The German HIV-1 Seroconverter Cohort Barbara Bartmeyer Robert Koch-Institute, Berlin Dept. Infectious Disease Epidemiology HIV/AIDS, STI Unit www.rki.de
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 2
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– or EIA+ and indeterminate WB - date of infection: approximation to first reactive test 3
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 resistant highly resistant 4
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 • 5
Results – route of transmission 300 250 Patients n 200 unknown HPL 150 heterosexual occupational 100 IVDA MSM & bisexual 50 0 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 Year of seroconversion 6
Results - prevalence of resistance Prevalence 11.3%; CI 9.6-13.1; p for trend = 0.4 percentage of tested patients (%) 45 40 35 30 25 20 15 10 5 0 6 7 8 9 0 1 2 3 4 5 6 7 9 9 9 9 0 0 0 0 0 0 0 0 9 9 9 9 0 0 0 0 0 0 0 0 1 1 1 1 2 2 2 2 2 2 2 2 Study population N=1564 (seroconverted between 1996-2007) Genotyped N=1276/1312 (treatment naive samples available1997-2007) Resistant N=144 (SDRM list 2007) 7
Results – trends of resistance NRTI p=0.03 20 15 10 5 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Trend of resistance among p=0.08 NNRTI different drug classes 20 (SDRM list; Shafer R. et al, 2007) 15 calculated per year 10 5 of seroconversion 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 (p for trend ) PI p=0.4 20 10 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 8
Results – prevalence of NNRTI mutations 6 5 4 V106AM K103NS 3 % Y181CI G190AESQ P225H 2 1 0 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Prevalence of NNRTI mutations per year of seroconversion 9
Results – singletons within drug classes 100 93% (40/43) 90 80 67%(109/166) 70 57% (56/98) 60 52% (13/25) % 50 40 30 20 10 0 NRTI NNRTI PI overall 10
Results – prevalence of resistance mutations 2.8 M41L 1 D67NG K70R 0.7 F77L 1.2 M184VI 0.8 0.9 L210W T215CDEISV 3.7 4.6 T215ACDEGHILNSV T215YF 0.8 1.1 K219QE 2.3 K103NS 0.7 G190AESQ I54ALMSTV 0.8 V82AFTMS 0.7 0.8 L90M 0 1 2 3 4 5 Overall prevalence of resistance mutations (%) mutations present at a frequency ≤ 0.7% 11
STI -Screening 12
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 13
Results – overall 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 14
Results STI screening by route of transmission 100% 90% 80% 70% Syphilis 60% anti-HSV-2 IgM 50% anti-HSV2 IgG 40% anti-HSV2 IgG & IgM 30% 20% 10% 0% MSM IDU HET HPC unknown Prevalence of STI by route of transmission 1997-2007 15
Results – STI screening 60% 40% HSV-2 IgG HSV-2 IgM HSV2IgG & IgM Syphilis 20% 0% 1996 1997-1997 1998-2000 2001-2003 2004-2007 Prevalence by year of seroconversion 16
Results – STI screening 100% 90% 80% 70% antiHBc& antiHBs 60% HBsAg & antiHBc 50% 40% AntiHCV Elisa & Immunoblot 30% 20% 10% 0% MSM IVDA Hetero HPC unknown Prevalence of STI by route of transmission 1997-2007 17
Results – STI screening 45% 40% 35% anti-HBc & anti-HBs 30% 25% anti-HBsAg & anti-HBc 20% anti-HCV & anti-HCV- 15% immunoblot 10% 5% 0% vor 1996 1997-1997 1998-2000 2001-2003 2004-2007 prevalence STI by year of seroconversion 18
Results – STI screening 70% 60% 50% 40% MSM IVDA 30% 20% 10% 0% vor 1996 1997-1997 1998-2000 2001-2003 2004-2007 Prevalence of HCV among IDU and MSM in the study 19
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 20
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 21
Collaborators Aachen Dres. Knechten, Habets Hamburg ifi Allg.Krankenhaus St. Georg Augsburg Klinikum Augsburg ICH, Infektionsmedizinisches Centrum Hamburg Berlin Ärzteforum Seestraße Dr. Gellermann Augusta-Viktoria Krankenhaus (Vivantes) Universitätsklinik Eppendorf Dres. Bienieck, Cordes Dr. Claus Dr. Dobao Hannover Med. Hochschule Hannover Dres. Dupke, Carganico Dres. Buch, Leugner Dres. Freiwald, Rausch Karlsruhe Landratsamt Karlsruhe Dr. Glaunsinger Koblenz Krankenhaus Kemperhof Dres. Gölz, Moll, Schleehauf Köln Dr. Bihari Dr. Hintsche Dr. Ferdinand Dres. Jessen Universitätsklinik Köln Dres. Köppe Leipzig Universitätsklinik Leipzig Dr. Reuter Magdeburg Universitätsklinik Otto-v.-Guericke Universität Klinikum Dres. Schlote, Lauenroth-Mai, Schuler Mainz Joh.-Gutenberg-Universität Dr. Schmidt München Ludwig-Maximilians-Universität München Dr. Schüler-Maué Dr. Malm Dres. Schranz, Fischer Dres. Jäger, Jägel-Guedes Universitätsmedizin Berlin Charité Dr. Rieger Technische Universität München Münster Universitätsklinik Münster Norderstedt Dr. Soldan Bielefeld Krankenhaus MARA II Nürnberg Klinikum Nürnberg Bochum St. Joseph Hospital Osnabrück Städt. Klinik Natruper Holz Bonn Universitätsklinik Bonn Regensburg Universitätsklinik Regensburg Dortmund Klinikum Dortmund,ID Ambulanz Remscheid Dres. Steege, Walter Dresden Universitätsklinikum Carl Gustav Carus Dresden Dr. Kreft Klinik und Poliklinik für Dermatologie Rostock Universitätsklinik Rostock Duisburg Dr. Becker-Boost Dr. Kwirant Stuttgart Dres. Schnaitmann, Schaffert, Trein, Ißler Düsseldorf Universitätsklinik Düsseldorf Dres. Ulmer, Frietsch, Müller Frankfurt/M Universitätsklinik Joh.-W.-Goethe-Universität Justizvollzugsanstalt Stuttgart Frankfurt/O. Dr. Markus Freudenstadt Landratsamt Freudenstadt Ulm Universitätsklinik Ulm Halle/Saale Universitätsklinik M.-Luther-Universität Viernheim Dr. van Treek Wiesbaden Dr. Starke 22
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 23
Ergebnisse CCR5delta32-homozygoter Patient Ergebnisse Claudia Oh DY et al PLos One, 2008 24
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