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) P = .005 for Mean CVL 30,000 Mean Community Viral Load 1200 association Number of Newly Diagnosed Newly diagnosed and * 25,000 reported HIV cases 1000 (copies/mL) 20,000 HIV Cases 800 798 15,000 600 642 523 518 10,000 400 434 5000 200 0 0 2004 2005 2006 2007 2008 Yr *Data insufficient to prove significant association with reduced HIV incidence. Das-Douglas M, et al. CROI 2010. Abstract 33. Reproduced with permission.

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- - na naï ïve persons ve persons Prevalence of drug resistance in ART Germany 9 Germany 9 2001–5 2001–5 USA 2 USA 2 USA 4 London 8 USA 4 London 8 9% 9% 1999–2003 1999–2003 2000–4 2004–5 2000–4 2004–5 16% 16% 10% 7% 10% 7% Switzerland 1 Switzerland 1 1996–2005 1996–2005 8% 8% Los Angeles 7 Los Angeles 7 Chicago 7 Chicago 7 2003–5 2003–5 2003–5 2003–5 Europe 6 Europe 6 20% 20% 25% 25% 2002–3 2002–3 9-14% 9-14% San Francisco 3 San Francisco 3 2004 2004 STD STD 9% 9% Burkina Faso 10 Burkina Faso 10 PHI PHI 4.8% 4.8% 10% 10% USA/Australia 5 USA/Australia 5 2000–6 2000–6 13% 13% 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;

Primary Drug Resistance and Virological Efficacy Primary Drug Resistance and Virological Efficacy GS- - 934 Study 934 Study GS No B/L NNRTI resistance B/L NNRTI resistance 84 90 % VL < 400 c/mL at Wk 48 73 80 70 60 50 40 30 20 9 9 10 0 TDF/FTC + EFV ZDV/3TC + EFV Gallant JE. N Engl J Med 2006; 354: 251

The RESINA Study The RESINA Study (Genotypic HIV- - Resi Resistance in Treatment stance in Treatment- - Na Naives) ives) (Genotypic HIV • 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- - 2009 (n= 2078) 2009 (n= 2078) RESINA 2001 Prevalence of primary HIV drug resistance Prevalence of primary HIV drug resistance

RESINA 2001- - 2009 (n= 2078) 2009 (n= 2078) RESINA 2001 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- - 2008 (n= 662) 2008 (n= 662) Primary Drug Resistance in Austria, 2001 Resistance against NRTI or NRTI NRTI NNRTI NNRTI and and and 3-class- or PI NRTI NNRTI PI PI NNRTI PI 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%) AKH Linz LKH Salzburg LKH Innsbruck Maria Geit Mario Sarcletti Ninon Taylor Maria Kitchen AKH Wien Armin Rieger LKH Graz West LKH Klagenfurt Bernhard Haas Manfred Kanatschnig

Prevalence of Resistance by Class Prevalence of Resistance by Class Seroconverter (% ) RESI NA Austria Study 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

CDC Survey Update: CDC Survey Update: Patterns of Transmitted Drug Resistance Patterns of Transmitted Drug Resistance Any resistance NNRTI NRTI PI MDR 20 Patients With Transmitted 15.6 15 Resistance (%) 10.7 10.4 10 8.8 7.7 7.1 6.9 8.1 6.1 5 3.6 4.2 3.0 2.4 2.1 1.7 2.2 1.9 1.3 1.3 0.8 0 1999 [1] 2000 [1] 2003-2006 [2] 2007 [3] (n = 239) (n = 299) (n = 3130) (n = 2480) 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.

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

HIV- - 1 Seroconverter Study 1 Seroconverter Study HIV Transmission of resistant HIV in Germany Transmission of resistant HIV in Germany 45 40 proportion of resistant HIV (%) 35 30 25 20 15 10 5 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 year of seroconversion Prevalence 11,3% (95%-CI, 9.7 -13. 1) [n=1276] Kücherer C, SÖDAK 2009

45 40 proportion of resistant HIV (%) 35 30 25 20 15 10 5 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 year of seroconversion

45 40 proportion of resistant HIV (%) 50 35 45 Prozent mit Resistenz 40 30 35 25 30 25 20 20 11,6 15 10,7 9,4 15 9,3 8,4 12,7 10 3,3 5 10 0,0 0 5 2001 2002 2003 2004 2005 2006 2007 2008 Jahr des positiven HIV-Tests 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 year of seroconversion

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

Virological efficacy of HAART Virological efficacy of HAART guided by resistance testing, OT- - analysis analysis guided by resistance testing, OT p= 0,07 p= 0,89 p= 0,01 p= 0,57 n = 1427 n = 1221 n = 1049 n = 929 n = 694 resi = 136 resi = 117 resi = 98 resi = 91 resi = 67

Virological efficacy of HAART Virological efficacy of HAART guided by resistance testing, OT- - analysis analysis guided by resistance testing, OT p= 0,07 p= 0,89 p= 0,01 p= 0,57 n = 1427 n = 1221 n = 1049 n = 929 n = 694 resi = 136 resi = 117 resi = 98 resi = 91 resi = 67

Virological efficacy of HAART Virological efficacy of HAART guided by resistance testing, ITT- - analysis analysis guided by resistance testing, ITT P= 0,12 p= 0,93 p= 0,24 n = 1427 resi = 137

Virological efficacy of HAART Virological efficacy of HAART guided by resistance testing, ITT- - analysis analysis guided by resistance testing, ITT P= 0,12 p= 0,93 p= 0,24 n = 1427 resi = 137

Median Evolution of CD4- - Cell Count Cell Count Median Evolution of CD4 p= 1,0 p=0,58 p= 0,32 p= 0,52 p= 0,84

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- - Study Study Primary HIV Drug Resistance: RESINA • 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)