Rescue therapy for drug resistant hepatitis B: Another argument for combination chemotherapy?

Abstract

Chemotherapeutic control of chronic hepatitis B (CH-B) infection has remained problematic since the hepatitis B virus (HBV) was identified as the major cause of serum hepatitis more than 30 years ago. Until recently, interferon α was the only drug available for use against CH-B, but its use frequently causes undesirable side effects, its efficacy is limited, and it must be administered by injection, so the need for more efficacious anti-HBV agents has long been evident.1Feld J. Lee J.Y. Locarnini S. New targets and possible new therapeutic approaches in the chemotherapy of chronic hepatitis B.Hepatology. 2003; 38: 545-553Crossref PubMed Scopus (46) Google Scholar Before the advent of antiretroviral drugs, most attempts to treat CH-B by using nucleoside analogues had to be aborted because of toxicity and/or lack of efficacy.2Shaw T. Locarnini S.A. Hepatic purine and pyrimidine metabolism implications for antiviral chemotherapy of viral hepatitis.Liver. 1995; 15: 169-184Crossref PubMed Scopus (53) Google Scholar The discovery that the unusual replication strategy used by HBV entails an obligatory reverse transcription step catalyzed by the viral polymerase3Seeger C. Mason W.S. Hepatitis B virus biology.Microbiol Mol Biol Rev. 2000; 64: 51-68Crossref PubMed Scopus (1220) Google Scholar prompted the investigation of antiretroviral nucleoside and nucleotide analogues for potential anti-HBV activity. Lamivudine (LMV) and adefovir (ADV), both of which had been previously identified as having antiretrovirus activity, were among the first of such compounds shown to possess more potent antihepadnaviral activity. Unfortunately, their long-term efficacy is compromised by the almost inevitable emergence of drug-resistant mutant HBV populations, a scenario analogous to the antiretroviral experience.4Delaney IV, W.E. Locarnini S. Shaw T. Resistance of hepatitis B virus to antiviral drugs current aspects and directions for future investigation.Antivir Chem Chemother. 2001; 12: 1-35Crossref PubMed Scopus (104) Google Scholar LMV ([-]-β-L-2′,3′-dideoxy-3′-thiacytidine) is a synthetic deoxycytidine analogue originally developed to treat human immunodeficiency virus (HIV) infection. It was found to inhibit HBV replication in patients who were coinfected with HIV and HBV, and, in 1998, it became the first oral treatment for CH-B to gain Food and Drug Administration approval.5Jarvis B. Faulds D. Lamivudine. A review of its therapeutic potential in chronic hepatitis B.Drugs. 1999; 58: 101-141Crossref PubMed Scopus (148) Google Scholar Treatment of CH-B patients with LMV results in a rapid decrease in viral load and reversal or arrest of existing liver disease in the majority of cases. Unfortunately, these improvements are rarely sustained because of the development of drug resistance. HBV resistance to LMV has been well characterized, both molecularly and clinically.4Delaney IV, W.E. Locarnini S. Shaw T. Resistance of hepatitis B virus to antiviral drugs current aspects and directions for future investigation.Antivir Chem Chemother. 2001; 12: 1-35Crossref PubMed Scopus (104) Google Scholar, 6Allen M.I. Deslauriers M. Andrews C.W. Tipples G.A. Walters K.A. Tyrrell D.L. Brown N. Condreay L.D. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group.Hepatology. 1998; 27: 1670-1677Crossref PubMed Scopus (783) Google Scholar, 7Lai C.L. Dienstag J. Schiff E. Leung N.W. Atkins M. Hunt C. Brown N. Woessner M. Boehme R. Condreay L. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B.Clin Infect Dis. 2003; 36: 687-696Crossref PubMed Scopus (558) Google Scholar, 8Stuyver L.J. Locarnini S.A. Lok A. Richman D.D. Carman W.F. Dienstag J.L. Schinazi R.F. Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region.Hepatology. 2001; 33: 751-757Crossref PubMed Scopus (362) Google Scholar Mutations that result in replacement of methionine (M) in the tyrosine-methionine-aspartate-aspartate catalytic site motif of HBV reverse transcriptase (rt) by valine (V), isoleucine (I), or serine (S), which have been designated rtM204V, rtM204I, and rtM204S, respectively,8Stuyver L.J. Locarnini S.A. Lok A. Richman D.D. Carman W.F. Dienstag J.L. Schinazi R.F. Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region.Hepatology. 2001; 33: 751-757Crossref PubMed Scopus (362) Google Scholar are sufficient to confer resistance to LMV. The rtM204I substitution has been detected in isolation, but rtM204V and rtM204S are found in association with other changes that may partially compensate for replicative defects imposed by rtM204V/I/S.9Delaney IV, W.E. Yang H. Westland C.E. Das K. Arnold E. Gibbs C.S. Miller M.D. Xiong S. 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 (235) Google Scholar LMV resistance results mainly from steric hindrance. Molecular modeling shows that, when rtM204 is replaced by valine or isoleucine, the side-chains of the substituted amino acids project into the deoxynucleoside triphosphate (dNTP) binding site, reducing the binding affinity for natural dNTPs and preventing LMV binding by occupying the space needed to accommodate its 3′ sulfur atom.10Das 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 (253) Google Scholar Mutations that confer LMV resistance decrease sensitivity to LMV from 20 to >1000-fold in in vitro assays.4Delaney IV, W.E. Locarnini S. Shaw T. Resistance of hepatitis B virus to antiviral drugs current aspects and directions for future investigation.Antivir Chem Chemother. 2001; 12: 1-35Crossref PubMed Scopus (104) Google Scholar, 5Jarvis B. Faulds D. Lamivudine. A review of its therapeutic potential in chronic hepatitis B.Drugs. 1999; 58: 101-141Crossref PubMed Scopus (148) Google Scholar, 6Allen M.I. Deslauriers M. Andrews C.W. Tipples G.A. Walters K.A. Tyrrell D.L. Brown N. Condreay L.D. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group.Hepatology. 1998; 27: 1670-1677Crossref PubMed Scopus (783) Google Scholar, 11Chin R. Shaw T. Torresi J. Sozzi V. Trautwein C. Bock T. Manns M. Isom H. Furman P. Locarnini S. In vitro susceptibilities of wild-type or drug-resistant hepatitis B virus to (-)-beta-D-2,6-diaminopurine dioxolane and 2′-fluoro-5-methyl-beta-L-arabinofuranosyluracil.Antimicrob Agents Chemother. 2001; 45: 2495-2501Crossref PubMed Scopus (115) Google Scholar The incidence of LMV resistance in patients with CH-B rises progressively at rates between 14% and 32% annually, approaching 100% after 4 years.7Lai C.L. Dienstag J. Schiff E. Leung N.W. Atkins M. Hunt C. Brown N. Woessner M. Boehme R. Condreay L. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B.Clin Infect Dis. 2003; 36: 687-696Crossref PubMed Scopus (558) Google Scholar, 12Akuta N. Suzuki F. Kobayashi M. Matsuda M. Sato J. Takagi K. Tsubota A. Suzuki Y. Hosaka T. Someya T. Kobayashi M. Saitoh S. Arase Y. Ikeda K. Kumada H. Virological and biochemical relapse according to YMDD motif mutant type during long-term lamivudine monotherapy.J Med Virol. 2003; 71: 504-510Crossref PubMed Scopus (19) Google Scholar This relatively slow development (compared with HIV) is probably caused by constraints imposed by overlapping reading frames in the HBV genome and by reduced opportunities for complementation and recombination imposed by the genetic haploidy of HBV.4Delaney IV, W.E. Locarnini S. Shaw T. Resistance of hepatitis B virus to antiviral drugs current aspects and directions for future investigation.Antivir Chem Chemother. 2001; 12: 1-35Crossref PubMed Scopus (104) Google Scholar High pretherapy serum HBV DNA and alanine aminotransferase (ALT) levels, longer duration of therapy, and incomplete suppression of viral replication are the main risk factors known to accelerate development of LMV resistance.13Huang Y.H. Wu J.C. Chang T.T. Sheen I.J. Lee P.C. Huo T.I. Su C.W. Wang Y.J. Chang F.Y. Lee S.D. Analysis of clinical, biochemical and viral factors associated with early relapse after lamivudine treatment for hepatitis B e antigen-negative chronic hepatitis B patients in Taiwan.J Viral Hepatol. 2003; 10: 277-284Crossref PubMed Scopus (36) Google Scholar These factors are consistent with the absolute dependence of mutagenesis on viral replication. In established CH-B, virtually all hepatocyte nuclei are infected with an apparently stable population of HBV mini-chromosomes.3Seeger C. Mason W.S. Hepatitis B virus biology.Microbiol Mol Biol Rev. 2000; 64: 51-68Crossref PubMed Scopus (1220) Google Scholar, 14Zhang Y.Y. Zhang B.H. Theele D. Litwin S. Toll E. Summers J. Single-cell analysis of covalently closed circular DNA copy numbers in a hepadnavirus-infected liver.Proc Natl Acad Sci U S A. 2003; 100: 12372-12377Crossref PubMed Scopus (122) Google Scholar The emergence of a new mutant HBV as the dominant population requires that HBV mini-chromosomes containing mutant genomes must displace the existing population. During active liver disease, hepatocyte turnover and proliferation increases, providing what has been termed “replication space,” that is, a fresh supply of infectible hepatocytes for colonization by mutant HBV.14Zhang Y.Y. Zhang B.H. Theele D. Litwin S. Toll E. Summers J. Single-cell analysis of covalently closed circular DNA copy numbers in a hepadnavirus-infected liver.Proc Natl Acad Sci U S A. 2003; 100: 12372-12377Crossref PubMed Scopus (122) Google Scholar Under these conditions and appropriate selection pressure, a new HBV population may become predominant. ADV, an acyclic deoxyadenosine monophosphate analogue, is the biologically active component of is its oral prodrug (9-{2-[bis[(pivaloyloxy)methoxy](phosphoinyl]methoxy]ethyl}-adenine) dipivoxil, which gained Food and Drug Administration approval for use against CH-B in September 2002.15Dando T. Plosker G. Adefovir dipivoxil a review of its use in chronic hepatitis B.Drugs. 2003; 63: 2215-2234Crossref PubMed Scopus (109) Google Scholar It belongs to a class of broad-spectrum antiviral agents, the nucleoside phosphonates, and was originally investigated as a potential antiretroviral drug. It underwent clinical trials for treatment of HIV infection but is not currently used as an antiretroviral drug because continued administration of the relatively high dose required to suppress HIV replication (100–120 mg/day; at least 10-fold greater than for HBV) was found to have the potential to cause nephrotoxicity.15Dando T. Plosker G. Adefovir dipivoxil a review of its use in chronic hepatitis B.Drugs. 2003; 63: 2215-2234Crossref PubMed Scopus (109) Google Scholar Clinical experience with ADV as an anti-HBV drug is limited but increasing. Large-scale multicenter clinical trials longer than 48 weeks have shown that its efficacy is comparable to that of LMV.15Dando T. Plosker G. Adefovir dipivoxil a review of its use in chronic hepatitis B.Drugs. 2003; 63: 2215-2234Crossref PubMed Scopus (109) Google Scholar, 16Marcellin P. Chang T.T. Lim S.G. Tong M.J. Sievert W. Shiffman M.L. Jeffers L. Goodman Z. Wulfsohn M.S. Xiong S. Fry J. Brosgart C.L. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.N Engl J Med. 2003; 348: 808-816Crossref PubMed Scopus (1289) Google Scholar, 17Hadziyannis S.J. Tassopoulos N.C. Heathcote E.J. Chang T.T. Kitis G. Rizzetto M. Marcellin P. Lim S.G. Goodman Z. Wulfsohn M.S. Xiong S. Fry J. Brosgart C.L. Adefovir Dipivoxil 438 study groupAdefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B.N Engl J Med. 2003; 348: 800-807Crossref PubMed Scopus (954) Google Scholar Viral resistance did not develop during 60 weeks treatment with ADV; on the contrary, increasing suppression of viremia was observed as treatment progressed.18Westland C.E. Yang H. Delaney IV, W.E. Gibbs C.S. Miller M.D. Wulfsohn M. Fry J. Brosgart C.L. Xiong S. 437 and 438 Study TeamsWeek 48 resistance surveillance in two phase 3 clinical studies of adefovir dipivoxil for chronic hepatitis B.Hepatology. 2003; 38: 96-103PubMed Google Scholar, 19Yang H. Westland C.E. Delaney IV, W.E. Heathcote E.J. Ho V. Fry J. Brosgart C. Gibbs C.S. Miller M.D. Xiong S. Resistance surveillance in chronic hepatitis B patients treated with adefovir dipivoxil for up to 60 weeks.Hepatology. 2002; 36: 464-473Crossref PubMed Scopus (158) Google Scholar However, an HBV mutant that exhibited a 6- to 15-fold reduction in sensitivity to ADV in vitro was isolated from 2 of 124 hepatitis B e antigen (HBeAg)-negative patients who had been treated with ADV for 96 weeks.20Angus P. Vaughan R. Xiong S. Yang H. Delaney W. Gibbs C. Brosgart C. Colledge D. Edwards R. Ayres A. Bartholomeusz A. Locarnini S. 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 (534) Google Scholar Resistance to ADV in these isolates was caused by substitution of threonine for asparagine at rt236 (rtN236T), which appears to be sufficient to confer ADV resistance.20Angus P. Vaughan R. Xiong S. Yang H. Delaney W. Gibbs C. Brosgart C. Colledge D. Edwards R. Ayres A. Bartholomeusz A. Locarnini S. 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 (534) Google Scholar, 21Bartholomeusz A. Locarnini S. Ayres A. Thompson G. Edwards R. Colledge D. Angus P. Sievert W. Tillmann H. Tehan B. Chalmers D. Molecular modeling and functional studies of adefovir resistant mutations in the hepatitis B virus polymerase selected during therapy.Hepatology. 2003; 38 (abstr): 273ACrossref PubMed Google Scholar The rtN236T change does not affect sensitivity to LMV.20Angus P. Vaughan R. Xiong S. Yang H. Delaney W. Gibbs C. Brosgart C. Colledge D. Edwards R. Ayres A. Bartholomeusz A. Locarnini S. 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 (534) Google Scholar At the molecular level, ADV resistance appears to be caused by indirect perturbation in the triphosphate binding site within the dNTP binding pocket.21Bartholomeusz A. Locarnini S. Ayres A. Thompson G. Edwards R. Colledge D. Angus P. Sievert W. Tillmann H. Tehan B. Chalmers D. Molecular modeling and functional studies of adefovir resistant mutations in the hepatitis B virus polymerase selected during therapy.Hepatology. 2003; 38 (abstr): 273ACrossref PubMed Google Scholar The different mechanism may explain why HBV resistance to ADV is less common than resistance to LMV and does not confer as great a reduction in drug sensitivity. LMV and ADV are taken up and activated by different biochemical pathways: their activated products compete with different dNTPs (dCTP and dATP, respectively) and their toxicities do not appear to overlap.5Jarvis B. Faulds D. Lamivudine. A review of its therapeutic potential in chronic hepatitis B.Drugs. 1999; 58: 101-141Crossref PubMed Scopus (148) Google Scholar, 15Dando T. Plosker G. Adefovir dipivoxil a review of its use in chronic hepatitis B.Drugs. 2003; 63: 2215-2234Crossref PubMed Scopus (109) Google Scholar There is some evidence that ADV is active against HBV in cells other than hepatocytes22Nicoll A. Locarnini S. Chou S.T. Smallwood R. Angus P. Effect of nucleoside analogue therapy on duck hepatitis B viral replication in hepatocytes and bile duct epithelial cells in vivo.J Gastroenterol Hepatol. 2000; 15: 304-310Crossref PubMed Scopus (8) Google Scholar and it has also been shown that LMV and ADV act at least additively in vitro.23Colledge D. Civitico G. Locarnini S. Shaw T. In vitro antihepadnaviral activities of combinations of penciclovir, lamivudine, and adefovir.Antimicrob Agents Chemother. 2000; 44: 551-560Crossref PubMed Scopus (89) Google Scholar Finally, it has been reported that the rtL180M+rtM204V changes that confer LMV resistance fortuitously confer a 5-fold increase in sensitivity to ADV in vitro.11Chin R. Shaw T. Torresi J. Sozzi V. Trautwein C. Bock T. Manns M. Isom H. Furman P. Locarnini S. In vitro susceptibilities of wild-type or drug-resistant hepatitis B virus to (-)-beta-D-2,6-diaminopurine dioxolane and 2′-fluoro-5-methyl-beta-L-arabinofuranosyluracil.Antimicrob Agents Chemother. 2001; 45: 2495-2501Crossref PubMed Scopus (115) Google Scholar Collectively, these data amount to a strong argument for the clinical use of ADV and LMV in combination. Preliminary clinical trials have already shown that ADV is effective against LMV-resistant HBV in vivo, either when used alone or in combination with LMV.24Benhamou Y. Bochet M. Thibault V. Calvez V. Fievet M.H. Vig P. Gibbs C.S. Brosgart C. Fry J. Namini H. Katlama C. Poynard T. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus an open-label pilot study.Lancet. 2001; 358: 718-723Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 25Walsh K.M. Woodall T. Lamy P. Wight D.G. Bloor S. Alexander G.J. Successful treatment with adefovir dipivoxil in a patient with fibrosing cholestatic hepatitis and lamivudine resistant hepatitis B virus.Gut. 2001; 49: 436-440Crossref PubMed Scopus (92) Google Scholar, 26Barcena Marugan R. Cid Gomez L. Lopez Serrano P. Use of adefovir in the treatment of the chronic hepatitis B virus infection with resistance to lamivudine.Transplant Proc. 2003; 35: 1841-1843Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 27Mutimer D. Feraz-Neto B.H. Harrison R. O’Donnell K. Shaw J. Cane P. Pillay D. Acute liver graft failure due to emergence of ν resistant hepatitis B virus rapid resolution during treatment with adefovir.Gut. 2001; 49: 860-863Crossref PubMed Scopus (70) Google Scholar Two new reports in this issue of Gastroenterology record the longer-term results of separate large-scale multicenter, controlled trials of ADV alone or in combination with LMV in cases of LMV resistant CH-B. Perrillo et al.28Perrillo R. Hann H.-W. Mutimer D. Willems B. Leung N. Lee W. Moorat A. Gardner S. Woessner M. Bourne E. Brosgart C.L. Schiff E. Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus.Gastroenterology. 2004; 126: 81-90Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar studied a total of 135 cases of LMV resistant CH-B. All cases continued LMV therapy (100 mg/day); in addition, 86 patients received ADV (10 mg/day) whereas the remaining 49 were administered a placebo. Forty of those receiving combination treatment had signs of decompensated liver disease or had recurrent posttransplant hepatitis. One hundred twenty-six patients (80 and 46 in the ADV and placebo groups, respectively) completed the 52 week study, in which the primary endpoint was a decline in serum HBV DNA to ≤105 copies/mL or ≥2 log10 reduction from baseline at both weeks 48 and 52. The endpoint was achieved in an overwhelming majority (>85%) of patients after ADV treatment, whereas only a small minority (11%) of the placebo group responded, a difference that was highly statistically significant (P < 0.001). In addition, ALT normalization was observed in 30% of those receiving the drug combination but in only 6% of those who continued LMV monotherapy. A majority of patients (88%) were HBeAg positive pretreatment: HBeAg loss occurred in 15% and 2% of combination and monotherapy patients, respectively. Responses to combination therapy were similar regardless of disease status, and adverse side effects were not observed. The authors conclude that the addition of ADV to LMV treatment is beneficial to patients with compensated or decompensated liver disease caused by LMV-resistant CH-B. This raises 2 new issues: (1) whether ADV alone would be sufficient to control LMV-resistant HBV and (2) whether the combination of LMV and ADV would be more efficacious than monotherapy with either drug alone in treatment-naive patients. Results of the second study by Peters et al.29Peters M.G. Hann H.W. Martin P. Heathcote E.J. Buggisch P. Rubin R. Bourliere M. Kowdley K. Trepo C. Gray D.F. Sullivan M. Kleber K. Ebrahimi R. Xiong S. Brosgart C.L. The GS-00-461 Study GroupAdefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B.Gastroenterology. 2004; 126: 91-101Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar provide partial clarification. The cohort of 59 patients in this study were all HBeAg positive with LMV-resistant CH-B, had compensated liver disease, and fulfilled entry criteria similar to those applied in the study by Perrillo et al.28Perrillo R. Hann H.-W. Mutimer D. Willems B. Leung N. Lee W. Moorat A. Gardner S. Woessner M. Bourne E. Brosgart C.L. Schiff E. Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus.Gastroenterology. 2004; 126: 81-90Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar Patients were randomized into 3 groups: those who either continued LMV monotherapy, received a combination of LMV and ADV, or received ADV alone. The primary endpoint was the time-weighted average reduction in serum HBV DNA up to week 16, although treatment was continued and patients monitored for at least 48 weeks. Results and conclusions were similar to those of the first study: a rapid virologic response was observed only in ADV recipients and not in those continuing LMV monotherapy. At week 48, median serum HBV DNA decreases were 3.59 and 4.04 log10 from baseline in the groups receiving the ADV/LMV combination and ADV, respectively, with no change in the group on LMV monotherapy. In addition, ALT normalized in approximately half the patients who received ADV compared with only 5% of those given LMV alone. After randomization, patients in the ADV monotherapy arm experienced hepatitic flares, which were not observed in the combination arm, suggesting the need for more effective virologic suppression in this setting. Both studies used conservative primary endpoints based on serum viral load reductions from baseline measurements because no liver tissue was available for histologic or virologic analysis. Although assays of different sensitivity were used in the respective studies, the median decrease in viral load from baseline to week 48 was around 4 log10 copies/mL in the patients receiving ADV/LMV or ADV monotherapy. Patients with decompensated liver disease appeared to respond equally well to ADV as those patients with compensated disease. In HBeAg-positive patients, HBeAg loss was confined to patients receiving ADV, with the exception of 1 patient receiving LMV and placebo. Although it was shown from the studies that several patients lost HBeAg, the inadequacy of using this as an endpoint was reported by Peters et al.,29Peters M.G. Hann H.W. Martin P. Heathcote E.J. Buggisch P. Rubin R. Bourliere M. Kowdley K. Trepo C. Gray D.F. Sullivan M. Kleber K. Ebrahimi R. Xiong S. Brosgart C.L. The GS-00-461 Study GroupAdefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B.Gastroenterology. 2004; 126: 91-101Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar who showed that the response was not durable and the majority of their patients with HBeAg loss regained HBeAg during the posttreatment follow-up. One patient in this study underwent hepatitis B surface antigen (HBsAg) seroconversion and 2 patients in the Perillo Study lost HBsAg on treatment.28Perrillo R. Hann H.-W. Mutimer D. Willems B. Leung N. Lee W. Moorat A. Gardner S. Woessner M. Bourne E. Brosgart C.L. Schiff E. Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus.Gastroenterology. 2004; 126: 81-90Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar However, both patients in the latter study had undergone liver transplantation and had received hepatitis B immunoglobulin posttransplant. These 2 studies28Perrillo R. Hann H.-W. Mutimer D. Willems B. Leung N. Lee W. Moorat A. Gardner S. Woessner M. Bourne E. Brosgart C.L. Schiff E. Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus.Gastroenterology. 2004; 126: 81-90Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar, 29Peters M.G. Hann H.W. Martin P. Heathcote E.J. Buggisch P. Rubin R. Bourliere M. Kowdley K. Trepo C. Gray D.F. Sullivan M. Kleber K. Ebrahimi R. Xiong S. Brosgart C.L. The GS-00-461 Study GroupAdefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B.Gastroenterology. 2004; 126: 91-101Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar confirm that ADV dipivoxil is active against LMV-resistant HBV in vivo and also indicate that LMV provides little, if any, antiviral or clinical benefit for patients in whom LMV-resistant HBV is already present. Unfortunately, they provide few insights to the probable responses to ADV and LMV—given either sequentially in that order or simultaneously in combination—of treatment-naive cases. Combination chemotherapy has already proven successful in suppressing HIV infection, with consequent improvement in quality of life for those treated, and there seems little doubt that it will soon become more routinely used to treat patients with CH-B.30Shaw T. Locarnini S. Combination chemotherapy for hepatitis B virus the final solution?.Hepatology. 2000; 32: 430-432Crossref PubMed Scopus (38) Google Scholar, 31Lewin S. Walters T. Locarnini S. Hepatitis B treatment rational combination chemotherapy based on viral kinetic and animal model studies.Antiviral Res. 2002; 55: 381-396Crossref PubMed Scopus (44) Google Scholar Mutations that confer LMV resistance are different from those that confer ADV resistance, and cross-resistance between ADV and LMV has not been observed to date. Clearly, ADV can be used to rescue cases in which LMV resistance has developed and, presumably, vice versa. In such cases, continuation of LMV after ADV rescue therapy has been initiated appears to provide little benefit, but will the converse be true? Should LMV and ADV be used sequentially or simultaneously, and will their simultaneous use accelerate development of dual or multidrug resistance? Currently, the wholesale cost of treatment with LMV is less than two-thirds the cost of ADV treatment (approximately US$260 versus US$450 per month, respectively). Other nucleosidic drugs, including emtricitabine, entecavir, and telbivudine, have progressed to advanced phase II or phase III clinical trials, and may become available in the near future,1Feld J. Lee J.Y. Locarnini S. New targets and possible new therapeutic approaches in the chemotherapy of chronic hepatitis B.Hepatology. 2003; 38: 545-553Crossref PubMed Scopus (46) Google Scholar, 4Delaney IV, W.E. Locarnini S. Shaw T. Resistance of hepatitis B virus to antiviral drugs current aspects and directions for future investigation.Antivir Chem Chemother. 2001; 12: 1-35Crossref PubMed Scopus (104) Google Scholar but whether they will be active against ADV-resistant HBV in vivo is presently unknown. Monotherapy with LMV, ADV, or the newer nucleosidic agents consistently produces rapid and dramatic decreases in viremia.31Lewin S. Walters T. Locarnini S. Hepatitis B treatment rational combination chemotherapy based on viral kinetic and animal model studies.Antiviral Res. 2002; 55: 381-396Crossref PubMed Scopus (44) Google Scholar Unfortunately, only a small proportion (12%–25%) of treated individuals lose HBeAg and show normalization of serum ALT liver histology, accompanied by improvements in liver histology.32Dienstag J.L. Goldin R.D. Heathcote E.J. Hann H.W. Woessner M. Stephenson S.L. Gardner S. Gray D.F. Schiff E.R. Histological outcome during long-term lamivudine therapy.Gastroenterology. 2003; 124: 105-117Abstract Full Text Full Text PDF PubMed Scopus (674) Google Scholar Moreover, HBeAg seroconversion is uncommon and HBsAg seroconversion is a rare event.33van Nunen A.B. Hansen B.E. Suh D.J. Lohr H.F. Chemello L. Fontaine H. Heathcote J. Song B.C. Janssen H.L. de Man R.A. Schalm S.W. 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Locarnini S. Hepatitis B treatment rational combination chemotherapy based on viral kinetic and animal model studies.Antiviral Res. 2002; 55: 381-396Crossref PubMed Scopus (44) Google Scholar It would not be overly optimistic to predict that acceleration of the rate of virus elimination during the second phase would be enhanced by rational combination chemotherapy.31Lewin S. Walters T. Locarnini S. Hepatitis B treatment rational combination chemotherapy based on viral kinetic and animal model studies.Antiviral Res. 2002; 55: 381-396Crossref PubMed Scopus (44) Google Scholar Optimism must be tempered by recognition that even long-term combination chemotherapy with safe and efficacious nucleosidic drugs will probably be insufficient to eliminate HBV mini-chromosomes from the nuclei of infected cells, which will require additional drugs and almost certainly immunomodulators.1Feld J. Lee J.Y. Locarnini S. 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