TY  - JOUR
AB  - BACKGROUND: Entecavir is an efficient inhibitor of hepatitis B virus (HBV) reverse transcriptase (RT) and widely used for therapy of chronic hepatitis B. Entecavir treatment of HBV patients with Lamivudine-resistant viral strains, however, often fails, but the mechanism of cross-resistance development is not fully understood. METHODS: Using nonlinear regression models, dose response curves of cloned HBV strains from patients pre-treated with RT inhibitors were established in human hepatoma cell lines after transfection with HBV genomes containing HBV polymerase genes from patient isolates. 50% and 90% inhibitory concentrations (IC50, IC90) and antiviral resistance factors (RF50 and RF90) were calculated. RESULTS: The Entecavir dose-response curve of Lamivudine-resistant HBV RT mutants rtM204 for the replication of HBV decreased less than expected with increasing drug dose. Remarkably, due to the flat dose-response curves, RF90 values against Entecavir of samples with rtM204 substitutions were up to 30 times higher than their RF50 values. CONCLUSIONS: The unexpectedly high IC90 indicates a strong residual replication capacity of Lamivudine-resistant HBV rtM204 variants under Entecavir therapy, although IC50 values are initially within the therapeutic range of Entecavir. This characteristic favors rapid selection of additional mutants with overt resistance against Entecavir. Thus, the current phenotypic resistance assays should include determination of IC90.
AU  - Geipel, A.*
AU  - Seiz, P.L.*
AU  - Niekamp, H.*
AU  - Neumann-Fraune, M.*
AU  - Zhang, K.
AU  - Kaiser, R.*
AU  - Protzer, U.
AU  - Gerlich, W.H.*
AU  - Glebe, D.*
AU  - HOPE Consortium (*)
C1  - 47633
C2  - 39371
CY  - London
SP  - 779-787
TI  - Entecavir allows an unexpectedly high residual replication of HBV mutants resistant to lamivudine.
JO  - Antivir. Ther. (Lond.)
VL  - 20
IS  - 8
PB  - Int Medical Press Ltd
PY  - 2016
SN  - 1359-6535
ER  - 

TY  - JOUR
AB  - OBJECTIVES: Single use of genotypic antiretroviral resistance testing (GART) after first failure of highly active antiretroviral therapy (HAART) was reported to be cost effective; its use prior HAART initiation is unknown. Guidelines recommend GART after each treatment failure. We assessed the cost effectiveness of GART used routinely after first and subsequent treatment failures. Furthermore, we determined the minimum effectiveness required for GART prior to the first HAART to be as cost effective as after treatment failure. DESIGN AND METHODS: We developed a decision-analytic Markov model to estimate lifetime clinical and economic outcomes in a cohort of HIV patients starting HAART. Rates of treatment failure, estimates of GART effectiveness and data on disease progression were derived from published trials and observational studies. A cost effectiveness analysis was performed from the perspective of the healthcare system using cost data from a Central European healthcare setting. Deterministic and probabilistic sensitivity analyses using Monte Carlo technique were performed. RESULTS: GART after treatment failures increased life expectancy by 9 months and undiscounted life-time costs per case by 16,406 euros. The discounted incremental cost effectiveness ratio was 22,510 euros per life-year gained (euros/LY). Best- and worst-case scenarios yielded 16,512 euros/LY and 42,900 euros/LY, respectively. GART prior to the initiation of HAART would be equally cost effective if it could reduce the probability of first HAART failure by at least 36%. CONCLUSION: Routine use of GART after treatment failures is cost effective. GART prior to the first HAART would be equally cost effective if it could lower the probability of first HAART failure by approximately a third.  
AU  - Corzillius, M.*
AU  - Mühlberger, N.
AU  - Sroczynski, G.*
AU  - Jaeger, H.*
AU  - Wasem, J.*
AU  - Siebert, U.*
C1  - 3039
C2  - 21953
SP  - 27-36
TI  - Cost effectiveness analysis of routine use of genotypic antiretroviral resistance testing after failure of antiretroviral treatment for HIV.
JO  - Antivir. Ther. (Lond.)
VL  - 9
IS  - 1
PY  - 2004
SN  - 1359-6535
ER  -