Year : 2006 | Volume
: 3 | Issue : 1 | Page : 35--53
Entecavir : A review
Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
Department of Gastroenterology and Hepatology, Singapore General Hospital, Outram Road 169608
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
|How to cite this URL:|
Tan CK. Entecavir : A review. Hep B Annual [serial online] 2006 [cited 2021 Oct 24 ];3:35-53
Available from: https://www.hepatitisbannual.org/text.asp?2006/3/1/35/32772
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 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 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 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 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 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 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 ( 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 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 Renal impairment/dialysis
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].
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.
|1||Bisacchi GS, Chao TS, Bachard C, Daris JP, Innaimo S, Jacobs GA, et al . BMS-200475: A novel carbocyclic 2´-deoxyguanosine analog with potent and selective anti-hepatitis B virus activity in vitro . Bioorg Med Chem Lett 1997;7:127-32.|
|2||Seifer M, Hamatake RK, Colonno RJ, Standring DN. In vitro inhibition of hepadnavirus polymerases by the triphosphates of BMS-200475 and lobucavir. Antimicrob Agents Chemother 1998;42:3200-8.|
|3||Marion PL, Salazaar FH, Winters MA, Colonno RJ. Potent efficacy of entecavir (BMS-200475) in a duck model of hepatitis B virus replication. Antimicrob Agents Chemother 2002;46:82-8.|
|4||Levine S, Hernandez D, Yamanaka G, Zhang S, Rose R, Weinheimer S, et al . Efficacies of entecavir against lamivudine-resistant hepatitis B virus replication and recombinant polymerases in vitro. Antimicrob Agents Chemother 2002;46:2525-32.|
|5||Colonno RJ, Genovesi EV, Medina I, Lamb L, Durham SK, Huang ML, et al . Long-term entecavir treatment results in sustained antiviral efficacy and prolonged life span in the woodchuck model of chronic hepatitis infection. J Infect Dis 2001;184:1236-45.|
|6||Yamanaka G, Wilson T, Innaimo S, Bisacchi GS, Egli P, Rinehart JK et al . Metabolic studies on BMS-200475, a new antiviral compound active against hepatitis B virus. Antimicrob Agents Chemother 1999;43:190-3.|
|7||de Man RA, Wolters LM, Nevens F, Chua D, Sherman M, Lai CL, et al . Safety and efficacy of oral entecavir given for 28 days in patients with chronic hepatitis B virus infection. Hepatology 2001;34:578-82.|
|8||Chang TT, Gish RG, Hadziyannis SJ, Cianciara J, Rizzetto M, Schiff ER, et al . A dose-ranging study of the efficacy and tolerability of entecavir in lamivudine-refractory chronic hepatitis B patients. Gastroenterology 2005;129:1198-209.|
|9||Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, et al . A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006;354:1000-10.|
|10||Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, et al . Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. New Engl J Med 2006;354:1011-20.|
|11||Sherman M, Yurdaydin C, Sollano J, Silva M, Liaw YF, Cianciara J, et al . Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology 2006;130:2039-49.|
|12||Shouval D, Senturk H, Gish RG, Chang TT, Yurdaydin C, Lai CL, et al . Entecavir demonstrates consistent responses throughout baseline demographic subgroups for the treatment of nucleoside-naοve, HBeAg(+) and HBeAg(-) patients with chronic hepatitis B. J Hepatol 2005;42:192.|
|13||Lurie Y, Manns MP, Gish RG, Chang TT, Yurdaydin C, Lai CL, et al . The efficacy of entecavir is similar regardless of disease-related baseline subgroups in treatment of nucleoside-naive, HbeAg(+) and HbeAg(-) patients with chronic hepatitis B. J Hepatol 2005;42:184.|
|14||Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, et al . A one-year trial of lamivudine for chronic hepatitis B. New Engl J Med 1998;339:61-8.|
|15||Yurdaydin C, Senturk H, Boron-Kaczmarska A, Raptopoulou-Gigi M, Batur Y, Goodman Z, et al . Entecavir demonstrates consistent responses throughout baseline disease and demographic subgroups for the treatment of lamivudine-refractory patients with chronic hepatitis B. J Hepatol 2006;44:S190.|
|16||Chang TT, Chao YC, Wu SS, Tan CK, Rosmawati M, et al . Efficacy and safety of entecavir and lamivudine in compensated, cirrhotic patients with chronic hepatitis B. Shanghai-Hong Kong International Liver Congress 2006.|
|17||Simsek H, Schiff E, Goodman Z, Brett-Smith H, Klesczewski K, Kreter B. Effects of entecavir and lamivudine on advanced liver fibrosis after 48 weeks of treatment in patients with chronic hepatitis B infection: Results of three pivotal trials. J Hepatol 2006;44:S191.|
|18||Gish RG, Chang TT, de Man RA, Gadano A, Sollano J, Han KH, et al . Entecavir results in substantial virologic and biochemical improvement and HbeAg seroconversion through 96 weeks of treatment in HBeAg(+) chronic hepatitis B patients (Study ETV-022). Hepatology 2005;42:267A.|
|19||Shouval D, Akarca US, Hatzis G, Kitis G, Lai CL, Cheinquer H, et al . Continued virologic and biochemical improvement through 96 weeks of entecavir treatment in HBeAg(-) chronic hepatitis B patients (Study ETV-027). J Hepatol 2006;44:S21.|
|20||Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al . Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295:65-73.|
|21||Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ, et al . Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130:678-86.|
|22||Yurdaydin C, Sollano J, Hadziyannis S, Kaymakoglu S, Sherman M, Brett-Smith H, et al . Entecavir results in continued virologic and biochemical improvement and HBeAg seroconversion through 96 weeks of treatment in lamivudine-refractory, HBeAg(+) chronic hepatitis B patients (ETV-026). J Hepatol 2006;44:S36.|
|23||Lai CL, Dienstag J, Schiff E, Leung NW, Atkins M, Hunt C, et al . Prevalance and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis 2003;36:687-96.|
|24||Tenney DJ, Levine SM, Rose RE, Walsh AW, Weinheimer SP, Discotto L, et al . Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine. Antimicrob Agents Chemother 2004;48:3498-507.|
|25||Colonno RJ, Rose RE, Baldick CJ, Levine SM, Klesczewski K, Tenney DJ. High barrier to resistance results in no emergence of entecavir resistance in nucleoside naοve subjects during the first two years of therapy. J Hepatol 2006;44:S182.|
|26||Colonno RJ, Rose RE, Levine SM, Baldick CJ, Pokornowski K, Plym M, et al . Entecavir two year resistance update: No resistance observed in nucleoside naοve patients and low frequency resistance emergence in lamivudine refractory patients. Hepatology 2005;42:573A.|
|27||Wilber R, Brett-Smith H, Zhu J, Mencarini K, Colonno R, Cross A, et al . Entecavir vs adefovir: HBV DNA reduction in chronically infected HBeAg(+) nucleoside-naοve adults in a 12-week viral kinetics study. National Institutes of Health Workshop on Management of Hepatitis B 2006.|
|28||Shakil AO, Lilly L, Angus P, Gerken G, Thomas N, Jean M, et al . Entecavir significantly reduces viral load in liver transplant recipients failing lamunivudine therapy for HBV. J Hepatol 2002;36:122.|
|29||Pessoa MG, Huang A, Nelson M, Cassetti L, Correa M, Miro JM, et al . Entecavir in HIV-HBV co-infection: Week 48 results. Interscience Conference on Antimicrobials Agents and Chemotherapy 2005.|