HBV drug resistance: Mechanisms, detection and interpretation
2006; Elsevier BV; Volume: 44; Issue: 3 Linguagem: Inglês
10.1016/j.jhep.2006.01.001
ISSN1600-0641
AutoresTimothy J. Shaw, Angeline Bartholomeusz, Stephen Locarnini,
Tópico(s)HIV/AIDS drug development and treatment
Resumo1. IntroductionBesides interferon, only two drugs—lamivudine and adefovir dipivoxil—are approved as first-line therapy for chronic hepatitis B (CHB) in the EU [1Buti M. Esteban R. Drugs in development for hepatitis B.Drugs. 2005; 65: 1451-1460Crossref PubMed Scopus (27) Google Scholar, 2Craxi A, Antonucci G, Camma C. Treatment options in HBV. J Hepatol 2006; 44(Suppl 1): S77–S83.Google Scholar]. Each is a nucleoside or nucleotide analogue that acts mainly as a specific inhibitor of the viral polymerase/reverse transcriptase (for convenience, the acronym Nucleos(t)ide Reverse Transcriptase Inhibitor (NRTI) will be used here to refer all nucleoside and nucleotide derivatives that act by inhibiting functions of the HBV polymerase). Several other NRTIs besides lamivudine and adefovir dipivoxil have been found to be effective against HBV [[1]Buti M. Esteban R. Drugs in development for hepatitis B.Drugs. 2005; 65: 1451-1460Crossref PubMed Scopus (27) Google Scholar]. They include entecavir, which is licensed in the USA [[3]Shaw T. Locarnini S. Entecavir for the treatment of chronic hepatitis B.Expert Rev Anti Infect Ther. 2004; 2: 853-871Crossref PubMed Scopus (42) Google Scholar], and tenofovir, which is used to treat HIV-1 infection [4Kuo A. Dienstag J.L. Chung R.T. Tenofovir disoproxil fumarate for the treatment of lamivudine-resistant hepatitis B.Clin Gastroenterol Hepatol. 2004; 2: 266-272Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 5Thio C.L. Sulkowski M.S. Thomas D.L. Treatment of chronic hepatitis B in HIV-infected persons: thinking outside the black box.Clin Infect Dis. 2005; 41: 1035-1040Crossref PubMed Scopus (22) Google Scholar]. In most cases, treatment of CHB with any single NRTI produces rapid suppression of HBV replication in the short-term, an effect that is not often sustainable due to the emergence of drug-resistant HBV strains [1Buti M. Esteban R. Drugs in development for hepatitis B.Drugs. 2005; 65: 1451-1460Crossref PubMed Scopus (27) Google Scholar, 6Mailliard M.E. Gollan J.L. Emerging therapeutics for chronic hepatitis B.Annu Rev Med. 2005; Google Scholar]. Although a variety of other factors including adverse short-term side effects, long-term toxicity, previous sub-optimal treatment regimes, inadequate drug exposure (due to pharmacological properties of particular drugs, poor patient compliance with prescribed treatment, or host genetic polymorphisms) influence the efficacy of treatments for chronic HBV, drug resistance is emerging as the single most significant factor in treatment failure [[7]Locarnini S, Mason WS. Cellular and virological mechanisms of HBV drug resistance. J Hepatol 2006; 44: 422–431.Google Scholar]. Failure of NRTI treatment presents a significant clinical challenge, because remaining treatment options are limited [2Craxi A, Antonucci G, Camma C. Treatment options in HBV. J Hepatol 2006; 44(Suppl 1): S77–S83.Google Scholar, 8Locarnini S. Hatzakis A. Heathcote J. Keeffe E.B. Liang T.J. Mutimer D. et al.Management of antiviral resistance in patients with chronic hepatitis B.Antivir Ther. 2004; 9: 679-693PubMed Google Scholar]. Here, we attempt to summarise the current state of knowledge of HBV resistance to NRTI, briefly describe available methods for detecting and quantifying drug resistance and discuss the interpretation of drug resistance and its clinical applications.1.1 What constitutes drug resistance?Resistance can be defined in technical, virological or clinical terms. Technically, resistance is defined by either (1) a statistically significant change in the test parameter (increase in EC50, for example) or (2) the minimum change in a parameter that is required for statistical significance (for example, a single log10 change). Technical definitions only describe the attributes of specific tests and have no biological or clinical significance.Virological resistance is now commonly described as high-, intermediate- or low-level based on fold-changes in EC50 in vitro. Such ranking, unfortunately, does not relate directly to clinical observations. For example, lamivudine failure is associated with >100 fold increase in EC50 in vitro, but HBV isolates responsible for adefovir resistance exhibit only low-level ( 2RRRRRRRR0.30.30.20.30.70.1Emtricitabine1.2RRRRRNDRRRR0.80.70.30.60.60Telbivudine1.0>2>2>2>2>2ND>2RRRTorcitabine>2>2>2Clevudine1.0RRRRRRRRRRDeoxyguanosine analoguesEntecavir−0.5 3.0 (>1000-fold increase in EC50). In some cases, accurate estimates not possible because of inefficient replication of mutant. Data from the SeqHepB database and results of phenotyping carried out in the authors' laboratory using the recombinant HBV-baculovirus system. Single letter amino acid abbreviations: A, alanine; D, aspartate; G, glycine; I, isoleucine; L, leucine; M, methionine; N: asparagines; Q, glutamine; S, serine; T, threonine; V, valine. Primary resistance changes are boxed. As the table shows, many cross-resistance profiles are incomplete, but it is clear that resistance to lamivudine confers cross-resistance to other l-nucleosides and clinical clinical failure of penciclovir, adefovir and tenofovir is associated with relatively small changes in EC50 in vitro. 3′-Fluoro-ddG: 2′,3′-dideoxy-3′-fluoroguanosine (see Fig. 2). Open table in a new tab Not surprisingly, primary resistance to any individual drug appears to confer at least some degree of cross-resistance to other members of its group, and may also diminish sensitivity to NRTI from other groups. Mutations that confer resistance to lamivudine confer cross-resistance to other l-nucleosides and reduce sensitivity to entecavir but not to adefovir or tenofovir [[9]Lada O. Benhamou Y. Cahour A. Katlama C. Poynard T. Thibault V. In vitro susceptibility of lamivudine-resistant hepatitis B virus to adefovir and tenofovir.Antivir Ther. 2004; 9: 353-363PubMed Google Scholar]. Conversely, mutations that confer resistance to adefovir and/or tenofovir do not confer significant cross-resistance to l-nucleosides and entecavir, at least in vitro [10Brunelle M.N. Jacquard A.C. Pichoud C. Durantel D. Carrouee-Durantel S. Villeneuve J.P. et al.Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir.Hepatology. 2005; 41: 1391-1398Crossref PubMed Scopus (236) Google Scholar, 11Yang H. Qi X. Sabogal A. Miller M. Xiong S. Delaney W.Et. Cross-resistance testing of next-generation nucleoside and nucleotide analogues against lamivudine-resistant HBV.Antivir Ther. 2005; 10: 625-633PubMed Google Scholar]. Multiple mutations in addition to those that confer resistance to lamivudine are required for high-level resistance to entecavir [[12]Tenney D.J. Levine S.M. Rose R.E. Walsh A.W. Weinheimer S.P. 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: 3498-3507Crossref PubMed Scopus (487) Google Scholar] (see Table 1).3. Molecular modelling identifies mechanisms for resistance to NRTILaboratory studies of mechanisms for HBV resistance to NRTI have been frustrated by the inability to obtain sufficient quantities of purified polymerase. However, it has been possible to create three-dimensional models of the reverse transcriptase (rt) region of HBV polymerase have based on its homology with related polymerases, including HIV-1 rt. Using these models, the amino acid changes resulting from mutations that confer antiviral resistance can be mapped to functional regions to provide a better understanding of mechanisms for resistance [13Das K. Xiong X. Yang H. Westland C.E. Gibbs C.S. Sarafianos S.G. Arnold E. Molecular modeling and biochemical characterization reveal the mechanism of hepatitis B virus polymerase resistance to lamivudine (3TC) and emtricitabine (FTC).J Virol. 2001; 75: 4771-4779Crossref PubMed Scopus (249) Google Scholar, 14Bartholomeusz A. Tehan B.G. Chalmers D.K. Comparisons of the HBV and HIV polymerase, and antiviral resistance mutations.Antivir Ther. 2004; 9: 149-160PubMed Google Scholar, 15Bartholomeusz A. Locarnini S. Ayres A. Thompson G. Bowden S. Sozzi V. et al.Mechanistic basis for hepatitis B virus resistance to acyclic phosphonate analogues, adefovir and tenofovir. (Abstract 1011).Hepatology. 2005; 42: 594AGoogle Scholar].3.1 Resistance to lamivudine and other l-nucleosidesLamivudine resistance, which occurs at a cumulative rate of about 14–20% per year, is most frequent in individuals who are co-infected with HIV-1 and HBV [[16]Benhamou Y. Bochet M. Thibault V. Di Martino V. Caumes E. Bricaire F. et al.Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients.Hepatology. 1999; 30: 1302-1306Crossref PubMed Scopus (384) Google Scholar]. Mutations that result in replacement of methionine in the tyrosine–methionine–aspartate (YMDD) catalytic site motif by valine, leucine or (rarely) serine are necessary and sufficient to confer resistance to lamivudine [17Bartholomew M.M. Jansen R.W. Jeffers L.J. Reddy K.R. Johnson L.C. Bunzendahl H. et al.Hepatitis-B-virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation.Lancet. 1997; 349: 20-22Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar, 18Allen M.I. Deslauriers M. Andrews C.W. Tipples G.A. Walters K.A. Tyrrell D.L. et al.Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group.Hepatology. 1998; 27: 1670-1677Crossref PubMed Scopus (776) Google Scholar]. These changes are designated rtM204V, rtM204I and rtM204S, respectively, using the genotype-independent nomenclature proposed in 2001 [[19]Stuyver L.J. Locarnini S.A. Lok A. Richman D.D. Carman W.F. Dienstag J.L. et al.Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region.Hepatology. 2001; 33: 751-757Crossref PubMed Scopus (360) Google Scholar]. The rtM204I substitution has been detected in isolation, but rtM204V/S are found only in association with other changes, some of which may be compensatory, in particular rtL180M/C and rtV173L [20Delaney IV, W.E. Yang H. Westland C.E. Das K. Arnold E. Gibbs C.S. et al.The hepatitis B virus polymerase mutation rtV173L is selected during lamivudine therapy and enhances viral replication in vitro.J Virol. 2003; 77: 11833-11841Crossref PubMed Scopus (232) Google Scholar, 21Nakanishi H. Kurosaki M. Asahina Y. Onuki Y. Ueda K. Nishimura Y. et al.Polymerase domain B mutation is associated with hepatitis relapse during long-term lamivudine therapy for chronic hepatitis B.Intervirology. 2005; 48: 381-388Crossref PubMed Scopus (8) Google Scholar, 22Pai S.B. Bozdayi A.M. Pai R.B. Beker T. Sarioglu M. Turkyilmaz A.R. et al.Emergence of a novel mutation in the FLLA region of hepatitis B virus during lamivudine therapy.Antimicrob Agents Chemother. 2005; 49: 2618-2624Crossref PubMed Scopus (15) Google Scholar]. Genotyping of HBV mutants identified in clinical isolates implicated in lamivudine resistance reveals numerous amino acid substitutions in the polymerase protein besides rtM204I/V/S [[23]Fu L. Cheng Y.C. Role of additional mutations outside the YMDD motif of hepatitis B virus polymerase in l(−)SddC (3TC) resistance.Biochem Pharmacol. 1998; 55: 1567-1572Crossref PubMed Scopus (122) Google Scholar]. Phenotyping of individual HBV mutants is incomplete, but the majority of mutations may not contribute significantly to drug resistance, probably merely compensating for enzymatic deficiencies associated with resistance.Molecular modelling suggests that lamivudine resistance conferred by rtM204I/V/S is due to both steric hindrance and electrostatic repulsion, since the substituted amino acids decrease the size of the dNTP binding pocket as well as changing the surrounding charge distribution [[24]Chong Y. Stuyver L. Otto M.J. Schinazi R.F. Chu C.K. Mechanism of antiviral activities of 3′-substituted l-nucleosides against 3TC-resistant HBV polymerase: a molecular modelling approach.Antivir Chem Chemother. 2003; 14: 309-319PubMed Google Scholar]. Phenotyping shows that rtL180M/C alone is insufficient to confer lamivudine resistance, but that when present in association with rtM204I/V/S it enhances both replication and lamivudine resistance [21Nakanishi H. Kurosaki M. Asahina Y. Onuki Y. Ueda K. Nishimura Y. et al.Polymerase domain B mutation is associated with hepatitis relapse during long-term lamivudine therapy for chronic hepatitis B.Intervirology. 2005; 48: 381-388Crossref PubMed Scopus (8) Google Scholar, 22Pai S.B. Bozdayi A.M. Pai R.B. Beker T. Sarioglu M. Turkyilmaz A.R. et al.Emergence of a novel mutation in the FLLA region of hepatitis B virus during lamivudine therapy.Antimicrob Agents Chemother. 2005; 49: 2618-2624Crossref PubMed Scopus (15) Google Scholar, 23Fu L. Cheng Y.C. Role of additional mutations outside the YMDD motif of hepatitis B virus polymerase in l(−)SddC (3TC) resistance.Biochem Pharmacol. 1998; 55: 1567-1572Crossref PubMed Scopus (122) Google Scholar, 25Melegari M. Scaglioni P.P. Wands J.R. Hepatitis B virus mutants associated with 3TC and famciclovir administration are replication defective.Hepatology. 1998; 27: 628-633Crossref PubMed Scopus (339) Google Scholar, 26Ono S.K. Kato N. Shiratori Y. Kato J. Goto T. Schinazi R.F. et al.The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance.J Clin Invest. 2001; 107: 449-455Crossref PubMed Scopus (251) Google Scholar]. Molecular modelling predicts that the presence of rtL180M decreases affinity for the oxothiolane ring of lamivudine-triphosphate by increasing local electronegativity around the deoxyribose-binding site, allowing better discrimination between lamivudine triphosphate and dCTP [[24]Chong Y. Stuyver L. Otto M.J. Schinazi R.F. Chu C.K. Mechanism of antiviral activities of 3′-substituted l-nucleosides against 3TC-resistant HBV polymerase: a molecular modelling approach.Antivir Chem Chemother. 2003; 14: 309-319PubMed Google Scholar]. Better discrimination is manifest as higher copying fidelity in vitro [[27]Hong Y.B. Choi Y. Jung G. Increased DNA polymerase fidelity of the Lamivudine resistant variants of human hepatitis B virus DNA polymerase.J Biochem Mol Biol. 2004; 37: 167-176Crossref PubMed Google Scholar].Phenotyping also shows that rtV173L, which has been detected in 9% of cases of lamivudine resistance and is more common in liver transplant patients, compensates for replication defects of lamividine resistant HBV mutants [[20]Delaney IV, W.E. Yang H. Westland C.E. Das K. Arnold E. Gibbs C.S. et al.The hepatitis B virus polymerase mutation rtV173L is selected during lamivudine therapy and enhances viral replication in vitro.J Virol. 2003; 77: 11833-11841Crossref PubMed Scopus (232) Google Scholar]. Modelling indicates that rtV173L may alter either the alignment of the nucleic acid template and/or the environment around catalytic site in such a way as to increase polymerisation efficiency.By contrast, rtL80V/I, which was initially detected in genotype C HBV isolates from patients with severe hepatitis due to apparent lamivudine failure [[28]Ogata N. Fujii K. Takigawa S. Nomoto M. Ichida T. Asakura H. Novel patterns of amino acid mutations in the hepatitis B virus polymerase in association with resistance to lamivudine therapy in japanese patients with chronic hepatitis B.J Med Virol. 1999; 59: 270-276Crossref PubMed Scopus (80) Google Scholar], has been found to enhance replication without contributing to lamivudine resistance (N. Warner, A. Bartholomeusz and S. Locarnini personal communication); it has also been associated with poor response to adefovir [[29]Lee Y.-S. Chung Y.-H. Ryu S.H. Kim J.A. Choi M.H. Jung S.W. et al.Hepatitis B virus with rtL80V/I mutation associates with poor response to adefovir dipivoxil therapy (Abstract 965).Hepatology. 2005; 42: 575ACrossref Google Scholar]. Modelling locates rtL80 within a beta sheet that interacts with a conserved alpha helix to form the enzyme's hydrophobic core, away from the active site but in close proximity to a conserved catalytic aspartic acid residue (rtD83), catalytic function of which is presumably altered by the rtL80V/I substitution. It seems likely that rtQ215S and rtA181T/V may also allosterically alter the geometry of the active site in a way that contributes to drug resistance by decreasing affinity for both lamivudine and adefovir.The rtA181T substitution was first observed (surprisingly, without rtM204I/V) in clinical isolates from patients undergoing long-term lamivudine treatment [[30]Yeh C.T. Chien R.N. Chu C.M. Liaw Y.F. Clearance of the original hepatitis B virus YMDD-motif mutants with emergence of distinct lamivudine-resistant mutants during prolonged lamivudine therapy.Hepatology. 2000; 31: 1318-1326Crossref PubMed Scopus (208) Google Scholar], but has also recently been detected during treatment with adefovir [[31]Fung S.K. Andreone P. Han S.H. Rajender Reddy K. Regev A. Keeffe E.B. et al.Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation.J Hepatol. 2005; 43: 937-943Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar] (see below). Similarly, rtI169T and rtT184S/G, which have been implicated in lamivudine resistance, may also contribute to entecavir resistance [[12]Tenney D.J. Levine S.M. Rose R.E. Walsh A.W. Weinheimer S.P. 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: 3498-3507Crossref PubMed Scopus (487) Google Scholar] (see below). These observations exemplify the way that prior treatment may compromise or reduce options for further treatment.Clinical resistance to l-nucleosides other than lamivudine has yet to be studied in detail, but the molecular mechanisms involved can be expected to be similar. Two observations justify this assumption (1) lamivudine resistance confers high-level cross-resistance to other l-nucleosides in vitro and (2) in clinical trials of other l-nucleosides, primary resistance, when observed has been found to be due to rtM204I/V [[32]Gish R.G. Clinical trial results of new therapies for HBV: implications for treatment guidelines.Semin Liver Dis. 2005; 25: 29-39Crossref PubMed Scopus (26) Google Scholar].3.2 Resistance to acyclic nucleoside phosphonates3.2.1 Adefovir resistanceAdefovir resistance emerges more slowly than lamivudine resistance, occurring at a cumulative annual rate of approximately 2.5% over 4 years [33Westland C. Delaney Wt. Yang H. Chen S.S. Marcellin P. Hadziyannis S. et al.Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil1.Gastroenterology. 2003; 125: 107-116Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 34Yuen M.F. Lai C.L. Adefovir dipivoxil in chronic hepatitis B infection.Expert Opin Pharmacother. 2004; 5: 2361-2367Crossref PubMed Scopus (27) Google Scholar], although a recent long-term (5 year) study indicates higher rates in HBeAg-negative CHB [35Hadziyannis S.J. Tassopoulos N.C. Heathcote E.J. Chang T.T. Kitis G. Rizzetto M. et al.Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B.N Engl J Med. 2005; 352: 2673-2681Crossref PubMed Scopus (497) Google Scholar, 36Mitsoula P. Dimou E. Laras A. Koskinas J. Hadziyannis S.J. Frequency and clinical significance of HBV resistance to nucleos(t)ide analogues during the treatment of HBeAg(−) chronic hepatitis B. (Abstract 1335).Hepatology. 2005; 42: 725AGoogle Scholar]; it may also be more frequent in individuals infected with genotype D HBV, especially after lamivudine failure [35aFung S.K. Chae H.B. Fontana R. Conjeevaram H. Marrero J. Oberhelman K. et al.HBV genotype D and switch to adefovir (ADV) monotherapy are associated with increased risk of ADV resistance in chronic hepatitis B (Abstract 1001).Hepatology. 2005; 42: 590AGoogle Scholar, 36Mitsoula P. Dimou E. Laras A. Koskinas J. Hadziyannis S.J. Frequency and clinical significance of HBV resistance to nucleos(t)ide analogues during the treatment of HBeAg(−) chronic hepatitis B. (Abstract 1335).Hepatology. 2005; 42: 725AGoogle Scholar].Single nucleotide changes that produce rtN236T and/or rtA181V/T substitutions are sufficient to cause clinical failure of adefovir [31Fung S.K. Andreone P. Han S.H. Rajender Reddy K. Regev A. Keeffe E.B. et al.Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation.J Hepatol. 2005; 43: 937-943Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar, 35Hadziyannis S.J. Tassopoulos N.C. Heathcote E.J. Chang T.T. Kitis G. Rizzetto M. et al.Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B.N Engl J Med. 2005; 352: 2673-2681Crossref PubMed Scopus (497) Google Scholar, 37Angus 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: 292-297Abstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar, 38Villeneuve J.-P. Durantel D. Durantel S. Westland C. Xiong S. Brosgart C.L. et al.Selection of a hepatitis B virus strain resistant to adefovir in a liver transplantation patient.J Hepatol. 2003; 39: 1085-1089Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar]. Other rt sequence changes implicated in adefovir failure include L80V/I, V84M, V214A, S85A Q215S, P237H and N238T/D, which may appear alone or in conjunction with rtN236T/rtA181V/T.Molecular modelling reveals that rtN236, which is in the D domain and is hydrogen bonded to rtS85, interacts with the gamma triphosphate of incoming dNTPs. Substitution of T for rtN236 increases preference for the natural substrate dATP over its analogue adefovir diphosphate. Modelling shows that substitution of V or T for rtA181causes an allosteric change in conformation of the catalytic site by forcing the repositioning of rtM204 [[15]Bartholomeusz A. Locarnini S. Ayres A. Thompson G. Bowden S. Sozzi V. et al.Mechanistic basis for hepatitis B virus resistance to acyclic phosphonate analogues, adefovir and tenofovir. (Abstract 1011).Hepatology. 2005; 42: 594AGoogle Scholar]. Other substitutions in this region—rtV84M, rtS85A, rtP237H and rtN238T/D—occur infrequently and probably have a similar effect. Since changes in the HBV polymerase are detected in only a minority of clinical isolates during adefovir failure, additional unidentified factors are suspected of contributing to clinical adefovir resistance [39Hann H.-W. Platt J. Reappearance of wild-type hepatitis B virus during adefovir monotherapy for patients with lamivudine resistance (Abstract 963).Hepatology. 2005; 42: 574AGoogle Scholar, 40Lampertico P. Marzano A. Levrero M. Santantonio T. Andreone P. Brunetto M. et al.A multicenter Italian study of rescue adefovir dipivoxil therapy in lamivudine resistant patients: a 2-year analysis of 604 patients (Abstract 1003).Hepatology. 2005; 42: 591ACrossref Scopus (202) Google Scholar]. Although adefovir is active against lamivudine resistant HBV mutants both in vitro and in vivo [[41]Westland C.E. Yang H. Delaney IV, W.E. Wulfsohn M. Lama N. Gibbs C.S. et al.Activity of adefovir dipivoxil against all patterns of lamivudine-resistant hepatitis B viruses in patients.J Viral Hepat. 2005; 12: 67-73Crossref PubMed Scopus (73) Google Scholar], recent observations that lamivudine failure predisposes to more rapid development of clinical adefovir resistance is cause for concern [35aFung S.K. Chae H.B. Fontana R. Conjeevaram H. Marrero J. Oberhelman K. et al.HBV genotype D and switch to adefovir (ADV) monotherapy are associated with increased risk of ADV resistance in chronic hepatitis B (Abstract 1001).Hepatology. 2005; 42: 590AGoogle Scholar, 42Lee C.H. Yeon J.E. Hong S.P. Kim J.H. Chung H.J. Moon M.S. et al.More frequent and earlier emergence of adefovir (ADV) resistance mutations in lamivudine resistant patients treated with ADV compared to previously reported nucleoside treatment naive patients (Abstract 1009).Hepatology. 2005; 42: 593ACrossref Google Scholar].3.2.2 Tenofovir resistanceTenofovir resistance, conferred by rtA194T in association with the changes that cause lamivudine resistance has recently been observed in individuals who were co-infected with HBV and HIV-1 [[43]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: 727-734PubMed Google Scholar]. Residue rtA194 is located in a loop at end of the B domain, which contains the alpha helix that interacts with the nucleic acid template. The rtA194T substitution may affect polymerisation efficiency by causing allosteric changes that result in misalignment between the template and dNTP-binding site. Alternatively, since rt194 is external in models of the reverse transcriptase region of the polymerase, it may affect interaction of the P protein with other components of the replication complex, which include cellular chaperones and the viral nucleocapsid [[15]Bartholomeusz A. Locarnini S. Ayres A. Thompson G. Bowden S. Sozzi V. et al.Mechanistic basis for hepatitis B virus resistance to acyclic phosphonate analogues, adefovir and tenofovir. (Abstract 1011).Hepatology. 2005; 42: 594AGoogle Scholar]. Results of recent studies suggest that tenofovir is more efficacious in the long-term than adefovir, especially in patients infected with lamivudine-resistant HBV [44Im G.Y. Uriel A.J. Carriero D. Park J. Jaffe D.L. Dieterich D.T. Comparison of tenofovir versus adefovir based combination therapy in subjects with chronic hepatitis B.Hepatology. 2005; 42: 589AGoogle Scholar,
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