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Resistance Collaborative Group ReAnalysis of Studies and Review of Ongoing Prospective Studies

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ACTG 333, CNAA 2007, Frankfurt cohort. Review of prospective studies in progress ... Frankfurt. V. Miller. 0 / 50. Heavily pretreated. PT (Virco) 5.5. 95 ... – PowerPoint PPT presentation

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Title: Resistance Collaborative Group ReAnalysis of Studies and Review of Ongoing Prospective Studies


1
Resistance Collaborative Group Re-Analysis of
Studies and Review of Ongoing Prospective Studies
  • John W. Mellors, MD
  • Director, HIV/AIDS Program
  • Chief, Division of Infectious Diseases
  • University of Pittsburgh and Pittsburgh VA

2
Outline
  • 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

3
HIV Resistance Collaborative GroupClinical
Validation Subcommittee
  • John Mellors (Chair, Pitt)
  • Richard DAquila (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)

4
Goals 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)

5
Outline
  • 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

6
HIV Resistance Collaborative Group Clinical
Validation Subcommittee WorkshopApril 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

7
Clinical Validation Subcommittee Workshop 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

8
Outline
  • 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

9
Development of Standardized Data Analysis Plan
(DAP)
  • Victor DeGruttola (Chair, Harvard)
  • Dan Holder (Merck)
  • Andrew Phillips (Royal Free, UK)
  • Lynn Dix (Glaxo Wellcome)

10
Presentation of Data Analysis Plan by Victor
DeGruttola
11
Outline
  • 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

12
DAP 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

13
Nucleoside Reverse Transcriptase Inhibitors
Zidovudine 70R 215Y/F 41L 67N 210W
219Q Stavudine See MNR-1 and MNR-2 Didanosine 74
V 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
14
Nucleotide Reverse Transcriptase Inhibitors
Adefovir 65R 70E MNR-2 184V causes increased
susceptibility
Non-nucleoside Reverse Transcriptase Inhibitors
Nevirapine 103N 106A 108I 181C/I Y188C/L/H
G190A/S Delavirdine 103N 181C
236L Efavirenz 103N 188L 190S/E Secondary
100I 101E/Q 108I 188H 225H
15
Protease 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
16
Calculation ofGenotypic 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

17
Calculation ofPhenotypic 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
  • gt 4-fold or gt 10-fold decrease in susceptibility
    (increase in IC50)
  • separate analyses for each cut-off

18
Outline
  • 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

19
Selection of Studies forRe-Analysis
  • Criteria
  • Study completed
  • Adequate size for multivariate analysis
  • 12 of 15 studies qualified
  • 10 retrospective
  • 2 prospective, intervention based

20
Description of Re-analyzed Studies
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)
21
Description 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
22
Outline
  • 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

23
Composite 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

24
Meta-Analysis from Surrogate Marker Working Group
25
Baseline HIV-1 RNA (Odds Ratio per 1.0 log10
Increase)Unadjusted - Retrospective Studies -
Dropouts as Failures
26
Baseline HIV-1 RNA (Odds Ratio per 1.0 log10
Increase)Adjusted for Genotypic Sensitivity
Score and New Drug Covariates
27
Baseline Genotypic Sensitivity Score (Odds Ratio
per 1.0 Unit Increase)Unadjusted - Retrospective
Studies - Dropouts as Failures
28
Baseline Genotypic Sensitivity Score (Odds Ratio
per 1.0 Unit Increase)Adjusted for Baseline HIV
RNA and New Drug Covariates
29
Baseline of NRTI Mutations (Odds Ratio per 1
additional)Adjusted for Other Classes in Regimen
30
Baseline of NRTI Mutations (Odds Ratio per 1
additional)Adjusted for Baseline HIV RNA, New
Drug Covariates and Other Classes
31
Baseline of PI Mutations (Odds Ratio per 1
additional)Adjusted for Other Classes in Regimen
32
Baseline of PI Mutations (Odds Ratio per 1
additional)Adjusted for Baseline HIV RNA, New
Drug Covariates and Other Classes
33
4-FR Phenotypic Sensitivity Score (Odds Ratio per
1.0 Unit Increase)Adjusted for Baseline HIV RNA,
New Drug Covariates
34
10-FR Phenotypic Sensitivity Score (Odds Ratio
per 1.0 Unit Increase)Adjusted for Baseline HIV
RNA, New Drug Covariates
35
Re-Analysis of Prospective StudiesVIRADAPT and
GART
36
Post-Meeting CorrectionBaseline HIV-1 RNA (Odds
Ratio per 1.0 log10 Increase)Adjusted for
Genotypic Sensitivity Score, New Drug Covariates
Prospective Studies - Dropouts as Failures
37
Baseline Genotypic Sensitivity Score (Odds Ratio
per 1.0 Unit Increase)Adjusted for Baseline HIV
RNA, New Drug CovariatesProspective Studies
Dropouts as failures
38
Outline
  • 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

39
Presentations by M. Para, M. Ait-Khaled, V. Miller
40
Outline
  • 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

41
Ongoing 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

42
VIRA3001
  • 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
43
VIRA3001 Study Design
Screening (Week 5)
No therapy changes permitted
Baseline (Day 1)
Antivirogram (n 144)
Control (n 130)
Follow-up Wk 2, 4, 8, 12 16
Follow-up Wk 2, 4, 8, 12 16
44
Patient 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

45
HIV-1 RNA ResponseModified ITT (Observed Data)
46
HIV-1 RNA ResponseModified ITT (LOCF)
47
Outline
  • 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

48
Summary 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

49
MELLORS END
50
BACKUP SLIDES
51
4-FR PI Phenotypic Sensitivity Score (Odds Ratio
per 1.0 Unit Increase)Adjusted for Baseline HIV
RNA, New Drug Covariates and Other Classes
52
10-FR NRTI Phenotypic Sensitivity Score (Odds
Ratio per 1.0 Unit Increase)Adjusted for
Baseline HIV RNA, New Drug Covariates, Other
Classes
53
10-FR PI Phenotypic Sensitivity Score (Odds Ratio
per 1.0 Unit Increase)Adjusted for Baseline HIV
RNA, New Drug Covariates, and Other Classes
54
Number of New Drugs in Regimen (Odds Ratio per
Additional New Drug) Retrospective Studies -
Dropouts as Failure
55
Baseline of NRTI Mutations (Odds Ratio per 1
additional)Adjusted for Baseline HIV RNA, New
Drug Covariates and Other Classes Prospective
Studies - Dropouts as Failure
56
Baseline of PI Mutations (Odds Ratio per 1
additional)Adjusted for Baseline HIV RNA, New
Drug Covariates and Other Classes
57
4-FR NRTI Phenotypic Sensitivity Score (Odds
Ratio per 1.0 Unit Increase)Adjusted for
Baseline HIV RNA, New Drug Covariates, and Other
Classes
58
Potent New Drug (Odds Ratio for Change from No to
Yes)All Studies - Dropouts as Failures
59
Number of New Drugs in Regimen (Odds Ratio per
Additional New Drug) Prospective Studies -
Dropouts as Failure
60
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 lt400 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 gt0.5 log10
    increase above nadir after Week 8

Analyses performed on subjects who started
therapy at Day 1
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