Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hepatitis B virus infection

Maria Buti, Naoky Tsai, Joerg Petersen, Robert Flisiak, Selim Gurel, Zahary Krastev, Raul Aguilar Schall, John F Flaherty, Eduardo B Martins, Prista Charuworn, Kathryn M Kitrinos, G Mani Subramanian, Edward Gane, Patrick Marcellin, Maria Buti, Naoky Tsai, Joerg Petersen, Robert Flisiak, Selim Gurel, Zahary Krastev, Raul Aguilar Schall, John F Flaherty, Eduardo B Martins, Prista Charuworn, Kathryn M Kitrinos, G Mani Subramanian, Edward Gane, Patrick Marcellin

Abstract

Background: Long-term tenofovir disoproxil fumarate (TDF) treatment for chronic hepatitis B (CHB) is associated with sustained viral suppression and regression of fibrosis and cirrhosis at year 5 (240 weeks) and no TDF resistance through 6 years (288 weeks).

Aim: We assessed the efficacy, safety, and resistance of TDF for up to 7 years (336 weeks) in HBeAg-positive and HBeAg-negative CHB patients.

Methods: Patients who completed 1 year (48 weeks) of randomized treatment with TDF or adefovir dipivoxil were eligible to receive open-label TDF for a total duration of 8 years (384 weeks).

Results: Of 641 patients initially randomized, 585 (91.3 %) entered the open-label phase; 437/585 (74.7 %) remained on study at year 7. For patients on treatment at year 7, 99.3 % maintained viral suppression (HBV DNA < 69 IU/mL), 80.0 % achieved serum alanine aminotransferase normalization, and in HBeAg-positive patients, 84/154 (54.5 %) and 25/154 (11.8 %) achieved HBeAg and HBsAg loss, respectively. One/375 (0.3 %) HBeAg-negative patients achieved HBsAg loss. No resistance to TDF was detected through 7 years. During the open-label phase, grade 3/4 drug-related adverse events were uncommon (1.0 %); ten (1.7 %) patients had elevation of serum creatinine ≥ 0.5 mg/dL above baseline. No significant change in bone mineral density was observed from year 4 to year 7 (week 192 to week 336).

Conclusions: Long-term TDF treatment was associated with sustained virologic, biochemical, and serologic responses, without resistance. TDF treatment was well tolerated, with a low incidence of renal and bone events. These data confirm the safety and efficacy of long-term TDF for CHB.

Trial registration: ClinicalTrials.gov NCT00116805 NCT00117676.

Figures

Fig. 1
Fig. 1
Patient disposition at year 7
Fig. 2
Fig. 2
Disposition at year 7 (week 336) of patients who experienced confirmed HBsAg loss. aCompleted through year 7. bOne patient experienced seroreversion, restarted on treatment, and seroconverted again

References

    1. Lok AS. Chronic hepatitis B. N Engl J Med. 2002;346:1682–1683. doi: 10.1056/NEJM200205303462202.
    1. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65–73. doi: 10.1001/jama.295.1.65.
    1. Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678–686. doi: 10.1053/j.gastro.2005.11.016.
    1. Di Marco V, Di Stefano R, Ferraro D, et al. HBV-DNA suppression and disease course in HBV cirrhosis patients on long-term lamivudine therapy. Antivir Ther. 2005;10:431–439.
    1. De Clercq E, Ferir G, Kaptein S, Neyts J. Antiviral treatment of chronic hepatitis B virus (HBV) infections. Viruses. 2010;2:1279–1305. doi: 10.3390/v2061279.
    1. Heijtink RA, Kruining J, de Wilde GA, Balzarini J, de Clercq E, Schalm SW. Inhibitory effects of acyclic nucleoside phosphonates on human hepatitis B virus and duck hepatitis B virus infections in tissue culture. Antimicrob Agents Chemother. 1994;38:2180–2182. doi: 10.1128/AAC.38.9.2180.
    1. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:2442–2455. doi: 10.1056/NEJMoa0802878.
    1. Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381:468–475. doi: 10.1016/S0140-6736(12)61425-1.
    1. Kitrinos KM, Corsa A, Liu Y, et al. No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B. Hepatology. 2013;59:434–442. doi: 10.1002/hep.26686.
    1. Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011;140:132–143. doi: 10.1053/j.gastro.2010.10.011.
    1. Marcellin P, Chang TT, Lim SG, et al. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2008;48:750–758. doi: 10.1002/hep.22414.
    1. Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003;348:808–816. doi: 10.1056/NEJMoa020681.
    1. Lok AS, Lai CL, Leung N, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology. 2003;125:1714–1722. doi: 10.1053/j.gastro.2003.09.033.
    1. Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology. 2009;49:1503–1514. doi: 10.1002/hep.22841.
    1. Zoutendijk R, Reijnders JG, Brown A, et al. Entecavir treatment for chronic hepatitis B: adaptation is not needed for the majority of naive patients with a partial virological response. Hepatology. 2011;54:443–451. doi: 10.1002/hep.24406.
    1. Park JW, Kim HS, Seo DD, et al. Long-term efficacy of entecavir in adefovir-refractory chronic hepatitis B patients with prior lamivudine resistance. J Viral Hepat. 2011;18:e475–e481. doi: 10.1111/j.1365-2893.2011.01479.x.
    1. Berg T, Zoulim F, Moeller B, et al. Long-term efficacy and safety of emtricitabine plus tenofovir DF vs. tenofovir DF monotherapy in adefovir-experienced chronic hepatitis B patients. J Hepatol. 2014;60:715–722. doi: 10.1016/j.jhep.2013.11.024.
    1. Fung S, Kwan P, Fabri M, et al. Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2013;146:980–988. doi: 10.1053/j.gastro.2013.12.028.
    1. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521–1531. doi: 10.1056/NEJMoa033364.
    1. Gish RG, Chang TT, Lai CL, et al. Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside-naive HBeAg-positive patients with chronic hepatitis B. J Viral Hepat. 2010;17:16–22. doi: 10.1111/j.1365-2893.2009.01146.x.
    1. Chang TT, Lai CL, Kew Yoon S, et al. Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2010;51:422–430.
    1. McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology. 2009;49:S45–S55. doi: 10.1002/hep.22898.

Source: PubMed

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