Similar articles

Abstract: Objective: To study the clinical features of chronic hepatitis B (CHB) patients with tyrosine-methionine-aspartate-aspartate (YMDD) mutation after lamivudine therapy. Methods: This investigation was a retrospective study of 63 CHB patients with YMDD mutation during lamivudine therapy. Clinical data, including period and types of YMDD mutation; hepatitis B virus (HBV) DNA levels and alanine aminotransferase (ALT) levels before and after YMDD mutation were measured. YMDD mutation in the HBV DNA polymerase gene was determined using polymerase chain reaction (PCR) and direct sequencing. HBV DNA quantification was determined using real-time PCR. Relevant serum markers of HBV were measured. The follow-up period was 12 months after YMDD mutation. Results: YMDD mutation occurred 7~44 months (median, 21.5 months) after the start of lamivudine therapy. The majority of the cases (42/63, 66.6%) had YMDD mutants detected between 12 and 24 months. Four types of YMDD mutation were observed in this study, rtL180M/M204V mutation was the predominant type (26/63, 41.3%). A proportion of patients (16/63, 25.4%; 12/63, 19.1%) had higher HBV DNA levels and ALT levels (after mutation vs before mutation), respectively. Conclusion: The majority of patients with YMDD mutants had similar or lower HBV DNA levels and ALT levels compared with baseline values. This subset of patients might have benefited from the continued lamivudine therapy. The patients with increased ALT and HBV DNA levels (breakthrough hepatitis) should benefit from the addition of a newer nucleotide analogue (e.g. adefovir).

[1] Allen, M.I., Deslauriers, M., Andrews, C.W., Tipples, G.A., Walters, K.A., Tyrell, D.L., Brown, N., Condreay, L.D., 1998. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Hepatology, 27(6):1670-1677.

[2] Bartholomew, M.M., Jansen, R.W., Jeffers, L.J., Reddy, K.R., Johnson, L.C., Bunzendahl, H., Condreay, L.D., Tzakis, A.G., Schiff, E.R., Brown, N.A., 1997. Hepatitis-B-virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation. Lancet, 349(9044):20-22.

[3] Bozdayi, A.M., Eyigun, C.P., Turkyilmaz, A.R., Avci, I.Y., Pahsa, A., Yurdaydin, C., 2004. A novel pattern (sW195a) in surface gene of HBV DNA due to YSDD (L180M plus M204S) mutation selected during lamivudine therapy and successful treatment with adefovir dipivoxil. J. Clin. Virol., 31(1):76-77.

[4] Chayama, K., Suzuki, Y., Kobayashi, M., Kobayashi, M., Tsubota, A., Miyano, Y., Koike, H., Kobayashi, M., Koida, I., Arase, Y., et al., 1998. Emergence and takeover of YMDD motif mutant hepatitis B virus during long-term lamivudine therapy and re-takeover by wild-type after cessation of therapy. Hepatology, 27(6):1711-1716.

[5] Chen, C.H., Lee, C.M., Lu, S.N., Wang, J.H., Tung, H.D., Hung, C.H., Chen, W.J., Changchien, C.S., 2004. Comparison of clinical outcome between patients continuing and discontinuing lamivudine therapy after biochemical breakthrough of YMDD mutants. J. Hepatol., 41(3):454-461.

[6] de Clercq, E., 2001. Antiviral drugs: current state of the art. J. Clin. Virol., 22(1):73-89.

[7] de Clercq, E., 2004. Antiviral drugs in current clinical use. J. Clin. Virol., 30(2):115-133.

[8] Dienstag, J.L., Schiff, E.R., Wright, T.L., Perrillo, R.P., Hann, H.W., Goodman, Z., Crowther, L., Condreay, L.D., Woessner, M., Rubin, M., et al., 1999. Lamivudine as initial treatment for chronic hepatitis B in the United States. N. Engl. J. Med., 341(17):1256-1263.

[9] Dienstag, J.L., Goldin, R.D., Heathcote, E.J., Hann, H.W., Woessner, M., Stephenson, S.L., Gardner, S., Gray, D.F., Schiff, E.R., 2003. Histological outcome during long-term lamivudine therapy. Gastroenterology, 124(1):105-117.

[10] Ganem, D., Prince, A.M., 2004. Hepatitis B virus infection−natural history and clinical consequences. N. Engl. J. Med., 350(11):1118-1129.

[11] Guan, R., Lai, C.L., Liaw, Y.F., Lim, S.G., Lee, C.M., 2001. Efficacy and safety of 5-years lamivudine treatment of Chinese patients with chronic hepatitis B [abstract]. J. Gastroenterol. Hepatol., 16(Suppl 1):A60.

[12] Lai, C.L., Ching, C.K., Tung, A.K., Li, E., Young, J., Hill, A., Wong, B.C., Dent, J., Wu, P.C., 1997. Lamivudine is effective in suppressing hepatitis B virus DNA in Chinese hepatitis B surface antigen carriers: a placebo-controlled trial. Hepatology, 25(1):241-244.

[13] Lai, C.L., Chien, R.N., Leung, N.W., Chang, T.T., Guan, R., Tai, D.I., Ng, K.Y., Wu, P.C., Dent, J.C., Barber, J., et al., 1998. A one-year trial of lamivudine for chronic hepatitis B. N. Engl. J. Med., 339(2):61-68.

[14] Liaw, Y.F., Chien, R.N., Yeh, C.T., Tsai, S.L., Chu, C.M., 1999. Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy. Hepatology, 30(2):567-572.

[15] Liaw, Y.F., Leung, N.W., Chang, T.T., Guan, R., Tai, D.I., Ng, K.Y., Chien, R.N., Dent, J., Roman, L., Edmundson, S., Lai, C.L., 2000. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. Gastroenterology, 119(1):172-180.

[16] Liaw, Y.F., Sung, J.J., Chow, W.C., Farrell, G., Lee, C.Z., Yuen, H., Tanwandee, T., Tao, Q.M., Shue, K., Keene, O.N., et al., 2004. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N. Engl. J. Med., 351(15):1521-1531.

[17] Lok, A.S.F., McMahon, B.J., 2004. Chronic hepatitis B: update of recommendations. Hepatology, 39(3):857-861.

[18] Marcellin, P., Lau, G.K., Bonino, F., Farci, P., Hadziyannis, S., Jin, R., Lu, Z.M., Piratvisuth, T., Germanidis, G., Yurdaydin, C., et al., 2004. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N. Engl. J. Med., 351(12):1206-1217.

[19] Melegari, M., Scaglioni, P.P., Wands, J.R., 1998. Hepatitis B virus mutants associated with 3TC and famcicloviir administration are replication defective. Hepatology, 27(2):628-633.

[20] Ono-Nita, S.K., Kato, N., Shiratori, Y., Masaki, T., Lan, K.H., Carrilho, F.J., Omata, M., 1999. YMDD motif in hepatitis B virus DNA polymerase influences on replication and lamivudine resistance: a study by in vitro full-length viral DNA transfection. Hepatology, 29(3):939-945.

[21] Pillay, D., Bartholomeusz, A., Cane, P.A., Mutimer, D., Schinazi, R.F., Locarnini, S.A., 1998. Mutations in the hepatitis B virus DNA polymerase associated with antiviral resistance. Int. Antiviral. News, 6:167-169.

[22] Tipples, G.A., Ma, M.M., Fischer, K.P., Bain, V.G., Kneteman, N.M., Tyrrell, D.L., 1996. Mutation in HBV RNA-dependent DNA polymerase confers resistance to lamivudine in vivo. Hepatology, 24(3):714-717.

[23] Wands, J.R., 2004. Prevention of hepatocellular carcinoma. N. Engl. J. Med., 351(15):1567-1570.