A r e v i r Analysis of resistance mutations of HI-Virus Eugen - PowerPoint PPT Presentation

Institut für Virologie A r e v i r Analysis of resistance mutations of HI-Virus Eugen Schülter

The same procedure as last year, Miss Sophie ? 10 Years of Arevir ! 2

Arevir Project 2000 - 2009 The Arevir project 1) is founded by Daniel Hoffmann, Rolf Kaiser and 1999 Joachim Selbig. Aim: develop computer based methods to enhance the interpretation of genotipic resistance tests. 2000 Niko Beerenwinkel created the basis for Arevir in his dissertation: Computational Analysis of HIV Drug Resistance Data 2001 Barbara Schmidt, Hauke Walter and Klaus Korn provided ~ 650 genotype � phenotype pairs 2001 First version of geno2pheno available online, predicting drug resistance from genotype 1) The project was funded by the German Research Foundation (Grants HO 1582/1-1 to -3 and KA 1569/1-1 to -3) 3

Arevir Project 2000 - 2009 2005 Data cleansing 2006 Start of collaboration with Eu Resist (www.euresist.org), data cleansing 2007 Data cleansing 2008 New Arevir DB and user interface version, data cleansing Situation in June 2005: 5,990 patient records ( ~ 3000 patients ) ( > 2000 with bad dates, 1583 overlapping ) 12,382 therapies ( different values for same day, same value 75,742 isolates, 174,249 values for different days, values out of range, etc.) 3,200 sequences ( 958 duplicates, 170 with quality problems ) 4

Arevir Project 2005 ? ? 5990 patient records (only ~ 3000 patients?) Patient names? Taboo!! Solution: use of pseudonyms (SHA-1 hash values) instead of names Pitfall: pseudonyms were dependent on exact spelling "Hans Joachim; Meier; 11.04.1963" � "FD2A6528C6DD2AC66..." "Hans - Joachim; Meier; 11.04.1963" � "234E9E2AFF2B78DB11.." 5

Arevir Project 2006 - 2008 Excel list at the Institute of Virology Name Geboren PIN PCR Meier, Hans-Joachim 11.04.1963 1204 pos Meier, Hans Joachim 11.04.1963 1433 pos Meier, Hans-Joachim 01.04.1963 1922 neg Sève, Jacques 23.10.1969 203 pos Seve, Jaques 23.10.1969 2351 pos Peter, Werner 00.01.1900 97 neg Werner, Peter 05.03.1952 2483 pos Mbele, Mgadibba 14.11.1971 233 pos Mobele, Mgadiba 14.11.1971 1863 pos After creating pseudonyms for all names, only ~ 60% matched those stored in Arevir! New "fuzzy" pseudonym algorithm (2006) MS-Access based program instead of � Nov 2007 Excel list (2006 - 2007) 6

Arevir Project 2008 / Rosie Connection to Arevir is only possible: � With SSH (secure shell) � Using public/private key authorization � From a computer whose IP-Address is in a subnet known to Arevir Restricted access to the data � Only people involved in patient care (e.g. responsible for diagnostic findings) have access to "their" patients data � Researchers receive a copy of anonymized data 7

Arevir Project 2008 / Rosie Internet Internet SSH tunnel SSH User PC tunnel HTTP Mail Firewall FTP Telnet private key file … SSH-Daemon Rosie / Arevir security overview Arevir-DB Arevir- Server 8

Arevir Project 2008 / Rosie 9

Arevir Project 2008 / Rosie 10

Arevir Project 2008 / Rosie Situation in June 2005: 5,990 patient records ( ~ 3000 patients ) ( > 2000 with bad dates, 1583 overlapping ) 12,382 therapies ( different values for same day, same value 75,742 isolates, 174249 values for different days, values out of range, etc.) 3,200 sequences ( 958 duplicates ) Situation in 2009: ☺ > 3,803 patients with HIV genotypes � (600 overlapping) ~ 16,000 therapies � (>2000 to be checked) > 369,000 lab values (CD4, HIVRNA etc.) ☺ > 7,100 resistance tests ☺ > 5,800 sequences (6 with quality problems) 11

Sample reports Part 2 Arevir 12

Arevir Project 2009 (n = 7,118) Resistance tests and new patients samples patients new patients 350 325 300 275 250 225 200 N/qtr 175 150 125 100 75 50 25 0 00/1 00/3 01/1 01/3 02/1 02/3 03/1 03/3 04/1 04/3 05/1 05/3 06/1 06/3 07/1 07/3 08/1 08/3 13

Arevir Project 2009 (n = 3,705) Gender Nationality Germany 19.4% 5.6% unknow n 0.1% Turkey male 49.7% 32.7% Kenya female Thailand unknow n Cameroon indistinct Togo 1.6% Italy 1.3% others 75.0% 1.2% 10.8% 0.8% 0.9% 1.1% Ethnicity Transmission unknown 10.7% 1.9% MSM 8.9% 8.8% heterosexual 0.6% 0.4% 34.6% caucasian 4.6% pattern II 0.1% 33.9% unknow n 1.4% IVDA afro 0.1% 1.0% haemophiliac asian blood transfusion hispanic bisexual 0.4% 39.6% pre-/perinatal 53.9% occupational 14

Arevir Project 2009 Age - relative distribution (n=3705) males females 45% 40% 35% 30% 25% 20% 15% 10% Tested positive at age of (n=2073 of 3705) 5% 0% 50% 44.0% < 20 20–29 30–39 40–49 50–59 60–69 > 69 unknown 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% < 20 20–29 30–39 40–49 50–59 60–69 > 69 w/o date 15

Arevir Project 2009 Subtypes B A CRFs C urf others (G D F) 3.3% 7.0% 2.2% 8.8% 3.3% nonB trend 75.4% nonB % trend 35% 30% 25% Proportion of non B subtypes 20% not increasing since 2005 � 15% 10% 2000 2001 2002 2003 2004 2005 2006 2007 2008 16

Arevir Project 2009 Prevalence of AZT mutations (n=5,266) 80% 70.3% 70% 60% 50% 40% 30% 23.8% 20% 15.9% 10% 0% 2000 I 2000 II 2001 I 2001 II 2002 I 2002 II 2003 I 2003 II 2004 I 2004 II 2005 I 2005 II 2006 I 2006 II 2007 I 2007 II 2008 I 2008 II AZT: 41L 62V 67N 69+ 70R 75I 77I 116Y 151M 210W 215FY 219EQ 17

Arevir Project 2009 Incidence and prevalence of K103N/KN prevalence incidence 40% 35% 30% 25% 20% 15% 10% 5% 0% 00/1 00/2 01/1 01/2 02/1 02/2 03/1 03/2 04/1 04/2 05/1 05/2 06/1 06/2 07/1 07/2 08/1 08/2 18

Arevir Project 2009 K103N before therapy start with NNRTI 12% 11% 10% 9% 8% 7% 6% 5% 4% 3.2% 3% 2% 1% K103N before therapy start with NNRTI 0% 2000 2001 2002 2003 2004 2005 2006 2007 2008 Ø K103N in 90 days bf. switch Earlier 'hidden' K103N 12% 11% 10% 9% 8% 7% 6% 5% 4% 3% 2% 1% 0% 2000 2001 2002 2003 2004 2005 2006 2007 2008 Ø 19

Arevir Project 2009 Success rates 2000 - 2007 depending on number of previous treatments (PT) 1 to 5 PT (from failing) 1 to 5 PT (from succ.) > 5 PT (from failing) > 5 PT (from succ.) 100.0% 90.0% 80.0% 70.0% 67.7% 60.0% 50.0% 48.1% 40.0% 30.0% 29.4% 20.0% 14.2% 10.0% 2000 2001 2002 2003 2004 2005 2006 2007 20

Many thanks to… Achim Büch, Andre Altmann, Angelika Hergesell, Bernd Kupfer, Bettina Jaster, Björn Jensen, Björn Thorwirth, Christian von Behren, Claudia Müller, Clemens Kühn, Daniel Hoffmann , Daniel Gillor, Dörte Hammerschmidt, Elena Knops, Eu Resist , Eva Heger, Finja Schweitzer, Gerd Fätkenheuer, Hauke Walter, Heike Krause, Herbert Pfister, Jens Verheyen, Joachim Selbig , Jürgen Klein, Jürgen Rockstroh, Maria Faune, Mark Oette, Martin Däumer , Martin Zabe-Kühn, Melanie Balduin, Nadine Sichtig, Niko Beerenwinkel, Norbert Schmeißer, Resina , Roman Fischer, Saleta Sierra Aragon, Susanna Trapp, Stefan Reuter, Thomas Lengauer, ...many more... and Rolf Kaiser Institut für Viologie der Universität zu Köln 21

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