highlights of ias 2013.cco official conference coverage of the 7th ias conference on hiv...
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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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clinicaloptions.com/hivHIV/AIDS Update From IAS 2013
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
clinicaloptions.com/hivHIV/AIDS Update From IAS 2013
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
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
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.
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 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
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.
*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)
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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
Pat
ient
s, %
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.
Current Antiretroviral Agents
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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.
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 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.
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
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
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 = 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.
clinicaloptions.com/hivHIV/AIDS Update From IAS 2013
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
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 + 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.
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. 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)
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 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.
clinicaloptions.com/hivHIV/AIDS Update From IAS 2013
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
Spreen W, et al. IAS 2013. Abstract WEAB0103.
*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†)
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.
Adverse Events and Comorbidities
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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
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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
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 ↑ 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
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. Table used with permission.
Lower incidence of cutaneous AEs in screened group
– 13.2% vs 18.0%
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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
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