Kinetics, Dynamics, and Genetics Implications for HIV Therapeutics

1

Cardiovascular Risk HAART to HEART
Judith A. Aberg, MDAssociate Professor of
MedicineNew York University Medical Center
International AIDS SocietyUSA
2
Pre-Talk QuestionC-Reactive Protein and IL-6  

• Are useful markers that correlate with HIV
  viremia
• Have not been shown to be effective monitoring
  tools to evaluate cardiovascular risk in HIV
  infected persons
• Have been shown to correlate with cardiovascular
  risk in HIV infected persons
• May be used as a prognostic marker in HIV
  infected persons taking statins

3
HIV Infection and CV Risk

• Included in risk
• calculations
• Age
• Sex
• BP
• T-chol
• LDL
• Diabetic status
• Smoker status
• ECG LVH
• History

• Not included in risk calculations
• Insulin resistance
• Microvascular NO effects
• Particle size
• Endothelial dysfunction
• Chronic inflammatory states

Lipid abnormalities ? HDL ? LDL Cho ? TG
Insulin resistance
Increased visceral fat
Endothelial dysfunction
Chronic inflammation
4
INTERHEART Study In the General Population,
Multiple Traditional Risk Factors Confer
Synergistic Increases in the Risk of MI
Evaluated factors associated with MI in 15,000
(MI) patients versus 15,000 case controls
Odds Ratio (99 CI)
HTN(3)
PS
Risk Factor (Adjusted for All Others)
Smksmoking DMdiabetes mellitus
HTNhypertension Obesabdominal obesity
PSpsychosocial RFrisk factors.
gt90 of total risk can be attributed to these
factors
Yusuf S, et al. Lancet. 2004364937-952.
5
Prediction of CV risk based on the Framingham
Heart Study
Risk Factor
Units
Gender
male or female
m
Age
years
46
Total Cholesterol
mg/dL
245
HDL
mg/dL
35
Systolic Blood Pressure
mmHg
125
Treatment for Hypertension (Only if SBP gt120)
yes or no
n
y
Current Smoker
yes or no
Time Frame for Risk Estimate
10 years
10
0,19
19
Your Risk
low risk moderate risk high risk
hin.nhlbi.nih.gov/atpiii/calculator.aspy
6
DAD Study Is the Framingham Risk Estimation
Valid in HIV-Infected Patients?
Observed and predicted MI rates according to ART
exposure (DAD Study n23,468)
8
Incidence of MIs is low 345 over 94,469
patient-years follow-up (3.7/1,000 patient-years)
7
Observed rates
6
5
Best estimate of predicted rates
Rates Per Thousand Person Years
4
3
2
1
0
lt1
12
23
34
4
None
n8,890
n10,574
n5,292
n6,805
n9,050
n5,973
Duration of cART Exposure (Years) nART exposure
Law MG, et al. HIV Med. 20067218-230.
7
DAD StudyNRTI Use and Risk of MI

• DAD study
• 33,347 HIV patients on HAART
• 517 patients developed MI over 157,912
  person-years of follow-up
• Recent didanosine use (n124)
• Recent abacavir use (n192)
• Recent other NRTI use (n237)
• Recent use of abacavir and didanosine (but not
  cumulative or past use) associated with increased
  risk of MI
• Risk persists regardless of length of use
• Risk was reversible with discontinuation of drugs
• Most MIs occurred in patients with existing
  cardiovascular risk factors

Implications Use caution in the interpretation
of these preliminary findings and await further
studies
DAD Study Group. Lancet. 2008April 2. Epub
ahead of print.
8
SMART Subgroup Analysis Association of Abacavir
Use With Increased Risk of CVD Events

• Current use of abacavir without didanosine was
  significantly associated with
• Increased risk for all types of cardiovascular
  events compared with other NRTIs
• Increased risk for expanded major CVD events
  among patients with gt5 CVD risk factors and among
  those with ischemic abnormalities on ECG
• Hazard ratio versus other NRTIs was 3.1 for both
• Increased levels of IL-6 and hs-CRP
• Use of didanosine abacavir was not associated
  with an increased risk for any cardiovascular
  endpoint

Lundgren J, et al. 17th IAC. Mexico City, 2008.
Abstract ThAB0305.
9
The Reports on abacavir and its association with
CHD have

• Altered my prescribing habits and I do not
  prescribe abacavir at all
• Altered my prescribing habits and I do not
  prescribe to those with high CHD risk
• Altered my prescribing of abacavir in naïve
  patients but not treatment experienced patients
• I have switched all my patients on abacavir to
  another ARV if available
• Not affected my practice. I prescribe whatever is
  best for the individual
• Answers 2 and 4
• Answers 2 and 3

10
CROI 2009 UPDATE
The DAD Study

• Prior analyses from the DAD study showed an
  increased risk of MI associated with
• Cumulative exposure to PIs but not NNRTIs
• Current/recent exposure to abacavir (ABC) or
  didanosine (ddI)
• Drugs within PI and NNRTI classes associated with
  different metabolic profiles
• Previous NRTI analyses had insufficient follow-up
  to assess role of tenofovir
• Aim Sufficient follow-up has now accrued to
  explore associations between a total of 14 drugs
  from these classes and MI risk

DAD Study Group, NEJM 2007 DAD Study
Group, Lancet 2008.
Lundgren JD et al., CROI 2009
11
NRTIs and Risk of MI Recent and Cumulative
Exposure
The DAD Study
1.9 1.5 1.2 1 0.8 0.6
RR yes/no 95 CI
RR per year 95 CI

ZDV ddI ddC d4T 3TC ABC TDF PYFU
138,109 74,407 29,676 95,320 152,009 53,300
39,157 MI 523 331 148 405 554 221 139
Recent usecurrent or within the last 6 months.
Not shown (low number of patient currently on
ddC)
Lundgren JD et al., CROI 2009
12
PIs/NNRTIs and Risk of MI Cumulative Exposure
to Each Drug
The DAD Study
PI
NNRTI
1.2
1.13
RR/year 95 CI
1
0.9
IDV NFV LPV/r SAQ NVP EFV PYFU 68,469
56,529 37,136 44,657 61,855 58,946 MI 298
197 150 221 228 221
Approximate test for heterogeneity P0.02
Lundgren JD et al., CROI 2009
13
Clinical Data Suggest Increased Risk of MI or
CVD Associated with ABC is (Sub)acute and
Reversible
CVD Risk
Adapted from Reiss P, CROI 2009 152
14
Characteristics of Patients at Time of MI/Last
Follow-up
The DAD Study
Lundgren JD et al., CROI 2009
15
Channelling Bias
DAD

• Unlikely explanation because
• Risk of ABC not reduced by adjustment for known
  CVD risk factors including those possibly
  affected by ART
• Risk of ABC no longer present after drug
  discontinuation
• Risk of ABC specific for MI and other outcomes
  related to CAD, but not for stroke which shares
  many risk factors with MI and might, to some
  extent, be expected to be affected by the same
  bias
• Same effect not seen with tenofovir which like
  ABC could be expected to be preferentially
  prescribed to avoid metabolic complications and
  thereby mitigate CVD risk

DAD study group Lancet 2008 J Lundgren
and DAD study group, CROI 2009 LB abst 44
16
ANRS CVD Case Control Study

• Nested, case-control study to evaluate
  association between risk of MI and
• Cumulative exposure to specific NRTIs
• Recent (current or within last 6 months) and past
  exposure (gt6 months ago) to specific NRTIs
• Cumulative exposure to specific PIs
• Over 115,000 HIV-infected patients enrolled
  between 1989 and 2006
• Cases 289 Patients with a first definite or
  probable MI prospectively reported between
  January, 2000 and December, 2006
• Matched Controls For each MI case, up to 5
  controls with no history of MI matched for age,
  sex and clinical center
• Data collected for cases and controls
• Cardiovascular risk factors and treatments
• HIV history and treatment

Lang S, et al .16th CROI Montreal, Canada
February 8-11, 2009. Abst . 43LB.
17
FHDH Characteristics
18
Exposure to abacavir and risk of MI - II
Model 1
Model 2
For abacavir, there was evidence of an
interaction between recent/past and cumulative
exposure, while no such effect was observed for
any other NRTI

• A final model including exposure to abacavir as a
  five-class variable
• and cumulative exposure to all other ART was
  constructed
• no exposure
• exposure lt 1 year and last use lt 6 months prior
  to the MI
• exposure lt 1 year and last use gt 6 months prior
  to the MI
• exposure gt 1 year and last use lt 6 months prior
  to the MI
• exposure gt 1 year and last use gt 6 months prior
  to the MI

19
Exposure to abacavir and other NRTIs and risk of
MI - III
Final model
No interaction was found between exposure to
abacavir and numbers of CV risk factors on the
risk of MI (p 0.384) Similar results were
observed when restricting the analysis to
patients with first ART after inclusion in the
cohort
20
Exposure to PIs and risk of MI
Final model
Final model combining all PIs but SQV
Similar results were observed when restricting
the analysis to patients with first ART after
inclusion in the cohort
21
GSK analysis from 54 clinical studies of abacavir
(12 randomized ABC vs no ABC)
CVD Outcomes - Exposure to ABC Compared with No
Exposure to ABC
Cutrell A, Hernandez J, Brothers C et al. Lancet
2008 IAC Mexico 2008 Brothers CH, et al. JAIDS
20095220-28
Median VL gt 4 log10copies/mL
22
ACTG 5001ABC Not Associated with CV Risk

• Evaluation of association between ABC and risk of
  MI or severe CVD after starting HAART
• Patients randomized to first ART in 5 ACTG
  studies evaluated for CV risk factors (N3,205)
• 63 severe CVD, including 27 MI
• No association of ABC and severe CVD or MI found

Benson C, et al. 16th CROI Montreal, Canada
February 8-11, 2009. Abst. 721.
23
STEAL Randomized Simplification with fixed-dose
Tenofovir-Emtricitabine or Abacavir-Lamivudine in
adults with HIV-RNAlt50 c/mL
N 357 (179 ABC/3TC, 178 TDF/FTC) HLA-B5701
negative, 96 weeks follow-up
Serious non-AIDS events
A Carr NCHECR investigatorsCROI 2009 abs 576
P session 104
24
STEAL Baseline Cardiovascular Risk
n145 n136
Carr A, NCHECR investigators. CROI 2009. abstract
576, poster session 104.
25
ACTG 5206 CROI 2009

• Documented HIV infection, 18 years,
  dyslipidemia (TG 200 and non-HDL 160) and HIV
  VL lt400 copies/mL
• Subjects randomized to one of the following arms
• Arm A
• 12 weeks of tenofovir 300 mg PO QD
• 4 weeks of no study treatment
• 12 weeks of placebo PO QD
• Arm B
• 12 weeks of placebo PO QD
• 4 weeks of no study treatment
• 12 weeks of tenofovir 300 mg PO QD

26
A5206 TDF Intensification
27
Summary of Studies Assessing Association Between
Abacavir and CVD Risk
1. Lundgren J and DAD study group, CROI 2009
LB abst 44. 2. Lang S, et al .16th CROI
Montreal, Canada February 8-11, 2009. Abst.
43LB. 3. Lundgren, IAS 2008. 4. Carr A, NCHECR
investigators. CROI 2009. abstract 576, poster
session 104. 5. Cutrell A, et al. Lancet 2008
IAC Mexico 2008 JAIDS in press. 6. Benson C, et
al. 16th CROI Montreal, Canada February 8-11,
2009. Abst. 721.
28
In the HEAT and WIHS/MACS Cohort, IL-6 levels  

• Decreased only in those taking tenofovir
• Decreased only in those taking abacavir
• Similar increases in those taking any nucleoside
• Similar decreases among those taking either
  abacavir or tenofovir
• Remained constant throughout the course of follow
  up

29
ANSWER

• The correct answer is D- In the randomized trial
  of TDF/FTC vs ABC/3TC with boosted lopinavir
  (HEAT), there were declines in sVCAM, IL-6 and
  hsCRP observed at Weeks 48 and 96, with no
  difference in magnitude of reduction between
  ABC/3TC and TDF/FTC. Similarly in the WIHS and
  MACS cohorts, D-Dimer, IL-6 decreased regardless
  of nucleoside prescribed but interestingly the
  hs-CRP levels rose (also regardless of therapy.

30
Biomarkers Summary

• SMART (Lundgren, IAS 2008)
• Hs-CRP and IL-6 found to be significantly
  elevated at study entry in those on ABC versus
  Other NRTI group
• HEAT (McComsey, CROI 2009)
• Declines in sVCAM, IL-6 and hsCRP observed at
  Weeks 48 and 96, with no difference in magnitude
  of reduction between ABC/3TC and TDF/FTC
• MACS WIHS (Palella, CROI 2009)
• Biomarker level changes (D-dimer and IL-6
  decreases, hsCRP increases) comparable among
  persons who initiated ABC versus non-ABC
  containing HAART

31
Abacavir Risk Seems More Pronounced in Those With
Higher Underlying CVD Risk DAD
Rates of MI for Recent Use of Abacavir by
Predicted 10-year Coronary Heart Disease (CHD)
Risk
Stratified by recent abacavir use
35 30 25 20 15 10 5 0
SMART FHDB interaction not significant
Rate (per 1000 PY)
No recent abacavir Recent abacavir
Overall Low Moderate High Not known
Predicted 10-year CHD risk
Events 325 192 60 42 79
33 100 68 86 49 PY
126581 31331 57628 14754 13372 4300 6293
2095 49288 10182
Interaction between moderate/high CHD risk and
recent abacavir use p0.04
Recent still using or stopped within last 6
months
DAD study group, Lancet 2008
32
Cardiovascular Risk Summary

• Unclear if and why abacavir is associated with
  CHD. Need to understand the pathogenesis
• Traditional Risk Factors, regardless of the
  contribution from HIV and its therapies, need to
  be addressed and managed
• Insufficient data to recommend using inflammatory
  markers and subclinical atherosclerosis imaging
  studies.

33
Post-Talk QuestionC-Reactive Protein and IL-6
 

• Are useful markers that correlate with HIV
  viremia
• Have not been shown to be effective monitoring
  tools to evaluate cardiovascular risk in HIV
  infected persons
• Have been shown to correlate with cardiovascular
  risk in HIV infected persons
• May be used as a prognostic marker in HIV
  infected persons taking statins