Combination therapy for chronic hepatitis B: Ready for prime time? Editorial
Journal of Hepatology April 2008 Advance pulication
Ira M. Jacobson
Division of Gastroenterology and Hepatology, Weill Medical College of Cornell University, New York Presbyterian Hospital, 525 East 68th Street, New York, NY 100765, USA
Associate Editor: F. Zoulim
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 , . Furthermore, a spontaneous decline in HBV DNA level has been correlated with improved outcomes , 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 , , .
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 , , , , . Although the evidence-based treatment guidelines promulgated by the international professional societies have featured defined viral load cutoffs and threshold levels of ALT above normal to define treatment candidacy , ,  there has been a trend among many clinicians to broaden the spectrum of patients with HBV infection in whom therapy is considered appropriate .
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 , , 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 . 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 recent pivotal trials of entecavir, telbivudine, and tenofovir have underscored the biologic difference underlying viral suppression and HBeAg seroconversion, and because these agents have proven to be effective in suppressing HBV DNA, 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  and 5% of HBeAg-positive patients receiving entecavir  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 . The rate of resistance to entecavir has been reported to be less than 1% cumulatively after four years . 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 1.0mg daily for as long as three additional years in a rollover study after the initial year of ETV 0.5mg daily. The data from this cohort , including a recently reported subset of 21 HBeAg-positive patients with virological nonresponse to ETV after 48 weeks , 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 , 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 . 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 , it seems prudent to avoid using drugs with cross-resistance, such as lamivudine and telbivudine, in combination. The latter 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 .
The present issue of the Journal features two papers which expand our knowledge about the potential advantages of oral combination therapy , . 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  and its final publication at this time  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.  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  cannot be extrapolated to the question of how frequently lamivudine resistance emerges when the two drugs are co-administered to treatment-naive patients.
Added perspective on combination regimens is provided by a second paper published in this issue of the Journal by Hui et al. , 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. , the difference in viral suppression was noted early in treatment by Hui et al. , 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-resistance 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 , 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 . 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 , only slightly lower than that observed with adefovir and emtricitabine in this study . 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. , but a complete absence of resistance. In contrast, in the emtricitabine monotherapy trial, resistance occurred in 13% at 48 weeks , 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 ,  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 four 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% . 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 , . It seems likely from these and other data , and experience in HBV-HIV coinfected patients , 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 two 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 .
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 , . 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 , 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 ; (c) in patients coinfected with HIV and HBV; and (d) in any setting in which there is established resistance to an 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.
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