Safety, Tolerability & Efficacy of Abacavir/Lamivudine/Zidovudine vs. Atazanavir &...

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

ESS100327: ACTION StudyESS100327: ACTION Study

No. H-1058No. H-1058

AcknowledgementsAcknowledgementsInvestigators:Investigators:

C AneziokoroC AneziokoroN BellosN BellosJ BoghossianJ BoghossianJ BrandJ BrandG CoodleyG CoodleyP CookP CookE DeJesusE DeJesusR DretlerR DretlerF FelizartaF FelizartaT FileT FileF GarciaF GarciaE GodofskyE GodofskyS GreenS GreenP Greiger-ZanlungoP Greiger-ZanlungoJ HernandezJ HernandezM HillM HillM Hoffman-TerryM Hoffman-TerryJ HorvathJ HorvathA HuangA HuangR JonesR Jones

StudyStudyCoordinatorsCoordinators

PatientsPatients

GlaxoSmithKlineGlaxoSmithKlineJ RoyallJ RoyallJ WeidnerJ WeidnerK FruscianteK FruscianteD Sutherland-PhillipsD Sutherland-PhillipsJ SallJ SallP WannamakerP WannamakerD McClernonD McClernonA Florance A Florance M MooreM MooreM WatsonM WatsonB MatthewsB MatthewsC BrothersC BrothersS ChriscoeS ChriscoeM ShaeferM ShaeferP PatelP Patel

P KumarP KumarP LackeyP LackeyA LaMarcaA LaMarcaH LampirisH LampirisF LutzF LutzA MillsA MillsJ Morales-ReyesJ Morales-ReyesR NahassR NahassD ParksD ParksR PeskindR PeskindD PitrakD PitrakR PobleteR PobleteJ Ramos-JimenezJ Ramos-JimenezA RodriguezA RodriguezJ RodriguezJ RodriguezP SalvatoP SalvatoJ SchrankJ SchrankR SchwartzR SchwartzR ScottR ScottCB SmallCB Small

D SweetD SweetE TedaldiE TedaldiJ TorresJ TorresM TribbleM TribbleW WeinbergW WeinbergR WilcoxR WilcoxD WrightD Wright

BackgroundBackground

• 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.

Study DesignStudy Design

ARV Naïve SubjectsARV Naïve SubjectsScreen HIV-1 RNA <200,000 c/mL Screen HIV-1 RNA <200,000 c/mL

CD4+ Count ≥ 100 cells/mmCD4+ Count ≥ 100 cells/mm33

Stratified by HIV-1 RNA Stratified by HIV-1 RNA < or < or ≥ 100,000 c/mL≥ 100,000 c/mL

ARV Naïve SubjectsARV Naïve SubjectsScreen HIV-1 RNA <200,000 c/mL Screen HIV-1 RNA <200,000 c/mL

CD4+ Count ≥ 100 cells/mmCD4+ Count ≥ 100 cells/mm33

Stratified by HIV-1 RNA Stratified by HIV-1 RNA < or < or ≥ 100,000 c/mL≥ 100,000 c/mL

ABC/3TC/ZDVABC/3TC/ZDV

Atazanavir 400mg daily + Atazanavir 400mg daily + 3TC/ZDV 1 tablet twice daily3TC/ZDV 1 tablet twice daily

N=140N=140

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)

1 tablet twice daily1 tablet twice dailyN=139N=139

Study EndpointsStudy Endpoints

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

Key Secondary EndpointsKey Secondary Endpoints EfficacyEfficacy

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 CriteriaVirologic Failure Criteria

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

22% 20%22% 20%

47% 41%47% 41% 32% 35%32% 35% 19% 21%19% 21%

1% 4%1% 4% 6% 7%6% 7% 0 <1%0 <1%

ABC/3TC/ZDV ATV+3TC/ZDVABC/3TC/ZDV ATV+3TC/ZDV N=139 N=140N=139 N=140

White White Black Black HispanicHispanic

Baseline CharacteristicsBaseline Characteristics


CDC Class C (%) 4% 4% CDC Class C (%) 4% 4%

Median HIV-1 RNA logMedian HIV-1 RNA log1010 c/mL c/mL

Median CD4+ (cells/mmMedian CD4+ (cells/mm33))

4.48 4.644.48 4.64

0% 5%0% 5% 24%24% 26% 26% 47% 44%47% 44%

HIV-1 RNA HIV-1 RNA <<100,000 c/mL (%)100,000 c/mL (%) 83% 82%83% 82%

274 262274 262

<100 <100 100 - <200 100 - <200 200 - <350 200 - <350 ≥ ≥ 350350

28% 28% 25% 25%

Subject DispositionSubject Disposition

Completed 48 Weeks 103 (74%) 98 (70%)Completed 48 Weeks 103 (74%) 98 (70%) Premature WithdrawalPremature Withdrawal

Reasons for Discontinuation Reasons for Discontinuation Virologic Failure*Virologic Failure* Lost to Follow-UpLost to Follow-Up Adverse EventAdverse Event OtherOther Investigator DecisionInvestigator Decision Subject Decision Subject Decision Protocol ViolationProtocol Violation

36 (26%) 41 (29%)36 (26%) 41 (29%)

16 (12%)16 (12%) 16 (11%)16 (11%)12 ( 9%) 14 (10%)12 ( 9%) 14 (10%) 6 ( 4%) 11 ( 8%)6 ( 4%) 11 ( 8%)

6 ( 4%) 06 ( 4%) 0

3 ( 2%) 1 (<1%)3 ( 2%) 1 (<1%)6 ( 4%) 06 ( 4%) 0


*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

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rop

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of

Su

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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

Switch = Failure AnalysisSwitch = Failure Analysis

ATV+3TC/ZDVATV+3TC/ZDV n = 140 115 25 112 89 23n = 140 115 25 112 89 23

Virologic RespondersVirologic RespondersHIV-1 RNA <50 c/mL at Week 48 HIV-1 RNA <50 c/mL at Week 48

Switch Switch ≠ Failure≠ Failure

64 6370

63

39

64

80 8086 83

50

70

0

20

40

60

80

100


Overall ITT-E

HIV-1 RNA <100,000 c/mL

HIV-1 RNA ≥100,000 c/mL

Overall Observed

S≠F

HIV-1 RNA <100,000 c/mL

HIV-1 RNA ≥100,000 c/mL

Pro

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s

ABC/3TC/ZDV n = 138 115 23 111 93 18

95% CI (-6.4, 9.5)

95% CI(-7.8, 7)

95% CI(-5.3, 19.2)

95%CI(-7.4, 13.9)

95%CI(-52.9, 3.1)

95% CI(-50.1, 11)

n = 140 115 25 110 87 23ATV+3TC/ZDV

S≠F

0

50

100

150

200

0 8 16 24 32 40 48

Study Week

Med

ian

CD

4+ C

ell

Co

un

t (

cell

s/m

m3)

TZV ATV+COM

Median Change from Baseline in CD4+ Cell Count

ABC/3TC/ZDV n= 138 128 122 117 110 104 101

+ 147

n=140 125 123 118 106 98 96ATV+3TC/ZDV

Median 274CD4+ 262

434419

Virologic Failure OutcomesVirologic Failure Outcomes

Reasons for Virologic Failure*, nReasons for Virologic Failure*, n

ABC/3TC/ZDV ATV+3TC/ZDVABC/3TC/ZDV ATV+3TC/ZDV

N=138 N=140N=138 N=140

* Subjects could have met multiple virologic failure criteria

1. Fail to have ≥1 log RNA drop by Week 121. Fail to have ≥1 log RNA drop by Week 12

2. Fail to have VL <400 c/mL by Week 242. Fail to have VL <400 c/mL by Week 24

3. Two VL <50 then confirmed 3. Two VL <50 then confirmed ≥400 c/mL by Wk 24≥400 c/mL by Wk 24

4. Two 4. Two ≥400 c/mL after Week 24≥400 c/mL after Week 24

5.5. VL VL ≥400 c/mL after Week 48 without ≥400 c/mL after Week 48 without confirmationconfirmation

Virologic FailuresVirologic Failures, n (%), n (%) 18 (13%) 17 (12%)18 (13%) 17 (12%)

3 3 3 3

2 22 2

6 116 11

3 43 4

7 37 3

HIV-1 RNA <100,000 c/mL HIV-1 RNA <100,000 c/mL HIV-1 RNA HIV-1 RNA ≥ 100,000 c/mL≥ 100,000 c/mL

10 12 10 12 8 58 5

Treatment Emergent ResistanceTreatment Emergent Resistance ABC/3TC/ZDV ATV+3TC/ZDVABC/3TC/ZDV ATV+3TC/ZDV

N=138 N=140N=138 N=140

Treatment-Emergent Mutations at VFTreatment-Emergent Mutations at VF

1010 1111

9 ( 90%) 9 (82%)9 ( 90%) 9 (82%) 1 ( 10%) 01 ( 10%) 0

PIPI Major Major MinorMinor

0 0 00 7 (70%) 6 (55%)7 (70%) 6 (55%)

NNRTINNRTI (K103N)(K103N)

1 (10%) 1 ( 9%)1 (10%) 1 ( 9%)

Protocol-Defined Virologic Failure, n (%)Protocol-Defined Virologic Failure, n (%) 18 (13%) 17 (12%)18 (13%) 17 (12%)

Paired BL and Failure GT/ PT Results Paired BL and Failure GT/ PT Results 17 1617 16

NRTI* NRTI* (M184V)(M184V)

(L210W, D67N, L74V, F77L)(L210W, D67N, L74V, F77L)

(L10I, I13V, I13L/V, G16E,K20M, (L10I, I13V, I13L/V, G16E,K20M, L24I, I31L/V, L33V, E35G, I54I/L, L24I, I31L/V, L33V, E35G, I54I/L, I62I/V, L63L/P, A71A/V, V77I/V, I62I/V, L63L/P, A71A/V, V77I/V, I85I/V, I93I, I93L)I85I/V, I93I, I93L)

Treatment-Related Grade 2-4 Treatment-Related Grade 2-4 Adverse Events in >2% of subjectsAdverse Events in >2% of subjects

* Includes 1 Suspected ABC HSR reported as grade 1

N=138 N=140

% (% Grade 3/4)% (% Grade 3/4)

Hyperbilirubinemia 0 21% (16%)Hyperbilirubinemia 0 21% (16%)

Nausea 11% (<1%) 4% (0)Nausea 11% (<1%) 4% (0)

Neutropenia 5% (4%) 6% (4%) Neutropenia 5% (4%) 6% (4%)

Fatigue 5% (0) 2% (0)Fatigue 5% (0) 2% (0)

Headache 4% (<1%) 4% Headache 4% (<1%) 4% (0) (0)

Suspected Abacavir HSR* 5% (0) 0Suspected Abacavir HSR* 5% (0) 0

Anemia <1% (<1%) 3% (3%)Anemia <1% (<1%) 3% (3%)

Scleral Icterus 0 4% (3%)Scleral Icterus 0 4% (3%)


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

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IDV+COM+ TZV PBO

Efficacy Outcomes

TZV ATV+COM N=138 N=140

* Protocol-defined virologic failure was based on multiple criteria

n (%)

All Responders 85 (62%) 83 (59%)

76 / 115 (66%) 68 / 115 (59%)

Response by Strata,

HIV-1 RNA < 100,000 c/mL

HIV-1 RNA ≥ 100,000 c/mL 9 / 23 (39%) 15 / 25 (60%)

n/N (%)

HIV-1 RNA <400 c/mL, ITT-E, M=F

HIV-1 RNA<50 c/mL, ITT-E, M/S=F

All Responders 93 (67%) 95 (68%)

Week 48

Adverse EventsAdverse Events

N=138 N=140N=138 N=140

ABC/3TC/ZDV ATV+3TC/ZDV ABC/3TC/ZDV ATV+3TC/ZDV

Serious Adverse EventsSerious Adverse Events 14 (10%) 17 (12%)14 (10%) 17 (12%)

Study Drug Discontinuation (G2-4 AE) Study Drug Discontinuation (G2-4 AE) 12 ( 9%) 13 ( 9%)12 ( 9%) 13 ( 9%)

ABC HSR ABC HSR 7 ( 5%) 07 ( 5%) 0Anemia Anemia 0 3 ( 2%)0 3 ( 2%)Abdominal Pain Abdominal Pain 0 1 (<1%)0 1 (<1%)

Drug Hypersensitivity* Drug Hypersensitivity* 7 ( 5%) 07 ( 5%) 0Scleral Icterus Scleral Icterus 0 4 ( 3%)0 4 ( 3%)Hyperbilirubinemia Hyperbilirubinemia 0 0 4 ( 3%)4 ( 3%)Jaundice Jaundice 0 2 ( 1%)0 2 ( 1%)Anemia Anemia 1 (<1%) 1 (<1%) 2 ( 1%) 2 ( 1%)Nausea Nausea 2 (1%) 2 (1%) 0 0Abdominal Pain Abdominal Pain 2 ( 1%) 2 ( 1%) 0 0Drug Eruption Drug Eruption 0 0 2 ( 1%) 2 ( 1%)

Treatment-Related SAEs Treatment-Related SAEs 7 ( 5%) 3 ( 2%)7 ( 5%) 3 ( 2%)

*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

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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


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

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20

40

60

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100

0 8 16 24 32 40 48

Study Week

Pro

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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

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9188

6564


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

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s


9188

6564


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

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9692

6768


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


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

2.2

2.9 3

2.4

0.59 0.54 0.58 0.54

1.5

2

2.5

3

3.5

4

4.5

5

0 4 8 12 16 20 24 28 32 36 40 44 48

Time (week)

HIV

-1 R

NA

Lo

g10

.

Subject 855: TZVRT: L74V, F77L, V118IPRO: D30N, L63P, N88D ABC FC= 1.19 ATV FC = 4.793TC FC= 1.33ZDV FC= 0.85

WD RT: L74V, F77L, V118I, L210W PRO: D30N, M36I, L63P, N88D ABC FC= 5.90 ATV FC = 113TC FC= 8.59ZDV FC = 115

1.5

2

2.5

3

3.5

4

4.5

5

0 4 8 12 16 20 24 28 32 36 40 44 48

Time (week)

HIV

-1 R

NA

Lo

g10

.

Subject 573: TZV

RT: WTPRO: L63PABC FC= 0.95 ATV FC = 0.58 3TC FC= 1.27ZDV FC= 0.65

RT: WTPRO: L63PABC FC= 0.82 ATV FC = 0.72 3TC FC= 1.22ZDV FC= 0.59

1.5

2

2.5

3

3.5

4

4.5

5

0 4 8 12 16 20 24 28 32 36 40 44 48

Time (week)

HIV

-1 R

NA

Lo

g10

.

Subject 668: TZVRT: WTPRO: L63PABC FC= 0.72 ATV FC = 0.923TC FC= 1.03ZDV FC= 1.10

RT: M184VPRO: L63PABC FC= 3.00 ATV FC = 0.80 3TC FC= 104ZDV FC= 0.48

1.5

2

2.5

3

3.5

4

4.5

5

5.5

0 4 8 12 16 20 24 28 32 36 40 44 48

Time (week)

HIV

-1 R

NA

Lo

g10

.

Subject 852: ATV/COM

RT: WTPRO: L63PABC FC= 0.76 ATV F = 0.83 3TC FC= 1.05ZDV FC= 0.63

RT: K103NPRO: L63PABC FC= 0.84 ATV FC = 1.053TC FC= 1.21ZDV FC= 0.60

3log

3.2 log

1.5

2

2.5

3

3.5

4

4.5

5

0 4 8 12 16 20 24 28 32 36 40 44 48

Time (week)

HIV

-1 R

NA

Lo

g10

.

Subject 918: ATV/COMRT: K103NPRO: L63PABC FC= 0.57 ATV FC = 0.953TC FC= 1.01ZDV FC= 0.22

RT: K103N, M184VPRO: K20M, L24I, L63PABC FC= 2.99 ATV FC = 0.58 3TC FC= 104ZDV FC= 0.43

1.5

2

2.5

3

3.5

4

4.5

5

0 4 8 12 16 20 24 28 32 36 40 44 48

Time (week)

HIV

-1 R

NA

Lo

g10

.

Subject 592: ATV/COM

RT: L74V, P225HPRO: L10I, K20I, A71V, L90MABC FC= 0.99 ATV FC = 1.59 3TC FC= 1.06ZDV FC= 1.27

RT: L74V, M184V, P225HPRO: L10I, K20I, I54L, A71V, L90MABC FC= 2.85 ATV FC = 1.83 3TC FC= 87ZDV FC= 0.91

Safety, Tolerability & Efficacy of Abacavir/Lamivudine/Zidovudine vs. Atazanavir &...

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Transcript of Safety, Tolerability & Efficacy of Abacavir/Lamivudine/Zidovudine vs. Atazanavir &...