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Clinical application / / Clinical application relevance relevance H.-J. Stellbrink, Hamburg

Estimated prevalence of triple-class drug resistance in patient groups defined by available GT and previous drug exposure Overall 19.93 Genotype (n = 607) ■ Genotype & NRTI, NNRTI & PI use (n = 437) 27.23 ■ Non-HAART as first ART 25.79 Genotype (n = 376) ■ 34.66 Genotype & NRTI, NNRTI & PI use (n = 277) ■ HAART as first ART 10.38 ■ Genotype (n = 231) 14.38 ■ Genotype & NRTI, NNRTI & PI use (n = 160) 0 5 10 15 20 25 30 35 40 45 50 Prevalence of TC-DR and 95% confidence intervals Adapted from Napravnik S, et al . AIDS 2007; 21: 825. 2

Class-wide resistance (CWR) is strongly associated with disease progression and death 1.0 No CWR 0.9 Multivariate analysis Cumulative survival 1 CWR showed that 2 and 3 0.8 CWR associated with 2 CWR 2- and 3-fold 0.7 increased risk of death and DIDS/death 3CWR 0.6 respectively CWR = Class Wide resistance 0.5 0 20 40 60 80 Months Zaccarelli M, et al . AIDS 2005; 19: 1081. 3

Changing ARV therapy following diagnosis of MDR HIV-1 associated with improved survival 1.00 Change: higher GSS Minor changes to therapy Estimated probability of survival No change to therapy 0.75 Change: same/lower GSS Stop therapy 0.50 0.25 0.00 0 12 24 36 48 Months Grover D, et al . J of Antimicrobial Chemotherap 2008; 61: 705. 4

Time to loss of 1 fully suppressive ARV among subjects continuing to receive a partially suppressive regimen 100 Individuals without the loss of 75 1 drug equivalent (%) 50 25 Loss of 1 drug equivalent 0 0 4 8 12 16 20 24 Time (months) No. at risk: 105 81 42 32 22 16 12 Hatano H, et al . CID 2006; 43: 1329. 5

Maintaining patients on a failing regimen may diminish future treatment options First Second Sequence Sequence P Test* Test* Value CD4 (cells/mm 3 ) 336 339 0.8 Viral load (log 10 copies/mL) 3.7 4.0 0.002 Number of total resistance 8 10 <0.001 mutations GSS 0.5 0.3 <0.001 *The study included patients who had two genotypic resistance tests separated by more than 2 months without an intervening change in their ARV regimen; the median time period between the two sequences was 14 months (IQR, 8–22 months). Kantor R, et al. AIDS 2004;18:1503-1511 . 6

How to deal with resistance Clinical consequences Clinical consequences Interpretation Interpretation Detection Detection Sample collection Sample collection Availability Availability 7

How to deal with resistance Clinical consequences Toxicity, Clinical consequences Toxicity, Adherence Adherence Interpretation Interpretation Algorithms Algorithms Detection Plasma viremia Detection Plasma viremia minorities minorities Sample collection Sample collection Treatment interruption Treatment interruption Availability gp41, Integrase, Availability gp41, Integrase, CCR5 CCR5 8

Fallbeispiel: CD4+-Zellen und HIV-RNA bis 5/06 Patient 2728 5E5 220 200 180 50000 160 140 120 5000 100 80 500 60 40 20 07.10.1996 25.08.1997 08.07.1998 14.04.1999 19.01.2000 14.11.2000 14.08.2001 31.07.2002 07.05.2003 27.02.2004 25.11.2004 26.09.2005 HIV-RNA CD4+-Zellen Datum 9

Fallbeispiel und Resistenzanalyse 69SSS M184 K103 V106 V118 Q151 V179 Y181 Y188 G190 H208 R211 K219 L210 L214 T215 M41 K65 D67 K70 T69 L74 V75 RT N D R I N I V F Q aktuell N DN R I N I V A F Q "worst case" K20 D30 M36 M46 G48 A71 G73 L10 L33 L63 V77 V82 L90 I50 I84 I93 Protease FIV R F I IL V P V A M L aktuell FIV R F I IL V P V A M L "worst case" ZDV d4T TDF ddI ABC 3TC FTC NVP EFV DLV ETV ANRS 2005 ANRS 2006 Stanford REGA HIV-GRADE SQV IDV RTV NFV LPV (f)APV AZV TPV DRV high ANRS 2005 int ANRS 2006 low Stanford pot REGA sen HIV-GRADE ? 10

Verfügbare Medikamente für vorbehandelte Patienten Substanz-Klasse Substanz Zulassung Fusionsinhibitor Enfuvirtide Mai 2003 Tipranavir Oktober 2005 Proteaseinhibitor Darunavir Februar 2007 CCR5-Antagonist Maraviroc September 2007 Integrase-Inhibitor Raltegravir Dezember 2007 US: Zulassung Nicht nukleosidischer durch FDA Etravirine RT-Inhibitor (NNRTI) EU: Early Access- Programm http://www.emea.europa.eu/htms/human/epar/a.htm http://www.fda.gov/bbs/topics/NEWS/2008/NEW01783.html http://www.tibotec.com/bgdisplay.jhtml?itemname=EAP2_ROW. 11

Fallbeispiel: CD4+-Zellen und HIV-RNA ab 5/06 Patient 2728 5E5 220 200 TPV DUETT-Studie (DRV + ETV/Placebo) 180 50000 160 140 5000 120 100 80 500 60 40 50 20 12.08.2004 28.10.2004 20.01.2005 18.04.2005 08.08.2005 27.01.2006 17.05.2006 10.08.2006 22.12.2006 16.04.2007 19.08.2007 HIV-RNA CD4+-Zellen Datum 12

Efficacy of darunavir at week 48 in the POWER studies by number of active ARVs in the OBT 100 Darunavir/r + OBT OBT 90 80 * p=0.04 ** p<0.0001 % of Patients HIV RNA 70 <50 copies/mL 56 60 50 ** 50 ** 40 30 20 17 20 * 10 3 0 0 0 1 ≥ 2 Number of active ARVs in OBT N= 25 18 34 40 48 60 Adapted from Clotet B, et al . Lancet 2007; 369: 1169. 13

Efficacy of raltegravir at week 48 in the BENCHMRK studies by GSS of the OBT 100 Raltegravir + OBT Placebo OBT 90 75 80 % of Patients HIV RNA 67 70 <50 copies/mL 59 60 45 50 37 40 30 20 10 3 0 0 1 ≥ 2 GSS of OBT N= 112 65 166 92 158 68 Adapted from Cooper D, et al . 15 th CROI. Abstract 788. 14

Efficacy of raltegravir at week 48 in the BENCHMRK studies by selected ARTs in OBT Subgroup Patients (%) HIV RNA <50 copies/mL N 443 64 Total 228 34 Enfuvirtide Darunavir 44 89 + + 68 22 45 80 + – 23 57 75 69 – + 47 47 191 60 – – 90 20 20 0 80 100 40 60 + : First use in OBT – : Not used in OBT Raltegravir + OBT Placebo + OBT Adapted from Cooper D, et al . 15 th CROI. Abstract 788. 15

Number of Baseline TMC125 RAMs Correlates with Virological Response (<50 copies/ml) to TMC125 <50 HIV-1 RNA copies/ml at Week 24 (%) 100 Patients with confirmed viral load TMC125 + BR (N=406) Placebo + BR (N=414) 80 RAM = Resistance Associated Mutation 75 60 58 60 44 41 38 40 25 25 25 17 20 161 147 121 157 64 68 32 24 28 18 0 0 1 2 3 ≥ 4 Number of TMC125 RAMs at baseline Vingerhoets J, et al. 11th EACS 2007 ; Abstract P7.3/05 16

Efficacy of maraviroc at week 48 in the MOTIVATE studies by number of active drugs in the OBT (GSS) 100 OBT alone 90 MVC BID + OBT % of Patients HIV RNA 80 <50 copies/mL 70 62 58 60 50 45 39 40 33 32 30 20 7 10 2 0 0 1 2 ≥ 3 GSS at baseline GSS = Genotypic Sensitivity Score http://www.emea.europa.eu/humandocs/PDFs/EPAR/celsentri/H-811-PI-en.pdf 17

1998 2003 2006 A history of failure … A history of failure … 18

… or a history of success ? CD4 GRA 1 GRA 2 GRA 3 pVL 19

PBMC-based resistance analyis in switch strategies Target cells in untreated infection Target cells in treated infection resistant sensitive High cellular activation -> many target cells Low cellular activation -> few target cells High level of virus production Expansion of uninfected CD4 cells Few if any resistant viral variants (low fitness ?) Low level of production of resistant virus -> PBMC HIV pDNA predominantly WT -> slow emergence of PBMC resistance 20

Undetectable HIV RNA: the magical condition ? Plasma HIV RNA Copies/mL Detection limit 50 copies/mL Time 21

Concept of resistance development If we accept that resistance development is ultimately • inevitable we should pursue strategies that minimize the risk Mutation Risk of resistance number of rounds X risk of resistance mutation per = mutation of replication round of replication Selection Prevalence of a resistant variant also depends on • prevalence of resistance mutations prior to cART • replicative fitness • susceptibility to humoral and cellular immune • responses 22

Life expectancy by period of therapy initiation 50 100 Exact age 20* % Surviving from 20 to 44* 78.6 40 80 33.2 27.1 30 60 54.1 24.3 Years Percent 43.8 20 40 10 20 0 0 1996 – 1999 2000 – 2002 2003 – 2005 1996 – 1999 2000 – 2002 2003 – 2005 Period of therapy initiation Period of therapy initiation *Estimate of years remaining to live and percentage of patients surviving from age 20 to 44 assuming cART initiated at the age of 20 years Hogg R. 14 th CROI 2007 Abstract 972. 23

Consequences • Resistance analysis is now predictive of success as well as failure. • Tools have to be improved in order to investigate earliest failure (RNA >50 and <500-1000). • For Switching due to toxicity, more sensitive tools are needed to detect resistant virus in reservoirs (has to be validated). 24

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