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In Vitro Tenofovir Sensitivity of HBV Populations from Clinical Specimens Containing rtA181T/V and/or rtN236T
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Reported by Jules Levin
AASLD No 3 2009 Boston
K Kitrinos1, F Myrick1, M Curtis1, J Schawalder1, Y Zhu1, F Zoulim2, K Borroto-Esoda1
1Gilead Sciences, Inc., Durham, NC, USA; 2INSERM, Lyon, France
Introduction
Tenofovir disoproxil fumarate (TDF) is approved for the treatment of HIV-1 and HBV infections, however the resistance profile in HBV has not been determined1
- Currently no evidence of clinically signifi cant HBV mutation(s)
The rtA181V and rtN236T adefovir-associated resistance mutations (ADV-R) exhibit some cross resistance to tenofovir (TFV) in vitro2,3
- The clinical significance of these mutations on TDF effi cacy is unknown
There are limited data to determine how changes in TFV in vitro EC50 (50% effective concentration) values will impact TDF clinical efficacy
OBJECTIVES
To determine the impact of ADV-R mutations on tenofovir susceptibility in vitro
To evaluate the potential correlation between changes in tenofovir susceptibility in vitro and clinical response
a. Results for ADV-R mutations only
b. ADV-R patients included in Figure 1 analysis
Table 2A. TFV EC50 Values for Isolates without ADV-R Mutations
a. Values represent average of 3-4 independent assays for isolates
b. pHY92 and ADV-R are genotype A laboratory strains used as controls
Table 2B. TFV EC50 Values for Isolates with ADV-R Mutations
a. Mutations detected in either INNO-LiPA or population sequencing
b. Values represent average of 3-4 independent assays for isolates
c. pHY92 and ADV-R are genotype A laboratory strains used as controls
Figure 1. HBV DNA Change from Baseline for TDF-Treated Patients with and without ADV-R Through 24 Weeks
Table 3. TFV EC50 Values for Clones From Patients 2003, 1003, and 1022
a. Mutations detected in either INNO-LiPA or population sequencing
b. Values represent average of 2-4 independent assays
c. Mutant percentages: rtA181V = 17%, rtN236T = 33%, rtA181V+rtN236T = 42%
d. Mutant percentage: rtN236T = 56%
e. Mutant percentage: rtA181T = 38%
Figure 2. HBV DNA Levels for TDF-Treated Patients 1003, 2003, and 1022 Through 24 Weeks
25/26 isolates had mean TFV EC50 values that fell within the 2-fold assay variability; 1 isolate (with rtA181V + rtN236T mutations in > 90% of the population) demonstrated 2.7-fold reduced susceptibility to TFV (Tables 2A-B)
No significant differences observed for mean EC50 (p = 0.140) and fold change (p = 0.133) when comparing RT pools from isolates with and without rtA181T/V and/or rtN236T (Tables 2A-B)
The reduction in HBV DNA over the first 24 weeks of treatment with TDF was similar between patients with and without ADV-R (Figure 1)
Phenotypic analysis of clones with and without ADV-R from three patients showed reduced TFV susceptibility in vitro for rtA181V and rtN236T, but not rtA181T (Table 3)
- All three patients had HBV DNA levels of <400 copies/mL by Week 24 (Figure 2)
REFERENCES
1. Snow-Lampart et al. 2009. AASLD, Poster 480
2. Delaney et al. 2006. AAC. 50: 2471-2477
3. Qi et al. 2007. Antiviral Therapy. 12: 355-362
4. Zhu et al. 2008. The Molecular Biology of Hepatitis B Viruses, Poster 127
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