Top Ten News for Clinicians. CROI 2012regist2.virology-education.com/2012/1stAsian/docs/31... · 2012. 5. 25. · Top Ten CROI 2012. Agenda. 1. QUAD non inferior to Atripla (Study:

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.









8. PI monotherapy



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









8. PI monotherapy



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%


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 (%

)


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.


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


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

)










8. PI monotherapy



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.

[email protected]

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









8. PI monotherapy



• 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)









8. PI monotherapy



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.


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)


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%


E Hulskotte. BOC and HIV-1 PIs interaction. CROI 2012. #771LB. De Kanter. BOC RAL DDI. CROI 2012. #772LB.









8. PI monotherapy



• 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









8. PI monotherapy



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









8. PI monotherapy



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.









8. PI monotherapy



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)


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.


● 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


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 )


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


● 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









8. PI monotherapy



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

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