Prim ary HI V Drug Resistance: Prim ary HI V Drug Resistance: The - - PowerPoint PPT Presentation

Prim ary HI V Drug Resistance: Prim ary HI V Drug Resistance: The RESI NA Study The RESI NA Study

Update 2010, AREVIR-Symposium Priv.-Doz. Dr. med. Mark Oette Klinik für Allgemeine Innere Medzin, Gastroenterologie und Infektiologie Krankenhaus der Augustinerinnen, Köln

Community Viral Load Mirrors Reduced Rate of Community Viral Load Mirrors Reduced Rate of New HIV Cases in San Francisco New HIV Cases in San Francisco

Relationship between community viral load and new HIV diagnoses (CVL; mean of summed individual HIV-1 RNA results per yr, retrospective analysis)

Das-Douglas M, et al. CROI 2010. Abstract 33. Reproduced with permission.

Mean CVL 5000 10,000 15,000 20,000 25,000 30,000 2004 2005 2006 2007 2008 Yr Mean Community Viral Load (copies/mL)

*Data insufficient to prove significant association with reduced HIV incidence.

Newly diagnosed and reported HIV cases 200 400 600 800 1000 1200 Number of Newly Diagnosed HIV Cases

P = .005 for

association * 798 642 523 518 434

Primary HIV Drug Resistance Primary HIV Drug Resistance

• Resistance-associated mutations of HIV in patients never

exposed to antiretroviral therapy

• Transmission of resistant virus strains

Prevalence of drug resistance in ART Prevalence of drug resistance in ART-

• na

naï ïve persons ve persons

Switzerland1 1996–2005

8%

Switzerland1 1996–2005

8%

USA2 1999–2003

16%

USA2 1999–2003

16%

San Francisco3 2004 STD

9%

PHI

10%

San Francisco3 2004 STD

9%

PHI

10%

USA/Australia5 2000–6

13%

USA/Australia5 2000–6

13%

Europe6 2002–3

9-14%

Europe6 2002–3

9-14%

USA4 2000–4

10%

USA4 2000–4

10%

Chicago7 2003–5

25%

Chicago7 2003–5

25%

Los Angeles7 2003–5

20%

Los Angeles7 2003–5

20%

London8 2004–5

7%

London8 2004–5

7%

• 1. Yerly et al. XV International Drug Resistance Workshop; June 13-17, 2006; Sitges, Spain. Abstract 105; 2. Eshleman et al. XV International Drug Resistance Workshop; June 13-17, 2006; Sitges, Spain. Abstract 109; 3. Truong et al.; XV

International Drug Resistance Workshop; June 13-17, 2006; Sitges, Spain. Abstract 102; 4. Ross, et al. XV International Drug Resistance Workshop; June 13-17, 2006; Sitges, Spain. Abstract 107; 5. Little S, et al. XV International Drug Resistance Workshop; June 13-17, 2006; Sitges, Spain. Abstract 97; 6. Wensing et al. XV International Drug Resistance Workshop; June 13-17, 2006; Sitges, Spain. Abstract 98; 7. Bennett, et al. XV International Drug Resistance Workshop; June 13-17, 2006; Sitges, Spain. Abstract 103; 8. Garcia A, et al. HIV Med 2006;7:1; 9. Oette et al. HIV 8, Glasgow 2006, P236; 10. Tebit et al. J AIDS 2006:43:144;

Germany9 2001–5

9%

Germany9 2001–5

9%

Burkina Faso10

4.8%

Burkina Faso10

4.8%

Gallant JE. N Engl J Med 2006; 354: 251

84 9 73 9 10 20 30 40 50 60 70 80 90 TDF/FTC + EFV ZDV/3TC + EFV No B/L NNRTI resistance B/L NNRTI resistance % VL < 400 c/mL at Wk 48

Primary Drug Resistance and Virological Efficacy Primary Drug Resistance and Virological Efficacy GS GS-

• 934 Study

934 Study

The RESINA Study The RESINA Study

(Genotypic HIV (Genotypic HIV-

• Resi

Resistance in Treatment stance in Treatment-

• Na

Naives) ives)

• Ongoing prospective study in Nordrhein-Westfalen
• Inclusion: Untreated HIV-infected subjects before HAART initiation
• Study period: 2001-2012
• Aims of study:

¤ Epidemiology of primary resistance in chronically HIV-infected patients ¤ Evaluation of efficacy of HAART guided by resistance testing ¤ Bioinformatic analysis of resistance data

• Classification of resistance: Shafer RW et al., Antiviral Therapy 2009
• Until end of 2009: 2078 patients in 34 centers
• Funding:

¤ Federal Ministry of Health and Social Security ¤ Heinz-Ansmann-Foundation for AIDS-Research

RESINA 2001 RESINA 2001-

• 2009 (n= 2078)

2009 (n= 2078) Prevalence of primary HIV drug resistance Prevalence of primary HIV drug resistance

RESINA 2001 RESINA 2001-

• 2009 (n= 2078)

2009 (n= 2078) Prevalence of primary HIV drug resistance Prevalence of primary HIV drug resistance

20,1 (Balduin M, J Clin Virol 2009)

Primary Drug Resistance in Austria, 2001 Primary Drug Resistance in Austria, 2001-

• 2008 (n= 662)

2008 (n= 662)

AKH Wien Armin Rieger LKH Graz West Bernhard Haas LKH Innsbruck Mario Sarcletti Maria Kitchen AKH Linz Maria Geit LKH Salzburg Ninon Taylor LKH Klagenfurt Manfred Kanatschnig

Resistance against

NRTI or NNRTI

• r PI

NRTI NNRTI PI NRTI and PI NRTI and NNRTI NNRTI and PI 3-class- Resist. 61 (9,2%) 39 (5,9%) 18 (2,7%) 11 (1,7%) 3 (0,5%) 4 (0,6%) 0 (0,0%) 0 (0,0%)

Prevalence of Resistance by Class Prevalence of Resistance by Class

(% ) RESI NA Seroconverter Study Austria Altogether 9,2 11,3 9,2 NRTI 5,8 6 5,9 NNRTI 2,8 3 2,7 PI 2,7 2 1,7 Multi 1,5 1,5 1,1

1.3 1.9 1.3

CDC Survey Update: CDC Survey Update: Patterns of Transmitted Drug Resistance Patterns of Transmitted Drug Resistance

5 10 15 20 Patients With Transmitted Resistance (%) NRTI Any resistance PI NNRTI 2007[3] (n = 2480) 15.6 8.1 6.1 4.2 1999[1] (n = 239) 8.8 2.1 7.1 0.8 2000[1] (n = 299) 10.7 1.7 7.7 3.0 2003-2006[2] (n = 3130) 10.4 6.9 3.6 2.4

• 1. Bennett D, et al. CROI 2002. Abstract 372.
• 2. Wheeler W, et al. CROI 2007. Abstract 648.
• 3. Kim D, et al. CROI 2010. Abstract 580.

MDR 2.2

Trends of primary HIV drug resistance: Trends of primary HIV drug resistance: RESINA (n= 2078) RESINA (n= 2078)

HIV HIV-

• 1 Seroconverter Study

1 Seroconverter Study

Transmission of resistant HIV in Germany Transmission of resistant HIV in Germany

Kücherer C, SÖDAK 2009

Prevalence 11,3% (95%-CI, 9.7 -13. 1) [n=1276]

5 10 15 20 25 30 35 40 45 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 year of seroconversion proportion of resistant HIV (%)

5 10 15 20 25 30 35 40 45 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 year of seroconversion proportion of resistant HIV (%)

5 10 15 20 25 30 35 40 45 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 year of seroconversion proportion of resistant HIV (%)

12,7 9,3 9,4 8,4 10,7 3,3 0,0 11,6

5 10 15 20 25 30 35 40 45 50 2001 2002 2003 2004 2005 2006 2007 2008 Jahr des positiven HIV-Tests Prozent mit Resistenz

Primary HIV Drug Resistance in Subgroups I Primary HIV Drug Resistance in Subgroups I

p= 0,46 p= 0,002 p= 0,15

Primary HIV Drug Resistance in Subgroups II Primary HIV Drug Resistance in Subgroups II

p= 0,003 p= 0,005 p= 0,00

Subtype Analysis I Subtype Analysis I

Subtype Analysis I Subtype Analysis I

Subtype Analysis II Subtype Analysis II

p= 0,00 p= 0,00 p= 0,00 p= 0,002

Subtype Analysis III Subtype Analysis III

p= 0,001 p= 0,008 p= 0,5 p= 0,14

p= 0,07 p= 0,89 p= 0,01 p= 0,57

Virological efficacy of HAART Virological efficacy of HAART guided by resistance testing, OT guided by resistance testing, OT-

• analysis

analysis

n = 1427 n = 1221 n = 1049 n = 929 n = 694 resi = 136 resi = 117 resi = 98 resi = 91 resi = 67

p= 0,07 p= 0,89 p= 0,01 p= 0,57

Virological efficacy of HAART Virological efficacy of HAART guided by resistance testing, OT guided by resistance testing, OT-

• analysis

analysis

n = 1427 n = 1221 n = 1049 n = 929 n = 694 resi = 136 resi = 117 resi = 98 resi = 91 resi = 67

P= 0,12 p= 0,93 p= 0,24

Virological efficacy of HAART Virological efficacy of HAART guided by resistance testing, ITT guided by resistance testing, ITT-

• analysis

analysis

n = 1427 resi = 137

P= 0,12 p= 0,93 p= 0,24

Virological efficacy of HAART Virological efficacy of HAART guided by resistance testing, ITT guided by resistance testing, ITT-

• analysis

analysis

n = 1427 resi = 137

Median Evolution of CD4 Median Evolution of CD4-

• Cell Count

Cell Count

p= 0,84 p= 1,0 p=0,58 p= 0,52 p= 0,32

RESINA: Future Plans RESINA: Future Plans

• Extension of cohort:

¤ Longitudinal ¤ Pediatric patients

• Bioinformatic analysis:

¤ Resistance pathways ¤ Development of new prediction tool for treatment-naives

• Comparison of data with other cohorts:

¤ German Seroconverter Study ¤ Austrian/ Swiss cohorts ¤ Euresist

• Further lab studies:

¤ HLA-subtyping ¤ Ultra-deep sequencing ¤ Coinfections

Primary HIV Drug Resistance: RESINA Primary HIV Drug Resistance: RESINA-

• Study

Study

• Definition, clinical relevance:

¤ Resistant virus in previously untreated patients ¤ Association with treatment failure

• In chronically infected patients:

¤ ~ 10 % prevalence of primary drug resistance, declining ¤ Risk groups: Males, caucasians, homosexuals, subtype B ¤ Distinct epidemiology in patients with non-B-subtype

• First-line HAART guided by resistance testing:

¤ Equally effective in patient groups with and without resistance

• Conclusions:

¤ Further surveillance/ research necessary ¤ No first-line HAART without genotypic resistance testing (German-Austrian Guidelines 2007/ 2009: A II)

Study centers of the RESINA Study centers of the RESINA-

• Project

Project

Praxis Arbter, Krefeld Praxis Baumann, Neuss Praxis Becker-Boost, Duisburg Praxis Busch, Christenen, Münster Praxis Carls, Huber, Düsseldorf Praxis Dresch, Köln Uniklinik Essen, S. Esser Uniklinik Köln, Prof. Fätkenheuer Praxis Ferdinand, Köln Praxis Gantke, Düsseldorf Praxis Gippert, Hartmann, Quaing, Münster Praxis Grüneberg, Münster Praxis Herrmann, Köln Klinik Westfalendamm, M. Hower, Dortmund Praxis Isernhagen, Römer, Köln Praxis Knechten, Habets, Aachen Praxis Köthemann, Neuwirth, Köln Praxis Kwirant, Duisburg Praxis Mauruschat, Wuppertal Praxis Mauss, Schmutz, Düsseldorf Praxis Miasnikov, Düsseldorf Augustinerkrankenhaus, D. Mitrenga, Köln Praxis Mutz, Osnabrück Uniklinik Düsseldorf, D. Häussinger, M. Oette Praxis Paffenholz, Köln Praxis Reith, Düsseldorf Klinik Kemperhof, A. Rieke, Koblenz Uniklinik Bonn, J. Rockstroh Praxis Schäfer, Bielefeld Praxis Schoelzel, Troisdorf Praxis Scholten, Köln Krankenhaus Hagen, T. Scholten, Hagen Praxis Schons, Düsseldorf Praxis Schuster, Wuppertal Praxis Stechel, Köln Praxis Strehlow, Petry, Düsseldorf Praxis Wichmann, Köln Praxis Wiesel, Theisen, Köln

Thank you !

Rolf Kaiser, Claudia Müller, Eugen Schülter, Melanie Balduin, Nadine Sichtig Institute for Virology, University of Köln, Germany Stefan Reuter, Carola Blondin Clinc for Gastroenterology, Hepatology and Infectious Diseases University Clinic of Düsseldorf, Germany

High Rate of Resistance High Rate of Resistance in Patients Failing First in Patients Failing First -

• line Regimens in Malawi

line Regimens in Malawi

• 94 patients who failed on first-line d4T/ 3TC/ NVP (or ZDV, EFV

substituted for toxicity) analyzed for resistance

Hosseinipour M, et al. IAC 2008. Abstract TUAB0105.

20 40 60 80 100

TAM(s) containing virus TDF mutations (K65R or K70E) TDF + TAM(s) Q151M complex Pan-NRTI (Q151 + TDF mutns

• r 69

insertion)

Patients (%) 17 19 7 23 56 81

M184V/I NRTI Mutations

93 5 16

WT M184V + NNRTI mutations

• nly

+ NNRTI mutations ± 184V

p= 0,79 p= 1,0 p= 1,0 p= 0,02

Virological Virological efficacy efficacy of HAART

• f HAART

by by subtype subtype, , OT OT-

• analysis

analysis (VL < 50/ mL) (VL < 50/ mL)

n = 677 n = 466 n = 359 n = 259 n = 214 Non-B-subtype with resistance n = 6 n = 5