Hepatitis B antivirals and resistance

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Highlights

  • •

    Antiviral therapy for chronic hepatitis B improves the outcome of patients.

  • •

    Agents with low potency and genetic barrier to resistance results in the selection of variants.

  • •

    These mutants have implications on patient outcome and public health.

Antiviral therapy for chronic hepatitis B (CHB) has improved the outcome of patients. However, due to the multiple selection pressures of different nucleos(t)ide analogue, drug resistant HBV variants have emerged. Because of the arrangement of overlapping reading frames in HBV genome, these variants not only have clinical implications such as drug resistance, but also the potential to pose public health issues via vaccine escape. Whilst emergence of these variants cannot be prevented, careful selection and institution of the appropriate rescue anti viral therapy based on high genetic barrier and high potency should minimize this outcome.

Introduction

The ultimate goal of treating a chronic infectious disease is the eradication of the infectious agent to prevent organ damage or death. The natural history of untreated chronic hepatitis B (CHB) can result in the development of cirrhosis, followed by hepatic decompensation and death [1, 2, 3, 4, 5]. Hepatocellular carcinoma (HCC) can also occur in patients with chronic hepatitis B virus (HBV) infection, with or without the presence of cirrhosis. Antiviral therapy with the current approved oral nucleos(t)ide analogue (NA) agents suppress viral replication but do not directly act on the covalently closed circular (ccc) DNA that resides within infected hepatocytes; it is the ccc DNA that is the major transcriptional template of HBV and its elimination is regarded as equivalent to curing the patient. Thus, the current approved oral therapy only controls HBV infection, it does not eradicate it [1, 3, 4, 5]. Although these oral antiviral agents are well tolerated with minimal side effects, prolonged viral suppression runs the risk of selecting for antiviral drug resistance, resulting in virologic breakthrough. Likewise, these treatments are probably ‘life-long’ and so decreased patient adherence with their antiviral treatment is not uncommon and is frequently associated with virological breakthrough. The potential consequences of antiviral drug resistance in chronic hepatitis B (CHB) are shown in Table 1. Therefore, the goal of ‘cure’ or eradication of HBV infection is unrealistic, at least with current therapy. Nevertheless, preventing the adverse clinical outcomes and sequelae of this disease remains important and are readily achievable with available treatment that includes the NA with high potency and high genetic barrier to resistance [3, 6].

Section snippets

Antiviral drug resistance and chronic hepatitis B

In most parts of the world, five HBV-specific NAs targeting the viral polymerase are approved for the treatment of chronic hepatitis B (CHB): lamivudine (LMV; a cytidine l-nucleoside analogue), adefovir (ADV; an acyclic phosphonate), entecavir (ETV; d-cyclopentane), telbivudine (LdT; a thymidine l-nucleoside analogue) and tenofovir disoproxil fumarate (TDF; an acyclic phosphonate structurally related to ADV). These agents are approved and prescribed as single agent treatment and due to the

Causes of antiviral drug resistance

Antiviral drug resistance reflects the reduced susceptibility of a virus to the inhibitory effect of a drug [27] and results from a process of adaptive mutations under NA drug therapy. Multiple factors are responsible for the timing and pattern of resistance and include HBV viral replication rates, fidelity of pol, antiviral therapy related selection pressure, the genetic barrier of the drug, role of replication space (hepatocyte turnover) and fitness of the resistance mutant [6, 25].

In a

Cross-resistance

Cross-resistance is defined as resistance to drug(s) that a virus has never been exposed to. The drug resistance-associated mutations selected by particular groups of NA (e.g. l-nucleosides, acyclic phosphonates or cyclopentanes) could diminish the antiviral activity of other drugs [3, 6]. This can be seen with ADV associated mutation (rtA181T and rtN236T) selected in the B domain of pol gene conferring cross resistance to TFV, resulting a poor response [34] see Table 2a. This should be

Public health impact of antiviral drug resistance

Hepatitis B virus has a compact and a highly efficient replicating mechanism. The partially double stranded viral DNA has four overlapping but frame shifted open reading frame that expresses the reverse transcriptase polymerase, envelope or surface protein, pre-core/core protein and X protein. Due to its reverse transcription mechanism of replication, which is a well recognized error prone method of replication, a pool of quasispecies is generated [36]. These HBV variants provide a robust

Conclusions and future directions

The current patterns of antiviral drug resistance in CHB are complex, yet, despite this complexity, four resistance pathways have been established, based on detection of rtM204V/I, rtN236T, rtA181T/V and ETV-associated mutations (rtL180M plus rtM204V plus one of rtT184, rtS202 or rtM250). With the recent emergence of multidrug resistance there is now a clear cause for concern in the longer term. Additionally, broad clusters of compensatory mutations during LMV therapy will compromise future

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

Acknowledgements

The authors would like to thank the National Health and Medical Research Council, Australia for Dr Uma Devi's PhD scholarship.

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