CCR5 Antagonists and Tropism Testing in Clinical Practice This activity is supported by educational...

CCR5 Antagonists and Tropism Testing inClinical Practice

This activity is supported by educational grants from

Faculty: W. David Hardy, M.D.Director, Division of Infectious Diseases Cedars-Sinai Medical Center; Los Angeles, California

W. David Hardy, M.D.

Copyright © 2008 Body Health Resources Corporation. All rights reserved.

The Body PRO Presents:

This activity is jointly sponsored by Postgraduate Institute for Medicine and The Body PRO.

The Body PRO

CCR5 Antagonists and Tropism Testing in Clinical Practice

2

Faculty for This ActivityFaculty for This Activity

W. David Hardy, M.D.

W. David Hardy, M.D., is an associate professor of medicine-in-residence at the David Geffen School of Medicine, University of California, Los Angeles (UCLA). He gained his medical degree from the Baylor College of Medicine in Houston, Texas, in 1981, completed a residency in internal medicine at Harbor-UCLA Medical Center in Torrance, California in 1984 and a clinical fellowship in infectious diseases and immunology in 1986 at UCLA School of Medicine. Later in his career he also completed a postdoctoral fellowship in basic retrovirology in 2002, also at the UCLA School of Medicine.

Dr. Hardy has conducted clinical trials with several antiretroviral agents beginning in 1986. He is a member of numerous professional societies including the American Academy of HIV Medicine, for whom he serves as a member of the National Board of Directors and Chairman of the California/Hawaii Chapter.

Disclosures

Dr. Hardy has received grants or research support from Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Pfizer and Tibotec. He has served as a consultant for Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Monogram, Pfizer and Tibotec. He has received fees for non-CME services from Gilead Sciences, Pfizer and Tibotec. He owns stock in Merck.

The Body PRO


3

Retrovirus Life CycleRetrovirus Life Cycle

Coreceptor, CD4 Binding Inhibitors

maravirocvicrivirocTNX 355

Reverse Transcriptase Inhibitors

Protease Inhibitors

Maturation Inhibitorbevirimat

Integrase Inhibitorsraltegravirelvitegravir

Fusion Inhibitorsenfuvirtide

zidovudine nevirapine

didanosine delavirdine

zalcitabine efavirenz

stavudine lamivudine

emtricitabine abacavir

tenofovir etravirine

rilpivirine

saquinavir indinavir

ritonavir nelfinavir

fosamprenavir lopinavir

atazanavir tipranavir

darunavir

The Body PRO


4

HIV Entry InhibitorsHIV Entry Inhibitors

Adapted from Moore JP, PNAS 2003;100:10598-10602.

The Body PRO


5

Targets Involved in HIV EntryTargets Involved in HIV Entry

Copyright © 2002-2008 Pfizer Inc. All rights reserved. Reprinted with permission.

The Body PRO


6

Structure of the HIV-1 Envelope GlycoproteinStructure of the HIV-1 Envelope Glycoprotein


The Body PRO


7

Binding of the gp120 Subunit to CD4Binding of the gp120 Subunit to CD4


The Body PRO


8

Conformational ChangeConformational Change


The Body PRO


9

gp120 Binds to the Coreceptor, CCR5gp120 Binds to the Coreceptor, CCR5


The Body PRO


10

Conformational Changes in the gp41 SubunitConformational Changes in the gp41 Subunit


The Body PRO


11

Fusion of the Viral and Cell MembranesFusion of the Viral and Cell Membranes


The Body PRO


12

HIV Natural History and Tropism Expression

The Body PRO


13

CCR5 Function and GeneticsCCR5 Function and Genetics

• CCR5 is a receptor for C-C chemokines (chemo-attractive cytokines)

– Expressed on immune effector cells and antigen presenting cells

– Molecules that bind to CCR5 include MIP-1, MIP-1, and RANTES

• Activation of CCR5 on T cells by chemokines leads to:

– T-cell migration to the site of inflammation

– Immune response to various antigens

• CCR5, together with CD4, are the primary receptors utilized by HIV for viral entry

Galvani AP et al. Proc Natl Acad Sci U S A. 2003;100:15276-15279. McNicholl JM et al. Emerg Infect Dis. 1997;3:261-271.Stephens JC et al. Am J Hum Genet. 1998;62:1507-1515.

The Body PRO


14

Mixed or Dual-Tropic Viruses Use CCR5 and/or CXCR4 (in vitro)Mixed or Dual-Tropic Viruses Use CCR5 and/or CXCR4 (in vitro)

Graeme Moyle et al. ICAAC 2006; abstract H-1667. Reprinted with permission.

The Body PRO


15

Coreceptor Usage of HIV-1 VariantsCoreceptor Usage of HIV-1 Variants

X4 R5

CXCR4 CCR5

CD4

T-cell lines Primary lymphocytes Monocyte/macrophages

CD4 Naive CD4 memory

CD4

Copyright © 2002-2008 Pfizer Inc. All rights reserved.

The Body PRO


16

Global Prevalence of CCR5 32 AlleleGlobal Prevalence of CCR5 32 Allele

Galvani AP et al. PNAS. 2003;100:15276-15279. McNicholl JM et al. Emerg Infect Dis. 1997;3:261-271.Stephens JC et al. Am J Hum Genet. 1998;62:1507-1515.

~14%

~6%Rare

10%-15%

Rare

Rare

~10%

~10%

Rare

• 5%-14% of Caucasians of European descent carry CCR5 32 (1% are CCR5 32 homozygous)

• The origin of the CCR5 D32 allele has been traced to European geography ~1,000 years ago

Possible selection by pandemic pathogen, likely smallpox or bubonic plague

The Body PRO


17

CCR5 Wild Type and CCR5 32CCR5 Wild Type and CCR5 32

CCR5 CCR5 wild type wild type CCR5 CCR5 32 32

wt/wtwt/wt wt/wt/3232 3232//3232

NormalNormal HeterozygotesHeterozygotes HomozygotesHomozygotes

Click on slide for animation.

Liu R et al. Cell. 1996;86:367-377. Huang Y et al. Nat Med. 1996;2:1240-1243. Samson M et al. Nature. 1996;382:722-725. Michael NL et al. Nat Med. 1997;3:1160-1162. Dean M et al. Science. 1996;273:1856-1862. Eugen-Olsen J et al. AIDS. 1997;11:305-310.

• Normal CCR5 exp• Progression of HIV• Normal immune fx*

• Decreased CCR5 exp• Delayed prog. to AIDS/death• Normal immune fx*

• No CCR5 exp• Rare infection with X4 • Normal immune fx*

*fx = function

The Body PRO


18

Patients Heterozygous for CCR5 32 Have Slower Progression to AIDS and DeathPatients Heterozygous for CCR5 32 Have Slower Progression to AIDS and Death

Adapted from de Roda Husman A-M, et al. Ann Intern Med. 1997;127:882-890.

The Body PRO


19

The Tropism Assay

The Body PRO


20

Why is a Tropism Test Required?Why is a Tropism Test Required?

• CCR5 antagonists block entry of HIV that uses CCR5 only, no effect on HIV that uses CXCR4

• Presence of X4 HIV has been associated with more rapid CD4 decline and disease progression

• The effect a CCR5 antagonist will have in patients with R5/X4 HIV is unknown

• Regulatory agencies likely to require tropism assay prior to use of a CCR5 antagonist


The Body PRO


21

The Monogram Tropism AssayThe Monogram Tropism Assay

HIV-1 Expression Vector (pHIVlucU3)

Envelope Expression Vector (pHIVenv)

P A+

HIV envelope

a/b c/d

Indicator Gene

U5

gag

pol

Luciferase

P R env

P

R A+

gp120 gp41

Copyright © Monogram Biosciences. Reprinted with permission.

The Body PRO


22

HIV Entry Cell AssayHIV Entry Cell Assay

Adapted from Petropoulos CJ et al. Antimicrob Agents Chemother. 2000;44:920-928.

The Body PRO


23

HIV Entry Cell Assay: R5 HIV OnlyHIV Entry Cell Assay: R5 HIV Only


The Body PRO


24

HIV Entry Cell Assay: X4 HIV OnlyHIV Entry Cell Assay: X4 HIV Only


The Body PRO


25

HIV Entry Cell Assay: R5/X4 Tropic HIVHIV Entry Cell Assay: R5/X4 Tropic HIV


The Body PRO


26

Demonstration of R5 VirusDemonstration of R5 Virus

Light Generated CCR5 UseR5 Virus

No Light GeneratedNo CXCR4 UseNot an X4 VirusVirus

Virus

Virus



CCR5 CXCR4

The Body PRO


27

Demonstration of Dual VirusDemonstration of Dual Virus

Light is generated on both CCR5 and CXCR4 cell lines.

This is a DUAL virus.

Virus

Virus Virus

Virus

CCR5 CXCR4



The Body PRO


28

This population shows CCR5 AND CXCR4 co-receptor use.

This is a mixed population.

Demonstration of Mixed Virus PopulationDemonstration of Mixed Virus Population

CCR5 CXCR4



The Body PRO


29

What Is This Population?What Is This Population?

Most of these viruses are R5: Strong luciferase activity

Some are X4: Lower level luciferase activity

CXCR4CCR5



The Body PRO


30

Comparison of Original Tropism to Enhanced Sensitivity Tropism TestComparison of Original Tropism to Enhanced Sensitivity Tropism Test

Standard Tropism Assay

(August 2007 – June 2008)

Enhanced Tropism Assay(June 2008 – Present)

Sensitivity

• 100% if X4-using HIV > 10% of viral population

• 83% if X4-using HIV > 5% of viral population

• 100% if X4-using HIV > 0.3% of viral population

Plasma Volume Required 3 mL 3 mL

Shipping Requirement Dry ice Dry ice

Viral Load Requirement > 1,000 copies/mL > 1,000 copies/mL

Turnaround Time ~ 2 weeks ~ 2 weeks


The Body PRO


31

Coreceptor Tropism: Epidemiological Data

The Body PRO


32

Percentage of HIV Coreceptor UsagePercentage of HIV Coreceptor Usage

Study/Source Population N R5 X4 R5/X4

Homer cohort1 Naive 979 82% < 1% 18%

C & W cohort2 Naive 402 81% < 1% 19%

Demarest3 Naive 299 88% 0% 12%

Study 10264 Naïve 1428 85% < 1% 15%

TORO 1/26 Experienced 612 62% 4% 34%

ViroLogic5 Experienced > 2000 48% 2% 50%

ACTG 52117 Experienced 391 49% 4% 47%

MOTIVATE 1/28 Experienced 2560 56% 3% 41%

1Brumme ZL et al. J Infect Dis. 2005;192:466-474. 2Moyle GJ et al. J Infect Dis. 2005;191:866-872. 3Demarest J et al. ICAAC 2004; abstract H-1136. 4Waters L et al. ICAAC 2006; abstract H-1667.

5Whitcomb JM et al. CROI 2003; abstract 557. 6Paxinos EE et al. ICAAC 2002; abstract 2040.7Wilkin T et al. CROI 2006; abstract 655. 8Coakley E et al. International Workshop on Targeting HIV Entry 2006; abstract 8.

This table may not include all available reported data; majority of data are generated in the developed world (subtype B)

The Body PRO


33

Prevalence of X4 Phenotype by Baseline CD4+ CountPrevalence of X4 Phenotype by Baseline CD4+ Count

Adapted from Brumme ZL et al. J Infect Dis. 2005:192;466-74

Baseline CD4

• Coreceptor use was determined in 1191 patients starting HAART

• Patients with D/M virus had a poorer clinical profile than patients with R5 virus

– Median CD4+ T-cell count of 110 versus 290 cells/mm3 (P<.0001)

– HIV RNA of 175,000 versus 120,000 copies/mL (P=.0006)

• The following were associated with the prevalence of D/M-tropic virus:

– Low baseline CD4+ T-cell count

– High baseline HIV RNA

– CCR5-Δ32 deletion heterozygous patients

– Basic mutations at gp120-V3 codons 11 or 25

92.8

45.6

7.2

54.4

0

20

40

60

80

100<

25

25-4

9

50-9

9

100-

199

200-

349

350-

499

≥ 50

0

Per

cen

tag

e o

f P

atie

nts

R5

D/M

The Body PRO


34

Tropism in Naive Patients: Impact on CD4+ Decline and Response to TreatmentTropism in Naive Patients: Impact on CD4+ Decline and Response to Treatment


• 402 treatment-naive subjects had tropism tested

– 326 R5

– 73 D/M

– 3 X4

• 340 started HAART by August 2006

– 229 R5

– 60 D/M

– 51 excluded from analysis

The Body PRO


35

CD4+ Decline Before HAARTCD4+ Decline Before HAART


DAVG analysis (time weighted differences in average. Censored at HAART; Error bars are 95% CI

The Body PRO


36

Time to Viral SuppressionTime to Viral Suppression


Survival analysis; Cox’s proportional hazards regression to adjust for baseline HIV RNA and HAART

The Body PRO


37

Tropism Does Not Affect Response to HAARTTropism Does Not Affect Response to HAART


R5 TropicR5/X4 Tropic

P Value

CD4+ T-Cell Count Rise at 12 Months, Cells/mm3 (95% CI)

185 (166-204)

182 (145-219)

.812

CD4+ T-Cell Count Rise at 24 Months, Cells/mm3 (95% CI)

247 (227-267)

292 (254-330)

.482

Patients With VL < 50 Copies/mL at 12 Months, n (%)

168 (73.4) 47 (78.3) .509

Patients With VL < 50 Copies/mL at 24 Months, n (%)

166 (72.4) 41 (68.3) .67

CI = confidence interval

The Body PRO


38

Clinical Trials

The Body PRO


39

MOTIVATE 1&2: Trial DesignMOTIVATE 1&2: Trial Design

David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.

The Body PRO


40

MOTIVATE 1&2: Demographics and Baseline CharacteristicsMOTIVATE 1&2: Demographics and Baseline Characteristics


The Body PRO


41

MOTIVATE 1&2: Mean Change in HIV-1 RNA* From Baseline to Week 48MOTIVATE 1&2: Mean Change in HIV-1 RNA* From Baseline to Week 48


The Body PRO


42

MOTIVATE 1&2: Percentage of Patients With Undetectable HIV-1 RNA

MOTIVATE 1&2: Percentage of Patients With Undetectable HIV-1 RNA


The Body PRO


43

MOTIVATE 1&2: Mean Change in CD4+ Cell Count From Baseline to Week 48MOTIVATE 1&2: Mean Change in CD4+ Cell Count From Baseline to Week 48


• CD4+ cell count increases up to 48 weeks were more

favorable in both the maraviroc groups than the placebo group

• The mean change from baseline in CD4+ cell count* was:

• +61 cells/mm3 in the placebo + OBT

• +116 cells/mm3 in maraviroc QD + OBT

• +124 cells/mm3 in the maraviroc BID + OBT group

* Last observation carried forward approach used to impute missing values

The Body PRO


44MOTIVATE 1&2: Patients With HIV-1 RNA < 50 Copies/mL by Screening Viral Loads and Baseline CD4+ Cell Count (Week 48)

MOTIVATE 1&2: Patients With HIV-1 RNA < 50 Copies/mL by Screening Viral Loads and Baseline CD4+ Cell Count (Week 48)


The Body PRO


45

MOTIVATE 1&2: Safety Analyses Unadjusted For Duration of ExposureMOTIVATE 1&2: Safety Analyses Unadjusted For Duration of Exposure


The Body PRO


46MOTIVATE 1&2: Maximum Liver Function Test Values Over 48 Weeks Without Regard To Baseline

MOTIVATE 1&2: Maximum Liver Function Test Values Over 48 Weeks Without Regard To Baseline


The Body PRO


47MOTIVATE 1&2: Percentage of Adverse Events Occurring in ≥ 5% of Patients in Any Group, Unadjusted for Treatment Exposure

MOTIVATE 1&2: Percentage of Adverse Events Occurring in ≥ 5% of Patients in Any Group, Unadjusted for Treatment Exposure


The Body PRO


48

VICTOR-E1: Phase IIb Trial of Vicriviroc in Treatment-Experienced PatientsVICTOR-E1: Phase IIb Trial of Vicriviroc in Treatment-Experienced Patients

Barry Zingman et al. CROI 2008; abstract 39LB. Reprinted with permission.

The Body PRO


49

VICTOR-E1: Virologic Efficacy of Vicriviroc vs. Placebo at Week 48VICTOR-E1: Virologic Efficacy of Vicriviroc vs. Placebo at Week 48

No clinically significant differences in adverse events between VCV arms and placebo

Mea

n C

ha

ng

e in

HIV

-1 R

NA

Fro

m

BL

(lo

g1

0 co

pie

s/m

L)

-1.77

-0.79

-2.0

-1.8

-1.0

-0.8

VCV 30 mgn = 39

0

VCV 20 mgn = 40

Placebon = 35

-1.75Difference:

-0.96P = .0028

Difference:-0.98

P = .0017

-1.6

-1.4

-1.2

-0.6

-0.4

-0.2

20

30

70

10

40

50

60

80

90

100

5653

14Pat

ien

ts W

ith

HIV

-RN

A-1

<

50

cop

ies/

mL

(%

)

VCV 30 mgn = 22

0 VCV 20 mg

n = 21 Placebo

n = 5

Barry Zingman et al. CROI 2008; abstract 39LB. Reprinted with permission.

The Body PRO


50

MERIT: Maraviroc vs. Efavirenz in Treatment-Naive PatientsMERIT: Maraviroc vs. Efavirenz in Treatment-Naive Patients

Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.

Antiretroviral-naive patients infected with

CCR5-tropic HIV-1 and HIV-1 RNA

2000 copies/mL

(N = 740)

MVC 300 mg twice daily + ZDV/3TC(n = 360)

EFV 600 mg once daily + ZDV/3TC(n = 361)

Week 48 primary endpoint

Stratified by HIV-1 RNA < or 100,000 copies/mL and by Northern or Southern

Hemisphere

MVC 300-mg once-daily arm discontinued early due to failure to demonstrate noninferiority to efavirenz at end of phase IIB (Week 16)

Week 96

Stringent noninferiority margin: -10% for lower bound of 1-sided 97.5% CI

The Body PRO


51

MERIT: Patients With Viral Load < 400 and < 50 Copies/mL by Week 48 (ITT)MERIT: Patients With Viral Load < 400 and < 50 Copies/mL by Week 48 (ITT)


VL < 400 copies/mL VL < 50 copies/mL

Pat

ien

ts, %

Pat

ien

ts, %

Time (weeks) Time (weeks)

0

20

40

60

80

100

70.6%

73.1%69.3%

65.3%

0

20

40

60

80

100

EFV (n = 361) MVC (n = 360)

24 8 16 24 32 40 480 24 8 16 24 32 40 480

MVC was noninferior to EFV only for < 400 copies/mL endpoint (70.6% vs 73.1%)

CD4+ cell count increases were higher in patients receiving MVC vs EFV (+170 vs +144 cells/mm3)

The Body PRO


52

MERIT: Patients With Viral Load < 50 Copies/mL by Baseline Viral LoadMERIT: Patients With Viral Load < 50 Copies/mL by Baseline Viral Load


71.6 69.6 66.659.6

Pat

ien

ts,

%

BL VL < 100,000 Copies/mL

BL VL ≥ 100,000 Copies/mL

0

10

20

30

40

50

60

70

80

90

100

n =

211 204

150 156

MVCEFV EFV patients more likely

to discontinue due to AE

– Overall : 25.2%

– AE: 13.6%

– Efficacy: 4.2%

MVC patients more likely to discontinue due to lack of efficacy

– Overall: 26.9%

– AE: 4.2%

– Efficacy: 11.9%

The Body PRO


53

MERIT: Week 48 Safety AnalysesMERIT: Week 48 Safety Analyses

All Causalities and Severities EFV + CBVN=361

MVC + CBVN=360

Patients With Adverse Events 340 (94.2) 331 (91.9)

Patients With Grade 3 AEs, n (%) 66 (18.3) 51 (14.2)

Patients With Grade 4 AEs, n (%) 24 (6.6) 22 (6.1)

Patients With SAEs, n (%)† 46 (12.7) 41 (11.3)

Patients With Category C events, n (%) 12 (3.3) 6 (1.7)

Malignancies 16 (4.4) 10 (2.8)

Deaths†*, n (%) 1 1

AEs = adverse events; SAEs = serious adverse events †Based on all data through 21 June 2007*Deaths reported up to 28 days after stopping study drug; one additional death on EFV

within 28 days, date of death not captured in database


The Body PRO


54

MERIT: Viral Suppression at Week 48 by Baseline TropismMERIT: Viral Suppression at Week 48 by Baseline Tropism

20

30

70

0

10

40

50

60

80

90

100

69.3

54.6

7.1

n = 11 14

68.0

339 331

Pa

tie

nts

Wit

h V

L <

50

c/m

L a

t W

ee

k 4

8 (

%)

EFV

MVC

69.365.3

Tropism at Screening (Overall)

361 360

Tropism at Baseline

(R5)

Tropism at Baseline

(D/M)

• Change in detected HIV-1 tropism from R5 at screening to D/M at BL and potentially adherence may explain some treatment failures on MVC

– 3.5% of patients experienced change in detected tropism between screening and BL

– 50.0% of patients with R5 virus at BL and without confirmed X4 at failure had plasma MVC concentrations below limit of detection

• Tropism changes more common in patients with lower mean CD4+ cell count at screening as well as with clade B or other/undetermined HIV-1 subtype vs clade C

Jayvany Heera et al. CROI 2008; abstract 40LB. Reprinted with permission.

The Body PRO


55

MERIT: Fewer Lipid Effects With Maraviroc vs. Efavirenz at Week 48MERIT: Fewer Lipid Effects With Maraviroc vs. Efavirenz at Week 48

Edwin DeJesus et al. CROI 2008; abstract 929. Reprinted with permission.

The Body PRO


56

Questions

The Body PRO


57

Main Discussion QuestionsMain Discussion Questions

• Does the use of CCR5 antagonists prevent the immune system from mounting an effective defense against West Nile virus infection and its complications?

• Is the new enhanced tropism test sensitive enough to more accurately identify patients who may have some X4-tropic virus?

• Is there going to be a second clinical trial of maraviroc in treatment-naive patients that uses the more sensitive assay?

• Who is the best patient to use a CCR5 antagonist?

The Body PRO


58

Case Studies

The Body PRO


59

Case 1

The Body PRO


60

• 37-year-old male with extensive ART history dating back to 1995

• Past ARVs included all NRTIs except ddC, all NNRTIs except DLV, and all PIs except FPV and full-dose RTV

• History of “buffalo hump” while taking IDV; removed with liposuction

• Former participant in the RESIST 1 trial (2003-2005); ART regimen—TPV/r, TDF-FTC, EFV, ddI and ENV

– HIV-1 RNA decreased from 510,000 to 5,200 copies/mL

– CD4+ increased from 75 to 120 cells/mm3

– Failed to achieve HIV-1 RNA < 50 copies/mL

• Discontinued ENF after 2.5 years due to lack of any available injection sites

Experienced low-level viremia prior to discontinuing ENF

Case 1: Patient HistoryCase 1: Patient History

The Body PRO


61

• Patient also a participant in the MOTIVATE 1 trial

• Randomized to placebo with OBR* of: SQV/RTV, TDF/FTC, ddI, EFV

– IDV/RTV predicted to have full activity by resistance testing, but refused by patient due to prior history of lipodystrophy (buffalo hump)

• After eight weeks, VL 734,000 copies/mL (from 1,162,500 copies/mL), CD4+ 75 cells/mm3 (7.8%)

– < 0.5 log10 decrease, thus considered a virologic failure

• Switched to open-label MVC 150 mg BID, IDV/RTV, TDF/FTC, ddI

– Patient achieved HIV-1 RNA < 50 c/mL by week 24 and CD4+ cells increase to 155/mm3 (22%); maintained for the next six months

– At this time, patient develops bilateral hip pain, is diagnosed with advanced aseptic necrosis of the right hip joint and undergoes right total hip replacement surgery

* Optimized Background Regimen

Case 1: Patient History ContinuedCase 1: Patient History Continued

The Body PRO


62

A. No

B. Not Sure

C. Yes

Case 1: Would You Consider Changing the Patient’s Regimen at This Time?Case 1: Would You Consider Changing the Patient’s Regimen at This Time?

The Body PRO


63

Case 1: Case ProgressionCase 1: Case Progression

• You convince the patient to remain on his current regimen to

maintain his HIV RNA < 50 copies/mL

• HIV-1 RNA increases to 580 copies/mL (repeat 1,280 copies/mL)

(You suspect that patient’s confidence in his ART regimen has

waned due to his hip surgery.)

• You determine that a change in regimen is indicated and order a

phenotype and tropism assay

The Body PRO


64

Case 1: Results of a Tropism AssayCase 1: Results of a Tropism Assay

Tropism Result


The Body PRO


65

Case 1: Results of Patient’s Resistance TestCase 1: Results of Patient’s Resistance Test

The Body PRO


66

Case 1: Should a Boosted PI Be Included in the Patient’s New Regimen?Case 1: Should a Boosted PI Be Included in the Patient’s New Regimen?

A. Yes

B. No

C. Not sure

The Body PRO


67

Case 1: If You Included a PI, Which Would You Use?Case 1: If You Included a PI, Which Would You Use?

A. Atazanavir + ritonavir

B. Darunavir + ritonavir

C. Fosamprenavir + ritonavir

D. Lopinavir/ritonavir

E. Saquinavir + ritonavir

F. Tipranavir + ritonavir

G. No PIs

The Body PRO


68

Case 1: Would You Switch the NRTI Component of the Patient’s Regimen?Case 1: Would You Switch the NRTI Component of the Patient’s Regimen?

A. No

B. Yes, I would drop ddI

C. Yes, I would drop tenofovir/FTC

D. Yes, I would not use NRTIs in his new regimen

The Body PRO


69

Case 1: Would You Include Raltegravir in the Patient’s New Regimen?Case 1: Would You Include Raltegravir in the Patient’s New Regimen?

A. Yes

B. No

C. Not sure

The Body PRO


70

Case 1: Would You Include Etravirine in the Patient’s New Regimen?Case 1: Would You Include Etravirine in the Patient’s New Regimen?

A. Yes

B. No

C. Not sure

The Body PRO


71

Case 1: Etravirine Resistance InformationCase 1: Etravirine Resistance Information

2008 Update

• Clinical cut offs (CCOs) determined for

phenotypic sensitivity

• Four additional etravirine RAMS identified

(17 total)

• Weighted scoring system developed

The Body PRO


72

Case 1: Response According to Phenotypic Etravirine CCOsCase 1: Response According to Phenotypic Etravirine CCOs

Etravirine

CCO

Proportion of Patients With Viral Load < 50 Copies/mL (DUET Week 24),

% (n)

Decrease in log10 Viral Load From Baseline (DUET Week 24),

Mean (SE)

< 3 71 (190/269) –2.67 (1.03)

3–13 50 (37/74) –2.39 (1.21)

> 13 37 (22/60) –1.79 (1.42)

Overall Placebo

36 (149/414) –1.51 (1.42)

The highest responses occurred in patients with a fold change < 3

Virological responses were greater than placebo in patients with a fold change < 13

The highest responses occurred in patients with a fold change < 3

Virological responses were greater than placebo in patients with a fold change < 13

The Body PRO


73

00

1010

2020

3030

4040

5050

6060

7070

8080

no muta

tion*

no muta

tion*

L100I

L100I

G190A

G190A

V90I

V90I

E138A

E138A

Y181I

Y181I

M23

0L

M23

0L

A98G

A98G

Y181C

Y181C

K101E

K101E

K101P

K101P

K101H

K101H

V179D

V179D

V106I

V106I

V179T

V179T

Y181V

Y181V

G190S

G190S

V179F

V179F

34 115 4 59 110 26 5 24 8 6 14 7Pat

ien

ts w

ith

co

nfi

rmed

VL

P

atie

nts

wit

h c

on

firm

ed V

L

<50

HIV

-1 R

NA

co

pie

s/m

L (

%)

<50

HIV

-1 R

NA

co

pie

s/m

L (

%)

Pat

ien

ts w

ith

co

nfi

rmed

VL

P

atie

nts

wit

h c

on

firm

ed V

L

<50

HIV

-1 R

NA

co

pie

s/m

L (

%)

<50

HIV

-1 R

NA

co

pie

s/m

L (

%)

*no detectable baseline NNRTI RAM from the list of 44; Dashed line indicates 75% of response in patients without NNRTI RAMs

22 12 8 53 9 n=n=

NewNew NewNewNewNew

NewNew

52

Effect of the Etravirine RAMs 2008(17) on Virological ResponseEffect of the Etravirine RAMs 2008(17) on Virological Response

The Body PRO


74

The Body PRO


75

§§

Y181IY181IY181VY181VK101PK101PL100IL100IY181CY181CM230LM230LE138AE138AV106IV106IG190SG190SV179FV179FV90IV90I

V179DV179DK101EK101EK101HK101HA98GA98GV179TV179TG190AG190A

§V179F was never present as single Etravirine RAM (always with Y181C)

Weight for Individual Mutations

Weight for Individual Mutations

Add TogetherAdd TogetherAdd TogetherAdd Together

Total Weighted

Score

Total Weighted

Score

33

2.52.52.52.51.51.51.51.51111111

Case 1: Weighting of 2008 Etravirine RAMsCase 1: Weighting of 2008 Etravirine RAMs

The Body PRO


76Case 1: Relation Between the 2008 Etravirine Genotypic Score and the Virological Response (< 50 Copies/mL At Week 24)

Case 1: Relation Between the 2008 Etravirine Genotypic Score and the Virological Response (< 50 Copies/mL At Week 24)

The Body PRO


77

Case 1: Would You Continue Maraviroc in the Patient’s New Regimen?Case 1: Would You Continue Maraviroc in the Patient’s New Regimen?

A. Yes

B. No

C. Not sure

The Body PRO


78

Case 1: Case ProgressionCase 1: Case Progression

• On his new regimen of MVC, DRV/r, ETV, RAL and

TDF/FTC his HIV-1 RNA remains < 50 copies/mL and

CD4+ cells slowly rise to 280 cells/mm3 (28%) over the

next eight months

• His left hip pain and MRI of it stabilize showing no further

progression

• He continues to tolerate his ART regimen well

The Body PRO


79

Case 2

The Body PRO


80

Case 2: Patient HistoryCase 2: Patient History

• 45-year-old man

• Diagnosed with HIV-1 in 1994 when he presented

with cutaneous Kaposi’s Sarcoma

– CD4+ cell count: 360 cells/mm³

– HIV-1 RNA test not available in 1994

• PMH: mild hypertension, controlled with diuretics

• FMH: diabetes, CVD

The Body PRO


81

Case 2: Patient ARV HistoryCase 2: Patient ARV History

• 1994: ZDV monotherapy

– Discontinued six months later due to anemia and

nausea

• ddI monotherapy

– Tolerated for nine months, then developed

pancreatitis

• Discontinued ARVs: KS quiescent, CD4+ cell count

stable at 360 cells/mm³

The Body PRO


82

Case 2: Patient History on HAART RegimensCase 2: Patient History on HAART Regimens

• Starting in 1996, various regimens including

– d4T + 3TC + SQV

– d4T + 3TC + NFV

– ABC + 3TC + EFV

– d4T + 3TC + LPV/RTV

– TDF + 3TC + LPV/RTV + FPV

• Intolerant to ZDV (anemia), ddI (pancreatitis), d4T

(peripheral neuropathy), NFV (diarrhea), dual-

boosted PIs (GI symptoms)

The Body PRO


83

Case 2: Patient History on HAART Regimens (Continued)Case 2: Patient History on HAART Regimens (Continued)

• Reached HIV-1 RNA < 400 copies/mL but never < 50 copies/mL

• First genotypic assay (after d4T + 3TC + SQV)

– RT gene: M41L, L74V, M184V, T215Y

PR gene: L10I, L63P, L90M

• Second genotypic assay (after ABC + 3TC + EFV)

– RT gene: M41L, L74V, K101P, K103N, Y181C, M184V, T215Y,

K219R

– PR gene: L10I, D30D/N, L63P, G73T, V77I, L90M

• CD4+ cell counts rose and fell, nadir: 240 cells/mm³

The Body PRO


84

Case 2: Current History: 2008Case 2: Current History: 2008

• Regimen: TDF + 3TC + LPV/RTV

– HIV-1 RNA: 1,500-2,500 copies/mL

– CD4+ cell count: 300-350 cells/mm³

• Hypertension poorly controlled with ACE

inhibitor/diuretic + β-blocker

• Fasting glucose > 180 mg/dL

• Serum creatinine 1.9 mg/dL (baseline 1.0-1.4 mg/dL)

• Patient wants to consider a new regimen

The Body PRO


85

Case 2: Drug Resistance Test ResultsCase 2: Drug Resistance Test Results

The Body PRO


86

Case 2: Viral Tropism AssayCase 2: Viral Tropism Assay

Tropism Result


The Body PRO


87

Darunavir Resistance Mutations

• 11I, 32I, 33F, 47V, 50V, 54L/M, 74P, 76V, 84V, 89V

Tipranavir Resistance Mutations

• 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, 84V

Case 2: Would You Use Darunavir or Tipranavir in the New Regimen?Case 2: Would You Use Darunavir or Tipranavir in the New Regimen?

A. Yes, I would use darunavir + ritonavir

B. Yes, I would use tipranavir + ritonavir

C. Yes, I would use both

D. No, I would not use either

The Body PRO


88

Case 2: Would You Use NRTIs inThis Regimen?Case 2: Would You Use NRTIs inThis Regimen?

Phenotype

• NRTIs: susceptible to TDF, ZDV, d4T

• NNRTIs: resistant to DLV, EFV, NVP

• PIs: partially susceptible to DRV

A. Yes

B. No

The Body PRO


89Case 2: How Many Additional Active Agents Does This Patient Need to Achieve HIV-1 RNA < 50 Copies/mL?

Case 2: How Many Additional Active Agents Does This Patient Need to Achieve HIV-1 RNA < 50 Copies/mL?

A. 1

B. 2

C. 3

D. Individualized for patient’s viral resistance

The Body PRO


90

BENCHMRK-1 and -2 with virologic failures carried forward

5

PSS GSS

63

34

61

41

87

79

57

71

56

37

71

6

44

0 1 ≥ 2 0 1 ≥ 2Overall

Efficacy Data

Pat

ien

ts W

ith

VL

< 5

0 c/

mL

At

Wee

k 2

4 b

y P

SS

/GS

S o

f O

BT

* (%

)

0

20

40

60

80

100 Raltegravir Placebo

BENCHMRK 1&2: Response by Number of Active Agents in OBT (24 Weeks)BENCHMRK 1&2: Response by Number of Active Agents in OBT (24 Weeks)

Adapted from PN Kumar et al. EACS 2007; abstract P7.2/06.

The Body PRO


91

DUET 1&2: Response by Number of Active Agents in OBT (24 Weeks)DUET 1&2: Response by Number of Active Agents in OBT (24 Weeks)

Anthony Mills and Christine Katlama et al. IAS 2007, abstract WESS204. Reprinted with permission.

The Body PRO


92

MOTIVATE 1&2: Response by Number of Active Agents in OBT (24 Weeks)MOTIVATE 1&2: Response by Number of Active Agents in OBT (24 Weeks)

0

20

40

60

80P

atie

nts

(%

)

3 or More 2 1 0

MVC BID + OBT

MVC QD + OBT

Placebo + OBT

3

58 61

5355

19

52

43 43

9

29

18

N= 121 132 64 104 88 59 134 130 44 56 51 35

Number of Active Drugs in OBT

Adapted from Mark Nelson et al. CROI 2007; abstract 104aLB. Adapted from Jacob Lalezari et al. CROI 2007; abstract 104bLB.

The Body PRO


93

Case 2: Which Regimen Would You Choose?Case 2: Which Regimen Would You Choose?

A. tenofovir/emtricitabine, darunavir + ritonavir,

etravirine, maraviroc

B. tenofovir/emtricitabine, darunavir + ritonavir,

maraviroc, raltegravir

C. tenofovir/emtricitabine, darunavir + ritonavir,

etravirine, raltegravir

D. tenofovir/emtricitabine, darunavir + ritonavir,

etravirine, maraviroc, raltegravir

E. Something else

The Body PRO


94

Case 2: EvolutionCase 2: Evolution

• New regimen: TDF/FTC + DRV/RTV + ETR + MVC + RAL

• HIV-1 RNA at 6 weeks: < 50 copies/mL

• CD4+ cell count at 10 weeks: 420 cells/mm³

• Serum creatinine ↑ to 2.7 mg/dL (from 1.9 mg/dL);

24-hour ClCr: 48 mL/min

The Body PRO


95

Case 2: What Would You Do Now With the NRTI Portion of the Regimen?

Case 2: What Would You Do Now With the NRTI Portion of the Regimen?

A. Continue TDF/FTC QD

B. Continue TDF/FTC but decrease the dose to QOD

C. Change TDF/FTC to ABC/3TC

D. Discontinue TDF/FTC

The Body PRO


96

Case 2: EvolutionCase 2: Evolution

• Tenofovir discontinued due to concerns about

decreased renal function

• New regimen: DRV/RTV + ETR + MVC + RAL

• HIV-1 RNA < 50 copies/mL

• CD4+ count ↑ to 550 cells/mm³ (from 420 cells/mm³)

• Serum creatinine to 1.8 mg/dL (from 2.7 mg/dL);

24-hour ClCr: ↑ to 80 mL/min (from 24 mL/min)

CCR5 Antagonists and Tropism Testing in Clinical Practice This activity is supported by educational...

Documents

Transcript of CCR5 Antagonists and Tropism Testing in Clinical Practice This activity is supported by educational...