# Presentation: 675979

## BMS-045Mean Percent Change (SE) in Fasting LDL Cholesterol From BaselineTreated Subjects

**Percent Change**

**Weeks**

- BMS-045**Mean Percent Change (SE) in Fasting LDL Cholesterol From Baseline**Treated Subjects

**-10**

**1**

**-8**

**6G-8**

## BMS-045Mean Percent Change (SE) in Fasting Triglycerides From BaselineTreated Subjects

- BMS-045**Mean Percent Change (SE) in Fasting Triglycerides From Baseline**Treated Subjects

**Percent Change**

**Weeks**

**-15**

**34**

**2**

**6J-8**

## Studies Conducted:  Atazanavir Comparative Metabolic Profile 

**Studies Conducted:  Atazanavir ****Comparative Metabolic Profile **

**Preclinical models used to study ATV and 6 other PIs**
**Glucose transport (GLUT-4, -1) in adipocytes, myocytes**
**Hepatocyte lipogenesis **
**Preadipocyte differentiation **
**Mature adipocyte lipogenesis**
**Gene expression profiles in PI-treated adipocyte and hepatocyte models (Affymetrics chips, q-PCR)**
**Proteasome activity inhibition *****in vitro***
**ATV exhibited weaker effects with higher concentration- dependency (******** Cmax) in above assays vs. other PIs, which exhibited more potent, higher magnitude effects consistent with published reports from several labs**** **

**6E-2**

## Relationship of Bilirubin vs ATV Cmin by Genotype

**Relationship of Bilirubin vs ATV Cmin ****by Genotype**

**6/6**

**6/7**

**7/7**

**Cmin (ng/mL)**

**4N-1**

## BMS-043-Efficacy Cohort  Week 24 TLOVR Proportions in Responseby Resistance Sub-Groups(PI Sensitivity, Prior PI, NRTI Mutations) (LOQ = 400 c/mL)

- BMS-043-Efficacy Cohort  **Week 24 TLOVR Proportions in Response****by Resistance Sub-Groups****(PI Sensitivity, Prior PI, NRTI Mutations) (LOQ = 400 c/mL)**

**Overall**

**PI****Phenotype******** 2.5 x IC****50****of Control**

**PI****Phenotype******** 2.5 x IC****50****of Control**

**One****Prior PI**

******1 Prior PI**

**No NRTI****Mutations**

******1 NRTI****Mutations**

**N =**

**114**

**115**

**84**

**101**

**26**

**12**

**85**

**83**

**28**

**31**

**32**

**26**

**82**

**89**

**2J-2**

## BMS-045Week 24 TLOVR Proportions in Response (LOQ = 400 c/mL) Effect of PI and NRTI Mutations and PI Sensitivity

**ATV/RTV**

**LPV/RTV**

**ATV/SQV**

**N =**

**120**

**115**

**123**

**88**

**83**

**88**

**32**

**30**

**33**

**81**

**77**

**78**

**39**

**38**

**45**

**18**

**22**

**17**

**102**

**93**

**106**

**Overall**

**PI****Phenotype******** 2.5 x IC****50**** ****of Control**

**PI****Phenotype******** 2.5 x IC****50****of Control**

****** ****4 PI****Mutations**

******1 NRTI****Mutations**

******4 PI****Mutations**

**No NRTI****Mutations**

- BMS-045**Week 24 TLOVR Proportions in Response ****(LOQ = 400 c/mL)**** Effect of PI and NRTI Mutations and PI Sensitivity**

**2K-2**

## Coverage of Resistant Clinical Isolates

**10A-2**

## ATV 14 Key Substitutions

**Analysis of 399 susceptible & 544 ATV resistant clinical isolates**

**10A-16**

## Key Substitutions vs Fold Change

**10A-18**

## Plasma Metabolites of ATV

**14-20% of plasma radioactivity**
**Cmax = 0.27 ********M **
**Steady state AUCm / AUCp = 0.14 **

**12-18% of plasma radioactivity**
**Cmax = 0.54 ********M**
**Steady state AUCm / AUCp = 0.29**

**11-14% of plasma radioactivity**
**Structure postulated**

**              ****ATV**
**47-54% of plasma radioactivity**
**Cmax = 4.6 ********M **
**16 metabolites; 8 in plasma **
**(3 metabolites ******** 3% of**
**plasma radioactivity)**

**Plasma Metabolites of ATV**

**13D-1**

## AI424034 TLOVR Response Rate Comparisonfor LOQ = 400, LOQ = 200 and LOQ = 50

**AI424034 TLOVR Response Rate Comparison****for LOQ = 400, LOQ = 200 and LOQ = 50**

**2A-2**

**Notes:**
The challenge is to identify individuals at increased vascular risk before they have a heart attack, stroke, or sudden cardiac death.  The standard approach to risk assessment begins with determining levels of cardiac risk factors.  The more severe the abnormality of the risk factor, the higher is the risk of a CHD event.  Similarly, more risk factors have a synergistic effect at increasing risk.  In some patients, noninvasive testing also may be useful

## BMS-034 Frequency of HIV RNABetween 50 and 400 c/mL at Week 48

- BMS-034** ****Frequency of HIV RNA****Between 50 and 400 c/mL at Week 48**

**Number of Subjects**

**ATV**

**EFV**

**HIV RNA (c/mL)**

**HIV RNA 50 - ********400**

**Number of Subjects**

**2A-3**

**Notes:**
The challenge is to identify individuals at increased vascular risk before they have a heart attack, stroke, or sudden cardiac death.  The standard approach to risk assessment begins with determining levels of cardiac risk factors.  The more severe the abnormality of the risk factor, the higher is the risk of a CHD event.  Similarly, more risk factors have a synergistic effect at increasing risk.  In some patients, noninvasive testing also may be useful

## Impact on NRTI Resistance 

*** Defined as  ******** 2 fold increase in phenotype to FC ******** 2.5, or evidence of ****I****50L substitution**

**10B-7**

## BMS-034 I50L Identified in All ATV-Resistant Isolates

- BMS-034** ****I50L Identified in All ATV-Resistant Isolates**

**	****	****	****                     ****Treatment Regimen**
**	****	****	****  ****ATV****	****   EFV****	****	****	****  N = 404****	****   N = 401**

**Reasons for no result include:  HIV RNA level ******** 1000 c/mL (n = 44), isolate non-typeable (n = 23)****or sample unavailable (n = 25) **
***TLOVR (LOQ = 400 c/mL)**

**Virologic failure through 48 weeks*****	****69****	****	****69**
**	****Phenotypeable, N****	****26****	****	****20**
**	****Phenotype ******** 2.5 x IC****50**** of control, N (%)**
**	****	****ATV****	****6****	****(23)****	****1****	****(5)**
**	****	****EFV****	****1****	****(4)****	****13****	****(65)**
**	****Genotypeable, N****	****26****	****	****20**
**	****I50L or I50I/L, N (%)****	****6****	****(23)****	****0****	****(0)**
**	****K103N or K103K/N, N (%)****	****1****	****(4)****	****13****	****(65)**
**	****41, 70, 210, or 215 (ZDV), N (%)****	****3****	****(12)****	****2****	****(10)**
**	****M184  (3TC), N (%)****	****14****	****(54)****	****11****	****(55)**

**Core Backup-41**

## Grade 3 – 4 ALT Elevations  Hepatitis B and/or C Co-Infection 

**Grade 3 – 4 ALT Elevations **** Hepatitis B and/or C Co-Infection **

*********** 5 x ULN**

**Experienced**

**Hep B/C +**

**Naïve**

**ATV 400 /**
**ATV 600**

**NFV**

**2/12 (17)**

**BMS -034**

**BMS -043**

**ATV 400**

**EFV**

**ATV 400**

**LPV / RTV**

**6/50 (12)**

**8/59 (14)**

**0/17  (0)**

**BMS -008**

**Hep B/C -**

**2/28 (7)**

**5/53 (9)**

**6/316 (2)**

**5/79 (6)**

**8/347 (2)**

**2/335 (<1)**

**6/114 (5)**

**1/128 (<1)**

**Frequency of ALT Grades 3 – 4*, N (%)**

**7B-11**

## Comparator Studies of PRData in HIV-infected Subjects

**Source:  Updated Summary of Clinical Safety**
**a ****Two cohorts, one each from Studies AI424007 and AI424009, rolled onto Study AI424041. ECG analyses were****performed on the AI424007 cohort only due to the very limited sample size of the AI424009 cohort.**

**Number with AV Block (%)**

**PR Interval (msec)**

**1° AV Block,****N (%)**

******2° or 3 ° AV Block, N (%)**

**ATV Combined**
**(N = 152)**

**NFV**
**(N = 48)**

**AI424041****a**

**8 (5)**

**5 (10)**

**0 (0)**

**0 (0)**

**ATV 400**
**(N = 353)**

**EFV**
**(N = 329)**

**AI424034**

**17 (5)**

**10 (3)**

**0 (0)**

**0 (0)**

**ATV 400**
**(N = 137)**

**LPV / RTV**
**(N = 141)**

**AI424043**

**8 (6)**

**8 (6)**

**0 (0)**

**0 (0)**

**AI424045**

**ATV 300 / RTV**
**(N = 117)**

**5 (4)**

**0 (0)**

**LPV / RTV**
**(N = 111)**

**5 (4)**

**0 (0)**

**ATV 400 / SQV**
**(N = 105)**

**6 (6)**

**0 (0)**

**5-BU-18**

## Comparator Studies of QTcFData in HIV-infected Subjects

**Source:  Updated Summary of Clinical Safety**
**a ****Two cohorts, one each from Studies AI424007 and AI424009, rolled onto Study AI424041. ECG analyses were performed on the AI424007 cohort only due to the very limited sample size of the AI424009 cohort.**

**                   ****QTcF Intervals**

**451 - 500**

**1**

**0**

**0**

**1**

**0**

**1**

**1**

**0**

**0**

**(N = 103)**

**(N = 30)**

**(N = 226)**

**(N = 224)**

**(N = 107)**

**(N = 116)**

**(N = 93)**

**(N = 84)**

**(N = 80)**

**Males**

**471 - 500**

**0**

**0**

**0**

**0**

**0**

**0**

**0**

**0**

**0**

**(N = 49)**

**(N = 18)**

**(N = 127)**

**(N = 105)**

**(N = 30)**

**(N = 25)**

**(N = 24)**

**(N = 27)**

**(N = 25)**

**Females**

**QTcF****(msec)**

**AI424041****a**

**AI424034**

**AI424043**

**AI424045**

**ATV Combined**

**NFV**

**ATV 400**

**EFV**

**ATV 400**

**LPV / RTV**

**ATV 300 / RTV**

**LPV / RTV**

**ATV 400 / SQV**

**5-BU-14**

## Concomitant Use of Lipid Lowering Therapy in ATV Phase III Studies

**Concomitant Use of Lipid Lowering ****Therapy in ATV Phase III Studies**

**Experienced Subjects**

**Naïve Subjects**

**ATV 400**
**(N = 404)**

**EFV**
**(N = 401)**

**1%**

**3%**

**-034**

**6T-9**

## DAD – Baseline Risk Factors for CVD

**DAD – Baseline Risk Factors for CVD**

**n = 23,468**

**Family History of CHD **
**Previous CVD**
**Smoking Ever**
**Hypertension**
**Obesity**
**Diabetes Mellitus**
**Elevated Total Chol.**
**Lowered HDL-c**
**Elevated Triglyc.**

**0**

**20**

**40**

**60**

**80**

**100**

**%**

**6A-5**

**Notes:**
Each year, 1.1 million Americans have a myocardial infarction (MI), 1/3 of which are fatal.  For 1/3 of people, the first CHD event is a nonfatal MI.  However, the incidence of death is high in the first year after an acute CHD event.  Furthermore, survivors experience significant physical and emotional morbidity from CHF, arrhythmias, and an increased risk of sudden cardiac death

## Risk of Cardiovascular Disease According to Total Cholesterol at Specified Levels of Other Risk Factors

**Framingham Study. 18-yr follow-up. Men aged 35**

**8-Year****Probability****(/1000)**

**Risk of Cardiovascular Disease According to Total Cholesterol at Specified Levels of Other Risk Factors**

**Kannel. Am J Cardiol. 1983;22:9B.**

**3.9**

**23.2**

**34.6**

**60.2**

**0**
**105**
**0**
**0**

**+**
**195**
**0**
**0**

**+**
**195**
**+**
**0**

**+**
**195**
**+**
**+**

**Glucose****Intolerance**
**Systolic BP**
**Cigarettes**
**LVH on ECG**

**Cholesterol**

**6U-5**

## Emergence of ATV Resistance

**Emergence of ATV Resistance**

**ATV**

**~21%**

**~79%**

**(33)**

**(9)**

**Treatment **
**Experienced**

**All lack an ****I****50L**
**Cross-resistance to several PIs**

**All have an**** ****I****50L**
**ATV-specific resistance**
**Increased susceptibility to other PIs**

**10B-1**

## Emergence of ATV Resistance:Impact of I50L on PI Susceptibility

**Emergence of ATV Resistance:****Impact of ****I****50L on PI Susceptibility**

**ATV ****+****I****50L**

**ATV/SQV****no ****I****50L**

**ATV****no ****I****50L **

**10B-2**

## Viral Evolution Beyond I50L?

**10B-14**

**Notes:**
Cartoon to help explain the observed I50L phenotype result
First thing virus must do in presence of inhibitor is survive by quickly selecting a change that will decrease the inhibitory pressure exerted by the inhibitor, even if the virus become significantly impaired
Once it has survived, it will select for additional changes that help it regain its viability or enzyme efficiency
This is easily understandable with the emergence of the I50L change in the presence of ATV
When ATV & SQV are used in combination, emergence of the I50L change would decrease susceptibility to ATV and increase susceptibility to SQV, resulting in viral inhibition and an unacceptable solution 
Selection of the I84V and other changes allows the virus to survive the inhibitory pressure of both ATV and SQV and live to fight another day

## Genotype at Baseline

**Resistance via ****I****50L pathway related to presence of changes****at residues 14R, 46I and 88D and absence of L90M at baseline**

**   ****Responders**

**10D-2**

## Growth Impaired Clinical Virus

**Growth Impaired Clinical Virus**

**810024D-1:          10, 13, ****23****, 30, 37, 41, 62, 63, 70, 71T, 88, 93**
**810024D-2: ****50L****, 10, 13,       30, 37, 41, 62, 63, 70, 71T, 88, 93**

**10C-10**