# Presentation: 772448

## The Predictive Quality of Genotype and Phenotype Data on Virological Response to Salvage Therapy in HIV-1 Infected Patients (CNAA2007)Resistance Collaborative Group Reanalysis

- M Ait-Khaled, J Scott, L Dix, J Falloon,A Rakik, P Griffin, D Thomas and L Pedneault
- for the CNA2007 study team

**Notes:**
- phase II salvage study submitted to the amprenavir NDA

## Background Information

- Open-label, single arm trial of ABC (300mg BID) + APV (1200mg BID) + EFV (600mg QD) as salvage therapy
- 101 subjects enrolled and 99 subjects exposed to study drugs
- Subjects had extensive prior antiretroviral experience
- 44% were nNRTI experienced
- 60% had prior experience with 3-4 PIs
- 72% had prior experience with 4-5 NRTIs
- Demography
- Median Age 42 years
- 84% males / 16% Females
- 82% White / 12% Black / 6% Other

**Notes:**
Subjects were heavily ART Experienced
Prior Therapy	All Subjects	nNRTI Naive	nNRTI Experienced	  4PIs	33%	22%	48%	
3 PIs	27%	24%	30%	
2 PIs	24%	32%	15%	
1 PI	16%	22%	8%	

5 NRTIs	34%	29%	43%	
4 NRTIs	40%	48%	30%	
3 NRTIs	17%	18%	15%	
2 NRTIs	8%	6%	10%	

Efficacy analyses are summarized by nNRTI experience and pre-entry VL
At least 30 subjects were required to be enrolled in each pre-entry VL stratum (>500-40,000 and >40,000) to assess the activity of the salvage regimen in subjects at different stages of their HIV infection
No more than 40 nNRTI experienced subjects were permitted to enroll since the efficacy of EFV had yet to be established in nNRTI experienced subjects 

## Methods

- Plasma HIV-1 RNA: Amplicor
- Genotyping; Plasma population sequencing (ABI)
- Phenotyping: Antivirogram (Recombinant Virus Assay)
- End Point: Week 24 HIV-1 RNA > 400 copies/mL
- Statistical analysis according to DAP

## Baseline Characteristics of Study Population

## Baseline HIV-1 Genotypes and Phenotypes of the Study Population

- 75% of isolates had  4 NRTI-associated mutations
- 45% had  1 NNRTI-associated mutation (21%  2)
- 81% had  4 PI-associated mutation (50%  5)
- 			Abacavir	Amprenavir	Efavirenz
- _<_ 4 Fold	   45%		   58%		    67%
- _<_ 10 Fold	   94%		   86%		    73%

## Genotypic Univariate Analysis:Odds Ratio of Virological Failure

## Genotypic Multivariate Analysis:Odds Ratio of Virological FailureGSS with Additional Baseline Covariates

## Genotypic Multivariate Analysis:Odds Ratio of Virological FailureNumber of Mutations by Class withAdditional Baseline Covariates

## Phenotypic Univariate Analysis:Odds Ratio of Virological Failure

## Phenotypic Multivariate Analysis:Odds Ratio of Virological FailurePSS with Additional Baseline Covariates

## Phenotypic Multivariate Analysis:Odds Ratio of Virological FailureClass Phenotypic Sensitivities withAdditional Baseline Covariates

## Conclusions

- Genotypic Sensitivity Score was the only predictor of virological response in the model with Baseline RNA, New Drug Covariate and GSS (p=0.07).
- The number of NRTI and NNRTI mutations were also predictors of virological response after adjusting for baseline viral load and new drug covariate (p=0.03, 0.008, respectively).

- Continued

## Conclusions (continued)

- In the univariate phenotypic analysis of this study the 4-fold but not the 10-fold cutoff was associated with virological failure.
- In heavily pre-treated patients the Phenotypic Sensitivity Score using the 4-fold cutoff was the best predictor of response, independent of baseline viral load and new drug covariate.

## Investigators
Joseph Eron, MD
Judy Falloon, MD
Judith Feinberg, MD
Timothy Flanigan, MD
Scott Hammer, MD
Susan Jacobson, MD
Peter Kraus, MD
Robert Murphy, MD
Ramon Torres, MD

- Joseph Eron, MD
- Judy Falloon, MD
- Judith Feinberg, MD
- Timothy Flanigan, MD
- Scott Hammer, MD
- Susan Jacobson, MD
- Peter Kraus, MD
- Robert Murphy, MD
- Ramon Torres, MD

- Glaxo Wellcome
- Mounir Ait-Khaled, PhD
- Seth Hetherington, MD
- Judith Millard, PhD
- Louise Pedneault, MD
- Mike Rogers, PhD
- William Spreen, Pharm D
- Deborah Thomas, PhD
- Margaret Tisdale, PhD
- Josie Wolfram, PhD
- Wendy Snowden, PhD
- Abdelrahim Rakik, MSc
- Philip Griffin, BSc

- NIH
- Henry Masur, MD
- DuPont Pharma
- Doug Manion, MD
- Betsy Dusak
- Statistics
- Janna Scott
- Lynn Dix
- Gillian Amphlett
- Richard Myers, MSc

- Acknowledgement

## Backups

## Genotypic Multivariate Analysis:Odds Ratio of Virological FailureNumber of Mutations

## Phenotypic Multivariate Analysis:Odds Ratio of Virological FailureClass Phenotypic Sensitivities