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Rescue Therapy for Lamivudine-Resistant Chronic

Hepatitis B: When and How?

See Article on Page 307.

Lamivudine (LAM), adefovir (ADV), entecavir(ETV), and telbivudine are 4 approved nucleosideor nucleotide analogs for treating chronic HBV

infection. These drugs have inhibitory effects on HBVpolymerase/reverse transcriptase activity but not directlyon covalently closed circular DNA (cccDNA) synthesis,thus prolonged therapy is usually required to ensuremaintained or sustained HBV suppression. LAM was thefirst drug to have been approved and has been used exten-sively for more than a decade with an excellent safetyrecord. However, LAM resistance has become a seriousclinical challenge because its incidence increases with in-creasing duration of therapy, and it is associated withvirologic/biochemical breakthrough, hepatitis flare, andeven hepatic decompensation or mortality.1 ADV andETV are associated with a delayed and low incidence ofresistance in treatment-nave patients; both drugs haveantiviral activity against LAM-resistant HBV, althoughETV displays some level of cross-resistance.2

Clinical studies show ADV monotherapy or ADVadd-on LAM combination therapy is effective in both

compensated and decompensated patients with LAM re-sistance.3-5 Among these studies, one small randomizedcontrolled trial showed that 1 year of ADV monotherapy

was as effective as ADV add-on LAM combination ther-apy. Although none of the patients experienced a virologicrebound during ADV monotherapy or combination ther-apy, elevated serum ALT levels of 5 to 10 times the upperlimit of normal occurred within 12 weeks in 7 (37%) ofthe 19 patients who were switched to ADV monotherapy;none of these ALT increases were associated with in-creases in HBV-DNA.5 Probably on the basis of this find-

ing, it was recommended that LAM therapy be continuedfor 2 to 3 months to minimize the risk of ALT flare during

the transition to ADV therapy.6 However, subsequentstudies in Asian patients with compensated and decom-pensated liver cirrhosis show that switching to ADVmonotherapy is not associated with an increased risk of

ALT flare and is a reasonably safe and cost-effective ap-proach.7,8 The strategy of switching to ADV mono-therapy was therefore included in the 2005 Asian-Pacificguidelines for patients with LAM resistance.9 Shortly af-terward, the alarming problem of ADV resistanceemerged. Case series studies have shown that, compared

with LAM-nave patients, ADV resistance occurs earlierand more frequently (up to 18% at 48 weeks and 25% at

24 months) in patients with LAM resistance who wereswitched to ADV monotherapy.10-12 In contrast, no ADVresistance was demonstrated during ADV add-on LAMcombination therapy for up to 2 years.11,13

In this issue of HEPATOLOGY, Rapti et al.14 report theirresults of a randomized controlled study of ADV therapyin 42 patients with genotype D HBV infection who hadgenotypic LAM resistance with virological and clinicalbreakthrough. The patients were randomized (1:2) to re-ceive 10 mg/day ADV monotherapy or ADV add-onLAM combination therapy for a median duration of 37.5

(9-53) months. No ALT flares were recorded after eitherswitching to or adding on ADV to LAM. Therapeuticefficacy, in terms of undetectable HBV-DNA and ALTnormalization in the first 12 months of ADV therapy, wassimilar between the 2 regimens. Patients with a baselineHBV-DNA level 107 copies/ml experienced signifi-cantly earlier and more frequent decline of serum HBV-DNA to undetectable levels. Of the 7 patients withpositive samples by PCR assay during combination ther-apy, genotypic LAM-resistant strain HBV persisted in allpatients atmonth 12, in 4 at month 18, in 3 atmonth 24,

and in 2 at month 36. No evidence of ADV resistance wasdetected in the 28 patients undergoing ADV add-onLAM combination therapy during a median duration of40 (9-53) months. In contrast, ADV-resistant mutation

was detected in 3 patients (21%) upon viral/biochemicalbreakthrough at 15 to 18 months after switching to ADVmonotherapy. Although the number of patients in thisstudy was relatively small, the randomized controlledstudy design and sufficiently long and careful follow-upevaluations provide solid evidence supporting the notionthat ADV add-on LAM combination therapy prevents or

delays ADV resistance. With these findings, switching to

Abbreviations: ADV, adefovir; cccDNA, covalently closed circular DNA; ETV,entecavir; LAM, lamivudine.

Address reprint requests to: Yun-Fan Liaw, M.D., Liver Research Unit, ChangGung University and Memorial Hospital, 199 Tung Hwa North Road, Taipei,Taiwan 105. E-mail: liveryfl@so-net.net.tw; fax: 886-3-3282824.

Copyright 2007 by the American Association for the Study of Liver Diseases.Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/hep.21546

Potential conflict of interest: Y.F. Liaw receives or received research support andserves on the advisory board of Roche, Bristol Myers-Squibb, Novartis, and Glaxo-

SmithKline.

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ADV monotherapy is clearly no longer an appropriaterescue therapy for LAM resistance.

Of note is that the study by Rapti et al.14 enrolledpatients with virological and biochemical breakthrough.Half their patients had a serum HBV-DNA level 107

copies/ml at the onset of ADV therapy, a level found to beassociated with insufficient virological response. Thus,the efficacy in terms of decline of serum HBV-DNA toundetectable level by sensitive PCR assay is insufficienteven in patients who received combination therapy, as

was demonstrated in earlier case series studies.10,13,15 Thisis consistent with the observation of Lampertico et al.13

that HBV was more rapidly and consistently suppressedin patients starting ADV early during the phase of geno-typic resistance than in patients starting ADV later duringthe phase of phenotypic resistance (median HBV-DNA 7.3 log10 copies/ml). These findings clearly indi-cate that ADV should be added to LAM as soon asgenotypic resistance is detected when the serum HBV-DNA level usually has not increased to a level too high tobe suppressed successfully.

Some problems associated with ADV add-on LAMcombination therapy deserve attention. It has been shownthat maintained LAM therapy provides a continuing se-lective advantage to a LAM-resistant strain over wild-typeHBV and that LAM-resistant HBV may persist in themajority of patients after 1 year of ADV add-on LAMcombination therapy.4,5,15 In addition, compensatory

mutations may emerge and restore replication fitness ofthe virus during continuing LAM therapy.1 The study byRapti et al.14 has also shown that a LAM-resistant strainmay persist up to 36 months in patients on combinationtherapy, and is a possible reason for suboptimal viral re-sponse. Perhaps the potency of ADV at the licensed, butactually suboptimal, daily dose of 10 mg is insufficient tosuppress LAM-resistant strain HBV. This notion is sup-ported by a study showing the superiority of 300 mgtenofovir treatments, another acyclic nucleotide analog,to 10 mg ADV in patients with LAM resistance.16 Like-

wise, a higher daily ETV dose of 1.0 mg is required totreat patients with LAM-resistant HBV more effectively,despite the fact that ETV is more potent than ADV in theactivity of HBV suppression. In addition, genotypic ETVresistance and virologic breakthrough may also occur, as

was detected in 10 and 2, respectively, of the 141 LAM-resistant patients during 52 weeks of ETV therapy; and it

was only observed in patients with LAM-resistant virus(M204 V/I and/or L180M) that had an additional sub-stitution at residues T184, S202, or M250.17 Consideringthe selection advantage of LAM-resistant strains, it is con-

ceivable that switching to ETV monotherapy is more ap-

propriate than ETV add-on LAM combination therapyfor LAM-resistant patients.18 On the other hand, the po-tential of developing multidrug resistance may be a con-cern, as dual resistance to LAM and ADV or ETV hasbeen reported;19,20 the former was associated with a 59-

fold decrease in susceptibility to combination of the 2drugs.19 Studies are needed to explore whether the dura-tion of continuing LAM during ADV therapy can beshortened to terminate LAM resistance earlier but still beable to prevent resistance to the add-on agent.

In summary, drug resistance is a serious challenge inantiviral therapy of chronic hepatitis B although nucleo-side (nucleotide) analogs with different resistance profilesare available. It is now clear that rescue therapy should beinstituted as soon as genotypic resistance is detected.Therefore, careful monitoring during direct antiviral

therapy is mandatory for early detection and early rescueof drug resistance. Although both initiation of ADVadd-on LAM combination therapy and switching to ETVmonotherapy are better strategies for managing LAM re-sistance, insufficient efficacy and potential multidrug re-sistance are unsolved problems. Tenofovir administered300 mg daily appears to be superior to ADV administered10 mg daily in suppressing LAM-resistant strain HBV,and no tenofovir resistance has been detected.16 However,the data for tenofovir are still limited, and the drug has notbeen approved for hepatitis B patients. Because cost is a

concern and a large number of patients are currentlybeingand will be treated with LAM, the least expensive drug,LAM resistance remains a serious clinical challenge for theforeseeable future. In addition, ADV and even ETVmonotherapy in LAM-nave patients will engender drugresistance if the duration of therapy is long enough. It istherefore very important to select the right patients andthe right antiviral agent(s) and to start antiviral therapy atthe right time to prevent or reduce drug resistance. Inother words, it is very important to ensure there is a clearindication for starting therapy and to take measures to

maximize antiviral activity and genetic or pharmacologi-cal barriers to resistance.1 The study by Rapti et al.14

proved the concept that combination therapy prevents ordelays drug resistance and underscores the need to evalu-ate de novo combination of antiviral agents to maintainlong-term and complete viral suppression. Such studiesare needed to determine the optimal strategy for the an-tiviral therapy of chronic hepatitis B.

YUN-FAN LIAWLiver Research Unit, Chang Gung University and Chang

Gung Memorial Hospital

Taipei, Taiwan

HEPATOLOGY, Vol. 45, No. 2, 2007 LIAW 267

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