11 th European AIDS Conference Madrid, Spain October 24-27, 2007

11th European AIDS Conference

Madrid, SpainOctober 24-27, 2007

Treatment of ARV-Naïve Patients

Richard Elion MD

George Washington University School of Medicine

Washington, DC

ARTEMIS: Phase III Study Design

▬ Primary end point- Proportion of patients with an HIV RNA <50 copies/ml at Week 48

▬ Primary objective- Demonstrate non-inferiority of DRV/r QD vs LPV/r based on that primary end point

▬ Secondary objectives- Evaluate long-term safety, tolerability and durability of virologic responses- Compare immunologic responses- Conduct pharmacokinetic evaluations

DRV/r 800/100mg QD + TDF 300 mg/FTC 200 mg

(N=343)

DRV/r 800/100mg QD + TDF 300 mg/FTC 200 mg

(N=343)

LPV/r* 400/100mg BID or 800/200mg QD + TDF 300 mg/FTC 200 mg

(N=346)

689 ARV-naïve patientsVL>5,000

*Dosing was based on regulatory approval; switch was made according to local regulatory approval and drug availability. LPV/r BID 77%; Capsule/tablet switch = 83%

Clumeck N, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. LBPS7/5.

Baseline Characteristics

DRV/r + TDF/FTC QD

(N=343)

LPV/r BID* +TDF/FTC QD

(N=267)

LPV/r QD* +TDF/FTC QD

(N=52)

Baseline demographics

Female, N (%) 104 (30) 96 (36) 6(12)

Caucasian, % 40 45 46

Baseline disease characteristics

Median HIV-1 RNA (cpm) 70,800 61,880 58,850

(range) (835–5,580,000) (667–4,580,000) (6400-880,000)

Median CD4 (cells/mm3 [range]) 228 (4–750) 218 (2–714) 228(218-659)

HBV/HCV co-infected, n (%) 43 (13) 439(15) 5(10)

Stratification factors at screening

CD4 count <200 cells/mm3 40% 41% 37%

Plasma HIV-1 RNA ≥100,000 cpm 36% 36% 35%

*27 patients receiving LPV/r BID and QD during the study excluded


ARTEMIS

Responses by LPV/r Dosing Schedule

*27 patients receiving LPV/r BID and QD during the study were excluded from this analysis

0 20 40 60 80 100

Patients with VL <50 copies/mL (%) at Week 48

DRV/r QD 84

LPV/r (All)78

LPV/r BID 81

LPV/r QD 71

343

346

267

52

N=

3% (95%

CI –3; 9)

13% (95%

CI 1; 24)

9% (95%

CI –3; 21)


ARTEMIS

Week 48 Response by Baseline Viral Load

†27 patients receiving LPV/r BID and QD during the study were excluded from this analysis

86

7985

Baseline viral load <100,000 copies/mL

0

20

40

60

80

100

Pat

ient

s w

ith V

L <

50 c

opie

s/m

L (%

)

86

79

67 71

56

N = 226 175 34 226 120 92 18 117

0

20

40

60

80

100

Pat

ient

s w

ith V

L <

50 c

opie

s/m

L (%

)

DRV/r QD

LPV/r (All)

LPV/rBID†

LPV/rQD†

DRV/r QD

LPV/r(All)

LPV/rBID†

LPV/rQD†

Baseline viral load ≥100,000 copies/mL

P<0.05

P<0.05


ARTEMIS

Virologic Failure and Resistance

DRV/r QD† (343) LPV/r† All (346) LPV/r† BID (267) LPV/r† QD (52)

VF >50 c/mL 34 (10%) 49 (14%) 31 (12%) 10 (19%)

Paired baseline & VF genotype available

10 18 11 4

IAS USA PI RAMS 0 1* 1* 0

IAS USA NRTI RAMS 1‡ 2‡ 1‡ 1‡

VF by TLOVR non-VF censored (at any time, regardless of reason for discontinuation) †All given with TDF/FTC QD*A71T, V77I‡M184V or M184I/V


ARTEMIS

Week 48

LPV/r (400/100 BID)+ TDF/FTC QD

(N = 170)

ART-naïve patients

SQV/r (1000/100 BID)+ TDF/FTC QD

(N= 167)

GEMINI: Comparison of SQV/r and LPV/r in ARV-naïve Patients

Baseline Characteristics81 % Male 77%

68% HIV-1 RNA > 100,000 64%

161 Median CD4 (cells/mm³) 157

5.2 log Median Viral Load 5.2 log

40 % CD4 <100 cells/mm 41 %

Inclusion CriteriaHIV RNA >10,000 c/mL

CD4+ ≤ 350

Walmsley S, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS1/4

Rates of Discontinuations and Grade II-IV Adverse Events

Reason for WithdrawalSQV/r

n=167 (%)LPV/r

n=170 (%)

Overall discontinuations 39 (23) 35 (21)

Safety 8 (5) 13 (8)

Adverse event 5 (3) 12 (7)

Death 3 1

Non-safety 22 (13) 19 (11)

GI related Adverse Events

Total patients with ≥ 1 AE 27 (17) 45 (27)

Individual AEs reported in >3% of patients Diarrhea 11 (7) 24 (14)

Nausea 10 (6) 15 (9)

Vomiting 10 (6) 10 (6)


GEMINI

Virologic Failures*

SQV/r (n = 167)

LPV/r(n = 170)

Virologic failures (VF): n (%) 11 (7) 5 (3)

Failed with W/T virus 1 1

Failed with virus present at baseline 5 0

Failed with new RT mutations 5 (all M184V/I) 4 (all M184V/I)

Failed with new PI mutations 1a 0

Analysis of new PI mutationsb:

BL = L33V, L63PVF = L10I/V,

L33V, G48V, I54V, L63P, V82A, I84V

VF subjects with documented poor adherence 6/11 2/5

*Virological failure defined as 2 consecutive counts of HIV RNA >400 copies/mL at week 16 or afteraDocumented poor adherence; also had M184VbNew PI mutations were described at week 24 in 2 separate subjects. On further ongoing analyses, in 1 subject, the D60E mutation was subsequently confirmed in the baseline sample; for the subject presented here, L10I/V was confirmed to be new, but baseline sample could not be amplified past codon 46


GEMINI

Baton Study: ATV/r + TDF/FTC

Single-arm, open-label, multicenter, prospective trialEntry criteria: HIV+ adult, ARV-naïve, plasma HIV RNA 1000 copies/mL, 40-60% HIV RNA ≥100,000 c/mL, GFR > 50

ml/min (CG)

Primary analysis at week 48 < 50 c/mlSecondary Analysis:< 400 c/ml, CD4 ∆, development of resistance

ATV 300 mg/RTV 100 mg + TDF/FTC FDC QD with food(N = 100)

Elion R, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. P7.3/20


Male 82%

Caucasian 58%

Age (Median) 39

Median CD4 (cells/mm³) 256

Median Viral Load (log10 copies/mL ) 4.8

Disposition of Patients

Number of patients enrolled 102

Number of patients who received study medication 100

Number of patients who discontinued early 17

Reasons for study drug discontinuation,

Safety or tolerability reasons (1 patient each)

- Tuberculosis, hepatitis, hyperbilirubinemia, maculo-papular rash, lactic acidosis, increase in Scr (Grade 2) 6

Lost to follow-up 5

Withdrew consent 3

Investigator discretion 2

Subject returned study drug (never dosed) 1Deaths (1 patient each) Multi-organ failure (not study drug-related; secondary to

non-Hodgkin’s lymphoma); lactic acidosis (study drug-related)2

BATON


Efficacy and Resistance

Median CD4+ ∆: 217 cells/mm3

Resistance

• Baseline: Thymidine analogue mutations (TAMs) in 4 pts M41L, T215 reversions (T215D/E) and K219R mutations

• Virologic failure: 5 pts, 1 with M184V; No ATV- or TDF-related mutations

Note: All ATV Ctroughs exceeded values associated with greater virologic response (Ctrough >150ng/mL)Elion R, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. P7.3/20

BATON

0 4 12 24 36 48

20

100

60

40

N=100 98 92 88 87 86Study Week

80

0

<50 c/mL<400 c/mL

Per

cent

age

of P

atie

nts

84%

81%

Estimated Renal FunctionBATON

*p-value denotes change from baseline

Glo

mer

ular

Filt

ratio

n R

ate


Baseline CG: 109 MDRD: 93

*p<0.001

*p<0.001

MDRD

CG

80

104

0 4 12 24 36 480

N=100 98 92 88 87 68

Study Week

20

40

60

80

100

120

140

Note: Similar results seen with African-American vs. non-African-American Pts

48-Week Fasting Lipids withATV/r + TDF/FTC

Med

ian

Cha

nge

fro

m B

asel

ine

(mg/

dL)

11

32

5

-5

0

5

10

15

20

25

Total Cholesterol HDL Cholesterol LDL Cholesterol Triglycerides


BATON

MONARK: LPV/r Monotherapy

▬ Prospective trial of LPV/r monotherapy in ARV-naïve pts (n=136)- LPV/r vs. LPV/r + AZT/3TC- HIV RNA ≤100,000 c/ml and CD4+

≥100 c/mm3

▬ Predictive factors for efficacy for monotherapy - Viral subtype B vs non B- Baseline Viral load- Early virologic response- LPV trough levels and compliance

evaluation were not associated with Virologic response

71

8475

98

0

20

40

60

80

100

120

ITT OT

LPV/r LPV/r + AZT + 3TC

P=0.03

Flandre P, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS1/2

<50

c/m

L at

Wee

k 48

LPV/r (400/100 BID)+ 2 NRTIs(N = 29)

ART-experienced patients with durable viral suppression on LPV/r + NRTI

ATV/r (300/100 QD)+ Nevirapine 200 BID

(N= 30)

Nevata : Maintenance with anNRTI-sparing Regimen

Inclusion CriteriaHIV RNA < 50c/mL

N=59

48 week data HIV RNA < 40Median CD4+

countHDL

CholesterolTriglycerides

ATV/r + NVP 27/28 495 1.57 mmol/l 1.55mmol/l

LPV/r +2 NRTI 20/27 540 1.30 mmol/l 2.30 mmol/l

P=0.025 ns P=0.020 P=0.053

Cattelan A, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS3/3.

Nevirapine Efficacy with Tenofovir

▬ Lapadulla reported on early failure in 5/7 patients with NVP BID + TDF/FTC QD- 2 pts discontinued (1 hepatotoxicity, 1 rash)

- 3 pts had early virologic failure with two class resistance

▬ Robertson reported excellent virologic efficacy with NVP + TDF/FTC (n=31)- At 48 weeks, 100% <50 c/mL (17/17)

- No patient D/C’d due to virologic failure or toxicity

- NVP dose adjusted in 7 pts (2 BID and 5 QD dosing) using TDM

Lapadula G, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS7.3/10; Robertson C, Ibid. P4.2/02.

GS 903E:Long-term Data on TDF + 3TC + EFV

TDF QDEFV QD3TC BIDd4T Placebo BID

Study 903

3 Years (144 weeks)

d4T BIDEFV QD3TC BIDTDF Placebo QD

TDF QDEFV QD3TC QD(Open-Label)

7 Years (336 weeks)

Study 903E Mean ± SD Age in yrs (Range) 33 ± 7 (19 to 51)

Male 62%

Race White Black Other

70%12%18%

Mean ± SD HIV-RNA in log10 c/mL 4.86 ± 0.6

Mean ± SD CD4 count in cells/mm3 299 ± 188

Casetti I, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS7.3/15.

GS 903E

Outcomes Through 6 Years (M=F)

< 400 c/mL TDF+3TC+EFV

3 patients discontinued due to virologic failure- 2 Wild type genotypes - 1 T69N, M184V, K103N at Week 240- No K65R

1 2 3 4 5 6Year

100

80

60

40

20

0

83%

N=86

< 50 c/mL TDF+3TC+EFV

80%

∆CD4+ Count: +413


0

160

20

40

60

80

100

120

140

mL/

min

Median Baseline GFR: 116

1 2 3 4 50Years

Cockcroft-Gault

128

6

160

0204060

80100120140

mL/

min

/1.7

3m2

0 1 2 3 4

Median Baseline GFR: 112

MDRD

117

5 6

N=73 (through 6 years)

GS 903E

Median GFR Through 6 Yearsof TDF+3TC +EFV


Mean Change from Baselinein Spine and Hip BMD on TDF+3TC+EFV

6 Fractures: All related to trauma

WeeksWeeks

BL 24 48 72 96 120 144 168 192 216 240 264 288

-6

-4

-2

0

2

4

6

-3.3%a

-1.7%a

Spine (N=69 at 6 years)

Hip (N=70 at 6 years)

a. p<0.05 for change from baseline using Wilcoxon Signed Rank test

GS 903E


Studies of HIV Resistance and Treatment Experienced Patients

Calvin Cohen MDHarvard Vanguard Medical Associates

CRI New EnglandBoston MA

FTC/TDF + EFVZDV/3TC + EFV

8 16 32 48 72 96 120 144

Weeks

0

20

40

60

80

100

Arribas J, et al. 4th IAS Conference; Sydney, Australia; July 22-25, 2007. Abstract WEPEB029.

Res

pond

er (

%) 71%

58%

<400 c/mLP = 0.004

64%56%

<50 c/mLP = 0.08

GS 934

Week 144 Results (TLOVR)

Genotypic Resistance Development

FTC/TDF + EFV (n=244)

ZDV/3TC + EFV (n=243)

p=0.02b

0

2

7

0

0

6

10

31

22

21

2

13

19

0 5 10 15 20 25 30 35

13

Genotypeda

Number of Patients

Any Resistance

EFV-R

M184V/I

K65R

TAMs

Wild Type

a. Confirmed ≥ 400 copies/mL after week 8 or at discontinuation. Genotyping of 2 on ZDV/3TC failed for technical reasons. b. Fisher’s exact test

mITT population - N=22 pts with baseline NNRTI resistance excluded

mITT population - N=22 pts with baseline NNRTI resistance excluded

GS 934

McColl D, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS3.1/08.

Virologic Failure by Baseline RT Mutation Pattern (ITT Population)

Mutation Pattern

Parameter TDF+FTC+EFV ZDV/3TC+EFV Combined

Any NAM

Any Change 2/18 (11%) 1/13 (8%) 3/31 (10%)

No Change 21/233 (9%) 35/237 (15%) 56/470 (12%)

p-value NS NS NS

K103N

Any Change 3/8 (38%) 5/9 (56%) 8/17 (47%)

No Change 20/243 (8%) 31/241 (13%) 51/484 (11%)

p-value 0.0279 0.0039 0.0002

Similar results for only Thymidine mutations and for any NNRTI mutationSimilar results for only Thymidine mutations and for any NNRTI mutation

Virologic failure with any genotypic change or no change (relative to the NL4-3 reference sequence)

McColl D, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS3.1/08.

GS 934

▬ Study Population: - Virologically suppressed

(<200 c/mL) HIV-1+ pts. on stable HAART regimenfor ≥ 3 months

▬ Primary Objective:- Compare proportion with

plasma VL<200 c/mL at week 48 between treatment arms using TLOVR† analysis

▬ Unplanned 24 week interim efficacy analysis presented

Stable HAART X ≥ 3 mo

Stratify PI vs. NNRTI

48weeks

†Time to loss of Virologic Response. *SBR: Stayed on Background Regimen

AI266073: Study Design

HAART toEFV/FTC/TDF Switch

2:1(EFV/FTC/TDF: SBR*)

EFV/FTC/TDF QD SBR

DeJesus E, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. LBPS7/6.


EFV/FTC/TDF

(n=203)

SBR

(n=97)

Total

(n=300)

Male (n/%) 181(89) 83 (86) 264(88)

Mean Age (years) 42.3 44.5 43.0

Black (n/%) 56 (28%) 30 (31%) 86(29%)

Regimen before randomization (n/%)

NNRTI

PI

95 (47%)

108 (53%)

45 (46%)

52(54%)

140 (47%)

160 (53%)

HIV-1 RNA (copies/mL)

<50

50<200

≥2001

194 (96%)

7(3%)

2 (<1%)

95 (98%)

2 (2%)

0 (0%)

289 (96%)

9 (3%)

2 (<1%)

CD4 cell count (cells/μL)

Mean

≤ 200

537

13(6%)549

13 (13%)

541

26 (9%)

NOTE: Most frequent NNRTI regimen was EFV + AZT/3TC. Most frequent PI regimen was ATV/r + FTC/TDF 1. All subjects had HIV-1 RNA <200 copies/mL at screening.

AI266073


Week 24 Efficacy Analyses

24 Wk endpoint (%)

EFV/FTC/TDF

(N=203)

SBR

(N=97)

Difference

EFV/FTC/TDF-SBR

(95% CI)

HIV-1 RNA <50 copies/mL

PVR* 96.5% 96.8%-0.4%

(4.7%to 4.0%)

M=F‡ 93.1% 90.7%2.4%

(-4.0%to 10.3%)

▬ Early treatment discontinuation through 24 weeks:▬ EFV/FTC/TDF: n = 16 (8%)

- 9/16 d/c due to AEs- 5/9 d/c for CNS events (all from PI stratum)

▬ SBR: n = 6 (6%)- 4/6 on SBR d/c due to consent withdrawal

*PVR: Lack of two confirmed VL>50 or one VL>50 c/mL if no subsequent test available; ‡Missing equals Failure

AI266073


OK04: Study Design

Primary endpoint: Therapeutic failure at 48 weeks

▬ 2 viral loads > 500 c/mL 2 weeks apart* (and lack of resuppression after restarting NRTI in the OK arm) OR

▬ Change of randomized therapy for reasons different from re-induction OR

▬ Treatment discontinuation OR

▬ Lost to follow-up

Failure on OK arm if NRTI intensification needed:

▬ Decrease in HIV-1 RNA < 1 log 4 wks after intensification OR

▬ Failure to achieve VL < 50 c/mL 16 wks after intensification

Visits: Screening, Baseline, Week 4 and 12, then every 12 weeks up to Week 96

▬ HIV-1 RNA < 50 c/mL for > 6 months

▬ No history of virological failure while taking a PI

▬ Receiving LPV/r for + 2 NRTIs > 1 month

LPV/r SGC 400/100 mg BID

+ 2 NRTIs (“Triple”)(n=100)

LPV/r SGC 400/100 mg BID

(“OK”)(n=100) LPV/r Tablet

(“OK”)400/100 mg BID

Week 96

Arribas JR, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS3/1.

BENCHMRK 1 and 2: Trial Design

Primary Endpoints (Week 16): HIV RNA and CD4 countsAdverse experiences

Raltegravir (400 mg BID) + OBT(n=462)

Placebo + OBT(n=237)

ART-Experienced Adult Patients

2 identical ongoing Phase III studies (in different countries)Randomized (2:1), double-blind, placebo controlled

Documented genotypic/phenotypic resistance to 1 drug in each of 3 classes (NNRTI + NRTI + PI)HIV RNA > 1000 copies/mL

Patients virologically failing after 16 weeks could enter open-label RAL arm

Kumar P, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. P7.2/06.

Baseline Patient Characteristics

BENCHMRK-1 BENCHMRK-2

RAL(n = 232)

Placebo (n = 118)

RAL(n = 230)

Placebo (n = 119)

Mean Age, yrs (SD)% Male% Caucasian

46 (9)8475

44 (8)8781

45 (9)9155

46 (8)9065

Mean CD4 Count, cells/mm3

GM Viral Load, copies/mL (log10HIV RNA)

% AIDSMedian Yrs of Prior ARTs (median # ART)

% Hep B+/% Hep C+

15640519 (4.6)

94 11 (12)

8/15

153 31828 (4.5)

9010 (12)

4/20

14648366 (4.7)

9110 (12)

10/3

16347789 (4.7)

9210 (12)

3/4

% GSS§ 0/1% PSS§ 0/1% new enfuvirtide in OBT% new darunavir in OBT

30/3319/29

2127

29/4118/33

2025

20/4410/34

1945

26/4019/27

2050

§ GSS/PSS = total ART in OBT to which pt’s virus showed geno/phenotypic sensitivity by Phenosense GT assay. Enfuvirtide and darunavir use in naïve patients were each counted as + 1 active agent and added to GSS/PSS.

BENCHMRK 1 & 2


Response RatesOverall and by GSS at Week 24

0

10

20

30

40

50

60

70

80

90

<400 <50 CD4

RAL

Pbo

*p<0.001*p<0.001

**** **

N = 448 on RAL arms; 230 on PboN = 448 on RAL arms; 230 on Pbo

0

10

20

30

40

50

60

70

80

90

0 1 2 or more

RAL

Pbo

n =111 64 173 94 157 70n =111 64 173 94 157 70

By GSS score of OBBy GSS score of OB


BENCHMRK 1 & 2%

<50

c/m

L

TITAN: Study Design

• LPV-naïve, treatment-experienced

• VL >1,000 copies/mL

• Stable HAART for ≥12 weeks (STI allowed)

DRV/r 600/100mg bid + OBR (n=298)

LPV/r 400/100mg bid + OBR (n=297)

Rollover and follow-up

phase after 1 and 4 weeks

Screening phase (4 weeks)

Treatment phase (96 weeks)

595 patients randomised and treated

STI = structured treatment interruption; OBR = optimized background regimen

De Meyer S, et al. 47th ICAAC; Chicago, IL; September 17-20, 2007; Abst. H-1020.

*excludes patients with missing LPV FC at baseline; †D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50V/L, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S or L90M11. Johnson VA, et al. Top HIV Med 2006;14:125–30.

Number of IAS-USA primary PI mutations1

DRV/r (n=263)

LPV/r (n=261)

All patients with LPV FC ≤10*

0

10

20

30

40

50

60

70

80

90

0 1 2 ≥3

HIV

RN

A <

50 c

opie

s/m

L (I

TT

-TLO

VR

, %)

66

59

50

43

69

78

6865

DRV/r (n=172)

LPV/r (n=174)

Patients with prior PI experience and LPV FC ≤10*

69

77

6863

6155

4743

0

10

20

30

40

50

60

70

80

90

0 1 2 ≥3H

IV R

NA

<50

cop

ies/

mL

(IT

T-T

LOV

R, %

)

DRV Median FCLPV Median FC

195 197 32 32 19 18 17 14n=

0.50 0.50 0.40 0.50 0.70 0.65 0.90 0.85

0.70 0.70 0.80 1.10 1.80 2.60 3.60 5.35

1.00 1.00 2.00 2.50 4.00 4.00 5.00 6.50Med LPV mutations

106 114 31 29 19 17 16 14

0.55 0.50 0.40 0.50 0.70 0.70 0.90 0.85

0.70 0.70 0.80 1.10 1.80 2.90 3.75 5.35

1.00 1.00 2.00 3.00 4.00 4.00 5.00 6.50

TITAN

Impact of IAS-USA Primary PI Mutations at Baseline on Week 48 Results

Berger D, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. P7.3/27.

DRV/r LPV/r

Laboratory term, n (%)

ACTG grade

Co-infected(n=52)

Notco-infected

(n=245)Co-infected

(n=37)

Not co-infected

(n=258)

ALT All grades 24 (49) 24 (10) 19 (53) 26 (10)

Grade 3–4 6 (12) 4 (2) 9 (25) 3 (1)

AST All grades 19 (39) 27 (11) 19 (53) 37 (15)

Grade 3–4 5 (10) 4 (2) 8 (22) 2 (1)

Hepatitis Status

- +

DRV/r 79% 193/245 67% 35/52

LPV/r 69% 179/258 51% 19/37

% < 50 c/mL at week 48% < 50 c/mL at week 48

TITAN

Efficacy and Safety Outcomesin HBV and/or HCV Co-infected Subset

Bánhegyi D, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. P7.3/03.

DUET-1 and 2: Combined Study Design

▬ Strata: ENF use (none, 1st use, re-use), prior DRV, screen VL (<30,000 or ≥30,000 c/mL)

▬ Inclusion criteria- Screening VL >5000 c/mL- Stable ART for > 8 wks prior to screen- Resistance to 1st generation NNRTI by >1 NNRTI mutation at screening or

prior genotype- ≥3 primary PI mutations at screening

*OBR = Darunavir/r 600/100mg bid with optimized NRTIs +/- ENF

24 Week primary analysis

Etravirine (TMC125) + OBR*

Placebo + OBR*

n=600

n=600

Screening6 weeks

1200 patients

Treatment Phase48 weeks with optional 48-week extension

Katlama C, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. P7.3/11.

Motivate 2: Trial Design

Randomization 1:2:2N=474

Maraviroc (150 mg† BID) + OBT*

Maraviroc (150 mg† QD) + OBT*

Placebo + OBT*

0 24w

* OBT = optimized background therapy of 3–6 ARVs (PK boosting doses of RTV not counted as an ARV)† Patients receiving a PI (except TPV) and/or delavirdine in their OBT received 150 mg dose of MVC, all other patients received 300 mg dose of MVC

Screening(6 weeks) 48w

Patients stratified by:•Enfuvirtide use in OBT •HIV-1 RNA < and ≥100,000 copies/ml at screening

Patient eligibility criteria: •R5 HIV-1 infection•HIV-1 RNA ≥5,000 copies/ml

• Stable pre-study ARV regimen, or no ARVs for ≥ 4 weeks• Resistance to and/or ≥ 6 months’ experience with ≥ one ARV

from three classes (≥ two for PIs)

Fätkenheuer G, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS3/5.

Pat

ient

s (%

)

HIV-1 RNA value imputed as baseline if missing or if patient discontinued before 48 weeks* P<0.0001 vs PBO + OBT # P<0.0005 vs PBO + OBTN (%) wk 48: PBO 39 (33%); MVC QD 143 (62%); MVC BID, 151 (64%)

PBO + OBT (N=91)

MVC QD + OBT (N=182)

MVC BID + OBT (N=191)

Week 48 Response: Virologic and CD4 Change from BL

0

10

20

30

40

50

60

70

80

90

100

Time (weeks)

45%*45%*

18%

<50 copies/ml

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

46%*

41%#

21%

P=0.0005*Difference: +52

(95% CI: +23, +81)

P<0. 0001*Difference: +59

(95% CI: +30, +87)

69

121128

0

50

100

150

CD4 change from BL at week 48CD4 change from BL at week 48

MOTIVATE 2


0

20

40

60

80

100

120

140

Mea

n ch

ange

fro

m b

asel

ine

in

CD

4+ c

ount

(ce

lls/m

m3 )

N = 111 92 96 33 24 35 41All failures* Failure with R5 Failure with X4 or D/M

*Includes patients with non-reportable/non-phenotypable or non-R5 tropism result at baseline and patients with no tropism result at failure

24

6474 77

133

4757

MVC QD + OBT (N=414)

MVC BID + OBT (N=426)

PBO + OBT (N=209)

MOTIVATE 1 and 2: CD4+ Change by Tropism Result at Rebound

MOTIVATE 1 & 2


Toxicities and Metabolism

Graeme Moyle MD

Chelsea and Westminster Hospital

London, UK

Effects of Fosamprenavir/r and Lopinavir/r on Insulin Sensitivity

FPV/r LPV/r

Insulin Sensitivity

(mg.min-

1.kg-1 .uU-

1.mL)

Baseline

Mean

0.161 0.142

Day 14 0.154 0.138

Percentage Change in Insulin Sensitivity

Mean

(SD)

-2.83

(13.30)

-0.91

(23.31)

Fosamprenavir Group

0

0.05

0.1

0.15

0.2

0.25

0.3

Day 1 Day 14

Insu

lin S

en

sitiv

ity

Lopinavir Group

0

0.05

0.1

0.15

0.2

0.25

0.3

Day 1 Day 14

Insu

lin S

en

sitiv

ity

Individual Subject Changes in Insulin Sensitivity

There was no statistically significant difference in the percentage change in the insulin sensitivity from baseline to Day 14 or between the 2 groups (P-value 0.791). Adjusting for baseline differences in CD4 count did not significantly affect results.

Randell P, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. LBP9.2/1.

Baseline levels, median (mg/dL)SQV/rLPV/r

Med

ian

Cha

nge

mg/

dL (

95%

CI)

n =

p = 0.1300

157.0, n = 130152.0, n = 134

p = 0.3912

p = 0.4436 p = 0.3615

p = 0.0007 p = 0.0022

89.0, n = 12989.0, n = 133

117.0, n = 130117.0, n = 133

TC TG

24 48 24 48 24 48Week

LPV/rSQV/r

24 48

HDLLDL

p = 0.4534 p = 0.9954

106 109 81 100 105 108 80 99 106 108 81 99 105 108 80 99

35.0, n = 12938.0, n = 133

19

9

10

25

8

45

18

9

14

31

16

11

55

0

20

40

60

80

100

26

116

GEMINI

Median Change in Fasting Lipid Levels

Walmsley S, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS1/4.

REAL Study: Study Design

HIV-1, PI/r regimen ≥ 12 weeks, virologic suppressionExcluded if virologic failure to >1 PI-containing regimen

Truncal adiposity

Randomization 2:1 (n = 201)

ATV/r300 mg/100 mg Once Daily

Maintain NRTIs

n=131

No change toPI/r regimen

Maintain NRTIs

n=70

24-week interim analysis

48-week primary analysis

96-week final analysis

Moyle G, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS5/6.

Demographics and Baseline Patient Characteristics

ATV/r (n=131)

PI/r Control (n=69)

Median age (years) 43 42

Male (%) 73 80

Caucasian/Mestizo/Black/Other (%) 63/24/11/<1 62/22/14/2

Europe/North America (%) 59/41 57/43

AIDS (%) 11 13

HIV RNA <400 copies/mL (%) 97 100

HIV RNA <50 copies/mL (%) 90 93

Median CD4 (cells/mm3) 470 437

Weeks on prior PI (mean ±SE) 205.6 ± 11.6 202.6 ± 15.3

Weeks on prior NRTI/NtRTI (mean ±SE) 284.2 ± 17.9 251.8 ± 20.3

Weeks on prior NNRTI (mean ±SE) 101.5 ± 13.7 97.1 ± 15.8

Prior PI/RTV Therapy LPV-SQV-IDV-FPV-AMP (%) 70-10-11-8-1 72-10-10-8-1

REAL

Moyle G, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS5/6.

SWEET: Study Design

▬ Undetectable viral load (≤ 50copies/ml) at screening

▬ Adequate Baseline Renal (CrCl ≥ 60ml/min) and Hepatic (AST / ALT ≤ 5 x ULN) function. HBsAg negative

▬ No known resistance to TDF, FTC, AZT, 3TC or EFV

SWEET = Simplification With Easier Emtricitabine and Tenofovir

TDF/FTC QD

EFV QD48 wks

Stable AZT/3TC + EFV ≥ 6 months

(N = 250)Randomised 1:1

DEXA sub-study (N = 100)

AZT/3TC BID

EFV QD

Fisher M, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS5/7.

Change in Median Limb Fat and Effect of Prior ZDV Exposure at Week 48*

* DEXA sub-study treated analysis set and sub-set of Whole Body Fat composition† Median Baseline Limb Fat with Week 48 data

SWEET

TDF/FTCZDV/3TC

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

All Subjects

Years on ZDV<1.5 1.5-3 3-4.5 >4.5-10

p=0.24

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

Week 48 Change in Limb Fat by Yearsof Previous Exposure to ZDV

5.62†

4.80† 5.06† 3.15†

4.78†

4.67†

p=0.073

p=0.039

5.69†

6.38†

3.75†

3.57†

Med

ian

Cha

nge

in L

imb

Fa

t (k

g)

Med

ian

Cha

nge

in L

imb

Fa

t (k

g)


Effect of Baseline Limb Fat on Change in Limb Fat at Week 48*

Effect of Baseline Limb Fat on Limb Fat

SWEET

≥ 5kg < 5kg

* DEXA sub-study treated analysis set and sub-set of Whole Body Fat composition† Median Baseline Limb Fat with Week 48 data

TDF/FTCZDV/3TC

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

All Subjects

Baseline Limb Fat

p=0.24

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

4.78†

4.67†

p=0.073

p=0.039M

edia

n C

hang

e in

Lim

b F

at

(kg)

Med

ian

Cha

nge

in L

imb

Fa

t (k

g)


Renal Function by Cockroft Gault and MDRD

SWEET

0 4 12 24 36 480

25

50

75

100

125

150

FTC+TDF+EFV

CBV+EFV

Weeks

mL

/min

/1.7

32m

2

0 4 12 24 36 480

25

50

75

100

125

150

FTC+TDF+EFV

CBV+EFV

Weeks

mL

/min

/1.7

32m

0 4 12 24 36 480

25

50

75

100

125

150

FTC+TDF+EFV

CBV+EFV

Weeks

mL

/min

0 4 12 24 36 480

25

50

75

100

125

150

FTC+TDF+EFV

CBV+EFV

Weeks

mL

/min

p<0.001 Week 48 change from baseline

p=0.001Week 48 change from baseline

Median Creatinine (µmol/L) – Week 48 - Change from Baseline, (TDF/FTC) 3, p<0.001, (ZDV/3TC) -1, p=0.57Median Phosphorus (mmol/L) – Week 48 - Change from Baseline: (TDF/FTC) -0.01, p=0.50, (ZVD/3TC) -0.04, p=0.67

MDRD (ml/min/1.732 m2) - Median (IQR)Cockroft Gault (ml/min)- Median (IQR)

Normal range (90-120)

No subject experienced a grade 3 or 4 renal abnormality in either arm


FTC+TDF+EFVZDV/3TC+EFV

FTC+TDF+EFVZDV/3TC+EFV

Median Estimated GFRGS903 AND 934

CG TDFMDRD TDF

CG ControlMDRD Control

0

20

60

100

120

160

Est

imat

ed G

FR

24 48 72 96 120 144

Weeks

0

140

40

80

Gallant J, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS9.7/05.

Est

imat

ed G

FR

020

60

100120

160

24 48 72 96 120 1440

140

40

80

Median eGFR: Patients with Mild Renal Impairment at Baseline* and Concomitant Anti-hypertensive/Anti-diabetic Medications

GS903 AND 934

CG TDFMDRD TDF

CG ControlMDRD Control

Weeks

Est

imat

ed G

FR

020

60

100120

160

24 48 72 96 120 1440

140

40

80

Gallant J, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS9.7/05.

*GFR 50-80 mL/min by Cockcroft-Gault

120120

No Differences in Renal Function by NRTI Use over 84 Months

No use TDF during follow-upNo use TDF during follow-upTDFTDF

Time (month)Time (month)

MD

RD

(ml/m

in/1

.73m

2)M

DR

D(m

l/min

/1.7

3m2)

Median According to Tenofovir (TDF) use,ANRS C08 APROCO-COPILOTE

Median According to Tenofovir (TDF) use,ANRS C08 APROCO-COPILOTE

110110

100100

9090

8080

7070

00 44 88 1212 1616 2020 2424 2828 3232 3636 4040 4444 4848 5252 5656 6060 6464 6868 7272 7676 8080 8484

Use TDF during follow-upUse TDF during follow-up

Ravasi G, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS9.7/03.

ANRS-APROCO Cohort

Cystatin C as a Marker of GFR:Cystatin C is Elevated by Untreated HIV

▬ All HIV+ patients starting antiretroviral therapy in a single centre were enrolled consecutively.

▬ Control patients were healthy individuals undergoing routine check-up.

Control HIV ART-naive p

total n 143 204

male 66 (46%) 182 (89%) <0.001

BMI (kg/m2) 22.7 (17.8 – 39.8) 22.8 (16.1 – 32.8) 0.124

age 45 (18 – 68) 37 (21 – 70) <0.001

creatinine (mg/dL) 0.84 (0.48 – 1.2) 0.87 (0.51 – 1.29) 0.100

cystatin C (mg/L) 0.68 (0.49 – 1.1) 0.83 (0.49 – 1.63) <0.001

eGFR cystatin (mL/min) 125 (66 – 194) 97 (39 – 194) <0.001

eGFR MDRD (mL/min) 93 (63 – 161) 103 (63 – 180) <0.001

eGFR C-G (mL/min) 97 (52 – 179) 101 (54 – 169) 0.059

Mauss S, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS2/5.

0

1

2

3

4

5

6

7

8

9

Inci

denc

e (%

)

3.4%(27/803)

7.8%(66/847)

2.7%(23/842)

OR 0.40P < 0.0001

OR 0.03P < 0.0001

Control arm

Prospective HLA-B*5701 screening arm

Clinically SuspectedHSR

Immunologically ConfirmedHSR

Clinically Suspected and Immunologically Confirmed ABC HSR

0.0%(0/802)

(0.25, 0.62)

(0, 0.18)

PREDICT 1

Molina J-M, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS5/1.

Management Issues

Brian Boyle MD

Weill Medical College of Cornell University

New York, NY

European Recommendations for Initiation of ARV Therapy

Symptomatic Asymptomatic Resistance testing Additional remarks

•CDC stage B and C: treatment recommended

•If OI, initiate as soon as possible*

•CD4 <200: Treatment recommended without delay.

•CD4 201-350: Treatment recommended.

•CD4 350-500: Treatment may be offered if VL>105 c/ml and/or CD4 decline >50-100/mm3/year or age >55 or hepatitis C co-infection.

•CD4 >500: Treatment should be deferred, independently of Plasma HIV RNA; closer follow-up of CD4 if VL > 105 c/ml.

Whatever CD4 and Plasma HIV RNA, treatment can be offered on an individual basis, especially if patient seeking and ready for ARV therapy.

Genotypic testing and subtype determination recommended, ideally at the time of HIV diagnosis, otherwise before initiation of first-line regimen.

If genotypic testing is not available, a ritonavir-boosted PI could be preferred in first-line regimen.

•Before starting treatment, CD4 should be repeated and confirmed

•Time should be taken to prepare the patient, in order to optimize compliance and adherence

*Pay particular attention to drug-drug interactions, drug toxicities, immune reconstitution syndrome and adherence, etc…

European AIDS Clinical Society (EACS) Guidelines (2007). Clumeck N, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS6.

Initial Combination Regimen for Antiretroviral-Naïve Patient

Select 1 drug in column A + 1 NRTI

combination in column B

A B Remarks

Recommended NNRTI• EFV1

• NVP4

or ritonavir-boosted PI

• fAPV/r• LPV/r• SQV/r

• ABC/3TC2-3

• TDF/FTC• ABC/3TC co-formulated• TDF/FTC co-formulated• fAPV/r: 700/100 mg bid or 1400/200 qd• LPV/r: 400/100 mg bid or 800/200 mg qd• SQV/r: 1000/100 mg bid or 1500/100 mg qd

or 2000/100 mg qd

Alternative ATV/r5 • ZDV/3TC• ddI/3TC or

FTC6

ZDV/3TC co-formulated

European AIDS Clinical Society (EACS) Guidelines (2007). Clumeck N, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS6.

1 EFV: not recommended in pregnant women or women with no reliable and consistent contraception; not active on HIV-2 and HIV-1 subgroup O2 Contra-indicated if HLA B*5701 positive. Even if HLA B*5701 negative, counseling on HSR risk still mandatory3 ABC + NVP contra-indicated, unless HLA B*5701 negative4 NVP: Use with extreme caution in women with CD4 >250 and men with CD4 >400/μL; not active on HIV-2 and HIV-1 subgroup O5 Approved by FDA but not yet approved by EMEA. Some physicians use ATV/r in first line regimen6 Only if unavailable or intolerant to other recommended NRTIs

Safety and Efficacy of TDF with PI

▬ Retrospective study of TDF + 3TC or FTC + PI or PI/r (n=704)- Baseline: mean CD4+ 354 cell/mm3;

median 56 mos. prior ARV Tx

- LPV/r 44%; ATV/r 23%, ATV 8%

▬ Efficacy:- Virologic failure = 9% (Mean F/U 8 mos.)

- CD4+ increase = 71 cells/mm3 (p<0.001; 12 mos., n= 150)

▬ Safety:- Most prevalent AEs: GI (5%) and

hyperbilirubinemia (2%)

- Mean serum creatinine rose and creatinine Clearance declined, but remained WNL

- 3 pts (0.4%) D/C’d due to renal toxicity

Laboratory parameters BaselineWeek 48

P value

AST (IU/L) 50 46 <0.05

ALT (IU/L) 54 52 0.118

GGT (IU/L) 93 73 <0.05

Total bilirubin (mg/dL) 0.87 1.14 <0.001

Serum creatinine (mg/dL)

0.89 0.96 <0.001

CrCL (CG, mL/min) 104.0 101.3 <0.001

Mallolas J, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. P7.3/07.

Risk of Virologic Failure and Resistance is Regimen Dependent

▬ Study of 2240 pts on stable HAART and HIV-RNA <50 copies/mL- Completed adherence questionnaire, followed for

subsequent 4 months

- NNRTI = 1479; single-PI = 200; boosted-PI = 561

▬ Tx type and baseline adherence significantly associated with virologic failure (VF)

▬ Resistance risk higher with NNRTIs with low adherence and Single PIs with high adherence

Percent with VF by Adherence Level

Adherence Rate NNRTI Single PI Boosted PI

>95% 0.8% 4.2% 0.4%

75-95% 3.6% 2.9% 1.3%

<75% 4.9% 0% 0%

Maggiolo F, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. P10.1/02.

Rate of Resistance by Adherence Level

Total

PI

Boosted PI

NN

0

10

20

30

40

50

60

70

80

90

100

% P = 0.170 P = 0.028 P = 0.018 P = 0.516

<55% 55-75% 75-95% >95%

Adherence Level

Comparison of ATV/r and LPV/r PK

▬ Study of plasma decay of ATV/r 300/100 QD and LPV/r 400/100 BID or 800/200 QD- Healthy volunteers Tx’d x 10 days

(n=16)

▬ Terminal T1/2: ATV 8.77h vs. LPV/r BID 2.33h vs. LPV/r QD 2.44h

▬ ATV QD levels declined at slower rate than LPV BID and QD levels- More subjects on ATV/r > minimum

effective concentration (MEC) at end of normal dosing period and 12 hours later

100%

69%

0%

56%

0

20

40

60

80

100

24 hours 36 hours

ATV/r QD LPV/r QD

Per

cen

t >

ME

C

Boffito M, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. LBPS7/4.

High rate of MDR-TB in Eastern Europe

▬ Retrospective analysis of clinical records of 704 HIV/TB-pts in St. Petersburg, Russia (2000-2006)

▬ 453 (64.3%) smear-positive (91.7% in sputum)

▬ 63.9% had MDR-TB- 31% resistant to 3 drugs; 23.4% to 5

drugs- High rates of Rifampicin and

Streptomycin resistance

60.6%

18.8%

57%

Drug Resistance

Rifampicin Isoniazid Streptomycin

Panteleev A, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS2/3.

Potential Benefits of Pneumococcal Vaccine

▬ Prospective study: Effect of 23-valent pneumococcal polysaccharide vaccine (PPV) on outcomes with invasive Pneumococcal Disease (IPD), 1996-2007- 119 episodes of IPD occurred in 98 HIV+ pts

- 15 (12.9%) had received the 23-valent PPV

▬ Most common serotype was one of the vaccine included serotypes (81.8% vs 84.1%, p=1)

▬ Mortality significantly lower in vaccinated pts- ICU admission and length of hospital stay

(mean of 7 vs. 11 days, p=0.63) also lower

0 0

23

16

0

5

10

15

20

25

Mortality ICU admission

PPV No PPV

Pat

ient

%

P=0.039

P=0.126

Imaz A, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. P11.5/01.

Metabolic Impact of ARV Drugs and Drug Classes

NNRTI NRTI PI

NVP3TC / FTC

ABCTDF

fAPV

EFV ZDVATV/rSQV/r

ddILPV/rfAPV/rDRV/r

d4TIDV/rTPV/r

RTV (full dose)

Less More

More

European AIDS Clinical Society (EACS) Guidelines (2007). Lundgren J, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS6.

Metabolic Impact

Met

abo

lic

Imp

act

EACS Guidelines for Lipodystrophy

Lipoatrophy

▬ Prevention- Avoid d4T and ZDV or pre-emptively switch

away from them

▬ Management- Switch d4t or ZDV to ABC or TDF- Switch to regimen not including NRTIs

▬ Surgical intervention- Offered for cosmetic relief of facial lipoatrophy

only

▬ Pharmacological interventions to treat lipoatrophy have not been proven to be effective and may introduce new complications

Lipohypertrophy

▬ Prevention- No proven strategy- Weight gain expected with effective ART- Weight reduction or avoidance of weight gain

may decrease visceral adiposity

▬ Management- Diet and exercise may reduce visceral

adiposity

▬ Pharmacological interventions to treat lipohypertrophy have not been proven to provide long-term effects and may introduce new complications- Growth Hormone- Metformin- Surgical therapy can be considered for

localized lipomas/buffalo humps

European AIDS Clinical Society (EACS) Guidelines (2007). Lundgren J, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS6.

Maraviroc Drug–Drug Interaction Studies

Effect of Maraviroc on other Drugs

▬ ARVsZidovudine (renal excretion)Lamivudine (renal excretion)

▬ OthersOral Contraceptives

EthinylestradiolLevonorgestrel

Midazolam (CYP3A4 probe)Debrisoquine metabolic ratio (CYP2D6 probe)6 β-hydroxycortisol/cortisol ratio (CYP3A4 induction probe)

Effect of other Drugs on Maraviroc

▬ ARVsAtazanavir (± RTV)Darunavir EfavirenzElvitegravirEtravirineLopinavir/r (± EFV)RitonavirSaquinavir Saquinavir/r (± EFV)TenofovirTipranavir/r

▬ OthersKetoconazoleRifampinSulfamethoxazole/trimethoprim

Davis J, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. P4.3/02; Mcfadyen M, et al. Ibid. P4.1/06

Includes a CYP3A4 inducerFor example:

Efavirenz, etravirineRifampicin

Includes a potent CYP3A4 inhibitorFor example:

Protease inhibitors* ± ritonavir (except tipranavir)

Elvitegravir, delavirdineKetoconazole, itraconazole,

clarithromycin, telithromycin, nefazadone, telithromycin

150 mg

YES

YES

Regardless of other agents in the regimen

NO CYP3A4 inhibitors or inducersFor example:

NRTIs, nevirapine, tipranavir/r

150 mg

Morning dose Evening dose

300 mg300 mg 300 mg300 mg

300 mg 300 mg

Concomitant treatment

Summary of Dose Modifications with Maraviroc

*including darunavir

Davis J, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. P4.3/02; Mcfadyen M, et al. Ibid. P4.1/06

NO

NO

Elvitegravir Drug-Drug Interaction Studies

NRTIs•FTC/TDF

•ddI

•d4T

•ABC

•ZDV

PIs• DRV/r

• TPV/r

• ATV/r

• LPV/r

• FPV/r

Other Agents• Antacids

• Omeprazole

• Rifabutin

• Ketoconazole

Other Studies• Ritonavir-boosting dose ranging

• Mass Balance

• QT/QTc

• Special populations (pediatrics, hepatic impairment)

New ARVs• TMC125

• Maraviroc

Ramanathan S, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS4/7.

Summary of Elvitegravir Drug-Drug Interaction Studies

Coadministered drug Impact of coadministration on exposure (AUC) Comment

Coadministered drug EVG

NRTIs

FTC/TDF (200/300mg QD) ↔ ↔ .

ddI (400mg) ↓15% ↔ .

d4T (40mg) ↔ ↔ .

ABC (600mg ) ↔ ↔ .

ZDV (300mg BID) ↔ ↔ .

PIs

DRV/r (600/100 BID) ↔ ↔ .

TPV/r (500/200 BID) ↔ ↔ .

ATV/r (300/100 QD) ↔ ↑100% EVG 85mg + ATV/r or

LPV/r ≈ EVG/r 150/100mgATV/r + 85 mg EVG ↔ ↔LPV/r (400/100 BID) ↔ ↑75%

FPV/r (700/100mg BID) ↔ ↔ .

New Agents

TMC125 (200 BID) ↔ ↔ .

MVC (150mg BID) ↑190% ↔ EVG/r ≈ PI/r on MVC

Concomitant Medications ↔ ↔Antacid: simultaneous . ↓50% Stagger ≥ 2 hr Antacid ± 2 or ± 4 hrs . ↔Omeprazole (40mg QD) ↔ ↔ .

Ramanathan S, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS4/7.

Raltegravir Drug-Drug Interactions

▬ RAL metabolized by UGT1A1- Neither substrate or inducer of

CYP3A4

▬ Study evaluating Cmin of RAL (400 mg BID) with ETV, DRV/r, ATV + DRV/r and TPV/r (n=93)- All ± ENF and 2 NRTIs

- RAL Cmin at 12 ± 2 hours after last dose

▬ Results- ETV and DRV/r minimal effect on RAL- ATV ↑↑RAL- TPV/r ↓↓RAL

66

82

143

18

RAL Cmin (ng/mL)

ETV DRV/rATV + DRV/r TPV

P=0.035

P=0.013

P=0.0007

P=0.0009

Long K, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS4/6.

No Effect of TDF/FTC on NVP Levels

▬ PK sub-study of open label trial of FTC, TDF, and NVP in ARV-naïve patients (n=7)- PK sampling at week 2 and week 8

▬ Mean NVP Cmin levels at weeks 2 and 8 were 2876 and 4971 ng/mL- Range and SD of the week 8 values was 2330-8300 ng/mL and 1985 ng/mL

- Week 2 normalized Cmin (Cmin/Dose) was 0.86

▬ The median reduction in HIV RNA at week 8 from baseline was 2.69 log10 copies/mL

▬ TDF/FTC have no effect on NVP concentrations and combination is associated with a potent antiviral response

Davis C, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. P4.1/03.

HBV Management in HIV/HBV Patients with No Immediate HAART Indication

*In general, 1 IU/ml ≈ 5 copies/ml**Metavir ≥A2 and/or F2

European AIDS Clinical Society (EACS) Guidelines (2007). Rockstroh J, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS6.

• No Treatment• Monitor every 6-12 months

• PEG IFN• Telbivudine• Adefovir + telbivudine• Early HAART including TDF + 3TC/FTC

• Monitor ALT every 3-12 months• Consider Biopsy and treat if

disease present**

HBV DNA<2,000 IU/mL*

HBV DNA≥2,000 IU/mL*

ALTNormal

ALTElevated

HIV/HBV

HBV Management in HIV/HBV Patients with HAART Indication

European AIDS Clinical Society (EACS) Guidelines (2007). Rockstroh J, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS6.

HAART Including TDF + 3TC or FTC

Substitute One NRTI with TDF or Add TDF

Refer for Liver Transplant Evaluation if Liver Decompensation Occurs

3TCResistance

Cirrhosis

HAARTincluding

TDF + 3TCor FTC

No 3TCResistance

HIV/HBV withImmediate

HAARTIndications

HBV DNA≥2,000 IU/mL

HBV DNA<2,000 IU/mL

HAART Regimen of Choice

20%

80%

Acute HCV (AHC) in HIV+ Patients

▬ Retrospective analysis of 150 HIV+ pts with AHC presenting 1999-2006- HCV sexually acquired in 87%

- 58% GT 1; median HCV RNA 5.93 log10 IU/L

▬ Spontaneous clearance in 11 pts (7.3%) and not associated with HCV RNA at week 12

▬ Spontaneous Clearance associated with :- Higher baseline median CD4 count

(623 cells/mm3 vs. 426 cells/mm3, p=0.05)

- Lower baseline median HCV RNA (5.3 log10 vs. 6.04 log10 c/mL, p=0.016)

- Presence of symptoms (32% vs. 13%, p=0.05)

Azwa A, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. PS8/5.

26%74%

Week 12 HCV RNA Negative (n=23)Week 12 HCV RNA Negative (n=23)

Week 12 HCV RNA Positive (n=25)Week 12 HCV RNA Positive (n=25)

Week 48 HCV RNA Positive

Week 48 HCV RNA Negative

Treatment of Acute HCV (AHC) in HIV+ Patients

▬ Multicenter, observational, cohort study of treatment of AHC (n=44)- 100% HCV GT1; 77% Sexual risk

factor- Tx: Pegylated interferon + Ribavirin

▬ SVR achieved in 57% overall - SVR strongly related to achieving

HCV RNA- by week 4- Not associated with baseline HCV

RNA level, HIV RNA, CD4-cell count, HAART use

- 10 pts D/C due to AEs, 1 LTFU

Rates of SVR

57%

90%

29%

0

10

20

30

40

50

60

70

80

90

100

Overall Week 4 HCV RNA- Week 4 HCV RNA+

Vogel M, et al. 11th EACS; Madrid, Spain; October 24-27, 2007. P13.2/08.

Pat

ient

Per

cent

P<0.0001

Documents

11 th European AIDS Conference Madrid, Spain October 24-27, 2007