Cco ias 2013_new_data

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

clinicaloptions.com/hiv
HIV/AIDS Update From IAS 2013
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Faculty
Andrew Carr, MBBS, MD,
FRACP, FRCPA
Professor of Medicine
University of New South Wales
Director, HIV, Immunology, and
Infectious Diseases Unit
St Vincent’s Hospital
Sydney, Australia
Joel E. Gallant, MD, MPH
Adjunct Professor of Medicine
Division of Infectious Diseases
Johns Hopkins University School of
Medicine
Associate Medical Director of Specialty
Services
Southwest CARE Center
Santa Fe, NM
Anton L. Pozniak, MD, FRCP
Consultant Physician
Director of HIV Services
Department of HIV and
Genitourinary Medicine
Chelsea and Westminster Hospital
NHS Trust
London, United Kingdom

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.

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
 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.

 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 48
Stratified 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/mL
at 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.
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)

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
0
Good Disease
Control
HIV-1 RNA
< 400 copies/mL
HIV-1 RNA
< 50 copies/mL
PI/NRTI
PI/RAL
PI Mono60
64
56
86 86
61
74 73
44

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%)

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.

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.

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 96
Stratified 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

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.

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
UninfectedPts(%)
mITT > 67% > 75% > 90% > 95% > 97.5%
Adherence
Pts Uninfected By Level of Adherence
49
54
58
68
72
84

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 + 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.

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
PercentageofSubjects(%)
Virologic
success
Virologic
nonresponse
No Wk
48 data
DTG + OBR
RAL + OBR
71
64
20
28
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 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.

GSK744
200 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
*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†
)

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
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 patients
with virologic failure
on first-line regimen
of 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
Martin A, et al. IAS 2013. Abstract WELBB05.
0
-1
-3
-4
-6
Mean%Change(SE)inBMD
FromBaselinetoWk48,%
-2
-5
Proximal Femur Lumbar Spine
-5.2
-2.9
-4.2
-2
P = .0001
P = .0006
LPV/RTV + 2-3 NRTIs
LPV/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 ↑ 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
1.5Age-SpecificHipFractureIncidence
per1000Person-Yrs
4.0
2.0
1.0
0.5
0
3.0
Age (yrs)
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
HIV-infected
HIV-noninfected

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
Sex
Male
Female
0.84
0.55
.491
.016
CD4+ count, cells/mm3
< 250
> 250
0.64
0.88
.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%

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
HCVReinfectionIncidenceper100Person-Yrs
7.8 9.6
4.2
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

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