| Abstract|| |
The currently available options for the treatment of chronic hepatitis B virus (HBV) infection include standard and pegylated interferon alfa and four oral antiviral agents (lamivudine, adefovir, entecavir, and telbivudine). These treatment strategies are either therapies of finite duration which aim to achieve sustained off-therapy responses or long term treatments that aim to maintain on-therapy remission. Most agents designed to target hepatitis B are hindered by the development of resistance, poor tolerability or limited efficacy; therefore, new agents and treatment strategies are needed. Pegylated interferon alfa may offer higher sustained off-therapy responses after one year, but most patients do not respond. Oral antivirals are the only candidates for long term treatment of patients with chronic HBV infection. Viral suppression has favorable effects on outcome outcome and modifies the natural history of the disease. The oral nucleos(t)ide analogues are generally better tolerated than interferon. This article attempts to provide an overview of the data available on the two new drugs entecavir and telbivudine.
Keywords: Chronic hepatitis B, drug resistance, entecavir, epidemiology, HBeAg, HBV DNA, hepatitis B virus, lamivudine, nucleoside analogue, seroconversion, telbivudine.
|How to cite this article:|
Singh SP. Comparison of entecavir and telbivudine in management of chronic Hepatitis B. Hep B Annual 2008;5:134-45
| Introduction|| |
Chronic hepatitis B (CHB) is caused by persistent infection with hepatitis B virus (HBV). Chronic infection with HBV accounts for an enormous burden of disease worldwide, including up to half of all cases of cirrhosis, end-stage liver disease, and hepatocellular carcinoma.  India belongs to the group of intermediate endemicity countries, with nearly three to four per cent of the population infected by the virus; besides, chronic hepatitis B constitutes more than 50% of the chronic hepatitis cases in the country.  With the development of newer antiviral drugs, hepatitis B infection is now being considered a treatable disease and the use of nucleot(s)ide analogues is a milestone in the treatment of CHB. The FDA of the USA approved the use of lamivudine in adult patients in 1998, adefovir dipivoxil in 2002, and entecavir in March 2005;  most recently, telbivudine.
The efficacy of lamivudine, the first nucleoside analogue used, is limited by the high rate of resistance. Adefovir has efficacy comparable to that of lamivudine but with low resistance rate. Entecavir has been particularly active in the control of hepatitis B virus replication and is associated with minimal resistance development, even during long treatment regimens.  Telbivudine has demonstrated potent activity against HBV in phase III clinical studies, with good tolerance, lack of mitochondrial toxicity and no dose-limiting side effects.  Telbivudine has not been compared directly with entecavir. However, in separate trials, both telbivudine and entecavir have shown greater antiviral effects than have adefovir and lamivudine.  In this review we will look at the efficacy and safety of the two nucleot(s)ide analogues, entecavir and telbivudine.
| Entecavir|| |
Entecavir, a new guanosine nucleoside analogue with specific activity against HBV DNA polymerase, is the third agent in the nucleoside/nucleotide HBV polymerase inhibitor class. It has distinct advantages over lamivudine and adefovir dipivoxil: it has a three-step mechanism of action, is the most potent inhibitor of HBV DNA polymerase, is not associated with any major adverse effects and has a limited potential for resistance.  Preclinical studies in Woodchucks demonstrated the antiviral activity of entecavir and its potential to reduce the incidence of hepatocellular carcinoma (HCC) and improve survival. 
In a randomized phase 2 trial in HBeAg-positive and HBeAg-negative patients who had not previously received a nucleoside analogue, entecavir at a dose of 0.5 mg once, daily, resulted in a significantly greater mean reduction in HBV DNA at 22 weeks than did lamivudine at a dose of 100 mg once daily (4.72 vs. 3.36 log copies per milliliter, P less than 0.001).  In patients treated with entecavir 0.5 mg/day, 83.7% had an HBV-DNA level below the lower limit of detection of the Quantiplex branched DNA (bDNA) assay, compared with 57.5% treated with 100 mg/day lamivudine (P = 0.008). 
A randomized, dose-ranging, phase 2 study compared the efficacy and safety of entecavir with lamivudine in lamivudine-refractory patients. In HBeAg-positive and HBeAg-negative lamivudine-refractory patients, treatment with entecavir was well tolerated and resulted in significant reductions in HBV DNA levels and normalization of alanine aminotransferase levels.  Entecavir has been compared to lamivudine in both HBeAg-positive and HBeAg-negative patients. ,
| HBeAg- Positive Patients|| |
In a double-blind, randomized phase 3 study of HBeAg-positive patients who had not previously received a nucleoside analogue, entecavir resulted in significantly higher rates of histologic, virologic, and biochemical improvement than did lamivudine, with a similar safety profile [Table 1].  Histologic improvement after 48 weeks occurred in 226 of 314 patients in the entecavir group (72%) and 195 of 314 patients in the lamivudine group (62%, P is equal to 0.009). More patients in the entecavir group than in the lamivudine group had undetectable serum HBV DNA levels according to a polymerase-chain-reaction assay (67% vs. 36%, P less than 0.001) and normalization of alanine aminotransferase levels (68% vs. 60%, P is equal to 0.02). The mean reduction in serum HBV DNA from baseline to week 48 was greater with entecavir than with lamivudine (6.9 vs. 5.4 log [on a base-10 scale] copies per milliliter, P less than 0.001). HBeAg seroconversion occurred in 21% of entecavir-treated patients and 18% of those treated with lamivudine (P is equal to 0.33). No viral resistance to entecavir was detected. Safety levels were similar in both the two groups. 
The results of follow-up of these patients for 96 weeks have recently been published  [Table 2]. Higher proportions of entecavir-treated than lamivudine-treated patients achieved cumulative confirmed HBV DNA less than 300 copies/mL by PCR (80% vs. 39%; P < 0.0001) and ALT normalization (87% vs. 79%; P = 0.0056) through 96 weeks. cumulative confirmed HBeAg seroconversion occurred in 31% of entecavir-treated versus 25% of lamivudine-treated patients (P = NS). Through 96 weeks, no patient experienced virologic breakthrough due to entecavir resistance. The safety profile was comparable in both groups. 
| HBeAg- Negative Patients|| |
In a phase 3, double-blind trial, 648 patients with HBeAg negative chronic hepatitis B who had not previously been treated with a nucleoside analogue were randomly assigned to receive 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks. Histologic improvement after 48 weeks of treatment occurred in 208 of 296 patients in the entecavir group which had adequate baseline liver-biopsy specimens that could be evaluated (70%), as compared with 174 of 287 such patients in the lamivudine group (61%, P = 0.01). More patients in the entecavir group than in the lamivudine group had undetectable serum hepatitis B virus (HBV) DNA levels according to a polymerase-chain-reaction assay (90% vs. 72%, P < 0.001) and normalization of alanine aminotransferase levels (78% vs. 71%, P = 0.045) [Table 3]. The mean reduction in serum HBV DNA levels from baseline to week 48 was greater with entecavir than with lamivudine (5.0 vs. 4.5 log [on a base-10 scale] copies per milliliter, P < 0.001). There was no evidence of resistance to entecavir. Safety and adverse-event profiles were similar for both groups. 
| Limitations/Concerns with Entecavir|| |
Entecavir has not been compared with adefovir in clinical trials. Its evaluation is based mainly versus lamivudine. In these trials, similar types and frequencies of adverse effects occurred with entecavir and lamivudine, mainly consisting of headache (about 20% of patients) and other neurological disorders. Hepatitis rebound occurred in less than 10% of patients during or after both treatments but at slightly different times. Entecavir was carcinogenic in experimental animals. No increase in the frequency of cancer has been seen in clinical trial participants thus far, but follow-up is limited. 
| Telbivudine|| |
Telbivudine (β-l-2'-deoxythymidine) is an orally bioavailable l-nucleoside with potent and specific anti-HBV activity. The phosphorylated metabolite of telbivudine interacts with the viral polymerase and inhibits viral replication and results in obligate chain termination of DNA synthesis. This inhibition mainly occurs in the step of synthesis of the second strand DNA (DNA-to-DNA transcription) for telbivudine (in contrast to lamivudine which strongly inhibited first strand DNA synthesis; RNA-to-DNA reverse transcription). Since the transcription fidelity is higher in the step of DNA-to-DNA synthesis than RNA-to-DNA synthesis, telbivudine treatment may have a slower rate of emergence of drug-resistant virus when compared to lamivudine. 
In preclinical toxicologic testing, telbivudine had no mutagenic or carcinogenic effects and no appreciable embryonic or fetal toxic effects - findings that are particularly relevant for men and women in their reproductive years.  It is the only available nucleoside agent with pregnancy category B label from FDA.
| Comparison with Lamivudine|| |
In initial clinical trials, treatment with telbivudine led to reductions in serum HBV DNA levels that were greater than those observed with lamivudine, and resistance to telbivudine developed less frequently than did resistance to lamivudine.  At week 52, telbivudine monotherapy showed a significantly (P < 0.05 for each comparison) greater mean reduction in HBV DNA levels, clearance of polymerase chain reaction-detectable HBV DNA, and normalization of alanine aminotransferase (ALT) levels compared with lamivudine monotherapy, with proportionally greater HBeAg seroconversion and less viral breakthrough.  This study also examined the prognostic significance of the magnitude of HBV DNA reduction at week 24 during therapy. For patients with HBV DNA less than three log at week 24 none developed viral breakthrough at week 52. More importantly, 100% of these patients had undetectable HBV DNA by PCR assay at week 52.
A phase 3 trial, designated Globe, compared the safety and efficacy of treatment with telbivudine with that of lamivudine, the most widely prescribed anti-hepatitis B agent worldwide, in 1370 patients with chronic hepatitis B. Patients with hepatitis B e antigen (HbeAg) positive chronic hepatitis B and those with HbeAg negative chronic hepatitis B were evaluated to assess differences in therapeutic outcomes that may arise as a result of well-recognized differences in disease characteristics. Associations between early suppression of HBV replication and subsequent efficacy and resistance outcomes were assessed. 
At week 52, a significantly higher proportion of HBeAg-positive patients receiving telbivudine than of those receiving lamivudine had a therapeutic response (75.3% vs. 67.0%, P = 0.005) or a histologic response (64.7% vs. 56.3%, P = 0.01); telbivudine also was not inferior to lamivudine for these end points in HBeAg-negative patients. In HBeAg-positive and HBeAg-negative patients, telbivudine was superior to lamivudine with respect to the mean reduction in the number of copies of HBV DNA from baseline, the proportion of patients with a reduction in HBV DNA to levels undetectable by polymerase-chain-reaction assay, and development of resistance to the drug [Table 4]. Elevated creatine kinase levels were more common in patients who received telbivudine but were not predictive of muscle-related adverse events, whereas elevated alanine aminotransferase and aspartate aminotransferase levels were more common in those who received lamivudine. 
Among patients with HBeAg-positive chronic hepatitis B, the rates of therapeutic and histologic response at one year were significantly higher in patients treated with telbivudine than in patients treated with lamivudine. In both the HBeAg-negative and the HBeAg-positive groups, telbivudine demonstrated greater HBV DNA suppression with less resistance than did lamivudine. 
The two-year results of this study  were presented at the AASLD annual meeting at Boston. At two years telbivudine showed significantly greater therapeutic response, a greater reduction in HBV DNA from baseline and greater HBV DNA clearance to PCR negative [Table 5].
Telbivudine showed significantly less primary and secondary failure, breakthrough and resistance. Clinical adverse event profiles were similar between the two treatment groups. Both study drugs were generally well-tolerated, with similar patterns of clinical adverse events. Clinical and virological efficacy at two years was also linked to magnitude of HBV suppression at week 24. 
| Comparison with Adefovir|| |
A major phase III study has compared the use of telbivudine and adefovir in HBeAg positive individuals with CHB for 24 weeks.  At the end of the study, a significantly greater HBV DNA reduction was seen in those individuals exposed to telbivudine (6.37 vs 5.11 log 10 copies/mL; P < 0.01). In individuals exposed to adefovir, 42% failed to reach a HBV DNA below five log 10 copies/mL, compared with five per cent in the telbivudine arm (P < 0.01). There was no significant difference in HBeAg loss or normalization of ALT levels between the two arms. There was no difference in adverse events between both the arms. 
| Comparison with Entecavir|| |
There is no study directly comparing the efficacy of telbivudine with entecavir. However, if we look at the data available from their individual studies, the therapeutic efficacy of both the drugs seems to be similar [Table 1],[Table 2],[Table 3],[Table 4]. However, certain limitations in the study methodology present challenges in interpreting the results obtained with entecavir. The specified response criteria that led to treatment discontinuation in the entecavir study were selected more than five years ago and no longer reflect current practice. During the conduct of this study, the bDNA assay was replaced by PCR assays. Also, the use of HBeAg loss rather than seroconversion and the absence of a period of consolidation treatment before discontinuation were less stringent criteria than in current practice. 
Further, the study design of the entecavir pivotal trials has been a subject of debate, predominantly related to the cohort of patients who were categorized as "nonresponders" at week 48 based on serum HBV DNA greater than or equal to 0.7 MEq/mL (~140,000 IU/mL) and discontinued therapy per protocol.  After week 52, it is not possible to provide an assessment in which all patients who originally started treatment are accounted for at a single time point under uniform treatment conditions. This design has been felt to underestimate the potential of entecavir therapy to result in the selection of antiviral drug-resistant mutants because therapy was not continued in these subjects.  Therefore, the results from this study cannot be compared directly with other studies that evaluate continuous treatment in all patients through two years, regardless of clinical course (e.g., Globe study with telbivudine).
| Conclusion|| |
The ultimate goal in managing patients with CHB is to improve long-term outcomes by decreasing deaths and liver transplantation procedures due to HBV-related cirrhosis and hepatocellular carcinoma. Active intervention and vaccination of individuals susceptible to HBV infection are key steps to decrease the risk of this global public health problem. First-line therapeutic regimens for the management of HBV infection include monotherapy with a U.S. Food and Drug Administration-approved agent that has potent on-treatment viral response and low rates of resistance. New oral treatments, characterized by potent antiviral effects, good tolerability, improved histology, stable seroconversion, and minimal resistance, are available. Long term data with oral medications have shown decreased rates of liver cancer development, liver disease reversal, and progression to liver failure. The efficacy of lamivudine, the first nucleoside analogue used, is limited by the high rate of resistance. Adefovir has efficacy comparable to that of lamivudine, but with low resistance rate. Entecavir has also been particularly active in the control of hepatitis B virus replication and is associated with minimal resistance development, even during long treatment regimens. Newer drugs such as entecavir and telbivudine hold the promise of better treatment options in the near future, and direct head to head studies are needed to provide more information on which of these is superior.
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Shivaram Prasad Singh
Department of Gastroenterology, S.C.B. Medical College, Cuttack - 753 007
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]