Safety, Tolerability & Efficacy of Safety, Tolerability & Efficacy of Abacavir/Lamivudine/Zidovudine Abacavir/Lamivudine/Zidovudine vs. vs. Atazanavir & Lamivudine/Zidovudine Atazanavir & Lamivudine/Zidovudine in Antiretroviral Naïve Subjects in Antiretroviral Naïve Subjects Kumar PN, Salvato P, DeJesus E, LaMarca A, Kumar PN, Salvato P, DeJesus E, LaMarca A, Patel P, Sutherland-Phillips D, McClernon D, Patel P, Sutherland-Phillips D, McClernon D, Florance A, Sall J, Wannamaker P, and Shaefer Florance A, Sall J, Wannamaker P, and Shaefer M for the ACTION study group M for the ACTION study group ESS100327: ACTION Study ESS100327: ACTION Study No. H-1058 No. H-1058
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Safety, Tolerability & Efficacy of Abacavir/Lamivudine/Zidovudine vs. Atazanavir & Lamivudine/Zidovudine in Antiretroviral Naïve Subjects Kumar PN, Salvato.
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Safety, Tolerability & Efficacy of Safety, Tolerability & Efficacy of Abacavir/Lamivudine/Zidovudine Abacavir/Lamivudine/Zidovudine
vs. vs. Atazanavir & Lamivudine/Zidovudine Atazanavir & Lamivudine/Zidovudine
in Antiretroviral Naïve Subjectsin Antiretroviral Naïve Subjects
Safety, Tolerability & Efficacy of Safety, Tolerability & Efficacy of Abacavir/Lamivudine/Zidovudine Abacavir/Lamivudine/Zidovudine
vs. vs. Atazanavir & Lamivudine/Zidovudine Atazanavir & Lamivudine/Zidovudine
in Antiretroviral Naïve Subjectsin Antiretroviral Naïve Subjects
Kumar PN, Salvato P, DeJesus E, LaMarca A, Patel P, Kumar PN, Salvato P, DeJesus E, LaMarca A, Patel P, Sutherland-Phillips D, McClernon D, Florance A, Sall J, Sutherland-Phillips D, McClernon D, Florance A, Sall J, Wannamaker P, and Shaefer M for the ACTION study groupWannamaker P, and Shaefer M for the ACTION study group
• Abacavir/Lamivudine/Zidovudine (ABC/3TC/ZDV, Abacavir/Lamivudine/Zidovudine (ABC/3TC/ZDV, Trizivir) & Atazanavir (ATV, Reyataz) are Trizivir) & Atazanavir (ATV, Reyataz) are alternative options in ARV-naïve patientsalternative options in ARV-naïve patients
• ABC/3TC/ZDV should be reserved for those who cannot ABC/3TC/ZDV should be reserved for those who cannot receive an NNRTI or PI-based regimenreceive an NNRTI or PI-based regimen11
• ATV without ritonavir is an alternative to the preferred ATV without ritonavir is an alternative to the preferred PI-based regimen, Lopinavir/ritonavir PI-based regimen, Lopinavir/ritonavir
• Both regimens are used in clinical practice in Both regimens are used in clinical practice in select patient populations as they are well-select patient populations as they are well-tolerated and convenient therapies. tolerated and convenient therapies.
11DHHS Guidelines, May 2006.DHHS Guidelines, May 2006.
Phase IV, randomized (1:1), multicenter, open-label, 48 week studyPhase IV, randomized (1:1), multicenter, open-label, 48 week study
Conducted at 46 sites in US and MexicoConducted at 46 sites in US and Mexico
Non-Inferiority established if the lower limit of the two-sided 95% CI was Non-Inferiority established if the lower limit of the two-sided 95% CI was ≥ ≥ -0.12-0.12
Switch allowed for ABC HSR (TDF) or jaundice or scleral icterus (FPV)Switch allowed for ABC HSR (TDF) or jaundice or scleral icterus (FPV)
Primary EndpointPrimary Endpoint– Proportion of subjects with HIV-1 RNA <50 c/mL at Week 48Proportion of subjects with HIV-1 RNA <50 c/mL at Week 48
• Subjects must not have met any definition of virologic failureSubjects must not have met any definition of virologic failure• ITT-E, Missing/Switch = Failure AnalysisITT-E, Missing/Switch = Failure Analysis
Proportion of subjects with HIV-1 RNA <50 c/mL, switch Proportion of subjects with HIV-1 RNA <50 c/mL, switch ≠ failure≠ failure Change in HIV-1 RNA and CD4 cell counts from BLChange in HIV-1 RNA and CD4 cell counts from BL Treatment-emergent genotype mutationsTreatment-emergent genotype mutations
SafetySafety Drug-related adverse events (Grade 2-4) and serious adverse Drug-related adverse events (Grade 2-4) and serious adverse
eventsevents Changes in lipid parameters, insulin sensitivity and resistanceChanges in lipid parameters, insulin sensitivity and resistance
Virologic failure was defined as any of the following:Virologic failure was defined as any of the following:
1.1. Failure to have Failure to have ≥ 1 log HIV-1 RNA drop by Week 12≥ 1 log HIV-1 RNA drop by Week 122.2. Failure to have HIV-1 RNA <400 by Week 24Failure to have HIV-1 RNA <400 by Week 24 3.3. Confirmed HIV-1 RNA <50 then ≥ 400 confirmed prior Confirmed HIV-1 RNA <50 then ≥ 400 confirmed prior
to Week 24 to Week 24 4.4. Confirmed HIV-1 RNA ≥ 400 after Week 24Confirmed HIV-1 RNA ≥ 400 after Week 24 5.5. HIV-1 RNA ≥ 400 at Week 48 without confirmationHIV-1 RNA ≥ 400 at Week 48 without confirmation
*Virologic responders could not have met any virologic failure criteria*Virologic responders could not have met any virologic failure criteria
Baseline DemographicsBaseline Demographics
Median age, years 38 36 Median age, years 38 36
Female, n (%)Female, n (%) Race, n (%)Race, n (%)
Hepatitis B positiveHepatitis B positiveHepatitis C positiveHepatitis C positiveHepatitis B & C co-infection Hepatitis B & C co-infection
*As reported on Study Conclusion Page. *As reported on Study Conclusion Page. Note: subjects with VL<1265 c/mL were allowed to stay on study.Note: subjects with VL<1265 c/mL were allowed to stay on study.
0 2 ( 1%)0 2 ( 1%)
62 5966
59
39
60
76 74
8176
50
65
0
20
40
60
80
100
ABC/3TC/ZDV ATV+3TC/ZDV
Overall Overall ITT-E ITT-E M/S=FM/S=F
HIV-1 RNA HIV-1 RNA <100,000 c/mL<100,000 c/mL
HIV-1 RNA HIV-1 RNA ≥≥100,000 c/mL100,000 c/mL
OverallOverall Observed Observed
S=FS=F
HIV-1 RNA HIV-1 RNA <100,000 c/mL<100,000 c/mL
HIV-1 RNA HIV-1 RNA ≥100,000 c/mL≥100,000 c/mL
Pro
po
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n o
f S
ub
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sP
rop
ort
ion
of
Su
bje
cts
ABC/3TC/ZDV n = 138 115 23 112 94 18ABC/3TC/ZDV n = 138 115 23 112 94 18
95% CI95% CI (-5.9, 10.4)(-5.9, 10.4)
95% CI95% CI(-6.7, 9.4)(-6.7, 9.4)
95% CI95% CI(-5.6, 19.5)(-5.6, 19.5)
95%CI95%CI(-7.5, 16.4)(-7.5, 16.4)
95% CI95% CI(-49.2, 27.4)(-49.2, 27.4)
95%CI95%CI(-46.2, 15.8)(-46.2, 15.8)
Virologic RespondersVirologic RespondersHIV-1 RNA <50 c/mL at Week 48 HIV-1 RNA <50 c/mL at Week 48
Percent Change in Fasting Lipids Percent Change in Fasting Lipids from Baseline to Week 48from Baseline to Week 48
511
-5
16
2 5 -6
21
-20
0
20
40
60
80
100
TZV ATV+COM
Total Cholesterol
Triglycerides
LDL-Cholesterol
HDL-Cholesterol
511
-5
16
2 5 -6
21
-20
0
20
40
60
80
100
TZV ATV+COM
Total Cholesterol
Triglycerides
LDL-Cholesterol
HDL-Cholesterol
% C
han
ge
in F
asti
ng
Lip
ids
% C
han
ge
in F
asti
ng
Lip
ids
SummarySummary
• In an ITT(E) M/S=F analysis, 62% vs. 59% of In an ITT(E) M/S=F analysis, 62% vs. 59% of subjects achieved HIV-1 RNA <50 copies/ml subjects achieved HIV-1 RNA <50 copies/ml in the overall population (ABC/3TC/ZDV vs. in the overall population (ABC/3TC/ZDV vs. ATV+3TC/ZDV, respectively)ATV+3TC/ZDV, respectively)
• Protocol-defined virologic failure occurred in Protocol-defined virologic failure occurred in 13% of subjects and were balanced between 13% of subjects and were balanced between armsarms
• No treatment-emergent primary PI mutations No treatment-emergent primary PI mutations in the ATV+3TC/ZDV arm were observed in the ATV+3TC/ZDV arm were observed through 48 weeks and the majority of NRTI through 48 weeks and the majority of NRTI mutations were attributed to M184Vmutations were attributed to M184V
• In this study, ABC/3TC/ZDV and In this study, ABC/3TC/ZDV and ATV+3TC/ZDV were well-tolerated ATV+3TC/ZDV were well-tolerated and had comparable efficacyand had comparable efficacy
• In select patients naïve to therapy In select patients naïve to therapy with HIV-1 RNA with HIV-1 RNA <<100,000 c/mL, 100,000 c/mL, ABC/3TC/ZDV remains a viable ABC/3TC/ZDV remains a viable option as an initial regimenoption as an initial regimen
ConclusionConclusion
Back-Up SlidesBack-Up Slides
Efficacy of ABC/3TC/ZDV Compared to Unboosted PIs and Efavirenz
0
20
40
60
80
100
ABC/3TC/ZDV Comparator Arms
CNAAB3005 CNA3014 CNAF3007 ACTG5095
HIV-1 RNA <50 c/mL over 48 Weeks
40%46%
60%
50%55%55% 61%
83%
Comparator: ABC/3TC/ZDV
ABC/3TC/ZDV + IDV+COM PBOS
NFV+COM
IDV+COM
EFV+COMEFV+TZV
Pro
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ub
ject
s
IDV+COM+ TZV PBO
Efficacy Outcomes
TZV ATV+COM N=138 N=140
* Protocol-defined virologic failure was based on multiple criteria
*Includes 1 subject with Grade 1 HSR*Includes 1 subject with Grade 1 HSR
64 64
56
7267
61
8891
86
9489 89
0
20
40
60
80
100
TZV ATV+COM
Overall M=F
CD4+ <200 cells/mm3
CD4+ ≥ 200 cells/mm3
Overall Observed
CD4+ <200 cells/mm3
CD4+ ≥ 200 cells/mm3
Per
cen
t o
f S
ub
ject
s
TZV n = 138 34 104 101 22 79
ATV+COM n = 140 43 97 99 33 66
HIV-1 RNA <50 c/mL at Week 48 Subjects without protocol-defined virologic failure
ITT-E, CD4 Subgroup Analysis
0
50
100
150
200
250
mg
/dL
TZV ATV+COM TZV ATV+COM
Baseline
Week 48
Cholesterol Triglycerides
Baseline n= 131 137 131 137
Week 48 n= 93 93 93 93
Median Fasting Lipids (mg/dL) at Baseline and Week 48
162 176 160 171
113 126 117 110
NCEP III
NCEP III
NCEP ATP III Guidelines consider TC <200 mg/dL and TG <150 mg/dL as desirable
0
50
100
150
mg
/dL
TZV ATV+COM TZV ATV+COM
Baseline
Week 48
LDL HDL
Baseline n= 127 133 130 135
Week 48 n= 89 92 93 93
Median Fasting Lipids (mg/dL) at Baseline and Week 48
98 99 97 102
36.5 44 33 44
NCEP ATP III Guidelines consider LDL <100 mg/dL and HDL > 40 mg/dL as desirable
NCEP III
NCEP III
The ACTION StudyThe ACTION Study• Phase IV, randomized, multicenter, open-label Phase IV, randomized, multicenter, open-label
study evaluating the safety and efficacy of study evaluating the safety and efficacy of ABC/3TC/ZDV vs. ATV + 3TC/ZDV in ART-naïve ABC/3TC/ZDV vs. ATV + 3TC/ZDV in ART-naïve subjects over 48 weekssubjects over 48 weeks
• 279 subjects were enrolled from 46 sites in the 279 subjects were enrolled from 46 sites in the U.S. & Mexico between May 2004 – March 2005.U.S. & Mexico between May 2004 – March 2005.
• 95% from U.S. sites.95% from U.S. sites.• Subjects experiencing toxicity from randomized Subjects experiencing toxicity from randomized
treatment were permitted to switch medicationstreatment were permitted to switch medications• Suspected ABC HSR reaction Suspected ABC HSR reaction 3TC/ZDV + 3TC/ZDV +
TenofovirTenofovir• Atazanavir-related jaundice or scleral icterus Atazanavir-related jaundice or scleral icterus
Fosamprenavir + 3TC/ZDVFosamprenavir + 3TC/ZDV• Virologic failure was based on multiple criteriaVirologic failure was based on multiple criteria
pgw60159
Seems to me that much of this could be verbalized while showing the next slide, saving the need to show this at all.
Study Discontinuation Due to Grade 2-4 Adverse Events
N=138 N=140
TZV ATV+COM
Study Discontinuation from AEs, n (%) 6 (4%) 8 (6%)
Abdominal pain 2 (1%) 0
Nausea 2 (1%) 0
Dyspepsia 0 1 (<1%)
Enteritis 0 1 (<1%)
Vomiting 1 (<1%) 0
Anemia 1 (<1%) 2 (1%)
Rash 0 3 (2%)
Fatigue 1 (<1%) 0
Hyperbilirubinemia 0 1 (<1%)
Jaundice 0 1 (<1%)
Headache 1 (<1%) 0
Toxicity Switches
N=138 N=140
Abacavir – Related
TZV ATV+COM
Suspected Abacavir HSR
7 (5%) 0
JaundiceScleral IcterusHyperbilirubinemia**
0 2 (1%)0 4 (3%)0 3 (2%)
Grade 3 (>2.5-5x ULN)
7 (5%) 9 (6%)
3
Atazanavir - Related
Toxicity Switches
**Although hyperbilirubinemia was not a protocol allowable toxicity switch reason, 3 subjects switched off ATV+COM due to ATV-related hyperbilirubinemia
HIV-1 RNA <400 c/mL at Week 48
7874
67 68
92 9287
96
0
20
40
60
80
100
TZV ATV+COM
Week 24 Week 48
M=F
Week 24 Week 48
Obs
Pro
po
rtio
n o
f S
ub
ject
s
0
20
40
60
80
100
0 8 16 24 32 40 48
Study Week
Pro
po
rtio
n o
f S
ub
ject
s
TZVATV+COMTZV, ObservedATV+COM, Observed
8684
6261
Virologic Response HIV-1 RNA <50 c/mL
n (obs)
TZV = 138 130 122 117 111 104 101
ATV+CO M = 140 128 123 118 109 100 99
ITT-E, M/S=F
ITT-E, S=F
0
20
40
60
80
100
0 8 16 24 32 40 48
Study Week
Pro
po
rtio
n o
f S
ub
ject
s
TZVATV+COMTZV, ObservedATV+COM, Observed
9188
6564
Virologic Response HIV-1 RNA <50 c/mL
n (obs)
TZV = 138 130 122 117 111 104 101
ATV+CO M = 140 128 123 118 109 100 99
ITT-E, M=F,S≠F
ITT-E, S≠F
0
20
40
60
80
100
0 8 16 24 32 40 48
Study Week
Pro
po
rtio
n o
f S
ub
ject
s
TZVATV+COMTZV, ObservedATV+COM, Observed
9188
6564
Virologic Response HIV-1 RNA <400 c/mL
n (obs)
TZV = 138 130 122 117 111 104 101
ATV+CO M = 140 128 123 118 109 100 99
ITT-E, M/S=F
ITT-E, S=F
0
20
40
60
80
100
0 8 16 24 32 40 48
Study Week
Pro
po
rtio
n o
f S
ub
ject
s
TZVATV+COMTZV, ObservedATV+COM, Observed
9692
6768
Virologic Response HIV-1 RNA <400 c/mL
n (obs)
TZV = 138 130 122 117 111 104 101
ATV+CO M = 140 128 123 118 109 100 99
ITT-E, M=F,S≠F
ITT-E, S≠F
Time to Loss of Virologic Response HIV-1 RNA<50 c/mL (TLOVR)
Time to Loss of Virologic Response HIV-1 RNA<50 c/mL (TLOVR)
M/S=F
0
1
2
3
4
5
Ca
lcu
lati
on
TZV ATV+COM TZV ATV+COM
Baseline
Week 48
HOMA-IR QUICK1
Baseline n= 110 112 110 112
Week 48 n= 83 87 83 87
Median Changes in Metabolic Parameters at Baseline & Week 48