SnoB SnoB INI-resistance in non-B Subtypes Stefan Esser, Saleta Sierra-Aragón, Melanie Balduin, Andre Altmann, Hauke Walter, Rolf Kaiser SnoB SnoB
SnoB Study Impact of HIV-1 integrase subtype-specific polymorphisms in therapy naïve non-B infected patients on the activity of Raltegravir (RAL, MK-0518, Isentress ) Dr. Stefan Esser Department of Dermatology and Venerology, University Hospital Essen, Germany SnoB SnoB
Why an HIV Subtype Non-B study in Germany? • HIV Non-B subtypes spread in different regions in the world • Migrants from different geographic regions, countries and continents migrate to Germany • Migrants in Germany do not migrate mainly from ancient colonies like in some other European countries • Many migrants come from regions with high HIV prevalence • Germans like to travel all over the world also in high prevalence regions • In Germany HIV centres have the chance to sequenze blood samples with many different HIV-subtypes SnoB SnoB
SnoB Study: Design • National pilot multicenter cohort-study to investigate the polymorphisms in the integrase genes of non-B-subtypes in respect to INI resistance. • Cooperating HIV-centres in Germany collect blood-samples of 100 ART naïve HIV-positive patients with clinical expected or known non-B subtype infection before initiating antiretroviral therapy. • Blood samples be sent to the investigators for sequencing integrase genes and constructing an interpretation system. • Special genotypes will be additionally analyzed in phenotypic assays. SnoB SnoB
Protocol: SnoB Study • Primary Endpoint: – To investigate the natural polymorphisms in the integrase genes of HIV non-B subtypes • Secondary Endpoints: – To compare non-B subtypes polymorphisms with HIV-1 subtype B and known genotypic integrase resistance mutations – To examine the impact of non-B subtypes polymorphisms on RAL activity in vitro – To determine whether non-B subtypes carry natural resistance to the INI Raltegravir • Patient Inclusion Criteria – Therapy-naïve HIV-positive patients with known or expected non-B subtype infection independent of transmitted resistance – Signed an informed consent prior to any study procedures • Patient Exclusion Criteria – Therapy-experienced HIV-positive patients SnoB SnoB
24 collaborating centres 24 collaborating centres Einsender n B non-B Ø To do MX01, Uniklinik Düsseldorf 121 60 36 22 3 Med. I, Uniklinik Köln 115 65 26 14 10 Dr. Markus Bicke l, Frankfu rt 53 2 44 7 Dr. Esser, Uniklinik Essen 45 17 21 7 24 Klinikum Osnabrück GmbH 14 5 2 3 13 Dr. Oette, Krankenhau s der Augustinerinnen 7 1 3 2 13 Labor Lad emannbogen, Hamburg 0 8 5 9 Charité, Berlin 0 6 3 5 Prof. Rockstro h, Uniklinik Bonn 1 4 0 5 Uniklinik Freiburg 1 2 2 4 Poliklinik, Uniklinik München 1 3 0 4 Uniklink Hamburg-Eppendorf 0 4 0 2 Dres. Carl s und Hube r, Düsseldorf 2 0 0 2 Dres. Mauss, Athmann, Hegene r, Schmutz 1 1 0 2 Medizinische Hochschul e Hannover 0 1 1 2 Studien und Projekte GmbH, Hamburg 0 2 0 1 Dr. Arbter, Krefeld 1 0 0 1 Dr. Becker-Boost, Duisburg 0 1 0 1 Dr. Kwirant, Duisburg 0 1 0 1 Dr. Stechel, Köln 1 0 0 1 Dres. Gippert, Hatman, Quaing, Münster 1 0 0 1 Dres. Rei th, Gottstein, Düsseldo rf 1 0 0 1 Klinikum Dortmund gGmbH 0 1 0 1 Labor Dr . Quade, Köln 0 1 0 427 175 168 66 18 SnoB SnoB
(All) patients characteristics (All) patients characteristics n = 427 Female Male Unknown 113 274 40 Gender (26.4%) (64.2%) (9.4%) Unknown 1 Median Max. Min. 22 Age 36 years 77 years 0 years (5.2%) 198 Time to analysis 1 4 months 19 years 0 months (46.4%) 166 VL 48282 5100000 <40 (38.9%) 296 CD4 + -T-cell counts 320 1056 3 (69.3%) Asia+ America Warshau Africa Unknown Middle East + EU Treaty 75 13 265 15 59 Nationality (3.0%) (62.1%) (3.5%) (13.8%) (17.6%) 1 Time-span from first HIV+ diagnosis to IN analysis SnoB SnoB
dataset: subtypes distribution dataset: subtypes distribution Samples: Current Status • 343 samples with sequence • 66 samples negative • 18 currently being processed n=427 Nationality Asia + Middle America Warsaw Subtype Africa Unknown + EU Treaty East Unknown 14 - 47 2 21 (16.7%) - (56.0%) (2.4%) (25.0%) (n=84) B 3 4 148 2 18 (1.7%) (2.3%) (84.6%) (1.1%) (10.3%) (n=175) non-B 58 9 70 11 20 (34.5%) (5.4%) (41.7%) (6.5%) (11.9%) (n=168) SnoB SnoB
Subtype B: patients ´ Subtype B: patients ´ characteristics characteristics n = 175 Female Male Unknown 14 156 5 Gender (8.0%) (89.1%) (2.9%) Unknown 1 Median Max. Min. 3 Age 37 years 77 years 0 months (1.7%) 83 Time to analysis 1 1 month 14 years 5 days (47.4%) 74 VL 74488 5100000 <40 (42.3%) 108 CD4 + -T-cell counts 295 989 3 (61.7%) Asia + America Warshau Africa Unknown Middle East + EU Treaty 148 3 4 2 18 Nationality (2.3%) (84.6%) (1.1%) (10.3%) (1.7%) 1 Time-span from first HIV+ diagnosis to IN analysis SnoB SnoB
dataset: subtypes distribution dataset: subtypes distribution Samples: Current Status • 343 samples with sequence • 66 samples negative • 18 currently being processed n=427 Nationality Asia + Middle America Warsaw Subtype Africa Unknown East + EU Treaty Unknown 14 - 47 2 21 (16.7%) - (56.0%) (2.4%) (25.0%) (n=84) B 3 4 148 2 18 (1.7%) (2.3%) (84.6%) (1.1%) (10.3%) (n=175) non-B 58 9 70 11 20 (34.5%) (5.4%) (41.7%) (6.5%) (11.9%) (n=168) SnoB SnoB
Subtype Non-B: patients ´ Subtype Non-B: patients ´ characteristics characteristics n = 168 Female Male Unknown 82 70 16 Gender (48.8%) (41.7%) (9.5%) Unknown 1 Median Max. Min. 12 Age 35 years 71 years 0 months (7.1%) 71 Time to analysis 1 6 months 11 years 8 days (42.3%) 42 VL 46100 163000 88 (25.0%) 113 CD4 + -T-cell counts 309 859 8 (67.3%) Asia + America Warshau Africa Middle Unknown + EU Treaty East 58 9 70 11 20 Nationality (5.4%) (41.6%) (6.6%) (11.9%) (34.5%) 1 Time-span from first HIV+ diagnosis to IN analysis SnoB SnoB
Subtype Non-B: subtype distribution Subtype Non-B: subtype distribution Nationality n=168 # of samples America + Warsaw Asia + Subtype Africa Unknown EU Treaty Middle East 44 20 - 11 2 11 02_AG (26.2%) (45.5%) - (25.0%) (4.5%) (25.0%) 42 18 10 2 7 5 A (25.0%) (42.9%) (23.8%) (4.8%) (16.7%) (11.9%) 23 11 - 2 8 1 C (13.7%) (64.7%) - (8.7%) (34.8%) (4.3%) 17 9 1 5 - - 01_AE (10.1%) (60.0%) (5.9%) (29.4%) - - 15 8 - 6 - - D (8.9 %) (60.0%) - (40%) - - 11 4 4 1 2 - G (6.6%) (36.4%) (36.4%) (9.1%) (18.2%) - 7 4 3 - - - F (4.2%) (57.1%) (42.9%) - - - 3 3 - - - - 06_CPX (1.8%) (100%) - - - - 3 1 - 1 - 1 11_CPX (1.8 %) (33.3%) - (33.3%) - (33.3%) 2 - - - 1 1 12_BF (1.2 %) - - - (50%) (50%) 1 1 - - - - 10_CD (0.6%) (100%) - - - - SnoB SnoB
Thanks to • the collaborating centres • The patients • MSD SnoB SnoB
Dr. Saleta Sierra-Aragón Institute of Virology, University of Cologne, Germany SnoB SnoB
INI-resistance associated mutations INI-resistance associated mutations Primary mutations N155H Q148R/H/K Y143R Secondary mutations L74M E92Q E138A/K L74M T97A Y143H G140S/A T97A V151I G163R SnoB SnoB Hazuda et al. 2007; Lataillade et al. 2007; Malet et al. 2008; Miller et al. 2008; Sichtig et al 2009
Detected INI-resistance associated mutations Detected INI-resistance associated mutations Primary mutations N155H Q148R/H/K Y143R Secondary mutations E92Q E138A/K L74M L74M G140S/A T97A Y143H T97A Secondary mutations with a V151I G163R prevalence of 0.3 - 2.6 %, and limited SnoB SnoB Hazuda et al. 2007; Lataillade et al. 2007; Malet et to ≤ 1 per genome. al. 2008; Miller et al. 2008; Sichtig et al 2009
INI-resistance associated mutations INI-resistance associated mutations Accessory mutations: Detected in cell culture under RAL / EVG. In vivo importance unknown. H51Y, T66AK, V72I, L74I, S119GPRT, T112I, F121Y, T125AK, A128T, Q146K, S147G, S153AY, M154I, K156N, E157Q, V165I, V201I, I203M, T206S, S230RN, V249I, R263K, C280Y SnoB SnoB
Detected INI-resistance associated mutations Detected INI-resistance associated mutations Accessory mutations: Detected in cell culture under RAL / EVG. In vivo importance unknown. H51Y, T66AK, V72I , L74I , S119GPRT , T112I , F121Y, T125A K, A128T , Q146K, S147G, S153A Y, M154I , K156N , E157Q , V165I , V201I , I203M , T206S , S230RN , V249I, R263K, C280Y accessory mutations with a prevalence of 0.6 - 73.5 % SnoB SnoB
INI-resistance associated mutations: subtypes INI-resistance associated mutations: subtypes B non B p value n=175 n=168 (two-tailed) n % n % Y143CR 0 0 0 0 1.000 primary Q148HKR 0 0 0 0 1.000 N155H 0 0 0 0 1.000 T66I 0 0 0 0 1.000 L74M 3 1.7 5 3.0 0.495 E92Q 0 0 0 0 1.000 T97A 2 1.1 7 4.2 0.448 secondary E138AK 0 0 0 0 1.000 G140AS 0 0 0 0 1.000 Y143H 0 0 1 0.6 0.490 V151I 3 1.7 3 1.8 1.000 G163R 0 0 1 0.6 0.490 SnoB SnoB
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