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 ddI) ) Cumulative ↓ ↓ 1 Log HIVRNA 1 Log HIVRNA ↓ ↓ CD4 counts counts = % = % CD4 Genetic Barrier 4/ 2009

Patient 18393 Start Entecavir 100000000 10000000 HIV-VL 1000000 HBV-VL 100000 10000 1000 100 10 1 0 1 1 2 0 1 2 0 0 1 2 0 8 8 6 4 2 1 9 8 . . . . . . . . . . 0 1 0 0 0 1 0 0 0 1 7 0 1 4 8 1 2 6 9 2 . . . . . . . . . . 2 2 2 2 2 2 2 2 2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 6 6 7 7 7 7 8 8 8 8 4/ 2009

Daten- bank HIVdb HIVdb Core Module HIV-SEQ Basis: Stanford HIVdb HIV-ALG 4/ 2009

Analysis flowchart Sequence data Mutation list Alignment on Pan- Genotype Consensus Identification of available genes Identification of genotype and re-alignment on genotype specific consensus-sequence Identification of mutations Analysis of mutations based on the algorithm Detailled output Tabular output 4/ 2009

AY206381.1 AY206373.1 C s AB219429.1 n X75665.1 consB o c AB064313.1 consD . 1 3 2 2 7 2 6 A J G s n o c AB056516.1 D Q 3 1 5 7 7 9 . 1 Genotyping basis 7 5 6 5 7 . 1 X A 2 Y 3 3 9 2 0 1 . AB126580.1 consE consA A Y 7 3 8 1 4 4 . 1 c AY090454.1 o n c s o F n AY179735.1 s A H B AP007261.1 0 0.01 3 6 9 0 7 . 1 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 4/ 2009

HBV drug resistance mutations 4/ 2009

4/ 2009

Algorithm RT-Inhibitors: Lamivudine Resistance Possible Resistance � 204ISV � 180M � 173L � 80VI Adefovir Resistance Possible Resistance � 236T � 233V � A181STV 4/ 2009

Algorithmus Entecavir Resistance Possible Resistance � 1 of (169T, 184AGILS, 202CGI, 250IV) � 204IV and 1 of (169T, 184AGILS, 202CGI, � 204IV and 1 of (173L, 180M) 250IV) 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 4/ 2009

Algorithm Telbivudine Resistance Possible Resistance � 204ISV � 180M 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, 147 S /T) J. Verheyen, University of Cologne 4/ 2009

Sequence input 4/ 2009

Output of sequence length and genotype 4/ 2009

Output of RT-Alignment 4/ 2009

Output of HBsAg alignment 4/ 2009

Analysis 4/ 2009

Analysis 4/ 2009

Analysis 4/ 2009

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 �