HAART for the treatment experienced patient Prema Menezes PA-C

HAART for the treatment HAART for the treatment experienced patientexperienced patient

Prema Menezes PA-CPrema Menezes PA-C

Treatment FailureTreatment FailureDefinition and ReasonsDefinition and Reasons

ImmunologicImmunologic No increase in CD4 Decrease in CD4

ClinicalClinical HIV related event at

least 3 months after ART

VirologicVirologic HIV RNA >400

(24wks), >50 (48 weeks)

VirusVirus Resistant

Drug TherapyDrug Therapy Sub optimal Sub therapeutic

PatientPatient Non adherence

Managing virologic failure:Managing virologic failure: make a distinction make a distinction between limited, intermediate, and extensive between limited, intermediate, and extensive prior treatment exposure and resistanceprior treatment exposure and resistance

Goal of treatment:Goal of treatment: re-establish maximal re-establish maximal virologic suppressionvirologic suppression

March 2004: Preservation of immune function and prevention of clinical progression

May 2006: Re-suppress HIV RNA levels maximally and prevent further selection of resistance mutations

DHHS Treatment GuidelinesDHHS Treatment Guidelines

New AgentsNew Agents

Protease InhibitorsProtease Inhibitors Tipranavir Darunavir

NNRTIsNNRTIs Etravirine

Integrase InhibitorIntegrase Inhibitor Raltegravir

CCR5 InhibitorCCR5 Inhibitor Maraviroc

Limited Treatment FailureLimited Treatment Failure

Case 1: First Line Virologic FailureCase 1: First Line Virologic Failure

31 yo woman s/p bilateral tubal ligation began 31 yo woman s/p bilateral tubal ligation began [fdc ZDV/3TC] + EFV 36 months ago[fdc ZDV/3TC] + EFV 36 months ago

Initial CD4 = 162; VL = 56,000Initial CD4 = 162; VL = 56,000 After starting HIV therapy, CD4 increased to 365 After starting HIV therapy, CD4 increased to 365

and VL fell to 340 and then to < 50 c/mLand VL fell to 340 and then to < 50 c/mL Difficulty taking medication over the past 2 Difficulty taking medication over the past 2

months due to relapse of substance abusemonths due to relapse of substance abuse Now returns with weight loss and thrushNow returns with weight loss and thrush

What is your next step?What is your next step?

1.1. Obtain HIV RNA, CD4, continue therapy and Obtain HIV RNA, CD4, continue therapy and have her return within a monthhave her return within a month

2.2. Obtain HIV RNA, CD4, stop therapy and have Obtain HIV RNA, CD4, stop therapy and have her return within a monthher return within a month

3.3. Obtain a resistance testObtain a resistance test

4.4. Choice 1 and 3Choice 1 and 3

5.5. Choice 2 and 3Choice 2 and 3

GS934: Resistance Development Through Week 96

TDF + FTC(n = 244)

ZDV/3TC(n = 243)

Patients genotyped, n 14 29

Wild-type, n 4 7

Any resistance, n 10 20

EFV resistance mutations, n

10 18

M184V/I, n 2 9*

TAMs, n 0 1

K65R, n 0 0

Gallant J, et al IAC 2006. Abstract TUPE0064.Comparative trial of ZDV/3TC/EFV vs. TDF/FTC/EFV in treatment naïve patients

KLEAN: Resistance FPV/r vs. LPV/rKLEAN: Resistance FPV/r vs. LPV/r(with ABC/3TC FDC)(with ABC/3TC FDC)

Eron JJ Jr, Lancet 2006.

FPV/r, n

LPV/r, n

Confirmed virologic failuresConfirmed virologic failures 1616 2424

Unable to sequenceUnable to sequence 22 33

No treatment-emergent mutationsNo treatment-emergent mutations 99 1414

Treatment-emergent mutations

TAMs (M41M/L)TAMs (M41M/L) 00 11

3TC-associated mutations (M184I, M184V, 3TC-associated mutations (M184I, M184V, M184M/V)M184M/V) 33 44

NNRTI-associated mutations (V106V/A)NNRTI-associated mutations (V106V/A) 00 22

PI-associated mutations: all minor (I54I/L, I93I/L, PI-associated mutations: all minor (I54I/L, I93I/L, K20K/R, I62I/V)K20K/R, I62I/V) 33 22


CD4 now = 98 and VL = 29,000CD4 now = 98 and VL = 29,000 Genotype reveals Genotype reveals 184V184V and and 103N103N mutations mutations ART is discontinued and PCP prophylaxis ART is discontinued and PCP prophylaxis

prescribed. The patient enters in-patient detox prescribed. The patient enters in-patient detox and 6 weeks later returns to restart HIV and 6 weeks later returns to restart HIV medications. medications.

She begins a series of adherence counseling She begins a series of adherence counseling sessionssessions

What ART to use?What ART to use?

1.1. Atazanavir + NRTIsAtazanavir + NRTIs

2.2. Atazanavir/ritonavir + NRTIsAtazanavir/ritonavir + NRTIs

3.3. Lopinavir/ritonavir + NRTIsLopinavir/ritonavir + NRTIs

4.4. Fos-Amprenavir/ritonavir + NRTIsFos-Amprenavir/ritonavir + NRTIs

5.5. [fdc ZDV/3TC/ABC] + tenofovir[fdc ZDV/3TC/ABC] + tenofovir

6.6. OtherOther


If you chose NRTI + PI – which NRTIsIf you chose NRTI + PI – which NRTIs

1.1. Abacavir + 3TC or FTCAbacavir + 3TC or FTC

2.2. Abacavir + tenofovirAbacavir + tenofovir

3.3. Didanosine plus 3TC or FTCDidanosine plus 3TC or FTC

4.4. Didanosine plus tenofovirDidanosine plus tenofovir

5.5. Tenofovir + 3TC or FTCTenofovir + 3TC or FTC

6.6. Tenofovir, ZDV + 3TC or FTCTenofovir, ZDV + 3TC or FTC

7.7. Something elseSomething else

3TC Alone vs Treatment Interruption3TC Alone vs Treatment Interruption

Castagna et al. AIDS 20:795 2006

-250

-200

-150

-100

-50

0BL 4 8 12 16 20 24

Weeks

3TCTI

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

BL 4 8 12 16 20 24Weeks

3TCTI

Mean CD4+ Decrease (ITT) Mean VL Increase (ITT)

In contrast to treatment interruption arm, 3TC alone resulted in: No recovery in RC No increase in RT mutations No reversion of PR mutations

Effects of M184V on other NRTIEffects of M184V on other NRTI Increases in susceptibilityIncreases in susceptibility

Zidovudine Stavudine Tenofovir

Minimal Change or decrease in susceptibilityMinimal Change or decrease in susceptibility Abacavir Didanosine

− Both of these agents can select for M184V in vivo.

First Line Virologic FailureFirst Line Virologic Failure

Good newsGood news Lots of treatment options

ConsiderationsConsiderations Keep 3TC/FTC in new regimen Genotype Resistance appears to be limited in first

HAART failure

ART Options for Extensively ART Options for Extensively Treatment Experienced PatientsTreatment Experienced Patients

Newer AgentsNewer Agents

DarunavirDarunavir

TipranavirTipranavir

*Based on IAS-USA March 2003 at start of studies; updated to October 2004 list during studiesVL = viral load, OBR = optimized background regimen (NRTIs ± enfuvirtide [ENF])

Investigator-Investigator-selected CPI(s) selected CPI(s) + OBR (without + OBR (without

NNRTIs)NNRTIs)

POWER 1 and 2 trials: designPOWER 1 and 2 trials: design

Investigator-selected CPI(s) + OBR

TMC114/r 400/100mg qd + OBR

TMC114/r 800/100mg qd + OBR

TMC114/r 400/100mg bid + OBR

TMC114/r 600/100mg bid + OBR

• PI-, NRTI- and NNRTI-PI-, NRTI- and NNRTI-experiencedexperienced

• ≥≥1 PI mutation1 PI mutation* *

• PI-based regimenPI-based regimen

• VL >1,000 copies/mLVL >1,000 copies/mL

Randomization

• The highest dose of TMC114/r (600/100mg bid) provided the greatest virologic response in the Week 24 analysis and is the selected dose for treatment-experienced patients

• The combined 48-week efficacy and safety interim analysis at this dose versus CPI(s) is reported here

Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104

POWER 1 and 2: BL characteristicsPOWER 1 and 2: BL characteristicsTMC114/r TMC114/r

600/100mg bid600/100mg bidn=131n=131

CPI(s)CPI(s)n=124n=124

DemographicsDemographicsGender (% male)Gender (% male)Mean age (years)Mean age (years)

89894444

88884444

Disease characteristicsDisease characteristicsCDC class C (%)CDC class C (%)Mean duration of infection (years)Mean duration of infection (years)Mean VL (logMean VL (log1010 copies/mL; SD) copies/mL; SD)Median CD4 count (cells/mmMedian CD4 count (cells/mm33; range); range)

363612.012.0

4.61 (0.69)4.61 (0.69)153 (3–776)153 (3–776)

434312.912.9

4.49 (0.78)4.49 (0.78)163 (3–1,274)163 (3–1,274)

Previous ARV experiencePrevious ARV experienceMean duration (months; SD)Mean duration (months; SD)

NRTINRTINNRTINNRTIPIPIFusion inhibitor (ENF)Fusion inhibitor (ENF)

100 (48)100 (48)28 (24)28 (24)65 (29)65 (29)14 (11)14 (11)

106 (45)106 (45)23 (15)23 (15)65 (28)65 (28)11 (9)11 (9)

Genotypic and phenotypic informationGenotypic and phenotypic informationMedian primary PI mutations* (n; range)Median primary PI mutations* (n; range)Median PI resistance-associated mutations* (n; range)Median PI resistance-associated mutations* (n; range)≥≥1 sensitive1 sensitive†† PI available (%) PI available (%) ≥≥1 sensitive1 sensitive†† NRTI in OBR (%) NRTI in OBR (%)

3 (0–5)3 (0–5)8 (0–12)8 (0–12)

36367272

3 (0–5)3 (0–5)8 (1–13)8 (1–13)

39397373

ARV = antiretroviral; SD = standard deviation*IAS-USA October 2004, †susceptibility was determined by Antivirogram®


POWER 1 and 2: patients with VL <50 copies/mL POWER 1 and 2: patients with VL <50 copies/mL over time to Week 48 (ITT-TLOVR)over time to Week 48 (ITT-TLOVR)

TMC114/r 600/100mg bidCPI(s)

45%*(n=59/131)

12% (n=15/124)

46%* (n=50/110)

10% (n=12/120)

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32 36 40 44 48Weeks

Pat

ient

s (%

)

12

*p<0.001 vs CPI(s)ITT = intent-to-treat, TLOVR = time to loss of virologic response

Not all patients had reached Week 48 at the time of analysis; patients who had not reached Week 48 were censored at their last available visit

TMC114/r n= 131 131 131 130 120 110CPI(s) n= 124 124 124 124 121 120


POWER 1 and 2: virologic response defined as VL POWER 1 and 2: virologic response defined as VL

<50 copies/mL by BL subgroups at Week 48<50 copies/mL by BL subgroups at Week 48 (ITT-TLOVR)(ITT-TLOVR)P

atie

nts

(%

)

70

60

50

40

30

20

10

0ENF used

(naïve)ENF used

(non-naïve)ENF

not used


21

/36

1/1

5 7/7

0

0 sensitive ARV

in OBR

≥1 sensitive ARV

in OBR5

/25

0/1

8

44

/82

11

/10

0

4/3

5 2/1

3

27

/61

ARV = antiretroviral drug; OBR = optimized background regimen; ENF = enfuvirtide.Use of ENF was not randomized in POWER 1 and 2.


POWER 1 and 2: mean change from BL in CD4 POWER 1 and 2: mean change from BL in CD4 count over time to Week 48 (LOCF)count over time to Week 48 (LOCF)


92*102*

17 19

*p<0.001 vs CPI(s)LOCF = last observation carried forward

2

20

40

60

80

100

120

140

0 4 8 12 16 20 24 28 32 36 40 44 48

Weeks

Mea

n c

han

ge

in C

D4

cou

nt

(cel

ls/m

m3 )

0

TMC114/r n= 131 131 131 130 120 110CPI(s) n= 124 124 124 124 121 120


Baseline Resistance and Response to DRV/rBaseline Resistance and Response to DRV/r

Baseline fold-change was strongest Baseline fold-change was strongest predictor of Week 24 responsepredictor of Week 24 response

11 mutations associated with 11 mutations associated with reduced responsereduced response V11I, V32I, L33F, I47V, I50V,

I54L, I54M, G73S, L76V, I84V and L89V

73% of pts had 2 of these mutations

DeMeyer S, et al. Resistance Workshop 2006. Abstract 73.

Δ V

L a

t W

k 24

, (N

C =

F)

FC 10(n = 255)

(70% of pts)

FC 11-40(n = 65)

(17% of pts)

FC > 40(n = 48)

(13% of pts)

VL < 50 c/mLat Wk 24 50% 25% 13%

Baseline DRV FC

No. of BL No. of BL mutationsmutations 00 11 22 33 44

% with VL % with VL < 50, Wk 24< 50, Wk 24 6464 5050 4242 2222 1010 -2.04

-1.08

-0.78

-2.5

-2.0

-1.5

-1.0

-0.5

0

POWER 1 and 2: observed incidence of the POWER 1 and 2: observed incidence of the most common treatment-emergent AEs* most common treatment-emergent AEs*

during treatment, regardless of severity and during treatment, regardless of severity and causalitycausality

*AEs = adverse events reported in ≥10% of patients and excluding ENF-associated injection site reaction (TMC114/r: 28%; CPI: 22%)

80

70

60

50

40

30

20

10

0Diarrhea Nausea Headache Naso-

pharyngitisFatigue

Pat

ien

ts (

%)

Pyrexia


Upper respiratory

tract infection

Herpes simplex


TITANTITAN DRV/RTV vs LPV/RTV in DRV/RTV vs LPV/RTV in

Tx-Experienced, LPV-Naive PatientsTx-Experienced, LPV-Naive Patients

Intermediate treatment experience Intermediate treatment experience Stratified by treatment site, NNRTI in OBR, HIV Stratified by treatment site, NNRTI in OBR, HIV

RNA > or < 50,000 c/mLRNA > or < 50,000 c/mL

Darunavir/ritonavir met criteria for superiority to Darunavir/ritonavir met criteria for superiority to lopinavir/ritonavir in proportions with HIV-1 RNA lopinavir/ritonavir in proportions with HIV-1 RNA < 400 copies/mL and < 50 copies/mL at week 48< 400 copies/mL and < 50 copies/mL at week 48

Safety comparable between darunavir/ritonavir Safety comparable between darunavir/ritonavir and lopinavir/ritonavirand lopinavir/ritonavir

The Randomized Evaluation of The Randomized Evaluation of Strategic Intervention in Multidrug Strategic Intervention in Multidrug

Resistant Patients With Resistant Patients With Tipranavir (RESIST) Tipranavir (RESIST)

Proportion of patients with viral load <400 and <50 copies/ml at week 96

Resist 1 and 2 – 96 weeks

Resist 1 and 2 – 96 weeks

Proportion of patients who took Enfuvirtide as a new drug and achieved virologic suppression.

TPV/r (%) CPI/r (%)

Grade 3/4 AST 6.1 1.8

Grade 3/4 ALT 9.7 4.2

Grade 3/4 total cholesterol 2.1 0.4

Grade 3/4 triglycerides 24.9 13.0

Safety - laboratory Safety - laboratory abnormalitiesabnormalities

Patients with Grade 3/4 elevations in liver enzymes or lipids Patients with Grade 3/4 elevations in liver enzymes or lipids were able to continue TPV/r therapy without developing were able to continue TPV/r therapy without developing clinical AEsclinical AEs

Highly Treatment ExperiencedPatients

Highly Treatment ExperiencedHighly Treatment Experienced

48 yo white man HIV + since 1991 (CD4 180)48 yo white man HIV + since 1991 (CD4 180) Received ZDV from 1994 to 1996, added 3TC Received ZDV from 1994 to 1996, added 3TC

then indinavirthen indinavir VL on this regimen was initially BDL and CD4 VL on this regimen was initially BDL and CD4

rose to 300 cells over two years. rose to 300 cells over two years. VL rose to 5,600 then 10,100, CD4 was 390.VL rose to 5,600 then 10,100, CD4 was 390. In 2000 treatment was interrupted VL peaked at In 2000 treatment was interrupted VL peaked at

386,000 and CD4 fell to 220386,000 and CD4 fell to 220

Case: Multi-drug ResistanceCase: Multi-drug Resistance

Over several years he was on a series of Over several years he was on a series of regimens:regimens: EFV, SQV/RTV, d4T Abacavir, ddI, LPV/r TDF, FTC, LPV/r plus SQV HIV RNA rebound was eventually observed on each regimen

He feels well and has had no AIDS defining He feels well and has had no AIDS defining illness. His current CD4 is 310 and his VL illness. His current CD4 is 310 and his VL repeated several times is between 10,000 and repeated several times is between 10,000 and 15,000 on therapy15,000 on therapy


Given long treatment history with only Given long treatment history with only intermittent suppression of HIV RNA to BDL you intermittent suppression of HIV RNA to BDL you order a genotypeorder a genotype This is the test available to you

RT mutations include:RT mutations include: 41L, 74V, 118I, 184V, 215Y and 219Q

Protease mutations include:Protease mutations include: 10V, 20R, 33F, 46L,54V, 82A, 84V and 90M


What will you do at this point?What will you do at this point?1. Change to > 1 NRTI, tipranavir/r and enfuvirtide

2. Change to > 1 NRTI, darunavir/r and enfuvirtide

3. Interrupt therapy and after 6 months begin > 1 NRTI, darunavir/r and enfuvirtide

4. Continue current therapy

5. Holding regimen

Need to Know Likelihood of Need to Know Likelihood of SuccessSuccess

CD4 310, clinically stableCD4 310, clinically stable

Let’s Look at GenotypeLet’s Look at Genotype

RT mutations include:RT mutations include:41L, 74V, 118I, 184V, 215Y and 219Resistance predicted to 3TC, FTC, ddI, ABC,

ZDVIntermediate activity to TDF and d4T

Protease mutations include:Protease mutations include:10V, 20R, 33F, 46L,54L, 82A, 84V and 90M

TPV Score and Treatment ResponseTPV Score and Treatment Response

Valdez H, et al. Resistance Workshop 2005. Abstract 27.

-2

-1

0

-3

Med

ian

Ch

ang

e in

VL

at

Wk

24*

(lo

g10

co

pie

s/m

L)

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

TPV Score Mutations10V, 13V, 20M/R/V, 33F, 35G,

36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, 84V

10V, 20R, 33F, 46L,54L, 82A, 84V, and 90M

Baseline Resistance and Response to DRV/rBaseline Resistance and Response to DRV/r

Baseline fold-change was strongest Baseline fold-change was strongest predictor of Week 24 responsepredictor of Week 24 response

11 mutations associated with 11 mutations associated with reduced responsereduced response V11I, V32I, L33F, I47V, I50V, I54L,

I54M, G73S, L76V, I84V and L89V 73% of pts had 2 of these

mutations

DeMeyer S, et al. Resistance Workshop 2006. Abstract 73.

Δ V

L a

t W

k 24

, (N

C =

F)

FC 10(n = 255)

(70% of pts)

FC 11-40(n = 65)

(17% of pts)

FC > 40(n = 48)

(13% of pts)

VL < 50 c/mLat Wk 24 50% 25% 13%

Baseline DRV FC

No. of BL No. of BL mutationsmutations 00 11 22 33 44

% with VL % with VL < 50, Wk 24< 50, Wk 24 6464 5050 4242 2222 1010 -2.04

-1.08

-0.78

-2.5

-2.0

-1.5

-1.0

-0.5

0

10V, 20R, 33F, 46L,54L, 82A, 84V, and 90M

Multi-Drug ResistanceMulti-Drug Resistance This case illustrates several points to This case illustrates several points to

consider when making the difficult decision consider when making the difficult decision of when to switchof when to switch

This patient is in no clinical danger.This patient is in no clinical danger. His CD4 cell count is above 300 His viral load is over 1 log10 lower than a peak off

therapy. He has had no AIDS defining illness and feels well

On the other hand his current therapy is On the other hand his current therapy is not optimal with sustained viral replicationnot optimal with sustained viral replication Continued current therapy may lead to CD4 cell

decline and further accumulation of resistance mutations

Case: Multi-drug ResistanceCase: Multi-drug Resistance There is no clinical urgency; what are treatment There is no clinical urgency; what are treatment

options?options? He is naïve to T-20 therefore likely very active initially

− T-20 low barrier to resistance; incomplete suppression leads to rapid resistance evolution

He has no NNRTI mutations− By history he had previous viral rebound while on EFV− NNRTI may add modest activity, − NRTI will likely have modest ADDITIONAL activity

There are substantial PI mutations limiting PI options

− He has 5 TPV-associated mutations decreasing the likelihood of a sustained response

− He has 3 DRV mutations which will impact activity

Should He Wait for New Should He Wait for New Agents?Agents?

How quickly will new mutations How quickly will new mutations evolve?evolve?

Risk of Delayed Switch on Stable HAARTRisk of Delayed Switch on Stable HAART

SCOPE cohort of ART-experienced SCOPE cohort of ART-experienced subjects (nsubjects (n = 106)= 106)[1][1]

Stable HAART for 120 days

HIV-1 RNA > 1000 c/mL

1 resistance mutation

Resistance testing every 4 mos until HAART modification

Emergence of new mutns at 1 yrEmergence of new mutns at 1 yr Any: 44% (95% CI: 33%-56%)

NAMs: 23% (95% CI: 15%-34%)

PI: 18% (95% CI: 9%-34%)

Those with persistent viremia on Those with persistent viremia on HAART run risk of limiting future HAART run risk of limiting future treatment optionstreatment options

Other studies show similar resultsOther studies show similar results[2-4][2-4]

1. Hatano H, et al. CROI 2006. Abstract 615. 2. Lafeuillade A, et al. IAC 2004. Abstract WeOrB1293. 3. Margot NA, et al. JAIDS. 2003;33:15-21. 4. Napravnik S, et al. JAIDS. 2005;40:34-40.

Pro

po

rtio

n W

ith

ou

t

New

Mu

tati

on

1 new major PI mutation1 new NRTI mutation*Any new mutation

Number of available antiretrovirals from the following: ZDV,

3TC, ddI, ABC,TDF, EFV, IDV, NFV, SQV, RTV, APV, LPV 0

0.25

0.50

0.75

1.00

0 4 8 12 16 20 24Time (Mos)

Time to loss of 1 drug equivalent

0 4 8 12 16 20 24

*PI-treated subjects (n = 71)0

0.25

0.50

0.75

1.00

Pro

po

rtio

n W

ith

ou

t

Lo

ss o

f 1

Dru

g

Case 1Case 1

Patient now has CD4 cell count of 120Patient now has CD4 cell count of 120 VL is 15,000VL is 15,000 Repeat Genotype – virtual phenotype Repeat Genotype – virtual phenotype

show no new mutationsshow no new mutations DRV fold change = 45 (cut-offs 3.4 – 96.8) TPV fold change = 4.0 (cut-offs 1.2 – 5.4) Intermediate susceptibility to TDF resistant to all NRTI No NNRTI mutations (failed EFV in the past)

Case 1Case 1

If you were to start the patient on new drugs If you were to start the patient on new drugs which would you use?which would you use?A. Maraviroc

B. Raltegravir

C. Etravirine

D. Raltegravir/Etravirine

E. Maraviroc/Etravirine

F. Maraviroc/Raltegravir

HIV-infected patients with VF on current HAART regimen,

history of ≥ 1 NNRTI resistance mutations, ≥ 3 primary PI mutations,

HIV-1 RNA > 5000 copies/mL

(DUET-1: N = 612; DUET-2: N = 591)

Placebo+ DRV/RTV-containing OBR*

(n = 604)

Etravirine 200 mg BID+ DRV/RTV-containing OBR*

(n = 599)

Week 48

*Investigator-selected OBR to consist of DRV/RTV (600/100 mg/mL) + ≥ 2 NRTIs ± enfuvirtide.†Planned Week 24 analysis: primary endpoint HIV-1 RNA < 50 copies/mL (TLOVR).

Week 24†

DUET-1 and -2: Etravirine + DRV/RTV-Containing OBR Phase III Trials

Madruga JV, et al. Lancet. 2007;370:29-38. Lazzarin A, et al. Lancet. 2007;370:39-48. Mills A, et al. IAS 2007. Abstract WESS204.1. Katlama C, et al. IAS 2007. Abstract WESS204.2. Cahn P, et al. ICAAC 2007. Abstract H-717.

DUET-1 and -2: Pooled Virologic and DUET-1 and -2: Pooled Virologic and Immunologic Responses Immunologic Responses

Outcome at Week 24 Etravirine(n = 599)

Placebo (n = 604)

P Value

HIV-1 RNA < 50 copies/mL, %

59 41 < .0001

Mean change in HIV-1 RNA from baseline, log10

copies/mL-2.4 -1.7 < .0001

Mean change in CD4+ cell count from baseline, cells/mm3

+86 +67 < .0001

In patients using enfuvirtide for the first time (n = 201), the difference between treatment In patients using enfuvirtide for the first time (n = 201), the difference between treatment arms (67% and 62% for etravirine vs placebo, respectively) was not significant (arms (67% and 62% for etravirine vs placebo, respectively) was not significant (P P = .427)= .427)

Cahn P, et al. ICAAC 2007. Abstract H-717.

DUET-1 and -2: Response Based on DUET-1 and -2: Response Based on Active Agents in OBR Active Agents in OBR

Cahn P, et al. ICAAC 2007. Abstract H-717.

0

20

40

60

80

100

HIV

-1 R

NA

< 5

0 co

pie

s/m

L a

t W

eek

24 (

%)

45

8

60

74

30

67

Etravirine + OBR Placebo + OBR

n = 88 25725821119991

No. of Fully Active Agents in OBR (assessed by PSS)0 1 ≥ 2

DUET-1 and -2: BL ETR Mutations and DUET-1 and -2: BL ETR Mutations and Virologic Response at Week 24Virologic Response at Week 24

0 1 2 3

Pat

ien

ts W

ith

HIV

-1

RN

A <

50

cop

ies/

mL

(%

)

0

102030

4050607080

90100

4 5

No. of BL ETR Mutations

Patients (%) 40 30 16 8 5 1

13 mutations associated with ETR resistance

V90I A98G

L100I K101E/P

V106I V179D/F

Y181C/I/V G190A/S

Presence of ≥ 3 ETR mutations associated with response similar to placebo + OBR

– 70% of patients had 0 or 1 ETR resistance mutations at BL

– 14% of patients had ≥ 3 ETR resistance mutations at BL

– Response diminished by ~ 20% in presence of 1 or 2 mutations

Katlama C, et al. IAS 2007. Abstract WESS204.2.

Proportion of patients achieving HIV-1 RNA Proportion of patients achieving HIV-1 RNA < 50 copies/mL significantly greater in etravirine arms< 50 copies/mL significantly greater in etravirine arms

CD4+ cell count increase from baseline significantly greater in ETR arm in CD4+ cell count increase from baseline significantly greater in ETR arm in DUET-1DUET-1 DUET-1: 89 vs 64 cells/mm3 (P = .0002) DUET-2: 78 vs 66 cells/mm3 (P = .3692)

Presence of ≥ 3 mutations from list of 13 ETR RT mutations associated with Presence of ≥ 3 mutations from list of 13 ETR RT mutations associated with decreased responsedecreased response K103N not associated with ETR resistance

Incidence of adverse events and laboratoryIncidence of adverse events and laboratory abnormalities similar to placebo abnormalities similar to placebo armarm

DUET-1 and -2: Study ConclusionsDUET-1 and -2: Study Conclusions

BENCHMRK-1 and -2: Raltegravir in BENCHMRK-1 and -2: Raltegravir in Treatment-Experienced PtsTreatment-Experienced Pts

Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB.

Randomized, double-blind, placebo-controlled, parallel phase III studiesRandomized, double-blind, placebo-controlled, parallel phase III studies

Raltegravir 400 mg twice daily + OBRBENCHMRK-1 (n = 232)BENCHMRK-2 (n = 230)

Placebo + OBRBENCHMRK-1 (n = 118)BENCHMRK-2 (n = 119)

HIV infected;triple-class resistant; VL > 1000 copies/mL

BENCHMRK-1 (N = 350)(Europe, Asia/Pacific, Peru)

BENCHMRK-2 (N = 349)(North, South America)

Primary endpoints: Week 16

Planned duration: Week 48

Benchmark 1 and 2Patient Disposition at study entry

BENCHMRK 1 and 2: HIV-1 RNA < 50 BENCHMRK 1 and 2: HIV-1 RNA < 50 copies/mL (ITT, NC = F)copies/mL (ITT, NC = F)


P < .001 at Week 16

Per

cen

t o

f P

ati

en

ts w

ith

HIV

RN

A <

50 C

op

ies/

mL

P < .001 at Week 16

BENCHMRK-2

Weeks

0 2 4 8 12 16 240

20

40

60

80

100

0 2 4 8 12 16 240

20

40

60

80

100BENCHMRK-1

Weeks

61%

33%

62%

36%

Raltegravir + OBR Placebo + OBR

BENCHMRK 1 and 2: HIV-1 RNA < 400 BENCHMRK 1 and 2: HIV-1 RNA < 400 c/mL at Wk 16 by Agents in OBRc/mL at Wk 16 by Agents in OBR


+ : First use in OBR– : No use in OBR

Overall Efficacy Data

––

% of Patients

0 20 40 60 80 100

n

447230

Efficacy by Agents in OBR

Enfuvirtide Darunavir

+

+

+

+

–

–

879844

23

639042

24

559080

47

2974191

90

7943


BENCHMRK 1 and 2: HIV-1 RNA < 400 BENCHMRK 1 and 2: HIV-1 RNA < 400 c/mL at Wk 16 by PSS/GSS of OBRc/mL at Wk 16 by PSS/GSS of OBR


(PSS)

0

1

2 or more

(GSS)

0

1

2 or more

Overall Efficacy Data

% of Patients

615

6244

7641

14168

8757

222110

5710

11163

8543

17093

8971

15970

0 20 40 60 80 100

n

447230

7943


Case SummaryCase SummaryCD4 now 200 cell/mmCD4 now 200 cell/mm33, VL is 65,000; patient is symptomatic , VL is 65,000; patient is symptomatic RT mutations include:RT mutations include:

41L, 74V, 118I, 184V, 215Y and 219 Resistance to 3TC, FTC, ddI, ABC, ZDV Intermediate activity to TDF and d4T

Protease mutations include:Protease mutations include: 10V, 20R, 33F, 46L,54L, 82A, 73S, 84V and 90M Predicted phenotype TPV = 4.0 (1.2, 5.4) DRV 64 (3.4,

96.9) above upper cut-off for all other PI.

Previous NNRTI experiencePrevious NNRTI experience

Raltegravir, etravirine and maraviroc are now available.Raltegravir, etravirine and maraviroc are now available. Entry phenotype is dual-mixed

SummarySummaryTreatment experienced patientsTreatment experienced patients

Re-suppress HIV RNA levels maximally Re-suppress HIV RNA levels maximally and prevent further selection of resistance and prevent further selection of resistance mutationsmutations

Need to know likelihood of successNeed to know likelihood of success Must have at least two active drugsMust have at least two active drugs

World AIDS Day 2006

What Is the “Resistance Penalty” of What Is the “Resistance Penalty” of Continued Nonsuppressive Therapy?Continued Nonsuppressive Therapy?

Studies of resistance accumulation in states of Studies of resistance accumulation in states of “incomplete viral suppression”“incomplete viral suppression” 68% with new mutations after median of 22 mos[1]

33% with new TAMs, 2% K65R during 96 wks of FU[2]

60% with new mutations after median of 9.3 mos, but no shift on virtual phenotype[3]

Studies lack results of subsequent switches Studies lack results of subsequent switches No fully powered randomized studies of early vs deferred No fully powered randomized studies of early vs deferred

switchingswitching

1. Lafeuillade A, et al. IAC 2004. Abstract WeOrB1293. 2. Margot NA, et al. J Acquir Immune Defic Syndr. 2003;33:15-21. 3. Napravnik S, et al. J Acquir Immune Defic Syndr. 2005;40:34-40.

Documents

HAART for the treatment experienced patient Prema Menezes PA-C