| Abstract|| |
The last five years have emerged as a new era in the treatment of chronic hepatitis B (CHB). Advances in therapeutics and the approval of new drugs have been accompanied by a better understanding of the natural history and pathogenesis, as well as better diagnostics. In the treatment of CHB, no therapy has been proven to eradicate the virus completely from the human body due to the persistence of the covalently closed circular hepatitis B virus (HBV) DNA in the hepatocytes. Long-term maximal viral suppression is of utmost importance for the prevention of disease progression and hepatocellular cirrhosis development.
Telbivudine is one of the more potent options, with phase III studies indicating its antiviral potency with 6- to 6.5-log 10 copies / mL reductions in HBV DNA levels at year one, comparable to other potent agents such as entecavir or tenofovir. The increasing rates of hepatitis B e antigen (HBeAg) seroconversion were achieved in HBeAg-positive patients during periods of up to four years of continuous telbivudine treatment, and seroconversion was durable in most patients throughout a two-year, off-treatment follow-up, indicating the potential for a finite treatment period in this group of patients. Long-term telbivudine treatment offers effective viral suppression to CHB patients, with certain baseline characteristics and on-treatment virological response. It is also one of the few drugs in the treatment of CHB under FDA pregnancy Category B. Telbivudine is well-tolerated, with elevations in creatine phosphokinase being the most common abnormality observed in the clinical trials. Most often, elevations have been asymptomatic.
There are few new drugs for hepatitis B in the pipeline, with the agent farthest along in development, clevudine, halted for problems with muscle toxicity. Future research in hepatitis B will focus on the best ways to use the existing therapies, including telbivudine, sequentially or in combination, in order to maximize viral suppression and minimize the development of antiviral resistance.
Keywords: Epidemiology, familial, hepatitis B surface antigen, hepatitis B virus, prevention and control, transmission
|How to cite this article:|
Singh SP, Lawate P. Telbivudine: A valuable treatment option in chronic hepatitis B. Hep B Annual 2011;8:84-106
| Introduction|| |
Chronic HBV infection is a serious clinical problem because of its worldwide distribution and potential adverse sequelae. Chronic hepatitis B (CHB) affects nearly 350 million people worldwide, with prevalence varying geographically, from > 8% in areas of endemicity such as Asia and Sub-Saharan Africa to < 1% in Western countries.  It is the leading cause of hepatocellular carcinoma (HCC),  present in 53% of the cases. Chronic infection with hepatitis B can also lead to cirrhosis and its complications.
In India, hepatitis B surface antigen (HBsAg) prevalence among the general population ranges from 2 to 8%, placing India in the intermediate HBV endemicity zone, and the number of HBV carriers is estimated to be 50 million, forming the second largest global pool of chronic HBV infections.  Re-evaluation of the data from a published meta-analysis on the prevalence of hepatitis B in India, using weights proportional to the size of the population, was done.  The overall country prevalence was shown to be 3.70 (CI: 3.17-4.24) (corresponding to a chronic carrier rate of 2.96%).  Earlier studies have shown that the prevalence ranges from 1.1 to 12.2%, with maximum incidence in Madhya Pradesh, Arunachal Pradesh, and South India, and the least in Kashmir and Kerala.  There is peak prevalence after the second decade of life. Most (90%) of these HBV-infected subjects are HBeAg-negative; the majority (80%) have normal ALT.  The prevalence of HBeAg among asymptomatic HBsAg-positive persons varies from 9-20%. ,
| Treatment options for chronic hepatitis B|| |
The course of CHB varies between individuals and will depend on the host and viral factors, as well as the efficacy of treatment strategies. In endemic areas, such as Asia, the hepatitis B virus (HBV) is most commonly acquired in the perinatal period or during early childhood. The immune tolerance and immune clearance phases are prolonged.  Eventually, the infection will progress to a hepatic phase, which is characterized by inflammation and liver fibrosis. 
Patients with CHB present as either hepatitis B e antigen (HBeAg)-positive or -negative. HBeAg-positive disease results from infection with wild-type HBV, which typically represents the early phase of infection, whereas, HBeAg-negative disease results from the emergence of nucleotide substitutions in the precore and / or basic core promoter regions of the genome, and typically represent a later and more severe phase of the disease.  The prevalence of HBeAg-positive or -negative disease varies geographically, with relatively higher proportions of patients with HBeAg-positive disease in endemic areas such as Asia-Pacific, than in the EU, where patients are predominantly HBeAg-negative. 
Hepatitis B therapy cannot cure infection and has not been shown to improve mortality or development of HCC, although in theory, the reduction of viral replication and amelioration of hepatic inflammation should decrease the likelihood of progression to the complications of hepatitis B. The efficacy of hepatitis B therapies are therefore measured by such surrogate endpoints as HBV DNA suppression, normalization of biochemical markers (alanine aminotransferase [ALT], aspartate aminotransferase [AST]), loss of HBeAg and seroconversion to hepatitis B e antibody (anti-HBe), and loss of HBsAg. 
The two classes of agents for CHB treatment currently available are immunomodulatory therapy and the nucleoside / nucleotide analogs (NA). The former includes conventional interferon (IFN) and pegylated interferon (PEG IFN)-α2a and -α2b . These agents are to be used with a finite duration of therapy. However, the side effects are poorly tolerated, and long-term benefits, in terms of lower incidence of cirrhosis complications and HCC, in Asian patients, are controversial. ,, The five approved oral NAs for the treatment of CHB include lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate.  NAs are potent antivirals that are well-tolerated and are administered orally. Relative disadvantages of these agents are an indefinite duration of treatment, risk of resistance, and lower rates of HBe and HBs seroconversion. 
Guidance with regard to which HBV-infected patients to treat and when to start is fairly consistent across the current treatment guidelines and is based on viral loads, HBeAg status, serum ALT levels, and liver biopsy findings. ,, Similarly, the endpoints of therapy and definitions of response are in general agreement with the current guidelines. ,, Therapy must reduce HBV DNA levels as effectively as possible, with a target of below the lower limit of detection (< 300 copies / mL) using the real time PCR assay. This degree of virological suppression will achieve biochemical (mainly based on serum ALT levels) and histological remission, as well as reduce the risk of complications and antiviral resistance.  HBeAg seroconversion of HBeAg-positive patients to anti-HBe is also an important endpoint, as studies have shown that seroconversion leads to improved outcomes, including a sustained reduction in HBV DNA levels and a higher incidence of complication-free survival. , Seroconversion of HBeAg also appears to lead to HBsAg clearance, which is the marker most closely associated with a 'cure'. Furthermore, early, as opposed to delayed seroconversion is associated with an improved prognosis. 
Selecting the optimum therapy for an individual patient can be a complex process because of the number of options that exist. ,, Choice of therapy is likely to depend on several factors, including drug efficacy, probability of sustained response, severity of liver disease, patient age, adverse events, associated resistance rates, and route of administration. , In reference to these parameters we would like to highlight the effective and sustained viral suppression with telbivudine, in patients with CHB.
| Telbivudine|| |
Telbivudine (β-L-2-deoxythymidine) is a β-L-nucleoside analog of thymidine that impairs the hepatitis B virus (HBV) DNA replication by leading to chain termination. It differs from the natural nucleotide only with respect to the location of the sugar and base moieties, taking on a levorotatory configuration versus a dextrorotatory configuration, as do the natural deoxynucleosides. 
Telbivudine is rapidly absorbed after oral administration, reaching peak plasma concentration from 0.8 to 3 hours.  The long intracellular half-life of 14 hours allows for once daily dosing. Oral absorption is not affected by food intake, and therefore, can be administered orally with no regard to the timing of meals. It is predominantly excreted unchanged by passive diffusion in the kidneys. For patients with moderate-to-severe renal impairment (creatinine clearance < 50 ml / minute), dose adjustment is required, which is done by extending the dosing interval accordingly to every two, three or four days.  It should be given after hemodialysis. Its pharmacokinetics is not affected in patients with hepatic impairment and so no dosage modifications are required in these patients. 
| Clinical efficacy of telbivudine|| |
The approval of telbivudine was based on several large, double-blind, multicenter, randomized studies and comparing it with other approved hepatitis B agents. These include two pivotal, two-year, phase III studies (GLOBE , and 015 , ) that compared telbivudine with lamivudine, as well as an extension (study 2303) of patients from both trials, for periods of up to four years. ,,, A number of other studies will also be discussed in this section.
The phase III international GLOBE trial enrolled 1370 HBeAg-positive and HBeAg-negative antiviral-naοve subjects and randomized them to receive either 600 mg of telbivudine or 100 mg of lamivudine once daily.  In the GLOBE trial, the primary outcome was a 'therapeutic response,' which was defined as a decrease in the HBV DNA level to < 5 log 10 copies / mL along with either a loss of HBeAg or ALT normalization. Secondary outcomes were, the histological response, change in HBV DNA levels, HBeAg loss, HBsAg loss, HBeAg seroconversion, HBsAg seroconversion, and normalization of ALT. The authors also looked for a virological breakthrough, defined as a > 1 log 10 copies / mL increase in HBV DNA over the nadir. Treatment-emergent resistance mutations were screened for anyone with virological breakthrough as well as those with detectable HBV DNA at pre-specified timepoints. 
The GLOBE study included 683 patients randomized to receive telbivudine (458 HBeAg-positive and 222 HBeAg-negative) and 687 patients randomized to receive lamivudine (463 HBeAg-positive and 224 HBeAg-negative). Results through year two are summarized in [Table 1]. In this study, telbivudine showed a more potent HBV DNA reduction at one year compared to lamivudine, in both HBeAg-positive and HBeAg-negative patients, with an average drop of -6.45 log 10 copies / mL drop in HBeAg-positive patients and -5.23 log 10 copies / mL in HBeAg-negative patients, in the telbivudine groups, nearly a full log over the changes in the lamivudine groups. The mean time to HBV DNA negativity was also shorter with telbivudine, 34 weeks versus 39 weeks with lamivudine in HBeAg-positive (P < 0.001) and 20 weeks versus 26 weeks with lamivudine in HBeAg-negative (P < 0.001).  Telbivudine also outperformed lamivudine in therapeutic response, with 75 to 85% HBeAg-positive patients and 63 to 71% HBeAg-negative patients experiencing this endpoint. Primary treatment failure (failure of treatment to suppress HBV DNA to < 5 log 10 copies / mL) seems to be rare with telbivudine, occurring in < 5% of the study subjects.
|Table 1: Results of the phase III GLOBE trial comparing telbivudine 600 mg daily to lamivudine 100 mg daily in nucleoside-naïve hepatitis B e-antigen positive and e-antigen negative subjects12 |
Click here to view
After one year of telbivudine, the HBeAg loss rates and HBeAg seroconversion rates were no different from lamivudine. By year two, however, telbivudine gained a slight, although not a statistically significant advantage. ALT normalization occurred commonly with telbivudine and lamivudine in both HBeAg-positive and HBeAg-negative subjects. The favorable effect on ALT, a marker of inflammation, was also mirrored by improvements in histology on paired liver biopsies at baseline and one year, which were seen in 65 to 66% of the telbivudine-treated patients, significantly more than the proportion of HBeAg-positive patients treated with lamivudine, with a histological response 56%, (P = 0.01). 
The smaller study 015 completed in China, randomized 147 HBeAg-positive and 20 HBeAg-negative patients to telbivudine and 143 HBeAg-positive and 22 HBeAg-negative patients to lamivudine. The results were strikingly similar to the results from the GLOBE study, indicating little ethnic variation in the efficacy of telbivudine. , HBV DNA reduction was -6.3 log 10 copies / mL in HBeAg-positive patients and -5.5 log 10 copies / mL in HBeAg-negative patients, again nearly a 1 log increase over the changes seen in lamivudine-treated patients, at one year. Telbivudine was associated with a higher rate of therapeutic response compared to lamivudine at years one and two (85 vs. 62%, P < 0.001 and 70 vs. 44%, P < 0.05, respectively). Telbivudine also outperformed lamivudine in terms of undetectable HBV DNA by PCR at years one and two (67 vs. 38%, P < 0.001 and 63 vs. 39%, P < 0.05, respectively). ,
Participants in both the GLOBE and 015 studies were offered participation in a phase IIIb extension study, offering two years additional treatment with continued monitoring of treatment responses. ,,, Results from the 2303 extension study demonstrated that telbivudine 600 mg once daily continued to provide effective viral suppression over the long term (up to four years) and the proportion of patients achieving HBeAg seroconversion increased continuously , [Table 2].
|Table 2: Long-term efficacy of telbivudine (LdT) in patients (pts) with compensated chronic hepatitis B virus infection |
Click here to view
Similar results to those demonstrated in the 2303 extension study were reported in extension phases of individual studies [Table 2]. , A preliminary efficacy analysis of the patients who received continuous telbivudine treatment for four years showed increasing rates of undetectable HBV DNA by PCR in both HBeAg-positive and HBeAg-negative patients (79 and 84%, respectively) and ALT normalization (86 and 91%, respectively). 
Chinese CHB patients included previously in study A2303 with undetectable HBV DNA (< 300 copies / ml) for ≥ 12 months were enrolled in the ACN04 study and followed for 52 weeks. Efficacy and safety at year five was analyzed. A virological breakthrough was defined as an increase in serum HBV DNA by > 1 log above nadir. 
After five years of telbivudine treatment, 93.65% of HBeAg-positive patients and 96.43% of HBeAg-negative patients maintained undetectable HBV DNA. ALT normalization was achieved in 84.6 and 79.3% of HBeAg-positive and HBeAg-negative patients, respectively. Virological breakthrough was observed in 4.84 and 3.57% of HBeAg-positive and HBeAg-negative patients, respectively; 45.31% of the patients achieved HBeAg seroconversion at year five, and the cumulative HBeAg seroconversion rate over five years was 67.16%. 
Efficacy versus adefovir
Telbivudine has also been compared to adefovir in one trial in HBeAg-positive patients.  In this randomized, controlled, open-label study telbivudine 600 mg daily for 52 weeks was compared to adefovir 10 mg daily for 52 weeks; or 24 weeks of adefovir followed by 28 weeks of telbivudine, with approximately 45 patients randomized to each group [Table 3].
|Table 3: Clinical efficacy of telbivudine (LdT) compared with adefovir (ADV) in hepatitis B e antigen (HBeAg)-positive patients (pts) with compensated chronic hepatitis B virus (HBV) infection |
Click here to view
At 24 weeks, the mean log 10 HBV DNA reductions were - 6.30 versus - 4.97 copies / ml, P < 0.001 for the telbivudine and adefovir groups, respectively. The telbivudine group was associated with a higher rate of undetectable HBV DNA than the adefovir group (39 vs. 12%, respectively, P = 0.001). At 52 weeks, the mean log 10 HBV DNA reductions from baseline were - 6.56 versus - 5.99 copies / ml, respectively (P = 0.012)  [Table 3].
There was also a much higher primary failure rate in both adefovir groups (29% in the adefovir only group, 11% among the adefovir to telbivudine group, and 2% in the telbivudine only group), which was statistically significant. This was consistent with the prior data confirming the suboptimal antiviral activity of adefovir against hepatitis B and its relative lack of potency compared to other available hepatitis B agents. 
Efficacy versus entecavir
The early antiviral efficacy of telbivudine 600 mg once daily was compared with that of entecavir 0.5 mg once daily in a randomized, open-label, 24-week trial, in HBeAg-positive treatment-naοve adults (n = 131).  Both agents caused rapid and effective viral suppression, with a mean reduction in serum HBV DNA levels at week 24 (primary endpoint) of 6.0 log 10 copies / mL in the telbivudine group versus 5.8 log10 copies / mL in the entecavir group. HBeAg seroconversion rates at week 24 in the corresponding groups were 24.6% versus 13.6%. 
Predictors of response
The predictive value of both baseline factors and early on-treatment virological and biochemical responses have now been analyzed for most of the approved medications except for standard interferon. Although most of these data have been accumulated through small pilot studies or retrospective analyses, the most comprehensive data have been collected prospectively during the GLOBE study, which represents the largest study to date, of antiviral therapy against chronic hepatitis B. 
A multivariate logistic regression analysis of the intent-to-treat population of telbivudine-treated patients in the GLOBE trial included all pretreatment patient characteristics and early (week 12 or 24) on-treatment responses, and evaluated their impact alone and together, to identify the predictors of response for telbivudine treatment outcomes at two years.  The baseline predictors of favorable virological outcomes in HBeAg-positive patients treated with telbivudine were HBV DNA < 9 log 10 copies / mL and serum ALT levels ≥ 2 x the ULN.
In HBeAg-negative patients there was a trend for higher rates of efficacy and lower resistance at two years in patients with baseline HBV DNA < 7 log 10 copies / mL. 
The week 24 HBV DNA levels remained a strong predictor of virological response throughout the third and fourth years of telbivudine treatment, as demonstrated in patients enrolled in the extension of the GLOBE trial.  For example, after four years of telbivudine treatment in patients in the GLOBE extension, more patients who had achieved undetectable serum HBV DNA at treatment week 24 maintained undetectable serum HBV DNA (92% vs. 79% of HBeAg-positive patients and 86% vs. 84% of HBeAg-negative patients) and HBeAg seroconversion (51% vs. 42%) than patients in the total HBeAg-positive or -negative patient populations. 
The course of chronic HBV infection involves complex interactions between the virus, hepatocytes, and the host's immune response. Studies have shown that the clearance of HBV DNA, one of the primary goals of the therapy, is dependent on the T-cell response as well as on the humoral immune response. Based on the current understanding of the host-virus interactions and the natural course of HBV infection, management strategies have focused on enhancement of the host's HBV-specific T-cell response and direct suppression of HBV replication, to attain sustained viral control and remission of liver disease. Of the currently available anti-HBV therapies, only interferon (IFN)-α and pegylated IFN- α have demonstrated an immunomodulatory effect on HBV.  The relatively high HBeAg seroconversion rate attained with telbivudine differs from the rates obtained with other potent anti-HBV agents and suggests that telbivudine has potentially immunomodulatory activities. 
A study characterized the effects of telbivudine on the cytokine profile and T-cell response in vitro and in vivo using a previously characterized mouse model of viral hepatitis, induced by the coronavirus mouse hepatitis virus strain 3 (MHV-3). The results showed that telbivudine had immunomodulatory effects both in vitro and in vivo, independent of its potent antiviral activity. 
Telbivudine has had no inhibitory effects on the replication of MHV-3 in the macrophages. This finding is consistent with the fact that telbivudine is highly selective for HBV and lacks activity against other viruses. In the in vitro study telbivudine treatment has been associated with a significant (p < 0.01) increase in the production of tumour necrosis factor-α (TNF α) and interleukin (IL)-12, when compared with the control treatment. In the in vivo study in MHV- 3-infected C3H mice, telbivudine treatment has promoted the production of interferon-g and has been associated with increased survival and reduced histological lesions. In contrast, the serum IL-4 levels are significantly (P < 0.01) decreased compared with the control levels, following telbivudine treatment. Furthermore, telbivudine treatment increases the ability of the T cells to undergo proliferation and secrete cytokines, but has no effect on the cytolytic function of the T cells.  These results demonstrate the immunomodulatory properties of telbivudine, independent of its antiviral activity.
Predictability of HBsAg clearance
HBsAg clearance is considered the ultimate goal in the treatment of patients with CHB, because several studies have established that spontaneous or treatment-induced HBsAg loss is associated with sustained disease remission and improved survival. Recent data indicate that quantitation of serum HBsAg during therapy, with pegylated interferon, may be useful in predicting the likelihood of HBsAg loss. 
The information regarding HBsAg kinetics during treatment with direct antiviral agents is limited. The nucleoside / nucleotide analogs are potent inhibitors of HBV replication, targeting the HBV polymerase without a direct effect on HBsAg transcription and translation. Thus, HBsAg loss during treatment with these agents can occur only after a prolonged period of inhibition of HBV replication, with undetectable serum HBV DNA and HBeAg clearance. 
In 162 HBeAg-positive patients, with undetectable serum HBV DNA by PCR, after two years of telbivudine treatment in the GLOBE trial, nine lost HBsAg at three years, and of these nine, eight (89%) experienced a rapid decline (≥1 log10 IU / mL) in HBsAg levels during the first year of telbivudine therapy.  The study showed that rapid on-treatment declines in HBsAg levels, occurring up to week 24, by year one were associated with future HBsAg clearance. In patients with subsequent HBsAg loss, viral antigens were already undetectable in liver biopsy samples after one year of treatment. This was associated with markedly enhanced antiviral T cell reactivity. 
In another study in Chinese patients, the serum HBsAg levels of < 2 log 10 copies / mL, after two years' of treatment with telbivudine 600 mg once daily, were highly predictive of a sustained virological response at two years of treatment. 
| Safety of Telbivudine|| |
Because of its specificity for hepatitis B and selectivity for the viral polymerase rather than the host cellular polymerase, there are few adverse effects associated with the use of telbivudine.  In the phase III GLOBE and study 015, there were no serious adverse events that led to drug discontinuation or death. ,
In the GLOBE study, telbivudine had a similar safety and tolerability profile compared to lamivudine, with the exception of creatine phosphokinase (CPK) elevation. The frequency of adverse events through week 104 was similar for both medications. Most were constitutional symptoms, mild, transient, and not attributed to the study drug. Four percent of the patients in both the telbivudine (n = 680) and lamivudine groups (n = 687) had adverse events leading to treatment interruption or discontinuation in the 104-week period. 
In both these studies, elevations in the CPK were seen more frequently and were higher than in those subjects receiving lamivudine. Grade 3 / 4 CPK elevations occurred in 12.9% of telbivudine subjects versus 4.1% of lamivudine patients in the GLOBE trial (P < 0.001), after a mean period of 56.9 weeks to the first elevation.  In most cases, the elevations in CPK were not correlated with musculoskeletal symptoms, and were transient, resolving with the next laboratory check. Grade 3 / 4 elevations in CPK were also seen with more frequency in the telbivudine group in study 015 (8.4% vs. 3.0% in the lamivudine group), but this did not reach statistical significance (P = 0.06). 
Tolerability analyses performed after 3 , and 4 , years of continuous telbivudine 600 mg once daily, demonstrated a similar profile to that observed after one or two years of treatment. In the 2303 extension study (n = 518), after four years' telbivudine treatment, myalgia was reported in 4.8% of the patients, and peripheral neuropathy (paraesthesia [0.8%], neuralgia [0.2%], polyneuropathy [0.2%], and sensory loss [0.2%]) in 1.4%.  New onset grade 3 / 4 CK elevation (usually transient) was observed in 15.6% of the patients, and 3.3% reported ALT flare. 
The risk of developing peripheral neuropathy-like symptoms during monotherapy with once daily telbivudine treatment was low, but increased when telbivudine was co-administered with peg interferon- α.  Results from the telbivudine global clinical safety database demonstrated that telbivudine monotherapy was associated with serious peripheral neuropathy in 0.45% (10 of 2200) of the patients after an average of 14 months' treatment, and was associated with non-serious peripheral neuropathy in 0.42% (5 of 1200) of the patients. In contrast, when telbivudine was co-administered with peg interferon-α-2a, 19% (9 of 48) of the patients reported serious peripheral neuropathy, with a mean time to onset of 4.5 months, and 17% (8 of 48) of the patients reported non-serious peripheral neuropathy. 
Safety in special populations
Chronic Hepatitis B in pregnancy presents a unique challenge, but also an important opportunity to interrupt the perinatal transmission of HBV. As maternal-fetal transmission is the major route of acquisition of HBV worldwide, strategies to eradicate HBV or to reduce the global burden of disease must target this critical step in HBV disease propagation. 
Data regarding the safety and efficacy of telbivudine in preventing perinatal transmission of HBV are emerging. The Food and Drug Administration (FDA) has classified telbivudine as category B medication. 
A placebo-controlled trial with telbivudine in 61 pregnant CHB patients was performed in China. Except for one patient who was enrolled in the telbivudine group at 12 weeks of gestation, the rest  enrolled in the telbivudine group at 28-32 weeks of gestation. Compared with the control group,  the mean HBV DNA was significantly lower in the telbivudine group before parturition. All newborns from both groups received hepatitis B immunoglobulin and HBV vaccination at zero, one, and six months of age. The HBsAg-positive rates of newborns at month seven were 0 versus 13.3% (4 / 30) in the telbivudine and control groups, respectively (P < 0.05). There was no adverse effect noted in any patient or the newborns. No birth defects were found in the newborns from telbivudine-treated patients. 
Pan et al. compared the outcomes in 53 HBeAg-positive mothers treated with telbivudine from the second to the third trimester until four weeks post-partum, with 35 untreated control patients. In this study, baseline HBV DNA was > 6 log copies / mL and ALT >40 IU / mL, but less than 10 X upper limit of normal. All infants received active and passive immunization. At birth, 4 and 23% the newborns were HBsAg-positive in the telbivudine and control groups, respectively (P < 0.001). 
| Resistance|| |
The development of resistance to NA results from mutations in the polymerase gene. This is often followed by an increase in viral load and increase in serum ALT, several weeks to months later, and there may be progression of liver disease.
In the GLOBE study, telbivudine was shown to have less viral resistance compared to lamivudine at years one and two. In HBeAg-positive patients, the incidence of virological resistance with telbivudine was 5% at year one and 25.1% at year two compared to 11% at year one and 39.5% at year two with lamivudine (P < 0.001). In HBeAg-negative patients, the incidence of virological resistance with telbivudine was 2.2% at year one and 10.8% at year two compared to 10.7% at year one and 25.9% at year two with lamivudine (P < 0.001). , In the study 015, virological breakthrough was also found to be lower with telbivudine than with lamivudine at 48 weeks (7.5 vs. 17.5%, P = 0.009). 
In a further multivariate analyses of the GLOBE study data, in telbivudine-treated patients, the viral resistance rate at 104 weeks was 11.3% in HBeAg-positive patients with baseline HBV DNA < 9 log10 copies / ml, and 3.1% in HBeAg-negative patients with baseline HBV DNA < 7 log 10 copies / ml. Furthermore, the viral resistance rate at the end of 104 weeks was lower in patients with low HBV DNA at treatment week 12 or 24, being 6% for HBeAg-positive patients and 3% for HBeAg-negative patients when the serum HBV DNA at week 12 was PCR undetectable (< 300 copies / ml). 
| Conclusion|| |
The management of CHB has improved markedly in recent years with the introduction of potent antivirals that are able to be administered orally and have a generally favorable tolerability profile. Currently, drugs licensed globally for use in patients with CHB include the interferons (e.g., interferon-alfa and peg interferon-alfa), which have predominantly immunomodulatory effects, and the NAs (e.g., lamivudine, telbivudine, entecavir, adefovir, and tenofovir), which have predominantly antiviral effects. 
Selecting the optimum therapy for an individual patient can be a complex process because of the number of options that exist. Choice of the therapy is likely to depend on several factors, including drug efficacy, probability of sustained response, severity of liver disease, patient age, adverse events, associated resistance rates, and route of administration. In Asia-Pacific, which has the greatest disease burden compared with the rest of the world, the current first-line options recommended in the treatment guidelines for HBeAg-positive or -negative patients, without liver decompensation, include standard interferon, peg interferon-alfa, telbivudine, lamivudine, adefovir, and entecavir; adefovir is not recommended in patients with ALT levels > 5 X the ULN, because of its lower relative antiviral potency. 
Telbivudine is a potent antiviral that provides effective and sustained viral suppression in patients with compensated CHB. In clinical trials, treatment outcomes were improved significantly more with telbivudine 600 mg once daily than with lamivudine 100 mg or adefovir 10 mg once daily and telbivudine-treated patients had significantly less viral resistance than lamivudine-treated patients. Increasing rates of HBeAg seroconversion were achieved in HBeAg-positive patients during a periods of up to four years of continuous telbivudine treatment, and seroconversion was durable in most patients throughout a two-year, off-treatment follow-up, indicating the potential for a finite treatment period in this group of patients. Telbivudine is generally well-tolerated in clinical trials for periods of up to four years, and has a similar tolerability profile to that of lamivudine. A minority of telbivudine-treated patients experience CK elevation, usually transient, and myopathy occurs rarely. Thus, telbivudine is a valuable treatment option in CHB. 
| References|| |
Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 2004;11:97-107.
Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006;45:529-38.
Datta S. An overview of molecular epidemiology of hepatitis B virus (HBV) in India. Virol J 2008;5:156.
Batham A, Gupta MA, Rastogi P, Garg S, Sreenivas V, Puliyel JM. Calculating prevalence of hepatitis B in India: using population weights to look for publication bias in conventional meta-analysis. Indian J Pediatr 2009;76:1247-57.
Thyagrajan SP, Jayaram S, Hari R, Mohan KV, Murugavel KG. Epidemiology of hepatitis B in India - A comprehensive analysis. In: Sarin SK, Okuda K, editors. Hepatitis B and C carrier to cancer. 1 st
ed. New Delhi: Harcourt India Private Ltd; 2002. p. 25-39.
Tandon BN, Acharya SK, Tandon A. Epidemiology of hepatitis B virus infection in India. Gut 1996;38 Suppl 2:S56-9.
Chowdhury A, Santra A, Pal S, Chakravarty R, Banerji A, Pal S, et al
. Community based epidemiological study of Hepatitis B virus infection (HBV). Indian J Gastroenterol 2001;20Suppl 2:A2.
Lai CL, Yuen MF. The natural history of chronic hepatitis B. J Viral Hepat 2007;14(Suppl 1):6-10.
Cooke GS, Main J, Thursz MR. Treatment for hepatitis B. BMJ 2010;340:87-91.
EASL clinical practice guidelines: Management of chronic hepatitis B. J Hepatol 2009;50:227-42.
Berg T, Benhamou Y, Calleja JL, Levrero M, Johnson W, Ellis N. A survey of chronic hepatitis B patient management practices in the European Union. J Viral Hepat 2010;17:624-30.
Osborn MK. Safety and efficacy of telbivudine for the treatment of chronic hepatitis B. Ther Clin Risk Manag 2009;5:789-98.
Yuen MF, Hui CK, Cheng CC, Wu CH, Lai YP, Lai CL. Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: the effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications. Hepatology 2001;34:139-45.
Truong BX, Seo Y, Kato M, Hamano K, Ninomiya T, Katayama M, et al
. Long-term follow-up of Japanese patients with chronic hepatitis B treated with interferon-alpha. Int J Mol Med 2005;16:279-84.
Lin SM, Yu ML, Lee CM, Chien RN, Sheen IS, Chu CM, et al
. Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma. J Hepatol 2007;46:45-52.
But DY, Yuen MF, Fung J, Lai CL. Safety evaluation of telbivudine. Expert Opin Drug Saf 2010;9:821-9.
Lok AS, McMahon BJ. Chronic hepatitis B: Update 2009. Hepatology 2009;50:661-2.
Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, Han KH, et al
. Asian-Pacific consensus statement on the management of chronic hepatitis B: A 2008 update. Hepatol Int 2008;2:263-83.
Liaw YF, Lau GK, Kao JH, Gane E. Hepatitis B e antigen seroconversion: A critical event in chronic hepatitis B virus infection. Dig Dis Sci 2010;55:2727-34.
Chu CM, Liaw YF. Predictive factors for reactivation of hepatitis B following hepatitis B e antigen seroconversion in chronic hepatitis B. Gastroenterology 2007;133:1458-65.
Keeffe EB, Dieterich DT, Han SH, Jacobson IM, Martin P, Schiff ER, et al
. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol 2008;6:1315-41.
Standring DN, Bridges EG, Placidi L, Faraj A, Loi AG, Pierra C, et al
. Antiviral beta-L-nucleosides specific for hepatitis B virus infection. Antivir Chem Chemother 2001;12(Suppl 1):119-29.
Zhou XJ, Lim SD, Lloyd DM, Chao GC, Brown NA, Lai CL. Pharmacokinetics of telbivudine following oral administration of escalating single and multiple doses in patients with chronic hepatitis B virus infection: Pharmacodynamic implications. Antimicrob Agents Chemother 2006;50:874-9.
Zhou XJ, Swan S, Smith WB, Marbury TC, Dubuc-Patrick G, Chao GC, et al
. Pharmacokinetics of telbivudine in subjects with various degrees pf renal impairment. Antimicrob Agents Chemother 2007;51:4231-5.
Zhou XJ, Marbury TC, Alcorn HW, Smith WB, Dubuc Patrick G, Chao GC, et al
. Pharmacokinetics of telbivudine in subjects with various degrees of hepatic impairments. Antimicrob Agents Chemother 2006;50:1721-6.
Liaw YF, Gane E, Leung N, Zeuzem S, Wang Y, Lai CL, et al
. 2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology 2009;136:486-95.
Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, Wang Y, et al
. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med 2007;357:2576-88.
Hou J, Yin YK, Xu D, Tan D, Niu J, Zhou X, et al
. Telbivudine versus lamivudine in Chinese patients with chronic hepatitis B: Results at 1 year of a randomized, double-blind trial. Hepatology 2008;47:447-54.
Wang Y, Jia J, Hou J, Yin Y, Xu D, Tan D, et al
. A phase III comparative trial of telbivudine vs lamivudine in Chinese patients with chronic hepatitis b: two year results. Gastroenterol 2007;132 (4 Suppl 1):A-763.
Hsu CW, Chen YC, Liaw YF, Gane E, Manns M, Zeuzem S, et al
. Prolonged efficacy and safety of 3 years of continuous telbivudine treatment in pooled data from GLOBE and 015 studies in chronic hepatitis B patients. J Hepatol. 2009;50:S331. doi: 10.1016/S0168-8278(09)60913-2.
Chen YC, Hsu CW, Liaw YF, Jia J, Leung N, Hou J, et al
. Efficacy of 3 years of telbivudine treatment for patients with genotype B / C chronic hepatitis B J Hepatol. 2009;50:S329. doi: 10.1016/S0168-8278(09)60908-9.
Jia JD, Hou JL, Yin YK. Prolonged efficacy and safety of 3 years' continuous telbivudine treatment in Chinese chronic hepatitis B patients [abstract plus poster]. Hong Kong: 19th Asian Pacific Association for the Study of the Liver (APASL) Conference; 2009 Feb 13-16.
Ren H, Wang Y, Thongsawat S, Wan MB, Hou JL, Gane E, et al
. Telbivudine-induced HBeAg seroconversion in chronic hepatitis B (CHB) patients is durable during 2 years off-treatment follow-up. Hepatol Int 2010;4:145.
Jia JD, Gane E, Wang YM, Thongsawat S, Ren H, Chen YC, et al
. Prolonged efficacy and safety of 4 years continuous telbivudine treatment in chronic hepatitis B (CHB) patients from GLOBE and 015 studies. Hepatol Int 2010;4:56.
Wang Y, Thongsawat S, Gane EJ, Liaw YF, Jia J, Manns MP, et al
. Efficacy and Safety Outcomes After 4 Years of Telbivudine Treatment in Patients with Chronic Hepatitis B [abstract]. Hepatology 2009;S4:533A.
Jia J, Xu D, Xie Q, Shi G, Wei L, Wu S, et al
. Five years efficacy and safety of telbivudine treatment on Chinese chronic hepatitis B (CHB) patients with undetectable HBV DNA. Thailand: 21 st
Conference of the Asian Pacific association for the study of the Liver (APASL); 2011 February 17-20.
Chan HL, Heathcote EJ, Marcellin P, Lai CL, Cho M, Moon YM, et al
. Treatment of hepatitis B e antigen positive chronic hepatitis with telbivudine or adefovir: A randomized trial. Ann Intern Med 2007;147:745-54.
Zheng MH, Shi KQ, Dai ZJ, Chen YP. A 24-week, parallel group, open-label, randomized clinical trial comparing the early antiviral efficacy of telbivudine and entecavir in the treatment of HBeAg-positive chronic hepatitis B. Journal of Hepatology 52 (2010):S401.
Zeuzem S, Gane E, Liaw YF, Lim SG, DiBisceglie A, Buti M, et al
. Baseline characteristics and early on-treatment response predict the outcomes of 2 years of telbivudine treatment of chronic hepatitis B. J Hepatol 2009;51:11-20.
Wu ZG, Yan WM, Guo W, Chen T, Zou Y, Wang HW, et al
. Telbivudine preserves T-helper 1 cytokine production and downregulates programmed death ligand 1 in a mouse model of viral hepatitis. J Viral Hepat 2010; 17[Suppl 1]:24-33.
Wursthorn K, Jung M, Riva A, Goodman ZD, Lopez P, Bao W, et al
. Kinetics of hepatitis B surface antigen decline during 3 years of telbivudine treatment in hepatitis B e antigen-positive patients. Hepatology 2010;52:1611-20.
Cai W, Xie Q, An B, Wang H, Zhou X, Zhao G, et al
. On-treatment serum HBsAg level is predictive of sustained off-treatment virological response to telbivudine in HBeAg-positive chronic hepatitis B patients. J Clin Virol 2010;48:22-6.
Laeufle R, Mayer H, Avila C. Assessment of the risk of peripheral neuropathy with telbivudine: analysis of the telbivudine global clinical safety database [abstract plus poster no. PP010]. Hong Kong: 19th Asian Pacific Association for the Study of the Liver (APASL) Conference; 2009 Feb 13-16.
Yogeswaran K, Fung SK. Chronic hepatitis B in pregnancy: Unique challenges and opportunities. Korean J Hepatol 2011;17:1-8.
McKeage K, Keam SJ. Telbivudine: A review of its use in compensated chronic hepatitis B. Drugs 2010;70:1857-83.
Colonno R, Rose RE, Pokornowski K, Baldick CT, Eggers B, Yu D, et al
. Four year assessment of ETV resistance in nucleoside-naive and lamivudine refractory patients. J Hepatol 2007;46(Suppl 1):S294.
Pan C, Han GR, Zhao W, Jiang HX, Cao MK. A prospective open-label study to evaluate the efficacy, safety and tolerability of telbuvidine (Ltd) in HBeAg+Chronic Hepatitis B (CHB) pregnant women. [Abstract]. Hepatology 2010;52(Suppl 1):500A.
Shivaram Prasad Singh
Plot No: 1362 / B, Sector 6, Abhinava Bidanasi, Cuttack – 753 014, Orissa
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]