INSERM U271, 151 Cours Albert Thomas, 69003 Lyon, France
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Abstract |
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Keywords: HBV , antiviral , therapy
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Introduction |
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The major questions are whether a combination of nucleoside analogues can achieve antiviral synergy, thereby reducing the risk of resistance development? Can it prevent the formation of cccDNA in newly infected cells? Can it decrease the pool of cccDNA in already chronically infected cells? Has the use of drugs that do not share the same cross-resistance profile the capacity to delay the development of multidrug-resistant mutants? And can all these effects on HBV replication result in restoration of immune response to achieve a sustained control of viral replication?
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Mechanism of action of nucleoside analogues |
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Combination of drugs and antiviral synergy |
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In a recent study, we showed in the DHBV model an additive effect of the combination of drugs acting on the priming of reverse transcription (amdoxovir), elongation of minus-strand DNA (emtricitabine), elongation of plus-strand DNA (clevudine) on the viral polymerase activity, intracellular viral DNA synthesis in primary duck hepatocyte cultures and on virus production in vivo in experimentally infected animals.13
Antiviral synergy per se was not observed, which may suggest that the combination strategies should use drugs with clearly distinct mechanisms of action, such as polymerase inhibitors and interferon- (as demonstrated in recent clinical trials of lamivudine plus pegylated interferon14
), or the use of new compounds inhibiting viral assembly or morphogenesis or viral entry, etc. In the woodchuck model, we found that the combination of clevudine and emtricitabine resulted in a sharp decrease in viraemia levels,5
which seemed to be more pronounced than in historical controls receiving single drugs alone. Interestingly, as also observed previously in woodchucks treated with clevudine alone, a slow rebound of viraemia was observed after treatment cessation in animals who received the combination therapy. This unusual evolution of viraemia following drug withdrawal compared with all the other nucleoside analogues tested so far may be attributable to an unknown effect of clevudine.5,15,16
Furthermore, in Phase II clinical trials this slow rebound of viraemia was also observed in patients.7
This unique antiviral activity profile may lead to a new concept of antiviral therapy for chronic hepatitis B.
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Effect of combination therapy on viral cccDNA |
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Another issue is to determine whether antiviral therapy may have an effect on already formed cccDNA in chronically infected cells, thus resulting in cell curing. As polymerase inhibitors do not have a direct effect on cccDNA formation, this may be due to the inhibition of intracellular recycling of viral nucleocapsid to the nucleus secondary to the inhibition of viral DNA synthesis. This has been observed with single drug administration in the woodchuck model with clevudine and entecavir,16,20 and in clinical trials with entecavir and adefovir dipivoxil.21 Interestingly, it was shown that a combination of nucleoside analogues may have an additive effect on the intracellular cccDNA levels in already infected cells, which suggests that the additive effect observed on viral DNA synthesis may also result in an additive effect on cccDNA levels.13 Therefore, this implies an important role of combination therapy to decrease intrahepatic viral load during long-term therapy.
The decrease in cccDNA levels observed in woodchucks treated with clevudine alone or in combination with emtricitabine may explain the slow relapse of viral replication post-treatment. In some animals this was accompanied by a decline in the number of infected cells to undetectable levels as assessed by immunostaining of liver sections for viral antigens.5 It is also noteworthy that in one study, the combination of clevudine followed by vaccination against the woodchuck hepatitis virus (WHV) envelope proteins led to the clearance of circulating viral antigens.22
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Influence of the cross-resistance profile of nucleoside analogues |
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Restoration of specific anti-HBV immune response |
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In our study in the woodchuck model, the intrahepatic delivery of recombinant adenovirus vectors encoding the woodchuck interferon- did not lead to an added benefit to the combination of emtricitabine and clevudine, suggesting that chronically infected woodchuck hepatocytes may be refractory to the anti-WHV activity of interferon-
.5
This has been confirmed by other teams, one study showing that interferon-
had more antiviral efficacy than interferon-
in the woodchuck model.28,29
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Perspectives for the treatment of chronic hepatitis B |
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Acknowledgements |
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References |
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