REYATAZ Safety & Tolerability Issues for HIV ‑ Infected Patients Requiring Protease Inhibitor Therapy

REYATAZREYATAZ

Safety & Tolerability Issues for HIV‑Infected Patients Requiring

Protease Inhibitor Therapy

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Evolution of HIV TherapyEvolution of HIV Therapy

19831983 19871987 ‘‘91 91 ‘‘9292 ‘‘9393 ‘‘9494 ‘‘9595 ‘‘9696 ‘‘9797

PIsPIsintroducedintroduced

NNRTI’sNNRTI’sAIDSAIDS

deathsdeathsdeclinedecline

3TC3TCSQVSQV

RTV, IDVRTV, IDVNVPNVP

NFVNFVDLVDLV

viral causeviral causeof AIDSof AIDSisolatedisolated

long long latencylatencyperiod period presumedpresumed

acuteacuteinfectioninfectiondatadatapublishedpublished

current theorycurrent theoryof viral of viral dynamicsdynamicspublishedpublished

clinicalclinicaluse ofuse ofviral viral loadload

monotherapymonotherapy combocombouseuse

triple ARVtriple ARV (HAART)(HAART)

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firstfirstARARVV

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clinicalclinicaluse ofuse ofgenotypinggenotypingphenotypingphenotyping

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LPV/rLPV/r

AIDS Timeline 1985-2004. http://www.projectinform.org/20/time.pdf. ; http://www.kff.org/hivaids/timeline/index.cfm

Accessed 5.13.05

‘‘0101

TFVTFV

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ATVATVT20T20FTCFTC

Patients are Living Longer in the Era of HAART Patients are Living Longer in the Era of HAART D

eath

s pe

r 10

0 pe

rson

-yea

rs

Mortality and frequency of HAART including a PI among HIV-infected patients with CD4+ <100 cells/mm3

Palella FJ et al. N Eng J Med. 1998; 338: 853–860

1994 1995 1996 1997

Therapy w

ith a PI

(% of patient-days)

Deaths

Use of PIs

10040

5020

0 0

PI = protease inhibitors; HAART = highly active antiretroviral therapy

Treating the diseaseAvoiding complications and

optimizing treatment acceptance

Therapeutic Goals of ARTTherapeutic Goals of ART

• Primary goals of ART include:

– Reduce HIV-related morbidity and mortality

– Improve quality of life

– Restore and preserve immunologic function

– Maximally and durably suppress viral load

• Secondary goal:

– Select a safe and effective regimen

US DHHS. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_040705.pdf Accessed May 11, 2005.

Reasons for ART FailureReasons for ART Failure

• Causes of treatment failure include:

– Patient factors (CD4 nadir, VL, comorbidities, etc)

– Suboptimal adherence

– Toxicity and intolerance (adverse events)

– Pharmacokinetic problems

– Drug-drug interactions

– Suboptimal drug potency

– Development of viral resistance

Hugen PWH et al. J Acquir Immune Defic Syndr. 2002;30:324-334. US DHHS. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_040705.pdf

Accessed May 11, 2005.

Toxicity Failure Nonadherence Other

58% n=182

20% n=61

8% n=25

14% n=44

ICONA Study: ICONA Study: Reasons for Failure of Initial HAARTReasons for Failure of Initial HAART

d'Arminio Monforte A, et al. AIDS. 2000;14:499-507.Ammassari A et al. J Acquir Immune Defic Syndr. 2001;28:445-449.

ART and AdherenceART and Adherence

• “Adherence to antiviral medication is the key determinant in the degree and duration of virologic suppression.” — DHHS, 2004

• Factors affecting nonadherence include:

– Complex dosing schedules

– Heavy pill burden

– Adverse effects

• Nonadherence can lead to the development of resistance to ARV medications, which may result in treatment failure and limit future therapeutic options for the management of HIV

US DHHS. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_040705.pdf . Accessed May 11, 2005.Yun LWH et al. J Acquir Immune Defic Syndr. 2005;38:432-438.

How Much Adherence is Enough?How Much Adherence is Enough?

0

20

40

60

80

100

Pat

ien

ts w

ith

Vir

olo

gic

Fai

lure

, %

Adherence, %

≥95 90-95 80-90 70-80 <70

P<0.001

Paterson DL et al. Ann Intern Med. 2000;133:21-30.

Medication-Related Factors and AdherenceMedication-Related Factors and Adherence

• Adverse effects (AEs) have been reported with virtually all ARV medications and are among the most common reasons for switching or discontinuation of therapy and for medication nonadherence

• “Minor” common side effects may be as important to the patient as major grade 3/4 events– Nausea, vomiting, abdominal discomfort or cramping, and diarrhea

are common reasons why patients stop their medications

• Most patients are asymptomatic when treatment is started– Development of even minor symptoms can therefore be distressing

Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124. O’Brien ME et al. J Acquir Immune Defic Syndr. 2003;34:407-414.

http://clinicaloptions.com/04nrti.

Common Adverse Events Common Adverse Events Associated with ARTAssociated with ART

• Short-term (acute)

– Usually occur within hours or days of beginning treatment

– Rash, CNS disturbances, nausea, vomiting, diarrhea

• Long-term (chronic)

– Lipodystrophy

– Diabetes

– Hyperlipidemia

– Cardiovascular (CV) risk

• Life-threatening

– Liver failure, renal failure

Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124.

Adverse Events in PI-Based ART Adverse Events in PI-Based ART

• Most common PI AEs: – GI intolerance

– Nausea

– Headache

– Hyperlipidemia

– Insulin resistance and diabetes

– Lipodystrophy

US DHHS. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_040705.pdf Accessed April 21, 2005. Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124.

• IDV nephrolithiasis, hyperbilirubinemia, GI intolerance

• SQV diarrhea

• LPV/r diarrhea

• NFV diarrhea

• RTV GI intolerance, hepatitis

• f-APV rash, diarrhea

• ATV indirect hyperbilirubinemia, PR interval

prolongation

Some PIs are Known for Specific Adverse EventsSome PIs are Known for Specific Adverse Events

US DHHS. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_040705.pdf Accessed April 21, 2005. Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124.

Impact of PI-based ART on GI Impact of PI-based ART on GI SystemSystem

ART-related GI Disturbances ART-related GI Disturbances

• Common occurrence with all ART

• Generally not life threatening

• Includes dyspepsia, nausea, vomiting, diarrhea

• Can usually be controlled with OTC drugs or prescription drugs


Common PI-Related GI Adverse EventsCommon PI-Related GI Adverse Events

AE f-APV

(2800 mg)

f-APV/r (1400/ 200 mg)

ATV (400 mg)

IDV (2400

mg)

LPV/r (800/ 200

mg)

NFV (2500 mg)

RTV (1200 mg)

SQV (1800 mg)

Abdominal pain 1% 1% 6% 17% 4% – – 2%

Diarrhea 5% 13% 6% 3% 16% 20% 15% 20%

Nausea 5% 3% 16% 12% 7% 3% 26% 11%

Vomiting 2% 3% 6% 8% 2% – 14% 3%


ATV vs NFV in Treatment-Naïve Patients:ATV vs NFV in Treatment-Naïve Patients:GI Adverse Event Profile*GI Adverse Event Profile*

0

10

20

30

40

50

60

Diarrhea Pain(abdomen)

Nausea

Gra

de

1-4

Rel

ated

A

Es

in %

*Reported with a frequency of >20% in any treatment group

P<0.0001ATV 400 mg QD (n=178)

NFV 1250 mg BID (n=91)

Murphy RL et al. AIDS 2003; 17: 2603–2614

BMS-008: NaBMS-008: Naïïveve

ATV vs LPV/r in Treatment-Experienced Patients:ATV vs LPV/r in Treatment-Experienced Patients:GI Adverse Event Profile*GI Adverse Event Profile*

0

1

2

3

4

5

Diarrhea Nausea

* = 2% of Patients

Gra

de

2-4

Rel

ated

A

Es

in %

ATV 400 mg QD (n=144)

LPV/r 400/100 mg BID (n=146)

Adapted from: Cohen C et al. 2nd IAS, Paris, July 2003. Oral presentation 117

BMS-043: PI experienced (unboosted vs boosted PI)BMS-043: PI experienced (unboosted vs boosted PI)

ATV/r vs LPV/r in Treatment-Experienced Patients:ATV/r vs LPV/r in Treatment-Experienced Patients:GI Adverse Event Profile*GI Adverse Event Profile*

0

2

4

6

8

10

12

Diarrhea Nausea Vomiting

*5% of patients

ATV/r 300/100 mg QD (n=119)

LPV/r 400/100 mg BID (n=118)

Johnson M et al. AIDS. 2005; 19:685-694

BMS-045: Experienced (boosted ATV vs boosted LPV)BMS-045: Experienced (boosted ATV vs boosted LPV)

ATV/r vs LPV/r: Use of Antidiarrheal AgentsATV/r vs LPV/r: Use of Antidiarrheal Agents

0

5

10

15

20

25

30

% o

f P

ati

en

ts

ATV/r

LPV/r

ATV 400/SQV

Loperamide

Antidiarrhea/Intestinal Antiinflammatory Agents• Antidiarrheal

• Atropine/diphenoxylate (lomotil)

• Attapulgite

• Bismuth subsalicylate

• Lactobacillus acidophilus

• Loperamide

• Nystatin

• Sacchromyces cervislae

• Sulfasalazine

Antidiarrhea/Intestinal Antiinflammatory Agents


6

13

24

17

8

3

P=0.001 P=0.04

P=0.0005

Impact of PI-based ART on Hepatic Impact of PI-based ART on Hepatic SystemSystem

ART-Related Liver IssuesART-Related Liver Issues

• Severe hepatotoxicity in 5-10% within the first 12 months

• Risk increases with treatment duration

• Risk factors – hepatitis, alcoholism, NVP or RTV regimens

• Most cases resolve within months

• Therapy should be stopped if liver enzymes are very elevated or there are symptoms of hepatitis.

Dore G. J HIV Ther. 2003;8:96-100; US DHHS. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_040705.pdf Accessed April 21, 2005.

PI-Related Liver IssuesPI-Related Liver Issues

• For the PIs, onset of hepatotoxicity generally takes weeks or months vs onset of hepatotoxicity with NRTIs, which takes months to years

• Clinical manifestations

– Generally asymptomatic

– Some patients present with anorexia, weight loss, and/or jaundice associated with indirect hyperbilirubinemia

US DHHS. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_040705.pdf Accessed April 21, 2005; Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124

Common PI-Related Hepatic Effects Common PI-Related Hepatic Effects

f-APV

(2800 mg)

f-APV/r (1400/ 200 mg)

ATV (400 mg)

ATV/r (300/ 100 mg)

IDV

(2400 mg)

LPV/r (800/200

mg)

NFV (2500

mg)

RTV (1200 mg)

SQV (1800mg)

Adverse event

Jaundice – – 8% 2% – – – –

Lab abnormality (grade 3/4)

ALT

AST

Lipase

Bilirubin

6%

6%

8%

–

4%

4%

5%

–

6%

3%

4%

22%

3%

–

4%

22%

4%

3%

–

12%

7%

8%

–

3%

1%

1%

–

–

8%

10%

–

–

2%

4%

–

2%


ATV/r vs LPV/r: Hepatic Effects*ATV/r vs LPV/r: Hepatic Effects*

*5% of patients, No patients withdrew treatment due to jaundice or bilirubin elevations

Jaundice 6 20

Scleral icterus 3 00

n=119 n=110n=118

ATV300 mg QD

ATV 400/SQV

LPV400 mg BID

Grade 2-4 related adverse events in %

RTV 100 mg

RTV 100 mg



Total bilirubin

ALT/SGPT

AST/SGOT

49

4

3

20

4

2

<1

3

3

Grade 3-4 Laboratory parameter in %

PI-Related HyperbilirubinemiaPI-Related Hyperbilirubinemia

• IDV causes hyperbilirubinemia in <25%1

• Most common lab abnormality seen with ATV2

– Dose dependent

– 62% of patients

– Grade 1 or 2

• Discontinuation of either PI results in ↓ bilirubin levels

1. Zucker S et al. DDW 2001. Abstract 233; 2. Squires K et al. CROI 2001. Abstract 15.

Steps at Which Bilirubin Metabolism is EffectedSteps at Which Bilirubin Metabolism is Effected

*Intracellular transport

MRP2

UGT-1A1enzyme

Canaliculus

GST + B

B G1 or G2

hepatocyte

SinusoidB

1. Hemolysis

3. Uptake

4. IC Transport*

2. Transport

6. Export

5. Glucuronidation

RBC

B*ALBUMIN

Indirect Bilirubin Elevations With ATV:Indirect Bilirubin Elevations With ATV:

• Elevated indirect (unconjugated) bilirubin

• ATV inhibits UGT-1A1

• Decreased UGT-1A1 activity similar to the effect observed with Gilbert’s syndrome and mechanistically similar to that seen with IDV

• No evidence of a hepatotoxic process: Grade 3-4 elevations in total bilirubin were rarely associated with grade 3-4 elevations in ALT/AST

• Readily reversible upon discontinuation of ATV

• No difference in frequency of bilirubin elevations or virologic suppression in HBV/HCV co-infected patients

• <1% discontinuation in clinical trials due to bilirubin increases in studies 034 and 043

Mechanism Meaning

100

80

60

40

20

0

10

<15

2

12

2

14

<1

2933

<10

HBV/HCV: Liver Function and BilirubinHBV/HCV: Liver Function and Bilirubin

BMS-034: NaïveBMS-034: Naïve

ATV ATV ATVEFV EFV EFV

Hepatitis co-infected

Not co-infected

AST/SGOT ALT/SGPT Bilirubin

% w

ith

Gra

de

3-4

Lab

Ch

ang

es

Elevations in bilirubin seen with ATV treatment are not associated with

hepatotoxicity, and are not influenced by HBV or HCV co-infection

Adapted from: Cahn P et al. 6th ICDTHIV, Glasgow, Nov 2002. Poster P281

Impact of PI-based ART on LipidsImpact of PI-based ART on Lipids

Contribution of PI Therapy to DyslipidemiaContribution of PI Therapy to Dyslipidemia

• Most PIs have demonstrated association with dyslipidemia

• Lipid abnormalities associated with PI therapy include:– Hypercholesterolemia

LDL-c– Hypertriglyceridemia

• Up to 80% of HIV+ patients on a PI regimen may experience elevated plasma lipid concentrations

• Clinical consequences of PI-associated dyslipidemia: risk of CAD in younger HIV+ patients

– Peripheral atherosclerosis

– Abnormalities of glucose homeostasis

– Pancreatitis risk long-term CVD

Dubé MP et al. Clin Infect Dis 2003; 37: 613–627Calza L, et al. Int J Antimicrob Agents. 2003;22:89-99.

Kannel WB, Giordano M. Am J Cardiol. 2004;94:901-906.

Comparative Lipid Profiles of Different PIsComparative Lipid Profiles of Different PIs

LPV/r(n=65)

SQV/r(n=20)

NFV(n=12)

ATV/r(n=14)

ATV(n=13)

TC 18644 18840 19961 18035 14737

TG 288188 354210 231104 212160 14773

HDL-C 3715 328 389 4114 3511

LDL-C 9330 9331 10840 10423 8223

Lipid profiles associated with different antiretroviral drugs: data from two German outpatient clinics

Data presented in mg/dLAll highlighted segments are at least p<0.05

Presumably negative differences

Mauss S et al. 6th International Conference on Adverse Drug Reactions and Lipodystrophy in HIV patients. Washington 2004.

Poster presentation

• Further data now available:– ATV/r has less effect than LPV/r on TC and fasting TG (p0.005)3

– FosAPV/r and LPV/r associated with similar increases in TC and TG levels4

– SQV/r has less effect than LPV/r on TG (p=0.0004), but similar effect on TC; LDL-cholesterol could not be reliably assessed5

Dyslipidemia in Adults on ART Dyslipidemia in Adults on ART Effects of PIs on LipidsEffects of PIs on Lipids

RTV*LPV/rAPVNFVIDVSQVATV

Little, if any Fewest Intermediate Most markedIncludes cross-study comparisons; direct comparisons for all PIs are not available *At therapeutic doses2

1. Dubé MP et al. Clin Infect Dis 2003; 37: 613–627; 2. Hsu A et al. Antimicrob Agents Chemother 1997; 41: 898–905;

3. Johnson M et al. AIDS. 2005; 19:685-694; 4. DeJesus E et al. 10th CROI, Boston 2003, #178;

5. Walmsley S et al. 11th CROI, 2004; Poster 90

• CV subcommittee of ACTG summarized effects of PIs on ‘lipids’ by degree of abnormality:1

ATV = atazanavir; SQV = saquinavir; IDV = indinavir; NFV = nefinavir; APV = amprenavir; LPV/r = lopinavir/ritonavir; RTV = ritonavir; fosamprenavir/ritonavir; ATV/r = atazanavir/ritonavir

Effects of ATV and NFV on Lipids in Effects of ATV and NFV on Lipids in Naïve Patients at Week 48Naïve Patients at Week 48

P<0.01 for all comparisons to baseline

0

10

20

30

40

50

5.1 5.9

24.6

5.27.1

23.2

7.2 7.6

49.5

TC

ATV 400 mg qd (n=181)

ATV 600 mg qd (n=195)

NFV 1250 mg bid (n=91)

LDL-C TGs

Mea

n ch

ange

from

base

line

to 4

8 w

eeks

(%

)

NRTI backbone: d4T + 3TC bid

p<0.0001for both

p<0.001 p<0.01

p<0.001 p<0.0001

Baseline mean 168/ 165/ 169 99/ 97/ 102 128/ 108/ 121value (mg/dL)


Mea

n %

ch

ang

e fr

om

b

asel

ine

at W

eek

48

-8 -7-4

61 2

30

-4 -3

-10-14

4

-20

0

20

40

ATV/r (n=119) LPV/r (n=118) ATV/SQV (n=110)

Censoring: patients on lipid-lowering therapy excluded

Minimal Effect of ATV/r on Lipid Metabolism:Minimal Effect of ATV/r on Lipid Metabolism:ATV/r vs LPV/r in Treatment-Experienced PatientsATV/r vs LPV/r in Treatment-Experienced Patients

p0.005 for both

p0.005for both

Baseline median 183/ 178/ 166 100/ 103/ 96 38/ 37/ 40 164/ 163/ 153 value (mg/dL)


TC HDL-CLDL-C Fasting TGs

Additional Safety Issues with ATV-Additional Safety Issues with ATV-based ARTbased ART

ATV-Related Cardiology Issues ATV-Related Cardiology Issues

• ATV can prolong PR interval

• AV conduction abnormalities are asymptomatic and limited to 1º AV block

• In clinical trials, 1º AV block was seen in: – 5.9% of ATV-treated patients (n = 920)

– 5.2% of LPV/r-treated patients (n = 252)

– 10.4% of NFV-treated patients (n = 48)

– 3.0% of EFV-treated patients (n = 329)

• Use ATV with caution in patients with pre-existing conduction diseases (marked 1º, or 2º or 3º AV block)

Reyataz [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co; 2004.

cpellecchia

Could not find similar issues with Kaletra. If available, please advise.

Drug Interactions Drug Interactions

• Didanosine (Videx-EC)

– No interaction

• Famotidine (Pepcid)

– Coadministration the AUC and Cmin of ATV

• Methadone (Dolophine)

• Omeprazole (Prilosec)


• Rifampin (Rifadin)

– Coadministration AUC of rifampin; a dosage reduction of rifampin is recommended.

• Tenofovir (Viread)


Reyataz [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co; 2004.

cpellecchia

I don't have all the drug-interaction information - can that be provided?

Pregnancy and ART Pregnancy and ART

• ATV is a pregnancy category “B” drug in the US

• All other FDA-approved ART agents are in category “B”, “C”, or “D”

– “B” – No risk to fetus but not studied in pregnant women

– “C” – Animal studies show risk to fetus and not studied in pregnant women (benefits must outweigh the risks)

– “D” – Human data show no risk, benefit may outweigh risk

• Women should not breast feed while on a PI

Dore G. J HIV Ther. 2003;8:96-100; US DHHS. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_040705.pdf ; Accessed April 21, 2005.

ART and AdherenceART and Adherence

• Medication adherence is key to obtaining optimal benefit from ART

• Recognition of the factors that influence nonadherence, and selection of regimens that can strengthen adherence, are therefore key issues for the long-term success of ART

• There is increasing emphasis on choosing patient-friendly regimens to which patients can readily adhere

ATV Tolerability Summary ATV Tolerability Summary

• ATV is safe and generally well tolerated in naïve and experienced patients

• ATV and ATV/r are associated with significantly less diarrhea than are other PIs (LPV/r or NFV)

– Improved GI tolerability may improve adherence

• The most noticeable lab value change seen with ATV is bilirubin– Not associated with hepatotoxicity, even in hepatitis co-infected

patients

• ATV has demonstrated a distinctly minimal effect on lipid levels in PI-naive and PI-experienced patients

Back-up SlidesBack-up Slides

Body Systems Affected by ARTBody Systems Affected by ART

• ART can affect a number of different body systems including:

– GI

– Liver

– Bilirubin

– Lipids

– Heart

– Kidney

– CNSNot affected by ATV

AEs Have Different Severities AEs Have Different Severities

• Grades were developed using the following general guidelines:

– 0: No adverse event or within normal limits

– 1: Mild adverse event

– 2: Moderate adverse event

– 3: Severe adverse event

– 4: Life-threatening or disabling adverse event

– 5: Fatal adverse event

What is atazanavir (ATV)? What is atazanavir (ATV)?

• Protease inhibitor (PI)

• Azapeptide

• Dosed as 2 capsules daily

• Can be boosted with ritonavir 100 mg to enhance the pharmacokinetics

Reyataz [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.

ATV PharmacokineticsATV Pharmacokinetics

• Absorption– Rapidly absorbed (Tmax ~2.5 hours)– Food: exposure, intersubject variability

• Distribution– Measurable concentrations in CSF and semen– Protein binding ~86% (albumin and 1-AG)

• Metabolism– Primarily metabolized by CYP3A4– Inhibitor of CYP3A4 (Ki ~ 2 M) and UGT 1A1 (not 2B7)

• Elimination– Primarily eliminated in bile – Urinary excretion—7% unchanged drug

– T½ ~7 hours

Reyataz [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.

Efficacy of ATVEfficacy of ATV

• Treatment-naïve patients

– ATV is as effective as EFV in treatment-naïve patients1

– Both regimens are teamed with zidovudine and lamivudine

• Treatment-experienced patients

– ATV/r is as effective as LPV/r in treatment-experienced patients2

1. Squires K et al. J Acquir Immune Defic Syndr. 2004;36:1011-1019.2. Johnson M et al. AIDS. 2005;19:685-694.

Metabolic Profile of ATVMetabolic Profile of ATV

• In naïve patients

– No effect on blood lipids or glucose1

• In experienced patients

– Reduction in LDL, triglycerides, and total cholesterol/HDL2

1. Squires KE et al. ICAAC 2002; 2. Johnson M et al. AIDS. 2005;19:685-694.

Improved Tolerability with ATV Improved Tolerability with ATV

• In naïve patients:

– ATV associated with less diarrhea than NFV1

• In experienced patients:

– ATV/r associated with less diarrhea than LPV/r2

• Less diarrhea could lead to improved adherence

1. Panteleo G et al. ECCATHI, 2001; 2. Cohen C et a. IAS, 2003

Excellent Resistance Profile Excellent Resistance Profile

• Resistance in naive patients: – Rare (2%) and, if present, always associated with I50L

mutation]

• I50L mutation does not confer cross-resistance to other PIs

Colonno R et al. J Infect Dis. 2004;189:1802-1810.

Common Short-Term PI-Related AEsCommon Short-Term PI-Related AEs

AE f-APV

(2800 mg)

f-APV/r (1400/ 200 mg)

ATV (400 mg)

IDV (2400

mg)

LPV/r (800/ 200

mg)

NFV (2500 mg)

RTV (1200 mg)

SQV (1800 mg)

Fatigue 2% 1% 2% – – – 10% –

Abdominal pain 1% 1% 6% 17% 4% – – 2%

Diarrhea 5% 13% 6% 3% 16% 20% 15% 20%

Nausea 5% 3% 16% 12% 7% 3% 26% 11%

Vomiting 2% 3% 6% 8% 2% – 14% 3%

Headache 2% 4% 14% 5% 2% – 6% 5%

Jaundice – – 8% 2% – – – –

Nephrolithiasis – – – 9% – – – –

Paresthesias – – 1% – – – 6% –

Rash 8% 3% 9% 1% 1% 2% – –


Common Grade 3/4 Lab Abnormalities with PI-Common Grade 3/4 Lab Abnormalities with PI-based ARTbased ART

Parameter f-APV

(2800 mg)

f-APV/r (1400/ 200 mg)

ATV (400 mg)

ATV/r (300/ 100 mg)

IDV (2400 mg)

LPV/r (800 mg)

NFV (2500

mg)

RTV (1200 mg)

SQV (1800mg)

Hemoglobin

Thrombo-cytopenia

Neutropenia

–

–

3%

–

–

–

–

–

5%

–

–

4%

1%

1%

2%

–

4%

2%

2%

–

5%

–

–

–

1%

–

3%

ALT

AST

Lipase

Bilirubin

6%

6%

8%

–

4%

4%

5%

–

6%

3%

4%

22%

3%

–

4%

22%

4%

3%

–

12%

7%

8%

–

3%

1%

1%

–

–

8%

10%

–

–

2%

4%

–

2%


ATV vs NFV in Treatment-Naïve PatientsATV vs NFV in Treatment-Naïve Patients

Phase II, 48-week, multicentre trial in ART-naïve patients blinded

to ATV dose, randomized 2:1:2

ATV400 mg qd

NFV 1250 mg bid

ATV 600 mg qd

d4T + 3TC bid d4T + 3TC bid d4T + 3TC bid

n=181 n=91 n=195


BMS-008


ATV vs NFV: Adverse Event Profile*ATV vs NFV: Adverse Event Profile*

n=195n=91

Any adverse event 9192

Diarrhea 1556**

Infection 5548

Headache 2726

Periph neuro symptoms 2221

Pain (abdomen) 2213

Nausea 1818

Rash 1719

n=178

93

20

42

25

18

19

21

22


ATV400 mg QD

ATV600 mg QD

NFV 1250 mg BID

*Reported with a frequency of >20% in any treatment group**P<0.0001

Grade 1-4 Related adverse events in %


Phase III, open-label, multicenter study, randomized 1:1

Patients were screened for prior PI failure

ATV vs LPV/r in PI-Experienced PatientsATV vs LPV/r in PI-Experienced Patients


Adapted from: Cohen C et al. 2nd IAS, Paris, July 2003. Oral presentation 117

BMS-043

ATV400 mg QD

LPV400 mg/

100 mg BID

+2 NRTIs +2 NRTIs

n=150 n=150NRTI backbone: Physician choice

RTV

ATV vs Boosted LPV: Adverse Events* ATV vs Boosted LPV: Adverse Events*

n=144 n=146

Total 17 23

Headache 4 3

Jaundice 3 0

Diarrhea 1 3

Lipodystrophy 3 1

Nausea <1 3


ATV400 mg QD

LPV400 mg BID

Adapted from: Cohen C et al. 2nd IAS, Paris, July 2003. Oral presentation 117 * = 2% of Patients

Grade 2-4 related adverse events in %

RTV

ATV/r vs LPV/r: Study DesignATV/r vs LPV/r: Study Design

Wk 1-2

Wk 2-48

Patient Treatment History (N=358)

Baseline Regimen

PI or NNRTI

Previous Regimens

Failed 2

ARV History

Failed 2 regimens and failed 1 from each class

Randomization 1:1:1

ATV 300 mg QD

Maintain NRTIs

TDF + 1 NRTI

n=120

ATV 400 mg QD

SQV 1200 mg QD

Maintain NRTIs

TDF + 1 NRTI

n=115

LPV 400 mg BID

Maintain NRTIs

TDF + 1 NRTI

n=123


RTV

RTV100 mg

RTV100 mg


ATV/r vs LPV/r: Adverse Events*ATV/r vs LPV/r: Adverse Events*

*5% of patients, **No patients withdrew treatment due to jaundice

Total

Diarrhea

Jaundice

Nausea

29

3

6

3

26

6

2

8

25

11

0

2

Vomiting

Scleral icterus

0

3

4

0

<1

0

Withdrawal due to AE ** 5 74

n=119 n=110n=118

ATV300 mg QD

ATV 400/SQV

LPV400 mg BID Grade 2-4 related

adverse events in %

RTV 100 mg

RTV 100 mg



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