kimberly smith, winkler weinberg, edwin dejesus, margaret fischl, qiming liao, lisa ross and

Kimberly Smith, Winkler Weinberg, Edwin DeJesus, Margaret Fischl, Qiming Liao, Lisa Ross and Tracey Lancaster

The ALERT Study:The ALERT Study:

A Planned Week 24 Interim Analysis of A Planned Week 24 Interim Analysis of Once Daily Boosted Fosamprenavir or Once Daily Boosted Fosamprenavir or Atazanavir with Tenofovir/Emtricitabine Atazanavir with Tenofovir/Emtricitabine

BackgroundBackground

IAS Guidelines recently added boosted FPV IAS Guidelines recently added boosted FPV and ATV + 2 nucs as recommended initial and ATV + 2 nucs as recommended initial therapytherapyFPV/r dose in US product label is 1400mg FPV/r dose in US product label is 1400mg FPV + 200mg RTV once daily for naïve FPV + 200mg RTV once daily for naïve subjectssubjectsThis study used a reduced FPV/r dose of This study used a reduced FPV/r dose of 1400 mg FPV + 1400 mg FPV + 100 mg RTV100 mg RTV once daily once daily that has not been previously studiedthat has not been previously studied

ObjectiveObjective

To compare the efficacy, safety, and To compare the efficacy, safety, and tolerability of RTV-boosted FPV versus tolerability of RTV-boosted FPV versus RTV-boosted ATV, both in combination RTV-boosted ATV, both in combination with TDF/FTCwith TDF/FTC

Study DesignStudy DesignRandomized (1:1), open-label, 48 week pilot study

Entry criteria: HIV-1 RNA >1000 c/mL No CD4 cell count restrictions

Stratified by entry HIV-1 RNA <100,000 c/mL or 100,000 c/mLBaseline resistance testing was not done prior to entry

ART-naïve subjects,

n=106

FPV 1400 mg QD +

RTV 100 mg QD +

TDF/FTC QD

ATV 300 mg QD +

RTV 100 mg QD +

TDF/FTC QD

EndpointsEndpoints

PrimaryPrimary

– Proportion of patients with plasma HIV-1 Proportion of patients with plasma HIV-1 RNA <50 copies/mL at 48 weeksRNA <50 copies/mL at 48 weeks

SecondarySecondary

– Proportion of patients with plasma HIV-1 Proportion of patients with plasma HIV-1 RNA <50 copies/mL at 24 weeksRNA <50 copies/mL at 24 weeks

– Proportion of patients with plasma HIV-1 Proportion of patients with plasma HIV-1 RNA <400 copies/mL at 24 and 48 RNA <400 copies/mL at 24 and 48 weeksweeks

Endpoints cont.Endpoints cont.

SecondarySecondary

– Change from baseline in CD4 cell counts Change from baseline in CD4 cell counts at 24 and 48 weeksat 24 and 48 weeks

– HIV treatment-emergent resistance HIV treatment-emergent resistance patternspatterns

– Differences between treatment arms in Differences between treatment arms in incidence, type and severity of adverse incidence, type and severity of adverse eventsevents

Definition of Definition of Virologic FailureVirologic Failure

Confirmed plasma HIV-1 RNA ≥400 c/mL at Week 24 or later

Baseline CharacteristicsBaseline Characteristics FPV/rFPV/r ATV/r ATV/r Total Total (N=53)(N=53) (N=53) (N=53) (N=106) (N=106)

Median age, yearsMedian age, years 40 40 40 40 40 40

MaleMale 79% 79% 89% 89% 84% 84%Race-African AmericanRace-African American 34% 45% 40% 34% 45% 40% -Causasian-Causasian 64% 49% 56% 64% 49% 56% -Other-Other 2% 6% 4% 2% 6% 4%Ethnicity- HispanicEthnicity- Hispanic 23% 23% 23% 23% 23% 23%

CDC Class CCDC Class C 9 (17%) 9 (17%) 11 (21%) 20 (19%) 11 (21%) 20 (19%)

Median HIV-1 RNA, logMedian HIV-1 RNA, log1010 c/mL 4.88 c/mL 4.88 4.88 4.88 4.88 4.88HIV-1 RNA <100,000 c/mLHIV-1 RNA <100,000 c/mL 37 (70%) 37 (70%) 36 (68%) 73 (69%) 36 (68%) 73 (69%)HIV-1 RNA HIV-1 RNA 100,000 c/mL100,000 c/mL 16 (30%) 16 (30%) 17 (32%) 33 (31%) 17 (32%) 33 (31%)

Median CD4 count, cells/mmMedian CD4 count, cells/mm3 3 161161 188 188 172 172<50 cells/mm<50 cells/mm33 14 (26%) 14 (26%) 9 (17%) 23 (22%) 9 (17%) 23 (22%)50 - <200 cells/mm50 - <200 cells/mm33 21 (40%) 21 (40%) 19 (36%) 19 (36%) 40 (38%)40 (38%) 200 cells/mm200 cells/mm33 18 (34%) 18 (34%) 25 (47%) 43 (41%) 25 (47%) 43 (41%)

Completion Status at 24 WeeksCompletion Status at 24 WeeksFPV/rFPV/r ATV/rATV/r TotalTotal

CompletedCompleted 49 (92%)49 (92%) 50 (94%)50 (94%) 99 (93%)99 (93%)

Prematurely Prematurely withdrawnwithdrawn

4 (8%)4 (8%) 3 (6%)3 (6%) 7 (7%)7 (7%)

Primary Reason for Primary Reason for Withdrawal:Withdrawal:

Non-ResponseNon-Response 1 (2%)1 (2%) 00 1 (<1%)1 (<1%)

Adverse EventAdverse Event 1 (2%) 1 (2%) 1 (2%)1 (2%) 2 (2%)2 (2%)

Lost to follow upLost to follow up 1 (2%) 1 (2%) 2 (4%)2 (4%) 3 (3%)3 (3%)

Protocol ViolationProtocol Violation 1 (2%)1 (2%) 00 1 (<1%)1 (<1%)

0

20

40

60

80

100

0 4 8 12 16 20 24

Study Week

% o

f S

ub

ject

s

FPV/r, MD=FATV/r, MD=FFPV/r, ObservedATV/r, Observed

HIV-1 RNA <400 c/mLHIV-1 RNA <400 c/mL

= 89%= 89%= 94%= 94%

0

20

40

60

80

100

0 4 8 12 16 20 24

Study Week

% o

f S

ub

ject

s

FPV/r, MD=FATV/r, MD=FFPV/r, ObservedATV/r, Observed

HIV-1 RNA <50 c/mLHIV-1 RNA <50 c/mL

= 79%= 83%= 84%= 88%

Mean CD4+ Cell Count with 95% Mean CD4+ Cell Count with 95% Confidence Intervals Confidence Intervals

FPV/r ATV/r

361342

205

W0 W12 W24

302276

176

100

150

200

250

300

350

400

450

W0 W12 W24

Cells

/ mm3

160

177

153

180

116

160

127 133

0

50

100

150

200

250

m g

/d L

FPV/r ATV/r FPV/r ATV/r

Baseline

Week 24

Cholesterol Triglycerides

Baseline n= 48 46 48 46

Week 24 n= 38 39 38 39

Median Fasting LipidsMedian Fasting Lipidsat Baseline and Week 24at Baseline and Week 24

95 99 97103

38 41 3845

0

50

100

150

m g

/d L

FPV/r ATV/r FPV/r ATV/r

Baseline

Week 24

LDL HDL

Median Fasting LipidsMedian Fasting Lipidsat Baseline and Week 24at Baseline and Week 24

Baseline n= 48 45 48 46

Week 24 n= 36 39 38 39

1

1.5

2

2.5

3

3.5

4

4.5

5

5.5

6

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

Time (week)

HIV

-1 R

NA

Lo

g10

cp

/mL

Subject 1: TDF/FTC+FPV/rSubject 1: TDF/FTC+FPV/rRT: S68G, K70T, V118I, L210W, T215CPRO: K20I, M46I, L63P, A71V, V77I

TDF FC=0.95; APV FC= 3.8 FTC FC=1.5

RT: S68G, K70T, V118I, L210W, T215C, M184V PRO: K20I, M46I, I54I/L/M L63P, A71V, V77I

TDF FC= 0.61; APV FC= 13FTC FC > 112.8

Clade B

Week 0

Week 20

1

1.5

2

2.5

3

3.5

4

4.5

5

5.5

6

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

Time (week)

HIV

-1 R

NA

Lo

g10

cp

/mL

Subject 2: TDF/FTC+FPV/rSubject 2: TDF/FTC+FPV/r

RT: WTPRO: L10V, L63L/P, V77V/INo phenotypic resistance

RT: K65RPRO: L10V, V32I, M46M/I, I47V

TDF FC= 2.2 APV FC= 8.6FTC FC= 5.6

RT: K65RPRO: L10V, L63L/P, V77V/INo phenotypic resistance

Clade B

Week 0

Week 12

Week 24

1

1.5

2

2.5

3

3.5

4

4.5

5

5.5

6

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

Time (week)

HIV

-1 R

NA

Lo

g10

cp

/mL

Subject 3: TDF/FTC+ATV/rSubject 3: TDF/FTC+ATV/r

RT: WTPRO: M36I, L63A

TDF FC= 1.1 ATV FC= 0.9FTC FC= 1.04

WD



Clade B

Week 0

Week 24

Adverse Event Related Adverse Event Related Study DiscontinuationsStudy Discontinuations

One pt. DC’d FPV/r due to AE- Grade 3 Rash

One pt. DC’d ATV/r due to SAE- new onset Kaposi’s Sarcoma

Adverse Event Related Adverse Event Related Study Drug DiscontinuationsStudy Drug Discontinuations

Two pts.* DC’d TDF/FTC (then switched to individual components of ABC/3TC) due to declining renal function, defined in protocol as:

eGFR change >25% below baseline, or

eGFR <50mL/min (confirmed)

*61% of subjects had baseline GFR >50 and <90 mL/min by MDRD

Treatment-Related Treatment-Related AEs by Overall Frequency >4%AEs by Overall Frequency >4%

Grades 2-4Grades 2-4

FPV/rFPV/r

n=53n=53

ATV/rATV/r

n=53n=53

Any EventAny Event 6 (11%)6 (11%) 28 (53%)28 (53%)

Bilirubin Bilirubin ↑↑ 00 22 (41%)22 (41%)

DiarrheaDiarrhea 3 (6%)3 (6%) 1 (2%)1 (2%)

NauseaNausea 2 (4%)2 (4%) 1 (2%)1 (2%)

Scleral IcterusScleral Icterus 00 2 (4%)2 (4%)

ConclusionsConclusions

Both arms provided similar rates of Both arms provided similar rates of virologic suppression and immunologic virologic suppression and immunologic improvement at Week 24improvement at Week 24

Lipid changes were similarLipid changes were similar

Overall, fewer severe adverse effects Overall, fewer severe adverse effects occurred with FPV/r than with ATV/r; occurred with FPV/r than with ATV/r; differences due primarily to bilirubin- differences due primarily to bilirubin- associated AEsassociated AEs

AcknowledgementsAcknowledgements

Cynthia Brinson- Austin, TXCynthia Brinson- Austin, TXCal Cohen- Boston, MACal Cohen- Boston, MAEdwin DeJesus- Orlando, FLEdwin DeJesus- Orlando, FLMargaret Fischl- Miami, FLMargaret Fischl- Miami, FLJoseph Horvath- Columbia, SCJoseph Horvath- Columbia, SCRicky Hsu- New York, NYRicky Hsu- New York, NYLewis McCurdy- Charlotte, NCLewis McCurdy- Charlotte, NCCheryl McDonald- Ft. Worth, TXCheryl McDonald- Ft. Worth, TX

Support was provided by GlaxoSmithKlineSupport was provided by GlaxoSmithKline

Bruce Rashbaum- Wash., DCBruce Rashbaum- Wash., DCRobert Scott- Oakland, CARobert Scott- Oakland, CAKimberly Smith- Chicago, ILKimberly Smith- Chicago, ILFord Kinder- Miami, FLFord Kinder- Miami, FLWinkler Weinberg- Atlanta, GAWinkler Weinberg- Atlanta, GABen Young- Denver, COBen Young- Denver, CO

ALERT was made possible by the contributionsALERT was made possible by the contributionsof patients and staff at the following US sites*:of patients and staff at the following US sites*:

*Also wish to thank the CRO, MediStaf Research, for their contributions.

Backup Slides (Additional Data)Backup Slides (Additional Data)

Fasting CholesterolFasting Cholesterol

158165 173 182

Fasting TriglyceridesFasting Triglycerides

141 144 192145

Fasting LDLFasting LDL

94101 98 105

Fasting HDLFasting HDL

37 3640

47

Mean CD4+ Cell Count Change Mean CD4+ Cell Count Change from Baseline with 95% CI from Baseline with 95% CI

Baseline mean: 176

Baseline mean: 205

Week 12 Week 24

148

105

124132

50

70

90

110

130

150

170

190

Cel

ls /

mm

3

FPV/r

ATV/r

17

10

20

7 6

-3

4

8

-5

5

15

25

m

g /

d

L

C h

a n

g e

Chol Trig LDL HDL

FPV/r

ATV/r

n= 36 37 36 37 34 36 36 37

Fasting LipidsFasting LipidsMedian Change from Baseline at Median Change from Baseline at

Week 24Week 24

20%

3%

3%

10%

5%

3%

11%

5%

3%

11%

8%

0%

10%

20%

30%

%

o f

S u

b j

e c

t s

FPV/r ATV/r FPV/r ATV/r FPV/r ATV/r

g3

g2

g1

n= 40 39 40 39 38 38

Treatment Emergent Fasting LipidTreatment Emergent Fasting LipidToxicities by Intensity GradingToxicities by Intensity Grading

Cholesterol Triglycerides LDL

eGFR by MDRD (FPV/r) eGFR by MDRD (FPV/r) Wk 0 to Wk 24 Wk 0 to Wk 24

2 04

10

58 60

3630

0

10

20

30

40

50

60

% of Subjects

<30 30-<60 60-<90 >/=90

Wk 0 Week 24

eGFR by MDRD (ATV/r) eGFR by MDRD (ATV/r) Wk 0 to Wk 24Wk 0 to Wk 24

0 0 210

5866

40

24

010203040506070

% of Subjects

<30 30-<60 60-<90 >/=90

Wk 0 Week 24

eGFR by MDRD (All Subjects) eGFR by MDRD (All Subjects) Wk 0 to Wk 24Wk 0 to Wk 24

1 03

10

58 63

38

27

010203040506070

% of Subjects

<30 30-<60 60-<90 >/=90

Wk 0 Week 24

Two pts. DC’d Truvada due to declining renal function, defined as eGFR change >25% below baseline or eGFR <50mL/min (confirmed)

1

1.5

2

2.5

3

3.5

4

4.5

5

5.5

6

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

Time (week)

HIV

-1 R

NA

Lo

g10

cp

/mL

Subject 1: TDF/FTC+FPV/rSubject 1: TDF/FTC+FPV/rRT: S68G, K70T, V118I, 210W,T215CPRO: K20I, M46I, L63P, A71V, V77I

TDF FC=0.95 APV FC= 3.8 FTC FC=1.5

RT: S68G, K70T, V118I, M184V, L210W, 215C, K219K/QPRO: K20I, M46I, I47I/V, F53F/L, I54I/L, L63P, A71V, V77I

TDF FC= 0.61 APV FC= 2.98FTC FC > 78.3

RT: S68G, K70T, V118I, M184V, L210W, 215C, PRO: K20I, M46I, I54I/L/M L63P, A71V, V77I

TDF FC= 0.61 APV FC= 13FTC FC > 112.8

Clade B

Week 0

Week 12

Week 20

1

1.5

2

2.5

3

3.5

4

4.5

5

5.5

6

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

Time (week)

HIV

-1 R

NA

Lo

g10

cp

/mL

Subject 2: TDF/FTC+FPV/rSubject 2: TDF/FTC+FPV/r



RT: K65RPRO: L10V, V32I, M46M/I, I47V

TDF FC= 2.2 APV FC= 8.6FTC FC= 5.6

RT: K65R, D67D/N,PRO: L10V, V32I, M46I, I47V

TDF FC= 1.8 APV FC= 19FTC FC= 8.5

RT: K65RPRO: L10V, L63L/P, V77V/INo phenotypic resistance

Clade B

Week 0

Week 4

Week 12

Week 24

Week 28

1

1.5

2

2.5

3

3.5

4

4.5

5

5.5

6

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

Time (week)

HIV

-1 R

NA

Lo

g10

cp

/mL

Subject 3: TDF/FTC+ATV/rSubject 3: TDF/FTC+ATV/r



WD



Clade B

Week 0

Week 12

kimberly smith, winkler weinberg, edwin dejesus, margaret fischl, qiming liao, lisa ross and

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