Journal of Hepatology
Volume 51, Issue 4 , Pages 787-791, October 2009

Myopathy and neuropathy associated with nucleos(t)ide analog therapy for hepatitis B☆

  • Russell D. Fleischer

      Affiliations

    • Division of Antiviral Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
    • ,
  • Anna S.F. Lok

      Affiliations

    • Division of Gastroenterology and Hepatology, University of Michigan Health System, 3912 Taubman Center, SPC 5362, Ann Arbor, MI 48109, USA
    • Corresponding Author InformationCorresponding author. Fax: +1 734 9367392.

published online 01 July 2009.

Associate Editor: M. Colombo

Article Outline

The development of clevudine as a treatment for hepatitis B was terminated recently because of case reports of myopathy. In each case, the onset of symptoms occurred between 8 and 13 months after the initiation of treatment. Electromyography and muscle biopsy confirmed the presence of myonecrosis. One report also found evidence of mitochondrial toxicity. The delayed onset and the finding of mitochondrial damage are reminiscent of fialuridine toxicity. Telbivudine has also been reported to be associated with myopathy and neuropathy, particularly when used in combination with pegylated interferon. These findings serve as a sober reminder of the lack of data on long-term safety of nucleos(t)ide analogs for hepatitis B, the importance of balancing benefits versus risks before initiating treatment, and the need for more stringent post-marketing surveillance for drug toxicities.

Keywords: Clevudine, Telbivudine, Mitochondrial toxicity, Pegylated interferon

 

Back to Article Outline

1. Introduction 

On April 20, 2009 Pharmasset Inc. announced that after a discussion with its independent Data Safety Monitoring Board and the Food and Drug Administration (FDA), the company decided to voluntarily terminate its phase III QUASH studies of clevudine for the treatment of chronic hepatitis B virus (HBV) infection [Pharmasset Inc. press release April 20, 2009]. Pharmasset indicated that the company became aware of a number of spontaneous serious adverse event reports and events of special interest in patients receiving clevudine as prescribed therapy for hepatitis B in South Korea. Although it is too early to know the full extent of the problem, at least 10 cases of myopathy have been reported in the QUASH studies with most cases having an onset of symptoms after roughly 1 year of therapy [personal communications, Michelle Berrey, Pharmasset Inc.]. A much larger number of cases have been reported to Bukwang (the company that markets clevudine in South Korea) from post-marketing surveillance studies as well as spontaneous reports submitted by physicians and consumers in South Korea where clevudine was approved in 2006 [personal communications, Michelle Berrey, Pharmasset Inc.]. While these reports are not available, two publications shed light on the onset, clinical manifestations, reversibility, and possible mechanisms of clevudine myopathy.

Back to Article Outline

2. Clevudine myopathy 

2.1. Clinical case reports 

In this issue of the Journal, Kim et al. reported two patients developed muscle weakness of the legs after 11 and 12 months of clevudine therapy for hepatitis B [1]. Both patients had elevation in creatine kinase (CK) levels, electromyography (EMG) changes of myopathy and muscle biopsy findings of degenerating and necrotic myofibers infiltrated by macrophages. One patient had resolution of symptoms 1 month after clevudine withdrawal while the other patient had improvement in symptoms 2 months after clevudine withdrawal. Electron microscopy of the muscle biopsies of these two patients did not reveal any mitochondrial changes.

In another report, also from Korea, Seok et al. reported 7 patients with severe muscle weakness after 8–13 months of clevudine therapy. None of the patients were taking concomitant medications except for one patient who had been taking colchicine for 1 year [2]. Three patients complained of muscle pain, all 7 patients had symmetric proximal limb weakness and 2 also had weakness of bulbar and neck muscles. Six patients had elevated CK levels (highest 8082U/L) and 2 of 3 patients tested had elevated lactate levels. EMG showed myopathic changes while nerve conduction studies were normal. Muscle biopsy revealed severe myonecrosis. Electron microscopy showed mitochondrial proliferation and enlarged mitochondria that contained rectangular inclusions. Quantification of mitochondrial DNA content using polymerase chain reaction demonstrated a depletion of mitochondrial DNA in the skeletal muscles. Although all patients regained muscle strength within 16 weeks after discontinuation of clevudine and none had evidence of organ failure, the findings are reminiscent of fialuridine (FIAU) toxicity [3].

These two reports highlight the importance of post-marketing surveillance particularly with drugs that are used for much longer durations than in the pivotal trials. They also raise questions whether there were hints in the preclinical or phase I/II clinical studies that would have prevented this unfortunate outcome.

2.2. Preclinical studies 

A study on the preclinical aspects of clevudine, a l-nucleoside 1-(2-fluoro-5-methyl-β-l-arabino-furanosyl)uracil (l-FMAU), found that clevudine was not incorporated into mitochondrial DNA and it was not an inhibitor or a substrate for DNA polymerase γ; therefore, mitochondrial toxicity was not expected [4]. However, mitochondrial toxicity may arise not only from inhibition of DNA polymerase γ but also from mitochondrial DNA mutations and mitochondrial oxidative stress [5]. Studies of nucleoside reverse transcriptase inhibitor (NRTI) such as azidothymidine (AZT)-associated mitochondrial toxicity highlighted the important role of the intracellular location where the nucleoside is phosphorylated. The enzyme involved in the first step of phosphorylation – thymidine kinase exists in 2 isoforms, one which is located in the cytoplasm (TK1) and the other in the mitochondria (TK2). The susceptibility of a given tissue to NRTI-induced mitochondrial toxicity is related to the presence of a high concentration of TK2 relative to TK1. One study published in 1996 found that both fialuridine and clevudine are more efficient substrates for TK2 than for TK1 [6]. Another study published in 2008 confirmed that clevudine is preferentially phosphorylated by TK2 [7]. Interestingly, clevudine has been investigated as a positron emission tomography tumor-imaging tracer [8], [9]. These studies revealed that phosphorylated clevudine is retained in cells, particularly cells of mitochondrial rich tissues such as heart or muscles, and retention is increased during cellular stress [7]. These findings indicate that long-term use of clevudine may lead to accumulation of clevudine-triphosphate and to mitochondrial toxicity. The lack of mitochondrial changes in Kim et al.’s study may be related to the small number of patients (n=2), timing of the biopsies, or sensitivity of the technique used [1]. By contrast, Seok et al.’s study demonstrated clear evidence of mitochondrial damage based on electron microscopy and polymerase chain reaction [2]. It should be mentioned that initial studies of fialuridine also found that there was no effect on mitochondrial function [10] but subsequent studies indicated otherwise [3], [11].

2.3. Clinical studies 

A unique feature of clevudine is the lag in viral rebound after treatment is stopped. This has led to questions regarding drug accumulation. Initial studies found that the half-life of clevudine after a single dose was 8–12h but a subsequent study found that the mean half-life of clevudine measured at steady state, after 12 weeks of treatment, was approximately 70h [12]. Given that clevudine is administered daily, accumulation of the drug is expected to occur during long-term treatment. It is possible that the half-life of intracellular clevudine-triphosphate may be longer. Accumulation of intracellular clevudine-triphosphate after prolonged administration of clevudine may in part explain the lack of toxicity in earlier trials of shorter (4–24 weeks) duration of treatment [12], [13], [14], [15], [16], [17] and the late onset of toxicity (around 12 months). Similarly, initial studies of 2 and 4 week courses of fialuridine did not reveal any safety concerns and side effects were minimal during the first 8 weeks of therapy in the final study [3]. Numbness and tingling in the feet followed by sudden onset of hepatic failure, shock and lactic acidosis manifested after 9.5–13 weeks of treatment.

Using a sensitive radioimmunoassay, Bowsher et al. found that fialuridine had a long elimination half-life of 29.3h in healthy volunteers instead of the previous estimate of 3–4h and fialuridine accumulated in genomic DNA of all tissues with the highest concentration in the liver [18], [19]. Manifestation of neurotoxicity associated with adenine arabinoside monophosphate (ARA-AMP), a drug that was evaluated for the treatment of hepatitis B in the late 1970s and early 1980s, was also delayed. In one study, peripheral neuropathy developed in 1 of 15, 1 of 11 and 5 of 5 patients who received ARA-AMP for 4, 7, and ⩾8 weeks, respectively [20]. Of note, 3 of these 7 patients had onset of symptoms 1–2 weeks after the withdrawal of therapy. This highlights the importance of continued monitoring of patients in whom clevudine is discontinued.

Elevated CK level is an early indicator of muscle injury but elevated CK may be nonspecific and is often observed after strenuous exercise. In a study of 32 patients who received varying doses of clevudine for 4 weeks, grade 3 or 4 elevation in CK levels (⩾7 time the upper limit of normal) was recorded in 3 patients [13]. In another study, 3 of 66 patients who received 12 weeks of clevudine had grade 3 or 4 elevation in CK levels compared to 0 of 32 who received placebo [15]. A third study comparing 24 weeks of emtricitabine alone versus emtricitabine plus clevudine found that a similar percentage of patients in both groups had grade 3 or 4 elevation in CK levels, 2% vs. 7% during treatment and 5% vs. 4% during 24 weeks of post-treatment follow-up [14]. Reports of the two pivotal trials of clevudine conducted in Korea in which the drug was administered for 24 weeks did not provide any information on CK levels [16], [17]. Despite the lack of reports of clinical myopathy, the elevation in CK levels observed in earlier trials were concerning. Therefore, an algorithm for the management of subjects who develop signs and symptoms of possible skeletal myopathy was incorporated in the phase III QUASH study. It is not clear whether this algorithm led to earlier awareness of clevudine myopathy and termination of the trial before more patients were exposed to the risk.

Back to Article Outline

3. Myopathy/neuropathy associated with other nucleos(t)ide analogs used for treatment of hepatitis B 

3.1. Telbivudine 

Myopathy and neuropathy have been reported in patients who received telbivudine treatment. In the worldwide phase III GLOBE trial, grade 3 or 4 elevation in CK levels was observed in 88 of 680 (12.9%) patients who received telbivudine and in 28 of 687 (4.1%) patients who received lamivudine for 104 weeks (p<0.001) [21]. Myopathy, characterized by muscle pain and weakness and moderately elevated CK levels during treatment, was reported in 2 patients, both of whom had resolution of symptoms after telbivudine was discontinued. Rhabdomyolysis was not observed in any patient. Preliminary data of 667 patients in the GLOBE trial and another phase III trial in China (NV-02B-015) who received telbivudine for 3 years found that 9 (1.4%) patients had new onset grade 3 or 4 CK elevation and 9 (1.4%) had myalgia or myositis between weeks 104 and 156 [22].

Telbivudine has also been reported to be associated with peripheral neuropathy, particularly when used in combination with pegylated interferon. Of 3500 patients who had received telbivudine monotherapy in clinical trials, 10 (0.28%) were reported to have peripheral neuropathy compared to 9 of 48 (18.75%) patients who received combination therapy of pegylated interferon and telbivudine [23]. Combination of pegylated interferon and telbivudine was also associated with an earlier onset of peripheral neuropathy: median of 4.5 (range 2–6) months vs. 14 (range 4–25) months and a lower likelihood of improvement 6 of 9 vs. 9 of 10 who received telbivudine monotherapy.

The mechanism(s) of telbivudine associated myopathy or peripheral neuropathy is unknown. To date, there are no reports of EMG, muscle biopsies or nerve conduction studies. In vitro studies found that telbivudine at concentrations up to 10-fold maximal clinical exposure had no effect on human hepatocytes, skeletal muscle or neuronal cells and was not associated with mitochondrial toxicity [24]. It is also not clear how interferon increase or accelerate telbivudine-induced neuropathy. Interferon had also been reported to increase the incidence of ARA-AMP induced neuropathy [25].

3.2. Other approved HBV treatments 

Data from 3 placebo-controlled trials of lamivudine in patients with HBV monoinfection found that grade 3 or 4 CK elevation was observed in 9% of patients who received lamivudine and in 5% of those who received placebo while myalgia was reported in 14% and 17%, respectively [see package insert, www.fda.gov]. Rhabdomyolysis has been reported in 2 liver transplant patients who received lamivudine. In one case, this occurred after 13 days of lamivudine in a patient with acute exacerbation of chronic hepatitis B and liver failure [26]. In the other case, this occurred 16h after the first dose of lamivudine in a patient who had just received a liver transplant [27]. The rapidity of onset and the presence of other medical conditions and medications make it difficult to ascertain the causal relationship although re-challenge of the latter case with a single dose of lamivudine 6 days later was reported to lead to recurrence of myoglobinemia and increase in CK levels. Despite many years of marketing experience and extensive use at doses exceeding that for the treatment of hepatitis B, lamivudine has not appeared to be causally associated with myopathy in patients with human immunodeficiency virus (HIV) infection.

Elevation in CK levels has also been observed in patients who received adefovir, tenofovir or entecavir; however, the incidence is similar to patients who received placebo or active control drug, and overt myopathy or neuropathy has been rarely reported in pivotal trials [see package insert, www.fda.gov].

Back to Article Outline

4. Long-term safety of nucleos(t)ide analog treatment for hepatitis B 

The approval of 5 orally administered, well tolerated nucleos(t)ide analogs for hepatitis B in the past 10 years has stimulated enthusiasm for expanding the indications for treatment of hepatitis B. Some experts have argued that treatment should be initiated based on high serum HBV DNA levels alone and that treatment should be continued indefinitely to avoid post-treatment relapse or reactivation of hepatitis B. The withdrawal of clevudine from development is a sober reminder that while the nucleos(t)ide analogs for hepatitis B have excellent safety profiles based on clinical trials of 1-year duration, there is paucity of data on long-term safety of these compounds. Among the approved therapies, lamivudine has the best long-term safety record but it is associated with an unacceptably high rate of drug resistance. Adefovir and tenofovir can cause nephrotoxicity and renal tubular damage and tenofovir has been reported to decrease bone mineral density [see package insert, www.fda.gov] [28], [29]. Although these adverse events are rare in clinical trials of 1–2 years duration, nephrotoxicity defined as reproducible increase in serum creatinine by ⩾0.5mg/dL was observed in 3% of patients who received adefovir for up to 5 years [30]. As discussed above, telbivudine has been reported to be associated with myopathy and neuropathy. Preclinical studies found that entecavir in doses up to 30 times the approved dose in humans was associated with a wide variety of tumors in rodents [see package insert, www.fda.gov]. These findings raised a lot of concerns at the time entecavir was approved and led Bristol-Myers Squibb to pledge a 10-year follow-up study of up to 10,000 patients receiving entecavir. To date, there have been no serious reports of entecavir-related toxicity but data from the long-term surveillance study are not yet available.

Back to Article Outline

5. Monitoring of toxicities during drug development 

The unfortunate situation with clevudine is a reminder of the difficulties in predicting drug-related adverse events. Although each new drug has to be rigorously tested in in-vitro and in animal toxicity studies, the ability of preclinical studies to predict toxicities in humans, particularly rare or idiosyncratic events, is low. Preclinical or phase I/II clinical studies may identify safety signals leading to the incorporation of monitoring and management plans in phase III trials that may mitigate risks or detect toxicity at an early stage. Whether the development of a drug with safety concerns in phase III trials is allowed to continue depends on the balance between the risks (frequency, severity and reversibility of the events) and the potential benefits of the drug (efficacy of the drug, availability of alternative therapies, and prognosis of the disease if untreated). Not all toxicities are evident during phase III trials. In the past 10 years, several drugs have been withdrawn from the market only after these drugs have been used in hundreds of thousands of patients in clinical practice. Establishing a causal relationship between an approved drug and a major adverse event is hampered by the lack of an efficient and comprehensive surveillance program. In most countries, monitoring of drug safety post-marketing is dependent on voluntary reporting by physicians who are often too busy or unfamiliar with the process or who simply could not be bothered. Moreover, an individual physician seeing a patient with a previously unreported adverse event may not associate the event with a drug unless he or she has knowledge of similar events. Thus, under-reporting is a major barrier to assessment of the safety of approved drugs.

Kim and colleagues should be applauded for their vigilance in monitoring their patients, the thorough evaluation, and the prompt reporting of their cases, thereby alerting the hepatitis community and hopefully averting more cases of clevudine myopathy. The decision to terminate the development of clevudine was appropriate given the availability of several alternative therapies that are safer.

Back to Article Outline

6. Conclusion 

Substantial progress has been made in the treatment of hepatitis B in the past decade. The availability of well tolerated orally administered nucleos(t)ide analogs has prompted many experts to recommend expansion of treatment to patients with quiescent or minimally active liver disease. The case of clevudine myopathy is a sober reminder that the decision to initiate treatment should balance benefits against risks. Although the drug approval process is rigorous, toxicities may not be detected during preclinical or clinical studies if these events are rare, or if the drugs are used in patient populations that were not included in the clinical trials or for longer durations than in clinical trials. The latter is particularly relevant because most patients with hepatitis B treated with nucleos(t)ide analogs remain on treatment for at least 4–5 years and some are on lifelong treatment.

Back to Article Outline

References 

  1. Kim BK, Oh J, Kwon BK, Choe WH, Ko SY, Rhee KH, et al. Clevudine myopathy in patients with chronic hepatitis B. J Hepatol. 2009;51:829–834
  2. Seok JI, Lee DK, Lee CH, Park MS, Kim SY, Kim HS, et al. Long-term therapy with clevudine for chronic hepatitis B can be associated with myopathy characterized by depletion of mitochondrial DNA. Hepatology. 2009;49:2080–2086
  3. McKenzie R, Fried MW, Sallie R, Conjeevaram H, Di Bisceglie AM, Park Y, et al. Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. N Engl J Med. 1995;333:1099–1105
  4. Chu CK, Boudinot FD, Peek SF, Hong JH, Choi Y, Korba BE, et al. Preclinical investigation of l-FMAU as an anti-hepatitis B virus agent. Antivir Ther. 1998;3:S113–S121
  5. Lewis W, Day BJ, Copeland WC. Mitochondrial toxicity of NRTI antiviral drugs: an integrated cellular perspective. Nat Rev Drug Discov. 2003;2:812–822
  6. Wang J, Eriksson S. Phosphorylation of the anti-hepatitis B nucleoside analog 1-(2′-deoxy-2′-fluoro-1-beta-d-arabinofuranosyl)-5-iodouracil (FIAU) by human cytosolic and mitochondrial thymidine kinase and implications for cytotoxicity. Antimicrob Agents Chemother. 1996;40:1555–1557
  7. Tehrani OS, Douglas KA, Lawhorn-Crews JM, Shields AF. Tracking cellular stress with labeled FMAU reflects changes in mitochondrial TK2. Eur J Nucl Med Mol Imaging. 2008;35:1480–1488
  8. Sun H, Sloan A, Mangner TJ, Vaishampayan U, Muzik O, Collins JM, et al. Imaging DNA synthesis with [18F]FMAU and positron emission tomography in patients with cancer. Eur J Nucl Med Mol Imaging. 2005;32:15–22
  9. Bading JR, Shahinian AH, Bathija P, Conti PS. Pharmacokinetics of the thymidine analog 2′-fluoro-5-[(14)C]-methyl-1-beta-d-arabinofuranosyluracil ([(14)C]FMAU) in rat prostate tumor cells. Nucl Med Biol. 2000;27:361–368
  10. Colacino JM, Malcolm SK, Jaskunas SR. Effect of fialuridine on replication of mitochondrial DNA in CEM cells and in human hepatoblastoma cells in culture. Antimicrob Agents Chemother. 1994;38:1997–2002
  11. Cui L, Yoon S, Schinazi RF, Sommadossi JP. Cellular and molecular events leading to mitochondrial toxicity of 1-(2-deoxy-2-fluoro-1-beta-d-arabinofuranosyl)-5-iodouracil in human liver cells. J Clin Invest. 1995;95:555–563
  12. Lim SG, Leung N, Hann HW, Lau GK, Trepo C, Mommeja-Marin H, et al. Clinical trial: a phase II, randomized study evaluating the safety, pharmacokinetics and anti-viral activity of clevudine for 12 weeks in patients with chronic hepatitis B. Aliment Pharmacol Ther. 2008;27:1282–1292
  13. Marcellin P, Mommeja-Marin H, Sacks SL, Lau GK, Sereni D, Bronowicki JP, et al. A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B. Hepatology. 2004;40:140–148
  14. Lim SG, Krastev Z, Ng TM, Mechkov G, Kotzev IA, Chan S, et al. Randomized, double-blind study of emtricitabine (FTC) plus clevudine versus FTC alone in treatment of chronic hepatitis B. Antimicrob Agents Chemother. 2006;50:1642–1648
  15. Lee HS, Chung YH, Lee K, Byun KS, Paik SW, Han JY, et al. A 12-week clevudine therapy showed potent and durable antiviral activity in HBeAg-positive chronic hepatitis B. Hepatology. 2006;43:982–988
  16. Yoo BC, Kim JH, Kim TH, Koh KC, Um SH, Kim YS, et al. Clevudine is highly efficacious in hepatitis B e antigen-negative chronic hepatitis B with durable off-therapy viral suppression. Hepatology. 2007;46:1041–1048
  17. Yoo BC, Kim JH, Chung YH, Lee KS, Paik SW, Ryu SH, et al. Twenty-four-week clevudine therapy showed potent and sustained antiviral activity in HBeAg-positive chronic hepatitis B. Hepatology. 2007;45:1172–1178
  18. Bowsher RR, Compton JA, Kirkwood JA, Place GD, Jones CD, Mabry TE, et al. Sensitive and specific radioimmunoassay for fialuridine: initial assessment of pharmacokinetics after single oral doses to healthy volunteers. Antimicrob Agents Chemother. 1994;38:2134–2142
  19. Richardson FC, Engelhardt JA, Bowsher RR. Fialuridine accumulates in DNA of dogs, monkeys, and rats following long-term oral administration. Proc Natl Acad Sci USA. 1994;91:12003–12007
  20. Lok AS, Wilson LA, Thomas HC. Neurotoxicity associated with adenine arabinoside monophosphate in the treatment of chronic hepatitis B virus infection. J Antimicrob Chemother. 1984;14:93–99
  21. 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;136:486–495
  22. Avila C, Laeufle R, Bao W. CK elevation during chronic hepatitis B (CHB) treatment with telbivudine: experience from the combined globe (NV-02B-007/CLDT600A2302) and NV-02B-015 (015) study clinical safety database. In: Poster #PE 140 presented at the 19th asian pacific association for the study of the liver (APASL); February 13–16, 2009, Hong Kong; 2009.
  23. Goncalves J, Laeufle R, Avila C. Increased risk with combination of telbivudine and pegylated-interferon Alfa-2A in study CLDT600A2406, compared to uncommon rate with telbivudine monotherapy from the novartis global database. J Hepatol. 2009;50:S329;Abstract #907
  24. Weaver M, Wolf A, Persohn E, Grenet O, Pognan F, Dong M. Absence of Mitochondrial toxicity of telbuvidine in skeletal muscle cells, hepatocytes, and neuronal cells from rat or human. In: Abstract from the 19th asian pacific association for the study of the liver (APASL); February 13–16, 2009, Hong Kong; 2009.
  25. Garcia G, Smith CI, Weissberg JI, Eisenberg M, Bissett J, Nair PV, et al. Adenine arabinoside monophosphate (vidarabine phosphate) in combination with human leukocyte interferon in the treatment of chronic hepatitis B. A randomized, double-blinded, placebo-controlled trial. Ann Intern Med. 1987;107:278–285
  26. Yahagi K, Ueno Y, Mano Y, Shimosegawa T. Rhabdomyolytic syndrome during the lamivudine therapy for acute exacerbation of chronic type B hepatitis. Liver Transpl. 2002;8:1198–1199
  27. Adani GL, Baccarani U, Risaliti A, Bresadola F, Della Rocca G, Viale P. Rhabdomyolysis due to lamivudine administration in a liver transplant recipient. Am J Transplant. 2005;5:634
  28. Marcellin P, Chang T, Lim SG, Tong M, Sievert W, Schiffman M, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003;348:808–816
  29. Nelson MR, Katlama C, Montaner JS, Cooper DA, Gazzard B, Clotet B, et al. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS. 2007;21:1273–1281
  30. Hadziyannis S, Tassopoulos N, Heathcote E, Chang T, Kitis G, Rizzetto M, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. 2006;131:1743–1751

☆ R.D.F. declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. A.S.F.L. receives research support from Bristol-Myers Squibb, GlaxoSmithKline, Schering, Novartis and Gilead and serves as an advisor for Gilead, Pharamasset, Schering and Roche.

PII: S0168-8278(09)00453-X

doi:10.1016/j.jhep.2009.06.011

Journal of Hepatology
Volume 51, Issue 4 , Pages 787-791, October 2009

Article Tools