Journal of Hepatology
Volume 51, Issue 2 , Pages 416-418, August 2009

Evolution of nucleoside/tide analogues for hepatitis B: Is the ideal drug here yet?☆

Division of Gastroenterology, University of Michigan Health System, 3912 Taubman Center, SPC 5362, Ann Arbor, MI 48109, USA

published online 27 March 2009.

Special Section Editors: Peter R. Galle, Peter L.M. Jansen, Francesco Negro

Article Outline

Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Washington MK, Sorbel J, Anderson J, Snow-Lampart A, Mondou E, Quinn J, Rousseau F.

Background

Tenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitor of human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus (HBV) polymerase.

Methods

In two double-blind, phase 3 studies, we randomly assigned patients with hepatitis B e antigen (HBeAg)-negative or HBeAg-positive chronic HBV infection to receive tenofovir DF or adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks. The primary efficacy end point was a plasma HBV DNA level of less than 400 copies per milliliter (69 IU per milliliter) and histologic improvement (i.e., a reduction in the Knodell necroinflammation score of 2 or more points without worsening fibrosis) at week 48. Secondary end points included viral suppression (i.e., an HBV DNA level of <400 copies per milliliter), histologic improvement, serologic response, normalization of alanine aminotransferase levels, and development of resistance mutations.

Results

At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir DF than of those receiving adefovir dipivoxil had reached the primary end point (P<0.001). Viral suppression occurred in more HBeAg-negative patients receiving tenofovir DF than patients receiving adefovir dipivoxil (93% vs. 63%, P<0.001) and in more HBeAg-positive patients receiving tenofovir DF than patients receiving adefovir dipivoxil (76% vs. 13%, P<0.001). Significantly more HBeAg-positive patients treated with tenofovir DF than those treated with adefovir dipivoxil had normalized alanine aminotransferase levels (68% vs. 54%, P=0.03) and loss of hepatitis B surface antigen (3% vs. 0%, P=0.02). At week 48, amino acid substitutions within HBV DNA polymerase associated with phenotypic resistance to tenofovir DF or other drugs to treat HBV infection had not developed in any of the patients. Tenofovir DF produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The safety profile was similar for the two treatments in both studies.

Conclusions

Among patients with chronic HBV infection, tenofovir DF at a daily dose of 300mg had superior antiviral efficacy with a similar safety profile as compared with adefovir dipivoxil at a daily dose of 10mg through week 48. (ClinicalTrials.gov numbers, NCT00116805 and NCT00117676.) 2008 Massachusetts Medical Society.

[Abstract reproduced by permission of N Engl J Med 2008;359:2442–2455.]

 

The goal of hepatitis B treatment is to prevent progression to cirrhosis, hepatic decompensation and hepatocellular carcinoma. This goal is best accomplished by complete suppression of hepatitis B virus (HBV) replication.

Lamivudine was the first oral antiviral agent approved for the treatment of chronic hepatitis B. The approval of lamivudine in 1998 brought a lot of hope and hype to the hepatitis field. The availability of an oral therapy that is well tolerated and safe for use in patients with hepatic decompensation or recurrent hepatitis B after liver transplantation was aptly hailed as a major breakthrough. However, it was quickly realized that while lamivudine was effective in suppressing serum HBV DNA, viral relapse was common when treatment was stopped. In some patients, viral relapse was accompanied by hepatitis flares and rarely, hepatic decompensation and death. Unfortunately, continued treatment was associated with increasing rates of antiviral drug resistance which resulted in virologic breakthrough and in some instances hepatitis flares and hepatic decompensation.

The conundrum to stop or to continue HBV treatment appeared to be resolved when adefovir dipivoxil, which has antiviral activity against wild-type as well as lamivudine-resistant HBV, was approved in 2002. Adefovir was hailed as an effective antiviral agent with “no resistance” based on year 1 data from phase III clinical trials and a life-saving rescue therapy for the increasing number of patients with lamivudine-resistant HBV [1], [2], [3]. However, the glow around adefovir dimmed when reports of inadequate virus suppression and drug resistance emerged [4], [5]. The lack luster performance of adefovir is likely due to the use of a suboptimal dose (10mg daily) in an attempt to minimize its nephrotoxic potential. Indeed, higher doses of adefovir had been shown to have more potent antiviral activity and inadequate initial response was not related to pre-existing drug-resistant mutations [2], [6].

The approval of entecavir in 2005 restored hope for hepatitis B treatment. Entecavir has been shown to have more potent antiviral activity than lamivudine or adefovir in head-to-head comparison studies [7], [8], [9]. More importantly, entecavir resistance is rare (∼1%) in nucleoside-naı¨ve patients after up to 5 years of treatment [10]. Thus far, entecavir has an excellent safety record in humans. The fact that entecavir had antiviral activity against lamivudine-resistant HBV provided initial hope that it may be “THE” treatment that would serve all HBV patients. However, it is now clear that the presence of methionine to valine or isoleucine substitution at position 204 (rtM204V/I) reduces the susceptibility to entecavir and increases the likelihood of selection of additional mutations which greatly decrease the susceptibility to entecavir [11]. These in vitro findings have been confirmed by a lower rate of virologic response and a very high rate of resistance in lamivudine-refractory patients despite the use of a higher dose of entecavir [10], [12]. Thus, while entecavir is an appropriate first-line treatment for nucleoside-naı¨ve patients, its role among the growing population of lamivudine-refractory patients is limited.

The approval of telbivudine in 2007 failed to advance the field of hepatitis B treatment. Although telbivudine had more potent antiviral activity than lamivudine or adefovir, it is associated with a high rate of drug resistance and is cross-resistant with lamivudine [13], [14]. Furthermore, rare cases of myopathy and peripheral neuropathy had been reported in patients who had received telbivudine particularly when used in combination with interferon.

The approval of tenofovir disoproxil fumarate as a hepatitis B treatment in 2008 and the recent report of the licensing trials comparing tenofovir and adefovir are encouraging. Marcellin et al. reported the results of 2 double-blind phase III studies: 1 in HBeAg-positive and 1 in HBeAg-negative patients [15]. In both studies, a significantly higher proportion of patients receiving tenofovir reached the primary endpoint of HBV DNA suppression to <400 copies/mL and reduction in Knodell necroinflammatory score of 2 or more points without worsening fibrosis at week 48 than those receiving adefovir. The major difference was more potent virus suppression in the tenofovir group: serum HBV DNA <400 copies/mL at week 48 was achieved in 76% vs. 13% (p<0.001) HBeAg-positive patients and in 93% vs. 63% (p<0.001) in HBeAg-negative patients. In vitro studies showed that tenofovir and adefovir are equipotent on a molar basis. Tenofovir has a better therapeutic ratio allowing it to be used in higher doses: 300mg vs. 10mg for adefovir. This dose difference likely accounts for the more potent virus suppression observed in patients receiving tenofovir. In Marcellin et al’s study, a difference in virus suppression was evident within 4–12 weeks of treatment.

The more rapid virus suppression associated with tenofovir treatment suggests that the rate of antiviral resistance will be substantially lower than that of adefovir. In Marcellin et al.’s study, antiviral-resistant mutations were sought in patients with persistent viremia or virologic breakthrough at week 48 [15]. Of the 426 patients who received tenofovir, 39 were viremic including 10 who had virologic breakthrough. Only 2 patients had conserved site changes in the reverse transcriptase domain of HBV polymerase, neither patient had virologic breakthrough and phenotypic studies showed full susceptibility to tenofovir or a non-viable, nonreplicative virus in cell culture. These data are encouraging but follow-up studies of patients who received longer durations of treatment are needed to determine the rate of tenofovir resistance. Tenofovir resistance had been reported in 2 patients after >12 months of treatment [16]. Although the mutation identified in that study, alanine to threonine substitution (rtA194T), was not confirmed to be associated with tenofovir resistance in another study, additional resistance surveillance is needed [17]. Marcellin et al. attributed nonadherence as the cause of virologic breakthrough in at least two-thirds of the patients but data supporting that claim were not provided. It is possible that tenofovir-resistant mutations may have been selected but were not detected because population sequencing cannot detect variants that constitute less than 20% of the virus pool.

As discussed in the accompanying editorial [18], tenofovir is not only a promising first-line treatment for nucleoside-naı¨ve patients with chronic hepatitis B; it is also expected to be the key therapy (replacing adefovir and displacing entecavir) for lamivudine-refractory patients. However, the role of tenofovir in the armamentarium of hepatitis B treatment depends on its long-term safety. Renal insufficiency, renal tubular abnormalities including Fanconi syndrome and decreased bone density had been reported in patients who have received tenofovir [19], [20]. The incidence of these adverse events is being studied in extensions of the licensing trials. These data are crucial given that many patients treated for hepatitis B are young and have mild liver disease and most patients will require years if not life-long treatment to derive clinical benefits.

Time will tell if tenofovir is a “home-run”. The last 10 years have been an exciting time for physicians treating chronic hepatitis B. The availability of entecavir and tenofovir which are associated with very low rates of drug resistance indicate that monotherapy will suffice for most patients.

Back to Article Outline

References 

  1. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med. 2003;348:800–807
  2. 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
  3. Schiff ER, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, et al. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology. 2003;38:1419–1427
  4. Angus P, Vaughan R, Xiong S, Yang H, Delaney W, Gibbs C, et al. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology. 2003;125:292–297
  5. Villeneuve JP, Durantel D, Durantel S, Westland C, Xiong S, Brosgart CL, et al. Selection of a hepatitis B virus strain resistant to adefovir in a liver transplantation patient. J Hepatol. 2003;39:1085–1089
  6. Carrouee-Durantel S, Durantel D, Werle-Lapostolle B, Pichoud C, Naesens L, Neyts J, et al. Suboptimal response to adefovir dipivoxil therapy for chronic hepatitis B in nucleoside-naive patients is not due to pre-existing drug-resistant mutants. Antivir Ther. 2008;13:381–388
  7. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354:1011–1020
  8. Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001–1010
  9. Leung N, Peng CY, Hann HW, Sollano J, Lao-Tan J, Hsu CW, et al. Early hepatitis B virus DNA reduction in hepatitis B e antigen-positive patients with chronic hepatitis B: A randomized international study of entecavir versus adefovir. Hepatology. 2009;49:72–79
  10. Tenney DJ, Rose RE, Baldick CJ, Eggers BJ, et al. Entecavir at five years shows long-term maintenance of high genetic barrier to hepatitis B virus resistance. Hepatology Int 2008:S76–77.
  11. Tenney DJ, Levine SM, Rose RE, Walsh AW, Weinheimer SP, Discotto L, et al. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to Lamivudine. Antimicrob Agents Chemother. 2004;48:3498–3507
  12. Sherman M, Yurdaydin C, Simsek H, Silva M, Liaw YF, Rustgi VK, et al. Entecavir therapy for lamivudine-refractory chronic hepatitis B: improved virologic, biochemical, and serology outcomes through 96 weeks. Hepatology. 2008;48:99–108
  13. 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;357:2576–2588
  14. 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
  15. Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:2442–2455
  16. Sheldon J, Camino N, Rodes B, Bartholomeusz A, Kuiper M, Tacke F, et al. Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir. Antivir Ther. 2005;10:727–734
  17. Delaney WE, Ray AS, Yang H, Qi X, Xiong S, Zhu Y, et al. Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicrob Agents Chemother. 2006;50:2471–2477
  18. Lai CL, Yuen MF. Chronic hepatitis B – new goals, new treatment. N Engl J Med. 2008;359:2488–2491
  19. 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
  20. Gilead Sciences Inc. – Foster City, CA. VIREAD® (tenofovir disoproxil fumarate) tablets. US Prescribing Information. November 2008.

☆ The author serves on advisory boards for Gilead Sciences and receives research support from Gilead Sciences, Bristol-Myers Squibb, Novartis and GlaxoSmith Kline.

PII: S0168-8278(09)00164-0

doi:10.1016/j.jhep.2009.03.003

Journal of Hepatology
Volume 51, Issue 2 , Pages 416-418, August 2009

Article Tools