The German HIV-1 Seroconverter Cohort Barbara Bartmeyer Robert - - PowerPoint PPT Presentation

The German HIV-1 Seroconverter Cohort

Barbara Bartmeyer

Robert Koch-Institute, Berlin

• Dept. Infectious Disease Epidemiology

HIV/AIDS, STI Unit www.rki.de

2

Aims

Influence by host and virus on HIV disease progression in patients with a known date of infection Host

• HLA and TLR-receptor polymorphism

(Cooperation: Charité, University Medicine Berlin; University of Erlangen)

• co-receptor polymorphism

(Cooperation: Charité, University Medicine Berlin)

• STI-screening

Virus

• spread and transmission of drug resistance
• persistence and viral fitness
• minority resistance

cART

• first line, second line, treatment success, switch

3

Methods - study design

• Prospective

multi centre study (since 1997)

• Inclusion criteria

Documented seroconverters

• last negative and first positive

HIV-Test ≤ 3 years

• date of infection: mean between both tests

Acute seroconverters

• HIV RNA+, EIA–
• r EIA+ and indeterminate WB
• date of infection: approximation to first reactive test

4

Methods – genotypic resistance analysis

• pol-population sequencing
• Identification of resistance associated mutations:
• IAS-Liste

2007;

• Surveillance drug resistance list 2007, SDRM list

(Shafer R. et al. 2007)

• Prediction of phenotype
• Stanford

algorithm

(http://hivdb.stanford.edu, version 4.3.1,Sep 2007)

levels of resistance: sensitive: sensitive + potentially resistant intermediate: low + intermediate highly resistant resistant

5

Results – study population

• study population genotyped (04/2009)

1412/1625; 87%

• sex

95% male; 5% female

• MSM

87%

• IDU

1.5%

• Heterosexuals

6%

• HPC

2% primary resistance 152 (11%, CI 9.3 - 12.8) sex 146 men (96%), 6 women (4%) age 34 (IQR, 27-39) CDC classification 96% A, 2% B, 0%C CD4 cells (cells/µl, median) 428 cells/µl HIV RNA (copies/ml, median) 115,000 copies/ml

6

Results – route of transmission

50 100 150 200 250 300

1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 unknown HPL heterosexual

• ccupational

IVDA MSM & bisexual

Year of seroconversion Patients n

7

Results - prevalence of resistance

5 10 15 20 25 30 35 40 45 1 9 9 6 1 9 9 7 1 9 9 8 1 9 9 9 2 2 1 2 2 2 3 2 4 2 5 2 6 2 7

percentage of tested patients (%)

Prevalence 11.3%; CI 9.6-13.1; p for trend = 0.4

Study population N=1564 (seroconverted between 1996-2007) Genotyped N=1276/1312 (treatment naive samples available1997-2007) Resistant N=144 (SDRM list 2007)

8

PI

10 20

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

NNRTI

5 10 15 20

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

NRTI

5 10 15 20

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Results – trends of resistance

Trend of resistance among different drug classes (SDRM list; Shafer R. et al, 2007) calculated per year

• f seroconversion

(p for trend)

p=0.03 p=0.08 p=0.4

9

Results – prevalence of NNRTI mutations

1 2 3 4 5 6 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

%

V106AM K103NS Y181CI G190AESQ P225H

Prevalence of NNRTI mutations per year of seroconversion

10

Results – singletons within drug classes

10 20 30 40 50 60 70 80 90 100 NRTI NNRTI PI

• verall

%

57% (56/98) 93% (40/43) 52% (13/25) 67%(109/166)

11

Results – prevalence of resistance mutations

Overall prevalence of resistance mutations (%) mutations present at a frequency ≤0.7% T215CDEISV G190AESQ

0.8 0.7 0.8 0.7 2.3 1.1 0.8 4.6 3.7 0.9 0.8 1.2 0.7 1 2.8 1 2 3 4 5

M41L D67NG K70R F77L M184VI L210W T215ACDEGHILNSV T215YF K219QE K103NS I54ALMSTV V82AFTMS L90M

12

STI -Screening

13

Methods – STI screening STI-Screening: n=1285

(antiretroviral naive HIV-1 Seroconverter samples 1996-2007)

Methods:

• HBV: anti-HBc; anti-HBs; HBsAG
• HCV: anti-HCV-EIA; anti-HCV-immunoblot;
• HSV-2: HSV-2 IgG; HSV-2 IgM
• Syphilis: syphilis screening; FTAG; FTAM;

VDRL

14

Results –

• verall prevalence of STI

Hepatitis B

• 27% (347/1285) positive for anti-HBc and anti-HBs
• 2% (26/1285) positive for anti-HBc and HBsAG
• 0.3% (3/912) positive for anti-HBs only

Hepatitis C

• 4.5% (56/1285) positive for anti-HCV-immunoblot;

Herpes simplex-2

• 39% (470/1285) positive for HSV-2-

IgG

• 11% (137/1285) positive for HSV-2-

IgM Syphilis

• 24% (307/1285) positive for syphilis EIA

15

Results STI screening by route of transmission

Prevalence of STI by route of transmission 1997-2007 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% MSM IDU HET HPC unknown Syphilis anti-HSV-2 IgM anti-HSV2 IgG anti-HSV2 IgG & IgM

16

Results – STI screening

0% 20% 40% 60% 1996 1997-1997 1998-2000 2001-2003 2004-2007 Prevalence by year of seroconversion HSV-2 IgG HSV-2 IgM HSV2IgG & IgM Syphilis

17

Results – STI screening

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% MSM IVDA Hetero HPC unknown antiHBc& antiHBs HBsAg & antiHBc AntiHCV Elisa & Immunoblot Prevalence of STI by route of transmission 1997-2007

18

Results – STI screening

0% 5% 10% 15% 20% 25% 30% 35% 40% 45% vor 1996 1997-1997 1998-2000 2001-2003 2004-2007 prevalence STI by year of seroconversion anti-HBc & anti-HBs anti-HBsAg & anti-HBc anti-HCV & anti-HCV- immunoblot

19

Results – STI screening

0% 10% 20% 30% 40% 50% 60% 70% vor 1996 1997-1997 1998-2000 2001-2003 2004-2007 MSM IVDA

Prevalence of HCV among IDU and MSM in the study

20

Conclusion

Drug resistance

• Significant decrease NRTI resistance
• Increasing trend of NNRTI resistance (Y181CI; G190AESQ)
• Mainly singleton resistance (PI, NNRTI)

STI

• Trend of increasing syphilis among MSM
• Increasing HSV-2 IgM in the study population
• Increasing prevalence of HCV among MSM

21

International cooperation

EHR, Europe HIV Resistance /SPREAD CASCADE, Concerted Action on Seroconversion and AIDS to Death CHAIN, Collaborative HIV and Anti HIV Drug Resistance Network

22

Aachen Augsburg Berlin Bielefeld Bochum Bonn Dortmund Dresden Duisburg Düsseldorf Frankfurt/M Frankfurt/O. Freudenstadt Halle/Saale

• Dres. Knechten, Habets

Klinikum Augsburg Ärzteforum Seestraße Augusta-Viktoria Krankenhaus (Vivantes)

• Dres. Bienieck, Cordes
• Dr. Claus
• Dr. Dobao
• Dres. Dupke, Carganico
• Dres. Freiwald, Rausch
• Dr. Glaunsinger
• Dres. Gölz, Moll, Schleehauf
• Dr. Hintsche
• Dres. Jessen
• Dres. Köppe
• Dr. Reuter
• Dres. Schlote, Lauenroth-Mai, Schuler
• Dr. Schmidt
• Dr. Schüler-Maué
• Dres. Schranz, Fischer

Universitätsmedizin Berlin Charité Krankenhaus MARA II

• St. Joseph Hospital

Universitätsklinik Bonn Klinikum Dortmund,ID Ambulanz Universitätsklinikum Carl Gustav Carus Dresden Klinik und Poliklinik für Dermatologie

• Dr. Becker-Boost
• Dr. Kwirant

Universitätsklinik Düsseldorf Universitätsklinik Joh.-W.-Goethe-Universität

• Dr. Markus

Landratsamt Freudenstadt Universitätsklinik M.-Luther-Universität Hamburg Hannover Karlsruhe Koblenz Köln Leipzig Magdeburg Mainz München Münster Norderstedt Nürnberg Osnabrück Regensburg Remscheid Rostock Stuttgart Ulm Viernheim Wiesbaden ifi Allg.Krankenhaus

• St. Georg

ICH, Infektionsmedizinisches Centrum Hamburg

• Dr. Gellermann

Universitätsklinik Eppendorf

• Med. Hochschule Hannover
• Dres. Buch, Leugner

Landratsamt Karlsruhe Krankenhaus Kemperhof

• Dr. Bihari
• Dr. Ferdinand

Universitätsklinik Köln Universitätsklinik Leipzig Universitätsklinik Otto-v.-Guericke Universität Klinikum Joh.-Gutenberg-Universität Ludwig-Maximilians-Universität München

• Dr. Malm
• Dres. Jäger, Jägel-Guedes
• Dr. Rieger

Technische Universität München Universitätsklinik Münster

• Dr. Soldan

Klinikum Nürnberg Städt. Klinik Natruper Holz Universitätsklinik Regensburg

• Dres. Steege, Walter
• Dr. Kreft

Universitätsklinik Rostock

• Dres. Schnaitmann, Schaffert, Trein, Ißler
• Dres. Ulmer, Frietsch, Müller

Justizvollzugsanstalt Stuttgart Universitätsklinik Ulm

• Dr. van Treek
• Dr. Starke

Collaborators

23

Funded by the German Ministry of Health

Robert Koch-Institut

• Dept. for Infectious Disease Epidemiology

FG 34 HIV/AIDS, STI Unit

• Dr. Osamah Hamouda

Christina Lindemann Claudia Houareau

• Dr. Nadine Spielmann

Parvin Ghassim Christian Kollan

HIV Variability and Molecular Epidemiology

• Dr. Claudia Kücherer

Sabrina Neumann Kathrin Keeren Stefan Loschen Hanno v. Spreckelsen

24

Ergebnisse

CCR5delta32-homozygoter Patient

Oh DY et al PLos One, 2008

Ergebnisse Claudia

25

Kooperationen/Publikationen national

• Einfluss wirts-assoziierter HLA-Polymorphismen auf HIV-

Krankheitsprogression,

Universitätsklinikum Erlangen, Prof. Dr. Harrer

• TLR8/7 assoziierte Polymorphismen, Einfluss auf HIV-

Krankheitsverlauf,

Charité, Universitätsmedizin Berlin, Institut für Mikrobiologie und Hygiene, Prof. Schumann

D.Y. Oh, H. Jessen, Kücherer C., Neumann K., Oh N., Poggensee G., Bartmeyer B., Jessen A., Pruss A., Schumann RR., Hamouda O., CCR5delta32 genotypes in a German HIV-1 seroconverter cohort and report of HIV-1 infection in a CCR5delta32 homozygos individual, Plos One 2008; Oh DY., Taube S., Hamouda O., Kücherer C., Poggensee G., Jessen H., Eckert JK., Storek A., Pouliot M., Borgeat P., Oh N., Pruss A., Hattermann K., Schumann RR. A functional toll-like receptor 8 variant is associated with HIV disease restriction. J Infect Dis, 2008

26

Publikationen

HIV-1 Serokonverterstudie

Poggensee G, Kücherer C, Werning J, Somogyi S, Bieniek B, Dupke S, Jessen H, Hamouda O; HIV-1 Seroconverter Study Group. Impact of transmission of drug- resistant HIV on the course of infection and the treatment success. Data from the German HIV-1 Seroconverter Study. HIV Med. 2007 Nov;8(8):511-915. Hendrik Streeck. Heiko Jessen, Claudia Kuecherer, Bin Li, Arne B. Jessen, Stephan Dupke, Axel Baumgarten, Ingrid Stahmer, Jan van Lunzen, Marcus Altfeld, Bruce D. Walker and Todd M. Allen. Epidemiologically linked transmission

• f HIV-1 illustrates the impact of host genetics on virological outcome. AIDS

2008: 22:1-4 in press Morozov VA, Morozov AV, Schürmann D, Jessen H, Kücherer C. Transmembrane protein polymorphisms and resistance to T-20 (Enfuvirtide, Fuzeon) in HIV-1 infected therapy-naive seroconverters and AIDS patients under HAART-T-20

• therapy. Virus Genes. 2007 Oct;35(2):167-74.

27

Background

Incidence / Prevalence of resistance

Incident and prevalent infections not yet diagnosed Newly diagnosed Incident and prevalent infections

Newly diagnosed HIV infections „Chronic“ HIV infections New („acute“) HIV infections Uninfected at risk

28

Background

Incidence / Prevalence of resistance

Newly diagnosed HIV infections Pre-existing („chronic“) HIV infections New („acute“) HIV infections

Assessment

• f incidence
• f

resistant HIV among newly infected individuals during a defined time intervall Analysis of time trends can

• nly

be carried

• ut based
• n

newly infected individuals Assessment

• f

prevalence

• f

resistant HIV among newly diagnosed individuals

29

Results

• first

line therapy

characteristics susceptible/first line resistant/first line

genotyped n=1276 (1997-2007) 378/1,119 (34%) 65/156 (42%) age 32 (IQR: 18-63) 31(IQR: 18-61)

NRTI/NNRTI-first regime

129/378 (34%) 24/65 (37%)

NRTI/PIr-first regime

228/378 (60%) 40/65 (61%) CD4 cells/µl (median) initial 331 cells/µl (IQR: 212 – 490) 345 cells/µl (IQR: 205 - 507) VL copies/ml (median) initial 182,500 copies/ml 129,500 copies/ml Duration first line regimen (median) Time between seroconversion and ART initiation d (median) 158 d (IQR: 51-359) 330 d (IQR: 66 - 652) 157 d (IQR: 27-319) 442 d (IQR:134 - 660)

30

Results treatment response

• ≤

12 months

Viral load ≤12 months after ART initation susceptible N=266/378 (70%) resistant N=52/65 (80%) VL >500 copies/ml after 6 months 151/266 (57%) 30/52 (58%) VL ≤500 copies/ml after 6 months 115/266 (43%) 14/52 (27%) VL ≤500 copies/ml within 12 months 57/266 (21%)

Single blips

• f viral

replication

36/266 (13%) 3/52 (6%)

31

Results

• first

line therapy

10 20 30 40 50 60 70 80 90 1 9 9 7 1 9 9 8 1 9 9 9 2 2 1 2 2 2 3 2 4 2 5 2 6 2 7

• ther

1NRTI/1NNRTI/1PI/RRI 1NRTI/1PI/RRI 3NRTI/1NNRTI 2NRTI/1NNRTI 2PIr 3NRTI/1PIr 2NRTI/1PIr 2NRTI/2PI 2NRTI/1PI 3NRTI 2NRTI

Initial HAART regimen (>3 of total number

• f drugs)