To determine differences in Chinese patients treated with adefovir (ADV) monotherapy or ADV in combination with lamivudine (3TC) after development of resistance to 3TC, with respect to biochemical improvement, HBV DNA suppression and development of subsequent ADV resistance.
Methods
All hepatitis B patients with 3TC resistance treated with ADV for 3 months or more at our centre were included, and monitored 3–6 monthly for biochemical and virological response, and development of ADV resistance.
Results
A total of 56 patients were included, 50% switched to ADV monotherapy and 50% received combination 3TC/ADV therapy. Median follow-up was 15.5 months. Normalization of alanine aminotransferase (ALT) occurred in 25 (89%) patients in the ADV group compared with 24 (86%) in the 3TC/ADV group (P=0.686). Virological response (VR) was achieved in seven (35%) patients in the ADV group at 12 months compared with five (28%) in the 3TC/ADV group (P=0.637). By 24 months, seven (64%) patients in the ADV group achieved VR compared with two (40%) in the 3TC/ADV group (P=0.377). Cumulative probability of developing genotypic ADV resistance in the ADV group at 24 months was 18% compared with 7% in the 3TC/ADV group (P=0.94).
Conclusions
There was no obvious improvement in ALT normalization and virological suppression or reduction in the development of ADV-resistant mutations with 3TC/ADV therapy compared with ADV monotherapy. Further studies with longer follow-ups are required to determine whether combination 3TC/ADV therapy will reduce the emergence of ADV resistance compared with ADV monotherapy.
AllenM., DeslauriersM., AndrewsC.W.Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group.Hepatology1998; 27: 1670–1677.
3.
LaiC., DienstagJ., SchiffE.Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B.Clin Infect Dis2003; 36: 687–696.
4.
HadziyannisS., TassopoulosN.C., ChangT.T.Long-term adefovir dipivoxil treatment induces regression of liver fibrosis in patients with HBeAg-negative chronic hepatitis B: results after 5 years of therapy.56th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA, USA, 11–15 November 2005. Late-Breaking Abstract 14.
5.
AngusP., VaughanR., XiongS.Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase.Gastroenterology2003; 125: 292–297.
6.
HussainM., FungS., LibbrechtE.Sensitive line probe assay that simultaneously detects mutations conveying resistance to lamivudine and adefovir.J Clin Microbiol2006; 44: 1094–1097.
7.
UsudaS., OkamotoH., IwanariH.Serological detection of hepatitis B virus genotypes by ELISA with monoclonal antibodies to type-specific epitopes in the preS2-region product.J Virol Methods1999; 80: 97–112.
8.
MihmU., GartnerB.C., FaustD.Viral kinetics in patients with lamivudine-resistant hepatitis B during adefovir-lamivudine combination therapy.J Hepatol2005; 43: 217–224.
9.
PetersM., HannH.W., MartinP.Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B.Gastroenterology2004; 126: 91–101.
10.
HadziyannisS., TassopoulosN.C., HeathcoteE.J.Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B.N Engl J Med2003; 348: 800–807.
11.
MarcellinP., ChangT.T., LimS.G.Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.N Engl J Med2003; 348: 808–816.
12.
PerrilloR., HannH.W., MutimerD.Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus.Gastroenterology2004; 126: 81–90.
13.
WestlandC., YangH., DelaneyW.E.Activity of adefovir dipivoxil against all patterns of lamivudine-resistant hepatitis B viruses in patients.J Viral Hepat2005; 12: 67–73.
14.
LiuC.J., KaoJ.H., ChenP.J.Overlap lamivudine treatment in patients with chronic hepatitis B receiving adefovir for lamivudine-resistant viral mutants.J Viral Hepat2006; 13: 387–395.
15.
ColledgeD., CiviticoG., LocarniniS.In vitro antihep-adnaviral activities of combinations of penciclovir, lamivudine, and adefovir.Antimicrob Agents Chemother2000; 44: 551–560.
16.
SungJ., LaiJ.Y., ZeuzemS.A randomised double-blind phase II study of lamivudine (LAM) compared to lamivudine plus adefovir dipivoxil (ADV) for the treatment naive patients with chronic hepatitis B (CHB): week 52 analysis.38th Annual Meeting of the European Association for the Study of the Liver. Geneva, Switzerland, 3–6 July 2003. Abstract 4313.
17.
GhanyM., LutchmanG., KleinerD.Lamivudine and adefovir versus adefovir alone for HBeAg-positive chronic hepatitis B.56th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA, USA, 11–15 November 2005. Abstract 1005.
18.
ChinR., ShawT., TorresiJ.In vitro susceptibilities of wild-type or drug-resistant hepatitis B virus to (-)- β-d-2,6-diaminopurine dioxolane and 2’-fluoro-5-methyl-β-l-arabinofuranosyluracil.Antimicrob Agents Chemother2001; 45: 2495–2501.
19.
WestlandC., YangH., DelaneyW.E.Week 48 resistance surveillance in two phase 3 clinical studies of adefovir dipivoxil for chronic hepatitis B.Hepatology2003; 38: 96–103.
20.
LocarniniS., QiS., ArterburnS.Incidence and predictors of emergence of adefovir resistant HBV during four years of adefovir dipivoxil (ADV) therapy for patients with chronic hepatitis B (CHB).40th Annual Meeting of the European Association for the Study of the Liver. Paris, France, 13–17 April 2005. Abstract 36.
21.
LamperticoP., ViganoM., ManentiE.Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine.Hepatology2005; 42: 1414–1419.
22.
LamperticoP., MarzanoA., LevreroM.A multicenter Italian study of rescue adefovir dipivoxil therapy in lamivudine resistant patients: a 2-year analysis of 604 patients.56th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA, USA, 11–15 November 2005. Abstract 1003.
23.
YuenM.F., SablonE., HuiC.K.Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy.Hepatology2001; 34: 785–791.
24.
FungS.K., ChaeH.B., FontanaR.J.Virologic response and resistance to adefovir in patients with chronic hepatitis B.J Hepatol2006; 44: 283–290.
LeeY.S., SuhD.J., LimY.S.Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy.Hepatology2006; 43: 1385–1391.
