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

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

Dr. med. Mark Oette

Clinic for Gastroenterology, Hepatology, and Infectious Diseases University Clinic Düsseldorf, Germany

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Bartlett JA

12. CROI 2005
Abs. 586

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Primary Primary HIV HIV Drug Drug Resistance 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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4 4 4 4 11 11 12 12 10 14 12 43 30 33 29 71

1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0

Primary Drug Resistance and Primary Drug Resistance and Virological Virological Efficacy Efficacy

FTC FTC-

301A Study

301A Study

Borroto-Esoda K. CROI 2004, Abs 672

Incidence of Virologic Failure (%)

Any NNRTI NRTI K103N Any NNRTI NRTI K103N

FTC + ddI + EFV n = 270 d4T + ddI + EFV n = 276

Without baseline mutation With baseline mutation Mutation type:

Naive pts, baseline VL > 5000 copies/mL

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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 Primary Drug Resistance and Virological Virological Efficacy Efficacy GS GS-

934 Study

934 Study

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The The RESINA RESINA Study Study

( ( 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

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RESINA 2001 RESINA 2001-

2005 (n= 1098)

2005 (n= 1098) Prevalence Prevalence of

f primary

primary HIV HIV drug drug resistance resistance

1 0 ,1 6 ,5 3 ,6 2 ,6 4 1 ,5 1 ,1 5 10 15

A l t

g

e t h e r N R T I N N R T I P I R e v e r t a n t s 2

C

l a s s

R

e s i s t a n c e 3

C

l a s s

R

e s i s t a n c e

Prevalence

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Virological Virological efficacy efficacy 24 24 weeks weeks (VL < 50 c/ mL) (VL < 50 c/ mL)

67,5 79,4 77,8 70,1

10 20 30 40 50 60 70 80 90 100 ITT OT Resistance positive Resistance negative

p = 1,0 p = 0,72

n = 455 n = 408

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Virological Virological efficacy efficacy 48 48 weeks weeks (VL < 50 c/ mL) (VL < 50 c/ mL)

72,5 82,9 86,8 75,9

10 20 30 40 50 60 70 80 90 100 ITT OT Resistance positive Resistance negative

p = 0,60 p = 0,70

n = 455 n = 398

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Virological Virological efficacy efficacy 24 24 weeks weeks (VL < 400 c/ mL) (VL < 400 c/ mL)

77,5 91,2 92 82,9

10 20 30 40 50 60 70 80 90 100 ITT OT Resistance positive Resistance negative

p = 0,75 p = 0,39

n = 455 n = 408

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Virological Virological efficacy efficacy 48 48 weeks weeks (VL < 400 c/ mL) (VL < 400 c/ mL)

77,5 88,6 95,3 83,4

10 20 30 40 50 60 70 80 90 100 ITT OT Resistance positive Resistance negative

p = 0,10 p = 0,38

n = 455 n = 398

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Evolution of CD4 Evolution of CD4-

cell

cell count count

100 200 300 400 500

wk. 0

24 wks. 48 wks. Resistance positive Resistance negative p= 0,56 p= 0,12 p=0,11

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n = 408 n = 398 n = 305 n = 243

20 40 60 80 100

wk. 0

24 wks. 48 wks. 72 wks. 96 wks. Resistance positive Resistance negative

p= 1,0 p= 0,6 p=0,56 p=0,5

Long Long term term follow follow-

up

up of

f virological

virological efficacy efficacy 96 96 wks wks, , OT OT-

analysis

analysis, , vl vl < 50 c/ mL < 50 c/ mL

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Predictors Predictors of

f virological

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

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)

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Predictors Predictors of

f virological

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

OR 95% -CI p-value Viral load at baseline (per log) 1,1 0,8-1,5 0,72 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

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Patients Patients´ ´ histories histories ( ( Cohort Cohort of 786

f 786 cases

cases) )

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

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Primary Primary resistance resistance and and treatment treatment outcome

utcome
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

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Primary Primary HIV Drug HIV Drug Resistance Resistance: : The The RESINA RESINA Study Study

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

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Study Study centers centers of

f the

the RESINA 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, Martin Däumer Institute for Virology University of Köln (that´ s Cologne), Germany Claudia Müller, Carola Blondin Clinc for Gastroenterology, Hepatology and Infectious Diseases University Clinic of Düsseldorf, Germany

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Bitte vormerken: Bitte vormerken:

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n % 95% -CI Prevalence including V118I, E44D 75 99 45 69 Of these: Revertants 32 3,9 2,5-5,2 3-class-resistance 4 0,5 0,01-1,0 25 20 7 9,0 7,1-11,0 Prevalence without V118I, E44D NRTI-mutations (without 118/ 44) NRTI-mutations (with 118/ 44) 8,3 6,4-10,2 NNRTI-mutations 3,0 11,9 9,7-14,1 PI-mutations 2,4 1,4-3,4 2-class-resistance 0,8 0,2-1,5 1,8-4,2 5,4 3,9-7,0