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

HIV Drug HIV Drug Resistance Resistance in in Clinical Clinical Routine Routine

• Dr. med. Mark Oette
• Dr. med. Mark Oette

Clinic Clinic for for Gastroenterology Gastroenterology, , Hepatology Hepatology, and , and Infectious Infectious Diseases Diseases University University Clinic Clinic D Dü üsseldorf sseldorf

Efficacy Efficacy of

• f First

First -

• line

line HAART HAART

VL < 50 c/ ml (48 weeks)

Bartlett JA, AIDS 2006; 20: 2051

N 1198 1108 1015 931 822 665 505 381 286

0% 20% 40% 60% 80% 100% 6 12 18 24 30 36 42 48

Monate seit HAART Beginn

Duration Duration of

• f First

First -

• line

line HAART HAART

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

10 20 30 40

Years Since Starting HAART 2 4 6 8 10

Cumulative Risk of Extensive Failure

Cumulative Risk (% )

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

NRTI PI NNRTI 3-class resistance Extensive 3-class resistance

HIV HIV-

• Resistance

Resistance and and Clinical Clinical Events Events

• EUROSIDA

EUROSIDA-

• Cohort

Cohort , 3941 , 3941 patients patients

• HAART

HAART from from 1996 to 2003 1996 to 2003

• Virological

Virological failure failure after after 2 2 years years: 14,8 % : 14,8 %

• 3,9 %

3,9 % developed developed AIDS, 4,8 % AIDS, 4,8 % died died

• Multivariate

Multivariate analysis analysis on

• n clinical

clinical progression progression

• ≥ 1 NRTI-resistance:

0,7 (95% -CI 0,3-1,3)

• ≥ 1 NNRTI-resistance:

2,1 (95% -CI 1,2-3,5)

• ≥ 1 PI-resistance:

1,7 (95% -CI 0,9-3,2)

• 3-class-resistance:

2,3 (95% -CI 1,4-3,8)

Cozzi-Lepri A, 10. EAC 2005, Abs. PS6/ 4

Meta Meta-

• Analysis:

Analysis: Studies Studies on

• n

Genotypic Genotypic Resistance Resistance Testing Testing (GART vs. SOC) (GART vs. SOC)

Panidou ET, et al. AIDS 2004

CERT CERT

CERT CERT

Wegner SA, Clin Infect Dis 2004

Minor Minor Variants Variants

Minor Minor Drug Drug Resistance Resistance before before 1st 1st -

• line HAART

line HAART and virological and virological efficacy efficacy

• Johnson. IDRW Sitges 2006, Abs. 69

No minor primary mutations in patients with virological success after 48 weeks on ABC + 3TC + EFV

Primary HIV drug resistance in patients with virological failure

• n ABC + 3TC + EFV (n = 69)

Mutation Conventional genotyping Sensitive genotyping Altogether Sensitivity of conventional genotyping K103N 2 4 6 2/ 6 (33% ) Y181C 1 1 2 1/ 2 (50% ) M184V 1 3 4 1/ 4 (25% )

NRTI NRTI

AZT + 3TC + ABC + TDF

M184V: M184V: Hypersusceptibility Hypersusceptibility of AZT + TDF

• f AZT + TDF

M184V

AZT + 3TC + ABC

Trizivir Trizivir + TDF: + TDF: Antagonistic Antagonistic selective selective Pressure Pressure

+ TDF

TAMs M184V K65R

NNRTI vs. PI NNRTI vs. PI

Therapy Therapy Options Options after after virological virological failure failure of

• f first

first -

• line

line HAART HAART

AD AD-

• Score

Score: : Number Number of

• f active

active drugs drugs in 2nd in 2nd-

• line HAART

line HAART

Bartlett JA. JAIDS 2006; 41: 323

Bartlett JA. JAIDS 2006; 41: 323

Therapy Therapy Options Options after after virological virological failure failure of

• f first

first -

• line

line HAART HAART

RC RC-

• Score

Score: : „ „ Resistance Resistance Cost Cost “ “ , , drugs drugs with with resistance resistance in in 2nd 2nd-

• line HAART

line HAART

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

• Resistance

Resistance

Etravirin Etravirin C227: C227: BL BL-

• Mutations and treatment efficacy

Mutations and treatment efficacy

1 10 100

• 2.5
• 2.0
• 1.5
• 1.0
• 0.5

Anzahl TAMs + M184V TMC125 fold-change Medianer Abfall HIV-RNA Woche 12 [log]

4 3 5 1 2

Woodfall B. HIV8, Glasgow 2006, Abs. PL5.6

62 57 46 25 16 45 11 10 20 30 40 50 60 70

Anzahl DRV relevanter 0 1 2 3 ≥4 alle DRV Kontroll-PI* PI Mutationen Anzahl IAS-USA PI Resistenz 7 8 8 9 10 8 assoziierte Mutationen Anzahl der Patienten 76 115 134 65 58 448

Responder (<50 RNA Kopien/ml) in %

Number of DRV Number of DRV-

• relevant PI

relevant PI -

• Mutations

Mutations and Treatment Outcome and Treatment Outcome

Cohen C. 44. ICAAC 2006. Abs. P688

TPV resistance score and Treatment Efficacy TPV resistance score and Treatment Efficacy

Valdez H. Resistance Workshop Sitges 2005, Abs. 27

• 2
• 1
• 3

Median Change in VL at Wk 24* (log10 copies/mL) 0-1 2-3 4-5 6-7 8-9

• 2.10

(n = 144)

• 0.89

(n = 242)

• 0.45

(n = 260)

• 0.49

(n = 68)

• 0.08

(n = 4)

TPV Score

Median FC: 0.7-0.9 1.1-1.4 2.0-3.1 3.3-3.9 14.7-52.5 *24-week data from patients in RESIST-1 and -2 given TPV/r

Number Number of

• f Active

Active Drugs in Drugs in Subsequent Subsequent Therapy Therapy

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

(PSS) 1 2 or more (GSS) 1 2 or more 62 44 141 68 222 110 111 63 170 93 159 70 447 230 Overall Efficacy Data n Raltegravir + OBR Placebo + OBR 61 5 76 41 87 57 57 10 85 43 89 71 20 40 60 80 100 79 43 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 VL< 50 c/ mL at at wk wk 24 24 by by Number Number of

• f Active

Active Drugs in OBT Drugs in OBT

Number of active drugs in OBR 10 20 30 40 50 60 70 80 90 100 35 51 56 88 104 64 132 121 3 18 29 9 43 43 19 52 53 55 61 58 44 130 134 59 1 2 ≥ 3 Patients (%) n = Combined Analysis: MOTIVATE 1 and 2 MVC QD + OBR MVC BID + OBR Placebo + OBR

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

Henry K. IAS 2002, Abs. LbOr19B ENF + OB 1-2 3-4 ≥ 5

• 2.0
• 1.0
• 3.0

OB Mean Change in HIV-1 RNA at Week 24 (ITT) (log10 copies/mL)

Number of Active Antiretrovirals in OB Regimen (Genotypic Sensitivity Score)

Resistance Resistance Testing Testing and Reporting and Reporting

Patient T.K., Patient T.K., born born 1959 1959

Patient K.N., Patient K.N., born born 1948 1948

Patient I.B., Patient I.B., born born 1965 1965

Wishes Wishes of

• f the

the Clinician Clinician

• Dear virologists:
• Tell us more about active substances and less about

mutations

• 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
• frequent,
• associated with an increased mortality, and
• 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:

• Maraviroc, Raltegravir, Etravirine, Darunavir
• Effective salvage therapy should consist of at least 2

(better 3) active drugs (Sensitivity Score ?)

• Goal: Suppression of viral replication

Thank Thank you you ! !

Swiss HIV Cohort Study: Resistance With First Swiss HIV Cohort Study: Resistance With First -

• Line

Line Boosted PI Boosted PI -

• and NNRTI

and NNRTI -

• Based Regimens

Based Regimens

• Patients initiating HAART 1999

Patients initiating HAART 1999-

• 2005

2005

• Boosted PI (n= 508)
• NNRTI (n= 805)
• > 94% received 3TC or FTC
• 69 virologic failures

69 virologic failures

• Boosted PI: 4.6%
• NNRTI: 5.6%
• Resistance test at failure: 84%

Resistance test at failure: 84%

• Conclusion

Conclusion

• Similar potency
• In virological failure, boosted

PI lead to less resistance

• Consider genetic barrier and

drug potency at start of HAART

von Wyl V. 14. CROI 2007, Abs. 667

20 40 60 80 100 0 1 2 >3

Patients (%) Virologic Failures by Mutations

Boosted PI: 0 (0-1)* NNRTI: 2 (0-3) Median (IQR) Number of IAS-USA Mutations 20 40 60 80 100 0 1 2 >3

Patients (%) Virologic Failures by Class Resistance

Boosted PI: 0 (0-1)† NNRTI: 2 (0-2) Median (IQR) Number of Classes Affected