Hepatobiliary & Pancreatic Diseases International

Current therapy with nucleoside/nucleotide analogs for patients with chronic hepatitis B Xiao-Wei Xu and Ya-Gang Chen Hangzhou, China BACKGROUND: Currently, more and more nucleos(t)ide analogs are appearing as therapeutic options in the treatment of chronic hepatitis B (CHB). Their efficacy and safety profile in hepatitis B virus (HBV) infection have already been studied in detail worldwide. This review summarizes the efficacy of lamivudine, adefovir, entecavir and newer antiviral agents such as emtricitabine, telbivudine and clevudine in the treatment of hepatitis B in different clinical situations. DATA SOURCES: An English-language literature search using OVID and MEDLINE was performed and a total of 40 articles on the treatment of chronic hepatitis with nucleos(t)ide analogues were selected. RESULTS: Nucleos(t)ide analogs such as lamivudine, adefovir and entecavir are well tolerated and induce a decrease in serum HBV-DNA levels associated with normalization of serum alanine aminotransferase (ALT) levels. But their sustained response with HBeAg to anti-HBe seroconversion is rarely obtained and HBsAg loss is exceptional. The response is maintained during therapy which needs to be continued indefinitely in the majority of patients since withdrawal of treatment is generally followed by a rapid reactivation of hepatitis B. However, drug resistant mutations can be induced in long-term treatment. Other newer antiviral agents such as emtricitabine, telbivudine and clevudine in the treatment of hepatitis B are still under phase Ⅱ or  Ⅲ  clinical trials. CONCLUSIONS: Nucleos(t)ide analogs play an important role in the therapy of hepatitis B now and in the future. Lamivudine is limited by the frequent emergence of drugresistant (HBV) mutants (YMDD). Adefovir and entecavir appear to be effective against both YMDD mutation and

Author Affiliations: Department of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Xu XW and Chen YG) Corresponding Author: Ya-Gang Chen, MD, Department of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Tel: 86-571-87236564; Fax: 86-571-87326599; Email: [email protected]) © 2006, Hepatobiliary Pancreat Dis Int. All rights reserved.

wild type. Therapeutic options against hepatitis B virus remain a major clinical challenge. (Hepatobiliary Pancreat Dis Int 2006; 5: 350-359) KEY WORDS: hepatitis B;  antivirus;  lamivudine;  adefovir;  entecavir;  emtricitabine;  telbivudine;  clevudine  

Introduction

C

hina is considered an area highly endemic for hepatitis B virus (HBV) infection. About 120 million people or 9.75% of the Chinese population have serological evidence of HBsAg. These HBV infections lead to chronic liver disease, cirrhosis and primary liver cancer. On the other hand, these people infected by HBV maintain reservoirs of infection and continue HBV transmission by vertical (mother to child or generation to generation through close contact and sanitary habits), early life horizontal transmission (through bites, lesions, and sanitary habits) and adult horizontal transmission (through sexual contact, intravenous administration of drugs, and medical procedure exposure). The incidence of new cases, the prevalence of carriers and the burden of acute and chronic disease place hepatitis B among the most important communicable diseases. Preventing the most severe consequences of HBV disease in infected individuals requires appropriate therapeutic agents. The use of nucleot(s)ide analogues is a milestone in the treatment of chronic hepatitis B (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. These agents are advantageous for oral administration and safety, but induce a sustained response (after withdrawal of therapy) in only a minority of patients. Thus the

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Current therapy with nucleoside/nucleotide analogs for patients with CHB treatment should be given in trials in a majority of patients for a long period. In addition, the long-term efficacy of lamivudine is limited by the frequent emergence of drug-resistant HBV mutants. Adefovir is associated with a low frequency of resistance but its antiviral effect is not optimal. Entecavir, the newest antiviral agent approved by FDA of the USA, is also effective in combating lamivudine-resistant mutant, but less effective in resisting wild type HBV. As a result, more effective therapy with more potent drugs used alone or in combination is needed and the treatment of CHB remains an issue. This review focuses on the efficacy of lamivudine, adefovir, entecavir and newer antiviral agents including emtricitabine, telbivudine and clevudine in the treatment of hepatitis B under different clinical conditions.

Current treatments Lamivudine Lamivudine, a nucleoside analog that inhibits HBVDNA synthesis through chain termination was first developed as a reverse transcriptase inhibitor for use in human immunodeficiency virus (HIV) infection. Lamivudine is a negative enantiomer and it is thought that this property may help explain the low rates of adverse events in the application of this agent. Randomized controlled trials have demonstrated the efficacy of lamivudine in the treatment of HBeAgpositive and HBeAg-negative CHB. HBeAg-positive CHB One randomized, placebo controlled trial[1] showed that almost all patients treated with lamivudine (98%) had a reduction of serum HBV-DNA levels. Serum HBV-DNA levels were undetectable after lamivudine (less than 0.7 mg/ml) therapy in 44% of patients compared with 16% of patients treated with placebo. After one year of treatment, the HBeAg seroconversion rates ranged from 17% to 6% in the lamivudine and placebo groups, respectively. Serum alanine aminotransferase (ALT) levels were normalized in 41% of the lamivudine-treated patients compared with 7% of the placebo group. Histological improvement defined by a decrease of at least[2] points of the Knodell score were observed in 52% of the lamivudine group compared with in 23% of the placebo group. The rates of virologic, biochemical and histological response in another 3 randomized controlled trials showed similar results, with HBeAg anti-HBeAb seroconversion rates ranging from 17%

to 21%.[1-4] Lamivudine therapy for 3 years reduces hepatic necroinflammatory activity and decreases fibrosis in most patients.[5] The tolerability and safety of lamivudine are excellent, and the frequency of adverse events is similar to that of the placebo group. Lamivudine therapy seems to be well-tolerated for up to 5 years; however, data on long-term therapy with lamivudine are limited to a small number of patients. Pre-treatment factors for a response to lamivudine are similar to those for a response to interferon, i.e., high levels of serum ALT and high degree of histological necroinflammation.[6] The pre-treatment ALT level seems to be the most important. Being similar to those in untreated patients, response rates in patients with ALT levels are two times lower than the upper limit of the normal value. The rate of HBeAg loss is the highest in patients with pretreatment ALT levels greater than 5 times the upper limit of the normal value. After withdrawal of lamivudine therapy, ALT flare-ups were reported in 41 patients treated with lamivudine for a minimum of 3 months and followed up for at least 6 months after therapy.[7] Marked flares were observed in 17% of the patients 7 to 44 weeks after treatment. These flares were associated with increased levels of HBV-DNA unlike spontaneous flares that were associated with HBeAg to anti-HBe seroconversion (decreased levels of HBV-DNA). Two of these flares were associated with hepatic decompensation. The major limitation of lamivudine treatment is the high rate of viral resistance related to mutations in the YMDD motif of the HBV polymerase gene. Indeed, even if the HBeAg seroconversion rate is increased by continuing treatment, the frequency of resistance to lamivudine increases with time: 24% at 1 year, 38% at 2 years, 50% at 3 years, and 67% at 4 years.[8, 9] The most important mutation is a substitution of valine or isoleucine for methionine. In many patients this mutation is accompanied by a second mutation in which methionine is substituted for leucine in an upstream region(rtL180M). Lamivudine resistance is more likely to occur in patients with high baseline levels of serum HBV-DNA. The emergence of lamivudine resistant mutants is usually associated with a breakthrough of hepatitis, with moderately increased levels of serum HBVDNA and ALT although these levels may be lower than the baseline (pretreatment) for several months. However, severe flares have been reported in patients with cirrhosis. In patients who develop resistance to lamivudine, adefovir should be given rapidly once

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Hepatobiliary & Pancreatic Diseases International the serum ALT level is increased. This is especially important in patients with cirrhosis who are at risk of hepatic decompensation. In order to detect the resistance early (before the appearance of detectable serum HBV-DNA by standard assays and before the increase in serum ALT level), monitoring of serum HBV-DNA level by a sensitive assay is useful.[10-14] Indeed, an increase in serum HBV-DNA level of more than one log unit generally reflects the appearance of a resistant mutant and allows institution of therapy with adefovir several months before the increase in serum ALT level is observed. In cases of HBeAg to anti-HBe seroconversion during lamivudine therapy, additional administration of lamivudine for 3 to 6 months is recommended to decrease the risk of reactivation.[10-14] In the absence of HBeAg seroconversion, withdrawal of the drug is almost invariably followed by reactivation of HBV. Therefore, lamivudine therapy should be continued as long as HBV replication is suppressed, serum ALT levels remain normal or until viral resistance occurs.[10-14] HBeAg-negative CHB In patients with HBeAg-negative CHB, a randomized controlled study showed an efficacy rate similar to that observed in patients with HBeAgpositive CHB. Both groups of patients had the same resistance.[15] HBV-DNA was undetectable by a nonpolymerase chain reaction (PCR) assay after 12 months of therapy in 90% of the patients and by a PCR assay in 70% of the patients. Serum ALT levels normalized in 75% of the patients. In this series, reduced serum HBV-DNA level and normal serum ALT were seen in 6% of patients on placebo. Histological response was observed in 60% of lamivudine-treated patients, but predictors of response to lamivudine were not established. In patients with a virological response at the end of 12-month treatment with lamivudine, the sustained response rate was less than 5% 6 months after the treatment. In a Glaxo-sponsored study of extended lamivudine therapy,[16, 17] 76 HBeAg-negative patients with CHB were given 100 mg LAM daily in a 5-year follow-up study. The incidence of YMDD was 39% at month 12, 54% at month 24 and 57% at month 36; correspondingly, the response declined from 67% at 6 months to 51%, 34% and 29% after 12, 24 and 36 months, respectively. A complete analysis at month 24 of follow-up was available. An increase of HBV-DNA and ALT levels was apparent in patients with YMDD variants. Among the patients who did not develop YMDD variants, 72% had normal ALT

and negative HBV-DNA whereas only 5% of the patients who developed YMDD mutants maintained normal ALT after one year. No major clinical events, liver decompensation in particular, occurred in the patients who developed mutants. Special groups Eight pregnant women treated with lamivudine [18] were HBeAg-positive. Among 3 of the 8 patients, who had been treated with nucleoside analogues (lamivudine and/or famciclovir), one patient became pregnant one month after stopping of lamivudine treatment, and the other two finished the treatment a year before pregnancy. Another one of the 8 patients also received interferon. No lamivudineresistant strains were found in any of these women. Lamivudine treatment was started at week 36, but after an early delivery in patient 3, the treatment continued at week 34. Patient 5 started the treatment at week 38 because of late referral. The duration of the treatment ranged from 6 to 40 days. In 5 of the 8 lamivudine-treated women, the median percentage of HBV-DNA decreased by 98.9% (range 0-99.9%). The levels of ALT were normal or near normal at the time of delivery (range 20-49 U/L). No side-effects were found in these patients during lamivudine treatment. After delivery, ALT levels increased in 7 of the 8 women, but remained below 5 times the upper limit of normal (ULN) in all women and below twice the ULN in 5 of the 8 women (follow-up for 1-7 months). Two women received additional antiviral therapy 2 years after delivery. In two other women, spontaneous HBeAg-seroconversion occurred 2 and 3 years after delivery. The characteristics of newborns born by these mothers were also described.[18] One child was delivered by Caesarean section and the others were conventional. Delivery was induced in patient 6 at week 38 because of growth retardation of her baby. Four children were HBsAg-positive at birth, and one (child 6) remained HBsAg-positive and HBV-DNA positive at the age of 9 months (12.5%). The other 3 children seroconverted to anti-HBs and remained anti-HBs-positive until the age of 12 months. HBVDNA was detected at birth in 1 child (child 7), and in 2 other children (children 4 and 5) until the age of 3 months, but not thereafter. In the control group, perinatal transmission occurred in 7 of 24 children (28%). In patients with decompensated cirrhosis, lamivudine has been a major treatment choice. Lamivudine therapy can induce marked improvement in liver disease and increase favorably the survival

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Current therapy with nucleoside/nucleotide analogs for patients with CHB of patients.[19, 20] In patients waiting for liver transplantation, time to death or transplantation is significantly longer and transplantation is less frequent(35% vs. 74%) in lamivudine-treated patients than in a historical cohort of untreated patients.[21] However, the clinical effects are slow and impaired by the risk of emergence of resistance, which can be associated with hepatic flares that lead to liver failure and death. In addition, patients in whom lamivudine resistance develops before transplantation have a higher risk of recurrent hepatitis B after transplantation. In this case, adefovir should be prescribed rapidly to prevent a flare if lamivudine resistance is suspected. Few data show that lamivudine (150 mg twice daily) is effective in inhibiting HIV and HBV replication in HIV/HBV-coinfected patients. In HIV/HBV-coinfected patients, lamivudine given for combating HIV infection as monotherapy or as part of an antiretroviral regimen promptly inhibits HBV replication.[22, 23] The anti-HBV activity of lamivudine was first assessed in a prospective open-label study of 40 patients with advanced HIV infection.[22] After one year of treatment, 96.3% of the patients had an undetectable serum level of HBV-DNA (5 pg/ml), increased serum ALT levels were observed 2-8 weeks after lamivudine therapy. Subsequently, after 52week treatment, ALT levels significantly decreased compared with baseline. A retrospective analysis of HIV/HBV-coinfected patients prospectively enrolled within the CAESAR trial has been reported.[23] This was a randomized, double-blind, placebocontrolled trial of lamivudine (150 mg twice daily) or lamivudine plus loviride added to zidovudinecontaining regimens for patients with advanced HIV infection.[24] In the patients of the CAESAR study, 122 were coinfected with HBV (97 in the lamivudine arm and 25 in the placebo arm). Although randomization was not based on HBV infection, there were no differences between patients in the lamivudine arm and those in the placebo arm with respect to baseline demographic characteristics, HIV disease, serum ALT levels, and HBV virological status. At week 52, the median reduction of serum HBV-DNA was 2.7 log10 copies/ml as measured by PCR (quantification range, 2.6-7.6 log10 copies/ml; Amplicor; Roche) in the lamivudine treatment arm, compared with no reduction in the placebo arm. With a sensitive method, serum HBV-DNA was not detected in 40%

of lamivudine-treated patients at week 52. Finally, the tolerance profile of lamivudine (150 mg twice daily) was described as excellent in both HIV-infected and HIV/HBV-coinfected patients. However, no information regarding the underlying liver disease was available in either of the two studies.[22,23]

Adefovir dipivoxil Adefovir dipivoxil has recently been approved for the treatment of CHB. Adefovir dipivoxil is the oral prodrug of adefovir, a nucleotide analog of adenosine monophosphate. In vivo, adefovir dipivoxil is converted to the parent compound, adefovir, and through two phosphorylation reactions, to adefovir diphosphate, the active intracellular metabolite that interacts with the HBV polymerase. Adefovir diphosphate acts as a competitive inhibitor and chain terminator of HBV replication. Two large randomized controlled trials have demonstrated that adefovir dipivoxil is effective in patients with HBeAg-positive or HBeAg-negative CHB. Also, adefovir dipivoxil effectively suppresses lamivudine-resistant HBV in patients with CHB after liver transplantation, compensated or decompensated liver disease, and co-infection with HIV. HBeAg-positive CHB Clinical studies of both double-blind placebo controlled and open label for evaluating efficacy, safety and mutation of adefovir in the treatment of CHB have been done in many areas of the world. The first study in the mainland of China, a randomized double-blind placebo controlled phase  Ⅲ  study of the safety and efficacy of adefovir, was completed by the end of 2004. A total of 480 HBeAg-positive patients with chronic hepatitis were enrolled to receive 100 mg adefovir daily for 52 weeks. Primary end-point was a log10 reduction of serum HBV-DNA at the end of week 12 compared to the baseline between adefovir dipivoxil 10 mg and matching placebo given once daily. Three study phases were included. The first 12 weeks of double-blind treatment were used to establish the control data on primary end-point, followed by 28 weeks of open label adefovir dipivoxil treatment to evaluate efficacy and safety of long-term therapy. The second double-blind treatment in the last 12 weeks was prescribed to investigate post-treatment response in those patients who were randomized into adefovir group at basebine. The virologic response decreased from 3.4 log10 copies/ml at week 12, and 4.5 log10 copies/ml at week 52. The normalized corresponding levels of serum ALT were 42.4% at week 12, 78.6% at

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Hepatobiliary & Pancreatic Diseases International week 52. The seroconversion rate of HBeAg was 8%. The tolerability and safety profile of adefovir at a dose of 10 mg was similar to that of placebo. Renal impairment was not observed in both adefovir and placebo groups.[25] The durability of response after withdrawal of the treatment was not known since the treatment was continued according to the design of the trial. After the second double-blind placebo controlled study, all patients received long-term treatment of open label adefovir dipivoxil for 4 years. However, cessation of therapy in some patients without HBeAg seroconversion was associated with relapse. Therefore, maintenance therapy should be recommended. Preliminary results have suggested that antiviral effect is maintained, and rates of virologic response with HBeAg seroconversion increases with the duration of therapy. However, the results after a longer period of follow-up (up to 5 years) are expected to confirm the maintained response and the possible increased efficacy of long-term treatment. A genotyping study was carried out in patients with detectable HBV-DNA (by PCR assay).[25] Systematic sequencing did not show any instance in which a mutant HBV resistant to adefovir emerged after 52 weeks of treatment with adefovir. Studies of large groups of patients treated with adefovir are in progress to assess the long-term frequency of resistance. The high threshold for resistance to adefovir may be due to the structural features of adefovir that distinguish it from nucleoside analogs, particularly its minimal flexible acyclic linker that closely resembles the natural substrate and the fact that it is a nucleotide, containing a phosphorus atom, not a nucleoside. The same situation of efficacy, safety of adefovir and mutation in treatment chronic hepatitis B was found in other studies of different countries. HBeAg-negative CHB A large randomized, placebo-controlled study of adefovir was done in 185 patients with HBsAgnegative CHB.[26] The patients were divided to receive either adefovir 10 mg (n=123) or placebo (n=62) for 48 weeks. Adefovir of 10 mg once daily resulted in a significant reduction in serum HBV-DNA levels at week 48 compared with placebo, with a median decrease of 3.9 log10 copies/ml compared with 1.3 log10 copies/ml for placebo (P