HIV Drug Resistance Resistance in in Clinical Clinical Routine - PowerPoint PPT Presentation

HIV Drug Resistance Resistance in in Clinical Clinical Routine Routine HIV Drug Dr. med. Mark Oette Dr. med. Mark Oette Clinic Clinic for for Gastroenterology Gastroenterology, , Hepatology Hepatology, and , and Infectious Infectious Diseases Diseases University Clinic University Clinic D Dü üsseldorf sseldorf

Efficacy of of First First - - line line HAART HAART Efficacy VL < 50 c/ ml (48 weeks) Bartlett JA, AIDS 2006; 20: 2051

Duration of of First First - - line line HAART HAART Duration 100% 80% 60% 40% 20% 0% 0 6 12 18 24 30 36 42 48 Monate seit HAART Beginn N 1198 1108 1015 931 822 665 505 381 286 Mocroft A, AIDS Res Hum Retroviruses 2005; 21: 743

United Kingdom CHIC Study: United Kingdom CHIC Study: Extensive Risk of Failure Extensive Risk of Failure Cumulative Risk of Extensive Failure 40 NRTI PI Cumulative Risk (% ) NNRTI 3-class resistance 30 Extensive 3-class resistance 20 10 0 2 4 6 8 10 Years Since Starting HAART Virologic failure: HIV RNA > 400 copies/ mL despite > 4 months on HAART. Extensive failure: NRTI: virologic failure of > 1 subclass: ZDV and d4T, 3TC and FTC, ddI and TDF and ABC. PI: virologic failure of > 1 ritonavir-boosted PI. NNRTI: virologic failure of EFV or NVP. Phillips A. 14. CROI 2007, Abs. 532

HIV- - Resistance Resistance and and Clinical Clinical Events Events HIV • • EUROSIDA- - Cohort Cohort , 3941 , 3941 patients patients EUROSIDA • • HAART from from 1996 to 2003 1996 to 2003 HAART • • Virological failure failure after after 2 2 years years: 14,8 % : 14,8 % Virological • • 3,9 % developed 3,9 % developed AIDS, 4,8 % AIDS, 4,8 % died died • • Multivariate analysis analysis on on clinical clinical progression progression Multivariate o ≥ 1 NRTI-resistance: 0,7 (95% -CI 0,3-1,3) o ≥ 1 NNRTI-resistance: 2,1 (95% -CI 1,2-3,5) o ≥ 1 PI-resistance: 1,7 (95% -CI 0,9-3,2) o 3-class-resistance: 2,3 (95% -CI 1,4-3,8) Cozzi-Lepri A, 10. EAC 2005, Abs. PS6/ 4

Meta- - Analysis: Analysis: Studies Studies on on Meta Genotypic Resistance Resistance Testing Testing (GART vs. SOC) (GART vs. SOC) Genotypic Panidou ET, et al. AIDS 2004

CERT CERT

Wegner SA, Clin Infect Dis 2004 CERT CERT

Minor Variants Variants Minor

Minor Drug Drug Resistance Resistance before before 1st 1st - - line HAART line HAART Minor and virological efficacy efficacy and virological Primary HIV drug resistance in patients with virological failure on ABC + 3TC + EFV (n = 69) Sensitivity of Conventional Sensitive conventional Mutation Altogether genotyping genotyping genotyping K103N 2 4 6 2/ 6 (33% ) Y181C 1 1 2 1/ 2 (50% ) M184V 1 3 4 1/ 4 (25% ) No minor primary mutations in patients with virological success after 48 weeks on ABC + 3TC + EFV Johnson. IDRW Sitges 2006, Abs. 69

NRTI NRTI

M184V: Hypersusceptibility Hypersusceptibility of AZT + TDF of AZT + TDF M184V: AZT + 3TC + ABC + TDF M184V

Trizivir + TDF: + TDF: Antagonistic Antagonistic selective selective Pressure Pressure Trizivir AZT + 3TC + ABC + TDF K65R M184V TAMs

NNRTI vs. PI NNRTI vs. PI

Therapy Options Options Therapy after virological virological failure failure of of first first - - line line HAART HAART after AD- - Score Score: : Number Number of of active active drugs drugs in 2nd in 2nd- - line HAART line HAART AD Bartlett JA. JAIDS 2006; 41: 323

Therapy Options Options Therapy after virological virological failure failure of of first first - - line line HAART HAART after RC- - Score Score: : „ „ Resistance Resistance Cost Cost “ “ , , drugs drugs with with resistance resistance in in RC 2nd- - line HAART line HAART 2nd Bartlett JA. JAIDS 2006; 41: 323

Salvage Therapy Therapy: : Salvage Treatment Outcome Outcome and and Baseline Baseline- - Resistance Resistance Treatment

Etravirin C227: C227: Etravirin BL- - Mutations and treatment efficacy Mutations and treatment efficacy BL 0 Anzahl 4 3 TAMs + M184V 5 Medianer Abfall HIV-RNA -0.5 Woche 12 [log] 2 -1.0 -1.5 1 -2.0 0 -2.5 10 100 1 TMC125 fold-change Woodfall B. HIV8, Glasgow 2006, Abs. PL5.6

Number of DRV- - relevant PI relevant PI - - Mutations Mutations Number of DRV and Treatment Outcome and Treatment Outcome 70 Responder (<50 RNA Kopien/ml) in % 62 57 60 50 46 45 40 30 25 20 16 11 10 0 3 ≥ 4 alle DRV Kontroll-PI* Anzahl DRV relevanter 0 1 2 PI Mutationen Anzahl IAS-USA PI Resistenz 7 8 8 9 10 8 assoziierte Mutationen Anzahl der Patienten 76 115 134 65 58 448 Cohen C. 44. ICAAC 2006. Abs. P688

TPV resistance score and Treatment Efficacy TPV resistance score and Treatment Efficacy TPV Score 0-1 2-3 4-5 6-7 8-9 Median FC: 0.7-0.9 1.1-1.4 2.0-3.1 3.3-3.9 14.7-52.5 0 Median Change in VL at Wk 24* (log 10 copies/mL) -0.08 (n = 4) -0.45 -0.49 (n = 260) (n = 68) -1 -0.89 (n = 242) -2 -2.10 *24-week data from patients in (n = 144) RESIST-1 and -2 given TPV/r -3 Valdez H. Resistance Workshop Sitges 2005, Abs. 27

Number of of Active Active Drugs in Drugs in Subsequent Subsequent Therapy Therapy Number

BENCHMRK 1 and 2: BENCHMRK 1 and 2: VL < 400 c/ mL at Wk 16 by PSS/ GSS of OBR VL < 400 c/ mL at Wk 16 by PSS/ GSS of OBR Raltegravir + OBR n Placebo + OBR Overall Efficacy Data 79 447 43 230 (PSS) 61 62 0 5 44 76 141 1 41 68 87 222 2 or more 57 110 (GSS) 57 111 0 10 63 85 170 1 43 93 89 159 2 or more 71 70 0 20 40 60 80 100 Patients (%) Statistical analysis: virologic failure carried forward. Cooper D. CROI 2007, Abs. 105aLB Steigbigel R. CROI 2007, Abs. 105bLB

MOTIVATE 1 and 2: MOTIVATE 1 and 2: VL< 50 c/ mL at at wk wk 24 24 by by Number Number of of Active Active Drugs in OBT Drugs in OBT VL< 50 c/ mL Placebo + OBR MVC QD + OBR MVC BID + OBR 100 90 Combined Analysis: MOTIVATE 1 and 2 80 70 61 Patients (%) 58 55 53 60 52 43 43 50 40 29 30 19 18 20 9 3 10 0 n = 35 51 56 44 130 134 59 88 104 64 132 121 Number of active drugs in OBR 0 1 2 ≥ 3 Nelson M. CROI 2007, Abs. 104aLB Lalezari J. CROI 2007, Abs. 104bLB

TORO: TORO: Impact of Number of Active Agents on Response Impact of Number of Active Agents on Response Number of Active Antiretrovirals in OB Regimen (Genotypic Sensitivity Score) Week 24 (ITT) (log 10 copies/mL) Mean Change in HIV-1 RNA at ≥ 5 0 1-2 3-4 0 ENF + OB OB -1.0 -2.0 -3.0 Henry K. IAS 2002, Abs. LbOr19B

Resistance Testing Testing and Reporting and Reporting Resistance

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Wishes of of the the Clinician Clinician Wishes • Dear virologists: o Tell us more about active substances and less about mutations o Minor mutations: Inform us about hidden risks • „Back mutation“ in legislation: Participation in more than one study should be possible for patients with limited options • More data on (long-term-) Outcome of salvage therapy guided by resistance testing including clinical end points necessary

Summary Summary • In the year 10 of HAART, HIV drug-resistance is o frequent, o associated with an increased mortality, and o perhaps to be prevented by strategic sequencing • Availability of resistance testing is likely to improve clinical outcome • New substances with good resistance profile licenced or in expanded access programmes: o Maraviroc, Raltegravir, Etravirine, Darunavir • Effective salvage therapy should consist of at least 2 (better 3) active drugs (Sensitivity Score ?) o Goal: Suppression of viral replication

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Swiss HIV Cohort Study: Resistance With First - - Line Line Swiss HIV Cohort Study: Resistance With First Boosted PI - - and NNRTI and NNRTI - - Based Regimens Based Regimens Boosted PI Virologic Failures by Mutations • Patients initiating HAART 1999 • Patients initiating HAART 1999- - 2005 2005 100 Median (IQR) o Boosted PI (n= 508) Patients (%) 80 Boosted PI: 0 (0-1)* o NNRTI (n= 805) NNRTI: 2 (0-3) 60 o > 94% received 3TC or FTC 40 20 • 69 virologic failures • 69 virologic failures 0 o Boosted PI: 4.6% 0 1 2 >3 Number of IAS-USA Mutations o NNRTI: 5.6% • Resistance test at failure: 84% • Resistance test at failure: 84% Virologic Failures by Class Resistance 100 • Conclusion • Conclusion Median (IQR) Patients (%) 80 Boosted PI: 0 (0-1) † o Similar potency NNRTI: 2 (0-2) 60 o In virological failure, boosted 40 PI lead to less resistance 20 o Consider genetic barrier and 0 0 1 2 >3 drug potency at start of HAART Number of Classes Affected von Wyl V. 14. CROI 2007, Abs. 667