SLIDE 1
04/ 2009
- M. Obermeier
Medizinisches Labor Berg
4/ 2009
Why HBV?
LdT FTC ADF ETV
ETV in LAM exp
LAM Genetic Barrier Potency
No anti-HIV activity Anti-HIV activity
HIV-GRADE HBV-Tool M. Obermeier 04/ 2009 Medizinisches Labor Berg - - PowerPoint PPT Presentation
HIV-GRADE HBV-Tool M. Obermeier 04/ 2009 Medizinisches Labor Berg - - PowerPoint PPT Presentation
HIV-GRADE HBV-Tool M. Obermeier 04/ 2009 Medizinisches Labor Berg Why HBV? No anti-HIV activity Anti-HIV activity TDF ETV LdT Potency FTC LAM ADF ETV in LAM IFN exp Cumulative toxicity toxicity with with ART (AZT, ART (AZT, ddI
SLIDE 2
SLIDE 3
4/ 2009
Patient 18393
1 10 100 1000 10000 100000 1000000 10000000 100000000 2 . 7 . 2 6 1 . 1 . 2 6 1 8 . 1 . 2 7 2 8 . 4 . 2 7 6 . 8 . 2 7 1 4 . 1 1 . 2 7 2 2 . 2 . 2 8 1 . 6 . 2 8 9 . 9 . 2 8 1 8 . 1 2 . 2 8
HIV-VL HBV-VL
Start Entecavir
SLIDE 4
4/ 2009
HIVdb Core Module
HIV-ALG HIV-SEQ HIVdb Daten- bank
Basis: Stanford HIVdb
SLIDE 5
4/ 2009
Analysis flowchart
Sequence data Mutation list
Identification of available genes Alignment on Pan- Genotype Consensus Identification of mutations
Analysis of mutations based on the algorithm Detailled output Tabular output
Identification of genotype and re-alignment on genotype specific consensus-sequence
SLIDE 6
4/ 2009
Genotyping basis
consA AB126580.1 A Y 2 3 3 2 9 . 1 AB056516.1 c
- n
s G AB064313.1 AB219429.1 consB AY206373.1 c
- n
s C AY206381.1 X75665.1 consD A J 6 2 7 2 2 3 . 1 D Q 3 1 5 7 7 9 . 1 X 7 5 6 5 7 . 1 consE A Y 7 3 8 1 4 4 . 1 c
- n
s F A B 3 6 9 7 . 1 AY179735.1 AP007261.1 c
- n
s H AY090454.1
0.01
SLIDE 7
4/ 2009
Algorithm Specification Interface (ASI)
Rules based algorithms can be
described in xml-format HBV-ruleset can be described in a format that is compatible to other algorithms
SLIDE 8
4/ 2009
HBV drug resistance mutations
SLIDE 9
4/ 2009
SLIDE 10
4/ 2009
Algorithm
RT-Inhibitors: Lamivudine Resistance Possible Resistance 204ISV 180M 173L 80VI Adefovir Resistance Possible Resistance 236T 233V A181STV
SLIDE 11
4/ 2009
Algorithmus
Entecavir Resistance Possible Resistance 204IV and 1 of (169T, 184AGILS, 202CGI, 250IV) 1 of (169T, 184AGILS, 202CGI, 250IV) 204IV and 1 of (173L, 180M)
Comment: 204VI => A mutation M204VI alone only slightly impairs the susceptibility to entecavir, however the dose of entecavir should be increased according to the manufacturers instructions
Tenofovir Resistance Possible Resistance 194T
SLIDE 12
4/ 2009
Algorithm
Telbivudine Resistance Possible Resistance 204ISV 180M
SLIDE 13
4/ 2009
Algorithm
HBs-antigen-escape
HBs-escape 1 of (100C, 101H/Y, 105L, 109R/V/H/I, 110M/R/H/I/V, 114R, 117T, 118K/R/S/P, 119R, 120A/E/LP/Q/S/T/R, 121S/Y, 123A/N, 124R/Y, 126N/S/V/I/T, 127R/S/T/L, 128V, 129H/K/P/R, 130D/R/N, 131D/I/S/K, 132A/P/F, 133I/L/T/V, 134H/N/R/S/V/T, 137R/S/W/Y, 139S, 140S, 141E/I/R/W, 142L/R/S, 143L/P/A, 144A/E/G/H, 145A/K/L/R, 146D/S, 147S/T)
- J. Verheyen, University of Cologne
SLIDE 14
4/ 2009
Sequence input
SLIDE 15
4/ 2009
Output of sequence length and genotype
SLIDE 16
4/ 2009
Output of RT-Alignment
SLIDE 17
4/ 2009
Output of HBsAg alignment
SLIDE 18
4/ 2009
Analysis
SLIDE 19
4/ 2009
Analysis
SLIDE 20
4/ 2009
Analysis
SLIDE 21
HIV-GRADE e.V.
- Thomas Berg, Medizinisches Labor Dr. Berg, Berlin
- Patrick Braun, PZB Aachen
- Martin Däumer, Institut für Immunologie und Genetik,
Kaiserslautern
- Josef Eberle, Pettenkofer-Institut, München
- Robert Ehret, PZB Aachen
- Rolf Kaiser, Institut für Virologie, Köln
- Klaus Korn, NRZ für Retroviren, Erlangen
- Claudia Kücherer, RKI, Berlin
- Harm Müller, Labor Fenner, Hamburg
- Martin Stürmer, Institut für Medizinische Virologie, Frankfurt
- Hauke Walter, NRZ für Retroviren, Erlangen
- Eva Wolf, MUC Research München