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REYATAZREYATAZ
Safety & Tolerability Issues for HIV‑Infected Patients Requiring
Protease Inhibitor Therapy
DisclaimerDisclaimer
This slide set has been developed by Reyataz Global Marketing for internal BMS use only. Utilization of
this monograph, in whole or in part, for any promotional purposes requires regional and local
legal, regulatory, and medical approval prior to use.
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)
d4Td4TddCddCddlddlAZTAZT
firstfirstARARVV
‘‘9898
EFVEFVABCABC
‘‘9999
APVAPV
clinicalclinicaluse ofuse ofgenotypinggenotypingphenotypingphenotyping
‘‘0000
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
‘‘0202
OraQuickOraQuick
‘‘0303
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
Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124.
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%
Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124.
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
BMS-045: Experienced (boosted ATV vs boosted LPV)BMS-045: Experienced (boosted ATV vs boosted LPV)
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%
Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124.
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
BMS-045: Experienced (boosted ATV vs boosted LPV)BMS-045: Experienced (boosted ATV vs boosted LPV)
Johnson M et al. AIDS. 2005; 19:685-694
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)
Murphy RL et al. AIDS 2003; 17: 2603–2614
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)
Johnson M et al. AIDS. 2005; 19:685-694
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.
Drug Interactions Drug Interactions
• Didanosine (Videx-EC)
– No interaction
• Famotidine (Pepcid)
– Coadministration the AUC and Cmin of ATV
• Methadone (Dolophine)
• Omeprazole (Prilosec)
– Coadministration the AUC and Cmin of ATV
• Rifampin (Rifadin)
– Coadministration AUC of rifampin; a dosage reduction of rifampin is recommended.
• Tenofovir (Viread)
– Coadministration the AUC and Cmin of ATV
Reyataz [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co; 2004.
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% – –
Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124.
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%
Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124.
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
Murphy RL et al. AIDS 2003; 17: 2603–2614
BMS-008
BMS-008: NaBMS-008: Naïïveve
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
BMS-008: NaBMS-008: Naïïveve
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 %
Murphy RL et al. AIDS 2003; 17: 2603–2614
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
BMS-043: PI experienced (unboosted vs boosted PI)BMS-043: PI experienced (unboosted vs boosted PI)
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
BMS-043: PI experienced (unboosted vs boosted PI)BMS-043: PI experienced (unboosted vs boosted PI)
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
BMS-045: Experienced (boosted ATV vs boosted LPV)BMS-045: Experienced (boosted ATV vs boosted LPV)
RTV
RTV100 mg
RTV100 mg
Johnson M et al. AIDS. 2005; 19:685-694
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
BMS-045: Experienced (boosted ATV vs boosted LPV)BMS-045: Experienced (boosted ATV vs boosted LPV)
Johnson M et al. AIDS. 2005; 19:685-694
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