The 17th Conference on Retroviruses and Opportunistic Infections San Francisco, CA February 16-19, 2010

The 17th Conference on Retroviruses and

Opportunistic Infections

San Francisco, CA

February 16-19, 2010

Studies in ARV-Naïve PatientsWhen to Start

Rick Elion, MDAssociate Professor, George Washington University

School of MedicineWashington, DC

Life Expectancy ofHIV-Positive Patients

Comparison of life expectancy of Athena cohort patients to general population (n=4174)

Age at week 24, country of birth and stage B symptoms were associated with a higher risk of death

Expected life years remaining at age 25 was 53.1 (44.9-59.5) for general population and 52.7 for asymptomatic HIV+ patients

The modeled life expectancy of patient presenting at an older age and women were slightly lower that general population

Years of Life Remaining

General PopulationAsymptomatic HIV+ Patients

Years of Life Remaining

Age at time of death

Remaining Life Years

Age at 24 weeks (years)Y

ea

rs li

ved

van Sighem A, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 526.

Increasing CD4 at First Presentation but Patients Still Present Late to Care

NA-ACCORD analysis regarding median CD4 on first presentation from 1996-2007 (N=35,009)

Median CD4 on presentation has increased from 234 to 327 cells/mm3 (P<0.01)

Proportion of CD4 ≥350 cells/mm3 at first presentation has increased from 34% to 47% (P≤0.01)

Althoff K, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 982.

Linkage of Testing to Routine Care Leads to Earlier Diagnoses

Washington DC has an estimated HIV seroprevalence of 3%

2006 DOH expanded HIV testing to be included in routine care with improved clinical linkages

From 2004 to 2006, HIV tests increased from 19,000 to 73,000

Among newly diagnosed, median CD4 count increased 57%

p<0.001

Castel A, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 34.

CD4 at Initiation of ARV Therapy Predicts Extent of CD4 Recovery

1,378 patients at 10 US clinics followed from 1996-2007

Median Peak CD4 was progressively higher for specific CD4 strata (p<0.001)

Multivariate analysis: Increased mortality with CD4 < 50 (HR=4.6) and CD4 50-199 (HR=2.6) compared to ≥200 cells/mm3

Lower BL CD4 at initiation also associated with increased risk of death from non-AIDS-related causes.

Med

ian

CD

4+ c

ell c

ou

nt

Palella F, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 983.

Correlation Between Nadir CD4+ T-cell Count and Cardiovascular Risk

Cross-sectional study of 80 HIV+ men on ARV Tx with undetectable HIV RNA Median age 47 years, nadir CD4+

T cell count 180 cells/mm3

CV risk assessed using arterial stiffness (AS) by pulse wave analysis and carotid-femoral pulse wave velocity (PWV)

Nadir CD4 count <350 cell/mm3 independently associated with significant increase in AS and PWV Other significant determinants of PWV

in multivariate analysis included age, systolic and diastolic BP, and diabetes.

AS was not affected by the duration of ARV therapy or exposure to PIs or ABC.

Significant determinants of PWV on Multivariate Analysis

Beta (95%) P-value

Age0.48

(0.26-0.70)<0.001

Systolic blood pressure

0.44(0.12-0.76)

0.007

Diastolic blood pressure

-0.29(-0.53-0.04)

0.03

Diabetes mellitus2.38

(1.38-3.38)<0.001

Nadir CD4 <3500.58

(0.15-1.01)0.008

Ho J, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 707.

Neurocognitive Disorders Associated with Nadir CD4 Counts

Multicenter cohort study (CHARTER) of 1526 pts evaluating HIV-associated Neurocognitive Disorders (HAND)

Complex testing consistent with defined criteria used to determine HAND 603 had HAND (without

a substantial confounder); 726 not impaired

Most with HAND (n=428) were asymptomatic and only a few (n=27) had frank dementia

Multivariate analysis: Higher CD4 nadir associated with lower risk of HAND

N Impaired Unimpaired OR (95% CI)

All 1525 799 726

Nadir CD4 < 50 387 222 165 1.00 (reference)

Nadir CD4 50-199 481 258 223 0.86 [0.66, 1.13]

Nadir CD4 200-349 370 189 181 0.78 [0.58, 1.03]

Nadir CD4 ≥350 287 130 157 0.62 [0.45, 0.84]

On ART, Plasma VL <50c/ml 589 320 269

Nadir CD4 < 50 185 112 73 1.00 (reference)

Nadir CD4 50-199 214 118 96 0.80 [0.54, 1.19]

Nadir CD4 200-349 133 64 69 0.60 [0.39, 0.95]

Nadir CD4 ≥350 57 26 31 0.55 [0.30, 0.99]

Odds Ratios for NP Impairment

Odds Ratio for Cognitive Impairment by CD4 Nadir

<50 50-199 200-349≥350

1.11

0.90.80.70.60.50.40.3

Odd

s R

atio

CD4 Nadir

Ellis R, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 429.

Impact of Expanded HAART Availability on New HIV Diagnoses

Evaluation of association between expansion of ART coverage, population level HIV viral load and new HIV diagnoses in British Columbia

Expansion of ART access in 2004-2009 associated with a significant decline in new HIV diagnoses

After 2007, ~50% decrease in new HIV diagnoses among IDU occurred and associated with a decline in proportion of HIV+ IDU with plasma HIV-1-RNA level >1500 copies/mL from ~50% (2000-2004) to ~20% (2009) (P<0.001)

New HIV + Diagnoses (All)

New HIV + Diagnoses (IDU)

Active on HAART

Montaner J, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 88LB.

Studies in ARV-Naïve PatientsWhat to Start

Joseph Eron, MDProfessor, University of North Carolina School of Medicine

Chapel Hill, NC

Elvitegravir and Cobicistat (GS-9350):Design of the Two Phase 2 Studies

• Randomization stratified by HIV RNA (≤ or >100,000 copies/mL)• Primary Endpoint: Proportions with HIV RNA <50 copies/mL at Week 24• 48-week trials

Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 58LB.

Treatment-naïveHIV RNA ≥5,000 copies/mLCD4 cells >50 cells/mm3 No Resistance to

NRTIs NNRTIs

PIsHBV- and HCV-negative

EVG/GS-9350/TDF/FTC + placebon=48

EFV/TDF/FTC + placebon=23

2:1

GS-9350 + placeboATV + FTC/TDF

n=50

RTV + placeboATV + FTC/TDF

n=29

2:1

Baseline Characteristics


Primary Endpoint: Percentage with HIV RNA <50 copies/mL (ITT M=F)


Week 24 stratum-weighted difference+5% (95% CI: -11.0% to 21.1%)

EVG/GS-9350/TDF/FTC EFV/FTC/TDF

EVG/GS-9350 vs. EFV

0 4 8 12 16 20 240

20

40

60

80

100

83%90%

Week

Per

cen

tag

e w

ith

HIV

RN

A <

50 c

op

ies/

mL

RTV + ATV + TDF/FTCGS-9350 + ATV + TDF/FTC

Week 24 stratum-weighted difference-1.9% (95% CI: -18.4% to 14.7%)

RTV vs. GS-9350

0 4 8 12 16 20 240

20

40

60

80

100

84%86%

Week

Per

cen

tag

e w

ith

HIV

RN

A <

50 c

op

ies/

mL

Adverse Events >5% Related to Randomized Drug


HIV-1 RNA ≥1000 c/mLAny CD4+ count≥16 years of age

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

HIV+, ART-naïve(N=1857)

TDF/FTC QD

ABC/3TC Placebo QD

ABC/3TC QD

TDF/FTC Placebo QD

TDF/FTC QD

ABC/3TC Placebo QD

ABC/3TC QD

TDF/FTC Placebo QD

ATV/rQD

ATV/rQD

EFVQD

EFVQD

A5202: Study Design

Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.

* Required for those with recent infection, otherwise optional

A5202: Overall Baseline Characteristics

EFV(n=465)

ATV/r(n=463)

EFV(n=464)

ATV/r(n=465)

ABC/3TC TDF/FTCMedian Age (years) 37 38 39 39

Male 79% 84% 85% 83%

Race/Ethnicity

White non-Hispanic 38% 41% 43% 40%

Black non-Hispanic 35% 33% 33% 32%

Hispanic 23% 23% 22% 24%

Median HIV RNA (log10 c/mL) 4.7 4.6 4.7 4.7

Median CD4 (cells/mm3) 225 236 234 224

History of AIDS 19% 15% 15% 15%

Genotype at screening* 43% 47% 47% 40%

HCV positive 6% 9% 9% 7%


A5202: Time to Virologic Failure in Patients with Baseline HIV RNA >100,000 c/mL

TDF-FTC (26 events)

ABC-3TC (57 events)P<0.001, log-rank testHazard ratio, 2.33 (95% CI, 1.46-3.72)

Probability of No Virologic Failure

Results similar between EFV and ATV/r arms

Sax PE, et al. NEJM 2009;361:2230-2240; Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.

Probability of No Virologic Failure and CD4+ Change at Week 96

Per

cen

t w

ith

ou

t V

iro

log

ic F

ailu

re

HR 1.26(0.76,2.05)

HR 1.23(0.77,1.96)

HR 1.13(0.82,1.56)

HR 1.01(0.70,1.46)

CD4 Change (cells/mm3)P=

250 251 221252

0.89 0.002

HIV RNA <100,000 c/mL All Subjects


ATV/r EFV ABC/3TC TDF/FTC

Per

cen

t w

ith

ou

t V

iro

log

ic F

ailu

re

A5202: Percent of Virologic Failures with Emergence of Major Resistance Mutations

P-values: ATV/r vs. EFV (among failures)*Major mutations defined by IAS-USA (2008) list plus T69D, L74I, G190C/E/Q/T/V for RT and L24I, F53L, I54V/A/T/S and G73C/S/T/A for PR


ABC/3TC TDF/FTC

P<0.0001

P=0.0003

P<0.0001

P=0.046Per

cent

Viral failuresNo baseline resistance (N)

76 63 54 48

ACTG 5208: Study DesignOctane Trial II

Only African sites; partner study to same comparison in women who had received sdNVP

Open-label comparison of NVP and LPV/r, both combined with TDF/FTC

Baseline Characteristics NVP (n=249) LPV/r (n=251)

Age 35 34

CD4 121 121

VL 5.16 5.15

ZDV exp 2% 1%

BL NVP Resistance 1% 0

Subtype C 75% 68%

ART-naïve women with CD4+ <200 cells/mm3

(N=500)

Two primary endpoints:•Time to VF/death•Time to discontinuation

Median F/U (weeks)

120

116

Boltz V, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 154.

OCTANE 1: Results Among Women with Prior sdNVP Exposure

Virologic Failure or Death

Pa

tie

nt

Per

ce

nt

NVP LPV/r

Adjusted HR 3.6 (95% CI: 1.7-7.5)


sdNVP=Single-dose NVP

ACTG 5208/OCTANE 2:Results at 168 Weeks

Virologic Failure or Death

Pat

ien

t P

erce

nt

NVP LPV/r

HR 0.85 (95% CI: 0.56-1.29)

• VF: LPV/r 17% vs. NVP 15%

• Death: LPV/r 3% vs. NVP 2%

HR 3.4 (95% CI: 2.2-5.5)

Discontinuation

• Pts D/C due to AE: NVP 35 vs. LPV/r 0− Hepatic events 20, rash 12, hepatic/rash 2


Pat

ien

t P

erce

nt

Studies in Treatment-Experienced Patients And

Investigational Compounds

Calvin Cohen, MDResearch Director, CRI New EnglandHarvard Vanguard Medical Associates

Boston MA

ODIN: Study Design

Phase IIIb, randomized, open-label study

DRV/r 800/100mg qd + OBT‡ (n=294)

DRV/r 600/100mg bid + OBT‡ (n=296)

• ARV-experienced patients, aged 18 years

• HIV-1 RNA >1000 copies/mL

• CD4 cell count >50 cells/mm3

• No DRV RAMs at screening*• Stable HAART for

12 weeks

Treatment phase (up to 48 weeks)

stratified by screening HIV-1 RNA (50,000,

>50,000 copies/mL)

ARV = antiretroviral; HAART = highly-active antiretroviral therapy; OBT = optimized background therapy;qd = once-daily; bid = twice-daily; RAMs = resistance-associated mutations

Cahn P, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 57

* DRV RAMs include the following mutations: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V‡ Individualized OBT included ≥2 N(t)RTIs based on ARV history and resistance testing Only restrictions on previous therapy: use of enfuvirtide, tipranavir, DRV, current use of investigational drugs

‡Using Antivirogram®


ODIN: Key Features of Population including Prior and Concurrent ARVs

ODIN: Virologic Response Rates and Resistance Outcomes


‡ Not significant; §Also DRV RAMs

Resistance SummaryDRV/r 800/100mg qd

Screening HIV-1 RNA (copies/mL)

N= 222 224 72 72

52.8%52.8%

76.8%78.4%

>50,00050,000

0

20

40

60

80

100

% H

IV-1

RN

A <

50

co

pie

s/m

L (

% [

95

% C

I])

DRV/r 600/100mg BIDDRV/r 800/100mg QD

DRV/r 600/100mg bid

Response by Screening HIV RNA

Meets NoninferiorityDifference in response qd vs. bid (ITT): 72.1–70.9 = 1.2% (95% CI = –6.1%, 8.5%)

ODIN: Summary of Safety and Lab Findings

* Includes deaths (2 in qd group; 6 in bid group; none considered by investigator as related to DRV treatment


VICTOR E3 & 4: DESIGN

2 randomized, identical, placebo-controlled, double-blind, phase 3 trials

Documented resistance to ≥2 available drug classes (NRTI, NNRTI, or PI) or ART experience of at least 6 months

Primary endpoint: % HIV RNA <50 copies/mL at 48 weeks

Gathe J, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 54LB

Treatment-experiencedR5-HIV only

(N=721)*

Treatment-experiencedR5-HIV only

(N=721)*

Vicriviroc 30 mg + OBT (n=486)Vicriviroc 30 mg + OBT (n=486)

Placebo + OBT (n=235)Placebo + OBT (n=235)

Week 24 Interim analysis

Week 48Final analysis

Randomized 2:1 to VCV:Placebo

*857 were enrolled but 721 R5 by Trofile ES; this is the MITT population and this subset was analyzed prior to any unblinding of results

VICTOR E3 & 4: Pooled Efficacy

70%

n=176

55%

n=85

≤2

61%

n=293

65%

n=145

≥3

% H

IV R

NA

<50

c/m

L

Response by Overall Sensitivity Score

80%

60%

40%

20%

0%

100% VCV Control

No. of Active Drugs in Background


Note: Subset with 0-1 active Drug: 47% VCV (n=19) vs. 12% (n=8) on Pbo responded

VICTOR E3 & 4: Virologic Failure, Resistance and

Discontinuations



Victor E3 & 4:Key Adverse Events

*Causes of Death (1 each): Intestinal obstruction & septicemia S/P prior abdominal surgery, Homicide; Myocardial infarction (recurrent while in OR for CABG); Chronic congestive heart failure with pericardial effusion; Acute cholecystitis with septicemia; Plasmablastic lymphoma; Multiorgan system failure accompanied by cholecystitis and pleural effusion

Potent Oral CCR5 and CCR2 receptor antagonist In vitro protein-adjusted EC50=0.29 nM for R5 Neither a CYP inducer nor inhibitor Additive / synergistic activity with other ART classes in vitro Oral bioavailability (current formulation) enhanced by food Once daily dosing (Plasma T ½=35-40 hours)

Study Design: Ten day monotherapy, R5-tropic pts

CCR2 receptors are associated with, and currently being studied in several inflammation-associated diseases (atherosclerosis, rheumatoid arthritis, insulin resistance)

Thus far no significant safety signals are identified with CCR2 antagonists

TBR-652: Characteristics and Potential for CCR2 Inhibition

Cohen C, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 53

TBR-652: Median and Nadir Antiviral Response with Ten Days Monotherapy


Median VL ResponseMedian VL Response

10 day dosing

Nadir Viral load ResponseNadir Viral load Response

Note: CCR2 inhibition observed using MCP-1 level increasesNote: CCR2 inhibition observed using MCP-1 level increases

TBR-652: Summary of Adverse Events

* AEs in 2 patients or more per cohort judged at least possibly related to study drug* AEs in 2 patients or more per cohort judged at least possibly related to study drug..


Studies in Resistance Issues

Andrew Zolopa, MDAssociate Professor, Stanford University School of Medicine

Palo Alto, CA

Octane 1: Low Level NNRTI Resistant Variants Explain Virologic Failures

Women prior SD NVP– For MTCT prevention

Randomized clinical trial: NVP vs. LPV/r– TDF/FTC backbone

NVP: Higher rate of VF (HR 3.5) Only 1/3 of NVP failures

had resistance by standard GT

Analyzed results by ASP Frequency of >0.8%

associated with increased risk of VF

(n=120) (n=119) (n=15) (n=18) (n=105) (n=101)

P=0.001 P=0.006 P=0.038

8%

26%

13%

19%

6%

9%

ASP=Allele specific PCR

Boltz V, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 154.

OCTANE 1: Virologic Outcomes by Resistance at baseline by Allele Specific PCR (ASP*)

Overall Baseline GT: no NNRTI R

% V

irolo

gic

Failu

re

Boltz V, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 154.

*ASP detects specific mutations; sensitivity to 0.1%

Transmitted Drug Resistance in US: Newly Diagnosed

2007 CDC surveillance for transmitted drug resistance (TDR) 10,496 with new HIV Dx 2,480 with genotype

TDR detected in 16% of patients with new HIV diagnosis Most common: NNRTI 83% had single mutation

No demographic risks factors identified

HIV TDR Surveillance Areas (2007)Seattle-King

County

HIV TDR (2007)

Per

cent

with

TD

R50% K103N

Kim D, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 580.

Superinfection Leads to Viral Load Increases

Report of HIV superinfection in MSM (M1 and M2)

Source patient (M2) MDR HIV on partially suppressive LPV/r + ABC/3TC regimen

Superinfected patient (M1) HIV RNA <50 c/mL on ABC/AZT/3TC Sudden increase in HIV RNA to >200 c/mL with further rebound Rebound associated with 3 class resistance that matched M1 Phylogenetically related viruses found in M1 and M2 M1 HIV displaced by M2 HIV

Castro E, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 480.

BENCHMRK: Trial Design and Week 156 Results

Week 240

HIV-1-infected Triple-class resistant HIV-1 RNA>1000 copies/mL; No CD4 cell cut-off

RAL 400mg BID + OBTP018 (n=234)P019 (n=232)

Placebo+ OBTP018 (n=118)P019 (n=119)

RAL 400mgBID + OBT

RAL 400mgBID + OBT

Primary endpoints:Week 16

Current Analysis:Week 156

2:1

Raltegravir + OBTPlacebo + OBT

462237

461237

462237

460237

459237

Number of Contributing PatientsWeeks

100

80

60

40

20

00 24 156*96*48*P

erc

en

t o

f P

ati

en

ts w

ith

H

IV R

NA

<5

0 C

op

ies

/mL

22%26%33%

50%57%

62%

Percent of Patients (95% CI) with HIV RNA<50 Copies/mL (NC=F Approach)

Raltegravir + OBTPlacebo + OBT

462237

435230

397208

418219

439228

Number of Contributing Patients

0

Ch

an

ge

fro

m B

as

eli

ne

CD

4 C

ell

Co

un

t (c

ell

s/m

m3 )

Weeks

200

150

100

50

024 156*96*48*

634945

124109

164

Change from Baseline in CD4 Cell Count(cells/mm3) (OF Approach)

Eron J, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 515.

28%

71%

87%

100%

71%

17%

BENCHMRK: Analysis by Early HIV RNA Response in RAL Treatment Group

*For HIV RNA, only discontinuations due to lack of efficacy counted as failures

Patients with low levelviremia demonstrated:

– Favorable wk 156 virologic and immunologic outcomes (CD4 increase from BL +226 cells/mm3)

– Significantly shorter time to loss of virologic response (TLOVR ≥400 cp/mL) compared to CS group

Category NameEarly Response Definition : Observed HIV RNA

(copies /mL) Week 16-48 (5 time points)RAL

N=462Continuous Suppression CS All time points <50 199Low Level Viremia LLV All <400 with one or more >50 111Not Suppressed NS Intermittent >400 (not consecutive) 63

Not Included - Pts. who discontinued double blind treatment prior wk 48* 89

Eron J, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 515.

Toxicities in Clinical Trials

Paul Sax, MDAssociate Professor, Harvard Medical School

Boston, MA

A5202: ATV/r vs. EFVMedian Change in Fasting Lipids (Week 48)

• In low HIV RNA stratum, in comparison between ABC/3TC vs. TDF/FTC: significantly greater increase in TC, LDL, HDL with both EFV and ATV/r; greater increase in TG with ATV/r

Median Change in Fasting Lipids (mg/dL)

TC LDL HDL TG

ABC/3TC

ATV/r 29 13 8 24

EFV 40 21 12 15

p-value <0.001 <0.001 <0.001 0.07

TDF/FTC

ATV/r 10 2 5 14

EFV 22 10 8 13

p-value <0.001 0.002 <0.001 0.26


A5202: ATV/r vs. EFV Median Change in Creatinine Clearance

Change in Calculated Creatinine Clearance (mL/min)

Week 48 Week 96

ABC/3TCATV/r 3.1 6.1

EFV 4.3 7.8

p-value 0.17 0.33

TDF/FTCATV/r -0.9 -2.6

EFV 4.1 4.9

p-value 0.001 <0.001


A5202: Pre-Specified Clinical Adverse Events

*Defined as coronary artery disease, infarct, ischemia, angina, cerebrovascular accident, transient ischemic attack or peripheral vascular disease.


TDF/FTC QD

ABC/3TC Placebo QD

ABC/3TC QD

TDF/FTC Placebo QD

TDF/FTC QD

ABC/3TC Placebo QD

ABC/3TC QD

TDF/FTC Placebo QD

ATV/rQD

ATV/rQD

EFVQD

EFVQD

A5224s: Metabolic Sub-Study of A5202

N=69

N=70

N=65

N=65

Enrolledin Substudy

Study Evaluations:-DXA at 0, 24, 48, 96 weeks, then yearly-CT abdomen at 0 and 96 weeks-Serum lipids and plasma

Primary endpoints (TDF/FTC vs. ABC/3TC): 1) Percent change in hip and lumbar spine BMD2) ≥ 10% loss of limb fat

Secondary endpoints: 1) bone and fat loss between EFV and ATV/r2) on-study fractures

EFVN=139

ATV/rN=130

EFV vs. ATV/r TDF/FTC vs. ABC/3TC

TDF/FTCN=139

ABC/3TCN=135

McComsey, G, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 106LB.

* linear regressionNo significant interaction of NRTI and NNRTI/PI components (P=0.63)

A5224s: Mean % Change in Lumbar Spine BMD

P=0.004P=0.035

McComsey G, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 106LB.

A5224s: Limb Fat Changes

• No statistically significant differences incidence of 10% and ≥ 20% loss of limb fat between NRTI components and NNRTI/PI components

• Most study subjects gained limb fat; ATV/r increased limb/trunk fat more than EFV

McComsey G, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 106LB.

STEAL: Switch to ABC/3TC or TDF/FTC

Primary Results: Similar virologic results Increased risk of CV events in ABC/3TC group (8 ABC/3TC vs 1 TDF/FTC, p=0.048) not

explained by lipid changes No difference in renal outcomes Loss of bone density in TDF/FTC vs gain in ABC/3TC group

Inflammatory Marker Substudy 14 biomarkers (inflammatory/renal, thrombotic, endothelial function) measured at weeks 0,

12, 24, and 48 Primary analysis (change from week 0-12): No significant association between use of

ABC/3TC and change in markers Alternative explanation for ABC/3TC association with CVD needed

HIV+Suppressed on 2 NRTI + PI or NNRTI

(N=357)

TDF/FTC FDC

n=179

ABC/3TC FDC

n=178

Martin Clin Infect Dis. 2009 Nov 15;49(10):1591-601; Humphries A, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 718.

Abacavir and CVD: Search for a Mechanism

Increased platelet reactivity1

Carbovir TP (ABC metabolite) inhibits soluble guanylyl cyclase, a known inhibitor of platelet function increases platelet activation

In vitro, ABC induces human leukocyte-endothelial cell interaction at clinically-relevant doses2

0

500

1000

1500

2000

2500

3000

0 20 40 60 80 100 120

Pla

tele

t P

-se

lec

tin

ex

pre

ss

ion

(M

FI)

Time (minutes) of incubation with 80µg/mL abacavir

0

200

400

600

800

1000

1200

1400

1600

3T

C

AB

C

AZ

T

d4

T

dd

C

dd

t

FT

C

PB

S

no

AD

P

RB

V

TD

F

Pla

tele

t P-s

ele

cti

n e

xp

ressio

n

(MF

I)

Drug added (50µg/mL)

1. Baum P, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 717; 2. de Pablo C, et al. ibid., 716.

Abacavir

Control

QUAD or GS-9350 Studies: Estimated GFR (Cockcroft-Gault)

No treatment discontinuations due to renal adverse events Separate study in normal volunteers receiving GS-9350 or placebo for 7 days

Creatinine increase occurs in days, rapidly reversible, due to inhibition of tubular secretion No effect on GFR as measured by iohexol clearance Effect similar to that seen with cimetidine or trimethoprim

*Estimated GFR by Cockcroft-Gault


STARTMRK Metabolic Study: RAL vs. EFV

Randomized, double-blind study comparing RAL vs EFV, both with TDF/FTC

Week 96 lipids (all pts, n=563) EFV increased TC, HDL-C, LDL-

C, TG, and glucose significantly more than RAL

No significant difference in total/HDL chol ratio

Dexa substudy (n=111) Limb fat increased over time Week 96, >20% loss of limb fat

3/37 (8%) on RAL 2/38 (5%) on EFV

‡ p <0.001* P =0.025

‡‡

‡

‡

*

18.2

17.0

18.1

17.7

Mean Percent Change in Appendicular Fat

Lipid Changes

DeJesus E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 720.

Metabolic Complications

Ian Frank, MDProfessor of Medicine

Director, Clinical-Therapeutics ProgramUniversity of Pennsylvania Center for AIDS Research

Philadelphia, PA

DAD: Triglycerides and MI Risk

Methods: Time from D:A:D enrollment to first MI by time-updated TG level Adjustments for associations of independence from other CAD risks TG without regard to fasting Subjects (n = 30,703): Age – 39; White – 54%; Current smoker – 37%;

CD4+ 407; HIV RNA BLQ – 33% Incidence of MI according to TG group• 580 MIs over 178,835 PY• After adjustments for

other CVD risks, doubling of TG associated with an 11% increased risk for MI

Worm S, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 127.

PY = Patient-Years

Markers Associated with CV Risk in NIH Studies

Case controlled study of CVD events 52 of 1892 patients since 1995

Significant traditional risk factors for events: smoking, family hx, lipids

Markers not associated with risk: hs-CRP, IL-6, IL-10, TNFa

Conclusions: Biomarkers may help stratify CVD risk in

HIV patients

D-dimer and sVCAM associated with Increased Risk for CVD

sVC

AM

-1 (

ng

/ml)

Ford E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 713.

CVD Cases

Controls

PTE=Prior to EventP value for all <0.05

Factors Associated with CVD Risk

Visceral Adiposity1

Observational study of 1325 HIV patients in metabolic clinic CVD in 51 Visceral adipose tissue was risk factor, but not waist size or BMI

B-type natriuretic peptide (BNP)2

SMART; 186 subjects with CVE and 329 controls Median BNP 48.1 in CVE group vs 25.7 in controls (p<0.0001) Adjusted OR 2.3 for CVE in highest vs. lowest quartile

Incomplete Immune Recovery on ARVs3

ATHENA cohort 3071 patients on ART >2 years; 58 CVE over 10 years of follow-up More CVE if CD4 <200 cells/mm3 (overall log rank, p=0.02) Adjusted hazard ratio* (95% CI) for CVE by CD4:

1. Guaraldi G, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 703; 2. Duprez D, et al. ibid., Abst. 712; 3. van Lelyveld S, et al. ibid., Abst. 714.

CVD=cardiovascular disease; CVE=cardiovascular event

<200 200-350 350-500 >500

Referent 0.45 (0.18-1.08) 0.70 (0.33-1.47) 0.54 (0.23-1.25)*Adjusted for age, gender, smoking, ARV regimen (PI vs. NNRTI) and family history of CVD

Increased Fracture Rate in HIV Outpatient Study Patients (HOPS)

Comparison of HOPS cohort (n=8,456) vs National Hospital Discharge Survey and National Hospital Ambulatory Medical Care Survey (NHAMCS) Adjusted for age and gender

HOPS: 276 Fractures during median 4.8 yrs follow-up Risk factors for fractures

Age >47 Nadir CD4+ count <200 HCV co-infection Diabetes Substance use

Conclusion: Fracture rates are higher in HIV infected population and rate is increasing with age

Gender-adjusted rates of fracture among adults aged 25-54 years

HOPS

NHAMCS-OPD

P value for trend = 0.01

P value for trend = 0.32

Dao C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 128.

Fracture Rate in HIV Infected Women in WIHS Cohort

Retrospective analysis of 1728 HIV+ and 663 HIV- individuals

Fractures at hip, spine, wrist or other site Ever or within past 6 months

Demographics (HIV+) 56% black, median age = 40, BMI = 28

Medical History (HIV+) Smoking 45%, Vitamin D supplements 42%, Menopause 20%, HCV+ 25% CD4+ count = 482 On ARVs – 66%; Median years ART 5 +/- 10

HIV + HIV -

No. Incident Fracture (%)

Fracture/ 100 py

No. Incident Fracture (%)

Fracture/100 py P-value

Any Site 148 (9%) 1.79 47 (7%) 1.41 0.13

Spine 15 (1%) 0.18 7 (1%) 0.21 0.92

Hip 15 (1%) 0.18 4 (1%) 0.12 0.32

Wrist 25 (1%) 0.29 11 (1%) 0.32 0.94

Other 105 (6%) 1.25 35 (4%) 1.04 0.29

Yin M, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 130.

High Prevalence of Vitamin D Deficiency in HIV Infection

Retrospective seasonal analysis of Vitamin D deficiency and insufficiency within Swiss cohort

Started ARV in: Fall (n=108); Spring (n=103) 75% men; age = 37; White = 87%;

CD4+ 227; BMI = 22.9 ARVs: TDF – 17%;

NNRTIs – 43%; PI -56%

Conclusions Vitamin D deficiency and

insufficiency are common, but seasonal

Blacks are at increased risk NNRTI use a risk factor

Vitamin D Deficiency is Not Influenced By ART

Baseline before cARTFall

(n=108)Spring (n=103)

Vitamin D Deficiency (<30 nmol/L) 14% 42%

Insufficiency (<75 nmol/L) 62% 53%

Target Level (≥75 nmol/L) 24% 5%

12 Months after cART Start

Vitamin D Deficiency 14% 47%

Insufficiency 63% 48%

Target Level 23% 5%

18 Months after cART Start

Vitamin D Deficiency 18% 52%

Insufficiency 59% 38%

Target Level 23% 10%

Mueller N, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 752.

EuroSIDA Study:Risk for Chronic Kidney Disease

Analysis of patients with ≥3 creatinine measurements + weight 6,842 patients with 21,482 person-years of follow-up

Definition of CKD (eGFR by Cockcroft-Gault) If baseline eGFR ≥60 mL/min/1.73 m2, fall to <60 If baseline eGFR <60 mL/min/1.73 m2, fall by 25%

225 (3.3%) progressed to CKD

•Incidence of CDK:• No TDF: 0.7/100 p-yrs (0.5 to 0.8)• ≥4 years TDF: 2.4/100 p-yrs (1.7 to 3.0)

•Risk factors for CKD on TDF: age, HTN, HCV, lower eGFR, lower CD4+ count

Kirk O, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 107LB.

Multivariable

IRR/year 95% CI P-value

Tenofovir 1.16 1.06-1.25 <0.0001

Indinavir 1.12 1.06-1.18 <0.0001

Atazanavir 1.21 1.09-1.34 0.0003

Lopinavir/r 1.08 1.01-1.16 0.030

Cumulative Exposure to ARVs and Risk of CKD

Malignancies and Hepatitis

Jürgen Rockstroh, MDProfessor, University of Bonn

Bonn, Germany

Cancer Incidence in AIDS Patients

Study of cancer risk in AIDS patients from 1980-2006 (N=372,364)

Predominantly male (79%), non-hispanic black (42%), MSM (42%)

Median age of 36 years at the onset of AIDS

Cancer risk in years 3 - 5 after AIDS onset increased for AIDS but also Non-AIDS defining cancers

Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.

Cancer type No. cases SIR 95% CI

AIDS-defining cancers

Kaposi sarcoma 3136 5321 5137 - 5511

Non-Hodgkin lymphoma

3345 32 31 - 33

Cervical cancer 101 5.6 5.5 - 6.8

Non-AIDS-defining cancers

Anal cancer 219 27 24 - 31

Liver cancer 86 3.7 3.0 - 4.6

Lung cancer 531 3.0 2.8 - 3.3

Hodgkin lymphoma 184 9.1 7.7 - 11

All non-AIDS related cancers

2155 1.7 1.5 - 1.8

SIR=Standardized Incidence Ratios

Cancer Mortality in AIDS Patients

Population attributable risk among people with AIDS in the US

Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.

Cum

ulat

ive

Inci

denc

e (%

)

HIV Infection and Lung Cancer

VA-Cohort (3,707 HIV-positive patients) Predominantly male (98%),

white (43%) Median age 47 years

Lung cancer risk factors Smoking and drug abuse

more often among HIV+ Similar rates of COPD

After adjustment for smoking, risk of lung cancer higher in HIV+ patients

Sigel K, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 30.

26 cases per 10,000 pt-yrs

15 cases per 10,000 pt-yrs

ClearanceChronic

HCVPredictive

value

pRVC 22 3 PPV 88%

No pRVC 4 23 NPV 85%

cEVC 32 4 PPV 89%

No cEVC 2 23 NPV 92%

Natural Course AHC in HIV-positive

Multicenter observational cohort study

HIV+ patients with acute hepatitis C (AHC) and 24 week follow-up after diagnosis or presumed date of infection (N=92)

HCV-RNA level 4 weeks after AHC diagnosis may identify patients unlikely to spontaneously clear HCV

pRVC (partial rapid virological control)=2 log drop of HCV-RNA at week 4

cRVC (complete rapid virological control)=HCV-RNA <600 IU/ml at week 4

cEVC (complete early virological control)=HCV-RNA <600 IU/ml at week 12

Clearance=HCV-RNA <600 IU/ml week 24

Vogel M, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 640.

Adherence and Pharmacokinetics

Edwin DeJesus, MD, FACPMedical Director, Orlando Immunology Center

Orlando, FL

HIV REACH cohort Difficult to treat population: marginally housed, substance abuse, psychiatric illness, etc. Started ART within 6 months

PI (n=11) PI/r (n=57) NNRTI (n=14) TDF/FTC/EFV (n=40)

Adherence and virologic outcomes evaluated among different treatment regimens Controlled for confounders: Age, gender, race, education, IVDA, homeless, depression, CD4 nadir

Adherence with a Once-daily Pill (EFV/TDF/FTC)

PI PI/r NNRTI EFV/TDF/FTC

ADHERENCE >90% BY TREATMENT GROUP

36.4% 37.5% 23.1% 67.5%

HIV RNA ≤50 c/mL BY TREATMENT GROUP

54.6% 47.4% 42.9% 70%

Bangsberg D, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 510.

Adherence and Virologic Success with Once-Daily Pill (EFV/TDF/FTC)

• In comparison to other commonly prescribed regimens, EFV/TDF/FTC exhibited higher rates of adherence and virologic suppression• Virological suppression was better with EFV/TDF/FTC even when comparing patients with lower adherence rates

• In comparison to other commonly prescribed regimens, EFV/TDF/FTC exhibited higher rates of adherence and virologic suppression• Virological suppression was better with EFV/TDF/FTC even when comparing patients with lower adherence rates

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1 2 3 4 5 6

Mea

n Ad

here

nce

Month

Mean Adherence by Regimen and Month

EFV/TDF/FTC NNRTI PI PI/r

Bangsberg D, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 510.

Raltegravir Concentrations in Cervicovaginal Fluid

PK study of RAL levels in cervicovaginal fluid (CVF) in 14 HIV+ women Virologically controlled on a stable

RAL containing regimen

Evaluated with paired sample of blood plasma and CVF Samples collected between

13-14.5 hours post last dose intake

Results: RAL levels in CVF > plasma All patients had undetectable CVF

HIV RNA

Similar study in men found Semen to blood plasma concentration ratio was higher at the end of dosing interval suggesting accumulation and persistence of RAL in semen

RAL concentrations in CVF were about 2.3 fold those in plasma, and 16 fold higher than the IC50 of wild type HIV-1

RAL concentrations in CVF were about 2.3 fold those in plasma, and 16 fold higher than the IC50 of wild type HIV-1

Distribution of RAL concentrations in Blood Plasma and Cervicovaginal fluid (n=14)

Distribution of RAL concentrations in Blood Plasma and Cervicovaginal fluid (n=14)

100

Cervicovaginal Fluid

Plasma

93 ng/mL

235 ng/mL

IV :127%

IV :176%

10

IC95 ~15 ng/mL for WT-HIV-1 with 50% Human SerumLo

g R

AL

Co

ncen

trat

ion

(n

g/m

L)

InterindividualVariability (IV)

IQR 75%

MedianIQR 25%

Legend

Cyril C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 608; Bonora S, et al. ibid., Abst. 609.

Darunavir Penetration in Seminal Plasma of HIV Positive Patients

47 men participating in the MONOI study receiving DRV 600/100 BID

Darunavir Concentrations From Paired Samples: Blood And Seminal Plasma Darunavir Concentrations From Paired Samples: Blood And Seminal Plasma

• Seminal plasma DRV level: Average of 6-fold above the DRV EC50 for wild type HIV-1; however, some close to or below EC50

Lo

g R

AL

Co

nce

ntr

ati

on

(n

g/m

L) 100000

10000

1000

100

10

10Blood PlasmaTotal Fraction

Blood PlasmaFree Fraction

SeminalPlasma

DRV EC50 Corrected forprotein binding of

WT HIV-1

DRV Concentration (ng/ml)

95%

75%

Median

25%

5%

Legend:

344 ng/mL

3200 ng/mL

212 ng/mL

Lambert-Niclot S, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 610.

Limitations of Current Therapies in Developed Countries

HIV persists despite suppressive therapy

Full life expectancy is not restored

Immune recovery may be incomplete

Immune activation and inflammation persist in many treated patients

Long term toxicity; known and undiscovered

Adherence to therapy remains a challenge

Antiretroviral drug resistance

Failure, as yet, to decrease transmission

Access to careEron J. 17th CROI; San Francisco, CA; February 16-19, 2010. Symposium 183 (Modified).

The 17th Conference on Retroviruses and

Opportunistic Infections

San Francisco, CA

February 16-19, 2010

Documents

The 17th Conference on Retroviruses and Opportunistic Infections San Francisco, CA February 16-19, 2010