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June 30 – July 3, 2013 Kuala Lumpur, Malaysia Highlights of IAS 2013 CCO Official Conference Coverage of the 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention This program is supported by educational grants from

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Page 1: Cco ias 2013_new_data

June 30 – July 3, 2013Kuala Lumpur, Malaysia

Highlights of IAS 2013 CCO Official Conference Coverage of the 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention

This program is supported by educational grants from

Page 2: Cco ias 2013_new_data

clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

About These Slides

Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent

These slides may not be published or posted online without permission from Clinical Care Options (email [email protected])

DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

Faculty

Andrew Carr, MBBS, MD, FRACP, FRCPAProfessor of MedicineUniversity of New South WalesDirector, HIV, Immunology, and Infectious Diseases UnitSt Vincent’s HospitalSydney, Australia

Joel E. Gallant, MD, MPHAdjunct Professor of MedicineDivision of Infectious DiseasesJohns Hopkins University School of MedicineAssociate Medical Director of Specialty ServicesSouthwest CARE CenterSanta Fe, NM

Anton L. Pozniak, MD, FRCPConsultant PhysicianDirector of HIV ServicesDepartment of HIV andGenitourinary MedicineChelsea and Westminster Hospital NHS TrustLondon, United Kingdom

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

Disclosures

Andrew Carr, MBBS, MD, FRACP, FRCPA, has disclosed that he has received funds for research support from Gilead Sciences and Merck Sharp & Dohme; has served as a consultant for Gilead Sciences, Merck Sharp & Dohme, and ViiV Healthcare; has served on advisory boards for Gilead Sciences, Merck Sharp & Dohme, and ViiV Healthcare; and has received lecture and travel sponsorships from Gilead Sciences, Merck Sharp & Dohme, Roche, and ViiV Healthcare.

Joel E. Gallant, MD, MPH, has disclosed that he has received consulting fees from Bristol‐Myers Squibb, Gilead Sciences, Janssen, Merck, and Takara Bio and funds for research support from Gilead Sciences.

Anton L. Pozniak, MD, FRCP, has disclosed that he has received funds for research support and consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, and ViiV Healthcare and has participated in company sponsored speaker’s bureau for Gilead Sciences.

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Antiretroviral Therapy in Resource-Constrained Settings

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

WHO 2013: Updated Treatment Guidelines for Adults, Adolescents, and Children Expanded ART eligibility

– Treatment initiation threshold: CD4+ ≤ 500 cells/mm3

– Prioritize severe or advanced HIV or CD4+ ≤ 350 cells/mm3

Viral load testing preferred for monitoring ART

Preferred initial regimen: fixed-dose TDF + 3TC (or FTC) + EFV

– Discontinue use of d4T due to toxicity

WHO Consolidated Treatment Guidelines. June 2013.

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

Randomized, double-blind, placebo-controlled, noninferiority phase III trial

– Part of ongoing effort to identify ARVs effective at lower doses (and cost)

No significant difference in SAEs between treatment arms

More pts with AEs for EFV 600 mg vs EFV 400 mg (47.2% vs 36.8%; P = .008)

More pts discontinued EFV 600 mg due to AE vs EFV 400 mg (1.9% vs 5.8%; P = .010)

ENCORE1: 400-mg EFV Noninferior to 600-mg EFV With TDF/FTC for Initial ART

Puls R, et al. IAS 2013. Abstract WELBB01.

EFV* 400 mg + placebo +TDF/FTC 300/200 mg

(n = 324)

EFV* 600 mg +TDF/FTC 300/200 mg

(n = 312)

ART-naive pts,CD4+ 50-500 cells/mm3,

HIV-1 RNA > 1000 copies/mL(N = 636)

Wk 48Stratified by clinical site and

HIV-1 RNA at screening (< 100,000 or ≥ 100,000 copies/mL)

*EFV administered as 200-mg tablets.

HIV-1 RNA < 200 c/mLat Wk 48, %

NC = F

90.0

85.8

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

EARNEST: Second-Line LPV/RTV-Based ART After Initial NNRTI Failure Randomized, controlled, open-label, phase III trial

Baseline demographics (medians): HIV-1 RNA 69,782 copies/mL; CD4+ 71 cells/mm3; time on ART, 4 yrs

Paton N, et al. IAS 2013. Abstract WELBB02.

WHO, World Health Organization.*Including clinical, CD4+ cell count (viral load confirmed), or virologic criteria.†Selected by physician according to local standard of care.

HIV-infected adults and adolescents, received first-line NNRTI-based ART > 12 mos, > 90%

adherence in previous mo,treatment failure by WHO

(2010) criteria*(N = 1277)

LPV/RTV + 2-3 NRTIs†

(n = 426)

LPV/RTV + RAL(n = 433)

LPV/RTV + RAL(n = 418)

Wk 144Wk 12

LPV/RTV monotherapy(n = 418)

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

EARNEST: Clinical Outcomes at Wk 96

“Good disease control” at Wk 96 defined as pt alive, no new WHO 4 events from Wks 0-96, and CD4+ cell count > 250 cells/mm3, and HIV-1 RNA < 10,000 copies/mL or > 10,000 copies/mL without PI resistance mutations

Paton N, et al. IAS 2013. Abstract WELBB02.

100

80

60

40

20

0Good Disease

ControlHIV-1 RNA

< 400 copies/mLHIV-1 RNA

< 50 copies/mL

PI/NRTIPI/RALPI Mono60 64

56

86 86

61

74 73

44

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

EARNEST: Other Outcomes

LPV/RTV monotherapy arm discontinued due to inferior virologic suppression, higher frequency of LPV resistance

No significant difference in 96-wk resistance rates between LPV/RTV + NRTIs and LPV/RTV + RAL

Similar rates of grade 3/4 AEs across treatment arms (range: 22% to 24%)

Paton N, et al. IAS 2013. Abstract WELBB02.

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Current Antiretroviral Agents

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

Meta-analysis of Efficacy of Initial ART Regimens in Prospective Trials Meta-analysis of 216 treatment arms from prospective

trials of initial ART, 1994-2010 (N = 40,124 pts)

Mean rate of undetectable HIV-1 RNA: 60% overall

– 66% at Wk 48, 60% at Wk 96, 52% at Wk 144

– 25% discontinued before end of study

Better mean efficacy with more recent year of initiation

– 43% in 1994 vs 78% in 2010

Lee FJ, et al. IAS 2013. Abstract WEAB0104.

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

Efficacy of Initial ART Associated With NRTI Backbone, Third Drug, Other Factors Mean efficacy 70% vs 62% with baseline VL < vs ≥ 100,000 copies/mL

Mean efficacy 75% vs 65% with DHHS “preferred” vs “alternative” ART

Number of pills or doses per day did not predict overall efficacy

Specific NRTI backbones, third drugs associated with efficacy

Lee FJ, et al. IAS 2013. Abstract WEAB0104.

Efficacy, % (SD) Coefficient (95% CI) P Value

NRTI backbone

TDF/FTC 73 (10) Ref

ABC/3TC 63 (7) -7.6 (-12.7 to -2.6) .003

Third drug class

NNRTI 61 (15) Ref  

INSTI 84 (5) 11.9 (4.6-19.2) .002

Boosted PI 67 (9) -0.9 (-4.7 to 3.0) .660

Adjusted for multivariable analysis including year of commencement, other drugs received, baseline patient characteristics, and duration of follow-up.

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

Efficacy of EVG/COBI/TDF/FTC vs EFV/TDF/FTC When Adherence < 95% Preplanned adherence analysis at Wk 96 of Study GS-US-236-0102

≥ 90% adherence in 93% with EVG/COBI/TDF/FTC, 89% with EFV/TDF/FTC

Significantly greater improvement in CD4+ cell counts with EVG/COBI/TDF/FTC vs EFV/TDF/FTC (317 vs 245; P = .039)

ART-naive pts, HIV RNA ≥ 5000

copies/mL, no CD4+ restrictions,eGFR ≥ 70 mL/min

(N = 700)

EVG/COBI/TDF/FTC QD + EFV/TDF/FTC placebo

(n = 348)

EFV/TDF/FTC QHS + EVG/COBI/TDF/FTC placebo

(n = 352)

Wk 96Stratified by HIV RNA

≤ 100,000 or > 100,000 copies/mL

Shalit P, et al. IAS 2013. Abstract TUPE293.

≥ 95% Adherence

< 95% Adherence

88 74

89 63

VL < 50 copies/mL at Wk 96

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

Bangkok Study: Directly Observed PrEP With TDF Reduces HIV Acquisition in IDUs Phase III, randomized, double-blind, placebo-controlled trial

– HIV-uninfected IDUs (N = 2,413) received TDF or placebo

– DOT at drug treatment clinics between 2005 and 2010

Significantly fewer new infections with TDF vs placebo (0.35/100 pys vs 0.68/100 pys; P = .01)

– Overall efficacy: 49%

– Detectable TDF at study end: 74%

Higher adherence associated with greater efficacy

Safety and tolerability similar to other TDF-containing PrEP trials

Choopanya K, et al. IAS 2013. Abstract WELBC05.

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Bangkok TDF Study: Adherence to PrEP and Risk of HIV Acquisition

Choopanya K, et al. IAS 2013. Abstract WELBC05.

100

80

60

40

20

0

Un

infe

cted

Pts

(%

)

mITT > 67% > 75% > 90% > 95% > 97.5%

Adherence

Pts Uninfected By Level of Adherence

4954

58

6872

84

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Investigational Antiretroviral Agents

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

SAILING: Dolutegravir vs Raltegravir in ART-Exp’d, Integrase Inhibitor–Naive Pts Phase III randomized, double-blind, double-dummy,

noninferiority study

Treatment-experienced, integrase inhibitor–naive patients with HIV-1 RNA

> 400 copies/mL and ≥ 2 class resistance

(N = 715)

Dolutegravir 50 mg QD + OBR(n = 354)

Raltegravir 400 mg BID + OBR(n = 361)

Stratified by number of fully active background agents, use of DRV,

screening HIV-1 RNA ≤ vs > 50,000 copies/mL

Wk 48

Cahn P, et al. IAS 2013. Abstract WELBB03.

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

SAILING: Superior Rate of Virologic Suppression With DTG vs RAL at Wk 48

Lower incidence of resistance at VF with DTG vs RAL

– Integrase resistance: 1% vs 5%

– OBR resistance: 1% vs 3%

Both regimens well tolerated with similar AE profiles

– Grade 2-4: 8% vs 9%

– Discontinuations: 3% vs 4%

No difference in outcome between study arms when combined with fully active DRV/RTV

Cahn P, et al. IAS 2013. Abstract WELBB03.

100

80

60

40

20

0

Per

cen

tag

e o

f S

ub

ject

s (%

)

Virologicsuccess

Virologicnonresponse

No Wk 48 data

DTG + OBRRAL + OBR

7164

2028

9 9

Δ 7.4 (95% CI, 0.7-14.2);P = .03

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

Long-Acting GSK1265744 and TMC278

Nanosuspensions: drug nanocrystals suspended in liquid

– Increased drug dissolution rate

– Nanocrystal design allows for low injection volume

Potential utility as long-acting injections for ART regimens, PrEP

– GSK1265744 (DTG analogue) dosed monthly or quarterly

– TMC278 nanosuspension of RPV dosed monthly

Spreen W, et al. IAS 2013. Abstract WEAB0103.

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

GSK744200 mg IM

GSK744 200 mg IM

GSK744 400 mg IM

GSK744 400 mg IM

Monthly

Oral Lead-in* Day 1 Wk 4 Wk 8 Wk 12 Wk 16 Wk 20 Wk 24

Cohort 1(n = 10)

Cohort 2(n = 10)

Cohort 3(n = 10)

Quarterly

Cohort 4(n = 10)

TMC278 (LD†)1200 mg IM

TMC278 900 mg IM

TMC278 (LD†)1200 mg IM

TMC278 600 mg IM

All cohorts followed for 52 wks after last injection (ongoing)

Coadministration of Long-Acting GSK1265744 and TMC278 Randomized, open-label, repeated-dose phase I trial in healthy adults

Spreen W, et al. IAS 2013. Abstract WEAB0103.

*Oral lead-in: GSK744 30 mg/day for 14 days, then 7-day washout.†Loading dose given as split injection dose (2 x 2 mL).

GSK744 800 mg IM

(LD†)

GSK744 800 mg IM

(LD†)

GSK744 800 mg IM

(LD†)

GSK744 200 mg

SC

GSK744 200 mg SC

GSK744 200 mg

SC

GSK744 200 mg

IM

GSK744 400 mg

IM

GSK744 800 mg IM

GSK744 800 mg IM

(LD†)

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

Favorable Drug Concentrations With GSK1265744 and TMC278 Injections PK results

– GSK1265744 injected every 4 wks or every 12 wks achieved plasma levels > protein-adjusted IC90

– TMC278 dosed every 4 wks achieved plasma levels comparable to those achieved by oral RPV 25 mg/day in HIV-infected patients

GSK1265744 safe, well tolerated alone and in combination with TMC278

Findings support phase II study of GSK1265744 + TMC278 as 2-drug ART regimen

Spreen W, et al. IAS 2013. Abstract WEAB0103.

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Adverse Events and Comorbidities

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

SECOND-LINE Subanalysis: BMD Loss With LPV/RTV + NRTIs vs LPV/RTV + RAL Subanalysis of randomized, open-label, multicenter,

international trial

Martin A, et al. IAS 2013. Abstract WELBB05.

LPV/RTV 400/100 mg BID +RAL 400 mg BID

(n = 108)

LPV/RTV 400/100 mg BID +2-3 NRTIs QD or BID

(n = 102)

HIV-infected patientswith virologic failureon first-line regimenof NNRTI + 2 NRTIs

(N = 211 consented to BMD substudy)

DXA scan at Wk 48

DXA scan at Wk 0

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

SECOND-LINE: Greater Mean BMD Loss With NRTI-Based Regimen at Wk 48

No significant difference in frequency of new osteopenia, osteoporosis

Greater decline in lumbar spine BMD associated with lower BMI, no TDF before study, and TDF initiation on study

Martin A, et al. IAS 2013. Abstract WELBB05.

0

-1

-3

-4

-6Mea

n %

Ch

ang

e (S

E)

in B

MD

Fro

m B

asel

ine

to W

k 48

, %

-2

-5

Proximal Femur Lumbar Spine

-5.2

-2.9

-4.2

-2

P = .0001

P = .0006

LPV/RTV + 2-3 NRTIsLPV/RTV + RAL

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

HIV Independently Associated With Increased Risk of Hip Fractures Population-based cohort study

SIDIAPQ database, 2007-2009; Catalonia, Spain (N = 1,118,587 pts aged ≥ 40 yrs)

– HIV-infected: 2489 (0.22%)

– Identified incident major osteoporotic and hip fractures

HIV infection associated with

– 4.72-fold ↑ hazard ratio for hip fracture

– 1.75-fold ↑ hazard ratio for all fractures

– Independent of age, sex, BMI, smoking, EtOH use

Knobel H, et al. IAS 2013. Abstract WEAB0205.

5.0

4.5

3.5

2.5

1.5A

ge-

Sp

ecif

ic H

ip F

ract

ure

In

cid

ence

per

10

00 P

erso

n-Y

rs

4.0

2.0

1.0

0.5

0

3.0

Age (yrs)

40-4545-50

50-5555-60

60-6565-70

70-7575-80

HIV-infectedHIV-noninfected

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

NVP Cutaneous Reactions Reduced By HLA-B*35:05 and CCHCR1 Screening CCHCR1 and HLA-B*35:05

associated with rash[1,2]

– HLA-B*35:05 uncommon except Southeast Asian and South Americans

Prospective, randomized, multicenter, controlled trial[3]

– N = 1103 assigned to screening vs no screening

– All started NVP-based therapy EXCEPT pts screened positive started EFV-based therapy

Group Relative Risk P Value

Overall, screened vs unscreened 0.68 .020

SexMaleFemale

0.840.55

.491

.016

CD4+ count, cells/mm3

< 250> 250

0.640.88

.027

.740

1. Chantarangsu S et al. Pharmacogenet Genomics. 2009;19:139-146. 2. Chantarangsu S et al. Clin Infect Dis 2011;53:341-348. 3. Kiertiburanakul S, et al. IAS 2013. Abstract WELBB04.

Lower incidence of cutaneous AEs in screened group

– 13.2% vs 18.0%

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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

High HCV Reinfection Rate Among HIV-Infected MSM Single-site, retrospective

study (2004-2012) of HIV-infected MSM at London clinic

– Cleared prior HCV infection spontaneously or after HCV treatment

Reinfection rates similar in pts with prior spontaneous clearance vs SVR

Martin T, et al. IAS 2013. Abstract TUAB0101.

P = .15

HC

V R

ein

fec

tio

n I

nc

ide

nc

e p

er

10

0 P

ers

on

-Yrs

7.8 9.64.2

23.2

0

5

10

15

20

25

30

35

40

45

50

Overall Reinfection

Rate

Reinfection Posttreatment

Reinfection After

Spontaneous Clearance

Second Reinfection Rate Following SVR or Clearance

of First Reinfection

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Go Online for More CCO Coverage of IAS 2013

Capsule Summaries of key studies selected by the faculty

Expert Highlights audio podcasts by expert faculty

clinicaloptions.com/ias2013