Clinical application / / Clinical application relevance relevance - - PowerPoint PPT Presentation

Clinical application Clinical application / / relevance relevance

H.-J. Stellbrink, Hamburg

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Estimated prevalence of triple-class drug resistance in patient groups defined by available GT and previous drug exposure

Adapted from Napravnik S, et al. AIDS 2007; 21: 825.

Genotype (n = 231) Genotype & NRTI, NNRTI & PI use (n = 160) Genotype (n = 376) Genotype & NRTI, NNRTI & PI use (n = 277) Genotype (n = 607) Genotype & NRTI, NNRTI & PI use (n = 437) Overall Prevalence of TC-DR and 95% confidence intervals

■ ■ ■ ■ ■ ■

5 10 15 25 40 20 50 30 35 45

HAART as first ART Non-HAART as first ART

14.38 10.38 19.93 27.23 25.79 34.66

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Class-wide resistance (CWR) is strongly associated with disease progression and death

Multivariate analysis showed that 2 and 3 CWR associated with 2- and 3-fold increased risk of death and DIDS/death respectively

Zaccarelli M, et al. AIDS 2005; 19: 1081.

20 40 60 80 1.0 0.9 0.8 0.7 0.6 0.5 No CWR CWR = Class Wide resistance 1 CWR 2 CWR 3CWR Months Cumulative survival

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Changing ARV therapy following diagnosis of MDR HIV-1 associated with improved survival

Grover D, et al. J of Antimicrobial Chemotherap 2008; 61: 705.

No change to therapy Minor changes to therapy Change: same/lower GSS Change: higher GSS Stop therapy

12 24 36 48 Months 1.00 0.75 0.50 0.25 0.00 Estimated probability of survival

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Time to loss of 1 fully suppressive ARV among subjects continuing to receive a partially suppressive regimen

100 75 50 25

Hatano H, et al. CID 2006; 43: 1329.

4 8 12 16 20 24 Loss of 1 drug equivalent Individuals without the loss of 1 drug equivalent (%) Time (months)

• No. at risk: 105

81 42 32 22 16 12

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Maintaining patients on a failing regimen may diminish future treatment options

First Sequence Test* Second Sequence Test* P Value CD4 (cells/mm3) 336 339 0.8 Viral load (log10 copies/mL) 3.7 4.0 0.002 Number of total resistance mutations 8 10 <0.001 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.

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

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Detection Detection Availability Availability Sample collection Sample collection Clinical consequences Clinical consequences Interpretation Interpretation

Toxicity, Adherence Toxicity, Adherence Algorithms Algorithms gp41, Integrase, CCR5 gp41, Integrase, CCR5 Treatment interruption Treatment interruption Plasma viremia minorities Plasma viremia minorities

How to deal with resistance

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Patient 2728 HIV-RNA CD4+-Zellen 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 Datum 500 5000 50000 5E5 20 40 60 80 100 120 140 160 180 200 220

Fallbeispiel: CD4+-Zellen und HIV-RNA bis 5/06

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RT M41 K65 D67 T69 69SSS K70 L74 V75 K103 V106 V118 Q151 V179 Y181 M184 Y188 G190 H208 L210 R211 L214 T215 K219 aktuell N D R I N I V F Q "worst case" N DN R I N I V A F Q Protease L10 K20 D30 L33 M36 M46 G48 I50 L63 A71 G73 V77 V82 I84 L90 I93 aktuell FIV R F I IL V P V A M L "worst case" FIV R F I IL V P V A M L

Fallbeispielund Resistenzanalyse

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 ?

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Verfügbare Medikamente für vorbehandelte Patienten

Substanz-Klasse Substanz Zulassung

Fusionsinhibitor Enfuvirtide Mai 2003 Tipranavir Oktober 2005 Darunavir Februar 2007 CCR5-Antagonist Maraviroc September 2007 Integrase-Inhibitor Raltegravir Dezember 2007 Nicht nukleosidischer RT-Inhibitor (NNRTI) Etravirine US: Zulassung durch FDA EU: Early Access- Programm Proteaseinhibitor

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.

12 Patient 2728 HIV-RNA CD4+-Zellen 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 Datum 50 500 5000 50000 5E5 20 40 60 80 100 120 140 160 180 200 220 DUETT-Studie (DRV + ETV/Placebo)

Fallbeispiel: CD4+-Zellen und HIV-RNA ab 5/06

TPV

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Efficacy of darunavir at week 48 in the POWER studies by number of active ARVs in the OBT

* ** **

10 20 30 40 50 60 70 80 90 100 1 ≥2

% of Patients HIV RNA <50 copies/mL

Number of active ARVs in OBT

25 34 48 18 40 60 N=

Darunavir/r + OBT OBT

* p=0.04 ** p<0.0001

20 50 3 56 17

Adapted from Clotet B, et al. Lancet 2007; 369: 1169.

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Efficacy of raltegravir at week 48 in the BENCHMRK studies by GSS of the OBT

10 20 30 40 50 60 70 80 90 100 1 ≥2

% of Patients HIV RNA <50 copies/mL

GSS of OBT

112 166 158 65 92 68 N=

Raltegravir + OBT Placebo OBT

45 3 67 37 75 59

Adapted from Cooper D, et al. 15th CROI. Abstract 788.

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Efficacy of raltegravir at week 48 in the BENCHMRK studies by selected ARTs in OBT

44 22 45 23 75 47 191 90

Enfuvirtide Darunavir Subgroup Total Patients (%) HIV RNA <50 copies/mL

N 443 228

+ + + + –

– – –

+ : First use in OBT – : Not used in OBT

64 34 89 68 80 57 69 47 60 20 20 40 60 80 100

Raltegravir + OBT Placebo + OBT

Adapted from Cooper D, et al. 15th CROI. Abstract 788.

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Number of Baseline TMC125 RAMs Correlates with Virological Response (<50 copies/ml) to TMC125

Patients with confirmed viral load <50 HIV-1 RNA copies/ml at Week 24 (%) Number of TMC125 RAMs at baseline

Placebo + BR (N=414) TMC125 + BR (N=406) 161 147 121 157 64 68 32 24 28 18 75 60 58 41 25 44 38 25 25 17 20 40 60 80 100 1 2 3 ≥4

Vingerhoets J, et al. 11th EACS 2007; Abstract P7.3/05

RAM = Resistance Associated Mutation

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Efficacy of maraviroc at week 48 in the MOTIVATE studies by number of active drugs in the OBT (GSS)

GSS at baseline

MVC BID + OBT OBT alone

1 2 ≥3

http://www.emea.europa.eu/humandocs/PDFs/EPAR/celsentri/H-811-PI-en.pdf

2 7 32 39 33 45 58 62 10 20 30 40 50 60 70 80 90 100

% of Patients HIV RNA <50 copies/mL

GSS = Genotypic Sensitivity Score

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1998 2003 2006

A history of failure … A history of failure …

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GRA 1 GRA 2 GRA 3 CD4 pVL

… or a history of success ?

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PBMC-based resistance analyis in switch strategies

Target cells in untreated infection Target cells in treated infection sensitive resistant High cellular activation -> many target cells High level of virus production Few if any resistant viral variants (low fitness ?)

• > PBMC HIV pDNA predominantly WT

Low cellular activation -> few target cells Expansion of uninfected CD4 cells Low level of production of resistant virus

• > slow emergence of PBMC resistance

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Undetectable HIV RNA: the magical condition ?

Detection limit 50 copies/mL

Time

Plasma HIV RNA Copies/mL

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Concept of resistance development

• If we accept that resistance development is ultimately

inevitable we should pursue strategies that minimize the risk

• Prevalence of a resistant variant also depends on
• prevalence of resistance mutations prior to cART
• replicative fitness
• susceptibility to humoral and cellular immune

responses

Risk of resistance mutation number of rounds

• f replication

X risk of resistance mutation per round of replication = Mutation Selection

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Life expectancy by period of therapy initiation

Hogg R. 14th CROI 2007 Abstract 972. *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

30 50 10 40 20

27.1 24.3

Period of therapy initiation

1996 – 1999 2000 – 2002 2003 – 2005 33.2

Years Exact age 20*

60 100 20 80 40

54.1 43.8

Period of therapy initiation

1996 – 1999 2000 – 2002 2003 – 2005 78.6

Percent % Surviving from 20 to 44*

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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).

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