the 18 th conference on retroviruses and opportunistic infections boston, ma february 27-march 2,...

The 18th Conference on Retroviruses and Opportunistic

InfectionsBoston, MA

February 27-March 2, 2011

CME Disclaimer

These slides may not bepublished, posted online, and/or presented

for Continuing Medical Education creditwithout written permission fromRush University Medical Center

and Practice Point Communications

Rush University Medical Center is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Rush University Medical Center designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (UPN #0012-9999-10-150-H02-P). This slide kit is accredited for one hour of continuing education credit. The University of Florida College of Pharmacy will mail Statements of Continuing Education Credit within 30 working days after receiving evidence of successful completion of the course. Successful completion means that you must attend the entire program and complete an evaluation form.

Supported by an independent educational grant from Gilead Sciences Medical Affairs.

Accreditation and Designation

The Association of Nurses in AIDS Care is an approved provider of continuing nursing education by the Virginia Nurses Association Continuing Education Approval Committee, an accredited approver by the American Nurses Credentialing Center’s Commission onAccreditation.

This activity is approved for 1.0 contact hours by the Association of Nurses in AIDS Care.

This program contains .25 hours of pharmacology content.

Faculty:CME Course Director

Harold A. Kessler, MDProfessor of Medicine and Immunology/Microbiology

Associate Director, Section of Infectious DiseasesRush University Medical Center

Chicago, Illinois

Faculty:Content Development and Training

Richard A. Elion, MDDirector of Clinical Research

Walker Whitman ClinicWashington, DC

Graeme J. Moyle, MD, MB BSAssociate Director of HIV Research

Chelsea & Westminster HospitalLondon, England

Jürgen K. Rockstroh, MD, PhDProfessor of Medicine

Department of MedicineHead, HIV Clinic

University of BonnBonn, Germany

Andrew R. Zolopa, MDAssociate Professor of Medicine

Stanford UniversityStanford, California

Faculty:CME Reviewer

David M. Simon, MD, PhDAssistant Professor

Section of Infectious DiseasesRush University Medical Center

Chicago, Illinois

Disclosure Information

• It is the policy of the Rush University Medical Center Office of Continuing Medical Education to ensure that its CME activities are independent, free of commercial bias and beyond the control of persons or organizations with an economic interest in influencing the content of CME

• Everyone who is in a position to control the content of an educational activity must disclose all relevant financial relationships with any commercial interest (including but not limited to pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the presentation topic) within the preceding 12 months

• If there are relationships that create a conflict of interest, these must be resolved by the CME Course Director in consultation with the Office of Continuing Medical Education prior to the participation of the faculty member in the development or presentation of course content

Disclosure Information:CME Course Director

• Harold A. Kessler, MD− Grants/Research Support

− None− Consultant

− None− Speakers’ Bureau

− None− Stock Shareholder

− Abbott Laboratories, GlaxoSmithKline, Merck− Other Financial or Material Support

− None

Disclosure Information:Content Faculty

• Richard A. Elion, MD− Grant/Research Support:

− Gilead Sciences, Merck, Rapid, Tibotec, ViiV, Wyeth− Consultant:

− Bristol-Myers Squibb, Gilead Sciences, Merck, Tibotec− Speakers’ Bureau:

− Bristol-Myers Squibb, Gilead Sciences, Merck, Tibotec− Stock Shareholder:

− None− Other Financial or Material Support:

− None


• Graeme J. Moyle, MD, MB BS− Grant/Research Support:

− Abbott Laboratories, Ardea Biosciences, Bionor, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Theratechnologies and Tibotec

− Consultant:− Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences,

GlaxoSmithKline, Merck, Prizer, TheraTechnologies, Tibotec, Viiv Healthcare

− Speakers’ Bureau: − Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences,

GlaxoSmithKline, Merck, Prizer, TheraTechnologies, Tibotec, Viiv Healthcare

− Stock Shareholder: − None

− Other Financial or Material Support: − None


• Jürgen K. Rockstroh, MD, PhD− Grant/Research Support:

− Abbott Laboratories, Merck, Roche− Consultant:

− Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Roche, Tibotec, ViiV

− Speakers’ Bureau: − None

− Stock Shareholder: − None

− Other Financial or Material Support: − None


• Andrew R. Zolopa, MD− Grant/Research Support:

− Bristol-Myers Squibb, Gilead Sciences, Pfizer, VIRxSYS− Consultant:

− Bristol-Myers Squibb, Gilead Sciences, Tibotec− Speakers’ Bureau:

− None− Stock Shareholder:

− None− Other Financial or Material Support:

− None

Disclosure Information:CME Reviewer

• David M. Simon, MD, PhD− Grants/Research Support

− None− Consultant

− None− Speakers’ Bureau

− None− Stock Shareholder

− None− Other Financial or Material Support

− None

Opinions and Off-Label Discussions

The opinions or views expressed in this educational program are those of the participants and do not necessarily reflect the opinions

or recommendations of Gilead Sciences Medical Affairs,Rush University Medical Center, Association of Nurses in AIDS Care,

or the University of Florida College of Pharmacy

The faculty may have included discussion on unlabeled usesof a commercial product or an investigational use of a

product not yet approved for this purpose

Please consult the full prescribing information before usingany medication mentioned in this program

Learning Objectives (CME, CE)

• Upon completion of this activity, the participant intends to incorporate the following objectives into their practice of medicine:− Initiate ARV therapy in ARV-naïve patients based upon the most

current clinical data indicating when the potential benefits of ARV therapy outweigh the potential risks.

− Prescribe ARV therapy in ARV-naïve patients based upon the most current clinical data indicating which ARV regimens are superior regarding efficacy and avoidance of toxicity and adverse events.

− Utilize recent study results regarding the medical management of HIV-positive patients in your clinical practice to improve patient care.

− Utilize the data presented regarding viral hepatitis to improve the health care you provide to HIV-positive patients.

Learning Objectives (CPE)

• Upon completion of this activity, the pharmacist should be able to:− Determine when the most current clinical data indicates the potential

benefits of ARV therapy outweigh the potential risks in ARV-naïve patients.

− Recommend the most superior ARV therapy for ARV-naïve patients based on efficacy and avoidance of toxicity and adverse events according to the most current clinical data.

− Utilize recent study results regarding the medical management of HIV-positive patients in your clinical practice to improve patient care.

− Utilize the data presented regarding viral hepatitis to improve the health care you provide to HIV-positive patients.

Studies in ARV-Naïve PatientsRick Elion, MD

Director of Clinical ResearchWhitman Walker Clinic

Washington, DC

2011 DHHS Guidelines: When to Start ART

Clinical CategoryCD4 Cell Count

(cells/mm3)2011 DHHSGuidelines Strength-Quality

AIDS-defining illness

Any value TreatA-I

Asymptomatic

<350 Treat

350 to 500 Treat A/B-II: 55% A vs. 45% B

>500 Treat/OptionalB/C-III: 50% B

vs. 50% C

Pregnancy, HIV-associated nephropathy, HIV/HBV when HBV treatment indicated

Any value Treat A-III

2011 DHHS Guidelines:When to Start with Active TB

CD4 Count (Cells/mm3) Recommendation

<200Initiate ART within 2–4 weeks of starting TB treatment

200–500

Initiate ART within 2–4 weeks, or at least by 8 weeks, of starting TB therapy

>500Initiate ART within 8 weeks of starting TB therapy

Adapted from US Department of Health and Human Services Guidelines; Revised January 10, 2011.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

Racial Differences in Efficacy of Initial ART Trials

in ACTG (1998-2005)

• 5 clinical trials in ACTG (N=2495)− 1344 non-Hispanic white vs.

1151 black• Black race associated with 40%

increased risk of viral failure after adjustment for covariates: 1.4 (1.2 to 1.6), p<0.001.

• Black race associated with greater improvement in CD4 count over 96 wks, but not shorter time periods (ITT: p=0.05)

Adjusted for sex, disease status co-morbidities, mode of HIV transmission, depression, education level, alcohol use, self-efficacy and perceived social support.

Ribaudo H, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 50.

Time to Virologic failure (Multivariable)

Black race 1.4 (1.2-1.6)

Gender (Female) 0.9 (0.8-1.1)

Age (per 10 yrs) 0.8 (0.8-0.9)

Baseline CD4 (per 50 cells/mm3) 1.0 (1.0-1.0)

Baseline VL (per log10 copies/ml)

For VF in 0-6 months 1.4 (1.2-1.7)

For VF in 6-12 months 1.1 (1.0-1.2)

For VF >12 months 1.1 (0.9-1.3)

Ever Hepatitis C positive 1.4 (1.1-1.8)

Ever Hepatitis B positive 1.1 (0.9-1.3)

Education (No high school diploma or GED) 1.2 (1.0-1.5)

Satisfied with support? (Not very satisfied) 1.2 (1.0-1.4)

Will ART have a positive effect? (Not sure) 1.1 (0.9-1.3)

Recent adherence (<100%) 2.6 (2.3-3.1)

Adjusted HR

1.0 3.0

A5202: Study Design

Multicenter, randomized, placebo-controlled, 96-week, non-inferiority studyEnrolled 2005-2007 and followed through Sept 2009

Stratified by screening HIV-1 RNA (< or ≥ 100,000 c/mL)

ART-naïve patients

(N = 1857)

≥ 16 years oldHIV RNA ≥ 1000 c/mL

3TC/ABC placebo (QD)

TDF/FTC FDC (QD) EFV (QD)

TDF/FTC placebo (QD)

3TC/ABC FDC (QD) EFV (QD)

3TC/ABC placebo (QD)

TDF/FTC FDC (QD) ATV/r(QD)

TDF/FTC placebo (QD)

3TC/ABC FDC (QD) ATV/r(QD)

Primary endpoint: Time to virologic failure, first grade 3-4 AE, or modification

of randomized regimenGrant P, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 535.

ACTG 5202 Differences Between Gender and Race

• Evaluated 1857 subjects in ACTG 5202− 40% White, 33% Black, 23% Hispanic− Blacks with lower baseline CD4 (24%

vs. 13% <50 cells/mL, p≤0.01) and VL (63% vs. 46% <50,000 cps/mL, p ≤0.01) than whites

• Results− Blacks had higher rates of VF,

nonadherence and 3rd agent intolerability

− Women had higher risk of virologic failure on ATV/r compared to EFV

• Conclusion: Results suggest certain interventions and regimens may be helpful in some populations with HIV

ABC/3TC P value TDF/FTC P value

Race(ref to W)*

B1.53

(1.02, 2.29)0.02

2.42 (1.52, 3.83)

<0.001

H0.81

(0.49, 1.32)0.96

(0.54, 1.70)

Sex (ref to M)*

F-EFV0.52

(0.26, 1.04)0.006

0.86(0.41, 1.80)

0.03

F-ATV/r1.72

(0.99, 2.98)2.35

(1.30, 4.26)

3rd agent(EFV ref)

F-ATV/r2.55

(1.20, 5.41)0.02

2.16(0.97, 4.80)

0.03

M-ATV/r0.94

(0.66, 1.34)0.80

(0.52, 1.23)

*Multivariable adjusted for sex, R/E, age at baseline, CD4, VL, h/o AIDS, Hep B/C, IVDU, scr HIV genotype

Time to Virologic Failure (ITT: HR, 95% CI)

Smith K, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 536.

Current DHHS Guidelines Regimens for Treatment-Naïve Patients

Preferred Regimens

• EFV• ATV/r • DRV/r (QD)• RAL[Pregnant Women Only: LPV/r (twice daily) + ZDV/3TC]

AlternativeRegimens

• EFV + (ABC or ZDV)/3TC• NVP + ZDV/3TC• ATV/r + (ABC or ZDV)/3TC• FPV/r (once or twice daily) + either [(ABC or ZDV)/3TC1] or TDF/FTC• LPV/r (once or twice daily) + either [(ABC or ZDV)/3TC1] or TDF/FTC

AcceptableRegimens

• EFV + ddI + (3TC or FTC)• ATV + (ABC or ZDV)/3TC• MVC + ZDV/3TC

InsufficientData

• MVC + either ABC/3TC or TDF/FTC• RAL + (ABC or ZDV)/3TC• (DRV/r or SQV/r) + (ABC or ZDV)/3TC

Adapted from US Department of Health and Human Services Guidelines; Revised January 10, 2011.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

+ TDF/FTC

A5202: Time to Virologic Failure by Baseline Viral Load and CD4 Count

ABC/3TC TDF/FTC

Pro

bab

ility

of

Rem

ain

ing

Fre

e o

f V

iro

log

ic F

ailu

re

Grant P, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 535.

• Increased risk of VF with baseline lower CD4 or higher VL in those assigned ABC/3TC

• Results confirm previously reported analysis based on screening viral load

n=9835 VF

n=7823 VF

n=8019 VF

n=15310 VF

n=396 VF

n=27328 VF

n=235 VF

n=18429 VF

Week 192 from Randomization

n=806 VF

n=8317 VF

n=709 VF

n=15819 VF

n=558 VF

n=28929 VF

n=202 VF

n=17324 VF

QDMRK:Raltegravir QD vs. BID in Initial ART

Raltegravir 800 mg QD + TDF/FTC n=382

Raltegravir 400 mg BID + TDF/FTCn=388

Treatment naiveHIV-1 RNA >5000 copies/mL

Primary endpointWeek 48

Secondary endpointWeek 96

Double-blind, randomized, multi-center studyAnalysis: Non-inferiority design (10% margin)

Eron J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 150LB.

QDMRK: Baseline Characteristics


RAL

QD + TDF/FTCRAL

BID + TDF/FTC

Age (median, years) 38 38

Male 82% 77%

Non-White 28% 30%

vRNA copies/mL (geometric mean)

67,968 70,942

HIV RNA >105 copies/mL 40% 39%

Mean CD4 count (cells/mm3)

291 279

QDMRK: HIV RNA <50 copies/mL (NC=F)


382 382 377 381 379 380 381 382388 388 386 387 386 387 386 386

RAL 800 mg QDRAL 400 mg BID

Number of Contributing Patients

BID 88.9%

QD 83.2%

Δ (QD-BID) [95% CI] = -5.7 [-10.7, -0.83]

0 4 8 12 16 24 36 48

Study Week

0

20

40

60

80

100P

erc

en

t o

f P

ati

en

ts w

ith

HIV

RN

A <

50

Co

pie

s/m

L

QDMRK: Virologic Efficacy Stratified by Baseline

Viral Load and CD4 Count

HIV RNA <50 copies/mL at Week 48 by Subgroup (NC=F)

Difference

RAL QD RAL BID% (95% CI)

n/N % n/N %

Baseline HIV RNA (copies/mL)

>100,000 copies/mL

113/152

74.3128/152

84.2

-9.9(-19.0, -0.8)

≤100,000 copies/mL

205/230

89.1215/234

91.9

-2.7(-8.3, 2.7)

Baseline CD4 (cells/mm3)

≤200 cells/mm3

63/89 70.8 80/99 80.8 -10.0

(-22.3, 2.2)

>200 cells/mm3

254/292

87.0262/286

91.6

-4.6(-9.8, 0.4)


QDMRK: Resistance at 48 Weeks

• Majority of pts failed with 2 or more mutations associated with RAL resistance

• Signature mutations : N155H (4 pts in QD arm) and Y143C/R (3 pts in QD, 1 pt in BID)

• No cases of TDF resistance


Raltegravir

QDRaltegravir

BID

Virologic Failures 53/382 (13.9%) 35/388 (9.0%)

VF >400 c/mL, (data available)

30 (27 with IN data)

16 (12 with IN data)

No Evidence of Resistance 7 7

Integrase Resistance and FTC Resistance

9 2

FTC Resistance Alone 11 4

QDMRK: Histograms for GM Ctrough and % with HIV RNA <50 copies/mL (Observed Failure)


GM C12hr (nM) GM C24hr (nM)

RangeMedian

RangeMedian

STARTMRK: 3 Year Results

281 Patients Treated with

RAL + TDF/FTC

282 Patients Treated with

EFV + TDF/FTC

Enrolled Patients Randomized 1:1

To RAL:EFV Arms

227 Patients (80.8%)

Completed156 Weeks

211 Patients (74.8%)

Completed156 Weeks

54 Patients (19.2%)Discontinued5 – lack of efficacy

12 – AEs8 – lost to follow-up29 – miscellaneous

71 Patients (25.2%)Discontinued7 – lack of efficacy

22 – AEs14 – lost to follow-up28 – miscellaneous

Rockstroh J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 542.

STARTMRK: HIV RNA <50 c/mL Through 156 Weeks (NC = F)

Rockstroh J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 542.

Δ (RAL-EFV) [95% CI] = +7.3 [-0.2, +14.7]

Non-Inferiority P-Value <0.001

281 281 278 280 281 281 280 281 281 277 279 280 281282 281 280 281 282 282 281 282 279 281 281 281 282

Raltegravir groupEfavirenz group

0 16 32 48 60 72 84 96 108 120 132 144 156

Weeks

0

20

40

60

80

100P

erc

en

t o

f P

ati

en

ts w

ith

HIV

RN

A <

50

Co

pie

s/m

L

Number of Contributing Patients

86

82

81

79

75

68

Darunavir/r + Raltegravir:NRTI Sparing Regimen for ARV-naïve Patients

Taiwo B, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 551.

DRV/r + RAL associated with high failure rate and should not be used

Single arm study of DRV/r (800/100 mg) QD + RAL (400 mg BID) (N=112)Age (years) Median (Q1,Q3) 36 (27, 45)

Sex Male 98 (88%)

Race White 49 (44%)

CD4 cell count (cells/mm3) <200200<350≥350

40 (36%)32 (29%)40 (36%)

HIV-1 RNA (copies/mL) ≤100,000≥100,000

63 (56%)49 (44%)

Proportion Of Subjects With HIV-1 RNA <200 and <50 copies/mL (ITT analysis, missing/off study= ignored

Mma Bana Study: Influence of ART on Premature Birth

• HIV-infected pregnant women with CD4 > 200 (n=530) in Botswana randomized to ZDV/3TC/ABC or ZDV/3TC + LPV/r− ART started at 26-34 wks

gestation− Rate of HIV transmission to

newborn low as previously reported

− Pre-term delivery analysis limited to women with singleton births

• After adjustment for maternal income, initiation of PI-based ART in late pregnancy was associated with a 2-fold increase in preterm delivery (AOR 2.02; 95% CI 1.25 – 3.27)

• Results confirm similar results reported in French observational study

Powis K, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 746; Sibiude J, et al. ibid., Abst. 743; N Engl J Med. 2010;362(24):2282-94.

Gestational Age at HAART Initiation

TZV(n)

% PretermCBV-KAL

(n)% Preterm

26 to 28 Weeks 177 10.2% 180 21.7%

29 to 31 Weeks 44 13.6% 63 19.1%

32 to 34 Weeks 42 16.7% 24 25.0%

Total 263 11.8% 267 21.4%

Efficacy and Safety of EFVwith ZDV/3TC or TDF/FTC

• Randomized, prospective, open-label study of EFV + TDF/FTC or ZDV/3TC (N=1045) in patients with CD4 <300 cells/mm3

• Results− Significantly fewer patients in

TDF/FTC arm met primary safety endpoint (P<0.0001)

− Significantly more treatment modifications for in ZDV/3TC arm vs. TDF/FTC arm (59 for neutropenia/anemia vs. 0)

− Significantly more metabolic complications with ZDV/3TC (19 vs. 3, P<0.001)

• Conclusion: Similar efficacy, but TDF/FTC safer

Comparison of Safety Endpoints

Campbell T, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 149LB.

Number of Events

Relative Hazard

TDF/ FTC EFV (N=526)

3TC/ ZDV EFV

(N=519)

EFV+TDF/FTC vs.

EFV+3TC/ZDV (95% CI)

P

Primary Safety (composite endpoint)

243 3130.64

(0.54, 0.76)<0.0001

All initial dose modification

140 2220.54

(0.44, 0.67)<0.0001

All initial Grade 3 or 4 lab abnormality

98 1540.55

(0.43, 0.71)<0.0001

Studies of Investigational Compounds and Resistance

Andrew Zolopa, MDAssociate ProfessorStanford University

Palo Alto, CA

VIKING Study: Dolutegravir (572) Following RAL Failure

RAL-failures with evidence of RAL-resistance andat least 3 ART-class resistant (includes INI)

*Q148H/K/R plus changes in L74 and/or E138 and/or G140**N155H and Y143H pathways or Q148H/K/R single mutants

Allocated to one of two groups based on genotype at screen to ensure broad sensitivity range

Functional Monotherapy Phase

Replace RAL with DTG or

add, if RAL already stopped

Continuation Phase

DTG + OBR

Day 1 Day 11 Week 24

Q148H/K/R + one or more secondary resistance mutations*

N~ 10 (cohort II)

All other mutations (including codon 148 single mutation)**

N~ 10 (cohort II)


VIKING Study: Resistance at Baseline

DTG 50mg QD

(N=27)

DTG 50mg BID

(N=24)

Q148+≥1* All 9 (33%) 11(46%)

Q148+2 3 (11%) 2 (8%)

Q148+1 4 (15%) 8 (33%)

Mixture** 2 (7%) 1 (4%)

Other All 18 (67%) 13 (54%)

N155 4 (15%) 6 (25%)

Y143 12 (44%) 6 (25%)

Other 2 (7%) 1 (4%)

* Q148H/K/R + ≥1 Q148 associated mutations at L74,E138 or G140** for 50mg BID: N=1 Q148H + G140S / Y143Y/H/R/C for 50mg QD: N=1 Q148H + G140S / Y143H

N=1 Q148H + E138A+G140S / Y143H

Ba

se

lin

e F

old

Ch

an

ge

64

32

16

8

4

2

1

0.5DTG 50mg QD

Cohort IDTG 50mg BID

Cohort II

5.9

2.5

1.51.0

5.4

2.7

1.4


*Primary endpoint: <400c/mL and/or ≥0.7log decline in HIV RNA

VIKING Study: Virologic Results

DTG 50mg QD

(n=27)DTG 50mg BID

(n=24)

All subjects: 1o endpoint*

21/27 (78%) 23/24 (96%)

With Q148 +≥1 3/9 (33%) 11/11 (100%)

With other pathways 18/18 (100%) 12/13 (92%)

All subjects: <400 c/mL

11/27 (41%) 13/24 (54%)


Phase I/II Study of GS 7340: Novel Tenofovir Pro-drug

• Amidate Prodrug that is designed to target lymphoid cells− Results in lower systemic exposures of TDF

• 14 day monotherapy study in HIV adults• ART naïve subjects randomized, double blinded

− TDF 300mg (n=10)− GS-7340 – 50 mg (n=10)− GS-7340 – 150 mg (n=10)

• PK in plasma AUC 24− GS-7340 50mg – 88% lower than TDF− GS-7340 150mg – 56% lower than TDF

• No safety issues over 14 days no resistance

Markowitz M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 152LB.

Phase I/II Study of GS 7340: Viral Dynamics

Treatment (10 pts/arm)

Mean ΔVLDay 14

[log10 c/mL]

p-value of mean ΔVL vs.TDF 300 mg

TDF 300 mg - 0.94 0.49 -

GS-7340 50 mg - 1.57 0.53 0.0257

GS-7340 150 mg - 1.71 0.24 0.0010

Markowitz M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 152LB.

-2

-1.5

-1

-0.5

0

0.5

0 7 14 21 28

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Day

BMS 663068: Pro-drug of an Attachment Inhibitor

No safety signal or concern regarding AEs based on data presentedSummary: Evidence of activity in once daily unboosted dosing; phase IIb planned

Nowicka-Sans B, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 518.

Median Maximum Change in HIV-1 RNA From Baseline with Monotherapy

• Novel attachment inhibitor• Study in pts either ARV-naïve or off ARVs: 8 day treatment period

DART: Second Line Therapy Following 3 NRTI Failure

• Patients failing first-line 3 NRTI therapy randomized to LPV/r + NNRTI (EFV/NVP) alone (n=67) or plus ddI (n=67) or 3TC (n=68)

Exact (3 randomized groups X 4 VL groups) P=0.24

Viral Load at Switch

Per

cen

t o

f P

ati

en

ts

Viral Load

Mambule I, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 541.

DART: Virologic Response at 24 Weeks

Exact (3 randomized groups X 5 VL groups) P=0.83VL < vs ≥50 c/ml P=0.42VL ≤ vs >1,000 c/ml P=0.44

Mambule I, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 541.

ACTG 5230: LPV/r Monotherapy Following Failure of First-line NNRTI

• Patients failing first-line NNRTI-containing combinations started LPV/r 400/100mg monotherapy (N=123)− NNRTI-regimen ≥6 months− HIV RNA 1,000-200,000 copies/mL− Resistance:

− 98% ≥1 NNRTI mutation− 95% ≥1 NRTI mutation

• At week 24, 107 subjects (87%) remained on LPV/r monotherapy without VF

• 13 subjects intensified ART with FTC/TDF− 85% suppressed to <400 copies/mL

• New major mutations: A71T (n=2), V82F (n=2)

Bartlett J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 583.

STAR Study: LPV/r With or Without TDF + 3TC Following

Failure of First-line NNRTI200 Patients who failed first-line NNRTI-containing randomized to

LPV/r BID monotherapy or LPV/r BID + TDF + 3TCResistance: M184V (82.1%, K65R (6.7%), ≥3 TAMS (33.3%), ≥4 TAMS (11.3%)

Proportion of Patients with Virological Suppression at 48 Weeks (M=F)

Bunupuradah T, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 584.

TRIO: Treatment of Heavily-Experienced Patients

• Single arm trial of combination of DRV/r, ETR and RAL (+/- nRTIs, ENF) in Heavily-Experienced Patients (Week 96 update)

Baseline Characteristics (n=100)

Years of ARV Use (Median) 13

CD4+ Nadir (Cells/mm3, Median) 80

# Mutations at ScreeningMajor PINRTIsNNRTIs

451

Fagard C, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 549.

88% HIV-1 RNA <50 copies/ml at Week 96

HIV RNA Suppression and CD4 Change

HIV

RN

A (

log

10 c

p/m

l) D

elt

a f

rom

We

ek

0M

ea

n a

nd

Sta

nd

ard

De

via

tio

nC

D4

(Ce

lls/m

m3) D

elta

from

We

ek

0 M

ea

n a

nd

Sta

nd

ard

De

via

tion

HIV RNA Delta from Week 0 (Log10 cp/ml)CD4 Cells per mm3 Delta from Week 0

Weeks

MONOI:Switch to DRV/r ± NRTIs

Valantin M-A, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 534.

Randomized study of DRV/r or DRV/r + NRTIs in Patients with HIV RNA <50 c/mL on ART and No Prior PI Failure and Naïve to DRV

P=0.07

71%

59%

Proportion with HIV RNA < 50 copies/ml (ITT)

Proportion with HIV RNA < 50 copies/ml at All Points from Baseline to Week 96

88%

84%

P=NS

MONOI: Response Predictors

• Conclusion: Favorable indicators for PI/r monotherapy include patient with undetectable HIV RNA when monotherapy begun, strict adherence to ART, and on ART for a long time before switching to monotherapy

All Patients (Week 96) Univariate Analysis Multivariate Analysis

Variables Associated with Rebound by W96 OR (95%CI) P OR (95%CI) P

Difficulty in Adherence (< 100% vs. 100% adherence) 2.04 (0.97, 4.32) 0.06

Randomized Group (Monotherapy vs. HAART) 3.15 (1.39, 7.13) 0.004 4.81 (1.91, 13.7) 0.002

Baseline US HIV-1 RNA (<1 copy/mL vs. Others) 0.47 (0.21, 1.04) 0.053

HIV-1 DNA at D 0 (per 1 log10 copies/106 cells increase) 1.70 (1.02, 2.84) 0.044 1.97 (1.10, 3.57) 0.02

HIV-1 RNA at D 0 (Blip vs. <50 copies/mL) 3.74 (0.85, 16.47) 0.010 0.023

Duration of Prior ART (per 5 years decrease) 1.74 (1.11, 2.73) 0.013 2.11 (1.23, 3.8) 0.009

Patients Randomized in the DRV/r Monotherapy ARM Univariate Analysis Multivariate Analysis

Variables Associated with Rebound by W96 OR (95%CI) P OR (95%CI) P

Difficulty in Adherence (< 100% vs. 100% adherence) 2.36 (0.94, 5.92) 0.07 3.84 (1.29, 12.49) 0.02

Randomized Group (Monotherapy vs. HAART) 2.38 (1.30, 4.38) 0.003 2.93 (1.43, 6.66) 0.006

Baseline US HIV-1 RNA ( <1 copy/mL vs. Others) 0.41 (0.16, 1.05) 0.06

HIV-1 DNA at D 0 (per 1 log10 copies/106 cells increase) 2.45 (1.07, 5.61) 0.03 2.66 (1.11, 7.48) 0.04

HIV-1 RNA at D 0 (Blip vs. <50 copies/mL) 4.05 (0.76, 21.5) 0.11

Valantin M-A, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 534.

MVC Intensification

• Randomized, placebo controlled, 24 week study (N=45)− Virologically suppressed pts, on ART for >1 yr with CD4 <350

• Primary outcome – change in activated CD8 T cells in peripheral blood

• Conclusions:− T cell activation increased in gut and blood− Lower LPS levels (p=0.41)− No impact on CD4 cell counts

Rectal lymph cells CD4 activation CD8 activation

Placebo No change No change

Maraviroc +22% (p<0.001) +9% (p<0.001)

Hunt P, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 153LB.

ACTG 5244: RAL Intensification

• Randomized Cross-over Study− Chronic patients on ART with full suppression (N=50)

• Results: No impact on 2-LTR levels, VL by U/S, HIV DNA levels, T cell activation

Gandhi R, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 51

Arm A: RAL first (immediate intensification)Arm B: Placebo first (deferred intensification)

% CD4+ CD38+HLA-DR+ % CD8+ CD38+HLA-DR+

More M184V When 3TC is Used with TDF Compared to FTC

French clinic cohort

• Evaluated resistance at failure with EFV or PI/r + TDF + 3TC or FTC

• Conclusion: Findings similar to those in clinical trials and suggests PK profile of the

whole regimen is an important factor in limiting failure and

drug resistance

Marcelin A-G, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 617.

Percentage of M184V

Role of NRTIs in RAL-based Salvage ART

Swiss Cohort• Patients who received RAL

as part of new ART regimen • Compared those with 2

NRTIs vs. <2 NRTIs and suppression rates at 24 wks

• Based on GT activity of background ART was higher in the <2 NRTI group (GSS=2.5 vs. 2.0)

• Median GSS for NRTI was 0.5 in both groups

• Multivariate analysis showed better response with 2 NRTI’s

Scherrer A, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 550.

0.01 0.1 1 10

Viral Suppression at Week 24

Per Protocol (n=83)

2 NRTIs better <2 NRTIs betterITT m=f (n=130)

Metabolics, Body Shape Changes and Adverse Events

Graeme J. Moyle, MD, MB, BSAssociate Director of HIV Research

Chelsea & Westminster HospitalLondon, England

ECHO/THRIVE: Grade of Psychiatric AEs by Randomized Group

Mills A, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 420.

RPV

EFV

RPV

EFV

RPV

EFV

RPV

EFV

RPV

EFV

RPV

EFV

Anx

iety

Dep

ress

ion

Inso

mni

aSl

eep

Dis

orde

rs

Abn

orm

alD

ream

s/ni

ghtm

ares

(com

bine

d)

All

slee

pdi

sord

ers

(com

bine

d)

Grade 1Grade 2Grade 3

Proportion of Patients (%)0 5 10 15 20

p<0.001

p<0.0001

ECHO/THRIVE: Mean Changeto Week 48 in Lipid Parameters

by Regimen

Mean lipid parameter, mg/dL

ABC/3TC ZDV/3TC TDF/FTC

RPVn=31

EFVn=30

RPVn=95

EFVn=86

RPVn=472

EFVn=459

Total Cholesterol 16.9 40 8.7 32.2 -0.4 25.7

LDL-C 5.8 22.3 1.7 17.4 -2.1 13.3

HDL-C 7.2 10.7 4.9 11.4 2.9 9.5

Triglycerides 13.2 43.3 11.8 9.4 -12.4 11.7

Change from baseline to Week 48 in 10-year Framingham CHD risk was the same in both treatment groups (–0.09)

Arribas J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 819.

Week 96 Cardiovascular Factors

Shaffer D, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 818.

OCTANE : LPV/r vs. NVP + TDF/FTCin Women Initiating ART in Sub-Saharan Africa

NVP(n=370)

LPV(n=371)

Adjusted Analysis

Mean Change Mean Change P value

TC (mg/dl) 26.6 34.3 0.014

HDL (mg/dl) 18.8 13.0 <0.001

TC/HDL ratio -1.6 -0.6 0.006

SBP (mm hg) 6.8 3.5 0.007

DBP (mm hg) 4.1 0.2 <0.001

BMI (kg/m²) 2.7 1.8 0.003

ATV/r N = 24

DRV/rN = 25

Male, n (%) 22 (92%) 23 (92%)

Age, mean 46 48

CD4 Count cells/mm3 mean (range)

554 (31-1066) 584 (249-996)

Viral Load copies/mL, median

< 50 < 50

LPV/r 23 23

FPV/r 1 2

TDF/FTC 17 15

ABC/3TC 5 5

LARD: Changing PI/r for Hypertriglyceridemia

• Similar % on ATV/r (55%) and DRV/r (48%) achieved a TG <200 mg/dL by week 24 • Changes in other lipid fractions were also similar• Virologic suppression was maintained in both arms

Tri

gly

ceri

des

, mg

/dL

Replace LPV/r (n=46) or FPV/r (n=3) with ATV/r or DRV/r for Hypertriglyceridemia

Skiest D, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 817.

Study ABC Non-ABC Risk Difference

(95% CI)

Non-ABC Worse ABC Worse

ACTG 368 xii 0/140 (0%) 0/143 (0%) 0 (-2.73, 2.87)

COL30305 0/58 (0%) 0/29 (0%) 0(-13.79, 6.38)

ACTG 372A xiii 4/116 (3.45%) 3/113 (2.65%) 0.79 (-4.77, 6.54)

ACTG A5202 xiv 2/923 (0.22%) 5/925 (0.54%) -0.32 (-1.08, 0.33)

ABCDE xv 0/115 (0%) 2/122 (1.64%) -1.64 (-6.17, 1.64)

FIRST xvi 0/93 (0%) 0/89 (0%) 0(-4.49, 4.13)

ACTG 5095 xvii 6/758 (0.79%) 1/376 (0.27%) 0.53 (-0.75, 1.5)

ACTG A5110 xviii 0/48 (0%) 0/53 (0%) 0 (-7.01, 8.34)

STEAL xix 4/178 (2.25%) 1/175 (0.57%) 1.68 (-1.27, 5.17)

NEFA xx 1/149 (0.67%) 0/311 (0%) 0.67 (-0.55, 4.04)

CNAF3007 1/96 (1.04%) 1/91 (1.1%) -0.06 (-5.23, 4.9)

CNA30017 0/80 (0%) 2/127 (1.57%) -1.57 (-5.61, 3.38)

ESS 40003 0/51 (0%) 0/44 (0%) 0 (-9.09, 7.08)

CNAA3006 0/102 (0%) 0/103 (0%) 0 (-3.79, 3.88)

NZTA4002 0/150 (0%) 3/152 (1.97%) -1.97 (-5.94, 0.58)

CNA109586 0/192 (0%) 1/193 (0.52%) -0.52 (-3.12, 1.55)

CNAB3014 0/165 (0%) 0/164 (0%) 0 (-2.42, 2.4)

ESS40002 1/85 (1.18%) 0/166 (0%) 1.18 (-1.14, 7.08)

BIOCOMBO xxi 1/167 (0.6%) 1/166 (0.6%) 0 (-3.15, 3.11)

CNAB3002 0/91 (0%) 0/93 (0%) 0 (-4.35, 4.19)

EPZ104057 1/343 (0.29%) 0/345 (0%) 0.29 (0.86, 1.75)

CNA30024 1/324 (0.31%) 0/325 (0%) 0.31 (0.91, 1.86)

CNAC3005 1/262 (0.38%) 0/264 (0%) 0.38 (-1.13, 2.29)

ESS100327 0/137 (0%) 1/141 (0.71%) -0.71 (-4.27, 2.21)

CNAC3003 1/156 (0.54%) 0/80 (0%) 0.64 (-4.21, 3.6)

CNAB3001 0/49 (0%) 1/50 (2%) -2(-11.05, 5.37)

Mantel-Haenszel 0.01 (-0.26, 0.27)

FDA Meta-AnalysisNo Association Between ABC and MI

• 26 RCTs involving ABC− 5028 subjects on

ABC, 4840 controls− Average 1.62 person/years of

F/U

• Overall events/subjects: 28/5628 ABC vs. 22/4840 controls (OR 1.02 95%CI 0.56, 1.84)

• Authors conclude that the findings ‘raise significant uncertainty about the likelihood of an ABC-MI risk association’

Forest Plot of Meta Analysis Results: Trials Sorted Based on Duration of Person –Years of Follow-up

Ding X, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 808.

-5.0% -2.5% 0.0% 2.5% 5.0%

PREPARE: Change in Limb Fat, Fat Mass and mtDNA

with ZDV/3TC to TDF/FTC• Design: On ZDV/3TC ≥2 years VL<50 c/ml randomized to continue or switch to TDF/FTC• Results: Subjects switched to TDF had significantly increase in both subcutaneous adipose tissue

and limb fat at week 48• Switch to TDF resulted in significantly greater increases in mtDNA content and mtDNA quality at

weeks 24 and 48 and adipocyte volume

Feeney E, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 846.

P<0.05 (W48 TDF vs W0 TDF)P=0.50 (W48 TDF vs ZDV)

P<0.01 (TDF W48 vs TDF W0)P=0.01 (TDF vs ZDV at W48)

ACTG 5224s: Visceral Fat Change by Regimen in A5202

• ATV/r led to greater gains in weight (1.1kg more), trunk fat and a trend to greater gain in VAT than EFV. There were no differences between NRTIs

• Changes in VAT correlated with changes in limb fat (r=0.48; p<0.001)• Age, sex, race/ethnicity, baseline HIV-1 RNA, CD4 count, and BMI were not associated

with week 96 absolute or percent change in VAT

0 10 20 30 40 50

ATV/rEFVABC/3TCTDF/FTC

NRTI ComponentSecondary Analysis

NNRTI/PI ComponentSecondary Analysis

VAT change from week 0 (%)

P=0.55

P=0.090

CT Results: Mean percent change in VAT (ITT, Week 96)

McComsey, G, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 77.

FRAM: Low Limb Muscle Massand Central Adiposity Associated with

5 Year Mortality

Arm SM:

LegSM:

VAT:

Tertile 1

Tertile 2

Tertile 3

Tertile 1

Tertile 2

Tertile 3

Tertile 1

Tertile 2

Tertile 3

reference

0.59 (0.35, 0.99)

0.51 (0.25, 1.04)

reference

0.92 (0.54, 1.57)

0.42 (0.21, 0.84)

reference

1.77 (1.03, 3.03)

2.12 (1.13, 3.98)

Lower Odds of Death Higher Odds of Death

0.10 1.00 10.00Odds Ratio (95% CI)

Odds Ratio (95% CI)

Scherzer R, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 76.a

Bone Resorption as an IRIS Event

• TDF/FTC+LPV/r (n=20) • Bone resorption markers (CTx, RANKL) increase from week 2.

Maximal change for CTx +93% at week 12, and RANKL +162% at week 24 (both p<0.01)

• In T-cell null mice undergoing T cell reconstitution with similar changes in RANKL

Change in Bone Resorption with HAART

C-T

erm

inal

Tel

op

epti

de

(% C

han

ge

fro

m B

ase

lin

e)

HAART(LPV/r + TDF/FTC)

-100

0

100

200

300

400

0 2 12 24 Time (Weeks)

P<0.001 P<0.001

Ofotokun I, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 78.

iPrEX: PrEP in HIV-Negative IndividualsMean Change in BMD Through Week 72

FTC/TDF(n=247)

Placebo(n=256) Difference (95% CI) P-value

Total hip

Wk 24 -0.33 (0.13) +0.36 (0.13) -0.69 (-1.06 to -0.33) < 0.001

Wk 48 -0.02 (0.21) +0.91 (0.21) -0.94 (-1.53 to -0.35) 0.002

Wk 72 +0.25 (0.27) +0.59 (0.27) -0.34 (-1.10 to 0.42) 0.38

Spine

Wk 24 -0.65 (0.20) +0.30 (0.20) -0.94 (-1.50 to -0.39) 0.001

Wk 48 -0.38 (0.24) +0.20 (0.24) -0.58 (-1.24 to 0.07) 0.081

Wk 72 -0.96 (0.31) +0.07 (0.30) -1.03 (-1.88 to -0.19) 0.017

• There were no differences in bone fractures between the groups (p=0.56)

Mulligan K, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 94LB.

ECHO: Severe Vitamin D Deficiency with Rilpiverine vs. Efavirenz

P <0.05P <0.05

Deficient at BL Deficient or Insufficient at BL

Per

cen

tag

e D

evel

op

ing

Sev

ere

Vit

amin

D D

efic

ien

cy

• Change in 25(OH)D levels over 48wks: RPV -0.6 nmol/l (p=0.57) vs. EFV -6.2 nmol/l (p<0.05)

• Baseline insufficiency or deficiency had significantly greater risk of developing severe deficiency with EFV vs. RPV

Wohl D, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 79LB.

Vitamin D TherapyEffect on PTH

• Randomized trial of Vit D 50,000 IU/wk x 12 weeks vs. PBO in patients on (n=118) or not on (n=85) TDF

• Higher baseline PTH levels at baseline in TDF group• Vitamin D had no impact on PTH levels in patients not on TDF

TDF No TDF

Day 0

ChangeDay

0Change

Vit D 47 -6 26 -2

PBO 37 +2 25 0

Changes in PTH on study

Havens P, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 80.

Mean Baseline PTH by Vitamin D status and Tenofovir Use PTH Differs by Tenofovir use, not Vitamin D status

52

35

43

27

P=0.001P=0.001 P<0.001P<0.001

Treatment Effects of Vitamin D

• Goal: Evaluate effect of vitamin D on flow mediated dilitation (FMD)1

• Design: Placebo-controlled trial of vitamin D 4000 mg daily in patients with HIV RNA <50 c/mL and 25(OH)D ≤20 ng/mL− 2:1 randomization, n=45

• Results− No impact of vitamin D on

FMD compared to placebo− In vitamin D group:

− Non-HDL cholesterol fell 7.0 mg/dL

− No impact on markers of coagulation

− HOMA-IR and insulin levels rose

• Goal: Evaluate effect of vitamin D therapy on Incidence of DM II2

• Design: Non-randomized cohort (n=1574) study comparing vitamin D

(30,000 IU weekly) treated and non-treated patients

1. Longenecker C, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 829; 2. Guaraldi G, et al. ibid., Abst. 827.

Inci

de

nce

(%

)

• Tesamorelin 2mg in HIV+ persons with excess abdominal fat increases bone turnover markers over 26 weeks

• Relative to placebo, increases in osteocalcin (bone formation) were greater than NTx (bone resorption); Changes correlated with IGF-1 levels

Tesamorelin Increases Markers of Bone Formation

Mean changes from baseline to Week 26 in osteocalcin by treatment group

p<0.001 vs.placebo and baseline

211 Completed the Study (77%)




273 Tesamorelin273 Tesamorelin 137 Placebo137 Placebo

412 Patients Randomized412 Patients Randomized

2 patients did not receive study drug

Mamputu J-C, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 834.

ManagementJürgen Rockstroh, MD

Professor, University of BonnBonn, Germany

Changing Patterns of the Causes of Death in a Swiss Cohort (SHCS)

• SHCS is a prospective observational cohort• Characteristics of participants that died from 2005-2009• 459 deaths/9,053 participants (5.1%)

Ruppik M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 789.

Causes of Death in Participants in the Swiss HIV Cohort Study in 3 different Time Periods, and in the Swiss Population in 2007

Years of Death of HIV+ Persons Versus Swiss Population

Study of immediate vs. early ART to reduce AIDS and death in HIV+ patients

with CD4+ cells <250 cells/mm3 and confirmed or suspected TB48 weeks analysis

N=405 TMP/SMX + TDF/FTC/EFV at 2 weeks post TB Tx

Arm 1 Immediate ART

(2 weeks after TB treatment)

N=401 TMP/SMX + TDF/FTC/EFV at 8-12 weeks post TB Tx

Arm 2 Early ART

(8-12 weeks after TB treatment)

Havlir D, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 38.

ACTG 5221: Starting ART in Patients on TB Therapy

ACTG 5221: Results

Immediate ART

Early ART p value

TB diagnosis confirmed 46% 54%

Median ART Start Time 10 days 70 days

Experienced AIDS or death by week 48

12.9% 16.1% p=0.45

Experienced AIDS or death by W48 with ≤ 50 cells/mm3 (n=285)

15.5% 26.6% p=0.02

>50cells/mm3 (n=521) 11.5% 10.3% p=0.67

Havlir D, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 38.

SAPiT: Reduced Survival ProbabilityWith Sequential vs Integrated

TB Therapy

N Engl J Med. 2010;362:697-706.

Su

rviv

al

Pro

ba

bil

ity

Mos after Randomization

0

0.70

0.75

0.80

0.85

0.90

0.95

1.00

0 2 4 6 8 10 12 14 16 18 20 22 24

Sequential therapy

Integrated therapy

SAPiT: Optimal Timing of ART Relative to TB Treatment

in Coinfected Patients

Early TreatmentInitiate ART within first 2 months of

starting TB treatment (n = 214)

Patients enrolled in the Integrated Treatment Arm of the SAPiT Trial:•HIV-infected patients •CD4+ < 500 cells/mm3

•Smear-positive TB(n=642)

Late TreatmentInitiate ART as soon as possible after 2 months

of intensive TB treatment phase completed(n = 215)

Karim S, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 39LB.

No discernable differences in AIDS/death

Early - Events / # at risk

Late - Events / # at risk


SAPiT: Kaplan-Meier Curve for AIDS or Death in Patients

with CD4 ≥50 cells/mm3

68% reduction of AIDS/death by starting ART Early (p=0.06)

Early - Events / # at risk

Late - Events / # at risk


SAPiT: Kaplan-Meier Curvefor AIDS or Death in Patients

with CD4 <50 cells/mm3

Treatment Outcome in Acute HCV in HIV-coinfection: RVR & EVR

• Prospective study of HIV-positive patients with acute HCV treated early with PegIFN alone (N=31) or with PegIFN/RBV (N=207)

Boesecke C, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 113.


Treatment Outcome in Acute HCV in HIV-coinfection: ETR & SVR


Treatment Outcome in AcuteHCV in HIV-coinfection:

Uni- and Multivariate AnalysisSVR n=161

no SVR n=77

Univariate p-value

Multivariate p-value

Multivariate Odds-Ratio

(95% CI)

RVR 65.4% 28.3% ≤0.0001 ≤0.00014.600

(2.336-9.059)

GT 2/3 21.7% 10.4% 0.046 0.0432.945

(1.034-8.385)

IL28B CC genotype 55.3% 34.8% 0.271

Median baseline CD4-cells [/µl] (95% range)

484 (368-632)

433 (347-602)

0.164

Baseline HIV-RNA <50 copies/ml

61.3% 56.7% 0.551

Baseline HCV-RNA >800,000 IU/ml

44% 58.1% 0.069

Median maximum ALT [U/l] (95% range)

398 (195-761)

325 (168-706)

0.227

Clinical symptoms 27% 22.4% 0.523

peg IFN/RBV 85.7% 88.3% 0.714

HAART 67.7% 63.6% 0.559

TW 8-24 HCV-RNA UndetectableTW 8-24 HCV-RNA Undetectable

TW 8-24 HCV-RNA DetectableTW 8-24 HCV-RNA Detectable

PR + Placebo PR + Placebo Follow-up

Follow-upFollow-up

BOCRGT

(N=368)

PR + Boceprevir PR + BoceprevirPRlead-in

BOC/PR48

(N=366)

PR + BoceprevirPR + Boceprevir Follow-upPRlead-in

SPRINT 2: Boceprevir in HCV Mono-infected Patients

Week 4 Week 48

PR + Placebo PR + Placebo Follow-upPRlead-in

Week 28 Week 72

Control48 P/R(N=363)

Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 115.

SPRINT-2: SVR and Relapse Rates (ITT)


p < 0.0001

p <0.0001

Non-Black Patients

p = 0.044

p =0.004

Black Patients

SVR

Relapse Rate

48 PR BOC RGT BOC/PR48

Median treatment duration (days) 203 197 335

Deaths (N) 4 1 1

Serious AEs 9% 11% 12%

Discontinued due to AEs 16% 12% 16%

Dose modification due to AEs 26% 40% 35%

Hematologic parameters

Neutrophil count (<750 to 500/mm3 / <500/mm3)

14% / 4% 24% / 6% 25% / 8%

Hemoglobin (<10 to 8.5 g/dL / <8.5 g/dL)

Discontinuation due to anemia

Dose reductions due to anemia

Erythropoietin use

Mean (median) days of use

26% / 4%

1%

13%

24%

121 (109)

45% / 5%

2%

20%

43%

94 (85)

41% / 9%

2%

21%

43%

156 (149)

SPRINT-2: Safety Profile Over Entire Course of Therapy


Study 110: Telaprevir in HIV/HCV Patients

Part A: no ARTPart A: no ART

240 48 72Weeks 12 36

PR PR

PR PR

T/PR TVR + PR Follow-upSVR

Follow-upPR48

(control)

SVRPbo + PR

PR PR

PR PR

Follow-upPR48

(control)

SVRPbo + PR

T/PR TVR + PR Follow-upSVR

Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC)Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC)

Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 146LB

Study 110: Demographics and Baseline Characteristics

Part A Part B

No ART EFV/TDF/FTCATV/r + TDF +

FTC/3TC

T/PRN=7

PRN=6

T/PRN=16

PRN=8

T/PRN=14

PRN=8

Gender, n (%): Male6 (86) 4 (67)

16(100)

7(88)

12(86)

7(88)

Race†, n(%) Caucasian Black/African American

2 (29)4 (57)

3 (50)3 (50)

12 (75)3 (19)

5 (62)3 (38)

12 (86)2 (14)

7 (88)1 (12)

Ethnicity†, n (%) Hispanic

3(43)

2(33)

5(31)

1(12)

3(21)

3(38)

Age, median years (range) 39(34-51)

48(43-65)

48(31-57)

47(31-53)

54(37-60)

39(26-53)

BMI, median kg/m2 (range) 29(22-37)

31(26-37)

24(21-32)

23(19-29)

24(23-33)

25(22-30)

HCV RNA ≥ 800,000 IU/mL**, n (%) 7(100)

5(83)

13(81)

7(88)

10(71)

7(88)

HCV Genotype Subtype*, n (%) 1a 1b

3 (43)4 (57)

3 (50)2 (33)

12 (75)4 (25)

6 (75)1 (12)

11 (79)3 (21)

5 (62)3 (38)

HIV RNA median copies/mL (range) 1495(155-53,450)

267 (25-21,950)

<50 <50 <50 <50

CD4+ median cells/mm3 (range) 604 (496-759)

672 (518-1189)

533 (299-1075)

514 (323-1034)

492(279-874)

535 (302-772)


Study 110: Undetectable HCV RNA at Week 4 (RVR)

No ARTNo ART

EFV/TDF/FTCEFV/TDF/FTC

ATV/r + TDF + FTC/3TCATV/r + TDF + FTC/3TC

5/75/7 12/1612/16 9/149/14 0/80/81/81/80/60/6

71717575

00

6464

1313

00

Per

cen

t o

f p

atie

nts

w

ith

HC

V R

NA

Un

det

ecta

ble

Per

cen

t o

f p

atie

nts

w

ith

HC

V R

NA

Un

det

ecta

ble

TVR + PRTVR + PR

n/N =n/N =

PRPR

0

10

20

30

40

50

60

70

80

90

100


Study 110: Undetectable HCV RNA at Week 12 (cEVR)

Per

cen

t o

f p

atie

nts

w

ith

HC

V R

NA

Un

det

ecta

ble

Per

cen

t o

f p

atie

nts

w

ith

HC

V R

NA

Un

det

ecta

ble

TVR + PRTVR + PR

n/N =n/N =

PRPR

0

10

20

30

40

50

60

70

80

90

100

71717575

1717

5757

1212 1212

5/75/7 12/1612/16 8/148/14 1/81/81/81/81/61/6


No ARTNo ART

EFV/TDF/FTCEFV/TDF/FTC

ATV/r + TDF + FTC/3TCATV/r + TDF + FTC/3TC

Part A Part B

No ART EFV/TDF/FTC ATV/r + TDF + FTC/3TC

T/PR(N=7)

PR(N=6)

T/PR(N=16)

PR(N=8)

T/PR(N=14)

PR(N=8)

Any AE 100% 83% 94% 88% 100% 100%

Serious AE 14% 0 0 0 21% 0

Discontinuation of all study drugs

Due to AE

Due to anemia

Due to rash

0

0

0

0

0

0

0

0

0

0

0

0

14%

7%

0

0

0

0

Study 110: Serious Events and Treatment Discontinuation

• Mild and moderate rash events occurred in 16% and 11% of T/PR patients, respectively and in 14% and <1% of PR patients


Pharmacokinetic Interactions Between ARVs and Telaprevir

TVR Dose ARV TVR AUC TVR Cmin ARV AUC ARVCmin

TVR 750 mg tid ATV/r0.80

(0.76-0.98)0.85

(0.75-0.98)1.17

(0.97-1.43)1.85

(1.40-2.44)

DRV/r0.65

(0.61-0.69)0.68

(0.63-0.74)0.60

(0.57-0.63)0.58

(0.52-0.63)

FPV/r0.68

(0.63-0.72)0.70

(0.64-0.77)0.53

(0.49-0.58)0.44

(0.40-0.50)

LPV/r0.46

(0.41-0.52)0.48

(0.40-0.56)1.06

(0.96-1.17)1.14

(0.96-1.36)

TVR 1250 mg tid EFV

0.82 (0.73-0.92)

0.75 (0.66-0.86)

0.82 (0.74-0.90)

0.90 (0.81-1.01)

TDF1.10

(1.03-1.18)1.17

(1.06-1.28)

TVR 1500 mg bid EFV

0.80 (0.73-0.88)

0.52 (0.42-0.64)

0.85 (0.79-0.91)

0.89 (0.82-0.96)

TDF1.10

(1.03-1.17)1.06

(0.98-1.15)

Van Heeswijk R, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 119.

PK of Rilpivirine Following EFV

• EFV is an inducer of Cyp3A; it can increase the metabolism of RPV

• 20 healthy volunteers treated sequentially− Part A: RPV x 2 wks, plus 2 wks washout

(control)− Part B: EFV X 2 weeks followed by C− Part C: RPV x 4 weeks (Switch)

• To compare RPV PKs during Part A andPart C

• Results:− RPV exposures lower after switch from EFV− Differences were very significant on day 1− RPV PK gradually improved over 4 weeks − Levels of EFV were detectable for

3 weeks post dose

• Concentrations of RPV may be affected after a switch from an EFV containing regimen

Crauwels H, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 630.

Outcomes Measurement Reminder

• CME providers are required to assess “changes in learners competence, performance or patient outcomes achieved as a result of their participation in a CME sponsored educational activity”

• As a result of this requirement you will receive via e-mail a short 1-page survey 2 to 3 months after completing this course− We consider the survey to be an additional component of your overall

participation in this educational activity and would urge you to reflect on what you learned in the activity and then complete this survey

• Please be certain that you have correctly written your e-mail address on the CME evaluation form that you complete at the end of today’s activity

The 18th Conference on Retroviruses and Opportunistic

InfectionsBoston, MA

February 27-March 2, 2011

the 18 th conference on retroviruses and opportunistic infections boston, ma february 27-march 2,...

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