the 48th interscience conference on antimicrobial agents and chemotherapy and 46th infectious...

The 48th Interscience Conference on Antimicrobial Agents and Chemotherapy and 46th

Infectious Disease Society of America MeetingWashington, DC

October 24-28, 2008

and

9th International Congress on Drug Therapy in HIV Infection

Glasgow, ScotlandNovember 9-13, 2008

When to Start

NA-ACCORD: Improved Survival When ART is Started with ≥350 CD4

● North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD)○ Regional collaboration of 22 HIV research cohorts from

United States and Canada

● Study patients: All HIV-infected individuals with CD4 count of 351-500 cells/mm3 while in active follow-up between 1996 and 2006

● Outcome: All-cause mortality● Groups compared from same CD4 count level:

○ Immediate treatment: Initiate ART within 1.5 yrs after 1st CD4 count between 351-500 cells/mm3

○ Deferred treatment: Do not initiate ART in this time frame

● Patients censored when not initiating within the 1.5 year interval after their target CD4 count for ART initiation

Kitahata M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896bKitahata M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896b

NA-ACCORD: Baseline Characteristics

Initiate HAART (n=2,473)

Defer HAART (n=5,901)

Follow up person-years 8,358 16,636

Males (%) 83 75

Median Age (years) 40 38

White (%) 39 38

Median CD4 count cells/mm3 421 432

Median log10 HIV RNA copies/mL 4.3 4.1

Hepatitis C virus infection (%) 27 34

History of Injection Drug Use (%) 16 21


NA-ACCORD: Results

Relative Hazard (RH)*

95% Confidence

IntervalP-value

Deferral of HAART at 351-500 cells/mm3 1.7 1.4, 2.1 <0.001

Female Sex 1.1 0.9, 1.5 0.290

Older Age (per 10 years) 1.6 1.5, 1.8 <0.001

Baseline CD4 count (per 100 cells/mm3) 0.9 0.7, 1.0 0.083

● HIV RNA was not an independent predictor of mortality● Rate of virologic suppression (<500 c/ml) similar between groups


*Stratified by Cohort and Year

What to Start

STARTMRK: Raltegravir vs Efavirenz

● HIV RNA >5000 c/mL● Susceptible to EFV, TDF and FTC

Randomized (1:1), double blind, study

ART-naïve subjects(N=561)

RAL (400 mg BID)+ TDF/FTC QD+ EFV Placebo

EFV (600 mg QHS)+ TDF/FTC QD

+ RAL Placebo

Lennox J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896aLennox J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896a

STARTMRK:Baseline Characteristics

RAL + TDF/FTC

(n=281)EFV + TDF/FTC

(n=282)

Age (mean, years) 38 37

% Male 81 82

% Non-White 59 56

vRNA copies/mL (geometric mean) 103,205 106,215

% with vRNA >105 copies/mL 55 51

Mean CD4 count (cells/μl) 219 217

% with CD4 ≤200 cells/μl 47 48

% Hepatitis B or C 7 7

% Non-Clade B 21 17


STARTMRK: Results

Lennox J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896a

Perc

en

t w

ith

HIV

RN

A <

50 c

/mL

0 2 4 8 12 16 24 32 40 48

0

20

40

60

80

100

82%

Non-inferiorityp-Value <0.001

86%

RAL + TDF/FTC

EFV + TDF/FTC

Weeks

CD4 change:+189 cells/mm3

+163 cells/mm3

(95% CI: 4,47)

STARTMRK: Results

● Time to virologic suppression faster with RAL (P<0.001)

● Virologic failures similar○ RAL 12 (4 with RAL, 3 with FTC resistance)○ EFV 8 (3 with EFV, 1 with FTC resistance)

● Lower incidence of drug-related adverse events with RAL

○ Overall: RAL 44% vs EFV 77% (P<0.001)○ CNS at week 8: RAL 10.3% vs 17.7% (P=0.015) – persisted

through week 48

Lennox J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896a

STARTMRK: Fasting Serum Lipid Changes from Baseline to Week 48

-3

10

4 610

33

16

37

-10

0

10

20

30

40

T CHOL HDL-C LDL-C TG

RAL+TDF/FTCEFV+TDF/FTC

Mea

n C

han

ge

(mg

/dL

)

P<0.001P<0.001P<0.001P<0.001


ARTEMIS: Phase III Study Design

96 Week Results Presented

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

(n=343)

LPV/r* 400/100mg BID or 800/200mg QD

+ TDF/FTC (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 75%; Capsule/tablet switch 86%*Dosing was based on regulatory approval; switch was made according to local regulatory approval and drug availability.LPV/r BID 75%; Capsule/tablet switch 86%

Mills A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250cMills A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250c

ARTEMIS: Baseline Characteristics

DRV/r + TDF/FTC QD

(n=343)

LPV/r +TDF/FTC QD

(n=267)

Baseline demographics

Female, N (%) 104 (30) 105 (30)

Caucasian 40% 44%

Baseline disease characteristics

Median HIV-1 RNA (c/mL) 70,800 62,100

Median CD4 (cells/mm3) 228 218

HBV/HCV co-infected 13% 14%

Stratification factors at screening

CD4 count <200 cells/mm3 41% 43%

Plasma HIV-1 RNA ≥100,000 c/mL 34% 35%


ARTEMIS: HIV RNA <50 c/mL to Week 96 (TLOVR)

79

93

71

87

0

20

40

60

80

100

ITT* VF Only

DRV/r + TDF/FTC LPV/r + TDF/FTC P=0.024

Perc

en

t H

IV R

NA

<50 c

/mL

*Estimated difference in response vs LPV/r for non-inferiority: PP = 8.4% (95% CI 1.9;14.8,

P<0.001)

*Estimated difference in response vs LPV/r for superiority: ITT = 8.3% (95% CI 1.8;14.7, P=0.012)


ARTEMIS: Response by VL and CD4 Strata and Adverse Events

● Higher rate of GI adverse events in LPV/r arm (Diarrhea 4% vs. 11% , P<0.001)● Grade 2-4 increases in total cholesterol (18% vs. 28%, P=0.0016) and

triglycerides (4% vs. 13%, P<0.0001) higher in LPV/r arm

DRV/r + TDF/FTC LPV/r + TDF/FTC

8176

≥100,000

75

<100,000Baseline viral load (copies/mL)

0

20

40

60

80

100

% H

IV R

NA

<5

0 c

opie

s/m

L (I

TT-T

LOV

R)

63

P=0.023

n = 226 226 117 120

P=0.174

79

65

≥2000

20

40

60

80

100

7975

<200

Baseline CD4 cell count (cells/mm3)202 198n=

P=0.009 P=0.345

141 148


ARTEMIS: Median Increase in Lipid Levels at Week 96

18

LPV/r + TDF/FTCDRV/r + TDF/FTC

0.0

10

20

40

Total cholesterol

LDLc cholesterol

HDL cholesterol Triglycerides

Media

n incr

ease

in

conce

ntr

ati

on (

mg/d

L)

26

17

5

35

15

8

56

30


50

60

ATV/r 300/100 mg QD+ TDF/FTC QD

(n=440)

CASTLE: Study Design

(1:1)

International, multicenter, open-label, randomized, 96-week study to determine the comparative clinical efficacy and safety of ATV/r and LPV/r in treatment-naïve HIV-1 infected subjects

HIV RNA 5000 c/mL, no CD4 cell count restrictionStratified by HIV RNA <100,000 c/mL vs 100,000 c/mL and geographic region

LPV/r 400/100 mg BID+ TDF/FTC QD

(n=443)

Molina J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250dMolina J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250d

CASTLE: Baseline Characteristics

ATV/r + TDF/FTC(n=440)

LPV/r + TDF/FTC(n=443)

Median Age (years) 34 36

Female (%) 31 31

CDC Class C (%) 4 5

HIV RNA median (log10 c/mL) 5.01 4.96

HIV RNA ≥100,000 c/mL (%) 51 47

CD4 median (cells/mm3) 205 204

CD4 <50 cells/mm3 (%) 13 11

HBV or HCV +ve (%) 14 12

HIV subtype B (%) 67 66


CASTLE: HIV RNA <50 c/mL (CVR, NC = F)

Perc

ent

HIV

RN

A <

50

c/m

L

Weeks

B/L 12 24 36 480

20

40

60

80

100

60 72 84 96

ATV/r + TDF/FTC (n=440)LPV/r + TDF/FTC (n=443)

HIV RNA <50 c/mL: 74% ATV/RTV vs 68% LPV/RTV

Difference estimate: 6.1 (95% CI, 0.3%–12.0%, P<0.05)


CASTLE: Response by Baseline HIV RNA and CD4

N=

0

20

40

60

80

100

30

50

70

90

10Resp

onder

(%)

<5

0 c

opie

s/m

L

217 218 223 225

75%70%

74%

66%

<100,000 c/mL ≥100,000 c/mL

ITT-Confirmed Virologic Response (NC =F) by Qualifying HIV Viral Load

ATV/r + TDF/FTC LPV/r + TDF/FTC

≥200 cells/mm3

100 - <200 cells/mm3

N=

0

20

40

60

80

100

30

50

70

90

10Resp

onder

(%)

<5

0 c

opie

s/m

L P=NS

ITT-Confirmed Virologic Response (NC =F) by Baseline CD4 Cell Count

222

76%71%

78%

71% 69% 70%

58%

69%

ATV/r LPV/r106 45 58 228 134 29 48

P=NS


50 - <100 cells/mm3

< 50 cells/mm3

CASTLE: Adverse Eventsat 96 Weeks

ATV/r + TDF/FTC(n=441)

LPV/r + TDF/FTC (n=437)

Death 1% 1%

SAE 14% 11%

AE leading to discontinuation 3% 5%

Jaundice/hyperbilirubinemia <1% 0

Diarrhea 0 2%

Renal <1% <1%


*Lipid Changes are Mean Percent Increase From Baseline

CASTLE: Mean Fasting Lipids at Baseline and Week 96

149

92

37

112

126

168

105

44

125

140

150

93

36

114

129

186

110

46

140

184

0

20

40

60

80

100

120

140

160

180

200

TC LDL-c HDL-c Non-HDL-c TG

Lip

id V

alu

es m

g/d

l

ATV/r + TDF/FTC Baseline

ATV/r + TDF/FTC Wk 96

LPV/r + TDF/FTC Baseline

LPV/r + TDF/FTC Wk 96

Difference Estimate

(95% CI) ATV/r-LPV/r

Difference Estimate

(95% CI) ATV/r-LPV/r

-8.9%*

(-11.6%, -6.1%)

-8.9%*

(-11.6%, -6.1%)

-1.7%

(-5.9%, 2.6%)

-1.7%

(-5.9%, 2.6%)

-5.5%

(-10.0%, -0.8%)

-5.5%

(-10.0%, -0.8%)

-9.7%*

(-13.0%, -6.3%)

-9.7%*

(-13.0%, -6.3%)

-24.5%*

(-29.9%, -18.8%)

-24.5%*

(-29.9%, -18.8%)

* P<0.0001* P<0.0001


Meta-Analysis of TDF/FTC vs ABC/3TC in Boosted PI Trials

● 12 clinical trials (N=4896)● Aggregate results favor TDF/FTC

50% 60% 70% 80% 90% 100%

% HIV RNA <50 copies (ITT TLOVR) at Week 48

SQV/r

DRV/r

FPV/r

LPV/r

TDF (n=53)

ABC (n=722)

TDF (n=2285)ABC (n=722)

TDF (n=166)

TDF (n=343)

TDF (n=493)ATV/r ABC (n=112)

Hill A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1254Hill A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1254

Convergence of First-line Regimens

● Treatment-naïve patients at U of Alabama not participating in a clinical trial● Over time, significant decline in first-line regimen variability● In 2007, 95% started one of two regimens: TDF/FTC/EFV or TDF/FTC + ATV/r● Fewer changes of therapy with TDF/FTC/EFV (10%) vs. ZDV/3TV + EFV (43%)

Nu

mb

er

Sta

rte

d o

n a

Un

iqu

e R

eg

ime

n/

Nu

mb

er

of

Pa

tien

ts S

tart

ed

on

AR

Vs

Annual Treatment Share for All Regimens Utilized as Initial Therapy

FTC/TDF/EFV3TC/ZDV/LPV/r3TC/ddI/EFV

2003 (n=67) 2004 (n=75) 2005 (n=68) 2006 (n=66) 2007 (n=65)

3TC/ZDV/EFV3TC/ZDV/NFVFTC/TDF/ATV/r

3TC/ABC/ZDV3TC/ZDV/NVPOther – (<5% Treatment Share)

0

20

40

60

80

100

30

50

70

90

10

McKinnell J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1260McKinnell J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1260

Issues Regarding ARV Therapy in Treatment-Experienced Patients

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

Bánhegyi D, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. P022.Bánhegyi D, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. P022.

TITAN: Results at 96 Weeks

60 5668

5662

5563

38

69

49

0102030405060708090

100

0 ≥1 0 ≥1

Pat

ien

ts <

50 c

op

ies/

mL

(%

)DRV/r LPV/r

Previously Used PIs**Primary PI Mutations**Overall

P=0.154 P<0.0001 P=0.078 P=0.007P<0.001*

*Non-inferiority; **at baseline

CD4 Cell Change: DRV/r 93 cells/mm3 vs. LPV/r 81 cells/mm3

Virologic Failures: DRV/r 14% vs. LPV/r 26% (p<0.001)


TITAN: Adverse Events and Median % Change in Lipids at Week 96

*p<0.05 vs LPV/r**p<0.01 vs LPV/r

• Notable Grade 2-4 AEs• Diarrhea: DRV/r 8% vs. LPV/r 15% (p=0.007)• Rash: DRV/r 3% vs. LPV/r 1% (p=0.09)

• No notable differences regarding laboratory abnormalities

DRV/r

LPV/r

Me

dia

n c

ha

ng

e f

rom

ba

se

lin

e (

%)

31%*

12%**10%

4%**

44%

18%13%

0

20

40

60

Triglycerides Totalcholesterol

LDLcalculated

HDL

10%


BENCHMRK: Resistance Analysis

● Genotyping of BENCHMRK virologic failures (VF)○ Population sequencing○ GT at Baseline, VF (HIV

RNA >400), and time point(s) post VF○ 105 VFs (out of 462 on RAL)○ 94 VFs with BL and VF data○ 30 VFs with no changes at

VF○ 64 VF included in this

analysis

● Patients who fail RAL develop mutational patterns associated with high level resistance

0

10

20

30

40

50

60

70

First Failure Genotype Post-failure Genotype

1 2 >2

• First failure: 27% at position 148

• Subsequent: 53% at position 148

Miller M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-898Miller M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-898

Number of Mutations

Changes from Baseline Genotype

Nu

mb

er

of

Ge

no

typ

es

BENCHMRK: Pharmacokinetics and Pharmacodynamics

• Trough concentrations do not predict RAL effectiveness• Prolonged pre-integration complex binding may explain the lack of correlation with trough concentration

Miller M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-898Miller M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-898

P24 at 48h

remove 6, 8, 10 or 12h post infection Infect

0

10

20

30

40

50

60

70

80

90

No Wash 6 h 8 h 10 h 12 h

No drug RAL

RAL “Post-Antibiotic” Effect (in vitro)

% p

atie

nts

wit

h H

IV R

NA

<40

0 c/

mL

GM Observed C12hr (nM)

GM Observed C12hr <33 nM

8 - 125 128 - 254 254 - 545 547 - 9151

0

20

40

60

80

100

RAL Effective Across Range of Trough Levels

ACTG 5211: Analysis Using Enhanced Sensitivity Tropism Testing

Trofile ES reclassified 25/114 individuals with R5 virusat screen using original Trofile

Original Trofile Trofile ES

Screen Entry At Failure DM at Screen (n, %)

R5 DM DM/X4 7/12, 58%

R5 R5 DM/X4 9/18, 50%

R5 R5 R5 9/84, 11%

Screening: R5 tropism by the original Trofile assay VCV 5*, 10 or 15 mg QD or Placebo

Optimized ART regimenFailing ART regimen

StudyScreen

StudyEntry

Day14

Week24

Week48

Su Z, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-895Su Z, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-895*Stopped early

ACTG 5211: Response Based on Trofile ES

Enhanced sensitivity tropism (Trofile ES) testing:● Detects greater numbers of D/M and X4 virus and improves response

rate with CCR5 antagonist regimen● Excludes only a small number of patients who would respond to CCR5

antagonist● Role of repeat tropism testing not yet clarified

Day 1

4W

eek 2

4

Trofile ES

D/M Screen R5 ScreenD/M Entry

R5 ScreenR5 Entry

N 15 5 64

Mean HIV RNA Change* -0.09 -0.66 -1.15

Adjusted p value** <0.0001 0.37 Reference

N 14 5 58

Mean HIV RNA Change* -0.57 -1.20 -1.95

Adjusted p value** 0.0001 0.10 Reference

Su Z, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-895Su Z, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-895

* log10 c/mL** From regression model adjusted for baseline HIV-1 RNA and study stratification factors

Randomization 1:1Patient eligibility criteria:

- Treatment naive- R5 HIV-1 infection with HIV RNA ≥2000 c/mL

- No resistance to EFV, 3TC or ZDV

Patients stratified by:- HIV-1 RNA < and ≥100,000 copies/mL at screening

- Geographic location: No. and So. Hemispheres

MVC (300 mg BID)* + ZDV/3TC**

MERIT: Efavirenz vs. Maraviroc in ARV-Naïve Patients

EFV+ ZDV/3TC**

Week 48Primary Analysis

Week 96

*MVC QD arm discontinued at week 16 for failure to meet protocol-defined criteria to continue**In event of toxicity, ZDV or 3TC switch to alternative NRTI allowed*MVC QD arm discontinued at week 16 for failure to meet protocol-defined criteria to continue**In event of toxicity, ZDV or 3TC switch to alternative NRTI allowed

Saag M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1232a

MERIT ES: Re-analysis of CCR5 Screening

Screened as R5 by Standard Trofile

Rescreened as D/Mby Trofile ES

N BL D/M on study

EFV + ZDV/3TCn/N (%)

MVC + ZDV/3TCn/N (%)

Totaln/N (%)

23 D/M - 4/10(40.0)

7/13(53.8)

11/23(47.8)

29 R5 YES 6/9(66.7)

10/20(50.0)

16/29(55.2)

615 R5 NO 46/314(14.6)

29/301(9.6)

75/615(12.2)


MERIT ES: Viral Suppression Using Enhanced Tropism Testing

*Lower bound of 1-sided 97.5% confidence interval; noninferiority margin = –10%


MVC + ZDV/3TCEFV + ZDV/3TC

<400 copies/mL

0

10

20

30

40

50

60

70

80

90

100

361 360

303 311

73.1 70.6

Pati

ents

(%

)

n=

–3.0 (–9.5*) 0.6 (–6.4*)

72.3 73.3

MERIT MERIT ES

<50 copies/mL

–0.2 (–7.4*)

361 360 303 311n=

68.3 68.5

0

10

20

30

40

50

60

70

80

90

100

69.365.3

–4.2 (–10.9*)

MERIT MERIT ES

MERIT ES: Summary of Discontinuations through 48 Weeks

Reason for discontinuation EFV + ZDV/3TC MVC + ZDV/3TC

MERIT (N=361)

MERIT ES (N=303)

MERIT(N=360)

MERIT ES (N=311)

All, n (%) 91 (25.2) 78 (25.7) 97 (26.9) 76 (24.4)

Adverse event*, n (%) 49 (13.6) 43 (14.2) 15 (4.2) 13 (4.2)

Lack of efficacy, n (%) 15 (4.2) 12 (4.0) 43 (11.9) 29 (9.3)

Other reason, n (%) 9 (2.5) 9 (3.0) 13 (3.6) 11 (3.5)

Withdrew consent or lost tofollow-up, n (%) 18 (5.0) 14 (4.6) 25 (6.9) 22 (7.1)

Only patients with an R5 screening result by enhanced Trofile assay are included in MERIT ES

*All cause eventsSaag M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1232a

Week 96 Data: Includes all patients who reached Week 48 with HIV-1 RNA <50 c/mL and continued on blinded therapy or open-label MVC BID

MOTIVATE 1 & 2: Trial Design

1076 ARV-experienced patients

MVC 150mg† BID(n=426)

MVC 150mg† QD (n=414)

Placebo(n=209)

R5 HIV-1 infection (44% screen failures)HIV-1-RNA ≥ 5,000 copies/mL

Stable pre-study ARV regimen, or no ARVs for ≥ 4 weeksResistance to and/or ≥ 6 months’ experience with ≥ 1 ARV from 3 classes (≥ 2 for PIs)

MOTIVATE 1 & 2

2 identical ongoing Phase IIb/III studiesRandomized (1:2:2), double-blind, placebo controlled

All received OBT*Stratified by ENF use and HIV-1 RNA < and ≥ 100,000 copies/mL

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

Hardy D, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O425.Hardy D, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O425.

MOTIVATE 1 & 2: HIV-1 RNA <50 Copies/mL at Week 96 (ITT, NC=F)

Placebo + OBT (N=209)MVC QD + OBT (N=414)MVC BID + OBT (N=426)

Patie

nts

(%)

Option to switch to open-label MVC BID

43.7%

45.1%

23.0%

43.5%

46.5%

16.7%

38.9%41.3%

7.2%

Time (weeks)

0

10

20

30

40

50

60

70

80

90

100

0 8 16 24 32 40 48 56 64 72 80 88 96

Blinded Phase

Hardy D, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O425.Hardy D, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O425.

Weighted OBT Sensitivity Score (wOBTSS)

MOTIVATE: Using a Weighted Score for the OBT to Predict Response

Any drug in continuous use, score = 0

IC50FC

S* R**

PI 1 0

NRTI 0.5 0

NNRTI 1 0

Genotype

S R

ENF 1 0

Full analysis set(N=1,049)

On-study at Week 48 or virologic failure (n=904)

Virologic Outcomes(VO) population (n=634)

Population included in regression modeling (n=628)

Valdez H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1221Valdez H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1221

*IC50 fold-change is less than or equal to the lower clinical cut-off **IC50 fold-change is greater than the lower clinical cut-off

Non-virologic failures excluded (n=145)

Missing / incomplete information (n=6)

Exclusions for protocol violations and other reasons (n=270)

MOTIVATE: Results of Using Weighted Score for OBT

Conclusions: Using a modified score of the optimized background regimen, and limiting the population to patients with a CD4 count >50, MVC was associated with an ~80% response rate at Wk 48

Proportion of subjects with HIV RNA <50 copies/mL at Week 48 by wOBTSS

Subjects ≥50 CD4+ cells/mm3 at baseline

n=

<5

0 c

op

ies/

mL

at

Week

48

(%

)

41 76 81 47 87 113 35 77 78

All subjects

Valdez H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1221Valdez H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1221

PBO + OBT MVC QD + OBT MVC BID + OBT

wOBTSS <1 1-<2 ≥2 <1 1-<2 ≥2

n= 31 60 61 35 67 94 32 63 64

Etravirine + Raltegravir + OBT: Data from the Expanded Access Programs

● Cohort Kaiser Permanente cohort starting ETR + RAL + OBT (n=53)○ Three class experienced and HIV viremia○ Resistance (or intolerance) within each class (NRTI, NNRTI, PI)

Baseline DemographicsGender, male, n (%) 50 (94%)

Mean age, years 49

Median baseline CD4 count, cells\mm3 (IQR) 171 (74-290)

Received boosted protease inhibitor (PI) as part of OBT, n (%) 47 (89%)

DRV/r 44 (83%)

de novo use 43 (81%)

not de novo use 1 (2%)

LPV/r 3 (6%)

de novo use 1 (2%)


ATV/r 1 (2%)

de novo use 0 (0%)


Received enfuvirtide as part of OBT, n (%) 6 (11%)

de novo use 4 (8%)

Kerrigan H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1263Kerrigan H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1263

Etravirine + Raltegravir + OBT:Outcomes at Week 24

Virologic and Immunologic Outcomes at Week 24 ( ITT)

HIV-1 RNA <75 c/mL, n (%) 50 (94%)

Mean CD4 cell count change +86 cells\mm3

Virologic Outcomes at Week 24 based on Baseline and Cumulative Resistance

ETR Weighted

Mutation Score

Number of Patients with HIV-1 RNA <75 c/mL at Week 24, Based on:

Baseline Resistance Assessment, n (%)

Cumulative Resistance Assessment, n (%)

0-2

Highest Predicted response35/37 (94.6%) 28/30 (93.3%)

2.5 – 3.5

Intermediate Predicted response

9/10 (90.0%) 10/10 (100%)

>3.5

Reduced Predicted response6/6 (100%) 12/13 (92.3%)

• The combination of ETR + RAL + OBT was safe and tolerable with minimal adverse events• Most common AEs were nausea (5), diarrhea (9) and rash (10)

Kerrigan H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1263Kerrigan H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1263

Bevirimat: Phase II Safety and Efficacy Data

● Maturation Inhibitor○ Not metabolized through CYP3A4

● Phase II study: Placebo vs. dose ranging BVM (n=88)○ PK: Target Cmin (≥20 μg/ml) achieved

with liquid dose of ≥250mg QD ○ Safety

○ Only grade 1 clinical AEs observed over 2 week period

○ Lab AEs grade >2: 4% AST, 8% glucose elevation

○ BVM activity affected by GAG polymorphism (PM) pattern at codons 369-371

○ 62% of 1034 patients are free of Gag PM pattern that predicts poor response to BVM

● Phase 3 planned with tablet formulation and GAG PM screening

-0.16-0.24

-0.32

-1.08

-1.26-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

369 370 371 No 369-371 No PM & Cmin>20

Lalezari J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-891Lalezari J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-891

Effect of GAG Polymorphisms on BVM Activity

Vir

al S

up

pre

ssio

n (

log

10 c

/mL

)

Elvucitabine: 48 Week Results in ARV-Naïve Patients

Novel L-cytosine NRTI: ● 80-100 hour half-life● In-vitro activity with M184V/I mutationStudy Design: ● Randomized to ELV (10mg) or

3TC (300mg) QD○ Plus TDF and EFV QD

(blinded for first 12 weeks)

Results:● Similar virologic suppression in

ELV and 3TC arms● More AE discontinuations with ELV

○ First 12 weeks - 6 more on ELV vs. LAM (multiple reasons)

○ After week 12 – DC rates the same

Conclusion: ○ ELV showed similar activity to

3TC to week 48

DeJesus E, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-892DeJesus E, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-892

95% CI:-0.7 (-10.7%, 9.3%)

Elvucitabine (25) Lamivudine (30)

Perc

enta

ge (

%)

0

10

20

30

40

50

60

70

80

90

100

Visit Week

0 2 4 6 8 10 12 14 16 20 24 28 32 36 40 44 48

96.7%

96%

Percent <50 c/mL (As-Treated)

RDEA806:Activity of a Novel NNRTI

● New NNRTI○ in vitro activity against K103N○ No inhibition / induction of

CYP450○ Half-life 9-12 hours

● Proof of Concept Study (n=48)

○ 7 day treatment period using multiple doses of RDEA806 vs. placebo

○ Activity demonstrated and dependent on Ctrough

○ No safety concerns identified○ Uric acid reduced

● Phase 2b in ARV treatment-naïve patients planned

Moyle G, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-893

Viral Load Reduction and Ctrough by Cohort

400 BID 600 QD 800 QD 1000 QD

0

-0.5

-1

-1.5

-2

-2.5

3

-3.5

0.00

10.00

1.00

0.10

0.01

Vir

al Lo

ad

Nadir

(Lo

g1

0 c

/mL)

Ctro

ug

h (µg/m

l)

VL reduction

Ctrough

Median VL reduction

Median Ctrough

DUET: Impact of Treatment on Hospitalization and Clinical Illness

0

5

10

15

20

25

ETR + BR (n=599)Placebo + BR (n=604)

Pro

port

ion o

f pati

en

ts

hosp

italiz

ed

(%

) 23%

17.5%

P=0.0006

Proportion of patients hospitalized by Week 48

Proportion of patients with any AIDS-defining illness or death

Pati

ents

wit

h a

ny

AID

S-d

efin

ing

illn

ess

or

death

(%

)

Overall population

ENF not de novoENF de novo

0

5.8%

9.8%

7.2%

8.8%

5.4%

10.1%

2

4

6

8

10

12

P=0.0408 P=0.6114 P=0.0086

Haubrich R, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1239Haubrich R, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1239

Management Strategies in Patients on ARV Therapy

FOTO: Five Days On, Two Days Off Study Design

VL < 50 c/mL on TDF / FTC /EFVVL < 50 c/mL on TDF / FTC /EFV

Continue daily ARV treatment (n=30)

Change to Five days On; Two Days Off (n=30)

Change to Five days On; Two Days Off (n=30)

Primary Outcome: 24 weeks*Primary Outcome: 24 weeks*

*At week 24 – pts. on Continuous arm offered change to FOTO; all followed for >48 weeks

Male (%) 83% 83%

White (%) 77% 63%

Age (years) 47 42

CD4 count (cells/mm3) 679 660

Cohen C, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O214.Cohen C, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O214.

FOTO Results: Primary Outcome

83%80%

0%

20%

40%

60%

80%

100%

ITT M=F*

Continuous FOTO

*p<0.05 to reject hypothesis that FOTO is inferior to continuous

Week 24: VL < 50 c/mLP

atie

nt P

erce

nt


FOTO: Additional Outcomes

97%

87%

96%

86%93% 90% 88%

100%

0%

20%

40%

60%

80%

100%

BL Week 4 Week 12 Week 24

Continuous FOTO

*Missing = Excluded; **p<0.05 for inferiority

****

%<

50

c/m

L t

o w

ee

k 2

4 (

OT

*)

● Adverse Events:○ No drug-related SAEs○ No grade >3 AEs in either arm○ Labs: No Grade >2 in either arm

● Pt. Preference Questionnaire – Week 4 on FOTO arm○ Scale: 0 (prefer Continuous) to 10 (prefer FOTO)○ Result: Median 9.5 (range 2-10)


AI-073: Switching Suppressed Patients to EFV/FTC/TDF

STR=EFV/FTC/TDF QD (n=203)

SBR=Stayed Baseline Regimen (n=97)

Randomization2:1

Stratify byPI or NNRTI

Continue

Switch•VL<200 c/mL •Stable ARV Regimen •On 1st regimen or suppressed on previous PI regimen •No H/O VF

Phase IV, multicenter (55 US sites), open-label study (N=300)

Primary Endpoint: Non-inferiority of STR vs. SBR for HIV-1 RNA <200 c/mL through Week 48 by TLOVR analysis

DeJesus E, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1234;Young B, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. P061. DeJesus E, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1234;Young B, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. P061.

87% 85%

0%

20%

40%

60%

80%

100%

STR SBR

AI-073: Results at 48 Weeks

Virologic failure STR 3 , SBR 1

AE’s all grades

STR: Higher incidence

-Sleep disturbance 14% vs 0

-Dizziness 11% vs 1%

-GI (nauseas, diarrhea) 6% vs 2%

DC due to AE’s STR 10 (5%), SBR 1 (1%)

GFR (CG, MDRD) No significant changes

Change TG (mg/dl) STR -20, SBR -3 (P=0.035)

Pt preference STR 91%, SBR 9% (P=0.001)

% w

ith

HIV

RN

A <

50 c

/mL

(T

LO

VR

)

Treatment Difference (STR – SBR)95% CI:2.6% (5.9%, 11.1%)

DeJesus E, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1234;Young B, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. P061. DeJesus E, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1234;Young B, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. P061.

The 48th Interscience Conference on Antimicrobial Agents and Chemotherapy and 46th

Infectious Disease Society of America MeetingWashington, DC

October 24-28, 2008

and

9th International Congress on Drug Therapy in HIV Infection

Glasgow, ScotlandNovember 9-13, 2008

the 48th interscience conference on antimicrobial agents and chemotherapy and 46th infectious...

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