Combination therapy for chronic hepatitis B: Ready for prime time?
Authors: Ira M. Jacobson
Journal: Journal of Hepatology (2008)

In recent years, major advances have been made in our understanding of the natural history and management of patients with chronic hepatitis B. Large cohort studies have clearly established the link between level of viremia and adverse outcomes, including both hepatocellular carcinoma (HCC) and cirrhosis [1Chen C.J. Yang H.I. Su J. Jen C.L. You S.L. Lu S.N. et al.Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.JAMA. 2006; 295: 65-73Google Scholar, 2Iloeje U.H. Yang H.I. Su J. Jen C.L. You S.L. Chen C.J. et al.Predicting cirrhosis risk based on the level of circulating hepatitis B viral load.Gastroenterology. 2006; 130: 678-686Abstract Full Text Full Text PDF Scopus (1308) Google Scholar]. Furthermore, a spontaneous decline in HBV DNA level has been correlated with improved outcomes [[1]Chen C.J. Yang H.I. Su J. Jen C.L. You S.L. Lu S.N. et al.Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.JAMA. 2006; 295: 65-73Google Scholar], suggesting that pharmacological suppression may achieve the same ends. Consistent with this, clinical trials have already confirmed a positive impact of antiviral therapy on disease outcomes [3Niederau C. Heintges T. Lenge S. Goldmann G. Niederau C.M. Mohr L. et al.Long-term follow-up of HbeAg-positive patients treated with interferon alfa for chronic hepatitis B.N Engl J Med. 1996; 334: 1422-1427Google Scholar, 4Liaw Y.F. Sung J.J. Chow W.C. Farrell G. Lee C.Z. Yuen H. et al.Lamivudine for patients with chronic hepatitis B and advanced liver disease.N Engl J Med. 2004; 351: 1521-1531Google Scholar, 5Di Marco V. Marzano A. Lampertico P. Andreone P. Santantonio T. Almasio P.L. et al.Clinical outcome of HBeAg-negative chronic hepatitis in relation to virological response to lamivudine.Hepatology. 2004; 40: 883-891Google Scholar]. In parallel with these developments has come evidence that relatively low viral levels, and normal or only slightly elevated ALT levels can be associated with significant liver disease and adverse clinical outcomes [1Chen C.J. Yang H.I. Su J. Jen C.L. You S.L. Lu S.N. et al.Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.JAMA. 2006; 295: 65-73Google Scholar, 2Iloeje U.H. Yang H.I. Su J. Jen C.L. You S.L. Chen C.J. et al.Predicting cirrhosis risk based on the level of circulating hepatitis B viral load.Gastroenterology. 2006; 130: 678-686Abstract Full Text Full Text PDF Scopus (1308) Google Scholar, 6Lai M. Hyatt B.J. Nasser I. Curry M. Afdhal N.H. The clinical significance of persistently normal ALT in chronic hepatitis B infection.J Hepatol. 2007; 47: 760-767Google Scholar, 7Yang L.M. Xu K.C. Zhao Y.L. Wu Z.R. Chen T.F. Qin Z.Y. et al.Clinical significance of liver biopsy in chronic hepatitis B patients with persistently normal transaminases.Chin J Dig Dis. 2002; 4: 150-153Google Scholar, 8Yuen M.F. Yuan H.J. Wong D.K.H. Yuen J.C. Wong W.M. Chan A.O. et al.Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications.Gut. 2005; 54: 1610-1614Google Scholar]. Although the evidence-based treatment guidelines promulgated by the international liver associations have featured defined viral load cut-offs and threshold levels of ALT above normal to define treatment candidacy [9Lok A.S. McMahon B.J. Chronic hepatitis B.Hepatology. 2007; 45: 507-539Google Scholar, 10EASL International Consensus Conference on Hepatitis B. J Hepatol 2003;38:S3–S25.Google Scholar, 11Liaw Y.F. Leung N. Guan R. Lau G.K. Merican I. McCaughan G. et al.Asian-pacific consensus statement on the management of chronic hepatitis B: a 2005 update.Liver Int. 2005; 25: 472-489Google Scholar] there has been a trend among many clinicians to broaden the spectrum of patients with HBV infection in whom therapy is considered appropriate [[12]Keeffe E.B. Dieterich D.T. Han S.H. Jacobson I.M. Martin P. Schiff E.R. et al.A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update.Clin Gastroenterol Hepatol. 2006; 4: 936-962Google Scholar]. The crystallization of the link between reduction in viremia and improved outcomes, and the inexorable increase in the population expected to be treated in the future, have sharpened the focus on what might be termed the “twin pillars” of HBV therapy: potent long-term viral suppression and avoidance of resistance. These pillars have been fortified with the introduction over the past decade of four approved oral antiviral agents, along with peginterferon alfa-2a. Other oral agents are in the late phase of development, such as tenofovir [13Marcellin P, Buti M, Krastev Z, Germanidis G, Kaita KD, Kotzev I, et al. A randomized, double-blind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg-negative chronic hepatitis B (CHB): Study GS-US-174-0102. American Association for the Study of Liver Diseases, 58th annual meeting, 2007: late breaking abstract 2. Hepatology 2007;46:290A.Google Scholar, 14Heathcote EJ, Gane E, DeMan R, Lee S, Flisiak R, Manns MP, et al. A randomized, double-blind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg positive chronic hepatitis B (CHB): Study GS-US-174-0103. American Association for the Study of Liver Diseases, 58th annual meeting, 2007: late breaking abstract 6. Hepatology 2007;46:861A.Google Scholar], already available as an approved treatment for human immunodeficiency virus (HIV), and clevudine, for which there is suggestive evidence of a capacity to induce sustained viral suppression after cessation of therapy, even in HBeAg-negative patients [[15]Yoo B.C. Kim J.H. Kim T.H. Koh K.C. Um S.H. Kim Y.S. et al.Clevudine is highly efficacious in hepatitis B e antigen-negative chronic hepatitis B with durable off therapy viral suppression.Hepatology. 2007; 46: 1041-1048Google Scholar]. Yet, despite the increased level of confidence, clinicians have in their ability to treat patients effectively, whether it be those with “conventional indications” on which all experts would agree, or with “expanded indications” that engender ongoing controversy, major limitations remain. These limitations can be classified as follows: (1) HBV DNA remains detectable in some patients even with the most potent agents, particularly those who are HBeAg-positive; (2) Even when HBV DNA becomes undetectable, HBeAg seroconversion does not ensue at proportional frequency. Indeed, the pivotal trials of entecavir, telbivudine, and tenofovir have underscored the biologic difference underlying viral suppression and HBeAg seroconversion. As effective as these agents have proven to be in reducing HBV DNA levels, HBeAg seroconversion rates have not improved substantially relative to those obtained with earlier treatments; (3) In HBeAg-negative patients, we still lack an oral agent(s) that allows for cessation of therapy with an acceptable rate of durable viral suppression subsequently; (4) Although oral agents are not wholly incapable of inducing HBsAg loss, the rates are low, with 3% of HBeAg-positive patients receiving tenofovir [[14]Heathcote EJ, Gane E, DeMan R, Lee S, Flisiak R, Manns MP, et al. A randomized, double-blind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg positive chronic hepatitis B (CHB): Study GS-US-174-0103. American Association for the Study of Liver Diseases, 58th annual meeting, 2007: late breaking abstract 6. Hepatology 2007;46:861A.Google Scholar] and 5% of HBeAg-positive patients receiving entecavir [[16]Gish R, Chang TT, Lai CL, de Man R, Gadano A, Poordad F, et al. Hepatitis B surface antigen loss in antiviral-treated patients with HBeAg-positive chronic hepatitis B infection: observations from antiviral-naïve patients treated with entecavir or lamivudine. 57th annual meeting of the American Association for the Study of Liver Diseases, 2006. Hepatology 2006;44:558A.Google Scholar] achieving this milestone after one and two years, respectively; and (5) All long-term monotherapies have been shown to be capable of selecting for resistance, although the resistance rates with drugs having a high genetic barrier to resistance have been reassuringly low. The resistance rate with adefovir in HBeAg-negative patients is only 6% at up to 192 weeks if HBV DNA is under 1000 copies/ml at one year of treatment. In the aggregate, however, the incidence of genotypic resistant mutations is 29% at five years [[17]Hadziyannis 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 for up to 5 years.Gastroenterology. 2006; 131: 1743-1751Google Scholar]. The rate of resistance to entecavir has been reported to be less than 1% cumulatively after four years [[18]Han S. Chang T.T. Chao Y.C. Yoon S.-K. Gish R.G. Cheinquer H. et al.Four-year entecavir treatment in nucleoside-naive HbeAg+ patients: results from studies ETV-022 and -901.Hepatology. 2007; 46: 654AGoogle Scholar]. Although a feature of the entecavir (ETV) pivotal trials was that a subset of patients, rather than all patients, received treatment beyond one year, many HBeAg-positive patients (predominantly those with “virologic only response” who failed to clear HBeAg at 48 weeks) did receive ETV 1.0 mg daily for as long as three additional years in a rollover study after the initial year of ETV 0.5 mg daily. The data from this cohort [[18]Han S. Chang T.T. Chao Y.C. Yoon S.-K. Gish R.G. Cheinquer H. et al.Four-year entecavir treatment in nucleoside-naive HbeAg+ patients: results from studies ETV-022 and -901.Hepatology. 2007; 46: 654AGoogle Scholar], including a recently reported subset of 21 HBeAg-positive patients with virological non-response to ETV after 48 weeks [[19]Sherman M. Rizzetto M. Lai C.L. Liaw Y.-F. Gadano A. Jacobson I.M. et al.Long-term follow-up of entecavir treated protocol-defined nonresponders in rollover study ETV-901.Hepatology. 2007; 46: 682AGoogle Scholar], support the conclusion that the drug’s resistance profile after prolonged therapy is very robust. Nevertheless, the drug is not entirely free of a risk of resistance. All these limitations have fuelled intense interest in combination regimens for chronic hepatitis B. In theory, at least, combination therapy might improve upon monotherapy with regard to any or all of the above endpoints. Support for this concept comes from the many lessons learned with human immunodeficiency virus (HIV) therapy, as well as the emerging story of therapy for chronic hepatitis C [[20]Kieffer T.L. Sarrazin C. Miller J.S. Welker M.W. Forestier N. Reesink H.W. et al.Telaprevir and pegylated interferon-alpha-2a inhibit wild type and resistant genotype 1 hepatitis C virus replication in patients.Hepatology. 2007; 46: 631-639Google Scholar], where it is widely anticipated that combinations of specifically targeted antiviral agents will be necessary to optimize responses and minimize problems with resistance. Very few studies exploring this approach to HBV therapy have been reported to date. The phase 2 trial of telbivudine featured three arms: lamivudine alone, telbivudine alone, and telbivudine combined with lamivudine [[21]Lai C.L. Leung N. Teo E.K. Tong M. Wong F. Hann H.W. et al.A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B.Gastroenterology. 2005; 129: 528-536Google Scholar]. The degree of viral suppression after one year was no greater with combination therapy than with telbivudine, though each was superior to lamivudine, and combination therapy was actually slightly inferior to telbivudine monotherapy in attaining clinical efficacy endpoints, including HBeAg loss or seroconversion and viral breakthrough. Although the reasons for these observations are not clear [[21]Lai C.L. Leung N. Teo E.K. Tong M. Wong F. Hann H.W. et al.A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B.Gastroenterology. 2005; 129: 528-536Google Scholar], it seems prudent to avoid using drugs with cross-resistance, such as lamivudine and telbivudine, in combination. This point has been underscored by recent data demonstrating excellent suppression, with virtually no long-term resistance to adefovir, when that drug is added to lamivudine in patients who have developed lamivudine resistance [[22]Lampertico P. Viganò M. Manenti E. Iavarone M. Sablon E. Colombo M. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients.Gastroenterology. 2007; 133: 1445-1451Abstract Full Text Full Text PDF Scopus (304) Google Scholar]. The present issue of the Journal features two papers which expand our knowledge about the potential advantages of oral combination therapy [23Sung J.J.Y. Lai J.Y. Zeuzem S. Chow W.C. Heathcote E.J. Perrillo R.P. et al.Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B.J Hepatol. 2008; 48: 728-735Abstract Full Text Full Text PDF Scopus (142) Google Scholar, 24Hui C.K. Zhang H.Y. Bowden S. Locarnini S. Luk J.M. Leung K.-W. et al.96 weeks combination of adefovir dipivoxil plus emtricitabine versus adefovir dipivoxil monotherapy in the treatment of chronic hepatitis B.J Hepatol. 2008; 48: 714-720Abstract Full Text Full Text PDF Scopus (59) Google Scholar]. The preliminary results of the placebo-controlled study in HBeAg-positive patients by Sung et al. of lamivudine monotherapy (n = 57) versus lamivudine plus adefovir (n = 54) were presented in abstract form shortly after adefovir was approved [[25]Sung J.J.Y. Lau J.Y. Zeuzem S. Chow W.C. Heathcote E. Perrillo R. et al.A randomised double-blind phase II study of lamivudine (LAM) compared to lamivudine and adefovir for treatment-naive patients with chronic hepatitis B (CHB): week 52 analysis.J Hepatol. 2003; 38: 25-26Google Scholar] and its final publication at this time [[23]Sung J.J.Y. Lai J.Y. Zeuzem S. Chow W.C. Heathcote E.J. Perrillo R.P. et al.Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B.J Hepatol. 2008; 48: 728-735Abstract Full Text Full Text PDF Scopus (142) Google Scholar] has long been awaited. Reductions in HBV DNA were comparable between the two treatment arms at week 16 (the primary study endpoint) and during the first 52 weeks, but after 104 weeks median HBV DNA reductions were −3.41log and −5.22log, respectively. Similarly, HBV DNA was <200 copies/ml in 41% and 40% at 52 weeks, but 14% versus 26% at 104 weeks. The difference in virologic outcome was associated with a higher rate of viral breakthrough in the monotherapy group than in the combination group (44% vs 19%). Not all the breakthroughs were associated with genotypic resistance, and a surprisingly small number of patients (only three in both groups combined) had genotypic mutations without virologic breakthrough, even though patients had to have not only a 1log increase in HBV DNA from nadir but at least one value >104 copies/ml to be classified as having had a breakthrough. In the lamivudine monotherapy group, the M204V/I mutation was detected in 20% and 43% at weeks 52 and 104, compared with 9% and 15% at the same time points in the combination therapy group. The N236T mutation was noted in only one adefovir recipient. Notably, the rate of HBeAg seroconversion was identical, at 35%, in each group. The results of this trial indicate that the addition of a nucleotide with an excellent short-term resistance profile to a nucleoside with a lower genetic barrier to resistance effectively decreases the risk of emergent resistance to the latter drug, despite the relative limitation on viral suppression by the former drug imposed by dosing constraints. However, such a combination does not provide additive viral suppression early in therapy, the increment in viral decline in the longer term presumably being attributable mostly or entirely to the prevention of viral breakthrough. Moreover, the risk of lamivudine resistance even in the combination group was far from negligible. Thus, the first “pillar” of HBV therapy, profound viral suppression, is not strengthened significantly by such a combination, while the second, prevention of resistance, is strengthened but only relatively. These findings reinforce the need for consideration of the features and limitations of the individual agents incorporated into studies of combination regimens. The results of the paper by Sung et al. [[23]Sung J.J.Y. Lai J.Y. Zeuzem S. Chow W.C. Heathcote E.J. Perrillo R.P. et al.Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B.J Hepatol. 2008; 48: 728-735Abstract Full Text Full Text PDF Scopus (142) Google Scholar] also warrant circumspection among clinicians who may have chosen in the past to use a combination of lamivudine and adefovir in patients in whom resistance could have particularly adverse implications, such as cirrhotic patients. Clearly, the results of studies in which adefovir resistance rarely occurs when it is added to lamivudine in lamivudine-resistant patients [[22]Lampertico P. Viganò M. Manenti E. Iavarone M. Sablon E. Colombo M. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients.Gastroenterology. 2007; 133: 1445-1451Abstract Full Text Full Text PDF Scopus (304) Google Scholar] cannot be extrapolated to the question of how frequently lamivudine resistance emerges when the two drugs are co-administered to treatment-naïve patients. Added perspective on combination regimens is provided by a second paper published in this issue of the Journal by Hui et al. [[24]Hui C.K. Zhang H.Y. Bowden S. Locarnini S. Luk J.M. Leung K.-W. et al.96 weeks combination of adefovir dipivoxil plus emtricitabine versus adefovir dipivoxil monotherapy in the treatment of chronic hepatitis B.J Hepatol. 2008; 48: 714-720Abstract Full Text Full Text PDF Scopus (59) Google Scholar], comparing adefovir (n = 16) alone to a combination of adefovir plus emtricitabine (n = 14), a nucleoside analog with activity and a resistance profile similar to that of lamivudine, in HBeAg-positive patients for 96 weeks. Despite the small number of patients in the study, a significant advantage for combination therapy was achieved, with median HBV DNA declines of −3.98log10 copies/ml versus −5.30log10 copies/ml for monotherapy and combination therapy, respectively, at 96 weeks (p = 0.05), and HBV DNA <300 copies/ml in 37.5% versus 78.5%. In contrast to the study by Sung et al. [[23]Sung J.J.Y. Lai J.Y. Zeuzem S. Chow W.C. Heathcote E.J. Perrillo R.P. et al.Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B.J Hepatol. 2008; 48: 728-735Abstract Full Text Full Text PDF Scopus (142) Google Scholar], the difference in viral suppression was noted early in treatment by Hui et al. [[24]Hui C.K. Zhang H.Y. Bowden S. Locarnini S. Luk J.M. Leung K.-W. et al.96 weeks combination of adefovir dipivoxil plus emtricitabine versus adefovir dipivoxil monotherapy in the treatment of chronic hepatitis B.J Hepatol. 2008; 48: 714-720Abstract Full Text Full Text PDF Scopus (59) Google Scholar], as early as 4 weeks as suggested in Fig. 1, thereby proving to be related to differences in the intrinsic antiviral efficacy of the two regimens. All four viral breakthroughs in the study occurred at 64 weeks and beyond; three of these occurred in the combination group but none was associated with drug-resistant mutations, nor were genotypic mutations noted in nine other patients from the adefovir monotherapy group. In a recurrent theme from the cumulative literature, there was no difference in the incidence of HBeAg seroconversion despite the difference in viral suppression between the two regimens. The design of this small trial makes it difficult to assess the degree to which the greater suppression of HBV DNA with the combination regimen was attributable to a contributory effect of adefovir or simply represented the efficacy of the more potent drug, emtricitabine. The limitation on interpretability posed by the absence of an emtricitabine monotherapy arm is fully acknowledged by the authors. In an earlier trial of emtricitabine versus placebo [[26]Lim S.G. Ng T.M. Kung N. Krastev Z. Volfova M. Husa P. et al.A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B.Arch Intern Med. 2006; 166: 49-56Google Scholar], 39% of HBeAg-positive patients receiving emtricitabine had undetectable HBV DNA at week 48 compared with 78.5% in the recipients of emtricitabine plus adefovir in the present study [[24]Hui C.K. Zhang H.Y. Bowden S. Locarnini S. Luk J.M. Leung K.-W. et al.96 weeks combination of adefovir dipivoxil plus emtricitabine versus adefovir dipivoxil monotherapy in the treatment of chronic hepatitis B.J Hepatol. 2008; 48: 714-720Abstract Full Text Full Text PDF Scopus (59) Google Scholar]. In the latter study, the limit of detection for HBV DNA was 300 copies/ml whereas in the former it was 400 copies/ml, perhaps underscoring a true difference in viral suppression, but cross-study comparisons are intrinsically problematic and especially so in this case given the very small number of patients in the present study. Moreover, the median decline of HBV DNA at 48 weeks in the trial of emtricitabine monotherapy was −4.7log10 copies/ml [[26]Lim S.G. Ng T.M. Kung N. Krastev Z. Volfova M. Husa P. et al.A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B.Arch Intern Med. 2006; 166: 49-56Google Scholar], only slightly lower than that observed with adefovir and emtricitabine in this study [[24]Hui C.K. Zhang H.Y. Bowden S. Locarnini S. Luk J.M. Leung K.-W. et al.96 weeks combination of adefovir dipivoxil plus emtricitabine versus adefovir dipivoxil monotherapy in the treatment of chronic hepatitis B.J Hepatol. 2008; 48: 714-720Abstract Full Text Full Text PDF Scopus (59) Google Scholar]. Perhaps the most striking apparent benefit of combination therapy in this study is that there was not only a relative decline in resistance to emtricitabine, as occurred with lamivudine resistance in the study by Sung et al. [[23]Sung J.J.Y. Lai J.Y. Zeuzem S. Chow W.C. Heathcote E.J. Perrillo R.P. et al.Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B.J Hepatol. 2008; 48: 728-735Abstract Full Text Full Text PDF Scopus (142) Google Scholar], but a complete absence of resistance. In contrast, in the emtricitabine monotherapy trial, resistance occurred in 13% at 48 weeks [[26]Lim S.G. Ng T.M. Kung N. Krastev Z. Volfova M. Husa P. et al.A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B.Arch Intern Med. 2006; 166: 49-56Google Scholar], reminiscent of, if not quite matching, resistance rates with lamivudine. Thus, although once again the relatively small number of patients precludes any notion of complete protection against resistance, this study provides another important indication that for drugs with a low genetic barrier to resistance, the concomitant administration of a HBV drug with a higher genetic barrier can prevent resistance to the former. The two studies reported in the Journal this month [23Sung J.J.Y. Lai J.Y. Zeuzem S. Chow W.C. Heathcote E.J. Perrillo R.P. et al.Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B.J Hepatol. 2008; 48: 728-735Abstract Full Text Full Text PDF Scopus (142) Google Scholar, 24Hui C.K. Zhang H.Y. Bowden S. Locarnini S. Luk J.M. Leung K.-W. et al.96 weeks combination of adefovir dipivoxil plus emtricitabine versus adefovir dipivoxil monotherapy in the treatment of chronic hepatitis B.J Hepatol. 2008; 48: 714-720Abstract Full Text Full Text PDF Scopus (59) Google Scholar] are of value in serving as prototypes for the important work still needed in this field, but they fall short of establishing a definitive role for routine combination therapy in all patients when potent monotherapies with robust long-term resistance profiles are available. For example, the 4-year data on entecavir suggest cumulative rates of HBV DNA undetectability exceeding 90% in HBeAg-positive patients after four years and, as cited above, a reported cumulative resistance rate of under 1% [[18]Han S. Chang T.T. Chao Y.C. Yoon S.-K. Gish R.G. Cheinquer H. et al.Four-year entecavir treatment in nucleoside-naive HbeAg+ patients: results from studies ETV-022 and -901.Hepatology. 2007; 46: 654AGoogle Scholar]. The recently presented pivotal trial data on tenofovir demonstrate potent suppression, with 93% and 76% of HBeAg-negative and HBeAg-positive patients having undetectable HBV DNA, respectively, after one year, and no genotypic resistance [13Marcellin P, Buti M, Krastev Z, Germanidis G, Kaita KD, Kotzev I, et al. A randomized, double-blind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg-negative chronic hepatitis B (CHB): Study GS-US-174-0102. American Association for the Study of Liver Diseases, 58th annual meeting, 2007: late breaking abstract 2. Hepatology 2007;46:290A.Google Scholar, 14Heathcote EJ, Gane E, DeMan R, Lee S, Flisiak R, Manns MP, et al. A randomized, double-blind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg positive chronic hepatitis B (CHB): Study GS-US-174-0103. American Association for the Study of Liver Diseases, 58th annual meeting, 2007: late breaking abstract 6. Hepatology 2007;46:861A.Google Scholar]. It seems likely from these and other data [[27]Van Bommel F. De Man R.A. Erhardt A. Huppe D. Stein K. Buggish P. et al.First multicenter evaluation of the efficacy of tenofovir in nucleos(t)ide analog experienced patients with HBV monoinfection.Hepatology. 2007; 46: 270AGoogle Scholar], as well as experience in HBV/HIV co-infected patients [[28]Benhamou Y. Fleury H. Trimoulet P. Pellegrin I. Urbinelli R. Katlama C. et al.Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients.Hepatology. 2006; 43: 548-555Google Scholar], that this drug, too, will prove to have a robust long-term resistance profile. Telbivudine, which confers excellent viral suppression but has a less robust resistance profile than entecavir or the nucleotides, has recently been associated with 2-year resistance rates of 2% or less in patients who meet certain criteria for baseline viral load and/or ALT and have undetectable HBV DNA at 24 weeks [[29]Zeuzem S. Buti M. Gane E.J. Liaw Y.-F. Di Bisceglie A.M. Heathcote E.J. et al.Baseline parameters predict both early virologic response and longer term outcomes for telbivudine-treated patients with chronic hepatitis B (the GLOBE Study).Hepatology. 2007; 46: 681AGoogle Scholar]. These considerations lead to challenges for those who wish, appropriately, to conduct additional trials of combination therapy for HBV infection. Even though prevention of resistance is a cornerstone of this concept, the practical design of trials with this as the primary endpoint is problematic when monotherapies that have high barriers to resistance and excellent proven long-term resistance profiles are already available. Thus, such studies must emphasize serological and virologic endpoints, such as greater rates of HBV DNA suppression, HBeAg seroconversion, HBsAg clearance, accelerated covalent closed circular DNA (cccDNA) clearance, and perhaps the capacity to stop therapy without virologic relapse, particularly in HBeAg-negative patients, at a definable time point. It may be that drugs with other mechanisms of action, such as immunomodulatory agents, including restoration of specific immune responses, small interfering RNAs (siRNAs), entry inhibitors (pre-S peptides), or assembly inhibitors, will be required. A notable feature of trials evaluating combinations of peginterferon and lamivudine is a more profound decrease in viral load than that observed with either monotherapy. However, post-treatment endpoints such as viral suppression, HBeAg seroconversion, and HBsAg clearance have not been significantly different from those noted with peginterferon alone, which is superior to lamivudine alone [30Marcellin P. Lau G.K. Bonino F. Farci P. Hadziyannis S. Jin R. et al.Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.N Engl J Med. 2004; 351: 1206-1217Google Scholar, 31Lau G.K. Piratvisuth T. Luo K.X. Marcellin P. Thongsawat S. Cooksley G. et al.Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.N Engl J Med. 2005; 352: 2682-2695Google Scholar]. These trials entailed the discontinuation of lamivudine, like peginterferon, after one year, which is not done in practice. While the search for alternative approaches to combination therapy continues, including the potential for combining peginterferon with other nucleos(t)ide analogs entailing more prolonged administration of the oral agent, further trials combining nucleos(t)ide analogs, such as those currently being conducted with such combinations as tenofovir and emtricitabine, entecavir and tenofovir, entecavir and adefovir, and tenofovir and telbivudine [[32]http://clinicaltrials.gov/.Google Scholar], are abundantly worthwhile. In the meantime, results such as those from the trials reported in this issue of the Journal, despite their limitations, provide support, along with other published data, for the use of oral combination therapy (albeit off-label) in selected situations such as (a) in patients with cirrhosis who can ill-afford emergent resistance; (b) when there has been suboptimal response to initial monotherapy at a specified time point, such as 24 weeks of a drug with a low genetic barrier to resistance or one year of a drug with a high barrier [[33]Keeffe E.B. Zeuzem S. Koff R.S. Dieterich D.T. Esteban-Mur R. Gane E.J. et al.Report of an international workshop: roadmap for management of patients receiving oral therapy for chronic hepatitis B.Clin Gastroenterol Hepatol. 2007; 5: 890-897Google Scholar]; (c) in patients co-infected with HIV and HBV; and (d) in any setting in which there is established resistance to a HBV drug. However, the universal application of combination therapy to all patients undergoing treatment for chronic hepatitis B requires a firmer foundation in comparative trials with potent agents used as monotherapy before it goes from the controversial to the routine.