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May 2012
Top Ten News for Clinicians.
CROI 2012
Bonaventura ClotetHospital Universitari Germans Trias i Pujol
Fundació irsicaixaBarcelona, Catalonia, Spain
Top Ten CROI 2012. Agenda.
1. QUAD non inferior to Atripla (Study: 236-0102). New STR for naives.
2. QUAD non inferior to ATV/r + TDF/FTC in naïves (Study 236-0103) .
3. Evolution of the K65R, K103N and M184V/I RT mutations prevalence.
4. Telaprevir/PR, confirmed efficacy in HCV infected patients.
5. Boceprevir/PR, confirmed efficacy in HCV infected patients.
6. GS7977 (NRTI) and MK5172. The upcomming anti-HCV therapy without pegIFN.
7. TDF/FTC PrEP for heterosexual men and women
8. PI monotherapy
9. Dolutegravir. 96 wks results.
10. Vorinostat, first time HIV-1 reservoir can be activated in vivo.
Top Ten CROI 2012. Agenda.
1. QUAD non inferior to Atripla (Study: 236-0102). New STR for naives.
2. QUAD non inferior to ATV/r + TDF/FTC in naïves (Study 236-0103) .
3. Evolution of the K65R, K103N and M184V/I RT mutations prevalence.
4. Telaprevir/PR, confirmed efficacy in HCV infected patients.
5. Boceprevir/PR, confirmed efficacy in HCV infected patients.
6. GS7977 (NRTI) and MK5172. The upcomming anti-HCV therapy without pegIFN.
7. TDF/FTC PrEP for heterosexual men and women
8. PI monotherapy
9. Dolutegravir. 96 wks results.
10. Vorinostat, first time HIV-1 reservoir can be activated in vivo.
The Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF (“Quad”)
Compared to Efavirenz/Emtricitabine/Tenofovir DF in Treatment Naïve HIV-1 Infected Subjects:
Primary Results of Study GS-US-236-0102
Paul Sax1, Edwin DeJesus2, Anthony Mills3, Andrew Zolopa4, Calvin Cohen5, David Wohl6, Joel Gallant7, Hui C Liu8, Kirsten White8, Erin Quirk8, and Brian
Kearney8
1Brigham and Women's Hospital, Harvard Medical School, Boston, MA, US; 2Orlando Immunology Center, Orlando, FL, US; 3Anthony Mills MD, Inc., Los Angeles, US; 4Stanford University, Palo Alto, CA, US; 5Community Research Initiative of New England, Boston, MA, US; 6University of North Carolina, Chapel Hill, NC, US; 7Johns Hopkins School of Medicine, Baltimore, MD, US; 8Gilead Sciences, Foster City, CA, US
19th Conference on Retroviruses and Opportunistic InfectionsMarch 7, 2012 Paper #: 101
Study Design: 236-0102
Treatment- naive (N = 700 planned)
Quad QDEFV/FTC/TDF QHS
Placebo
EFV/FTC/TDF QHS
Quad Placebo QD• Randomized 1:1• Stratification by HIV-1 RNA (>100,000 c/mL)
n=350
n=350
Primary Endpoint: Proportion with HIV-1 RNA < 50 copies/mL at Week 48 – FDA snapshot analysis, 12% noninferiority margin– HIV-1 RNA: Amplicor HIV-1 Monitor Test, version 1.5
Week 48 Week 192
Conducted in parallel with Study 236-0103 comparing Quad to FTC/TDF + ATV/r (DeJesus et al, Poster #627)
Primary Endpoint: HIV-1 RNA < 50 copies/mLStudy 236-0102
Quad was non-inferior to EFV/FTC/TDF at Week 48
95% CI for Difference
12%
-1. 6 8.8
FavorsEFV/FTC/TDF
3.6
FavorsQuad
0 -12%
88%
7% 5%7% 9%
84%
0%10%20%30%40%50%60%70%80%90%
100%
VirologicSuccess
Virologic Non-Suppression
No W48 Data
Quad EFV/FTC/TDF
Mean BL CD4: 391 and 382 cells.
Efficacy in Baseline HIV-RNA and CD4 SubgroupsStudy 236-0102
90%84% 83%
91%85% 82% 84% 84%
≤100,000 >100,000 CD4 ≤350 CD4 >350
Quad EFV/FTC/TDF
Viro
logi
c Su
cces
s (<
50 c
/mL)
Mean CD4 increase: 239 vs 206 (p=0.009)
Integrase & NNRTI Resistance Through Week 48Study 236-0102
Quad(n=348)
EFV/FTC/TDF(n=352)
Subjects Analyzed for Resistance*, n (%) 14 (4) 17 (5)
Subjects with Resistance to ARV Regimen, n (%) 8 (2) 8 (2)
Any Primary Integrase-R, n 7
E92Q 7
T66I 1
Q148R 1
N155H 1
Any Primary NNRTI-R n 8
K103N 7
V108I 2
Y188Y/F/H/L 1
G190A 1
Any Primary NRTI-R, n 8 2
M184V/I 8 2
K65R 3 2
*Subjects who experienced either suboptimal virologic response (two consecutive visits with HIV-1 RNA ≥50 c/mL and <1 log10below baseline after Week 8), virologic rebound (two consecutive visits with HIV-1 RNA either ≥400 c/mL after achieving HIV-1 RNA <50, or >1 log10 increase from nadir), or had HIV-1 RNA ≥400 c/mL at their last visit.
Quad(n=348)
EFV/FTC/TDF(n=352)
Treatment Emergent Adverse Events in ≥ 10% of subjects (%)Diarrhea 23% 19%Nausea * 21% 14%Abnormal Dreams ^ 15% 27%Upper Respiratory Infection 14% 11%Headache 14% 9%Fatigue 12% 13%Insomnia * 9% 14%Depression 9% 11%Dizziness ^ 7% 24%Rash # 6% 12%
Adverse Events Leading to Study Drug Discontinuation in > 1 subject (n)Depression 1 3Abnormal Dreams 0 2Blood Creatinine Increased 2 0Fatigue 1 1Paranoia 1 1Rash 0 2Renal Failure 2 0
Common Adverse Events and Discontinuations due to Adverse EventStudy 236-0102
* p < 0.05^ p < 0.001# p=0.009
Median Change from Baseline in Serum Creatinine
Median change at Week 48: 0.14 mg/dL vs. 0.01 mg/dL (Quad vs. EFV/FTC/TDF group, p<0.001)
Quad (n=): 348 341 345 345 337 335 328 323 320 320EFV/FTC/TDF (n=): 352 340 340 336 327 323 317 313 309 307
BL 2 4 8 12 16 24 32 40 48
0.28
0.24
0.20
0.16
0.12
0.08
0.04
0.0
-0.04
-0.08Cha
nge
from
BL
in S
erum
Cre
atin
ine
(mg/
dL)
(IQR
)
Week
Model for Inhibition of the Active Tubular Secretion of Creatinine
Proximal Tubule
Blood(Basolateral)
Urine(Apical)Active Tubular Secretion
Creatinine
Pgp
MATE2-K
OCTN1
OCTN2
ATP
H+MATE1
BCRPATP
MRP2ATP
ATP-BindingCassette
Solute CarrierDolutegravir Cobicistat RitonavirCimetidineTrimethoprim
Lepist et al. 51st ICAAC, Sep 17-20, 2011, Chicago, IL.
OCT2
Top Ten CROI 2012. Agenda.
1. QUAD non inferior to Atripla (Study: 236-0102). New STR for naives.
2. QUAD non inferior to ATV/r + TDF/FTC in naïves (Study 236-0103) .
3. Evolution of the K65R, K103N and M184V/I RT mutations prevalence.
4. Telaprevir/PR, confirmed efficacy in HCV infected patients.
5. Boceprevir/PR, confirmed efficacy in HCV infected patients.
6. GS7977 (NRTI) and MK5172. The upcomming anti-HCV therapy without pegIFN.
7. TDF/FTC PrEP for heterosexual men and women
8. PI monotherapy
9. Dolutegravir. 96 wks results.
10. Vorinostat, first time HIV-1 reservoir can be activated in vivo.
Study Design236-0103
Treatment naive(N = 700 planned)
Quad QD
ATV/r+FTC/TDF Placebo QD
ATV/r + FTC/TDF QD
Quad Placebo QD
• International • Randomized 1:1• Stratification by HIV-1 RNA
(>100,000 c/mL)
(n=350)
(n=350)
Primary Endpoint: Proportion with HIV-1 RNA < 50 c/mL at Week 48 – FDA snapshot analysis, 12% non-inferiority margin– HIV-1 RNA: Amplicor HIV-1 Monitor Test, version 1.5
Week 48 Week 192
Conducted in parallel with Study 236-0102 comparing Quad to EFV/FTC/TDFDeJesus E, et al., CROI 2012; Seattle. Poster 627.
Primary Endpoint: HIV-1 RNA < 50 c/mL236-0103
QUAD was non-inferior to ATV/r + FTC/TDF at Week 48
95% CI for Difference
12%
-1.9 7.8
FavorsATV/r + FTC/TDF
3.0
FavorsQuad
0 -12%
90%
5% 5%5% 8%
87%
0%10%20%30%40%50%60%70%80%90%
100%
Virologic Success Virologic Non-Suppression
No W48 Data
Quad ATV/r+FTC/TDF
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
Mean BL CD4: 364 vs 375 cells.
HIV-1 RNA < 50 c/mL through Week 48 (M=F)236-0103
100
908070605040302010
0
Sub
ject
s w
ith H
IV-1
RN
A <5
0 c/
mL
(%)
BL 2 4 8 12 16 24 32 40 48Week
QUAD (n=): 353 353 353 353 353 353 353 353 353 353ATV/r (n=): 355 355 355 355 355 355 355 355 355 354
Diff: 3.5% (95% CI: -1.0 to 8.0)
Quad: 92%
ATV/r + FTC/TDF: 88%
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
Efficacy in Baseline HIV-1 RNA and CD4 Subgroups236-0103
9385 89 9090
8288 86
0
20
40
60
80
100
≤100,000 c/mL >100,000 c/mL CD4≤350 CD4>350
QUAD ATV/r + FTC/TDF
Viro
logi
c S
ucce
ss (%
)
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
Mean CD4 increase: 239 vs 206 cells (p=0.009)
Integrase, PI, NRTI Resistance Through Week 48236-0103
Quad(n=353)
ATV/r + FTC/TDF(n=355)
Subjects Analyzed for Resistancea, n (%) 12 (3) 8 (2)Subjects with Resistance to ARV Regimen, n (%) 5 (1) 0Any Primary Integrase-R, n 4 -
E92Q 1 -T66I 1 -
Q148R 2 -N155H 2 -
Any Primary PI-R, n - 0Any Primary NRTI-R, n 4 0
M184V/I 4K65R 1
a. Subjects who experienced either suboptimal virologic response (two consecutive visits with HIV-1 RNA ≥50 c/mL and <1 log10 below baseline after Week 8), virologic rebound (two consecutive visits with HIV-1 RNA either ≥400 c/mL after achieving HIV-1 RNA <50, or >1 log10 increase from nadir), or had HIV-1 RNA ≥400 c/mL at their last visit.
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
Change from Baseline in Serum Creatinine236-0103
Median change W48: 0.12 mg/dL vs. 0.08 mg/dL (Quad vs. ATV/r + FTC/TDF group, p<0.001)
BL 2 4 8 12 16 24 32 40 48
0.28
0.24
0.20
0.16
0.12
0.08
0.04
0.0
-0.04
-0.08
Cha
nge
from
Bas
elin
e in
Ser
um C
reat
inin
e (m
g/dL
)
WeekQUAD (n=): 353 346 344 344 340 337 334 325 324 323ATV/r +FTC/TDF (n=): 355 344 342 339 335 332 329 323 316 314
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
10 11
688
11
5
23
0
5
10
15
20
25
Total Cholesterol LDL HDL Triglyceride
QUAD ATV/r + FTC/TDF
Change from Baseline in Fasting Lipids at Week 48236-0103
P =.006
Med
ian
Cha
nge
From
BL
at W
eek
48 (m
g/dL
)
DeJesus E, et al., CROI 2012; Seattle. Poster 627.
Top Ten CROI 2012. Agenda.
1. QUAD non inferior to Atripla (Study: 236-0102). New STR for naives.
2. QUAD non inferior to ATV/r + TDF/FTC in naïves (Study 236-0103) .
3. Evolution of the K65R, K103N and M184V/I RT mutations prevalence.
4. Telaprevir/PR, confirmed efficacy in HCV infected patients.
5. Boceprevir/PR, confirmed efficacy in HCV infected patients.
6. GS7977 (NRTI) and MK5172. The upcomming anti-HCV therapy without pegIFN.
7. TDF/FTC PrEP for heterosexual men and women
8. PI monotherapy
9. Dolutegravir. 96 wks results.
10. Vorinostat, first time HIV-1 reservoir can be activated in vivo.
Charlotte Charpentier1, Sidonie Lambert-Niclot2, Lucile Larrouy1, Alexandre Storto1, Roland Landman1, Dominique Tonelli3, Camille Aubron-Olivier2, Vincent Calvez2, Anne-Geneviève Marcelin2, Diane Descamps1
HIV‐1 infected patients experiencing virologic failure between 2005 and 2010 withRT genotypic resistance tests available at time of virologic failure were analyzed.
Patients were followed in two clinical centers in France: Pitié‐Salpêtrière Hospital,Bichat Claude Bernard Hospital
Virologic failure was identified as defined by French and European guidelines bythe occurrence of two consecutive HIV plasma viral loads > 50 copies/ml inpatients without prior viral escape.
Poster n°726
Among 9586 patients failingtheir ARV regimen from 2005to 2010, the prevalence ofthe K65R trended todecrease (p=0.054), whileK103N and M184V/Imutations frequenciesdecreased statisticallyovertime (p <0.0001).
The same results were foundwhen comparing theprevalence of thesemutations before and afterthe introduction ofEFV/FTC/TDF as a singletablet regimen in clinicalpractice.
Previous studies were conducted to assess the evolution of resistance mutationsprevalence when new antiretroviral and/or new formulations were introduced inclinical practice.
The objectives of our study were to determine in patients failing antiretroviral‐containing regimens between 2005 and 2010 if the switch from EFV‐based regimensto EFV as a single tablet regimen (EFV/FTC/TDF) was associated with a change in theprevalence of K65R, K103N and M184V/I mutations in the RT gene.
RT gene was amplified and amplicons were submitted to direct‐sequencing.
K65R, K103N and M184V/I reverse‐transcriptase mutations frequencies weredetermined each year from 2005 to 2010.
Statistical analyzes were performed using Fischer’s exact test.
Evolution of the K65R, K103N and M184V/I Reverse Transcriptase Mutations Prevalence in HIV‐1‐infected Patients
Experiencing Virologic Failure between 2005 and 2010.
AGENCE NATIONALE DE RECHERCHESSUR LE SIDA ET LES HÉPATITES VIRALES
Agence autonome de l’Inserm
1. APHP Bichat-Claude Bernard Hospital and EA4409 Paris Diderot University, Paris France; 2. APHP Pitié-Salpètriêre Hospital and INSERM UMR 946, Pierre et Marie Curie University, Paris, France; 3. Medical Affairs, Gilead, Paris, France.
CONCLUSIONS
BACKGROUND
OBJECTIVES
PATIENTS
METHODS
RESULTS
1.7 1.8 1.8 1 1 115.7 13.8 9.8 9.1 8.9 7.4
36.9 34.7 28.1 22.3 20.1 14.8
01020304050
20051405
2006
1359
20071412
2008
1763
2009
1828
2010
1819
% K65RK103NM184V/I
Patients (N)
Prevalence of K56R, K103N and M184V/I mutations between 2005 and 2010
Top Ten CROI 2012. Agenda.
1. QUAD non inferior to Atripla (Study: 236-0102). New STR for naives.
2. QUAD non inferior to ATV/r + TDF/FTC in naïves (Study 236-0103) .
3. Evolution of the K65R, K103N and M184V/I RT mutations prevalence.
4. Telaprevir/PR, confirmed efficacy in HCV infected patients.
5. Boceprevir/PR, confirmed efficacy in HCV infected patients.
6. GS7977 (NRTI) and MK5172. The upcomming anti-HCV therapy without pegIFN.
7. TDF/FTC PrEP for heterosexual men and women
8. PI monotherapy
9. Dolutegravir. 96 wks results.
10. Vorinostat, first time HIV-1 reservoir can be activated in vivo.
• RVR (rapid virological response):
Negative HCV-RNA 4 weeks after start of treatment
• EVR (early virological response):
Negative HCV-RNA 12 weeks after start of
treatment
• ETR (end of treatment response):
Negative HCV-RNA at the end of treatment
• SVR (sustained virological response):
Negative HCV-RNA 24 weeks after end of treatment
Treatment Response Terms
Douglas T. Dieterich1, Vincent Soriano2, Kenneth E. Sherman3, Pierre-Marie Girard4, Jürgen K. Rockstroh5, Bambang S. Adiwijaya6, Scott McCallister6,
Nathalie Adda6, Lisa Mahnke6, Mark S. Sulkowski7
On behalf of the Study 110 Team1Mount Sinai School of Medicine, New York, NY, United States, 2Hospital Carlos III, Madrid, Spain,
3University of Cincinnati College of Medicine, Cincinnati, OH, United States, 4Hôpital St Antoine, Paris, France, 5University of Bonn, Bonn, Germany, 6Vertex Pharmaceuticals Incorporated, Cambridge, MA, United
States, and 7Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Telaprevir in Combination with Peginterferon Alfa-2a/Ribavirin in
HCV/HIV Co-infected Patients:24-Week Treatment Interim Analysis
D Dieterich. Telaprevir. CROI 2012. # 46
Background
Telaprevir (TVR, T) in combination with peginterferon alfa-2a (P) and ribavirin (R) is approved for treatment-naïve and treatment-experienced mono-infected patients with genotype 1 chronic HCV infection, including patients with compensated cirrhosis1-3
Modest drug-drug interactions (DDI) between TVR and antiretroviral therapy (ART: EFV, ATV/r, and TDF) were observed; no dose adjustments of ART were deemed necessary4
Higher TVR doses (1125 mg q8h) could partly offset TVR interactions with EFV4; no other TVR dose adjustment was deemed necessary
1INCIVEK [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011; 2INCIVO [EU summary of product characteristics]. Beerse, Belgium: Janssen; 2011; 3INCIVEK [Canada product monograph]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011; 4Van Heeswijk et al. CROI 2011; Abstract 146LB
Part A: no ART
Follow-upPR48 (control) PR
SVRPbo + PR
T/PR TVR + PR Follow-upSVR
PR
Follow-upPR48 (control) PR
SVRPbo + PR
T/PR TVR + PR Follow-upSVR
PR
Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC)
(EFV)=efavirenz; (TDF)=tenofovir; (FTC)=emtricitabine; (ATV/r)=ritonavir-boosted atazanavir; (3TC)=lamivudine; (T) TVR=telaprevir 750 mg q8h or 1125 mg q8h (with EFV); Pbo=Placebo; (P) Peg-IFN=pegylated interferon alfa-2a (40 kD) 180 µg/wk; (R) RBV=ribavirin 800 mg/day or weight-based (1000 mg/day if weight <75 kg, 1200 mg/day for if weight ≥75 kg; France, Germany, n=5 patients)Roche COBAS® TaqMan® HCV test v2.0, LLOQ of 25 IU/mL, LOD of <10 IU/mL
Study 110 Design: Randomized, Double-blind, Placebo-controlled Trial
240 48 72Weeks 12 36 60
SVR12
SVR12
SVR12
SVR121:1
2:1
Patie
nts
with
SVR
(%)
No ART EFV/TDF/FTC ATV/r/TDF/FTC Total
n/N = 5/7 11/16 12/15 28/38
T/PR PR2/6 4/8 4/8 10/22
SVR Rates 12 Weeks Post-Treatment (SVR12*)
71
33
69
50
80
50
74
45
0
10
20
30
40
50
60
70
80
90
100
*Patient was defined as SVR12 if HCV RNA was < LLOQ in the visit window
Most Common Adverse Events: Overall Treatment Phase*
* Reported in >15% of patients regardless of severity in total T/PR or PR in overall treatment phase, in bold event occurring at >10% points difference between T/PR group vs PR. Abdominal pain occurred more frequently in the T/PR groups (≥10% difference) compared to PR as well. ‡ Rash and anemia were assessed with the use of a group of related terms to identify all dermatologic and anemia events, respectively. 18% (7/38) T/PR and 9% (2/22) PR patients overall had a serious adverse event.
N, (%) T/PR (N=38), % PR (N=22), %
Fatigue 16 (42) 9 (41)
Pruritus 15 (39) 2 (9)
Headache 14 (37) 6 (27)
Nausea 13 (34) 5 (23)
Rash‡ 13 (34) 5 (23)
Diarrhea 9 (24) 4 (18)
Dizziness 8 (21) 3 (14)
Pyrexia 8 (21) 2 (9)
Depression 8 (21) 2 (9)
Neutropenia 9 (24) 5 (23)
Anemia‡ 7 (18) 4 (18)
Vomiting 7 (18) 2 (9)
Myalgia 6 (16) 5 (23)
Chills 6 (16) 4 (18)
Insomnia 5 (13) 5 (23)
Decreased Appetite 4 (11) 4 (18)
Weight Decreased 5 (13) 5 (23)
Top Ten CROI 2012. Agenda.
1. QUAD non inferior to Atripla (Study: 236-0102). New STR for naives.
2. QUAD non inferior to ATV/r + TDF/FTC in naïves (Study 236-0103) .
3. Evolution of the K65R, K103N and M184V/I RT mutations prevalence.
4. Telaprevir/PR, confirmed efficacy in HCV infected patients.
5. Boceprevir/PR, confirmed efficacy in HCV infected patients.
6. GS7977 (NRTI) and MK5172. The upcomming anti-HCV therapy without pegIFN.
7. TDF/FTC PrEP for heterosexual men and women
8. PI monotherapy
9. Dolutegravir. 96 wks results.
10. Vorinostat, first time HIV-1 reservoir can be activated in vivo.
Boceprevir Plus Peginterferon/Ribavirin for the Treatment of HCV/HIV Co-Infected Patients
M Sulkowski1, S Pol2, C Cooper3, H Fainboim4, J Slim5, A Rivero6, M Laguno7, S Thompson8, J Wahl8,
W Greaves8
1John Hopkins University School of Medicine, Baltimore, MD; 2Hopital Cochin, Paris, France; 3The Ottawa Hospital, Ottawa, ON, Canada; 4F. J. Muñiz Hospital De
Infecciosas, Buenos Aires, Argentina; 5Saint Michael's Medical Center, Newark, NJ; 6Hospital Universitario Reina Sofia, Córdoba, Spain, 7Hospital Clinic i Provincial
Barcelona, Spain; 8Merck Sharp & Dohme, Whitehouse Station, NJ.
Oral Abstract Q-175 19th Conference on Retroviruses and Opportunistic Infections (CROI)
Seattle, WAMarch 6, 2012
Sulkowski MS, et al. Presented at The Conference on Retroviruses and Opportunistic Infection (CROI) 19th Annual Meeting March 5-8, 2012, Seattle, WA
3232
Study Design
• Two-arm study, double-blinded for BOC, open-label for PEG2b/RBV• 2:1 randomization (experimental: control)• Boceprevir dose 800 mg TID
• 4-week lead-in with PEG2b/RBV for all patients• PEG-2b 1.5 µg/kg QW; RBV 600-1400 mg/day divided BID
• Control arm patients with HCV-RNA ≥ LLOQ at TW 24 were offered open-label PEG2b/RBV+BOC via a crossover arm
Weeks 12 24 28 48 72
PEG2b+RBV4 wk
Placebo + PEG2b + RBV44 wk
Boceprevir + PEG2b + RBV44 wk
Follow-upSVR-24 wk
Follow-upSVR-24 wk
PEG2b+RBV4 wk
Arm 1
Arm 2
Futility Rules
M Sulkowski. Boceprevir. CROI 2012. # 47.
3333
Patient DispositionPR
(N=34)B/PR(N=64)
Treated 34 (100) 64 (100)Discontinued during treatment phase
Adverse eventTreatment failureLost to follow upDid not wish to continueNon-compliance with protocol
18 (53)3 (9)
14 (41)0
1 (3)0
24 (38)13 (20)
6 (9)1 (2)3 (5)1 (2)
Completed treatment phase 12 (35) 40 (63)
OngoingEntered crossover
04 (12)
0-
All data shown as number (%) of patients.
M Sulkowski. Boceprevir. CROI 2012. # 47.
3434
8.814.7
23.532.4 29.4 26.5
4.7
42.2
59.4
73.465.6
60.7
0
20
40
60
80
100
4 8 12 24 EOT SVR12Treatment Week
PR B/PR
% H
CV
RN
A U
ndet
ecta
ble
3/34 3/64 5/34 27/64 8/34 38/64 11/34 47/64
Virologic Response Over Time†
10/34 9/3442/64 37/61
† Three patients undetectable at FW4 have not yet reached FW12 and were not included in SVR12 analysis.
∆= 34.2(TLP= 29)
M Sulkowski. Boceprevir. CROI 2012. # 47.
3535
Most Common Adverse Events With a Difference of ≥10% Between Groups
PR (N=34)
B/PR(N=64)
Anemia 26% 41%
Pyrexia 21% 36%
Asthenia 24% 34%
Decreased appetite 18% 34%
Diarrhea 18% 28%
Dysgeusia 15% 28%
Vomiting 15% 28%
Flu-like illness 38% 25%
Neutropenia 6% 19%
M Sulkowski. Boceprevir. CROI 2012. # 47.
E Hulskotte. BOC and HIV-1 PIs interaction. CROI 2012. #771LB. De Kanter. BOC RAL DDI. CROI 2012. #772LB.
Top Ten CROI 2012. Agenda.
1. QUAD non inferior to Atripla (Study: 236-0102). New STR for naives.
2. QUAD non inferior to ATV/r + TDF/FTC in naïves (Study 236-0103) .
3. Evolution of the K65R, K103N and M184V/I RT mutations prevalence.
4. Telaprevir/PR, confirmed efficacy in HCV infected patients.
5. Boceprevir/PR, confirmed efficacy in HCV infected patients.
6. GS7977 (NRTI) and MK5172. The upcomming anti-HCV therapy without pegIFN.
7. TDF/FTC PrEP for heterosexual men and women
8. PI monotherapy
9. Dolutegravir. 96 wks results.
10. Vorinostat, first time HIV-1 reservoir can be activated in vivo.
• GS-7977 is a potent, specific HCV nucleotide analog
• Safe and well-tolerated in clinical studies
• Once daily (400 mg QD), with or without food• Potent antiviral activity• High barrier to resistance
– No virologic breakthrough to date
O
CHFHO
ON
NH
O
O
PO
O
NH
O
O CH3
GS-7977 Background
Lawitz E, et al. J Hepatol 2011; 54: S543.
ELECTRON Study Design for HCV Genotype 2/3
GS-7977 + RBVGS-7977 + RBV
GS-7977+RBV+PegGS-7977+RBV+Peg GS-7977 + RBVGS-7977 + RBV
GS-7977 +RBV + PegGS-7977 +RBV + Peg GS-7977 + RBVGS-7977 + RBV
GS-7977 + RBV + PegGS-7977 + RBV + Peg
n=9
100% SVR24n=10
n=10
n=11
• Treatment-naïve, non-cirrhotic, HCV RNA >50,000 IU/mL• Stratified by HCV genotype and IL28B status• Randomized 1:1:1:1 to IFN-free or IFN-sparing arms 1-4 • Additional 10 patients enrolled on GS-7977 monotherapy
4 8Wk 0 12
GS-7977GS-7977n=10
100% SVR24
100% SVR24
100% SVR24
60% SVR24AASLD Nov 2011
ELECTRON Study Design for HCV Genotype 1
Genotype 1 Treatment-naïve (GS-7977 + RBV)Genotype 1 Treatment-naïve (GS-7977 + RBV)
Genotype 1 Null Responders (GS-7977 + RBV)
n=25
SVR12
SVR12
n=10
4 8Wk 0 12 24
• To evaluate the antiviral activity of 12 weeks GS-7977 + RBV in genotype 1 patients who were either:– Prior null responders (<2 log10 reduction in HCV RNA at
Week 12 of a Peg/RBV regimen)– Treatment-naïve
• RBV dosing in all arms, independent of HCV genotype, was 1000 mg for patients <75 kg and 1200 mg for those ≥75 kg
E Gane. ELECTRON trial. CROI 2012. # 54LB
Null Responders: Individual Patient HCV RNA Levels
LOD
End of treatment
n/N <LOD 7/10 10/10 9/9 9/9 9/9 9/9 4/9 1/9T im e ( W e e k s )
0 2 4 6 8 1 0 1 2 1 4 1 6
HC
V R
NA
(log
10IU
/ml)
0
1
2
3
4
5
6
7
8
E Gane. ELECTRON trial. CROI 2012. # 54LB
Introduction
• MK-5172 is a once-daily macrocyclic next-generation HCV Protease Inhibitor• Expected to provide a high barrier to resistance
development in treatment-naïve patients• Has potent activity against early generation HCV PI
resistant variants• Pangenotypic (with EC50 values ranging from 1-200nM
against all six HCV genotypes in vitro)
R155
A156D168
MK5172
Pangenotypic Activity of MK-5172 in a cell-based HCV Protease Assay
Gen 1a
Gen 1b
Gen 2a
#1Gen
2a #2
Gen 2b
#1Gen
2b #2
Gen 2b
#3Gen
2b #4
Gen 2b
#5Gen
3a #1
Gen 3a
#2Gen
3a #3
Gen 3a
#4Gen
4a #1
Gen 4a
#2Gen
5a #3
Gen 5a
#4Gen
6
0
1000
2000
3000
4000
5000
6000
EC
50 (n
M) MK-5172
TMC-435Telaprevir
40 30Total
Follow-upMK-5172
MI-5172 Monotherapy Results by Dose in Genotype 1 Treatment-Naïve Patients
1 3 4 5 6 7 9 10 12 15 28-6
-5
-4
-3
-2
-1
0
1
Log
10H
CV
RN
A C
hang
e fr
om B
asel
ine
(IU
/mL
)
Placebo Pooled Across Panels. 1/2 LOD used to impute values that were BLOD, 1/2 LOQ used to impute values that were BLOQ; PBO = Placebo
2 8 21 56
Population Sequencing if VL >1,000 IU/ml
Petry et al., American association for the study of Liver Diseases (AASLD, 2011), San Francisco, CAFraser et al., HEPDART (2011) Kauai, HI
DosePts
(N)
Pts with VL
<LOQ (n)
PBO 8 --
50 5 2
100 5 4
200 5 3
400 5 5
600 5 3
800 15 13
Top Ten CROI 2012. Agenda.
1. QUAD non inferior to Atripla (Study: 236-0102). New STR for naives.
2. QUAD non inferior to ATV/r + TDF/FTC in naïves (Study 236-0103) .
3. Evolution of the K65R, K103N and M184V/I RT mutations prevalence.
4. Telaprevir/PR, confirmed efficacy in HCV infected patients.
5. Boceprevir/PR, confirmed efficacy in HCV infected patients.
6. GS7977 (NRTI) and MK5172. The upcomming anti-HCV therapy without pegIFN.
7. TDF/FTC PrEP for heterosexual men and women
8. PI monotherapy
9. Dolutegravir. 96 wks results.
10. Vorinostat, first time HIV-1 reservoir can be activated in vivo.
In discordant couples, Is there something better than this?
Partners PrEP Study: HIV Prevention Among Heterosexual Men and Women
4758 HIV-1 Serodiscordant Couples
Randomize HIV-1 Seronegative Partners
1° Endpoint: HIV-1 Infection in the HIV-1 Seronegative PartnerCo-1° Endpoint: Safety
TDF Once Daily
FTC/TDFOnce Daily
PlaceboOnce Daily
Follow Couples for up to 36 months
All Receiving Comprehensive HIV-1 Prevention Services
Baeten J, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 29.
TDF FTC/TDF PlaceboNumber of HIV-1 infections 17 13 52HIV-1 incidence, per 100 person-years 0.65 0.50 1.99HIV-1 protection efficacy,vs. placebo 67% 75%
95% CI (44.81%) (55.87%)P-value <0.0001 <0.0001
Baeten J, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 29.
Primary Efficacy Results
Relative Risk Associated with Detectable TenofovirTDF Arm: 86% (95% CI: 57%, 95%)FTC/TDF Arm: 90% (95% CI: 56%, 98%)
Cases (TDF = 17, FTC/TDF = 12)
Cohort(N=198)
Visits Prior to Seroconversion
Seroconversion Visits All Visits
TDF Arm 35/63 56% 6/17 31% 363/437 83%
FTC/TDF Arm 20/36 56% 3/12 25% 375/465 81%
Donnell D, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 30.
Risk reduction for detectable levels of TDF
Top Ten CROI 2012. Agenda.
1. QUAD non inferior to Atripla (Study: 236-0102). New STR for naives.
2. QUAD non inferior to ATV/r + TDF/FTC in naïves (Study 236-0103) .
3. Evolution of the K65R, K103N and M184V/I RT mutations prevalence.
4. Telaprevir/PR, confirmed efficacy in HCV infected patients.
5. Boceprevir/PR, confirmed efficacy in HCV infected patients.
6. GS7977 (NRTI) and MK5172. The upcomming anti-HCV therapy without pegIFN.
7. TDF/FTC PrEP for heterosexual men and women
8. PI monotherapy
9. Dolutegravir. 96 wks results.
10. Vorinostat, first time HIV-1 reservoir can be activated in vivo.
Long-Term Monotherapy With Lopinavir/ritonavir (>2 years) is not Associated with Greater HIV-Associated Neurocognitive Impairment
JR Santos1, JA Muñoz-Moreno1, J Moltó1, I Bravo1, A Prats1, DR McClernon2, A Curran3, P Domingo4, JM Llibre1, B Clotet1,51Lluita contra la Sida Foundation, HIV Clinic, Hospital Universitari Germans Trias i Pujol, Badalona, Spain, 2bioMONTR, Research Triangle Park, North
Carolina, USA, 3Infectious Diseases Department, Hospital Vall d'Hebron, Barcelona, Spain, 4Infectious Diseases Unit, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain, 5IrsiCaixa Foundation, HIV Clinic, Hospital Universitari Germans Trias i Pujol, Badalona, SpainAbstract: E-117Abstract: E-117
Contact Information:
Jose R. Santos, MDLluita contra la SIDA FoundationGermans Trias i Pujol HospitalBarcelona, Catalonia, Spaine-mail: [email protected]
ABSTRACTABSTRACTBackground: Monotherapy with boosted protease inhibitors might be insufficientlypotent to fully suppress HIV replication in the central nervous system (CNS), which hasbeen connected to HIV-associated neurocognitive decline. However, evidence tosupport such hypothesis is limited. The objective of this study was to compare thepresence of HIV replication in cerebrospinal fluid (CSF) and neurocognitive performancein HIV-infected patients on lopinavir/ritonavir (LPV/r) antiretroviral treatment withstandard triple therapy (HAART) or monotherapy (MT) for at least 96 weeks. Methods:Exploratory, cross-sectional study in HIV-infected patients on LPV/r-HAART or LPV/r-MT during at least 2 years, while maintaining plasmatic viral load <50 c/mL. Groupswere matched according nadir of CD4, age, gender and time on current LPV/r-HAARTor MT. Demographic and clinical variables were recorded, and HIV-1 RNA load inplasma and CD4+ count were analyzed. A CSF sample was obtained from eachparticipant, and HIV-1 RNA load in CSF was determined by a SuperLow assay (LLD1 c/mL). Patients underwent a neuropsychological battery covering 7 cognitive andmotor areas. The proportions of patients with viral load in CSF ≥1 c/mL andneurocognitive impairment were compared between groups. A neuropsychologicalglobal deficit score (GDS) was also used for comparisons. Results: A total of 37patients were eligible for the study. Three patients did not fulfill the inclusion criteria andwere excluded. Thus, 17 patients were included in each study group. Patients’characteristics: 85% male, with a mean (SD) age of 45 (±7) years, CD4+ count 664(±239) cells/mm3, nadir CD4+ count 199 (±144) cells/mm3, time on current LPV/rtherapy 3.7 (±1.2) years, time with undetectable plasmatic viral load 5.7 (±2.9) years,with no significant differences between groups regarding those variables. Viral load
INTRODUCTIONINTRODUCTION
METHODSMETHODS
• Interest in NRTIs-sparing strategies aimed to prevent NRTIs-related toxicity has grown during recentyears.• Monotherapy (MT) with protease inhibitors (PIs) as a NRTIs-sparing strategy, in cases where NRTIs-related toxicity has appeared, is still recognized in some guidelines.1 In addition, this strategy couldincrease the adherence, reduce costs, and preserve future treatment options.• According to data obtained from both clinical trials and routine clinical practice, lopinavir/ritonavirmonotherapy (LPV/r-MT) as treatment simplification or NRTIs-sparing strategies, seems to be equallyeffective compared to the present triple based standard of care therapy (HAART) for maintaining virologicalsuppression (HIV-1 RNA <50 copies/mL) in HIV-infected patients.2,3
• LPV/r shows intermediate penetration in cerebrospinal fluid (CSF),4 but both the virological efficacy ofLPV/r-MT in this compartment, and its possible consequences, have been questioned.5• Residual viral load in CSF has been associated with higher risk of developing neurocognitive functionimpairment.6• The objective of this study was to compare the presence of HIV replication in CSF and the neurocognitiveperformance in HIV-infected patients who had been receiving LPV/r-based standard HAART (LPV/r-HAART) or LPV/r-MT for at least 96 weeks.
Study design and patients• This was a single centre cross-sectional, exploratory, case-control study in HIV-1 infected patients whohad been receiving LPV/r-HAART or LPV/r-MT for at least 96 weeks and whose plasmatic HIV-1 RNA was<50 copies/mL.• Patients with self-reported treatment adherence <90%, voluntary interruptions of their treatments duringthe current regimen, and who had medical contraindications for lumbar puncture, neurological or psychiatricdisorders or were taking psychotropic drugs were not eligible.• Patients on LPV/r-HAART or LPV/r-MT were matched according to the age, gender, nadir of CD4+ andtime on LPV/r treatment before enrolment.EndpointsPrimary:•The proportion of patients with complete virological suppression (HIV-1 RNA <1 copy/mL) in CSF.Secondary:
• The proportion of patients with neurocognitive impairment (NCI), defined by performing at least 1 standard deviation below the standardized mean in at least 2 neurocognitive areas.7
• Differences on neurocognitive status in terms of global deficit score (GDS), which is a validated method to study compositely impairment on neurocognitive functioning.8
Data and sample collection•Demographic and clinical variables were recorded. •A plasma samples for HIV-1 RNA load, CD4+ T cell count, and routine haematology and chemistry tests were collected from each participant. •A 5 mL CSF sample was obtained within the 30 minutes before the plasma sample by standard lumbar puncture, and HIV-1 RNA in CSF was measured by SuperLow assay (LLD: 1 copy/mL).•The neurocognitive functioning was assessed using a comprehensive neuropsychological tests battery that covers 7 areas recommended to be evaluated in HIV infection.9•Standardized T scores were used for comparison of neurocognitive outcomes and were calculated by a converting process based on adjusting the raw scores according to available normative data. This adjustment covered age gender and education characteristics
RESULTSRESULTS
Figure 1. Flowchart of the study.
Out of 162 potential candidates, 37 patients agreed to participate in the study. Of these, 3 subjects were excluded because they did not fulfill inclusion criteria (Figure 1)
Table 1. Demographic and clinical characteristics of patients.
LPV/r-MT LPV/r-HAART P value
Age 45.2 (38.9-48.7) 47.3 (42.9-50.1) 0.547
Male 15 (88.2) 14 (82.4) 0.628
MSM 10 (58.8) 7 (41.2) 0.294
Median years of educationa
12 (9-17) 9 (8-12) 0.06
CDC stage C 2 (11.8) 3 (17.6) 0.064 Median CD4+ nadir (cells/mm3)a
186 (118-294) 169 (61-293) 0.744
Median prior ARV regimensa
6 (2-10) 2 (1-4) 0.018
Median prior NNRTIsa 1 (0-2) 0 (0-1) 0.085
All values are expressed as No. (%) except when specified. aMedian (interquartile range)Abbreviations: MSM, men-sex-men; CDC, Centers for Disease Control and Prevention; ARV, antiretroviral; PIs,protease inhibitors; NRTIs, nucleoside reverse transcriptase inhibitors; NNRTIs, nonnucleoside reversetranscriptase inhibitors; LPV/r, lopinavir/ritonavir; LPV/r-MT, lopinavir/ritonavir monotherapy; LPV/r-HAART,lopinavir/ritonavir triple-therapy; TDF, tenofovir; FTC, emtricitabine; ABC, abacavir, 3TC, lamivudine; AZT,zidovudine; ddI, didanosine; VL, viral load.
Virological outcomes
Abbreviations: LPV/r-MT, Lopinavir/ritonavir monotherapy; LPV/r-HAART, LPV/r triple-therapy; CSF, Cerebrospinal fluid.
• The proportion of patients with HIV-1 RNA <1 copy/mL in CSF in the LPV/r-MT group was similarto LPV/r-HAART group.
• Three patients on LPV/r-MT had determinations of CSF HIV-1 RNA of 1, 75 and 120 copies/mL.• One patient on LPV/r + ABC + 3TC ( LPV/r-HAART group) had a CSF HIV RNA of 2 copies/mL.
Neurocognitive outcomes
• The proportion of patients with complete virological suppression in CSF (ultrasensitive HIV-1 RNA <1copy/mL) was similar between LPV/r-MT and LPV/r-HAART groups.• Although the difference was not statistically significant, less patients on LPV/r-MT showedneurocognitive impairment compared to those on LPV/r-HAART.• In addition, neurocognitive functioning showed to be mildly better (close to statistical significance) inpatients on LPV/r-MT than patients on LPV/r-HAART.• This study suggests that in patients receiving prolonged LPV/r-MT, the CSF-HIV replication is fullysuppressed in most of them. Additionally, this strategy appears not to be associated with worseneurocognitive functioning.
• In the LPV/r-MT group 7 (41%) patients showed NCI while in LPV/r-HAART group this occurred in10 (59%); p=0.48.
• When patients with possible confounding comorbidities were excluded, the results were similar:6/13 (46%) patients showed NCI in LPV/r-MT group (46%) and 8/13 (61%) in LPV/r-HAART group(p=0.43).
• Considering neurocognitive functioning, values were mildly better in MT group. In total sample,GDS was 0.23 in MT group and 0.46 in HAART group (p=0.025), and in non-comorbities sample0.25 and 0.5 (p=0.04), respectively.
Figure 3. Percentages of subjects with neurocognitive impairment.
All sample Non-comorbidities sample0
20
40
60
80
100 LPV/r-MTLPV/r-HAART
7 (41%)
10 (59%)
6 (46%)
8 (61%)
p=0.48 p=0.43
% o
f im
pair
ed p
atie
nts
Figure 2. Patients with complete CSF-virological suppression (RNA HIV <1 copy/mL).
LPV/r-MT group LPV/r-HAART group0
20
40
60
80
100 p= 0.601
14 (82.4%)
16 (94.1%)
% o
f pat
ient
s
34 patients included
37 eligible patients
LPV/r-MTn=17
LPV/r-HAARTn=17
3 patients excluded:-1 patient with <48 weeks on
treatment.-1 patient was non-Spanish
speaker.-1 patient with plasmatic
VL >50 copies/mL.
CONCLUSIONSCONCLUSIONS
REFERENCESREFERENCES
ACKNOWNLEDGMENTSACKNOWNLEDGMENTSWe thank the staff at the clinical site where data were gathered for this study and the patients whoparticipated. We also wish to acknowledge the contribution of Nuria Pérez-Álvarez who gave hersupport advice on the statistical analysis and Dr. Jaume Canet for his assistance in lumbar punctureprocedure. This study received funding from “Lluita contra la SIDA” Foundation and from AbbottLaboratories
Confounding comorbidities included: depression or anxiety disorders, drug use,presence of a psychiatric diagnosis, psychopharmacologic treatment, or current orpast opportunistic infection involving CNS.
1Guidelines of European AIDS clinical Society (EACS 2011) version October 6th 2011; 2Pulido F, et al. AIDS 2008; 22: F1–F9;3Moltó J, et al. J Antimicrob Chemother 2007; 60(2): 436-9; 4Letendre S, et al. CID 2007; 45:1511-7; 5Gutmann C, et al. AIDS2010, 24:2347–2354; 6Muñoz-Moreno JA, et al. ISNV Meeting, Miami, FL; Abstract P-130; 7Antinori A, et al. Neurology 2007;69(18):1789-99; 8Carey et al. J Clin Exp Neuropsychol. 2004; 26(3):307-19; 9Muñoz-Moreno JA, et al. J Neurovirol 2010;16(3):208-18.
Top Ten CROI 2012. Agenda.
1. QUAD non inferior to Atripla (Study: 236-0102). New STR for naives.
2. QUAD non inferior to ATV/r + TDF/FTC in naïves (Study 236-0103) .
3. Evolution of the K65R, K103N and M184V/I RT mutations prevalence.
4. Telaprevir/PR, confirmed efficacy in HCV infected patients.
5. Boceprevir/PR, confirmed efficacy in HCV infected patients.
6. GS7977 (NRTI) and MK5172. The upcomming anti-HCV therapy without pegIFN.
7. TDF/FTC PrEP for heterosexual men and women
8. PI monotherapy
9. Dolutegravir. 96 wks results.
10. Vorinostat, first time HIV-1 reservoir can be activated in vivo.
19th Conference on Retroviruses and Opportunistic InfectionsMarch 5-8, 2012, Seattle, Washington
Shionogi-ViiV Healthcare LLC
Hans-Juergen Stellbrink,1 Jacques Reynes,2 Adriano Lazzarin,3 Eugene Voronin,4Federico Pulido,5 Franco Felizarta,6 Steve Almond,7 Marty St. Clair,8 Nancy Flack,8 and Sherene Min,8 on behalf of the extended SPRING-1 Team1ICH Study Center, Hamburg, Germany; 2Hopital Gui de Chauliac, Montpellier, France; 3Fondazione Centro San Raffaele del Monte Tabor, Milano, Italy; 4Hospital of Infectious Diseases, St. Petersburg, Russia; 5Hospital 12 Octubre, Madrid, Spain; 6Office of Franco Felizarta, Bakersfield, CA; 7,8GlaxoSmithKline, 7Mississauga, Canada, 8Research Triangle Park, NC, USA
Dolutegravir (DTG; S/GSK1349572) in Combination Therapy Exhibits Rapid and Sustained Antiviral Response in Antiretroviral-Naïve Adults: 96-Week Results from SPRING-1 (ING112276)
19th Conference on Retroviruses and Opportunistic InfectionsMarch 5-8, 2012, Seattle, Washington
Dolutegravir Attributes
● Once daily, unboosted1
● Low PK variability and predictable exposure-response relationship2
● Low potential for drug interactions2
● Improved in vitro resistance profile including higher genetic barrier to resistance3
● Highly potent antiviral activity in monotherapy1
– At 50mg DTG, 90% were <400 c/mL and 70% <50 c/mL after 10d of monotherapy
Dosing period Follow-up period
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1(BL)
2 3 4 7 8 9 1011 14 21(FU)Day
Mea
n C
hang
e fr
om B
asel
ine
in H
IV-1
RN
A
(log 1
0c/
mL
)
2 mg10 mg50 mgPBO
1. Min, S. et al. AIDS. 2011; 25:1737–1745.2. Min, S. et al. AAC. 2010; 54: 254–258.3. Kobayashi, M et al. AAC. 2011; 55(2):813-821.
19th Conference on Retroviruses and Opportunistic InfectionsMarch 5-8, 2012, Seattle, Washington
● Phase IIb dose-ranging, partially blinded, N~200 ART-naïve patients● All arms include 2 NRTI backbone given once daily ● Primary endpoint: % <50 c/mL at 16 weeks (TLOVR), for Ph3 dose selection● Planned analysis: % <50 c/mL at 96 weeks (TLOVR)
ING112276 Study Design
HIV-1 RNA >1000 c/mLCD4 ≥200 cells/mm3
1:1:1:1 Randomization
EFV 600 mg
DTG 50 mg
DTG 25 mg
DTG 10 mg
Stratified by• HIV RNA >100,000
or ≤100,000 c/mL• Epzicom/Kivexa
or Truvada
Week 96
DTG 50 mg
Selected Dose
19th Conference on Retroviruses and Opportunistic InfectionsMarch 5-8, 2012, Seattle, Washington
Dolutegravir: Rapid and Durable Antiviral ActivityWeek 96 Efficacy Analysis (<50 c/mL)
95% confidence intervals are derived using the normal approximation.
88%
78%79%
72%
Perc
ent S
ubje
cts
with
HIV
-1 R
NA
<50
c/m
L (T
LOVR
)
Week
19th Conference on Retroviruses and Opportunistic Infections05-08 March 2012 Seattle, Washington
Median (95% CI) Change from BaselineCD4+ Cell Count (cells/mm3)
Week 24 p=0.008; Week 48 p=0.076; Week 96 p=0.155Wilcoxon two-sample test, EFV vs. DTG total
Cha
nge
from
Bas
elin
e C
D4+
Cel
l Cou
nt
(cel
ls/m
m3 )
19th Conference on Retroviruses and Opportunistic Infections05-08 March 2012 Seattle, Washington
Laboratory Results: Creatinine & Urine Protein
● Small changes in mean serum creatinine (0.1 – 0.15 mg/dL) observed– Observed with both NRTI backbones, did not progress over time– No effect of DTG on GFR (as measured by iohexol clearance)1
● At Week 96, no evidence for higher urine protein in DTG arms
.
1Koteff J, et al. 51st ICAAC; September 17-20, 2011: Chicago, Illinois. Abstract A1-1728.
Arm n (Wk 96)
Mean Urine Alb/Cr ratio (mg/mmol Cr) at Wk96 (SD)
Min/Max
DTG 10mg 38 1.06 (1.699) 0.2 / 9.4DTG 25mg 33 0.91 (0.95) 0.3 / 5.2DTG 50mg 38 0.97 (1.113) 0.3 / 6.2EFV 600mg 34 1.56 (2.908) 0.2 / 16.3
In vitro and clinical data are consistent with non-significant inhibition of the renal transporter (OCT2) responsible for tubular secretion of creatinine
19th Conference on Retroviruses and Opportunistic Infections05-08 March 2012 Seattle, Washington
● DTG administered once-daily without a PK booster was associated with good treatment response at all doses
– Proportion with HIV RNA <50 c/mL for selected 50mg dose (88%) compares favorably with EFV (72%) through 96 weeks
– No INI mutations detected through 96 weeks, consistent with high barrier to resistance demonstrated in vitro
● Fewer subjects treated with DTG discontinued therapy due to adverse events when compared to EFV
● Data through 96 weeks continue to support 50mg once daily for INI-naïve subjects, and provide evidence for durable efficacy and tolerability for DTG in combination therapy
Conclusions
Top Ten CROI 2012. Agenda.
1. QUAD non inferior to Atripla (Study: 236-0102). New STR for naives.
2. QUAD non inferior to ATV/r + TDF/FTC in naïves (Study 236-0103) .
3. Evolution of the K65R, K103N and M184V/I RT mutations prevalence.
4. Telaprevir/PR, confirmed efficacy in HCV infected patients.
5. Boceprevir/PR, confirmed efficacy in HCV infected patients.
6. GS7977 (NRTI) and MK5172. The upcomming anti-HCV therapy without pegIFN.
7. TDF/FTC PrEP for heterosexual men and women
8. PI monotherapy
9. Dolutegravir. 96 wks results.
10. Vorinostat, first time HIV-1 reservoir can be activated in vivo.
Tim Brown
Rome, July 20, 2011
102
103
104
105
106
107
HIV
-1 R
NA
(cop
y/m
L)
HAART HAART
AML diagnosis2nd bone marrowtransplantation
Bone marrowtransplantation
2007 2008 2010
GI tract biopsy CSF
Hütter et al. NEJM. 2009Allers et al. Blood. 2010
Only well-documented case of HIV cureOnly well-documented case of HIV cure
This case does not offer a generalizable strategyThis case does not offer a generalizable strategy
Long-Term Control of HIV by CCR5 ∆32/∆32 Stem Cell Transplantation
Chromatin Reconfiguration for Purging HIV-1 from the Latent Reservoir
Rome, July 20, 2011
DNA methylation and histone deacetylation (HDAC) induce a closed-chromatin configuration and transcriptional repression
Closed chromatintranscriptional repression
Johnstone, Nat Rev Drug Discov, 200
HDACinhibitors
Methylationinhibitors
Histone acetylation and demethylation of DNA relaxes chromatin, and allows transcriptional
activation
Open chromatintranscriptional activation
HIV Lives within Chromatin
Reactivation
Reactivation ≠ Elimination
+
HAART
Viral cytopathic effect
Antigen-specific stimulation with HIV-Gag peptides enhances CTL response from patients on HAART
Time in co-culture (days)
Antigen-specific stimulation with HIV-Gag peptides enhances CTL response from patients on HAART
Time in co-culture (days)
Gag Preestimulated CTL are able to inhibit viral replication BUT at very high Effector:Target ratios
Half life of latently infected CD4+ T cells with the presence of autologous CD8+ T cells
Patie
nts
on H
AA
RT
ECs
Conclusions.
Single dose Vorinostat (Zolinza®) induces the expression of HIV-1 RNA in latently infected cells (lymphocytes)
This is the first time that it has been shown in vivo that HIV-1 latency can be activated.
In order to eliminate T memory cells in addition to reactivation a CTL response will be required (role for therapeutic vaccination).
N Archin. Vorinostat disrupts HIV-1 latency. CROI 2012. # 157LB. L Shan. Elimination Reservoir Requires CTL response. # 153.
Use of aggressive drug regimens➤ Rx intensification
Early initiation of antiretroviral treatment Enhancement of anti-HIV immunity
➤ IL-7, HIV-1-antigens, α-PD1, therapeutic vaccine Use of virus purging agents
➤ HDAC inhibitors (vorinostat), NF-kB activators (prostratin), methylation inhibitors (decitabine), disulfiram, …
New strategies➤ Gene/cell therapy: Zn Finger nucleases
Reduce inflammationRome, July 20, 2011
Multiple approaches will be required for eradication of HIV
Thank you very much
Gaudi’s buildings in Barcelona