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

HAART in Patients Patients w ith w ith HAART in Prim ary HI V Drug HI V Drug Resistance Resistance : : Prim ary The RESI NA RESI NA Study Study The Dr. med. Mark Oette Clinic for Gastroenterology, Hepatology, and Infectious Diseases University Clinic Düsseldorf, Germany

12. CROI 2005 Bartlett JA Abs. 586

Primary HIV HIV Drug Drug Resistance Resistance Primary • 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

Primary Drug Resistance and Virological Virological Efficacy Efficacy Primary Drug Resistance and FTC- FTC - 301A Study 301A Study Naive pts, baseline VL > 5000 copies/mL 8 0 71 Without baseline mutation Virologic Failure (%) 7 0 With baseline mutation 6 0 Incidence of 5 0 43 4 0 33 30 29 3 0 2 0 14 12 12 12 11 11 10 1 0 4 4 4 4 0 Any NNRTI NRTI K103N Any NNRTI NRTI K103N Mutation type: FTC + ddI + EFV d4T + ddI + EFV n = 270 n = 276 Borroto-Esoda K. CROI 2004, Abs 672

Primary Drug Resistance and Virological Virological Efficacy Efficacy Primary Drug Resistance and GS- - 934 Study 934 Study GS No B/L NNRTI resistance B/L NNRTI resistance 84 90 % VL < 400 c/mL at Wk 48 80 73 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 RESINA Study Study The ( Genotypic ( Genotypic HIV HIV- - Resi Resistance stance in Treatment in Treatment - - Na Naives) ives) • Ongoing prospective study in Nordrhein-Westfalen, the largest state of Germany • Inclusion: Untreated HIV-infected subjects before HAART initiation • Study period: 2001-2008 • 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 • Until end of 2006: 1098 patients in 34 centers • Funding: ¤ Federal Ministry of Health and Social Security ¤ Heinz-Ansmann-Foundation for AIDS-Research

RESINA 2001- - 2005 (n= 1098) 2005 (n= 1098) RESINA 2001 Prevalence of of primary primary HIV HIV drug drug resistance resistance Prevalence 15 1 0 ,1 Prevalence 10 6 ,5 4 3 ,6 2 ,6 5 1 ,5 1 ,1 0 s r e e I I I P e T T t c c n h R R n n a t N a a N e t N t t r g s s e o i i s s v t e e e l A R R R - - s s s s a a l l C C - - 2 3

Virological efficacy efficacy Virological 24 weeks weeks (VL < 50 c/ mL) (VL < 50 c/ mL) 24 100 p = 1,0 90 p = 0,72 80 70 79,4 77,8 Resistance 60 70,1 67,5 positive 50 Resistance 40 negative 30 20 10 0 ITT OT n = 455 n = 408

Virological efficacy efficacy Virological 48 weeks weeks (VL < 50 c/ mL) (VL < 50 c/ mL) 48 100 p = 0,60 90 p = 0,70 80 86,8 82,9 70 75,9 Resistance 72,5 60 positive 50 Resistance 40 negative 30 20 10 0 ITT OT n = 455 n = 398

Virological efficacy efficacy Virological 24 weeks weeks (VL < 400 c/ mL) (VL < 400 c/ mL) 24 p = 0,75 100 p = 0,39 90 92 80 91,2 82,9 70 77,5 Resistance 60 positive 50 Resistance 40 negative 30 20 10 0 ITT OT n = 455 n = 408

Virological efficacy efficacy Virological 48 weeks weeks (VL < 400 c/ mL) (VL < 400 c/ mL) 48 p = 0,10 100 p = 0,38 90 95,3 80 88,6 83,4 70 77,5 Resistance 60 positive 50 Resistance 40 negative 30 20 10 0 ITT OT n = 455 n = 398

Evolution of CD4- - cell cell count count Evolution of CD4 500 p= 0,12 p=0,11 400 Resistance positive 300 Resistance p= 0,56 negative 200 100 wk. 0 24 wks. 48 wks.

Long term term follow follow- - up up of of virological virological efficacy efficacy Long 96 wks wks, , OT OT- - analysis analysis, , vl vl < 50 c/ mL < 50 c/ mL 96 100 p= 0,6 p=0,56 p=0,5 p= 1,0 80 Resistance 60 positive Resistance 40 negative 20 0 wk. 0 24 wks. 48 wks. 72 wks. 96 wks. n = 408 n = 398 n = 305 n = 243

Predictors of of virological virological success success ( ( vl vl < 50 c/ mL) < 50 c/ mL) Predictors Univariate analysis analysis (ITT 48 (ITT 48 wks wks) ) Univariate • Association with treatment success: ¤ Homosexual transmission (p= 0,01) ¤ CDC stage of AIDS (p= 0,04) ¤ Presence of revertants (p= 0,03) ¤ Number of therapy switches within 48 weeks (p= 0,06) • No associaton with treatment success: Age, gender, time since HIV-diagnosis, CD4-cell count and viral load at baseline, ethnic origin, nationality, other transmission routes, resistance within substance groups NRTI, NNRTI and PI, multi-class-resistance, HIV subtype • Similar results for OT-analysis (48 wks, vl < 50 c/ mL)

Predictors of of virological virological failure failure ( ( vl vl > 50 c/ mL) > 50 c/ mL) Predictors Multivariate analysis analysis (ITT 48 (ITT 48 wks wks) ) Multivariate OR 95% -CI p-value Presence of revertants 3,4 1,3-9,0 0,01 CDC-stage of AIDS 1,6 1,0-2,6 0,04 Homosexual transmission 0,5 0,3-0,8 0,006 Therapy switch within 48 weeks 1,7 0,5-6,3 0,42 Viral load at baseline (per log) 1,1 0,8-1,5 0,72

Patients´ ´ histories histories ( ( Cohort Cohort of 786 of 786 cases cases) ) Patients • 5 of 21 patients with revertants and available follow-up data showed a viral load > 50 c/ mL at 48 weeks (24 % ) • 3 patients had a viral load > 400 c/ mL ¤ All of these had additional mutations: K103N (2 cases), V82A (2 cases), L90M (3 cases) • All patients with single mutations showed treatment success • Drug combinations without treatment failure: 3TC/ ABC/ EFV, TDF/ FTC/ NVP, AZT/ 3TC/ NVP, d4T/ 3TC/ NVP, TDF/ FTC/ LPV/ r, d4T/ 3TC/ LPV/ r, AZT/ TDF/ ATV/ r, TDF/ NVP/ LPV/ r • Drugs applied in the patients with virological failure: AZT, d4T, 3TC, ddI, TDF, FPV/ r, LPV/ r , APV/ LPV/ r • Consequence: Determination of revertants: ¤ High risk of treatment failure (in presence of further mutations) ¤ 3TC/ ABC/ EFV, TDF/ FTC/ NVP, TDF/ FTC/ PI/ r suggested

Primary resistance resistance and and treatment treatment outcome outcome Primary • Studies showing comparable efficacy of HAART in patients with and without primary resistance ¤ In seroconverters: Shet A, et al. Acquir Immune Defic Syndr 2006; 41: 439 ¤ In chronically infected subjects: Oette M, et al. J Acquir Immune Defic Syndr 2006; 41: 573 • Studies showing reduced efficacy of HAART in patients carrying resistant variants: ¤ de Mendoza C. AIDS Rev 2001; 3: 50 ¤ García-Lerma JG, et al. J Virol 2004; 78: 7545 ¤ Van Laethem K, et al. J Clin Virol 2007; in press ¤ Violin M, et al. AIDS 2004; 18: 227

Primary HIV Drug HIV Drug Resistance Resistance: : The The RESINA RESINA Study Study Primary • Definition/ Clinical relevance: ¤ Transmission of resistant virus with long persistence ¤ Association with treatment failure • Findings of RESINA Study: ¤ ~ 10 % prevalence of primary drug resistance, increasing trend ¤ Efficacy of HAART guided by resistance testing similar in patient groups with and without resistance ¤ Strongest predictors of virological failure: AIDS, revertants • Conclusions: ¤ No first-line HAART without genotypic resistance testing ¤ In case of revertants (especially in addition to other mutations): Risk of virological failure ! Potent HAART without AZT and d4T warranted

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