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SnoB SnoB INI-resistance in non-B Subtypes Stefan Esser, Saleta - PowerPoint PPT Presentation

Jun 30, 2023 •674 likes •1.06k views

SnoB SnoB INI-resistance in non-B Subtypes Stefan Esser, Saleta Sierra-Aragn, Melanie Balduin, Andre Altmann, Hauke Walter, Rolf Kaiser SnoB SnoB SnoB Study Impact of HIV-1 integrase subtype-specific polymorphisms in therapy nave non-B

  1. SnoB SnoB INI-resistance in non-B Subtypes Stefan Esser, Saleta Sierra-Aragón, Melanie Balduin, Andre Altmann, Hauke Walter, Rolf Kaiser SnoB SnoB

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. (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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. Thanks to • the collaborating centres • The patients • MSD SnoB SnoB

  14. Dr. Saleta Sierra-Aragón Institute of Virology, University of Cologne, Germany SnoB SnoB

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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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