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THE BODY PROThe HIV Resource for Health Professionals

The Body PRO Covers the XVII International AIDS Conference (AIDS 2008)Mexico City; August 3-8, 2008

This activity is supported by educational grants from

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

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

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

David Wohl, M.D.

The Body PRO

Antiretroviral Strategy Update: Highlights From AIDS 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 speakers 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.

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ACTG 5202: Study DesignACTG 5202: Study Design

• 96-Week, Randomized, Partially Blinded Study

• Comparing efficacy, safety and tolerability of regimens shown below as initial therapy for HIV-1 infection

Any CD4+ CountHIV-1 RNA ≥ 1,000 Copies/mL

≥ 16 Years of Age

Stratified by HIV-1 RNA (< or ≥ 100,000 Copies/mL)

ART-naïve N=1858

Randomized 1:1:1:1EFV

EFV QD

ATV/rQD

ATV/rQDART-Naïve

N = 1,858Randomized 1:1:1:1

QDTDF/FTC QD

ABC/3TC Placebo QD

ABC/3TC QD

TDF/FTC Placebo QD

TDF/FTC QD

ABC/3TC Placebo QD

ABC/3TC QD

TDF/FTC Placebo QD

Adapted from Paul Sax et al. AIDS 2008; abstract THAB0303.

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ACTG 5202: NIAID Therapeutic DSMB Findings and RecommendationsACTG 5202: NIAID Therapeutic DSMB Findings and Recommendations


January 29, 2008: First Efficacy Review

• ABC/3TC showed excess virologic failures

Data Combined and Analyzed as Two Arms (ABC/3TC vs. TDF/FTC) Per DSMB Request

• Found highly significant differences

• ABC/3TC: Excess virologic failures occurred in patients with viral load ≥ 100,000 copies/mL

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ACTG 5202: Primary Study End PointsACTG 5202: Primary Study End Points


EfficacyTime to Virologic Failure

Early FailureWeeks 16 to 24

Confirmed Viral Load ≥ 1,000 Copies/mL

Later FailureWeek 24 On

Confirmed Viral Load ≥ 200 Copies/mL

Safety

Lab Abnormality at Least One Grade Higher Than Baseline

OR

Time to First Grade 3 or 4 Sign/Symptom

Tolerability Time to Modification of Originally Randomized Regimen

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ACTG 5202: Timing and Type of Virologic FailureACTG 5202: Timing and Type of Virologic Failure

Tenofovir/Emtricitabine

(N = 399)

Abacavir/Lamivudine

(N = 398)

Total With VF* 26 (7%) 57 (14%)≥ 200 Copies/mL

≥ 24 Weeks

Prior < 200 Copies/mL

15 29

≥ 200 Copies/mL

≥ 24 Weeks

No Prior < 200 Copies/mL

2 9

≥ 1,000 Copies/mL

< 24 Weeks

No Prior < 200 Copies/mL

9 19

Post hoc analysis: There was no

significant difference in the risk of virologic rebound (P = 0.247)

for subjects achieving two

< 50 copies/mL on therapy.


*VF = virologic failure

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ACTG 5202: Proportion < 50 Copies/mL (95% CI)ACTG 5202: Proportion < 50 Copies/mL (95% CI)

Secondary, ITT: Regimen Change/Prior Virologic Failure IncludedP

rop

ort

ion

< 5

0 C

op

ies

/mL


Number with RNA ValueAbacavir/Lamivudine 388 357 324 293 245 212 163 114 59Tenofovir/Emtricitabine 393 352 325 285 244 211 169 109 69

Week 48: Abacavir/Lamivudine: 0.75 (0.69 – 0.80) Tenofovir/Emtricitabine 0.80 (0.74 – 0.85); P = 0.20

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8ACTG 5202: Selected Grade 3 or 4 Safety Events Among Those Reported in ≥ 5%

ACTG 5202: Selected Grade 3 or 4 Safety Events Among Those Reported in ≥ 5%


Safety Events Tenofovir/Emtricitabine Abacavir/Lamivudine

Total (All Events) 78 (19%) 130 (33%)

Metabolic (Lipids) 11 (3%) 41 (10%)

General Body 38 (10%) 58 (14%)

Aches and/or Pains 14 24

Asthenia 10 6

Headache 6 8

Itchy and/or Pruritis 2 9

Gastrointestinal 17 (5%) 26 (7%)

ALT 5 7

AST 4 12

Diarrhea and/or Loose Stool 7 7

Nausea and/or Vomiting 3 3

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ACTG 5202: ConclusionsACTG 5202: Conclusions


Patients With HIV RNA ≥ 100,000 Copies/mL

• Significantly shorter time to virologic failure associated with ABC/3TC

No obvious relationship between virologic failure and suspected hypersensitivity reactions

• Shorter time to first adverse event with ABC/3TC

Resistance and Other Analyses Ongoing

ACTG 5202 Continues Until November 2009

• Blinded NRTIs with HIV RNA < 100,000 copies/mL

• ATV/r vs. EFV

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Responding to ACTG 5202: Clinical Trials With Third Drugs (N ≥ 100)Responding to ACTG 5202: Clinical Trials With Third Drugs (N ≥ 100)

Keith Pappa et al. AIDS 2008; abstract THAB0304. Copyright GlaxoSmithKline. Used with permission 2008.

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Responding to ACTG 5202: 48-Week Protocol-Defined Virologic Survival by Baseline VL Using A5202 Efficacy End Point1

Responding to ACTG 5202: 48-Week Protocol-Defined Virologic Survival by Baseline VL Using A5202 Efficacy End Point1

Keith Pappa et al. AIDS 2008; abstract THAB0304. Copyright GlaxoSmithKline. Used with permission, 2008.

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ACTG 5202: Why Might These Results Differ From Other Studies?ACTG 5202: Why Might These Results Differ From Other Studies?


Studies Differ in Follow-Up, Design, Endpoints and Conduct

ACTG 5202 vs. HEAT1

• Sample size: ACTG 5202 = 1,858 vs. HEAT = 688

HIV RNA ≥ 5.0 log: ACTG 5202 = 797 vs. HEAT = 296

• Third drug: ACTG 5202 = ATV/r or EFV vs. HEAT = LPV/r QD capsules

Others Compared Different NRTI Strategies

• ABC/3TC BID + EFV vs. ABC/3TC QD, N = 7702

• ABC/3TC BID + EFV vs. ZDV/3TC BID + EFV, N = 6493

1K Smith. CROI 2008; abstract 774. 2G Moyle et al. JAIDS. 2005:38:417-25. 3E DeJesus. Clin Infect Dis. 2004;39:1038-46.

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Responding to D:A:D/SMART: MethodsResponding to D:A:D/SMART: Methods

Jaime Hernandez et al. AIDS 2008; abstract WEAB0106. Copyright GlaxoSmithKline. Used with permission, 2008.

• GSK-sponsored clinical trials with > 24 weeks of follow up with data from 1995-2006 were analyzed– Data from 54 clinical trials analyzed:

• 12/54 adult trials were randomized for ABC vs. control

• 33/54 trials included ABC in background ART

• 8/54 trials did not include ABC

• Includes data from 14,683 subjects (14,174 adults and 509 children)

• Descriptive statistics were summarized for naïve and experienced subjects treated with and without ABC

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14Responding to D:A:D/SMART: CV Outcomes - Exposure to ABC or No ABC (12 Adult Randomized Trials)

Responding to D:A:D/SMART: CV Outcomes - Exposure to ABC or No ABC (12 Adult Randomized Trials)

Jaime Hernandez et al. AIDS 2008; abstract WEAB0106. Copyright GlaxoSmithKline. Used with permission, 2008.

Exposure to

ABC

Events/Patients

FrequencyEvents

/Person-YearsRate/1,000

Person-YearsRelative Rate

(95% CI)

Any Myocardial Infarction or Acute Myocardial Infarction

None 6/1692 0.355% 7/1706 4.10

ABC CART 2/1570 0.127% 4/1863 2.15 0.523

(0.15 – 1.79)

Any Ischemic Coronary Artery Disease or Disorder

None 13/1692 0.768% 13/1702 7.64

ABC CART 5/1570 0.318% 8/1860 4.300.563

(0.23-1.36)

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SMART*: Primary and Major Secondary End Points

SMART*: Primary and Major Secondary End Points

Adapted from Wafaa El-Sadr et al. N Engl J Med. 2006;355(22):2283-2296.

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16SMART: Comparison of Hazard Ratios* for “ABC (No ddI)” and for “ddI (w/wo ABC)” vs. “Other NRTIs”

SMART: Comparison of Hazard Ratios* for “ABC (No ddI)” and for “ddI (w/wo ABC)” vs. “Other NRTIs”

Jens Lundgren et al. AIDS 2008; abstract THAB0305. Reprinted with permission.

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SMART: Hazard Ratios* for Using “ABC (No ddI)” vs. Using “Other NRTIs” According to CV Risk Status at Study Entry

SMART: Hazard Ratios* for Using “ABC (No ddI)” vs. Using “Other NRTIs” According to CV Risk Status at Study Entry


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18SMART: Adjusted Mean Differences in Biomarker Levels At Study Entry for Using “ABC (No ddI)” or “ddI (w/wo ABC)” vs. Using “Other NRTIs”

SMART: Adjusted Mean Differences in Biomarker Levels At Study Entry for Using “ABC (No ddI)” or “ddI (w/wo ABC)” vs. Using “Other NRTIs”


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Protocol 004: Part II DesignProtocol 004: Part II Design

Hypotheses- RAL + TDF/3TC will have similar antiretroviral activity versus EFV + TDF/3TC - RAL + TDF/3TC will be generally well tolerated

Key Inclusion Criteria- Antiretroviral-naïve- Susceptible to 3TC, EFV, TDF- CD4+ ≥ 100 cells/mm3; HIV RNA ≥ 5,000 copies/mL

Timepoints- Primary -- 24 weeks; Secondary -- 48 weeks and 96 weeks- 48-week data presented at AIDS 2007

Current Presentation is 96-Week Update- RAL doses of 100 mg, 200 mg, 400 mg or 600 mg BID (0 to 48 weeks)

- Doses could not be differentiated at 48 weeks- All RAL groups received 400mg BID after 48 weeks

- All RAL data after 48 weeks is shown as a single group (N = 160)

Endpoints- Adverse events, CD4+ counts, HIV RNA - Exploratory: Central nervous system and lipids

Adapted from Martin Markowitz et al. AIDS 2008; abstract TUAB0102.

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20Protocol 004: 96 Weeks Percent of Patients (95% CI) With HIV RNA < 50 Copies/mL [Non-Completer = Failure]

Protocol 004: 96 Weeks Percent of Patients (95% CI) With HIV RNA < 50 Copies/mL [Non-Completer = Failure]

0

20

40

60

80

100

Wk 4 Wk 12 Wk 24 Wk 32 Wk 40 Wk 48* Wk 60 Wk 72 Wk 84 Wk 96

Raltegravir 100 mg BID Raltegravir 200 mg BID Raltegravir 400 mg BID

Raltegravir 600 mg BID Efavirenz 600 mg QDWeek 96

Raltegravir: 83%Efavirenz: 84%

* After Week 48 patients in all RAL groups continued at 400 mg BID. All patients received TDF/3TC.

Week: 0 24 48* 60 72 84 96

RAL 100 mg BID 39 39 39

RAL 200 mg BID 40 40 40

RAL 400 mg BID 41 41 41 160 160 159 160

RAL 600 mg BID 40 40 40

EFV 600 mg QD 38 37 38 38 38 38


Per

cen

t of

Pa

tien

ts W

ith H

IV R

NA

< 5

0 C

op

ies/

mL

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Protocol 004: Treatment-Emergent MutationsProtocol 004: Treatment-Emergent Mutations


Group VF* Type 3TC EFV RAL TDF

RAL 100 NR† M184M/I/V K65K/R

V151I, N155H D232D/N, G163R/G

K65K/R

RAL 100 REL¹ M184M/I/V Y143C‡

RAL 200 NR† M184M/I/V N155H

RAL 200 NR† M184V

RAL 200 REL¹

RAL 200/400 REL¹,²

EFV NR† K65R G190E S230S/N∞ K65R

EFV REL¹,² M184VY188L

K103K/N

NOTE: Percentage of virologic failures in RAL 6/160 (3.8%) and in EFV 2/38 (5.3%).*VF = virologic failure†NR = non-response; > 400 copies/mL at week 24 or early discontinuation; All achieved > log10 decrease in HIV RNA at nadir.¹REL = virologic relapse; > 400 copies/mL after initial response of < 400 copies/mL or 1.0 log10 increase above nadir level.2Failure occurred after week 48.‡Mutation developed after patient was a virologic failure.∞A common polymorphism that does not affect raltegravir sensitivity in phenotypic assays. All other mutations listed were associated with reduced drug sensitivity.

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22Protocol 004: Percent of Patients With Grade 3 / 4* Laboratory Abnormalities

Protocol 004: Percent of Patients With Grade 3 / 4* Laboratory Abnormalities

Laboratory Test Toxicity Criteria*EFV (N = 38)

N (%)RAL (N = 160)

N (%)

Absolute Neutrophil Count < 750 cells/µL 0 (0.0) 1 (0.6)

Alanine Aminotransferase > 5 x ULN 2 (5.3) 2 (1.3)

Alkaline Phosphatase > 5 x ULN 0 (0.0) 1 (0.6)

Aspartate Aminotransferase > 5 x ULN 1 (2.6) 4 (2.5)

Creatine Kinase ≥ 10 x ULN 1 (2.6) 10 (6.3)

Fasting LDL Cholesterol ≥ 190 mg/dL 2 (5.3) 1 (0.6)

Fasting Total Cholesterol > 300 mg/dL 2 (5.3) 0 (0.0)

Fasting Triglycerides > 750 mg/dL 3 (7.9) 0 (0.0)

Lipase > 3 x ULN 0 (0.0) 2 (1.3)

Pancreatic Amylase > 2 x ULN 0 (0.0) 4 (2.5)


*No grade 3 or 4 abnormalities were reported in either treatment group for the following parameters: hemoglobin, platelet count, fasting glucose, creatinine, and total bilirubin.

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EFV vs. LPV/r: Study DesignEFV vs. LPV/r: Study Design

Juan Sierra Madero et al. AIDS 2008; abstract TUAB0104. Reprinted with permission.

Screened (N = 264)

ZDV/ 3TC 300/150 mg BIDZDV/ 3TC 300/150 mg BIDSubstitution of AZT for ABC allowedSubstitution of AZT for ABC allowed

(N = 14; EFV 6 and LPV/r 8)(N = 14; EFV 6 and LPV/r 8)

(1:1)

National Multicenter, Open-Label, Randomized, 48-Week Study to Compare the Virological Success of EFV vs. LPV/r in Treatment-Naïve HIV-1 Infected Subjects

EFV 600 mg QD (N = 95) LPV/r 400/100 mg BID (N = 94)

Screening Failure(N = 75)

189 ARV naïve; > 18 years; HIV RNA 1,000 copies/mL, CD4+ < 200Randomization stratified by CD4+ (> and < 100 cells/mL)

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EFV vs. LPV/r: Patient Disposition At Week 48EFV vs. LPV/r: Patient Disposition At Week 48


EfavirenzN = 95

Lopinavir/rN = 94

P Value

Completed 48 Weeks 68 (71) 55 (58) 0.05

Viral Load < 50 Copies/mL 67 (70) 50 (53) 0.01

Discontinuation

Virological Failure 7 (7) 17 (18) 0.02

Lost to Follow Up 15 (16) 11 (12) 0.4

Adverse Events 5 (5) 11 (12) 0.1 Death 2 (2) 5 (5) Tuberculosis 1 (1) 2 (2)

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EFV vs. LPV/r: Proportion of Patients With HIV RNA < 400 Copies/mLEFV vs. LPV/r: Proportion of Patients With HIV RNA < 400 Copies/mL


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EFV vs. LPV/r: Change of Median CD4+ Cell CountsEFV vs. LPV/r: Change of Median CD4+ Cell Counts


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TMC278–C204: Study DesignTMC278–C204: Study Design

Mario Santoscoy et al. AIDS 2008; abstract TUAB0103. Reprinted with permission.

Ongoing (extended to 5 years), randomized, active-controlled, dose-ranging Phase IIb study in ARV-naïve patients.

Primary objective to evaluate the TMC278 efficacy (ITT-TLOVR) and safety dose-response relationship at Week 48.

EFV = efavirenz; ITT = intent to treat; TLOVR = time to loss of virologic response NRTI backbone chosen by investigator and is either AZT/3TC or TDF/FTC administered as fixed-dose combinations where available

Screening and Randomization

1:1:1:1

ARV-Naïve Patients (N = 368)

HIV RNA 5,000 Copies/mL

Primary Analysis at 48 Weeks

Analysis at 96 Weeks

96 weeks

TMC278 25 mg QD + 2 NRTIs N = 93

TMC278 75 mg QD + 2 NRTIs N = 95

TMC278 150 mg QD + 2 NRTIs N = 91

EFV 600 mg QD + 2 NRTIs N = 89

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28TMC278–C204: High Response Rate and Sustained Virologic Response Over 96 Weeks Similar to EFV

TMC278–C204: High Response Rate and Sustained Virologic Response Over 96 Weeks Similar to EFV


HIV-1 RNA < 50 Copies/mL to Week 96 (ITT-TLOVR Algorithm)

CI = confidence interval

76%

72%

71%71%

100

80

60

40

20

0

02 4 8 12 16 20 24 32 40 48 56 64 72 80 88 96Time (Weeks)

Vir

olo

gic

Res

po

nd

ers

(%, 9

5% C

I)

TMC278 25 mg QD (N = 93) TMC278 75 mg QD (N = 95)TMC278 150 mg QD (N = 91) EFV 600 mg QD (N = 89)

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29TMC278–C204: Potent Antiviral Efficacy at Week 48 Sustained to Week 96

TMC278–C204: Potent Antiviral Efficacy at Week 48 Sustained to Week 96


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TMC278–C204: Doses Were Safe and Well Tolerated With No Consistent Association Between Safety Assessments and TMC278 Dose

TMC278–C204: Doses Were Safe and Well Tolerated With No Consistent Association Between Safety Assessments and TMC278 Dose


AE (%)

TMC278 groups

25 mg QD (N = 93)

75 mg QD (N = 95)

150 mg QD (N = 91)

All TMC278(N = 279)

EFV 600 mg QD(N = 89)

Any AE 90 97 92 93 93

AEs Leading to Discontinuation 9 12 14 12 9

Any Serious AEs 13 14 10 12 15

Any Grade 3/4 AEs 30 25 26 27 21

Investigations Reported as Grade 3/4 AEs*

16 8 12 12 9

Grade 3/4 Laboratory Abnormalities

33 22 24 27 24

Summary of Treatment-Emergent AEs, Regardless of Severity and Causality

*Investigations included laboratory assessments and electrocardiograms

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TMC278–C204: Additional InvestigationsTMC278–C204: Additional Investigations

Endocrine

• No clinically relevant changes in adrenal and thyroid parameters were observed

ECG

• Increases in QTc interval were seen with all TMC278 doses and EFV up to 48 weeks, which then stabilizedup to Week 96– increases were primarily seen with the AZT/3TC backbone– mean increase was lowest with TMC278 25 mg


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GRACE: Study Design andBaseline CharacteristicsGRACE: Study Design andBaseline Characteristics

Judith Currier et al. AIDS 2008; abstract THPDB202. Reprinted with permission.

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GRACE: 24-Week Interim Analysis: Efficacy and SafetyGRACE: 24-Week Interim Analysis: Efficacy and Safety

Virologic Response (VL < 50 Copies/mL)

• At Week 24, mean increase in CD4 cell count in women was 86 cells/mm3 (ITT-NC=F)

• At Week 24, discontinuation rate for women was 24.4% -- Discontinuations were generally unrelated to VF (0.6%) or AEs (7.8%)

Safety and Tolerability in Women

• Most common grade 2-4 adverse events at least possibly related to study drug:

—Nausea (6.1%)— Diarrhea (5.6%)— Rash (2.8%)— Weight gain (2.8%)

• Serious AEs were reported in 16.7% (N = 30) of women

— Most common was pneumonia, reported in 4.4% (N = 8) of women

• No major issues with Grade 2-4 laboratory abnormalities were noted

ITT, intention-to-treat;TLOVR, time to loss of virologic response algorithm;TLOVR-non-VF, algorithm excluded patients who discontinued for reasons other than virologic failure;NC=F, non-completer=failure

Judith Currier et al. AIDS 2008; abstract THPDB202. Reprinted with permission.

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• Visit The Body PRO for comprehensive coverage of AIDS 2008.This presentation was created to accompany The Body PRO's summaries of key research presented at AIDS 2008, by David Wohl, M.D. Learn more at: TheBodyPRO.com/AIDS2008

• In addition, be sure to browse through The Body PRO's extensive coverage of AIDS 2008, which 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/AIDS2008 today for a full listing of our conference materials!

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