HAART in Patients w ith HAART in Patients w ith Prim ary HI V Drug - PowerPoint PPT Presentation

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

Prevalence of virological 3- - class failure class failure Prevalence of virological 3 United Kingdom 2002 United Kingdom 2002 16,593 HIV+ patients 10,207 ever treated (61.5% ) 3,060 exposed to 3-classes 7% (38% ) 6 9 3 w ith 3 -class failure ( 2 3 .3 % ) C Sabin et al., BMJ 2005; 330: 695

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

Resistance per continent Resistance per continent 1 5% 11,4% 10,6% 1 0% 7,4% 6,4% 5,7% 5,5% 5% 0% Europe Africa Latin_America North_America East_Asia SSE_Asia Overall resistance: 9.2% Bowles E, 2006

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;

Reversion of Primary Drug Resistance Reversion of Primary Drug Resistance • 12 seroconverters • Median follow-up: 310 days • Replicative capacity: 85% of wild type virus Class n Mean time to mixed population NRTI 5 362 days NNRTI 10 375 days PI 4 No reversion until 689 days • 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

Transmission of genetically homogeneous isolates Transmission of genetically homogeneous isolates Index case Infected persons Wildtype virus Resistant virus

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

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

RESINA 2001- - 2007 (n= 1343) 2007 (n= 1343) RESINA 2001 Prevalence of primary HIV drug resistance Prevalence of primary HIV drug resistance

RESINA 2001- - 2007 (n= 1343) 2007 (n= 1343) RESINA 2001 Prevalence of primary HIV drug resistance Prevalence of primary HIV drug resistance 20,9 (Balduin M, DÖAK 2007)

Primary HIV drug resistance in subgroups I Primary HIV drug resistance in subgroups I p= 1,0 p= 0,42 p= 0,61

Primary HIV drug resistance in subgroups II Primary HIV drug resistance in subgroups II p= 0,04 p= 0,17 p= 0,002

HIV- - 1 Seroconverter Study 1 Seroconverter Study HIV Transmission of resistant HIV in Germany Transmission of resistant HIV in Germany 60 50 percent (%) 40 30 20 10 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 22,7 18,2 23,3 16,2 11,4 17,1 11,9 10,7 15 10,9 14,1 Prozent (%) Bartmeyer, B. AREVIR-GENAFOR-Symposium 2007

Trends of primary HIV drug resistance: Trends of primary HIV drug resistance: RESINA (n= 1343) RESINA (n= 1343) p= 0,77

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

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

Virological efficacy of HAART Virological efficacy of HAART guided by resistance testing, ITT- - analysis analysis guided by resistance testing, ITT 100 % Resist ance p= 0,34 p= 0,74 negat ive, VL< 400 80 Resist ance 60 posit ive, VL< 400 p= 0,39 p= 0,75 Resist ance 40 negat ive, VL< 50 20 Resist ance posit ive, VL< 50 0 wk. 0 24 wks. 48 wks. 72 wks. 96 wks. n = 677 n = 677 n = 677 n = 482 n = 482 resi = 66 resi = 66 resi = 66 resi = 46 resi = 46

Virological efficacy of HAART Virological efficacy of HAART guided by resistance testing, ITT- - analysis analysis guided by resistance testing, ITT 100 % Resist ance p= 0,34 p= 0,74 negat ive, VL< 400 80 Resist ance 60 posit ive, VL< 400 p= 0,39 p= 0,75 Resist ance 40 negat ive, VL< 50 20 Resist ance posit ive, VL< 50 0 wk. 0 24 wks. 48 wks. 72 wks. 96 wks. n = 677 n = 677 n = 677 n = 482 n = 482 resi = 66 resi = 66 resi = 66 resi = 46 resi = 46

Virological efficacy of HAART Virological efficacy of HAART guided by resistance testing, OT- - analysis analysis guided by resistance testing, OT p= 0,13 p= 1,0 100 % Resist ance negat ive, VL< 400 80 p= 0,23 p= 1,0 Resist ance 60 posit ive, VL< 400 40 Resist ance negat ive, VL< 50 20 Resist ance posit ive, VL< 50 0 wk. 0 24 wks. 48 wks. 72 wks. 96 wks. n = 677 n = 585 n = 569 n = 371 n = 350 resi = 66 resi = 54 resi = 55 resi = 34 resi = 32

Virological efficacy of HAART Virological efficacy of HAART guided by resistance testing, OT- - analysis analysis guided by resistance testing, OT p= 0,13 p= 1,0 100 % Resist ance negat ive, VL< 400 80 p= 0,23 p= 1,0 Resist ance 60 posit ive, VL< 400 40 Resist ance negat ive, VL< 50 20 Resist ance posit ive, VL< 50 0 wk. 0 24 wks. 48 wks. 72 wks. 96 wks. n = 677 n = 585 n = 569 n = 371 n = 350 resi = 66 resi = 54 resi = 55 resi = 34 resi = 32

Evolution of CD4- - cell count cell count Evolution of CD4 500 p= 0,88 p=0,77 400 Resistance positive 300 Resistance negative 200 p= 0,38 100 wk. 0 24 wks. 48 wks. 72 wks. 96 wks.