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Potency of tenofovir in chronic hepatitis B: Mono or combination therapy? Editorial
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Journal of Hepatology March 2008
J.G.P. Reijnders, H.L.A. JanssenCorresponding Author Informationemail address
Associate Editor: F. Zoulim
"Treatment strategies should however be focused on preventing development of resistance by suppressing viral replication as quickly and completely as possible, rather than adjustment of therapy after the emergence of resistance, thereby limiting treatment options due to cross-resistance, and allowing for development of multi-resistant HBV variants. The concept of combination therapy has long been established as the paradigm of therapy for a number of other chronic infections. In the treatment of HIV, it has not only been proven to diminish or delay the occurrence of resistance due to greater potency and a higher genetic barrier, but also to reduce mortality.... combination regimens should be compared to monotherapy with our most effective nucleos(t)ide analogues, such as entecavir and tenofovir. Clinical investigators, regulatory authorities, and, most of all, pharmaceutical companies should support this process."
The introduction of nucleos(t)ide analogues heralded a new era in the treatment of chronic hepatitis B, and provided a safe, effective, and well tolerated alternative to interferon. Nucleos(t)ide analogues target the reverse transcriptase of hepatitis B virus (HBV) and are potent inhibitors of viral replication. Initiation of treatment usually results in a rapid decline of serum HBV DNA levels, which is often accompanied by normalization of serum aminotransferases. Although treatment with nucleos(t)ide analogues profoundly suppresses serum HBV DNA levels and response can be maintained over prolonged periods with ongoing therapy, response to treatment may not be durable in a large proportion of patients after discontinuation of therapy, indicating the necessity for long-term, and maybe indefinite, treatment [1], [2]. However, development of antiviral resistance is a major limitation to long-term efficacy of nucleos(t)ide analogues and will thus be the most significant factor in treatment failures [3]. In order to prevent development of antiviral drug resistance a judicious use of nucleos(t)ide analogues in patients with chronic hepatitis B virus infection is needed [4].
Antiviral drug resistance reflects reduced susceptibility of a virus to the inhibitory effect of a drug. It results from a process of adaptive mutations under therapy. The first manifestation of antiviral resistance is virologic breakthrough which is defined as a >1log10 increase in serum HBV DNA from nadir during treatment in a patient who had an initial virologic response. It is usually also followed by a biochemical breakthrough [5]. Emergence of antiviral resistance can eventually lead to reversion of virologic and histologic improvement, and enhance the rate of disease progression [6], [7].
Obviously, the best strategy is to avoid the emergence of drug resistance. There are two basic approaches, either not to treat or to treat more effectively. The first option is rather a decision to postpone, and to treat only those patients with more active or advanced liver disease and others most likely to respond. The second option is to treat more effectively thereby strongly suppressing viral replication [8]. Only potent nucleos(t)ide analogues with a high genetic barrier should be used. In particular because a diversity of viruses (quasispecies), including mutants with single and double mutations potentially associated with drug resistance, may exist prior to therapy [9]. Furthermore, development and amplification of mutant populations is replication-dependent, and resistance emerges only when replication occurs in the presence of the drug selection pressure. Complete suppression of viral replication therefore allows little opportunity for resistance to develop, leading to the conclusion that no replication equates to no resistance [10]. Several studies have already shown that an initial virologic response is associated with lower rates of antiviral drug resistance in HBV patients in the long-term [11], [12], [13]. Therefore, antiviral therapy, once initiated, should aim to suppress viral replication as quickly and completely as possible.
In this issue, Tan et al. [14] describe five patients with a virologic breakthrough during adefovir dipivoxil (ADV) treatment in the absence of known ADV-resistant mutations, and four patients with a suboptimal virologic response to ADV, who were switched to tenofovir disoproxil fumarate (TDF) monotherapy. Of these nine patients, seven achieved undetectable serum HBV DNA levels within 3-18 months. By contrast, one patient with ADV-resistant mutations at baseline showed a suboptimal virologic response to TDF. After addition of emtricitabine (FTC) serum HBV DNA levels further declined. Two other patients with ADV-resistant mutations at baseline were directly switched to FTC-TDF combination therapy, and had undetectable HBV DNA after 3 and 12 months, respectively. Furthermore, it is interesting that HBV mutants harboring ADV-resistant mutations persisted during TDF treatment. The last patient (patient 9) had a suboptimal virologic response to ADV and was directly switched to FTC-TDF, which resulted in rapid HBV DNA undetectability. Yet, the study relies on a small heterogeneous group of patients and treatment regimens are not uniform. Therefore, conclusions from this study on the efficacy of TDF or FTC-TDF in an ADV-experienced population should be drawn with caution and these results need to be confirmed in larger populations.
Adefovir dipivoxil is an oral prodrug of adefovir, a phosphonate acyclic nucleotide analogue of adenosine monophosphate [15]. Previous studies demonstrated its efficacy in patients with HBeAg-positive and HBeAg-negative chronic HBV infection, showing significant virologic, biochemical, and histologic improvement after 48 weeks of treatment [16], [17]. However, genotypic resistance rates are up to 29% after 5 years of treatment with ADV [18]. Two mutations (N236T, A181V) have already been described to confer resistance to ADV [19], [20]. Other mutations have also been reported to be associated with reduced susceptibility to ADV, including the A181T and I233V mutations, but the significance of these mutations remains unclear [21], [22], [23], [24]. Furthermore, it is known that after 6 months of treatment approximately 30% of patients have a primary non-response to ADV, defined as a <2log10 drop in serum HBV DNA and 56% of patients are still above 4log10copies/mL, probably related to the suboptimal approved dose [25]. This assumption is supported by the cases described by Tan et al. [14] since no mutations were identified related to suboptimal response to ADV.
Tenofovir disoproxil fumarate is a nucleotide analogue similar in structure to ADV and is approved for the treatment of human immunodeficiency virus (HIV). It is a potent and selective inhibitor of hepatitis B virus in vitro [26], and studies in HBV/HIV co-infected patients confirmed its activity against HBV in both lamivudine-naive and lamivudine-resistant patients [27], [28], [29]. Recently, two phase III randomized clinical trials demonstrated a greater proportion of patients with undetectable HBV DNA (< 169copies/mL) after 48 weeks of treatment with tenofovir compared to adefovir in both HBeAg-positive (69% vs. 9%) and HBeAg-negative (91% vs. 51%) HBV infection [30], [31]. Similar to the results of Tan et al. [14], another study described 20 patients with lamivudine-refractory HBV and a suboptimal virologic response to ADV, in whom switching to TDF resulted in undetectable HBV DNA in 19 of 20 patients in a median time of 3.5 months [32]. Yet, another study in only 10 HBV mono-infected patients also confirmed that, although TDF shows significant antiviral efficacy in patients with genotypic ADV-resistance, undetectable HBV DNA is only achieved in a minority of the patients. Addition of lamivudine led to further decline in HBV DNA levels. Furthermore, ADV-resistance associated mutations persisted during TDF treatment [33]. Until now TDF resistance has only been described in two HIV-HBV co-infected patients demonstrating the A194T mutation in addition to LAM-resistance. However, in vitro studies regarding TDF susceptibility to the rtA194T mutation demonstrate conflicting results, and therefore its clinical significance needs to be determined [26], [34]. Another interesting finding is that HBV mutants harboring N236T and/ or A181V mutations seem to be cross-resistant to TDF, for ADV-resistance associated mutations persisted during TDF treatment. In vitro studies also showed that susceptibility of HBV isolates with N236T and A181V to TDF is decreased by 4-fold and 3.2-fold, respectively [35], [36]. On the other hand, TDF has been used successfully for the treatment of patients who failed consecutive therapy with lamivudine and lamivudine-adefovir combination [37]. Yet, patients with genotypic ADV-resistance should probably receive combination treatment of TDF or ADV plus lamivudine, telbivudine, emtricitabine, or entecavir. The combination of choice depends largely on the viral resistance profile. In HIV-HBV co-infected patients there is already much experience with treatment regimens containing TDF in combination with lamivudine or FTC, demonstrating no increased toxicity or drug interactions [27], [38], [39].
Despite the fact that the study by Tan et al. is small it should urge us to reconsider our current strategies to combat antiviral drug resistance in the treatment of chronic HBV infection. It is now recommended to start with monotherapy and to use an add-on strategy in case of development of resistant HBV mutants [4], [40]. Treatment strategies should however be focused on preventing development of resistance by suppressing viral replication as quickly and completely as possible, rather than adjustment of therapy after the emergence of resistance, thereby limiting treatment options due to cross-resistance, and allowing for development of multi-resistant HBV variants. The concept of combination therapy has long been established as the paradigm of therapy for a number of other chronic infections. In the treatment of HIV, it has not only been proven to diminish or delay the occurrence of resistance due to greater potency and a higher genetic barrier, but also to reduce mortality [41]. Therefore, rapid viral load reduction either by de novo combination therapy or early add-on strategies should be compared to current recommendations. Optimal clinical trials should be designed and conducted, using appropriate combinations of complementary and potent antiviral drugs, and having solid endpoints, such as development of genotypic resistance. Other important endpoints may include HBV dynamics and immunological control of the virus, both assessed in serum and the liver. In addition, combination regimens should be compared to monotherapy with our most effective nucleos(t)ide analogues, such as entecavir and tenofovir. Clinical investigators, regulatory authorities, and, most of all, pharmaceutical companies should support this process. We as hepatologists can benefit from the knowledge made by retrovirologists, and not confronting this challenge will postpone the availability of important data for years.
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