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Highlights of IAS 2013.CCO Official Conference Coverage of the 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention
1. Highlights of IAS 2013
CCO Official Conference Coverage
of the 7th IAS Conference on HIV Pathogenesis, Treatment, and Prevention
June 30 - July 3, 2013
Kuala Lumpur, Malaysia
Jointly sponsored by the Annenberg Center for Health
Sciences at Eisenhower and Clinical Care Options, LLC
This program is supported by educational grants from
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Faculty
Andrew Carr, MBBS, MD,
FRACP
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
Associate Medical Director of Specialty
Services
Southwest CARE Center
Santa Fe, New Mexico
Adjunct Professor of Medicine
Division of Infectious Diseases
Johns Hopkins University School of
Medicine
Baltimore, Maryland
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
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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.
5. 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
7. HIV/AIDS Update From IAS 2013
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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.
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ENCORE1: 400-mg EFV Noninferior to
600-mg EFV With TDF/FTC for Initial ART
Randomized, double-blind, placebo-controlled, noninferiority phase III trial
–
Part of ongoing effort to identify ARVs effective at lower doses (and cost)
HIV-1 RNA < 200 c/mL
at Wk 48, %
Wk 48
Stratified by clinical site and
HIV-1 RNA at screening
(< 100,000 or ≥ 100,000 c/mL)
ART-naive pts,
CD4+ 50-500 cells/mm3,
HIV-1 RNA > 1000 c/mL
(N = 636)
NC = F
EFV* 400 mg + Placebo +
TDF/FTC 300/200 mg
(n = 324)
EFV* 600 mg +
TDF/FTC 300/200 mg
(n = 312)
90.0
85.8
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)
Puls R, et al. IAS 2013. Abstract WELBB01.
*EFV administered as 200-mg tablets.
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EARNEST: Second-line LPV/RTV-Based
ART After Initial NNRTI Failure
Randomized, controlled, open-label, phase III trial
Wk 12
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)
Wk 144
LPV/RTV + 2-3 NRTIs†
(n = 426)
LPV/RTV + RAL
(n = 433)
LPV/RTV + RAL
(n = 418)
LPV/RTV monotherapy
(n = 418)
Baseline demographics (medians): HIV-1 RNA 69,782 copies/mL;
CD4+ 71 cells/mm3; time on ART 4 yrs
*Including clinical, CD4+ cell count (HIV-1 RNA confirmed), or virologic criteria.
†
Selected by physician according to local standard of care.
Paton N, et al. IAS 2013. Abstract WELBB02.
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EARNEST: Clinical Outcomes at Wk 96
100
86 86
Patients, %
60
60
64
PI/NRTI
PI/RAL
PI Mono
74 73
80
61
56
44
40
20
0
Good Disease
Control
HIV-1 RNA
< 400 copies/mL
HIV-1 RNA
< 50 copies/mL
“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.
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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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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.
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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
Efficacy, % (SD)
Coefficient (95% CI)
P Value
TDF/FTC
73 (10)
Ref
ABC/3TC
63 (7)
-7.6 (-12.7 to -2.6)
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
NRTI backbone
.003
Third drug class
Adjusted for multivariable analysis including year of commencement, other drugs received, baseline
patient characteristics, and duration of follow-up.
Lee FJ, et al. IAS 2013. Abstract WEAB0104.
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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
Stratified by HIV-1 RNA
≤ 100,000 or > 100,000 copies/mL
ART-naive pts,
HIV-1 RNA ≥ 5000
copies/mL,
no CD4+ restrictions,
eGFR ≥ 70 mL/min
(N = 700)
HIV-1 DNA < 50 copies/mL
at Wk 96
Wk 96
≥ 95%
< 95%
Adherence
Adherence
EVG/COBI/TDF/FTC QD +
EFV/TDF/FTC placebo
(n = 348)
88
74
EFV/TDF/FTC QHS +
EVG/COBI/TDF/FTC placebo
(n = 352)
89
63
≥ 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)
Shalit P, et al. IAS 2013. Abstract TUPE293.
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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.
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Bangkok TDF Study: Adherence to PrEP
and Risk of HIV Acquisition
100
84
80
Efficacy (%)
68
60
49
54
72
58
40
20
0
mITT
> 67
> 75
> 90
> 95
Adherence (%)
Choopanya K, et al. IAS 2013. Abstract WELBC05. Graphic used with permission.
> 97.5
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SAILING: Dolutegravir vs Raltegravir in
ART-Exp’d, Integrase Inhibitor–Naive Pts
Phase III randomized, double-blind, double-dummy,
noninferiority study
Stratified by number of fully active
background agents, use of DRV,
screening HIV-1 RNA ≤ vs
> 50,000 copies/mL
Treatment-experienced,
integrase inhibitor–naive
patients with HIV-1 RNA
> 400 copies/mL and
≥ 2 class resistance
(N = 715)
Wk 48
Dolutegravir 50 mg QD
+ Raltegravir placebo + OBR
(n = 354)
Raltegravir 400 mg BID
+ Dolutegravir placebo + OBR
(n = 361)
Cahn P, et al. IAS 2013. Abstract WELBB03. Cahn P, et al. Lancet. 2013;382:700-708.
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SAILING: Superior Rate of Virologic
Suppression With DTG vs RAL at Wk 48
Lower incidence of resistance
at VF with DTG vs RAL
100
Δ 7.4 (95% CI: 0.7-14.2;
Subjects (%)
80
– Integrase resistance: 1% vs 5%
P = .03)
71
64
DTG + OBR
RAL + OBR
60
40
– OBR resistance: 1% vs 3%
Both regimens well tolerated
with similar AE profiles
– Grade 2-4: 8% vs 9%
28
20
20
– Discontinuations: 3% vs 4%
9 9
0
Virologic Virologic
No Wk
Success Nonresponse 48 Data
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.
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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.
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Coadministration of Long-Acting
GSK1265744 and TMC278
Randomized, open-label, repeated-dose phase I trial in healthy adults
Oral Lead-in*
Day 1
Wk 4
Wk 8
Wk 12
Wk 16
Wk 20
Wk 24
Monthly
Cohort 1
(n = 10)
GSK744
800 mg IM
(LD†)
GSK744
200 mg
SC
GSK744
200 mg SC
GSK744
200 mg
SC
Cohort 2
(n = 10)
GSK744
800 mg IM
(LD†)
GSK744
200 mg
IM
GSK744
200 mg IM
GSK744
200 mg IM
TMC278 (LD†)
1200 mg IM
TMC278
900 mg IM
GSK744
800 mg IM
(LD†)
GSK744
400 mg
IM
GSK744
400 mg IM
GSK744
400 mg IM
TMC278 (LD†)
1200 mg IM
TMC278
600 mg IM
Cohort 3
(n = 10)
Quarterly
Cohort 4
(n = 10)
GSK744
800 mg IM
(LD†)
*GSK744 30 mg/day for 14 days, then 7-day washout.
†
Loading dose given as split injection dose (2 x 2 mL).
Spreen W, et al. IAS 2013. Abstract WEAB0103.
GSK744
800 mg IM
(LD†)
All cohorts
followed
for 52 wks
after last
injection
(ongoing)
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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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SECOND-LINE Subanalysis: BMD Loss
With LPV/RTV + NRTIs vs LPV/RTV + RAL
Subanalysis of randomized, open-label, multicenter,
international trial
DXA scan
at Wk 0
HIV-infected patients
with virologic failure
on first-line regimen
of NNRTI + 2 NRTIs
(N = 211 consented to
BMD substudy)
Hoy J, et al. IAS 2013. Abstract WELBB05.
DXA scan
at Wk 48
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)
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Mean % Change (SE) in BMD
From Baseline to Wk 48
SECOND-LINE: Greater Mean BMD Loss
With NRTI-Based Regimen at Wk 48
0
Proximal Femur
Lumbar Spine
-1
-2
-3
-2
-2.9
LPV/RTV + 2-3 NRTIs
LPV/RTV + RAL
-4
-5
-6
-5.2
P = .0001
-4.2
P = .0006
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.
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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
5.0
Age-Specific Hip Fracture Incidences
per 1000 Person-Yrs
HIV Infected
HIV Uninfected
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
45 50
55 60
65 70 75
80
0- 45- 50- 55- 60- 65- 70- 754
Knobel H, et al. IAS 2013. Abstract WEAB0205.
Güerri-Fernandez R, et al. J Bone Miner Res. 2013;28:1259-1263.
Age (yrs)
28. HIV/AIDS Update From IAS 2013
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NVP Cutaneous Reactions Reduced by
HLA-B*35:05 and CCHCR1 Screening
CCHCR1 and HLA-B*35:05
associated with rash[1,2]
Lower incidence of cutaneous
AEs in screened group
– 13.2% vs 18.0%
– 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. Table used with
permission.
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High HCV Reinfection Rate Among
HIV-Infected MSM
– Cleared prior HCV
infection spontaneously
or after HCV treatment
Reinfection rates similar in
pts with prior spontaneous
clearance vs SVR
50
HCV Reinfection Incidence per 100 Person-Yrs
Single-site, retrospective
study (2004-2012) of HIVinfected MSM at London
clinic
45
40
35
30
25
P = .15
20
15
10
5
7.8
0
Overall
Reinfection
Rate
Martin T, et al. IAS 2013. Abstract TUAB0101.
9.6
4.2
23.2
Second
Reinfection Reinfection
Reinfection Rate
Posttreatment
After
Spontaneous Following SVR
or Clearance
Clearance
of First
Reinfection
30. 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
Notas do Editor
This slide lists the faculty who were involved in the production of these slides.
Please review the slide notes for a complete discussion of each study by expert faculty Andrew Carr, MBBS, MD, FRACP; Joel E. Gallant, MD, MPH; and Anton L. Pozniak, MD, FRCP.
3TC, lamivudine; ART, antiretroviral therapy; d4T, stavudine; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir; WHO, World Health Organization.
Anton Pozniak, MD, FRCP:
This slide presents a summary of significant updates found in the 2013 World Health Organization (WHO) treatment guidelines. An important change is that treatment initiation is now recommended for patients with CD4+ cell counts ≤ 500 cell/mm3, an increase from the previous threshold of 350 cells/mm3. This change represents a reprioritization that has significant implications for antiretroviral therapy (ART) utilization in resource-limited settings.
The new guidelines further emphasize that HIV-1 RNA testing is the preferred method for monitoring patients receiving ART, and the single-tablet regimen of efavirenz/tenofovir DF/emtricitabine or lamivudine is the preferred initial regimen.
Finally, WHO has strengthened its position on the nonuse of stavudine and now recommends that it be completely phased out from clinical use due to associated toxicities. This represents a change from previous recommendations that stavudine should be avoided if at all possible but allowed for its continued use in patients already on a stavudine-based regimen. Now, the enhanced recommendation is to discontinue the use of stavudine altogether and switch to a fixed-dose combination if at all possible.
Reference
World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. June 2013. Available at: http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf. Accessed September 10, 2013.
AE, adverse events; ART, antiretroviral therapy; ARVs, antiretrovirals; EFV, efavirenz; FTC, emtricitabine; ITT, intent to treat; NC = F, noncompleters equals failure analysis; PP, per-protocol analysis; SAE, serious adverse event; TDF, tenofovir.
For detailed information on this study, go to:
http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB01.aspx
Joel E. Gallant, MD, MPH:
ENCORE1 was a randomized, placebo-controlled, noninferiority phase III trial comparing a lower dose of efavirenz (400 mg) vs the standard efavirenz dose (600 mg), each combined with tenofovir/emtricitabine. The study found that the lower dose of efavirenz was noninferior to the higher dose at Week 48.
Andrew Carr, MBBS, MD, FRACP:
Equally importantly, although there was no difference in overall rates of toxicity, there were significantly fewer study drug-related adverse events with the 400-mg dose as well as fewer discontinuations.
Anton L. Pozniak, MD, FRCP:
ENCORE1 may be a game-changing study for the developing world, and perhaps even for the developed world, if the low-dose efavirenz is adopted because of the cost difference between the 2 efavirenz doses. This would be especially true if a generic version of the 400-mg tablet were to become available. Large national health services such as the United Kingdom’s would certainly use the lower dose if it came with a lower cost, especially if patients receiving the lower dose also experience fewer adverse events. The reduction in cost to individual patients may or may not be significant, but when the reduced price is spread across a national program, the savings could have an enormous impact.
ART, antiretroviral therapy; LPV, lopinavir; RAL, raltegravir; RTV, ritonavir; WHO, World Health Organization.
For detailed information on this study, go to:
http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB02.aspx
Joel E. Gallant, MD, MPH:
The EARNEST trial was a large randomized open-label trial that compared strategies for second-line therapy after failure of an initial NNRTI-based regimen in resource-limited settings. The study included 3 arms comparing the standard of care consisting of lopinavir/ritonavir plus NRTIs vs lopinavir/ritonavir plus raltegravir vs lopinavir/ritonavir monotherapy after an initial 12-week period with lopinavir/ritonavir and raltegravir. At baseline, the study populations were well matched for CD4+ cell count, HIV-1 RNA level, and the amount of time on ART.
RAL, raltegravir; WHO, World Health Organization.
For detailed information on this study, go to:
http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB02.aspx
Joel E. Gallant, MD, MPH:
As shown in the graph, there was no significant difference between the PI plus NRTIs arm and the PI plus raltegravir arm at Week 96. However, the lopinavir/ritonavir monotherapy arm was associated with significantly poorer virologic outcomes.
AE, adverse event; LPV, lopinavir; RAL, raltegravir; RTV, ritonavir.
For detailed information on this study, go to:
http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB02.aspx
Joel E. Gallant, MD, MPH:
The lopinavir/ritonavir monotherapy arm was discontinued due to inferior virologic suppression. Although there was no significant difference in the 96-week resistance rates of the other treatment arms, patients in the monotherapy arm experienced a higher frequency of lopinavir resistance, which is not consistent with data from other trials.[1-4] Regimens were generally well tolerated with similar rates of grade 3/4 adverse events.
This study has important implications for resource-limited setting, where second-line regimens are chosen empirically, without resistance testing, after failure of first-line NNRTI-based regimens. The findings are consistent with those of the previously presented SECOND-LINE study,[5-6] supporting the current practice of combining a ritonavir-boosted PI with 2 NRTIs. The poorer outcome with boosted PI monotherapy is somewhat surprising, since participants in this trial had no previous PI experience and were fully suppressed before the switch to monotherapy.
Anton Pozniak, MD, FRCP:
I do not think we know if they were fully suppressed at Week 12; we do not know if those who had an HIV-1 RNA done at Week 12 and were < 50 copies/mL remained undetectable. There may have been a group still detectable at Week 12 switched to PI monotherapy who then failed. This study challenges the need for HIV-1 RNA or resistance testing in first-line failures in resource-limited settings and supports the current WHO strategy for second-line therapy.
References
Bartlett JA, Ribaudo HJ, Wallis CL, et al. Lopinavir/ritonavir monotherapy after virologic failure of first-line antiretroviral therapy in resource-limited settings. AIDS. 2012;26:1345-1354.
Arribas JR, Delgado R, Arranz A, et al. Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and 2 nucleosides for maintenance therapy of HIV: 96-week analysis. J Acquir Immune Defic Syndr. 2009;51:147-152.
Cameron DW, da Silva BA, Arribas JR, et al. A 96-week comparison of lopinavir-ritonavir combination therapy followed by lopinavir-ritonavir monotherapy versus efavirenz combination therapy. J Infect Dis. 2008;198:234-240.
Arribas JR, Pulido F, Delgado R, et al. Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study). J Acquir Immune Defic Syndr. 2005;40:280-287.
Hoy J, Martin A, Moore C, et al. Changes in bone mineral density over 48 weeks among participants randomised to either lopinavir/ritonavir (LPV/r) + 2-3N(t)RTI or LPV/r + raltegravir as second-line therapy: a sub-study of the SECONDLINE trial. Program and abstracts of the 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30 - July 3, 2013; Kuala Lumpur, Malaysia. Abstract WELBB05.
Humphries A, Boyd M; SECOND-LINE Study Team. SECOND-LINE: ritonavir-boosted lopinavir with 2-3N(t)RTI or raltegravir in HIV+ subjects virologically failing 1st-line NNRTI/2N(t)RTI. Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Atlanta, Georgia. Abstract 180LB.
ART, antiretroviral therapy.
For detailed information on this study, go to:
http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WEAB0104.aspx
Andrew Carr, MBBS, MD, FRACP:
This slide summarizes a systematic review and meta-analysis of trials of combination ARTs initiated from 1994-2010. The study population consisted of 216 treatment groups that included more than 40,000 patients. The study’s primary outcome measure was efficacy defined as an undetectable HIV-1 RNA, which in almost all cases was defined as HIV-1 RNA < 50 copies/mL, without change to assigned therapy.
Overall, the mean efficacy was 60% with a mean follow-up of 82 weeks. The longest treatment duration assessed was 144 weeks because very few studies had longer follow-up. Overall, the rate of treatment discontinuation was 25%, with the most common reasons reported as loss to follow-up and adverse events, which were much more common than virologic failure. Finally, a trend indicated a substantial increase in treatment efficacy over time.
ABC/3TC, abacavir/lamivudine; ART, antiretroviral therapy; DHHS, US Department of Health and Human Services; FTC, emtricitabine; INSTI, integrase strand transfer inhibitor; Ref, reference; SD, standard deviation; TDF, tenofovir.
For detailed information on this study, go to:
http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WEAB0104.aspx
Andrew Carr, MBBS, MD, FRACP:
This study was undertaken to assess the improvement in treatments for HIV and to determine the magnitude of those improvements. It should be noted that the data are only based on 18 months of treatment, on average. Preferred regimens performed better than alternative regimens, and initiation of treatment at HIV-1 RNA levels < 100,000 copies/mL was associated with better outcomes.
The number of pills did not independently predict efficacy; there was a strong association, but after adjusting for the type of drug, it was no longer a predictor of efficacy. This suggests that the most important factor is probably not the number of pills taken but improvements in the drugs themselves. In addition, specific NRTI backbones and third drugs were associated with differing outcomes, as summarized in the table.
The data suggest that guidelines should consider recommending initiation of ART if the HIV-1 RNA is increasing toward 100,000 copies/mL.
Joel E. Gallant, MD, MPH:
In addition, these data support current US treatment guidelines and demonstrate the steady improvement in effectiveness of antiretroviral regimens over time.
COBI, cobicistat; EFV, efavirenz; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; QD, once daily; QHS, at bedtime; TDF, tenofovir.
Joel E. Gallant, MD, MPH:
Data from the phase III trial comparing the single-tablet regimen of elvitegravir/cobicistat/tenofovir DF/emtricitabine vs the single-tablet regimen efavirenz/tenofovir DF/emtricitabine have previously been published. In this preplanned Week 96 analysis, the investigators evaluated outcomes in patients with suboptimal adherence, defined as < 95%.
The results suggested that with adherence of < 95%, elvitegravir/cobicistat/tenofovir DF/emtricitabine was associated with better HIV-1 RNA suppression and greater CD4+ cell count improvement. However, this study is limited by the fact that < 95% adherence encompasses everything from 0% (or complete nonadherence) to 94% (which is still a very high level of adherence). Hypothetically, it is possible that patterns of nonadherence with efavirenz/tenofovir DF/emtricitabine could be different from patterns of nonadherence with elvitegravir/cobicistat/tenofovir DF/emtricitabine, perhaps because of the adverse events associated with efavirenz.
Andrew Carr, MBBS, MD, FRACP:
The investigators did also report that very few patients in each arm were < 80% adherent. Overall, one can estimate that the large majority of patients with < 95% adherence still managed to achieve at least 90% adherence. Nevertheless, that relatively small degree of nonadherence was associated with a 15% to 25% reduction in virologic response rates. These data underscore that patients really do need to take their pill every single day to secure good outcomes.
Reference
Choopanya K, Martin M, Suntharasamai P, et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013;381:2083-2090.
DOT, directly observed therapy; IDU, injecting drug users; PrEP, pre-exposure prophylaxis; PY, person-years; TDF, tenofovir.
Anton Pozniak, MD, FRCP:
The Bangkok study was a randomized, placebo-controlled trial of tenofovir as pre-exposure prophylaxis (PrEP) conducted among injection drug users in Thailand. Participants received tenofovir or placebo daily as directly observed therapy at drug treatment clinics during a 5-year study period from 2005-2010. The results reinforce the findings of other studies with PrEP; namely, it is effective when patients are adherent to the regimen. In this study, the overall efficacy was 50%, and tenofovir levels were detectable in 74% of patients at study end. The safety and tolerability were also similar to other PrEP trials with tenofovir.
One curious aspect of the study data is that the reduction in the rate of HIV acquisition was not observed during the first 3 years of follow-up; the rates diverged only in Years 4 and 5. One hypothetical explanation is that during the first 3 years, the risk-reduction education provided to all participants was effective in achieving a low rate of infection in both study arms, but that its effectiveness waned over time, resulting in more infections in those not receiving PrEP.
Andrew Carr, MBBS, MD, FRACP:
Another contentious issue about this study was the lack of needle exchange. In the studies of PrEP to prevent sexual HIV transmission, participants were given condoms, but by contrast, in this study, participants did not receive safe injecting gear and clean needles. As a consequence, it is not clear whether these results are applicable to settings where harm-reduction measures, such as needle exchange programs, are available.
mITT, modified intent to treat; PrEP, pre-exposure prophylaxis; TDF, tenofovir.
Anton Pozniak, MD, FRCP:
The investigators also showed that increasing level of adherence to PrEP with tenofovir was associated with increasingly likelihood of remaining uninfected. To receive the maximum benefit from PrEP with tenofovir, which was an 84.0% reduction in risk, a patient needed to take as much as 97.5% of their scheduled doses. By contrast, taking only two thirds of the scheduled doses reduced the efficacy of PrEP in preventing HIV transmission to only 54%.
ART, antiretroviral therapy; BID, twice daily; DRV, darunavir; OBR, optimized background regimen; QD, once daily.
For detailed information on this study, go to:
http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB03.aspx
Andrew Carr, MBBS, MD, FRACP:
SAILING was a 48-week, double-blind, noninferiority phase III trial comparing the second-generation integrase inhibitor dolutegravir vs raltegravir, each combined with an optimized background regimen (OBR), in treatment-experienced but integrase inhibitor–naive patients with virologic failure and resistance to at least 2 drug classes. Patients were stratified by number of background drugs, darunavir/ritonavir use, and baseline HIV-1 RNA. In this instance, the stratification threshold was 50,000 copies/mL rather than the 100,000 copies/mL generally seen in trials of treatment-naive patients. Interim Week-24 results were previously presented at the 2013 Conference on Retroviruses and Opportunistic Infections.[1]
Reference
1. Pozniak A, Mingrone H, Shuldyakov A, et al. Dolutegravir (DTG) versus raltegravir (RAL) in ART-experienced, integrase-naive subjects: 24-week interim results from SAILING (ING111762). Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Atlanta, Georgia. Abstract 179LB.
AE, adverse event; DRV, darunavir; DTG, dolutegravir; OBR, optimized background regimen; RAL, raltegravir; RTV, ritonavir; VF, virologic failure.
For detailed information on this study, go to:
http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB03.aspx
Andrew Carr, MBBS, MD, FRACP:
The primary endpoint analysis demonstrated that dolutegravir was noninferior to raltegravir, with a numerically superior rate of virological success at Week 24, which was maintained out to Week 48. The differences between the 2 arms were due to a higher rate of virologic nonresponse with raltegravir, rather than differences in tolerability or in missing data.
Anton Pozniak, MD, FRCP:
Of note, SAILING is the first study in which treatment-emergent integrase resistance mutations have been observed at virologic failure with dolutegravir. Two patients who were integrase inhibitor–naive at study entry developed the R263K.
In a planned subanalysis, there was no difference in outcomes between the raltegravir or dolutegravir arms in patients who were fully susceptible to darunavir and received darunavir/ritonavir as part of their OBR. At the other end of the spectrum, there was also no difference between the arms among patients whose OBR did not contain any other fully active agent to combine with the integrase inhibitor.
Joel E. Gallant, MD, MPH:
The reason for the superiority of dolutegravir is not clear, but the results suggest that its barrier to resistance may be higher than that of raltegravir. Patients with full darunavir susceptibility would be expected to respond equally well to a combination of darunavir/ritonavir and any integrase inhibitor, whereas those with partial resistance to darunavir might benefit from combining it with an integrase inhibitor with a higher barrier to resistance.
ART, antiretroviral therapy; DTG, dolutegravir; PrEP, pre-exposure prophylaxis; RPV, rilpivirine.
For detailed information on this study, go to:
http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WEAB0103.aspx
Joel E. Gallant, MD, MPH:
A study by Spreen and colleagues evaluated the use of nanosuspensions of long-acting GSK1265744 and TMC278. Nanosuspension formulations are drug nanocrystals suspended in liquid providing a higher dissolution rate and allowing for a lower injection volume. These formulations have potential uses as long-acting injections both for ART regimens and PrEP. GSK1265744 is a dolutegravir analogue that would allow monthly or even quarterly dosing. TMC278-LA is a nanosuspension of rilpivirine that is dosed monthly.
IM, intramuscular; LD, loading dose; SC, subcutaneous.
For detailed information on this study, go to:
http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WEAB0103.aspx
Joel E. Gallant, MD, MPH:
In this study, the authors evaluated the coadministration of GSK1265744 and TMC278. It was a randomized, open-label, phase I study in 40 healthy adults divided equally between 4 treatment cohorts. Cohorts 1-3 were scheduled to receive GSK744 dosing on a monthly basis, and Cohort 4 received GSK1265744 quarterly. Each cohort received a loading dose of GSK1265744 800 mg intramuscularly (IM) after an oral lead in period that consisted of GSK1265744 30 mg/day for 14 days followed by a 7-day washout period. Cohorts 1 and 2 then received a dose of GSK1265744 200 mg either subcutaneously (Cohort 1) or IM (Cohort 2). Cohort 3 was dosed with GSK1265744 400 mg IM. Each cohort then received a second dose at Week 8 with Cohorts 2 and 3 adding a 1200-mg loading dose of TMC278 IM to their regimen. Cohort 1 received a fourth and final dose of GSK1265744 200 mg subcutaneously at Week 12. Also in Week 12, Cohorts 2 and 3 received second doses of its Week 8 regimen, except with the TMC278 dose reduced in both cohorts (Cohort 2 = 900 mg; Cohort 3 = 600 mg). Also in Week 12, Cohort 4 received its second and final dose of GSK1265744 800 mg IM. Follow-up is ongoing and is scheduled to continue for 52 weeks after the last injection.
ART, antiretroviral therapy; IC90, inhibitory concentration 90%; PK, pharmacokinetics; RPV, rilpivirine.
For detailed information on this study, go to:
http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WEAB0103.aspx
Joel E. Gallant, MD, MPH:
Plasma levels for GSK1265744 were substantially greater than the protein-adjusted IC90 dosing with either monthly or quarterly dosing. Plasma levels of TMC278 administered every 4 weeks were comparable to those seen with oral rilpivirine dosed at 25 mg/day. GSK1265744 was safe and well tolerated both alone and in combination with TMC278. This study certainly supports moving to phase 2 studies of the combination regimen.
BID, twice daily; BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry; LPV, lopinavir; QD, once daily; RAL, raltegravir; RTV, ritonavir.
For detailed information on this study, go to:
http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB05.aspx
Andrew Carr, MBBS, MD, FRACP:
SECOND-LINE was a randomized noninferiority study, similar to the EARNEST study, evaluating lopinavir/ritonavir combined with either raltegravir or NRTIs in patients who had failed a first‑line regimen comprising an NNRTI plus NRTIs. The efficacy results were presented at the 2013 Conference on Retroviruses and Opportunistic Infections and demonstrated that the raltegravir-containing regimen was noninferior to the NRTI-containing regimen,[1] validating the current strategy of using second-line regimens comprising a boosted PI plus NRTIs.
At IAS 2013, the investigators presented a subanalysis examining the rates of bone mineral density loss in the 211 consenting patients from the SECOND-LINE study. Almost all patients were from low- or intermediate-resource countries.
Reference
1. Humphries A, Boyd M; SECOND-LINE Study Team. SECOND-LINE: ritonavir-boosted lopinavir with 2-3N(t)RTI or raltegravir in HIV+ subjects virologically failing 1st-line NNRTI/2N(t)RTI. Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Atlanta, Georgia. Abstract 180LB.
BMD, bone mineral density; BMI, body mass index; LPV, lopinavir. TDF, tenofovir.
For detailed information on this study, go to:
http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB05.aspx
Andrew Carr, MBBS, MD, FRACP:
As the graph shows, there was a greater loss of bone mineral density (BMD) at the hip and at the lumbar spine in patients who received NRTIs with lopinavir/ritonavir, compared with those receiving raltegravir with lopinavir/ritonavir. In my estimation, the magnitude of loss is similar to that observed in treatment-naive patients starting first-line ART. There was no significant difference in the frequency of new osteopenia or osteoporosis, but the study was not powered to make a final determination. Lower body mass index, not being exposed to tenofovir prior to study enrollment, and initiating tenofovir while on-study were significant predictors of greater BMD loss at the lumbar spine.
Joel E. Gallant, MD, MPH:
These findings are somewhat surprising in that you might not expect that patients who continued using NRTIs and simply switched their third drug from an NNRTI to a boosted PI would have further loss in bone density. In treatment-naive patients, BMD typically declines when any first-line ART is initiated but then stabilizes and plateaus after a few months. However, in this study, most patients who switched to lopinavir/ritonavir plus NRTIs were switching from either a zidovudine‑ or stavudine‑based regimen to a regimen containing tenofovir, which is known to cause a greater decline in BMD than other NRTIs. This may explain the greater loss of bone density in patients switching to lopinavir/ritonavir plus NRTIs.
BMI, body mass index.
For detailed information on this study, go to:
http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WEAB0205.aspx
Anton Pozniak, MD, FRCP:
This population-based cohort study compared the incidence of major osteoporotic and hip fractures in the HIV‑infected population with a general population cohort of > 1.1 million persons in Catalonia, Spain. The HIV-infected population represented approximately 0.2% of the general population but accounted for a substantial number of the hip fractures reported during the study period from 2007-2009. This difference was independent of baseline factors such as age, sex, body mass index, smoking, and ethanol use. Unfortunately, the authors did not indicate if the fractures were traumatic or spontaneous. As the graph indicates, the incidence of age-specific hip fractures increased with increasing age and is particularly concerning among HIV-infected patients older than 65 years of age.
Andrew Carr, MBBS, MD, FRACP:
The age-specific rates for hip fracture are very intriguing. The rate of hip fracture in HIV-infected adults younger than 50 years of age appears similar to the rate in 65- to 70-year-old HIV-uninfected adults. This suggests that we may need to be more aggressive in managing low BMD in younger HIV-infected adults than in HIV-uninfected adults of the same age and not just confine intervention to older men and postmenopausal women, as is more typical in the general population.
Anton Pozniak, MD, FRCP:
Overall, the promotion of bone health should be encouraged, and studies are needed to look at the utility of screening HIV patients for osteopenia earlier than would be recommended for the general population.
Reference
Güerri-Fernandez R, Vestergaard P, Carbonell C, et al. HIV infection is strongly associated with hip fracture risk, independently of age, gender, and comorbidities: a population-based cohort study. J Bone Miner Res. 2013;28:1259-1263.
AE, adverse event; EFV, efavirenz; NVP, nevirapine.
Joel E. Gallant, MD, MPH:
HLA-B*35:05 and CCHCR1 have been associated with the development of rash during nevirapine-based therapy—a relationship similar to that of HLA‑B*5701 with abacavir hypersensitivity. Both alleles have been associated with rash, although it is worth noting that HLA-B*35:05 is relatively uncommon outside of southeast Asia and South America. In this large (N = 1103), prospective, randomized, multicenter trial, patients were separated into cohorts who either were screened prior to beginning nevirapine-based therapy or were not screened. This is reminiscent of the design of the abacavir hypersensitivity study. All patients began nevirapine‑based therapy except those who screened positive, who instead started efavirenz. There was a lower incidence of rash in those patients who were screened for the HLA-B*35:05 and CCHCR1 variants than those who were not screened (13.2% vs 18.0%, respectively).
Of note, a higher CD4+ cell count was associated with a higher rate of rash. Yet, among those patients at highest risk for developing rash—those with CD4+ cell counts > 250 cells/mm3—there was no predictive value associated with testing. In fact, screening was only found to be protective in women and patients with low CD4+ cell counts. Nevirapine use is now discouraged in patients with higher CD4+ cell counts, and these results suggest that screening will not change that recommendation. In addition, screening for nevirapine hypersensitivity may not be as broadly applicable as HLA-B*5701 screening for abacavir hypersensitivity because of racial differences in the prevalence of these alleles.
HCV, hepatitis C virus; MSM, men who have sex with men; SVR, sustained virologic response.
For detailed information on this study, go to:
http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/TUAB0101.aspx
Anton Pozniak, MD, FRCP:
In this single-site study from my center in London, United Kingdom, my colleagues retrospectively evaluated HIV-infected men who have sex with men who either spontaneously cleared an acute hepatitis C virus (HCV) infection or who were successfully treated for chronic HCV infection during an 8-year period from 2004-2012. Nearly 8% of these patients were reinfected with HCV annually. Furthermore, 23.2% of these reinfected patients who again cleared their HCV infection either spontaneously or with treatment were infected with HCV for a third time (ie, a second reinfection).
Some of the reinfections were with an HCV genotype different from the initial infection, indicating a different source for the reinfection. Of note, there was no significant difference in the reinfection rate when comparing individuals who spontaneously cleared their previous infection vs those who were cured following treatment, so these data do not provide evidence that the immune response associated with spontaneous clearance protects against subsequent reinfection.