# Presentation: 672673

## 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**

## 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**

## HIV Resistance Collaborative GroupClinical 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)**

## 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)**

## 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**

## HIV Resistance Collaborative Group Clinical Validation Subcommittee WorkshopApril 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**

## 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**

## 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**

## Development of Standardized  Data Analysis Plan (DAP)

**Victor DeGruttola (Chair, Harvard)**
**Dan Holder (Merck)**
**Andrew Phillips (Royal Free, UK)**
**Lynn Dix (Glaxo Wellcome)**

## Presentation of Data Analysis Plan by Victor DeGruttola

## 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**

## 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**

## Nucleoside Reverse Transcriptase Inhibitors

**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 Inhibitors**

## Nucleotide Reverse Transcriptase Inhibitors

**	****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**

**Nucleotide Reverse Transcriptase Inhibitors**

## Protease Inhibitors

**Ritonavir****	****32I; 82A/T/F/S; 84V; 90M****	**
**Saquinavir****	****48V; 82A/T; 84V; 90M**
**Nelfinavir****	****30N; 82F; 84V; 90M**
**Amprenavir****	****32I; 50V; 84V****	**

**Protease Inhibitors**

## Calculation ofGenotypic 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 **

## Calculation ofPhenotypic 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”**

## 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**

## Selection of Studies forRe-Analysis

_**Criteria**_**:**
**Study completed**
**Adequate size for multivariate analysis**
**12 of 15 studies qualified**
**10 retrospective**
**2 prospective, intervention based**

## Description of Re-analyzed Studies

**Study Name****	**
**Investigator**
**N with GT/PT**
**Treatment Experience**
**Resistance Technology**
**Median Baseline HIV RNA (range) [25****th**** – 75****th****]**
**Median Baseline CD4 (range) **
**[25****th**** – 75****th****]**

**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 Studies**

## Description of Re-analyzed Studies

**Name****	**
**Investigator**
**N with GT/PT**
**Treatment Experience**
**Resistance Technology**
**Median Baseline HIV RNA (range) [25****th**** – 75****th****]**
**Median Baseline CD4 (range)**
** ****[25****th**** – 75****th****]**

**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 Studies**

## 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**

## 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**

## Meta-Analysis from Surrogate Marker Working Group

## Baseline HIV-1 RNA (Odds Ratio per 1.0 log10 Increase)Unadjusted - Retrospective Studies - Dropouts as Failures

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

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

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

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

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

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

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

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

**4-FR Phenotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)****Adjusted 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

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

## Post-Meeting CorrectionBaseline HIV-1 RNA (Odds Ratio per 1.0 log10 Increase)Adjusted for Genotypic Sensitivity Score, New Drug Covariates  Prospective Studies - Dropouts as Failures 

## Baseline Genotypic Sensitivity Score (Odds Ratio per 1.0 Unit Increase)Adjusted for Baseline HIV RNA, New Drug CovariatesProspective Studies – Dropouts as failures

## 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**

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

## 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**

## 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**

## VIRA3001

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

**Preliminary Results**
**October, 1999**

## VIRA3001 Study Design

** ****(n = 144)**

**Control**
**(n = 130)**

**Follow-up**
**Wk 2, 4, 8, 12 & 16**

**Follow-up**
**Wk 2, 4, 8, 12 & 16**

**Screening (Week 5)**

**Baseline (Day 1)**

**No therapy changes permitted**

**VIRA3001 Study Design**

## 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**

## HIV-1 RNA ResponseModified ITT (Observed Data)

**HIV-1 RNA Response****Modified ITT (Observed Data)**

## HIV-1 RNA ResponseModified ITT (LOCF)

## 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**

## 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**

## MELLORS END

## BACKUP SLIDES

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

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

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

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

## 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

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

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

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

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

## 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**