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HAART in Patients w ith HAART in Patients w ith Prim ary HI V Drug Resistance: Prim ary HI V Drug Resistance: The RESI NA Study The RESI NA Study Priv.-Doz. Dr. med. Mark Oette Klinik fr Allgemeine Innere Medzin, Gastroenterologie und

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HAART in Patients w ith HAART in Patients w ith Prim ary HI V Drug Resistance: Prim ary HI V Drug Resistance: The RESI NA Study The RESI NA Study

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

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Prevalence of virological 3 Prevalence of virological 3-

  • class failure

class failure United Kingdom 2002 United Kingdom 2002

16,593 HIV+ patients 10,207 ever treated (61.5% ) 3,060 exposed to 3-classes (38% ) 6 9 3 w ith 3 -class failure ( 2 3 .3 % )

C Sabin et al., BMJ 2005; 330: 695

7%

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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
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SLIDE 4

5,5% 7,4% 10,6% 6,4% 11,4% 5,7%

0% 5% 1 0% 1 5%

Africa East_Asia Europe Latin_America North_America SSE_Asia

Resistance per continent Resistance per continent

Overall resistance: 9.2%

Bowles E, 2006

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SLIDE 5

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%

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SLIDE 6

Reversion of Primary Drug Resistance Reversion of Primary Drug Resistance

  • 12 seroconverters
  • Median follow-up: 310 days
  • Replicative capacity: 85% of wild type virus
  • 1 Patient: Wild type HIV after 1019 days

⇒ Long persistance of transmitted resistance, no shift of PI-resistance

Little S, 11. CROI 2004, Abs 36LB

Class n Mean time to mixed population NRTI 5 362 days NNRTI 10 375 days PI 4 No reversion until 689 days

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Transmission of genetically homogeneous isolates Transmission of genetically homogeneous isolates

Index case Infected persons Wildtype virus Resistant virus

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Resistant Minority Populations Resistant Minority Populations

  • 49 seroconverters in Hamburg 1999-2003
  • Screening for L90M, K103N, M184V
  • Resistance identified in 20,4 %

¤ Of these: 50% not detected in population based sequencing

Metzner KJ, AIDS 2005; 19: 1819

  • Similar results in 277 therapv naive patients in Canada (M41L, K70R,

K103N, M184V)

Johnson J, 13. CROI 2006; Abs. 642

  • Minorities in the Truvada-Cohort:
  • K65R in 2,1% of 193 patients, not detected in routine genotyping
  • 1 of 4 with treatment failure (adherence ?)

Metzner K. 11. EACS, Madrid 2007. Abs. P3.3/ 04

→ Primary drug resistance more prevalent than suspected

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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: 2001-2009
  • 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, AIDS 2007; 21: 215
  • Until end of 2007: 1373 patients in 34 centers (This week: 1500!)
  • Funding:

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

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RESINA 2001 RESINA 2001-

  • 2007 (n= 1343)

2007 (n= 1343) Prevalence of primary HIV drug resistance Prevalence of primary HIV drug resistance

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RESINA 2001 RESINA 2001-

  • 2007 (n= 1343)

2007 (n= 1343) Prevalence of primary HIV drug resistance Prevalence of primary HIV drug resistance

20,9 (Balduin M, DÖAK 2007)

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Primary HIV drug resistance in subgroups I Primary HIV drug resistance in subgroups I

p= 1,0 p= 0,42 p= 0,61

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Primary HIV drug resistance in subgroups II Primary HIV drug resistance in subgroups II

p= 0,04 p= 0,17 p= 0,002

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HIV HIV-

  • 1 Seroconverter Study

1 Seroconverter Study

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

Prozent (%) 10 20 30 40 50 60

percent (%)

Bartmeyer, B. AREVIR-GENAFOR-Symposium 2007

22,7 18,2 23,3 16,2 11,4 17,1 11,9 10,7 15 10,9 14,1 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

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Trends of primary HIV drug resistance: Trends of primary HIV drug resistance: RESINA (n= 1343) RESINA (n= 1343)

p= 0,77

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Primary HIV Drug Resistance Primary HIV Drug Resistance

  • Transmitted mutated virus
  • Long persistence of mutations
  • Epidemiology: 4 – 29 % , depending on

sampling method, geographic region, study period, classification of mutations

  • Primary drug resistance is associated with

inferior therapeutic outcome, compared to cases with wild type virus

Ref.: Borroto-Esoda, 11. CROI 2004: Abs 672 Chaix ML, Antivir Ther 2005; 10: S127 De Luca, Antivir Ther 2004; 9 : 743 Gallant JE, N Engl J Med 2006; 354: 251 Ghosn J, AIDS 2006; 20: 159 Grant RM, JAMA 2002; 288: 181 Little S, New Engl J Med 2002; 347: 385 McColl D, 3. IAS 2005: Abs TuPp0305 Violin M, AIDS 2004; 18: 227 Wensing AM, AIDS Rev 2003; 5: 140

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Treatment cohort (n= 677) Treatment cohort (n= 677)

  • Follow up in two prospective study arms of first-line HAART:

¤ Patients with wild type virus ¤ Patients with resistant virus, combination treatment according result of resistance testing and expert advice

  • Baseline parameters with significant difference in the

treatment arms: ¤ Viral load: 218.000 vs. 187.000 c/ mL (p= 0,04)

  • Baseline parameters without significant difference in the

treatment arms: ¤ Age, gender, ethnic origin, nationality, transmission group, HIV subtype, duration of HIV-diagnosis, CD-stage, CD4- cell count

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20 40 60 80 100

  • wk. 0

24 wks. 48 wks. 72 wks. 96 wks. %

Resist ance negat ive, VL< 400 Resist ance posit ive, VL< 400 Resist ance negat ive, VL< 50 Resist ance posit ive, VL< 50

p= 0,34 p= 0,74 p= 0,39 p= 0,75

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

  • analysis

analysis

n = 677 n = 677 n = 677 n = 482 n = 482 resi = 66 resi = 66 resi = 66 resi = 46 resi = 46

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20 40 60 80 100

  • wk. 0

24 wks. 48 wks. 72 wks. 96 wks. %

Resist ance negat ive, VL< 400 Resist ance posit ive, VL< 400 Resist ance negat ive, VL< 50 Resist ance posit ive, VL< 50

p= 0,34 p= 0,74 p= 0,39 p= 0,75

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

  • analysis

analysis

n = 677 n = 677 n = 677 n = 482 n = 482 resi = 66 resi = 66 resi = 66 resi = 46 resi = 46

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SLIDE 20

20 40 60 80 100

  • wk. 0

24 wks. 48 wks. 72 wks. 96 wks. %

Resist ance negat ive, VL< 400 Resist ance posit ive, VL< 400 Resist ance negat ive, VL< 50 Resist ance posit ive, VL< 50

p= 0,13 p= 1,0 p= 0,23 p= 1,0

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

  • analysis

analysis

n = 677 n = 585 n = 569 n = 371 n = 350 resi = 66 resi = 54 resi = 55 resi = 34 resi = 32

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20 40 60 80 100

  • wk. 0

24 wks. 48 wks. 72 wks. 96 wks. %

Resist ance negat ive, VL< 400 Resist ance posit ive, VL< 400 Resist ance negat ive, VL< 50 Resist ance posit ive, VL< 50

p= 0,13 p= 1,0 p= 0,23 p= 1,0

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

  • analysis

analysis

n = 677 n = 585 n = 569 n = 371 n = 350 resi = 66 resi = 54 resi = 55 resi = 34 resi = 32

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Evolution of CD4 Evolution of CD4-

  • cell count

cell count

100 200 300 400 500

  • wk. 0

24 wks. 48 wks. 72 wks. 96 wks. Resistance positive Resistance negative p= 0,38 p= 0,88 p=0,77

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Predictors of virological success (vl < 50 c/ mL) Predictors of virological success (vl < 50 c/ mL) Univariate analysis (ITT 48 wks) Univariate analysis (ITT 48 wks)

  • Association with treatment success:

¤ Homosexual transmission (76 vs. 67 % ; p= 0,01)

  • No associaton with treatment success:

Age, gender, time since HIV-diagnosis, CD4-cell and viral load at baseline, ethnic origin, nationality, other transmission routes, resistance within substance groups NRTI, NNRTI, PI, and revertants, HIV subtype

  • Similar results for OT-analysis (48 wks, vl < 50 c/ mL)
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Predictors of virological failure (vl > 50 c/ mL) Predictors of virological failure (vl > 50 c/ mL) Multivariate analysis (ITT 48 wks) Multivariate analysis (ITT 48 wks)

OR 95% -CI p-value Viral load at baseline (per log) 1,2 0,9-1,6 0,09 Presence of resistance 1,5 0,8-2,6 0,18 Homosexual transmission 0,6 0,5-0,9 0,01 CDC-stage of AIDS 1,3 0,9-1,9 0,15

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Predictors of virological failure (vl > 50 c/ mL) Predictors of virological failure (vl > 50 c/ mL) Multivariate analysis (ITT 48 wks) Multivariate analysis (ITT 48 wks)

OR 95% -CI p-value Viral load at baseline (per log) 1,2 0,9-1,6 0,09 Presence of resistance 1,5 0,8-2,6 0,18 Homosexual transmission 0,6 0,5-0,9 0,01 CDC-stage of AIDS 1,3 0,9-1,9 0,15

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Predictors of virological failure (vl > 50 c/ mL) Predictors of virological failure (vl > 50 c/ mL) Multivariate analysis (ITT 48 wks) Multivariate analysis (ITT 48 wks)

OR 95% -CI p-value Viral load at baseline (per log) 1,2 0,9-1,6 0,09 Presence of resistance 1,5 0,8-2,6 0,18 Homosexual transmission 0,6 0,5-0,9 0,01 CDC-stage of AIDS 1,3 0,9-1,9 0,15

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Primary resistance and treatment outcome Primary resistance and treatment outcome in seroconverters in New York in seroconverters in New York

  • Prospective study on the prevalence of primary resistance in

acutely and recently infected patients

  • Inclusion of 361 cases from 1995 to 2004
  • Monitoring of treatment outcome in 73 of 112 individuals recruited

in 2002 and 2003 (85: wild type HIV; 27: resistant HIV)

Shet A, J Acquir Immune Defic Syndr 2006; 41: 439

10 20 30 1995- 1998 1999- 2000 2001- 2002 2003- 2004

Prevalence of resistance

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Primary resistance and treatment outcome Primary resistance and treatment outcome in seroconverters in New York in seroconverters in New York

Shet A, J Acquir Immune Defic Syndr 2006; 41: 439

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Primary HIV Drug Resistance Primary HIV Drug Resistance

  • Definition/ Clinical relevance:

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

  • In chronically infected patients:

¤ ~ 10 % prevalence of primary drug resistance, stable

  • First-line HAART guided by resistance testing:

¤ Equally effective in patient groups with and without resistance ¤ Strongest predictors of virological outcome: viral load, homosexual transmission group ¤ Cost-effective, if prevalence > 1% (Sax. Clin Infect Dis 2005; 41: 1316)

  • Conclusion: No first-line HAART without genotypic resistance testing

¤ German-Austrian Guidelines 2007: A II

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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

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Thank you !

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