JWM 11/99

Resistance Collaborative Group Resistance Collaborative Group Re-Analysis of Studies and Review Re-Analysis of Studies and Review

of Ongoing Prospective Studiesof Ongoing Prospective Studies

John W. Mellors, MDJohn W. Mellors, MD

Director, HIV/AIDS ProgramDirector, HIV/AIDS ProgramChief, Division of Infectious DiseasesChief, Division of Infectious Diseases

University of Pittsburgh and Pittsburgh VAUniversity of Pittsburgh and Pittsburgh VA

JWM 11/99

OutlineOutline

• Goals of Clinical Validation Subcommittee (CVSC)

• Review of CVSC Workshop - April 21-22, 1999

• Development of standardized Data Analysis Plan (DAP)

• Review of Mutation Table used for DAP

• Description of re-analyzed studies

• Composite data from re-analyzed studies

• Presentation of representative studies

– ACTG 333, CNAA 2007, Frankfurt cohort

• Review of prospective studies in progress

• Summary of key points

JWM 11/99

HIV Resistance Collaborative GroupHIV Resistance Collaborative GroupClinical Validation SubcommitteeClinical Validation Subcommittee

John Mellors (Chair, Pitt)

Richard D’Aquila (Harvard)

Veronica Miller (Germany)

Louise Pedneault (GW)

Amy Patick (Agouron)

Victor DeGruttola (Harvard)

Andrew Phillips (UK)

Lynn Dix (GW)

Dan Holder (Merck)

Jeff Murray (FDA)

JWM 11/99

Goals of Clinical Validation SubcommitteeGoals of Clinical Validation Subcommittee

•Compile and evaluate existing data on clinical validation of resistance tests

•Review issues relevant to clinical validation of resistance tests– study design– patient populations studied– definitions of drug sensitivity and resistance– definitions of virologic endpoints– methods of analysis (control for covariates)

JWM 11/99

OutlineOutline

• Goals of Clinical Validation Subcommittee (CVSC)

• Review of CVSC Workshop - April 21-22, 1999

• Development of standardized Data Analysis Plan (DAP)

• Review of Mutation Table used for DAP

• Description of re-analyzed studies

• Composite data from re-analyzed studies

• Presentation of representative studies

– ACTG 333, CNAA 2007, Frankfurt cohort

• Review of prospective studies in progress

• Summary of key points

JWM 11/99

HIV Resistance Collaborative Group HIV Resistance Collaborative Group Clinical Validation Subcommittee WorkshopClinical Validation Subcommittee Workshop

April 21-22, 1999April 21-22, 1999

•Goal: review existing clinical data on relationship between genotype/phenotype and response– studies identified by review of meeting abstract– presentations by lead investigators– questions/clarifications by Subcommittee

• Studies presented and reviewed– 13 retrospective studies– 2 prospective, intervention-based studies

JWM 11/99

Clinical Validation Subcommittee Clinical Validation Subcommittee Workshop April 21-22, 1999Workshop April 21-22, 1999

• Impressions:– consistent associations between baseline genotype or

phenotype and virological response– highly variable methods of analysis• definitions of resistance (mutations/cut-offs)• virological endpoints• methods of analysis• control for key covariates

– need for standardized data analysis• Action Item:– develop Data Analysis Plan (DAP) for standardized

re-analysis of studies

JWM 11/99

OutlineOutline

• Goals of Clinical Validation Subcommittee (CVSC)

• Review of CVSC Workshop - April 21-22, 1999

• Development of standardized Data Analysis Plan (DAP)

• Review of Mutation Table used for DAP

• Description of re-analyzed studies

• Composite data from re-analyzed studies

• Presentation of representative studies

– ACTG 333, CNAA 2007, Frankfurt cohort

• Review of prospective studies in progress

• Summary of key points

JWM 11/99

Development of Standardized Development of Standardized Data Analysis Plan (DAP)Data Analysis Plan (DAP)

•Victor DeGruttola (Chair, Harvard)

•Dan Holder (Merck)

•Andrew Phillips (Royal Free, UK)

•Lynn Dix (Glaxo Wellcome)

JWM 11/99

Presentation of Data Analysis Presentation of Data Analysis Plan by Victor DeGruttolaPlan by Victor DeGruttola

JWM 11/99

OutlineOutline

• Goals of Clinical Validation Subcommittee (CVSC)

• Review of CVSC Workshop - April 21-22, 1999

• Development of standardized Data Analysis Plan (DAP)

• Review of Mutation Table used for DAP

• Description of re-analyzed studies

• Composite data from re-analyzed studies

• Presentation of representative studies

– ACTG 333, CNAA 2007, Frankfurt cohort

• Review of prospective studies in progress

• Summary of key points

JWM 11/99

DAP Mutation TableDAP Mutation Table

• Goal: Standardization of genotype analysis– not intended for patient management

• Consensus of RCG members (clinical data/opinion)– developed before re-analysis of studies

• Focus on primary mutations for each drug that would be expected to markedly reduced response to that drug– Not inclusive of all possible mutations that influence

susceptibility• Used to calculate genotypic sensitivity score and number

of mutations present for each drug class

Zidovudine 70R; 215Y/F; 41L; 67N; 210W; 219Q

Stavudine See MNR-1 and MNR-2

Didanosine 74V; 65R; 184V/I

Zalcitabine 65R; 69D; 74V; 184V/I

Lamivudine M184V/I

Abacavir Any 3 or more of: 184V/I; 65R; 74V; 115F; 41L; 67N; 70R; 210W; 215Y/F; K219Q

Multi-Nucleoside Q151M Resistance-1 (MNR-1) Secondary: 62V; 75I; 77L; 116Y

Multi-Nucleoside 3 amino acid insert between codons 69-70 (69Ins) Resistance-2 (MNR-2) 2’: 41L; 62V; 67N; 70R; 210W; 215Y/F; 219Q

Nucleoside Reverse Transcriptase InhibitorsNucleoside Reverse Transcriptase Inhibitors

Adefovir 65R; 70E; MNR-2 184V causes increased susceptibility

Non-nucleoside Reverse Transcriptase InhibitorsNon-nucleoside Reverse Transcriptase Inhibitors

Nevirapine 103N; 106A; 108I; 181C/I; Y188C/L/H; G190A/S

Delavirdine 103N; 181C; 236L

Efavirenz 103N; 188L; 190S/ESecondary: 100I; 101E/Q; 108I; 188H; 225H

Nucleotide Reverse Transcriptase InhibitorsNucleotide Reverse Transcriptase Inhibitors

Indinavir 32I; 82A/T/F; 84V; 90M

Ritonavir 32I; 82A/T/F/S; 84V; 90M

Saquinavir 48V; 82A/T; 84V; 90M

Nelfinavir 30N; 82F; 84V; 90M

Amprenavir 32I; 50V; 84V

Protease InhibitorsProtease Inhibitors

JWM 11/99

Calculation ofCalculation ofGenotypic Sensitivity ScoreGenotypic Sensitivity Score

•Mutation present for drug received = 0

•Mutation not present for drug received = 1

• Exceptions:– M184V for Adefovir = 1.5– AZT mutations for d4T, ddI, ddC = 0.75

• Total Score = sum of individual drug scores

JWM 11/99

Calculation ofCalculation ofPhenotypic Sensitivity ScorePhenotypic Sensitivity Score

•Resistance present for drug received = 0

•Resistance absent for drug received = 1

• Total Score = sum of individual drug scores

•Resistance defined as either– > 4-fold or > 10-fold decrease in

susceptibility (increase in IC50)– separate analyses for each “cut-off”

JWM 11/99

OutlineOutline

• Goals of Clinical Validation Subcommittee (CVSC)

• Review of CVSC Workshop - April 21-22, 1999

• Development of standardized Data Analysis Plan (DAP)

• Review of Mutation Table used for DAP

• Description of re-analyzed studies

• Composite data from re-analyzed studies

• Presentation of representative studies

– ACTG 333, CNAA 2007, Frankfurt cohort

• Review of prospective studies in progress

• Summary of key points

JWM 11/99

Selection of Studies forSelection of Studies forRe-AnalysisRe-Analysis

•Criteria:– Study completed– Adequate size for multivariate analysis

• 12 of 15 studies qualified– 10 retrospective– 2 prospective, intervention based

Study Name

Investigator

N with GT/PT

Treatment Experience

Resistance Technology

Median Baseline HIV RNA (range) [25th – 75th]

Median Baseline CD4 (range) [25th – 75th]

ABC Pooled

R. Lanier

134 / 84

nRTI exp,PI/NNRTI naïve

GT (ABI)PT (Virco)

3.7 (2.6 – 5.8)

417 (11– 1266)

ACTG 333

M. Para

46 / 0

nRTI/SQV exp, naïve to other PIs

GT (ABI/ clonal seq)

4.1

240

ACTG 364

D. Katzenstein

144 / 0

Heavily nRTI exp, naïve to PI/NNRTI

GT (Stanford)

4.1 [3.6 – 4.6]

323 [242 – 460]

ACTG 372

S. Hammer

96 / 80

Heavily nRTI exp, IDV exp

GT (Virco)PT (Virco)

4.6

196

CNAA 2007

M. Ait-Khaled

94 / 64

Heavily nRTI/ PI exp, 42% NNRTI exp

GT (ABI)PT (Virco)

5.1 (3.4 - 6.6)

160 (10 -782)

Description of Re-analyzed StudiesDescription of Re-analyzed Studies

Name

Investigator

N with GT/PT

Treatment Experience

Resistance Technology

Median Baseline HIV RNA (range) [25th – 75th]

Median Baseline CD4 (range) [25th – 75th]

Stanford

A. Zolopa

54 / 0

Heavily nRTI/PI exp

GT (Stanford)

5.0

245

BC Centre

R. Harrigan

58 / 53

nRTI exp,NNRTI naïve

GT (Virco)

PT (Virco)

4.8 (2.7 – 5.8)

160 (10 - 560)

Frankfurt

V. Miller

0 / 50

Heavily pretreated

PT (Virco)

5.5

95

Swiss

S. Yerly

62 / 0

HAART “failures”

GT (ABI)

5.2 (3.1 – 6.4)

113 (4 – 633)

GS 408

M. Miller

161 / 0

Heavily pretreated

GT (Pharmacia)

4.1*

338*

*Mean Values

Description of Re-analyzed StudiesDescription of Re-analyzed Studies

JWM 11/99

OutlineOutline

• Goals of Clinical Validation Subcommittee (CVSC)

• Review of CVSC Workshop - April 21-22, 1999

• Development of standardized Data Analysis Plan (DAP)

• Review of Mutation Table used for DAP

• Description of re-analyzed studies

• Composite data from re-analyzed studies

• Presentation of representative studies

– ACTG 333, CNAA 2007, Frankfurt cohort

• Review of prospective studies in progress

• Summary of key points

JWM 11/99

Composite Data PresentationsComposite Data Presentations

• 8 retrospective, then 2 prospective studies– GS 408 and Swiss studies not included– HIV RNA change modeled rather than

failure endpoint• Dropout = failures analyses (DAF)• Models (unadjusted and adjusted)– HIV RNA– Genotypic Sensitivity Score– Number of Mutations by Drug Class– Phenotypic Sensitivity Score

• Other analyses/models provided in documents

JWM 11/99

Meta-Analysis from Surrogate Meta-Analysis from Surrogate Marker Working GroupMarker Working Group

Baseline HIV-1 RNA (Odds Ratio per 1.0 logBaseline HIV-1 RNA (Odds Ratio per 1.0 log1010 Increase) Increase)Unadjusted - Retrospective Studies - Dropouts as FailuresUnadjusted - Retrospective Studies - Dropouts as Failures

0.1 1 10 100

ABC Pooled

ACTG 364

ACTG 364 - NFV or EFZ

ACTG 372 - Grps B&D

ACTG 372 - Grp B

CNAA 2007

Stanford

BC Centre

ACTG 333

Baseline HIV-1 RNA (Odds Ratio per 1.0 log10 Increase)Adjusted for Genotypic Sensitivity Score and New Drug Covariates

0.1 1 10 100

ABC Pooled

ACTG 364

ACTG 364 - NFV or EFZ

ACTG 372 - Grps B&D

ACTG 372 - Grp B

CNAA 2007

Stanford

BC Centre

Baseline Genotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)Baseline Genotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)Unadjusted - Retrospective Studies - Dropouts as FailuresUnadjusted - Retrospective Studies - Dropouts as Failures

0.1 1 10 100

ABC Pooled

ACTG 364

ACTG 364 - NFV or EFZ

ACTG 372 - Grps B&D

ACTG 372 - Grp B

CNAA 2007

Stanford

BC Centre

Baseline Genotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)Baseline Genotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)Adjusted for Baseline HIV RNA and New Drug CovariatesAdjusted for Baseline HIV RNA and New Drug Covariates

0.1 1 10 100

ABC Pooled

ACTG 364

ACTG 364 - NFV or EFZ

ACTG 372 - Grps B&D

ACTG 372 - Grp B

CNAA 2007

Stanford

BC Centre

Baseline # of NRTI Mutations (Odds Ratio per 1 additional)Adjusted for Other Classes in Regimen

0.1 1 10 100

ABC Pooled

ACTG 364

ACTG 364 - NFV or EFZ

ACTG 372 - Grps B&D

ACTG 372 - Grp B

CNAA 2007

BC Centre

Baseline # of NRTI Mutations (Odds Ratio per 1 additional)Adjusted for Baseline HIV RNA, New Drug Covariates and Other Classes

0.1 1 10 100

ABC Pooled

ACTG 364

ACTG 364 - NFV or EFZ

ACTG 372 - Grps B&D

ACTG 372 - Grp B

CNAA 2007

BC Centre

Baseline # of PI Mutations (Odds Ratio per 1 additional)Baseline # of PI Mutations (Odds Ratio per 1 additional)Adjusted for Other Classes in RegimenAdjusted for Other Classes in Regimen

0.1 1 10 100

ACTG 372 - Grps B&D

ACTG 372 - Grp B

CNAA 2007

Stanford

BC Centre

ACTG 333

Baseline # of PI Mutations (Odds Ratio per 1 additional)Baseline # of PI Mutations (Odds Ratio per 1 additional)Adjusted for Baseline HIV RNA, New Drug Covariates and Other Classes Adjusted for Baseline HIV RNA, New Drug Covariates and Other Classes

0.1 1 10 100

ACTG 372 - Grps B&D

ACTG 372 - Grp B

CNAA 2007

Stanford

BC Centre

ACTG 333

0.01 0.1 1 10 100

ACTG 372 B & D

ABC Pooled

CNA2007

BC Centre

Frankfurt

4-FR Phenotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)4-FR Phenotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)Adjusted for Baseline HIV RNA, New Drug CovariatesAdjusted for Baseline HIV RNA, New Drug Covariates

10-FR Phenotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)Adjusted for Baseline HIV RNA, New Drug Covariates

0.01 0.1 1 10 100

ABC Pooled

ACTG 372 - Grps B&D

ACTG 372 - Grp B

CNA2007

BC Centre

Frankfurt

JWM 11/99

Re-Analysis of Prospective Re-Analysis of Prospective Studies:VIRADAPT and GARTStudies:VIRADAPT and GART

Post-Meeting CorrectionPost-Meeting CorrectionBaseline HIV-1 RNA (Odds Ratio per 1.0 log10 Increase)Baseline HIV-1 RNA (Odds Ratio per 1.0 log10 Increase)

Adjusted for Genotypic Sensitivity Score, New Drug Covariates Adjusted for Genotypic Sensitivity Score, New Drug Covariates Prospective Studies - Dropouts as Failures Prospective Studies - Dropouts as Failures

0.1 1 10 100

Gart - noGenotyping

Viradapt - noGenotyping

Gart - Geno

Viradapt -Geno

Baseline Genotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)Baseline Genotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)Adjusted for Baseline HIV RNA, New Drug CovariatesAdjusted for Baseline HIV RNA, New Drug Covariates

Prospective Studies – Dropouts as failuresProspective Studies – Dropouts as failures

0.1 1 10 100

Gart - no Genotyping

Viradapt - no Genotyping

Gart - Geno

Viradapt - Geno

JWM 11/99

OutlineOutline

• Goals of Clinical Validation Subcommittee (CVSC)

• Review of CVSC Workshop - April 21-22, 1999

• Development of standardized Data Analysis Plan (DAP)

• Review of Mutation Table used for DAP

• Description of re-analyzed studies

• Composite data from re-analyzed studies

• Presentation of representative studies

– ACTG 333, CNAA 2007, Frankfurt cohort

• Review of prospective studies in progress

• Summary of key points

JWM 11/99

Presentations by M. Para, M. Presentations by M. Para, M. Ait-Khaled, V. MillerAit-Khaled, V. Miller

JWM 11/99

OutlineOutline

• Goals of Clinical Validation Subcommittee (CVSC)

• Review of CVSC Workshop - April 21-22, 1999

• Development of standardized Data Analysis Plan (DAP)

• Review of Mutation Table used for DAP

• Description of re-analyzed studies

• Composite data from re-analyzed studies

• Presentation of representative studies

– ACTG 333, CNAA 2007, Frankfurt cohort

• Review of prospective studies in progress

• Summary of key points

JWM 11/99

Ongoing Prospective TrialsOngoing Prospective Trials

Name Location (Sponsor) Design Status

RESA 2026 US (GW/Virco) PT vs SOC Closed

VIRA 3001 US (GW/Virco) PT vs SOC Interim Analysis

CERT US (Military) PT vs GT vs SOC Enrolled

CTCG 575 US (ViroLogics) PT vs SOC Enrolling

NARVAL FR (ARNS) PT vs GT vs SOC Enrolling

SEARCH US (VGI) GT vs SOC Enrolling

HAVANNA Spain 2 x 2 (GT x PT) Enrolling

ERA UK (MRC/Virco) PT vs GT vs SOC Opening

A5076 US (ACTG) PT vs GT vs GT/PT In Development

JWM 11/99

VIRA3001VIRA3001

An Open-Label, Randomized Trial Comparing the Effect on Viral Load of Standard HIV Treatment Practice (Delayed Phenotyping) with Treatment

Based on the Antivirogram™ (Immediate Phenotyping)

Preliminary Results

October, 1999

JWM 11/99

AntivirogramAntivirogram (n = 144)(n = 144)

ControlControl(n = 130)(n = 130)

Follow-upFollow-upWk 2, 4, 8, 12 & 16Wk 2, 4, 8, 12 & 16

Follow-upFollow-upWk 2, 4, 8, 12 & 16Wk 2, 4, 8, 12 & 16

Screening (Week 5)Screening (Week 5)

Baseline (Day 1)Baseline (Day 1)

No therapy changes permitted

VIRA3001 Study DesignVIRA3001 Study Design

JWM 11/99

Patient PopulationPatient Population

• Prior therapy history of 2 NRTIs and 1 PI

• Plasma HIV-1 RNA 2,000 copies/ml

• Stable ART for 1 month prior to screening

•No prior phenotypic testing

JWM 11/99

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0 2 4 8 12 16

Weeks of Study

Me

an

lo

g 10 C

ha

ng

e F

rom

Ba

se

lin

e

Antivirogram

Control

AVG

55

3962

3357CON

5145

4265 59

4955

p=.109 p=.005 p=.019 p=.056 p=.011

HIV-1 RNA ResponseHIV-1 RNA ResponseModified ITT (Observed Data)Modified ITT (Observed Data)

JWM 11/99

HIV-1 RNA ResponseHIV-1 RNA ResponseModified ITT (LOCF)Modified ITT (LOCF)

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0 2 4 8 12 16

Weeks of Study

Me

an

log

10 C

ha

ng

e F

rom

Ba

se

line

Antivirogram (n=62)

Control (n=65)

p=.692 p=.006 p=.014 p=.015 p=.007

JWM 11/99

OutlineOutline

• Goals of Clinical Validation Subcommittee (CVSC)

• Review of CVSC Workshop - April 21-22, 1999

• Development of standardized Data Analysis Plan (DAP)

• Review of Mutation Table used for DAP

• Description of re-analyzed studies

• Composite data from re-analyzed studies

• Presentation of representative studies

– ACTG 333, CNAA 2007, Frankfurt cohort

• Review of prospective studies in progress

• Summary of key points

JWM 11/99

Summary of Key PointsSummary of Key Points

• Standardized re-analysis of retrospective studies generally confirms associations between baseline genotype or phenotype and virological response

– small datasets variability (broad CIs)

• Prospective, intervention-based trials support the clinical value of resistance testing for selection of treatment regimens in experienced patients

• Data accumulating from ongoing clinical trials of approved and investigational agents will refine the interpretation and improve the predictive value of specific resistance test results

JWM 11/99

MELLORS ENDMELLORS END

JWM 11/99

BACKUP SLIDESBACKUP SLIDES

4-FR PI Phenotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)4-FR PI Phenotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)Adjusted for Baseline HIV RNA, New Drug Covariates and Other ClassesAdjusted for Baseline HIV RNA, New Drug Covariates and Other Classes

0.01 0.1 1 10 100

CNA2007

Frankfurt

10-FR NRTI Phenotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)10-FR NRTI Phenotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)Adjusted for Baseline HIV RNA, New Drug Covariates, Other ClassesAdjusted for Baseline HIV RNA, New Drug Covariates, Other Classes

0.01 0.1 1 10 100

ACTG 372 - Grps B&D

ACTG 372 - Grp B

Frankfurt

10-FR PI Phenotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)10-FR PI Phenotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)Adjusted for Baseline HIV RNA, New Drug Covariates, and Other ClassesAdjusted for Baseline HIV RNA, New Drug Covariates, and Other Classes

0.01 0.1 1 10 100

ACTG 372 - Grps B&D

ACTG 372 - Grp B

Frankfurt

Number of New Drugs in Regimen (Odds Ratio per Additional New Drug) Number of New Drugs in Regimen (Odds Ratio per Additional New Drug) Retrospective Studies - Dropouts as FailureRetrospective Studies - Dropouts as Failure

0.1 1 10 100

ACTG 364

ACTG 364 - NFV orEFZ

ACTG 372 - Grps B&D

ACTG 372 - Grp B

BC Centre

Baseline # of NRTI Mutations (Odds Ratio per 1 additional)Baseline # of NRTI Mutations (Odds Ratio per 1 additional)Adjusted for Baseline HIV RNA, New Drug Covariates and Other Classes Adjusted for Baseline HIV RNA, New Drug Covariates and Other Classes

Prospective Studies - Dropouts as FailureProspective Studies - Dropouts as Failure

0.1 1 10 100

Gart - no Genotyping

Viradapt - no Genotyping

Gart - Geno

Viradapt - Geno

Baseline # of PI Mutations (Odds Ratio per 1 additional)Baseline # of PI Mutations (Odds Ratio per 1 additional)Adjusted for Baseline HIV RNA, New Drug Covariates and Other Classes Adjusted for Baseline HIV RNA, New Drug Covariates and Other Classes

0.1 1 10 100

Gart - no Genotyping

Viradapt - noGenotyping

Gart - Geno

Viradapt - Geno

4-FR NRTI Phenotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)4-FR NRTI Phenotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)Adjusted for Baseline HIV RNA, New Drug Covariates, and Other ClassesAdjusted for Baseline HIV RNA, New Drug Covariates, and Other Classes

0.01 0.1 1 10 100

CNA2007

Frankfurt

Potent New Drug (Odds Ratio for Change from No to Yes)Potent New Drug (Odds Ratio for Change from No to Yes)All Studies - Dropouts as FailuresAll Studies - Dropouts as Failures

0.01 0.1 1 10 100

CNAA 2007

BC Centre

Gart - no Genotyping

Viradapt - noGenotyping

Gart - Geno

Viradapt - Geno

Number of New Drugs in Regimen (Odds Ratio per Additional New Drug) Number of New Drugs in Regimen (Odds Ratio per Additional New Drug) Prospective Studies - Dropouts as FailureProspective Studies - Dropouts as Failure

0.01 0.1 1 10 100

Gart - no Genotyping

Viradapt - noGenotyping

Gart - Geno

Viradapt - Geno

JWM 11/99

Planned Analyses*Planned Analyses*

• Virologic response - change in log10 RNA from baseline

– ITT Observed & LOCF (Wilcoxon Rank-Sum Test controlled for investigator site)

• Proportion of subjects with <400 HIV RNA copies/mL plasma

– Cochran-Mantel-Haenszel Test controlled for investigator site

• Immunologic (CD4 cell) response - change from baseline

– ITT Observed & LOCF (Wilcoxon Rank-Sum Test controlled for investigator site)

• Number of virologic endpoints reached

– Cochran-Mantel-Haenszel Test controlled for investigator site

– Virologic failure defined as failure to achieve 0.5 log10 decrease from baseline in HIV RNA at Week 8 or increase above baseline or >0.5 log10 increase above nadir after Week 8

*Analyses performed on subjects who started therapy at Day 1*Analyses performed on subjects who started therapy at Day 1