highlights of ias 2013.cco official conference coverage of the 7th ias conference on hiv...

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

Jointly sponsored by the Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC

clinicaloptions.com/hivHIV/AIDS Update From IAS 2013

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Faculty

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

Joel E. Gallant, MD, MPHAssociate Medical Director of Specialty ServicesSouthwest CARE CenterSanta Fe, New MexicoAdjunct Professor of MedicineDivision of Infectious DiseasesJohns Hopkins University School of MedicineBaltimore, Maryland

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


Disclosures

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

Joel E. Gallant, MD, MPH, has disclosed that he has received consulting fees from Bristol‐Myers Squibb, Gilead Sciences, Janssen, and Merck 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 and has participated in company-sponsored speaker bureaus for Gilead Sciences.

Please review the slide notes for analysis of each study

by expert faculty Andrew Carr, MBBS, MD, FRACP;

Joel E. Gallant, MD, MPH; and Anton L. Pozniak, MD, FRCP

Antiretroviral Therapy in Resource-Constrained Settings


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

HIV-1 RNA 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.


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 study drug–related 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 c/mL

(N = 636)

Wk 48Stratified by clinical site and

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

*EFV administered as 200-mg tablets.

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

NC = F

90.0

85.8


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.

*Including clinical, CD4+ cell count (HIV-1 RNA 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)


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


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

Pat

ient

s, %


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%)


Current Antiretroviral Agents


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 yr of initiation

– 43% in 1994 vs 78% in 2010

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


Efficacy of Initial ART Associated With NRTI Backbone, Third Drug, Other Factors Mean efficacy 70% vs 62% with baseline HIV-1 DNA < 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 to 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.


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

Among pts with < 95% adherence, 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-1 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-1 RNA

≤ 100,000 or > 100,000 copies/mL

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

≥ 95% Adherence

< 95% Adherence

88 74

89 63

HIV-1 DNA < 50 copies/mL at Wk 96


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

– HIV-uninfected IDUs (N = 2413) received TDF or placebo

– DOT at drug treatment clinics between 2005 and 2010

Significantly fewer new infections with TDF vs placebo (0.35/100 PY vs 0.68/100 PY; 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.


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

Choopanya K, et al. IAS 2013. Abstract WELBC05. Graphic used with permission.

100

80

60

40

20

0

Eff

icac

y (%

)

mITT > 67 > 75 > 90 > 95 > 97.5

Adherence (%)

4954

58

6872

84

New or Investigational Antiretroviral Agents


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 + Raltegravir placebo + OBR

(n = 354)

Raltegravir 400 mg BID + Dolutegravir placebo + 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. Cahn P, et al. Lancet. 2013;382:700-708.


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. Graphic used with permission.

100

80

60

40

20

0

Su

bje

cts

(%)

VirologicSuccess

VirologicNonresponse

No Wk 48 Data

DTG + OBRRAL + OBR

7164

2028

9 9

Δ 7.4 (95% CI: 0.7-14.2;

P = .03)


Long-Acting GSK1265744 and TMC278

Nanosuspensions: drug nanocrystals suspended in liquid

– Increased drug dissolution rate

– Nanocrystal design allows for low injection volume

Potential use 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.


Randomized, open-label, repeated-dose phase I trial in healthy adults

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


*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

(LD†)

GSK744 800 mg IM

(LD†)


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


Adverse Events and Comorbidities


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

international trial

Hoy J, 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


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

Hoy J, et al. IAS 2013. Abstract WELBB05. Graphic used with permission.

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


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 ↑ HR for hip fracture

– 1.75-fold ↑ HR for all fractures

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

Knobel H, et al. IAS 2013. Abstract WEAB0205. Güerri-Fernandez R, et al. J Bone Miner Res. 2013;28:1259-1263.

5.0

4.5

3.5

2.5

1.5A

ge-

Sp

ecif

ic H

ip F

ract

ure

In

cid

ence

sp

er 1

000

Per

son

-Yrs

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 Uninfected


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. Table used with permission.

Lower incidence of cutaneous AEs in screened group

– 13.2% vs 18.0%


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

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

http://www.clinicaloptions.com/ias2013

highlights of ias 2013.cco official conference coverage of the 7th ias conference on hiv...

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