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
Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 58LB.
Primary Endpoint: Percentage with HIV RNA <50 copies/mL (ITT M=F)
Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 58LB.
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
Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 58LB.
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%
Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.
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
Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.
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
Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.
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)
Boltz V, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 154.
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
Boltz V, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 154.
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®
Cahn P, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 57
ODIN: Key Features of Population including Prior and Concurrent ARVs
ODIN: Virologic Response Rates and Resistance Outcomes
Cahn P, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 57
‡ 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
Cahn P, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 57
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
Gathe J, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 54LB
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
Gathe J, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 54LB
Gathe J, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 54LB
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
Cohen C, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 53
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..
Cohen C, et al. 17th CROI; San Francisco CA USA; February 16-19, 2010. Abst. 53
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
Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.
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
Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.
A5202: Pre-Specified Clinical Adverse Events
*Defined as coronary artery disease, infarct, ischemia, angina, cerebrovascular accident, transient ischemic attack or peripheral vascular disease.
Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.
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
Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 58LB.
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