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PRESENCE OF rtA194T AT BASELINE DOES NOT REDUCE EFFICACY TO TENOFOVIR (TDF) IN PATIENTSWITH LAMIVUDINE (LAM)-RESISTANT CHRONIC HEPATITIS B
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Reported by Jules Levin
AASLD Nov 4 2008, San Francisco, CA
Scott K. Fung 1, Tony Mazzulli 1, Morris Sherman 1, Vladimir Popovic 2, Erwin Sablon 3
1. Department of Medicine, University of Toronto, Toronto, Canada 2. Gilead Sciences Canada, Mississauga, Canada 3. Infectious Diseases R&D Unit, InnoGenetics NV, Gent, Belgium
AUTHOR SUMMARY
rtA194T detected in 10 TDF-naïve HBV patients with lamivudine-resistanr CHB.
--always in association with L180M + M204V/I
-- usually as pure viral species or mixed population
TDF alone or in combination used as salvage therapy 7 patients.
--mean treatment of 9.6 months
--HBV DNA undetectable in 4 patients
--ALT normalized in 5 patients
AUTHOR CONCLUSIONS
rtA194T does not appear to be associated with reduced viral suppression or efficacy among LAM-resistant HBV patients salvaged with TDF in short term follow-up
These findings suggest rtA194T may represent a viral polymorphism or a LAM compensatory mutation rather than a signature TDF mutation
Further clinical studies are required to fully characterize antiviral substitutions associated with TDF resistance
BACKGROUND
Tenofovir (TDF) is a potent oral nucleotide analogue of adenosine.
TDF has demonstrated safety and efficacy in pivotal studies for the treatment of chronic hepatitis B.1 , 2
Antiviral-resistant mutations associated with virologic breakthrough on TDF therapy have not been fully characterized.
2/43 (5%) HIV-HBV coinfected patients treated with TDF plus lamivudine after 48-77 weeks were found to have a novel HBV pol mutation, rtA194T (alanine to threonine) in association with L180M + M204V.
In vitro phenotypic analysis of clones harboring A194T+L180M+M204V revealed 2 to 10 fold increase in IC50 to TDF compared to wild type virus. 3 , 4
In vitro susceptibility of A194T substitution was examined in a separate study.
A194T alone did not cause significant reduction in the TDF susceptibility.
Combination of A194T/L180M/M204V unlikely to cause clinical resistance to TDF in HBV patients.
However, no polymerase mutations associated with tenofovir resistance have been described to date in HBV monoinfected patients.
Clinical significance of rtA194T substitution is unknown in chronic hepatitis B patients.
AIM
To determine the effect of rtA194T on treatment response to TDF 300 mg daily in patients with LAM-resistant HBV.
Patients & Methods
Adult HBV patients receiving oral antiviral therapy at University Health Network Liver Clinics (Toronto, Canada) were monitored for genotypic antiviral resistance.
Routine bloodwork, HBV serology and HBV DNA levels were measured every 3 months on treatment.
Resistance testing was performed on all patients who developed virologic breakthrough.
-- confirmed rise in HBV DNA by > 1 log IU/mL compared to nadir
-- in those who failed to achieve undetectable HBV DNA 6 months after starting antiviral therapy.
Genotyping and detection of resistance mutations were performed using a line probe assay.
-- InnoLiPA HBV DR v3 (InnoGenetics, Ghent, Belgium)
HBV DNA was measured using real-time PCR (Roche, TaqMan 48, LLQ 12 IU/mL).
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