the body pro the hiv resource for health professionals faculty: david wohl, m.d. associate professor...

THE BODY PROThe HIV Resource for Health Professionals

Faculty: David Wohl, M.D.Associate Professor of Medicine at the University of North Carolina at Chapel Hill

The Body PRO Covers ICAAC/IDSA 2008Washington, D.C.; October 25-28, 2008

Copyright © 2008 The HealthCentral Network, Inc. All rights reserved.

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

David Wohl, M.D.

Evolving Options for First-Line Therapy: Highlights From ICAAC/IDSA 2008

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Faculty for This ActivityFaculty for This Activity

David Wohl, M.D.

Dr. Wohl is an associate professor of medicine at the University of North Carolina at Chapel Hill, and co-directs HIV services for the North Carolina Department of Corrections. Dr. Wohl is an investigator in the NIAID-sponsored AIDS Clinical Trials Group (ACTG) and a member of the ACTG Complications of HIV Disease Research Agenda Committee. His research focuses on metabolic and infectious complications of HIV and its therapies, as well as issues related to medication adherence and access to care -- particularly among incarcerated inmates with HIV infection.

DisclosuresDr. Wohl has been a consultant for Abbott Laboratories, Tibotec and Merck & Co. He has served on speaker bureaus for Abbott, Gilead, Roche Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim, Tibotec and Merck. In addition, he has received research support from Abbott, Roche and Merck.

This activity is supported by an educational grant from

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STARTMRK: Patient DispositionSTARTMRK: Patient Disposition

Jeffrey Lennox et al. ICAAC/IDSA 2008; abstract H-896a. Reprinted with permission.Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved.

281281Treated with RAL*Treated with RAL*

24 (8.5%)24 (8.5%)Discontinued due to:Discontinued due to:

8- Adverse events 8- Adverse events 4- Lack of efficacy 4- Lack of efficacy 3- Lost to follow-up3- Lost to follow-up9- Other events9- Other events

Randomized 1:1 toRandomized 1:1 toRAL or EFV armsRAL or EFV arms

282 282 Treated with EFV*Treated with EFV*

257 (91.5%)257 (91.5%)Completed Completed 48 weeks48 weeks

247 (87.6%)247 (87.6%)Completed Completed 48 weeks48 weeks

35 (12.4%)35 (12.4%)Discontinued due to:Discontinued due to:

17- Adverse events 17- Adverse events 2- Lack of efficacy 2- Lack of efficacy 7- Lost to follow-up7- Lost to follow-up9- Other events9- Other events

*In combination with TDF/FTC

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STARTMRK: Baseline Characteristics STARTMRK: Baseline Characteristics


RAL* EFV*

# Patients Treated n = 281 n = 282

Age (Mean, Years) 38 37

% Male 81 82

% Non-White 59 56

vRNA Copies/mL (Geometric Mean) 103,205 106,215

% With vRNA > 105 Copies/mL 55 51

Mean CD4+ Count (Cells/μl) 219 217

% With CD4+ ≤ 200 Cells/μl 47 48

% Hepatitis B or C 7 7

% Non-Clade B 21 17


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5STARTMRK: Percent of Patients With HIV RNA < 50 Copies/mL (95% CI)(Non-Completer = Failure)

STARTMRK: Percent of Patients With HIV RNA < 50 Copies/mL (95% CI)(Non-Completer = Failure)


281 279 281 279 281 279 278 280 280282 282 282 282 281 282 280 281 281

Raltegravir 400 mg BID*Efavirenz 600 mg QHS*

Number of Contributing Patients


Weeks

Per

cen

t o

f P

ati

en

ts W

ith

HIV

RN

A <

50

Co

pie

s/m

L

0 2 4 8 12 16 24 32 40 48

0

20

40

60

80

100

82%

Non-InferiorityP Value < 0.001

86%

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STARTMRK: Time to Virologic Response (HIV RNA < 50 Copies/mL)STARTMRK: Time to Virologic Response (HIV RNA < 50 Copies/mL)


Number of Patients at Risk

282 267 229 158 95 44 17 11 8 6281 214 134 71 42 23 13 8 3 2

Efavirenz 600 mg QHS*Raltegravir 400 mg BID*

Log-Rank

P Value < 0.001

0 2 4 8 12 16 24 32 40 48 56Weeks

0

20

40

60

80

100

Cu

mu

lati

ve V

iro

log

ic

Res

po

nse

Rat

e (%

)


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7STARTMRK: Change From Baseline in CD4+ Cell Count (95%)(Observed Failure)

STARTMRK: Change From Baseline in CD4+ Cell Count (95%)(Observed Failure)


∆ (95% CI) =26 (4, 47)

0 2 4 8 12 16 24 32 40 48Weeks

0

50

100

150

200M

ea

n C

ha

ng

e F

rom

Ba

se

lin

eC

D4

+ C

ell

Co

un

t (C

ell

s/m

m3 )

189

163

281 274 277 272 270 266 260 259 258281 272 272 268 269 266 260 254 251

Raltegravir 400 mg BID*Efavirenz 600 mg QHS*

Number of Contributing Patients


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STARTMRK: Resistance by Week 48 In Patients With Virologic Failure*STARTMRK: Resistance by Week 48 In Patients With Virologic Failure*


*Virologic failure: Non-responder: (1) HIV RNA > 50 copies/mL at the time of discontinuation or (2) HIV RNA > 50 copies/mL at Week 24 Virologic rebound: HIV RNA > 50 copies/mL (on 2 consecutive measurements at least 1 week apart) after initial response

No known RALNo known RALresistance mutationresistance mutation

n = 5n = 54 Sens to TDF/FTC, 1 not tested4 Sens to TDF/FTC, 1 not tested

Known RALKnown RALresistance mutationresistance mutation

n = 4n = 43 Res to FTC, 1 not tested3 Res to FTC, 1 not tested

IN gene couldIN gene couldnot be amplifiednot be amplified

n = 3n = 3

IN Mutations:IN Mutations:

n = 2n = 2 G140S+Q148H/RG140S+Q148H/R

n = 1n = 1 Y143H+L74M+E92Q+T97AY143H+L74M+E92Q+T97A

n = 1n = 1 Y143RY143R

RAL FailuresRAL FailuresvRNA > 400c/mLvRNA > 400c/mL

n = 12n = 12

No known EFVNo known EFVresistance mutationresistance mutation

n = 3n = 33 Sens to TDF/FTC3 Sens to TDF/FTC

Known EFVKnown EFVresistance mutationresistance mutation

n = 3n = 31 Res to FTC1 Res to FTC

RT geneRT geneno datano data

n = 2n = 2

EFV FailuresEFV FailuresvRNA > 400c/mLvRNA > 400c/mL

n = 8n = 8

VL FailuresVL Failuresn = 27 RALn = 27 RALn = 39 EFVn = 39 EFV

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9STARTMRK: Most Common‡ Drug-Related¥ Clinical Adverse Events Of Moderate or Severe Intensity

STARTMRK: Most Common‡ Drug-Related¥ Clinical Adverse Events Of Moderate or Severe Intensity


‡Present in ≥ 2% of either treatment group¥Determined by investigator to be possibly, probably or definitely related to any drug in the treatment regimen*In combination with TDF/FTC

8 (2.8) 0 (0.0)Rash

7 (2.5) 0 (0.0)Rash Maculo-Papular

8 (2.8) 3 (1.1)Diarrhea

8 (2.8) 4 (1.4)Fatigue

10 (3.5) 8 (2.8)Nausea

9 (3.2)10 (3.6)Insomnia

18 (6.4) 4 (1.4)Dizziness

13 (4.6)11 (3.9)Headache

n (%)n (%)

EFV*n = 282

RAL*n = 281

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STARTMRK: Grade 3/4‡ Laboratory AbnormalitiesSTARTMRK: Grade 3/4‡ Laboratory Abnormalities


Laboratory Blood Test Toxicity Criteria‡

RAL*n = 281

EFV*n = 282

n (%) n (%)

Absolute Neutrophil Count < 750 cells/µL 5 (1.8) 3 (1.1)

Hemoglobin < 7.5 gm/dL 2 (0.7) 2 (0.7)

Platelet Count < 50 k/µL 0 (0.0) 1 (0.4)

Fasting LDL Cholesterol ≥ 190 mg/dL 3 (1.1) 10 (3.6)

Fasting Total Cholesterol > 300 mg/dL 0 (0.0) 7 (2.5)

Fasting Triglycerides > 750 mg/dL 1 (0.4) 3 (1.1)

Fasting Glucose > 250 mg/dL 1 (0.4) 0 (0.0)

Total Bilirubin > 2.5 x ULN 2 (0.7) 0 (0.0)

Alkaline Phosphatase > 5 x ULN 0 (0.0) 2 (0.8)

Aspartate Aminotransferase > 5 x ULN 6 (2.1) 5 (1.8)

Alanine Aminotransferase > 5 x ULN 5 (1.8) 6 (2.1)‡Grades 3/4 by DAIDS criteria *In combination with TDF/FTC

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STARTMRK: Change From Baseline In Fasting Serum Lipids Week 48STARTMRK: Change From Baseline In Fasting Serum Lipids Week 48


64

10

-3

37

16

33

10

-10

0

10

20

30

40

T CHOL HDL-C LDL-C TG

Mea

n C

han

ge

(mg

/dL

)

Lipid-Lowering Rx RAL* # (%) EFV *# (%)

Added Rx 3 (1) 11 (4)

Increased Rx 4 (1) 4 (1)

‡P < 0.001‡

*

*


‡

‡

‡

-1

0T CHOL/HDL

Mea

n C

ha

ng

e (

Rat

io)

RAL

EFV

P = 0.292

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ARTEMIS: Phase III Study DesignARTEMIS: Phase III Study Design

Anthony Mills et al. ICAAC/IDSA 2008; abstract H-1250c. Reprinted with permission.

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ARTEMIS: Viral Load < 50 Copies/mL To Week 48 (ITT-TLOVR)ARTEMIS: Viral Load < 50 Copies/mL To Week 48 (ITT-TLOVR)

Estimated difference in response vs LPV/r for non-inferiority:

PP = 5.6% (95% CI –0.1;11.3) p<0.001

Estimated difference in response vs. LPV/r for non-inferiority:

PP = 5.6% (95% CI –0.1;11.3) P < 0.001

Estimated difference in response vs. LPV/r for superiority:

ITT = 5.5% (95% CI –0.3;11.2) P = 0.062

50

40

30

20

10

0

100

90

80

70

60

84%78%

4 8 12 16 24 36 48Time (weeks)

Pat

ien

ts W

ith

VL

< 5

0 C

op

ies/

mL

(%

[±S

E])

LPV/r QD or BID (n = 346)

DRV/r QD (n = 343)

2

Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.

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ARTEMIS: Viral Load < 50 Copies/mL To Week 96 (ITT-TLOVR)*ARTEMIS: Viral Load < 50 Copies/mL To Week 96 (ITT-TLOVR)*


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15ARTEMIS: Virologic Response at Week 96 in the TLOVR Non-VF Censored Population‡

ARTEMIS: Virologic Response at Week 96 in the TLOVR Non-VF Censored Population‡


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ARTEMIS: VF Analysis Over 96 WeeksARTEMIS: VF Analysis Over 96 Weeks


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ARTEMIS: Median Lipid Levels at Baseline and Week 96ARTEMIS: Median Lipid Levels at Baseline and Week 96


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CASTLE: Study DesignCASTLE: Study Design

Jean-Michel Molina et al. ICAAC/IDSA 2008; abstract H-1250d. Reprinted with permission.

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CASTLE: HIV RNA < 50 Copies/mL (CVR, NC = F)CASTLE: HIV RNA < 50 Copies/mL (CVR, NC = F)


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CASTLE: Selected Grade 3-4 Laboratory AbnormalitiesCASTLE: Selected Grade 3-4 Laboratory Abnormalities


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21CASTLE: CVR (HIV RNA < 50 Copies/mL) Treatment Outcomes at Week 96 Among Subjects With Advanced Disease

CASTLE: CVR (HIV RNA < 50 Copies/mL) Treatment Outcomes at Week 96 Among Subjects With Advanced Disease


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HEAT: MethodsHEAT: Methods

Ben Young et al. ICAAC/IDSA 2008; abstract H-1233.Copyright GlaxoSmithKline. Used with permission, 2008.

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HEAT: Virologic Failure by Baseline HIV-1 RNA Strata and Failure CriterionHEAT: Virologic Failure by Baseline HIV-1 RNA Strata and Failure Criterion


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24HEAT: Summary of Treatment Emergent Resistance in Subjects With Protocol-Defined Virologic Failure

HEAT: Summary of Treatment Emergent Resistance in Subjects With Protocol-Defined Virologic Failure


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ARIES: Study DesignARIES: Study Design

Kathleen Squires et al. ICAAC/IDSA 2008; abstract H-1250a.Copyright GlaxoSmithKline. Used with permission, 2008.

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26ARIES: Proportion of Subjects With vRNA < 50 Copies/mL and < 400 Copies/mL Through Week 36, ITT-E Population

ARIES: Proportion of Subjects With vRNA < 50 Copies/mL and < 400 Copies/mL Through Week 36, ITT-E Population


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27ARIES: Overall and Stratified Results by Baseline Viral Load Through Week 36, ITT-E Population

ARIES: Overall and Stratified Results by Baseline Viral Load Through Week 36, ITT-E Population


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MERIT: Phase III Trial DesignMERIT: Phase III Trial Design

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

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29MERIT: Percentage of Patients With Undetectable HIV-1 RNA at Week 48 (Primary Endpoint)

MERIT: Percentage of Patients With Undetectable HIV-1 RNA at Week 48 (Primary Endpoint)

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

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30MERIT: Patients With a D/M Tropism Result Using the Enhanced Sensitivity Trofile Assay

MERIT: Patients With a D/M Tropism Result Using the Enhanced Sensitivity Trofile Assay

Michael Saag et al. ICAAC/IDSA 2008; abstract H-1232a. Reprinted with permission.

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31MERIT: Re-analysis With Enhanced Trofile At Screening Identified ~50% of Patients Who Displayed D/M Virus on Study

MERIT: Re-analysis With Enhanced Trofile At Screening Identified ~50% of Patients Who Displayed D/M Virus on Study


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32MERIT: Percentage of Patients With HIV-1 RNA < 400 and < 50 Copies/mL At Week 48

MERIT: Percentage of Patients With HIV-1 RNA < 400 and < 50 Copies/mL At Week 48


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ACTG 5211: Coreceptor Tropism by The Original and Enhanced Trofile

ACTG 5211: Coreceptor Tropism by The Original and Enhanced Trofile

Zhaohui Su et al. ICAAC/IDSA 2008; abstract H-895. Reprinted with permission.

25/114

Enhanced Trofile reclassified 25 individuals with R5 virus at screen

15/25 were VCV recipients

12/15 had early detection of X4 virus on study (before week 8) by original Trofile

Original Trofile Enhanced Trofile

Screen Entry On study DM at Screen (n, %)

R5 DM DM/X4 7/12, 58%

R5 R5 DM/X4 9/18, 50%

R5 R5 R5 9/84, 11%

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34ACTG 5211: Viral Load Reduction in Subjects With R5 Virus at Screen by the Original & Enhanced Trofile Assays

ACTG 5211: Viral Load Reduction in Subjects With R5 Virus at Screen by the Original & Enhanced Trofile Assays

Zhaohui Su et al. ICAAC/IDSA 2008; abstract H-895. Reprinted with permission.

-2

-1.5

-1

-0.5

0

0.5P

lace

bo

5 10 15 Pla

cebo

5 10 15

Day 14 Week 24

Ch

ang

e in

Vir

al L

oad

(Lo

g10

HIV

-1 R

NA

)

Original

Enhanced

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NA-ACCORD: Distribution of 8,374 Study PatientsNA-ACCORD: Distribution of 8,374 Study Patients

First CD4+ Count Between 351 – 500 Measured 1996 – 2006

No Prior AIDS Diagnosis or ARVs (n = 8,374)

Defer HAARTn = 5,901

Initiate HAARTn = 2,473

Transit to CD4+ < 350

Defer HAARTn = 2,229

Initiate HAARTn = 1,220

No Transitn = 2,452

Deaths (Person-Years) in Cohort Analysis

100 (5,815) 137 (5,526) 209 (5,295) 221 (8,358)

Percent Censored in IPW Analysis

57% 0% 10% 0%

Adapted from Mari Kitahata et al. ICAAC/IDSA 2008; abstract H-896b.

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NA-ACCORD: Baseline Characteristics In Study PatientsNA-ACCORD: Baseline Characteristics In Study Patients

Defer HAART n = 5,901

Initiate HAART n = 2,473

Follow Up Person-Years 16,636 8,358

Hepatitis C Virus Infection (%)* 34 27

History of Injection Drug Use (%)* 21 16

Males (%) 75 83

Median Age Years (IQR) 38 (32, 45) 40 (34, 48)

Median CD4+ Count Cells/mm3 (IQR) 432 (391, 468) 421 (386, 459)

Median log10 HIV RNA Copies/mL (IQR)* 4.1 (3.3, 4.6) 4.3 (3.1, 4.9)

White (%) 38 39

*Among patients with known status


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NA-ACCORD: Results of Subset AnalysisNA-ACCORD: Results of Subset Analysis

• Both a history of IDU and HCV infection were significantly associated with increased risk of mortality

RH 95% CI P Value

When Restricting the Analysis to Patients With Data Regarding History of Injection Drug Use (IDU) and Adjusting for IDU

1.7 1.2, 2.3 0.003

When Restricting the Analysis to Patients With Data Regarding Hepatitis C Virus (HCV) Infection and Adjusting for HCV

1.7 1.3, 2.1 < 0.0001

RH = relative hazard of death for deferral of HAART; CI = confidence interval


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38NA-ACCORD: Inverse Probability Weighted Cox Regression Multivariate Analysis

NA-ACCORD: Inverse Probability Weighted Cox Regression Multivariate Analysis

RH* 95% CI P Value

Deferral of HAART at 351 – 500 1.7 1.4, 2.1 < 0.001

Older Age (Per 10 Years) 1.6 1.5, 1.8 < 0.001

Female Sex 1.1 0.9, 1.5 0.290

Baseline CD4 Count (Per 100 Cells/mm3) 0.9 0.7, 1.0 0.083

• Results were similar when restricting the analysis to the 77% of participants with baseline HIV RNA data• Adjusted RH for deferral vs. immediate treatment was also 1.7; 95% C.I. was 1.4, 2.2; and P value was < 0.0001• HIV RNA was not an independent predictor of mortality

RH = relative hazard; CI = confidence interval*Stratified by cohort and year


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• This presentation was created to accompany The Body PRO's summaries of key research presented at ICAAC/IDSA 2008, by David Wohl, M.D.

• The Body PRO's extensive coverage of ICAAC/IDSA 2008 also includes:– Summaries and analyses of research on a wide array of clinical

subjects.– Interviews with top researchers discussing the results of noteworthy

studies.– Audio podcasts you can play online or download to your computer or

MP3 player.– Narrated, online slide presentations highlighting major study results.

• Visit TheBodyPRO.com/ICAAC2008 today for a full listing of our conference coverage!

Disclaimer:The Body PRO is designed for educational purposes only and is not engaged in rendering medical advice or professional services. The information provided through The Body PRO should not be used for diagnosing or treating a health problem or a disease.

the body pro the hiv resource for health professionals faculty: david wohl, m.d. associate professor...

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