DTG HIV-GRADE update Resistent Intermedire Resistenz Eingeschrnkte - PowerPoint PPT Presentation

DTG HIV-GRADE update Resistent Intermediäre Resistenz Eingeschränkte Empfindlichkeit • Q148HKR + 2 out of • Q148HKR + 1 out of • L74IM • E92Q (G140ACS, L74I, (G140ACS, L74I, • T97A E138AKT) E138AKT) • 148RH + 140S • N155H + 1 out of ( • G118R • E138AKT E92Q, T97A, Y143R, • Y143R L74IM, E138AKT) • R263K • Q148HKR • G140ACS • N155H • V260I • S147G

HIV2EU Ruleset

Nucleoside reverse transcriptase Inhibitors Substance Resistant Intermediate Resistance •Q151M •S215ACFLY AZT •S215ACFLY + 1 of (N69ST, K70R, Y115F, K223R) •Q151M •S215ACFLY d4T •S215ACFLY + 1 of (K65R, N69ST, •K65R K70R, Y115F, K223R) • not recommended* •M184VI •K65R 3TC/FTC • Q151M •2 of (M184VI, S215ACFLY, D67N, K70RN) ABC • K65R • M184VI+1 of (L74V , Y115F ) • K65R TDF • Q151M+V111I • K65R ddI • L74V * Not recommended due to rapid • Q151M resistance development •not recommended*

Non-nucleoside reverse transcriptase Inhibitors Not effective against HIV-2, not recommended due to natural resistance

Protease Inhibitors Substance Resistant Intermediate Resistance •G48V • I84V SQV •L90M •2 of (I82F, I84V, L90M) • V62A+ L99F LPV •I54M • 1 of (I82F, I84V, L90M) •V47A • I50V • 1 of (I84V, L90M) DRV • I54M • I84V + L90M • I50L • I54L ATV • I82F • ATV not recommended •TPV natural resistance TPV •I54M IDV •I82F •I84V •V62A + L99F •L90M •IDV not recommended • fAPV natural resistance fAPV

Integrase Inhibitors Substance Resistant Intermediate Resistance • N155HR •E92Q RAL • Q148KR •Y143CGR • 1 of (E92Q, T97A) + Y143CGR • E92Q + T97A • E92QG • Y143C EVG* •Q148KR •T97A + Y143C •N155H •G140S + Q148R •Q148R DTG* •Q148K •N155H •E92Q + N155H •E92Q •T97A + N155H •Y143C + T97A *Rules based exclusively on in-vitro data

Fusion Inhibitors T-20 not recommended

Tropism Visseaux, Benoit, Margarita Hurtado-Nedelec, Charlotte Charpentier, Gilles Collin, Alexandre Storto, Sophie Matheron, Lucile Larrouy, Florence Damond, Françoise Brun-Vézinet, und Diane Descamps. „Molecular Determinants of HIV-2 R5–X4 Tropism in the V3 Loop: Development of a New Genotypic Tool“. Journal of Infectious Diseases 205, Nr. 1 (1. Januar 2012): 111–20. doi: 10.1093/ infdis/ jir698 .

External Quality Assessment I NSTAND e.V.

Evalution of results • Three level approach • Evaluation of sequence quality • Evaluation of resistance associated mutations • Evaluation of resistance interpretation

Genetic distance based calculation of sequence quality • Consensus Sequences were calculated for each of the EQA samples • Distances were calculated based on a distance matrix penalizing ambiguous nucleotides • Cutoffs were calculated based on the coefficient of variation of the distance distribution of all sequences or of all sequences belonging to one sample

Analysis of Sequence quality G10604/G10605, G10600/G10601/G10602, 383001 G10603, 383002 383003 383004 384001 384002 local global local global local global local global local global local global YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES/YES/NO YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES/YES/NO YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES/YES/NO YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES YES/YES/NO YES YES YES YES YES YES YES YES YES NO YES YES YES YES YES NO YES YES YES

Resistance associated mutations • Resistance Associated Mutations (RAM) • Identification of the RAMs based on HIV- GRADE mutation list from the consensus sequences for each samples

Sample 383001

Sample 383002 SeqID GeneName 69 75 100 103 115 118 151 179 184 210 219 221 14 RT T V L K Y V Q I M L K H 15 RT I I I N F I M L V F E Y 26 RT I I I N F I M L V F E Y 27 RT I I I N F I M L V F E Y 28 RT I I I N F I M L V F E Y 29 RT IT IV IL KN FY IV KLMQ LV MV FL E HY 30 Consensus RT I I I N F I M L V F E Y

Sample 383003 SeqID GeneName 41 67 118 184 210 215 227 27 RT M D V M L T F 28 RT LM DN IV MV LW NSTY FL 29 RT M D V M L T F 30 RT LM DN IV MV LW NSTY FL 31 RT L N I V W Y L 32 RT L N I V W Y L 33 RT L N I V W Y L 34 RT M D V M L T F 35 RT LM DN IV MV LW NSTY FL 36 RT L N I V W Y L 37 RT LM DN IV MV LW NSTY FL 38 RT LM D V M L T FL 39 RT LM DN IV MV LW NSTY FL 40 RT L N I V W Y L 41 RT LM DN IV MV LW NSTY FL 42 RT L N I V W Y L 43 RT M D V M L T F 44 RT LM DN IV MV LW NSTY FL 45 RT L N I V W Y L 46 Consensus RT L N I V W Y L

Sample 384001 V3 loop ....|....|....|....|....|....|....|. G10608_gp120_1 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC G10608_gp120_25 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC G10608_gp120_400 CTRPYNNIRQRTPI--GXGQAXYTTRRIEDIRRAHC G10608_gp120_2497 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC G10608_gp120_769 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC G10608_gp120_31281 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC G10608_gp120_2278 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC 384001_gp120_909 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC 384001_gp120_3571 CTRPNNNTRKSIRIQRGPGRAFVTIGKIGNMRQAHC 384001_gp120_6950 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC 384001_gp120_54 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC 384001_gp120_1888 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC 384001_gp120_29340 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC 384001_gp120_1056 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAXC 384001_gp120_2147 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC 384001_gp120_2362 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC 384001_gp120_8705 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAXC 384001_gp120_30006 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC 384001_gp120_769 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC 384001_gp120_427 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC 384001_gp120_308 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC 384001_gp120_190 CTRPYNNIRQRTPI--GLGQALYTTRRIEXIRRAXC 384001_gp120_30616 CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC Consensus CTRPYNNIRQRTPI--GLGQALYTTRRIEDIRRAHC

Interpretation • Based on interpretation of consensus sequence with ANRS, REGA, HIVDB and HIV- GRADE • Interpretations that are uniform on all interpretation systems are considered as decision criteria

Sample 384002 Results derived from consensus sequence

Sample 384002 participants results Sample-ID Algorithms DTG EVG RAL 384002 HIV-GRADE S R R 384002 geno2pheno I R R 384002 HIV-GRADE,geno2pheno I R R 384002 HIV-GRADE,HIV-DB (Stanford) S R R 384002 HIV-DB (Stanford) I R R 384002 HIV-DB (Stanford) S R R ANRS,HIV-DB 384002 (Stanford),REGA,geno2pheno,HIV-GRADE I R R 384002 HIV-DB (Stanford),geno2pheno S R R 384002 HIV-GRADE I R R 384002 HIV-GRADE S R R 384002 HIV-DB (Stanford),geno2pheno S R R 384002 geno2pheno I R R 384002 geno2pheno I R R 384002 ANRS,HIV-GRADE,HIV-DB (Stanford),REGA S R R 384002 HIV-DB (Stanford),HIV-GRADE I R R 384002 geno2pheno S R R 384002 geno2pheno I R R 384002 geno2pheno I R R

Tool update • New connectivity to geno2pheno (REST-API) • New connectivity options for HIV-GRADE (XML and REST-API)

Thank you Thomas Berg, Patrick Braun, Martin Däumer, Josef Eberle, Robert Ehret, Rolf Kaiser, Claudia Kücherer, Harm Müller, Christian Noah, Martin Obermeier, Martin Stürmer, Alexander Thielen, Jens Verheyen, Hauke Walter, Eva Wolf Special thanks to Marcel Schütze, Heinz Zeichhardt, Oliver Donoso and Hans-Peter Grunert