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

A r e v i r

Analysis of resistance mutations of HI-Virus

Eugen Schülter

Institut für Virologie

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The same procedure as last year, Miss Sophie ?

10 Years of Arevir !

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Arevir Project 2000 - 2009

1999 The Arevir project1) is founded by Daniel Hoffmann, Rolf Kaiser and Joachim Selbig. Aim: develop computer based methods to enhance the interpretation

• f 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)

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Arevir Project 2000 - 2009

2005 Data cleansing 2006 Start of collaboration with EuResist (www.euresist.org), data cleansing 2007 Data cleansing 2008 New Arevir DB and user interface version, data cleansing 5,990 patient records

( ~ 3000 patients )

12,382 therapies

( > 2000 with bad dates, 1583 overlapping )

75,742 isolates, 174,249 values

( different values for same day, same value for different days, values out of range, etc.)

3,200 sequences

( 958 duplicates, 170 with quality problems )

Situation in June 2005:

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Arevir Project 2005

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.."

5990 patient records

(only ~ 3000 patients?)

? ?

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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)

Nov 2007

MS-Access based program instead of Excel list (2006 - 2007)

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Arevir Project 2008 / Rosie

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

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

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Arevir Project 2008 / Rosie

Arevir-DB SSH tunnel SSH tunnel Firewall SSH-Daemon

Arevir- Server

User PC

Internet Internet

HTTP Mail FTP Telnet …

Rosie / Arevir security

• verview

private key file

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Arevir Project 2008 / Rosie

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Arevir Project 2008 / Rosie

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Arevir Project 2008 / Rosie

> 3,803 patients with HIV genotypes

☺

~ 16,000 therapies

(600 overlapping)

> 369,000 lab values (CD4, HIVRNA etc.)

(>2000 to be checked)

> 7,100 resistance tests

☺

> 5,800 sequences

☺

(6 with quality problems)

( ~ 3000 patients )

12,382 therapies

( > 2000 with bad dates, 1583 overlapping )

75,742 isolates, 174249 values

( different values for same day, same value for different days, values out of range, etc.)

3,200 sequences

( 958 duplicates )

Situation in June 2005:

Situation in 2009:

5,990 patient records

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Arevir Part 2 Sample reports

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Arevir Project 2009

Resistance tests and new patients

25 50 75 100 125 150 175 200 225 250 275 300 325 350

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

N/qtr

samples patients new patients

(n = 7,118)

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Arevir Project 2009

Gender

75.0% 19.4% 5.6% 0.1% male female unknow n indistinct

Nationality

32.7% 1.1% 49.7% 1.2% 1.6% 0.9% 0.8% 10.8% 1.3% Germany unknow n Turkey Kenya Thailand Cameroon Togo Italy

• thers

Ethnicity

53.9% 34.6% 8.9% 1.9% 0.6% caucasian unknow n afro asian hispanic

Transmission

39.6% 33.9% 10.7% 8.8% 4.6% 1.4% 0.4% 0.1% 0.1% 0.4% 1.0% unknown MSM heterosexual pattern II IVDA haemophiliac blood transfusion bisexual pre-/perinatal

• ccupational

(n = 3,705)

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Arevir Project 2009

0% 5% 10% 15% 20% 25% 30% 35% 40% 45% < 20 20–29 30–39 40–49 50–59 60–69 > 69 unknown

Age - relative distribution (n=3705)

males females 44.0%

0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% < 20 20–29 30–39 40–49 50–59 60–69 > 69 w/o date

Tested positive at age of (n=2073 of 3705)

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Arevir Project 2009

Subtypes

3.3% 8.8% 7.0% 3.3% 2.2% 75.4% B A CRFs C urf

• thers (G D F)

nonB trend

10% 15% 20% 25% 30% 35% 2000 2001 2002 2003 2004 2005 2006 2007 2008 nonB % trend

Proportion of non B subtypes not increasing since 2005

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Arevir Project 2009

Prevalence of AZT mutations (n=5,266)

15.9% 23.8% 70.3% 0% 10% 20% 30% 40% 50% 60% 70% 80%

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

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Arevir Project 2009

Incidence and prevalence of K103N/KN

0% 5% 10% 15% 20% 25% 30% 35% 40%

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 prevalence incidence

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Arevir Project 2009

3.2% 0% 1% 2% 3% 4% 5% 6% 7% 8% 9% 10% 11% 12% 2000 2001 2002 2003 2004 2005 2006 2007 2008 Ø

K103N before therapy start with NNRTI

0% 1% 2% 3% 4% 5% 6% 7% 8% 9% 10% 11% 12% 2000 2001 2002 2003 2004 2005 2006 2007 2008 Ø

K103N before therapy start with NNRTI

K103N in 90 days bf. switch Earlier 'hidden' K103N

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Arevir Project 2009

Success rates 2000 - 2007 depending on number of previous treatments (PT)

67.7% 29.4% 14.2% 48.1% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0% 2000 2001 2002 2003 2004 2005 2006 2007

1 to 5 PT (from failing) 1 to 5 PT (from succ.) > 5 PT (from failing) > 5 PT (from succ.)

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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, EuResist,

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

Many thanks to…

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