 37 patients stopped ETV before 96 weeks, because they achieved complete response (i.e., loss of HBeAg and HBV DNA <0.7 MEq/mL) and another eight patients stopped ETV before 96 weeks, because HBV DNA was >0.7 MEq/mL (non-responder). The latter group of non-responders will be discussed in greater detail later. In the LAM treatment group, 165 patients were partial/virologic responders and 164 went on to year 2 of the trial, of which only 85 completed 96 weeks of LAM as there were 26 complete responders and 53 non-responders who stopped LAM before week 96. The large number of non-responders in the LAM group was largely due to the development of YMDD mutants during the second year of continuous LAM dosing. ETV continued to provide additional benefit through the second year with 81% achieving undetectable HBV DNA by PCR. This is an additional 17% of patients, in contrast to the LAM where the number of patients in the second year achieving undetectable DNA by PCR fell by 1% [Table - 4]. Similarly the number of patients achieving normalization of ALT increased from 66 to 79% whereas in the LAM group, it fell from 71 to 68% [Table - 4]. In both ETV and LAM groups, HBeAg to anti-HBeAb seroconversion continue to improve and spontaneous loss of HBsAg also continued to increase, albeit the latter in very small numbers, as patients continue on medication into the second year [Table - 5]. Durability of response was equally good in both ETV and LAM groups, with 76 and 72%, respectively, maintaining response 24 weeks after discontinuation of medication [Table - 5].
In the HBeAg-negative treatment-naοve trial (027 study), 26 patients in the ETV arm (out of an original 325 patients) who did not achieve normalization of ALT (i.e., ALT <1.25xULN) but whose HBV DNA was <0.7 MEq/mL by bDNA assay (i.e, partial/virologic responders) at week 48 continued on ETV. Of these 26 patients, only 15 received continuous ETV for 96 weeks as 11 achieved complete response (i.e., normalization of ALT and undetectable DNA by bDNA assay) and stopped ETV before 96 weeks as per protocol design. No patient developed resurgence of HBV DNA. In the LAM arm, 28 patients who did not achieve normalization of ALT (i.e., ALT <1.25xULN) but whose HBV DNA was <0.7 MEq/mL by bDNA assay (i.e., partial/virologic responders) were continued on LAM. Of these 28 patients, 13 did not complete 96 weeks of treatment (8 subsequent complete responders and five non-responders that is HBV DNA >0.7 MEq/mL by bDNA assay). At week 96, there seems to be no difference in the ETV and LAM groups maintaining undetectable DNA by PCR [Table - 4] but the cumulative rate of undetectable HBV DNA by PCR (from day 1 of study) was significantly higher in the ETV group compared to the LAM group (94 vs. 77%, respectively, P <0.0001). The clinical significance of such profound suppression of HBV DNA has yet to be demonstrated in a prospective fashion, but a recent large retrospective study has shown that serum HBV DNA levels down to 10 3 copies/mL correlated with risk of development of cirrhosis and also of hepatocellular carcinoma., The rate of normalization of ALT also continued to improve going into the second year of dosing for both ETV and LAM groups [Table - 4] and did not appear to differ between the two groups. However, at 24 weeks after discontinuation of medication the relapse rates in both ETV and LAM groups were dismally high [Table - 5].
In the LAM-refractory trial (026 study), 77 out of 80 and three out of seven patients who were virologic/partial responders in the ETV and LAM groups, respectively, continued dosing of medication into the second year. These were patients whose HBV DNA was <0.7 MEq/mL at week 48 but still HBeAg positive. As they continue treatment with ETV, the patients continue to improve in terms of reduction of HBV DNA to <300 copies/mL, normalization of ALT and HBeAg to anti-HBeAb seroconversion [Table - 4],[Table - 5]. However, 9% of patients have virologic rebounds due to resistance to ETV during the second year. This will be discussed in greater detail later.
At week 96, safety data were similar to that of week 48. There were no new major adverse effects discovered during the increased period of ETV exposure.
| Resistance to entecavir|| |
LAM treatment is associated with frequent emergence of drug-resistant HBV mutants due to substitutions at the Tyr-Met-Asp-Asp (YMDD) nucleotide binding site motif of HBV DNA polymerase. LAM-resistant (LAM-R) mutations occur in up to 70% of patients after 4 years of therapy. In vitro enzymatic studies showed that LAM-R HBV polymerases have reduced susceptibility to ETV. However, because of the high potency and efficient phosphorylation of ETV, sufficient intracellular concentrations of active ETV-TP are still being generated in cell cultures to effect potent inhibition of LAM-R HBV. This has been demonstrated in the recent LAM-refractory trial where ETV has been shown to be efficacious in patients with LAM-refractory chronic HBV infection (026 study).
Several forms of viral resistance to NAs can be differentiated. Genotypic resistance refers to the emergence of AAS in the HBV DNA genome in the presence of a NA but does not result in reduced susceptibility to the NA. When there is reduced susceptibility to the NA, it is then known as phenotypic resistance. On the clinical front, virologic breakthrough or rebound is defined as loss of virological response in patients who achieved an initial response or a documented and consistent of >10 times (i.e., 1 log 10 ) of HBV DNA from a previous nadir during continuation of therapy.
Early studies showed that pre-existing LAM-R signature amino acid substitutions (AAS) (rtL180M, rtM204V/I) are a pre-requisite to the development of clinical ETV resistance. ETV still retained nanomolar potency (about 100-fold less potent compared to wild type HBV) to such LAM-R mutants with double AAS (i.e., rtL180 M and rtM204 V). A third ETV-associated AAS is required together with the 2 LAM-R AAS to confer clinical ETV resistance. Although there are several signature AAS associated with exposure to ETV, rtM250V is probably the most important as once it occurs together with the double LAM-R AAS, susceptibility to ETV crashes by >1,000-fold and this manifests as clinical resistance. AAS rtM250V by itself, does not manifest as clinical resistance as it results in only about 10-fold decrease in sensitivity to ETV. Another AAS associated with ETV therapy is rtI169T. This AAS by itself or in association with LAM-R AAS does not result in reduced susceptibility to ETV. Other ETV-related AAS are rtT184G and rtS202I. Each of these AAS alone by itself does not result in reduced sensitivity to ETV (unlike rtM250 V) but when it occurs together with LAM-R AAS, susceptibility to ETV is reduced. The highest level of resistance is seen when both rtT184G and rtS202I occur together with the LAM-R AAS i.e., when all 4 AAS occur simultaneously. Thus clinical viral resistance to ETV occurs only in the background of AAS of LAM-R. ETV-R HBV mutants are still sensitive to ADF. This is because AAS conferring resistance to ADF occurs in a different domain of the HBV DNA polymerase from that of LAM-R and ETV-R AAS.
Currently, there are data available for viral resistance after 2 years of ETV therapy. Up to week 96, no cases of clinical resistance occurred in the treatment-naοve patients regardless of HBeAg status (022 and 027 studies)., Further studies done on a selected subgroup of ETV-treated patients with virologic rebounds (³1 log increase in HBV DNA from nadir by PCR) or who fail to reduce their HBV DNA to <300 copies/mL by week 96 revealed no evidence of resistance emergence. There were some instances of AAS but none showed reduced susceptibility to ETV. Genotypic analysis of all 18 virologic rebounds and five suboptimal responders did not show any emerging ETV-resistance (ETV-R) AAS.
In the LAM-refractory trial (026 study), 1 and 9% had clinical resistance (i.e., virologic rebound) at week 48 and 96, respectively. All these patients had pre-existing LAM-R AAS and emerging ETV-R AAS at residues T184 and/or S202. At baseline, 6% of all study patients already had ETV-R AAS. In the 14 patients (9%) who eventually went on to develop clinical ETV resistance, 42% of them had pre-existing ETV-R AAS even before exposure to ETV in the trial.
The overall conclusion from all these data on ETV-R is that virologic rebound due to ETV-R is only seen when LAM-R patients with HBV mutants containing M204I/V ± L180M AAS acquire additional AAS at residues T184, S202 or M250. None of the AAS that emerged in NA-naοve patients resulted in reduced susceptibility to ETV. Thus, prior use of LAM can set the stage for subsequent resistance to ETV by 48 weeks of ETV therapy whereas LAM-naοve patients do not show any resistance to ETV after up to 96 weeks of continuous ETV therapy. This is a strong reason to avoid using LAM as first line therapy for chronic HBV infection. These data are also connote that genotypic analysis of the HBV before instituting treatment with a NA can forebode eventual resistance to the NA and this knowledge will be useful in choosing and planning therapy for the patient.
Entecavir vs. Adefovir clinical trials
There are two trials of head-to-head comparison of ETV with ADF involving two distinctly different population groups. The trial on decompensated patients with chronic HBV infection is still enrolling. The other trial is a 12-week viral kinetics study comparing ETV and ADF in NA-naοve adults with HBeAg(+) chronic HBV infection (E.A.R.L.Y study). It is an important trial as it is the first direct comparison between ETV and ADF as well as the first prospective study of the early viral kinetics of ETV. Preliminary results of this trial will now be discussed.
The primary objective was to compare the early antiviral efficacy of ETV vs. ADF for the treatment of HBeAg(+) nucleoside-naοve adults with chronic HBV infection. Secondary objectives are to explore the HBV kinetics in response to initiation of treatment of ETV or ADF through week 12, to compare the proportion of patients achieving clinically significant reduction of HBV DNA (<10 4 copies/mL at week 12) and to assess the safety of ETV compared to ADF. As this is a viral kinetics study, baseline HBV DNA of enrolled patients must be >10 8 copies/mL. All patients have compensated liver disease. Patients are randomized in an open-label fashion to either ETV 0.5 mg/day or ADF 10 mg/day. ETV was significantly superior to ADF in the primary endpoint of mean reduction of HBV DNA from baseline at week 12. At week 12, 52% (17/33) of ETV-treated patients achieved HBV DNA less than 10 4 copies/mL compared to 25% (8/32) of ADV-treated patients ( P <0.0001). The rate of viral decline is dependent on the effectiveness of the NA in blocking HBV production from infected cells, clearance rate of free HBV, death rate of productively infected cells and effectiveness of the medicine in blocking de novo infection of susceptible cells. Both ETV and ADF showed biphasic viral kinetics with a first phase of rapid decline for the initial 10 days. After day 10, ETV caused a significantly faster rate of viral decline. The safety profile at week 12 was comparable between ETV and ADF. There was no discontinuation of any patient due to adverse effects.
| Entecavir in special patient groups|| |
Entecavir has been used in post-liver transplant patients who failed LAM treatment. These patients ( n =9) were all more than 100 days post-transplant, with compensated liver disease and were on stable doses immuno-suppression drugs. In this small study, ETV was shown to be a highly effective monotherapy in reducing viral load in liver transplant recipients who have failed LAM or HBIG therapy. It was also safe and had no clinically important adverse events. Thus ETV is a new therapeutic option available to liver transplant recipients with chronic HBV infection.
A study was done to test for superiority of ETV over placebo when added to LAM in HBV/HIV co-infected patients who had incomplete HBV response to LAM. Study subjects were patients with compensated liver disease, HBV DNA ≥10 5 copies/mL and HIV RNA <400 copies/mL. Results at week 24 showed that addition of ETV to a LAM-containing HAART showed antiviral superiority to continued HAART without affecting HIV-related parameters and this superiority was maintained through week 48.
Although ETV itself is not nephrotoxic, its dosing needs to be adjusted according to creatinine clearance as are excreted via the kidneys. The recommended dosage adjustments are shown in [Table - 6].
| Conclusions|| |
ETV is significantly more effective in the control of HBV replication when directly compared to LAM and ADV. It has been shown to be as safe as ETV and ADV. There is no nephrotoxicity unlike ADF. It also has the important advantage of absence of viral resistance after 96 weeks of continuous usage in NA-naοve patients. ETV resistance occurs only in the background of patients previously exposed to LAM. Patients with ETV resistance are sensitive to ADF. As the development of viral resistance is the Achille's heel of NA therapy of chronic HBV infection, the way forward may be to combination therapy of ETV, with its high potency and low inherent resistance rate, together with a second NA from the ADF/tenofovir lineage.
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Department of Gastroenterology and Hepatology, Singapore General Hospital, Outram Road 169608
Source of Support: None, Conflict of Interest: None
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6]