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. 2007 Dec;51(12):4533–4534. doi: 10.1128/AAC.00840-07

Novel Lamivudine Resistance

Oliver Schildgen 1
PMCID: PMC2168002  PMID: 18025122

With great interest I have read and appreciate the recent publication by Warner and coworkers (6). Those authors described the effects of a novel mutation in the hepatitis B virus (HBV) polymerase reverse transcriptase domain, namely, the rtL80I substitution that confers resistance to lamivudine. This mutation was initially described to occur in Japanese patients with lamivudine treatment failure, but its impact remained to be investigated (3).

Not surprisingly, based on molecular modeling of the reverse transcriptase domain of the HBV polymerase, Warner et al. (6) concluded that this novel mutation is not located in the supposed drug binding domain. Nevertheless, the fact that rtL80I is able to mediate lamivudine resistance also in vitro, as shown by phenotyping, is of high general interest and deserves foremost attention for two reasons. First, the fact that mutations in the periphery of the nucleos(t)ide binding site may lead to resistance has to be taken into account in all future resistance testing approaches. Second, the observation by Warner and colleagues (6) may be true not only for lamivudine but also for other drugs and may thus have an impact also on further therapy and monitoring regimens, mainly as the therapy for chronic HBV infection is becoming more and more complex (1). Especially for adefovir, it is believed that besides mutations, host factors such as failures in liver uptake, defective or nonappropriate esterases, and phosphorylation failures may also confer resistance to the drug (5). Yet, although extensively discussed, novel mutations (e.g., see references 2 and 4) or mutations in the periphery of the nucleos(t)ide binding site have been taken into account only marginally or even disbelieved (5). Based on the observations of Warner et al., investigators should systematically check as to whether new or unexpected mutation patterns in the nucleos(t)ide binding site in concert with or even without mutations in the periphery lead to resistance or predispose to resistance to antivirals.

REFERENCES

  • 1.Hoofnagle, J. H., E. Doo, T. J. Liang, R. Fleischer, and A. S. Lok. 2007. Management of hepatitis B: summary of a clinical research workshop. Hepatology 45:1056-1075. [DOI] [PubMed] [Google Scholar]
  • 2.Laoi, B. N., C. Herra, S. Norris, and B. Crowley. 2007. Hepatitis B virus resistance to adefovir in a nucleotide naive patient with chronic hepatitis B virus infection. J. Antimicrob. Chemother. 59:807-809. [DOI] [PubMed] [Google Scholar]
  • 3.Ogata, N., K. Fujii, S. Takigawa, M. Nomoto, T. Ichida, and H. Asakura. 1999. 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. 59:270-276. [PubMed] [Google Scholar]
  • 4.Schildgen, O., H. Sirma, A. Funk, C. Olotu, U. C. Wend, H. Hartmann, M. Helm, J. K. Rockstroh, W. R. Willems, H. Will, and W. H. Gerlich. 2006. Variant of hepatitis B virus with primary resistance to adefovir. N. Engl. J. Med. 354:1807-1812. [DOI] [PubMed] [Google Scholar]
  • 5.Tillmann, H. L. 2007. Antiviral therapy and resistance with hepatitis B virus infection. World J. Gastroenterol. 13:125-140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Warner, N., S. Locarnini, M. Kuiper, A. Bartholomeusz, A. Ayres, L. Yuen, and T. Shaw. 2007. The L80I substitution in the reverse transcriptase domain of the hepatitis B virus polymerase is associated with lamivudine resistance and enhanced viral replication in vitro. Antimicrob. Agents Chemother. 51:2285-2292. [DOI] [PMC free article] [PubMed] [Google Scholar]
Antimicrob Agents Chemother. 2007 Dec;51(12):4533–4534.

Authors' Reply

Tim Shaw 2,*, Nadia Warner 2

Dr. Schildgen's comment on our recently published work on lamivudine-resistant HBV (7) is a timely reminder that, despite increasing availability of effective antiviral drugs, chemotherapy for chronic hepatitis B is likely to become more complicated in the future because of problems arising from drug resistance due to mutations that affect the viral polymerase gene. Citing cases in which amino acid changes at locations remote from the conserved YMDD deoxynucleoside triphosphate (dNTP) binding motif in polymerase domain C have been shown to influence or confer resistance to nucleos(t)ide analogues, he warns that this must be borne in mind when developing future testing and treatment strategies.

It is unsurprising that any mutation that produces even a subtle change in three-dimensional structure may influence catalytic properties such as fidelity and processivity, as maintenance of precise spatial relationships between the template primer, incoming dNTP, and proximal amino acid residues is essential for optimal polymerization. Consequently, mutations that confer drug resistance are not necessarily restricted to the C domain. For example, an early report identified rtV30I and rtN76D (in the G and A domains, respectively) as being associated with clinical failure of famciclovir (3), and there is an accumulating body of evidence that genetic background can affect drug resistance phenotypes (1, 6), indicating that even genetic polymorphisms in sequences outside the conserved domains have the potential to affect enzymatic properties. Indeed, allosteric effects on DNA polymerase fidelity were first observed more than 40 years ago by Speyer (5), who noted that “the replicating enzyme is involved more directly in the selection of the base [so that] the information of the parental DNA strand is transmitted sequentially by the enzyme to an allosteric site where selection of the nucleotide occurs. Such an enzymatic mechanism may permit selection by criteria other than the relatively weak hydrogen bonds postulated in the template hypothesis and account for the high accuracy of DNA replication.” Nevertheless, it is important to be able to distinguish between mutations that confer primary drug resistance and those that merely compensate for replication defects that are almost invariably associated with the acquisition of drug resistance. For example, whereas rtL180M does contribute slightly to lamivudine resistance, rtV173L does not contribute to drug resistance and confers no replicative advantage except in conjunction with rtL180M and rtM204V (2). Like rtV173L, rtL80I is not strictly a resistance mutation since in isolation it does not confer drug resistance.

In general, acquisition of primary resistance to nucleos(t)ide analogue inhibitors can be attributed to two distinct, usually mutually exclusive, molecular mechanisms. The first mechanism entails increased discrimination by the polymerase against the dNTP analogue, either at the binding step or—more commonly—at the catalytic step; the second involves excision of the dNTP analogue from the 3′ terminus of a nascent DNA chain by a reversal of the normal polymerization reaction. Resistance mutations that directly affect the dNTP binding site most frequently increase discrimination and fidelity and decrease processivity; effects of those that do not are less predictable and more dependent on genetic background. Establishing the extent to which specific mutations contribute to drug resistance and/or replication efficiency is important but difficult because the wide variations in the replication efficiency of different mutants confounds standardization and interpretation of drug resistance phenotyping assays (4). In future, we expect that resolution of the latter issues will increase our understanding of polymerase function and provide a rational basis for design of more effective antiviral drugs and combination therapies.

REFERENCES

  • 1.Brunelle, M. N., A. C. Jacquard, C. Pichoud, D. Durantel, S. Carrouee-Durantel, J. P. Villeneuve, C. Trepo, and F. Zoulim. 2005. Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir. Hepatology 41:1391-1398. [DOI] [PubMed] [Google Scholar]
  • 2.Delaney, W. E. T., H. Yang, C. E. Westland, K. Das, E. Arnold, C. S. Gibbs, M. D. Miller, and S. Xiong. 2003. The hepatitis B virus polymerase mutation rtV173L is selected during lamivudine therapy and enhances viral replication in vitro. J. Virol. 77:11833-11841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Gunther, S., F. von Breunig, T. Santantonio, M. C. Jung, G. B. Gaeta, L. Fischer, M. Sterneck, and H. Will. 1999. Absence of mutations in the YMDD motif/B region of the hepatitis B virus polymerase in famciclovir therapy failure. J. Hepatol. 30:749-754. [DOI] [PubMed] [Google Scholar]
  • 4.Shaw, T., R. Edwards, T. Sozzi, N. Warner, and S. Locarnini. 2006. Large variation in the replication efficiencies of HBV mutants: implications for phenotypic assays for antiviral drug resistance. Hepatology 44(Suppl. 1):252A.16799968 [Google Scholar]
  • 5.Speyer, J. F. 1965. Mutagenic DNA polymerase. Biochem. Biophys. Res. Commun. 21:6-8. [DOI] [PubMed] [Google Scholar]
  • 6.Tenney, D. J., S. M. Levine, R. E. Rose, A. W. Walsh, S. P. Weinheimer, L. Discotto, M. Plym, K. Pokornowski, C. F. Yu, P. Angus, A. Ayres, A. Bartholomeusz, W. Sievert, G. Thompson, N. Warner, S. Locarnini, and R. J. Colonno. 2004. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine. Antimicrob. Agents Chemother. 48:3498-3507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Warner, N., S. Locarnini, M. Kuiper, A. Bartholomeusz, A. Ayres, L. Yuen, and T. Shaw. 2007. The L80I substitution in the reverse transcriptase domain of the hepatitis B virus polymerase is associated with lamivudine resistance and enhanced viral replication in vitro. Antimicrob. Agents Chemother. 51:2285-2292. [DOI] [PMC free article] [PubMed] [Google Scholar]

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