# Presentation: 319885

## NDA 21-567 Atazanavir

- Kendall A. Marcus, M.D.
- Medical Reviewer
- Division of Antiviral Drug Products

## Presentation Outline

**NDA Submission Overview**
**Efficacy Summary - Tom Hammerstrom, Ph.D.**
**Clinical Virology - Lisa Naeger, Ph.D.**
**Safety Issues**
**Hyperbilirubinemia**
**Lipid Profiles**
**Effects on the QT and PR Interval **
**Conclusions**

## NDA Overview

**Submission Date: December 20, 2002**
**Proposed Dosage: Atazanavir 400 mg once daily**
**Proposed Indication:  Treatment of HIV infection**

## Phase 2 Dose-Finding Studies  Treatment Naïve Patients

_**AI424-007**_**  ****	**** N=420 **
**ATV: 200 mg, 400 mg, and 500 mg **
**NFV 750 mg tid**
**	****Each given with d4T/ddI.**
_**AI424-008**_** ****	****N=467 **
**ATV: 400 mg and 600 mg**
**NFV 1250 mg bid**
**	****Each given with d4T/3TC**.

## Phase 3 Studies

_**AI424-034**_**  Treatment-naïve subjects (n=810) **
**ATV 400 mg daily**
**EFV 600 mg daily**
**	****Each given with AZT/3TC (Combivir********)**
_**AI424-043**_**  Subjects failing PI based regimens (n=300)**
**ATV 400 mg daily**
**LPV/RTV bid**
**	****Optimized background of 2 NRTIs based on ****	****phenotypic testing.**

## Phase 3 Studies

_**AI424-045**_***   Patients failing at least 2 regimens containing drugs from  all three classes  (n=358) **
**ATV 300 mg/RTV 100 mg once daily**
**ATV 400 mg/SQV 1200 mg once daily**
**LPV/RTV bid**
**   ****Background therapy of tenofovir and one NRTI.**
**  *****16 week data on roughly 33 patients/arm      submitted with initial NDA submission.**

## Other Supportive Studies

_**AI424-041**_** and **_**AI424-044**_** **
**Rollover studies for Phase 2**
_**PACTG 1020-A**_
**PK and safety study in infants, children, and adolescents**
_**AI424-900**_** - Expanded access protocol**
_**AI424-009**_** (N=85)**
**Small Phase 2 study of treatment experienced patients comparing ATV/SQV to RTV/SQV**

## Atazanavir Resistance

Lisa K. Naeger, Ph.D.
Antiviral Advisory Committee Meeting
May 13, 2003

- Lisa K. Naeger, Ph.D.
- Antiviral Advisory Committee Meeting
- May 13, 2003

## In vitro Selection

**             ****Virus strain****: mutations**
- RF**:**  **V32I, L33F, ****M46I, A71V, I84V, **
**         ****N88S**
- LAI**:**  **L10Y/F,**** I50L****, L63P, ****A71V, **
**         ****N88S**
- NL4-3**:  V32I, ****M46I, I84V****, L89M**

- 3 Different Strains of HIV-1 were serially
- selected with ATV for 4-5 months
- (200 - 500 nM)

**Fold ATV Resistance**
**183**
**93**
**96**

## I50L Mutation

- ATV resistance corresponded to the presence of I50L and A71V in the protease of recombinant viruses from 8 clinical isolates.
- 2- to 17-fold decreases in ATV susceptibility were observed in viruses containing the I50L and A71V mutation

## I50L Mutation

- Viruses containing the I50L mutation either alone or in combination with A71V remained susceptible to APV, IDV, NFV, and RTV.
- Insertion of the I50L substitution into HIV-1 resulted in replication impaired viruses.   The addition of the A71V change with I50L restores some viability.

## ATV Clinical Resistance Analyses

- Mutations Associated with ATV-Resistance
- Phenotypic and genotypic analyses of evaluable clinical isolates from patients on ATV-containing regimens who experienced virologic failure or discontinued before suppression from studies 007, 008, 034, 009 and 043
- Baseline Phenotype and Genotype Analysis
- Cross-Resistance

## Evaluable Clinical Isolates from Patients on ATV-Containing Regimens who Experienced Virologic Failure or Discontinued before Suppression 

## Mutations Associated with ATV-Resistance in Naïve-trials

**14 ATV-resistant clinical isolates**
- 11 (79%) developed the I50L mutation
- Median 9-fold change in ATV resistance
- 7 of these 11 also developed the A71V mutation
- Development ranged from 2 to 80 weeks
-    (mean = 40 weeks)

## Phenotype of ATV-Resistant Isolates that Developed the I50L Mutation In Naïve Trials 

- * Average fold-change from reference strain

## Mutations Associated with ATV-Resistance in Experienced trials

- 32 ATV-resistant clinical isolates
- ATV Treatment  (21)
- 5 isolates developed the A71V or T mutation
- 2 isolates developed the I84V mutation (5-fold change from BL)
- 2 developed the N88S or D mutation (4-fold change from BL)

## Mutations Associated with ATV-Resistance in Experienced trials

- ATV/SQV Treatment (11)
- 5 isolates developed the I84V mutation (14-fold change from BL)
- 4 isolates developed the A71V or T mutation
- 2 isolates developed the L90M mutation
- 2 isolates developed the M46I mutation

## Cross-Resistance of the Virologic Failure Clinical 

**Isolates that were ATV-Resistant from Treatment- **
**Experienced Patients in Trials 009 and 043**

- (N = 32)

## Baseline Analysis

## 56%

- 74%

- 20%

## 24% of the Isolates from 
  009 and 043 showed ATV-Resistance at Baseline

-   009 and 043 showed ATV-Resistance at Baseline

## % Resistance

- 100%

- 47%

- 43%

- 62%

- 59%

## Response Based on Baseline Genotype

## Slide 24

## Cross-Resistance

## Cross-resistance of HIV-1 Clinical Isolates by Phenotype

## Cross-Resistance of HIV-1 Clinical Isolates by Genotype

## ATV Resistance Against PI-Resistant Clinical Isolates  (n = 551)

## ATV Susceptibility Against PI-Resistant Clinical Isolates  (n = 551)

## ATV Resistance Summary

- I50L mutation is specific for ATV resistance and is the predominant mutation developing in antiretroviral therapy-naïve patients
- Viruses with the I50L mutation remain susceptible to other PIs
- Mutations L90M, I84V, N88S/D and A71V/T appear to confer ATV resistance and reduce the clinical response to ATV
- There is a clear trend toward ATV resistance as isolates become resistant to three or more PIs

## Atazanavir Efficacy Results

- Thomas Hammerstrom, PhD
- Division of Antiviral Drug Products

## Phase II and III Clinical Trials

**Pivotal Phase III Trial - 34**
**Endpoint = Percent Sustained < 400 copies/mL to Week 48, Time Averaged Difference from Baseline (TAD)**
**ART Naïve Population**
**Control is Efavirenz**
**Phase II Trials - 7 and 8**
**Endpoint = Percent < 400, TAD**
**ART Naïve Population**
**Control is Nelfinavir**

## Phase II and III Clinical Trials

**Pivotal Phase III Trial - 43**
**Endpoint = TAD**
**ART Experienced Population**
**Control is Kaletra**

## Results in Trials with ART Naïve Subjects

##  Percent Sustained <400 copies/mL to Week 48

_**Trial**_**	**_**Arm**_**	**** **_**%<400**_**	****	****	**_**95% Interval  ATV - Con**_
**34****	****	****EFV****	****251 / 405 ****	****62%****	**
**	****	****ATV****	****271 / 405****	****67%****	****-1.5%,  11.6%**
** ****7****	****	****NFV****	****62 / 103****	****60%****	**
**	****	****ATV****	****62 / 103****	****60%****	****-13.8%,  13.0%**
** ****8****	****	****NFV****	****54 / 91****	****	****63%****	**
**	****	****ATV****	****121 / 181****	****69%****	****-5.0%,  19.4%**

## Results in Trial with ART Experienced Subjects

##  Trial 43, ATV vs Kaletrafor 24 Weeks

_**Endpoint**_**	**_**Arm**_**	**_**Estimate**_**	****	**_**95% Interval  **_
**%<400****	****	****KAL ****	****98 / 150 = 65%****	**
**	****	****	****ATV****	****70/150 = 47%****	****	****-30%,  -7.9%**
** ****TAD****	****	****KAL****	****-1.65****	****	**
**	****	****	****ATV****	****-1.39****	****	****	****.078,  .44**

## Is ATV Better than Placebo ART Experienced Subjects?

**Two Meta-analysis Methods:**
**1. Calculate Difference of ATV and Placebo from Trial 43 and Kaletra Trials**
**2. Compare Confidence Intervals for ATV + 2 NRTI’s in Trial 43 with Confidence Intervals for 2 NRTI’s alone from other NDA’s**

##  ATV vs Placebo% <400

_**Source**__**	**_**	**_**Arm**_**	**_**Estimate**_**	****	**_**DIFF**__**	**__**SEE  **_
_**Trial 43**__**	**_**	****ATV****	****70/150 = 47%****	****	****	****	****	****	****KAL ****	****98 / 150 = 65%****	****	****-19%****	****5.73%**
_**Trial 863**_**	****KAL ****	****259 / 326 = 79%****	**
**	****	****	****NFV****	****233 / 327 = 71%****	****8%****	****3.36%**
_**Trial 511**_**	****NFV****	****66/ 99 = 67%****	****	**
**	****	****	****PLA****	****7/ 101 = 7%****	****	****60%****	****5.37%**
**Imputed****	****ATV**
**	****	****	****PLAC****	****	****	****	****49%****	****8.54%**

##  ATV vs Placebo% <400

_**Source**__**	**_**	**_**Arm**_**	**_**Estimate**_**	****	**_**DIFF**__**	**__**SEE  **_
_**Trial 43**__**	**_**	****ATV****	****70/150 = 47%****	****	****	****	****	****	****KAL ****	****98 / 150 = 65%****	****	****-19%****	****5.73%**
_**Trial 888**_**	****KAL ****	****84 / 148 = 57%****	**
**	****	****	****S. PI****	****46 / 140 = 33%****	****	****24%****	****5.69%**
**Imputed****	****ATV**
**	****	****	****Selected PI****	****	****	****5%****	****8.07%**

##  ATV vs Control% <400

_**Source**_**	****	**_**Control**_**	****	**_**Difference**_**	**_**95% Interval  **_
**Trial 43****	****	****KAL ****	****	****-19%****	****	****-30%,  -7.9%**
**Imputed****	****Sel PI****	****	**** 5%****	****	****-10.8%,  21%**
**Discounted****	****Sel PI****	****	**** 4.5%****	****	****-12.3%, 23%**
**Imputed****	****PIacebo****	****49%****	****	****32%,  66%**

## Slide 42

##  ATV vs PlaceboTAD, Week 24

_**Source**__**	**_**	**_**Arm**_**	**_**Estimate**_**	****	**_**DIFF**__**	**__**SEE  **_
_**Trial 43**_**	****	****ATV****	****-1.39****	****	****	****	****	****	****	****KAL ****	****-1.65****	****	****	****.26****	****.093**
_**Trial 863**_**	****KAL ****	****-1.798****	**
**	****	****	****NFV****	****-1.801****	****	****	****.003****	****.057**
_**Trial 511**_**	****NFV****	****-1.77****	****	**
**	****	****	****PLA****	****-1.40****	****	****	****-.37****	****.083**
**Imputed****	****ATV**
**	****	****	****PLAC****	****	****	****	****-.107****	****.137**

##  ATV vs PlaceboTAD, Week 24

_**Source**__**	**_**	**_**Arm**_**	**_**Estimate**_**	****	**_**DIFF**__**	**__**SEE  **_
_**Trial 43**__**	**_**	****ATV****	****-1.39****	****	****	****	****	****	****	****KAL ****	****-1.65****	****	****	****.26****	****.093**
_**Trial 888**_**	****KAL ****	****-.972****	**
**	****	****	****S. PI****	****-.867****	****	****	****-.104****	****.078**
**Imputed****	****ATV**
**	****	****	****Selected PI****	****	****	****.156****	****.121**

##  ATV vs ControlTAD, Week 24

_**Source**_**	****	**_**Control**_**	****	**_**Difference**_**	**_**95% Interval  **_
**Trial 43****	****	****KAL ****	****	****.26****	****	****.078,  .44**
**Imputed****	****Sel PI****	****	**** .156****	****	****-.081,  .393****	**
**Imputed****	****Placebo****	****-.107****	****	****-.376,  .162**

## Slide 46

## Efficacy Conclusions

**1.  Equal or Better than NFV or EFV on %<400 at week 48 in 3 Trials with Naïve Subjects**
**2. 95% Lower Limits on %<400 no more than 5% worse than NFV or EFV in 2 out of 3 Trials**

## Efficacy Conclusions

**3.  Equal or Better than NFV or EFV on TAD at week 48 in 2 out of 3 Trials with Naïve Subjects**
**4. 95% Upper Limits on TAD no more than .28 log copies worse than NFV or EFV in all 3 Trials**

## Efficacy Conclusions

**5. Statistically Significantly Worse than Kaletra on both %<400 and TAD at week 24 in 1 Trial with Experienced Subjects**
**6. Indirect Imputations: Support for Efficacy on Primary Endpoint, Ambiguity on Secondary Endpoint**

## Efficacy Conclusions

**6.  Indirectly shown at least 33% better  than placebo, no more than 10% worse than selected PI on %<400**
**7. 95% Confidence Limits on %<400 higher than limits seen on all 2 drug combinations in previous NDA’s**

## Efficacy Conclusions

**8.  Indirectly shown no more than .16 log copies worse than Placebo on TAD at week 24**
**9. 95% Confidence Limits on TAD comparable to limits seen on several 2 drug combinations in previous NDA’s**

## Safety Issues

**Hyperbilirubinemia**

## HyperbilirubinemiaToxicity Grading Scale

**Total bilirubin toxicity grading scale**
**	****	****Grade 1        1.1 – 1.5 x ULN**
**	****	****Grade 2        1.6 – 2.5 x ULN**
**	****	****Grade 3        2.6 – 5.0 x ULN**
**	****	****Grade 4              > 5.0 x ULN**
**Upper limit of normal for total bilirubin ******** 1.0 - 1.5 mg/dL**
**Upper limit of normal for direct bilirubin ******** 0.2 - 0.5 mg/dL**

## Studies 007 & 008HyperbilirubinemiaDose Dependence

## Percentage of Subjects with HyperbilirubinemiaAtazanavir - 400mg

- Percentage of Subjects with HyperbilirubinemiaAtazanavir - 400mg

## Incidence of Jaundice and Scleral Icterus 	Phase 2 and 3 Clinical Studies	

**Atazanavir - 400 mg**

**Three patients in 034 (1%) and 2 patients in 043 (1%) discontinued for jaundice or scleral icterus without grade 4 hyperbilirubinemia.**

## Grade 4 Hyperbilirubinemia and Dose Reduction

**Atazanavir - 400 mg**

## Study 034 Mean Total and Direct Bilirubin Atazanavir - 400 mg

## Total Bilirubin > 10 mg/dL

- Occurred in 10 patients across clinical trials
- 4/10: transient, predominantly unconjugated (DB  0.3 mg/dl)
- 1/10: diagnosed w/SHL, DB - 0.6 mg/dl
- 5/10: also with other LFT abnormalities
- 4 with viral hepatitis (A, B, C)
- One had a total bilirubin > 10 mg/dl prior to randomization which resolved prior to treatment and then worsened temporarily on study.

## LFT Abnormalities -  ATV versus NFV Background:  ddI/d4T

## LFT Abnormalities: ATV versus EFV Background: AZT/3TC

## Discontinuations Due to Hepatotoxicity/Abnormal LFTsAll Studies

_**Atazanavir**_** - 15/1596 (1%) **
**Ten had chronic hepatitis B or C**
**One had acute hepatitis B**
**One had history of hepatic steatosis**
**Three subjects with no apparent risk factors**
_**Comparators**_** - 8/892 (1%)**
**Five had chronic hepatitis B or C**
**One had acute hepatitis B**
**One was hep B core Ab positive but surface Ab and antigen negative**
**One on RTV/SQV w/ no apparent risk factors**

## HyperbilirubinemiaConclusions

- Inhibition of UGT 1A1
- Predominantly unconjugated
- Reversible upon discontinuation of atazanavir
- Jaundice/scleral icterus are likely to be common adverse events in clinical practice resulting in more frequent discontinuations than seen in clinical trials.
- Risk for hepatotoxicity similar to other marketed ARV

## Lipid Profiles

## Study 034 Lipid Profiles at Week 48Percent Change from Baseline 

- Percent Change from Baseline

## Study 034 Lipid Profiles at Baseline and Week 48

**Percentage of Subjects**

**TC>240**

**LDL>160**

**TG>400**

## Study 043Lipid Profiles at Week 24Percent Change from Baseline

**Percent Change from Baseline**

## Study 043 Lipid Profiles at Baseline and 24 Weeks

**mg/dL**

**TC>240**

**LDL>160**

**TG>400**

## Slide 69

## LipodystrophyTreatment-Naïve Studies

- * Includes events of lipoatrophy, lipohypertrophy, and lipodystrophy.

## CV Events -Myocardial Infarction

- Three MIs in atazanavir-treated patients and three MIs in patients receiving comparators
- One subject receiving RTV/SQV underwent three vessel bypass surgery

## Lipid ProfilesConclusions

- Lipid effects of atazanavir appeared to persist through 108 weeks of treatment, although data from phase 2 trials is limited by study design.
- Benefits for treatment-experienced patients less well defined as factors other than current protease inhibitor use appear to contribute at least to hypertriglyceridemia.
- Lipid effects do not appear to be associated with a reduced incidence of lipodystrophy.
- Cardiovascular benefit is unknown at this time.

## Evaluation of the QT Interval

## In Vitro Evaluation of Potential Cardiac Effects

- Modest inhibition of IKr (HERG) - 15% at 30 μM
- Moderate inhibition of Ca channels - IC50 of 10 μM
- Weak inhibition of Na channels -  IC50 > 30 μM
- In Purkinje fiber studies, a dose-dependent increase in mean action potential duration was observed.

## Study 076

- 3-treatment, 3-period crossover study
- 72 subjects received multiple, once-daily doses of atazanavir
- Subjects assigned atazanavir 400 mg, 800 mg, and placebo in six different sequences
- Washout period of  14 days

## QTc Changes by Correction Formula

-  QTcB at Tmax from baseline to 800 mg dose is 7.9 msec
-     (95% CI 2.8, 12.9)
-  QTcF at Tmax from baseline to 800 mg dose is    -1.6 msec
-     (95% CI -4.2, 1.1)

## Studies 034 and 043Prolonged QTc Intervals

_**Study 034**_
- Incidence of prolonged QTc intervals similar between atazanavir and efavirenz regimens (2%).
- One subject receiving efavirenz had a QTc interval > 500 msec.
_**Study 043**_
- Nine subjects (ATV, 2 subjects; LPV/RTV, 7 subjects) experienced a post-baseline QTc prolongation.

## Study 034 and 043 CV Events Potentially Related to Arrhythmia

- Sudden death or torsades de pointes
- CV events leading to treatment discontinuation
- CV events coded as SAEs
- Grade 3 - 4 CV events
- All CV events
- Events reviewed - No events of sudden death, torsades de pointes, events suspicious for TdP, or an imbalance between treatment arms in events potentially attributable to TdP was observed.

## Effect of Atazanavir on the QT IntervalConclusions

- Data from placebo-controlled study 076 limited by lack of positive control (e.g. moxifloxacin)
- Current data indicates that atazanavir has little or no effect on the QT interval; however, the overall risk is unknown
- No signal for increased risk relative to comparators was identified in clinical trials

## Evaluation of the PR Interval

## Causes of PR Interval Prolongation and AV Block

- Medications - e.g. antihypertensives, digoxin
- Fibrosis of the conduction system
- Ischemic heart disease
- Valvular or congenital heart disease
- Cardiomyopathy
- Myocarditis

## First Degree AV BlockClinical Significance

**ACC/AHA/NASPE 2002 Guidelines for Implantation of Cardiac Pacemakers and Antiarrythmic Devices**
- _Class II B recommendation_:
- 	First degree AV block greater than 300 msec in patients with LV dysfunction and symptoms of congestive heart failure in whom a shorter AV interval results in hemodynamic improvement

## Study 076 (Healthy Volunteers)Plot of Mean PR Versus Time Since Dosing

## Study 034 PR Interval 

**	****	****	****   **_**Time**_**         **_**Mean PR Interval**_
_**	**__**	**__**	**__**Post-dose**__**	**_**     (min, max)**
_**	**__**	**__**	**__**	**__**	**_**          ****msec**
**   ****EFV**		2-3 hours	   153 (101, 251)
**   ****ATV***	2-3 hours	   160 (110, 287)
- *Maximum PR intervals: 265 - 307

## Study 034 First Degree AV Block

**Treatment**	   **Incidence of First Degree AV Block ****	****	****	****	****	****     (%)**
- 			         _**Males**_        _**Females**_         _**Total**_
- Efavirenz                     **3                   0                  2**
- Atazanavir		 **4                   6                 4.5**

## Study 041 PR Interval

_**	**__**	**__**	**__**Time**__**	**__**	**__**Mean PR Interval**_
_**	**__**	**_**          **_**Post-dose**__**	**_**    (min, max)**
_**	**__**	**__**	**__**	**_**    ****	****         ****msec**
**     ****NFV          **2-3 hours	  158 (97, 203)
**	**** ****ATV***         2-3 hours	  164 (120, 243)
- *Maximum PR intervals: 234 - 250

## Studies 041 and 044First Degree AV Block

**  **_**Study**_**	****  **_**Dose**_**	**** **_**N**_**	****   **_**1st Degree**_
**	****	****	****	****	****	****   **_**AV Block (%)**_
- 	**041****	**	ATV 400	148	     	 5
- 			NFV		  47		 9
- 	**044****	**	ATV 400	172		 9
- 			ATV 600	127	           14

## Study 043 PR Interval

- _	__	__	__**Time**__**	**__**	**__**Mean PR Interval**_
_**	**__**	**_**          **_**Post-dose**__**	**_**    (min, max)**
_**	**__**	**__**	**__**	**_**    ****	****         ****msec**
**	****   ****LPV/r**     2-3 hours	  157 (114, 250)
**        ****ATV*     **2-3 hours	  157 (114, 209)
- *Maximum PR Intervals: 194 - 218

## Study 043 First Degree AV Block

**Treatment**	   **Incidence of First Degree AV Block ****	****	****	****	****      (%)**
- 			         _**Males**_        _**Females**_         _**Total**_
**Lopinavir/r****	****	**** 6                   4                  6**
**Atazanavir**		 **7                   3                  6**

## Case Narratives - Other Conduction Abnormalities Potentially Related to Atazanavir

- On day 1053 of therapy in study 007/041, a 43 year old male intentionally ingested a large number of ATV/3TC/d4T pills
- Received activated charcoal
- Severely prolonged PR interval with bifascicular block was observed on ECG
- Patient was monitored for 5 days until ECG normalized

## Case Narratives - Other Conduction Abnormalities Potentially Related to Atazanavir

- A 50 year old male with HTN was hospitalized on day 11 of ATV/ 3TC/DLV/TDF for angina and SOB
- On verapamil SR for HTN
- An ECG showed junctional rhythm with retrograde atrial activation. ARV medications held
- One day following admission an ECG showed persistence of junctional rhythm
- Two days following admission the patient was found unresponsive with idioventricular rhythm
- Autopsy showed 90% LAD without infarct

## Effects on PR Interval Conclusions

- Dose dependent prolongation of the PR interval
- First degree AV block most common abnormality observed
- Incidence of first degree block appears to be similar to that observed with selected PIs
- Severe prolongation (> 300 msec) or more serious events appear to be rare

## Pediatric ProtocolPACTG 1020-A

- Atazanavir + 2 NRTIs
- 48 enrolled; 29 continuing on study
- Adverse event profile in these patients appears similar to adults
- Due to wide variability of pK data in all age cohorts, a dose has not yet been defined for any group

## Drug-Drug Interactions

## Drug-Drug Interactions

- Potential interaction with ATV
- CYP3A inhibitor, inducer, or substrate
- drugs that increase pH
- drugs that cause PR prolongation
- 2C9 (e.g. warfarin) or 1A2 (e.g. theophyline) -not studied

## Drug Interactions - Diltiazem

- Diltiazem
- CYP 3A substrate + inhibitor
- PR prolongation
- ATV  diltiazem Cmax and AUC ~ 100%

## Drug Interactions - Oral Contraceptives

- Co-administration of atazanavir and ethinyl estradiol/norethindrone (Ortho-Novum 7/7/7) was evaluated
- 				          _Cmax_		_AUC_
- Ethinyl estradiol		1.15		1.48
- Norethindrone		1.67		2.10

## AtazanavirOverall Conclusions

- Antiviral activity similar to efavirenz or nelfinavir in treatment-naive patients
- Inferior to lopinavir/r in treatment-experienced patients, but multiple analyses indicate activity in this population
- Low pill burden may enhance compliance in selected patients
- Unique resistance pathway in treatment-naïve subjects

## AtazanavirOverall Conclusions

- Hyperbilirubinemia appears to be due to inhibition of UGT 1A1 and reversible with treatment discontinuation
- Risk for hepatotoxicity appears to fall within the range of that seen with other ARV medications

## AtazanavirOverall Conclusions

- Dose-dependent prolongation of the PR interval
- Incidence of first degree AV block appears to be similar to that observed in lopinavir/ritonavir and nelfinavir treated patients
- Clinically significant events due to prolongation of the PR interval appear to be rare
- Effects of atazanavir on the QT interval appear to be minimal

## AtazanavirOverall Conclusions

- Favorable lipid profile as compared to selected protease inhibitors and efavirenz
- Impact on cardiovascular events unknown
- Does not appear to “reverse” triglyceride elevations seen in treatment-experienced patients
- Does not appear to result in a decreased incidence of lipodystrophy

## Questions 

## Question 1 

- Do the efficacy and safety of atazanavir support its approval for the treatment of HIV infection?  As part of your discussion please comment on:
- Treatment effects seen in naїve and experienced patients
- Hyperbilirubinemia observed in clinical trials
- The effect of atazanavir on the PR and QT intervals

## 	Question 2

- If atazanavir is recommended for approval, does its safety profile warrant additional clinical or laboratory monitoring?

## Question 3

- Does the effect of atazanavir on lipid parameters offer patients a clinically significant advantage over other treatment options?

## Question 4

- Based on the resistance data, what recommendations would you have regarding its use in naïve and experienced patients?

## Question 5

- Please provide recommendations for any Phase 4 studies of atazanavir?