1. Introductory talk
D Costagliola

2. THE CURRENT DEBATE ON ABACAVIR
Chapter 1
THE CURRENT DEBATE ON ABACAVIR

3. Can we extrapolate the results to naive patients?
Summary of studies on the association between exposure to abacavir the risk of myocardial infarction
Study
Design
CV Events
Effect of ABC?
D:A:D[1] (N of MI = 580)
Observational cohort
Prospective, predefined
Yes
FHDH[2] (N of MI = 289)
Case control study
Prospective, MI retrospectively validated
1st yr of exposure
SMART[3] (N of MI = 19)
RCT, observational analyses
STEAL[4] (N of MI = 3 )
RCT
Prospective
GSK analysis[5] (N of MI = 11 )
12 RCTs
Retrospective database search No
ALLRT ACTG A5001[6] (N of MI = 27 )
5 RCTs
Retrospective by 2 independent reviewers
HEAT[7] (N of MI = 0 )
All or majority of patients antiretroviral-experienced at ABC initiation
All or majority of patients antiretroviral naive at ABC inclusion
Can we extrapolate the results to naive patients?
Adapted from: 1. Lundgren JD, et al. CROI Abstract 44LB; 2. Lang S, et al. CROI Abstract 43LB; 3. SMART. AIDS. 2008;22:F17-F24; 4. Carr A, et al. CROI Abstract 576; 5. Cutrell A, et al. IAC Abstract WEAB0106; 6. Benson C, et al. CROI Abstract 721; 7. McComsey G, et al. CROI Abstract 732.

4. Exposure to abacavir and other NRTIs and risk of MI, FHDH Study
N exposed
N exposed cases
Univariate model
OR [ 95% CI ]
Model 1: cumulative exposure only
Abacavir, cumul expo
410
127
1.05 ( )
0.97 ( )
Didanosine, cumul expo
691
186
1.02 (0.95 – 1.09)
0.91 (0.82 – 1.01)
Lamivudine, cumul expo
1043
269
1.06 (1.00 – 1.13)
0.96 (0.86 – 1.08)
Stavudine, cumul expo
718
199
1.09 (1.02 – 1.16)
1.11 (0.99 – 1.24)
Tenofovir, cumul expo
238 65
1.19 (0.99 – 1.44)
1.01 (0.79 – 1.30)
Zalcitabine, cumul expo
314 92
1.08 (0.94 – 1.24)
0.99 (0.82 – 1.21)
Zidovudine, cumul expo
998
256
1.03 (0.98 – 1.08)
1.09 (1.00 – 1.19)
This is different from D:A:D
Without D:A:D, we would have found no association
Adjusted for hypertension, smoking, family history of premature CAD, use of cocaine and/or IV drug use, plasma HIV-1 RNA level, CD4/CD8 cells ratio, exposure to emtricitabine, atazanavir, ritonavir and tipranavir

5. Exposure to abacavir and other NRTIs and risk of MI, FHDH Study
N exposed
N exposed cases
Univariate model
OR [ 95% CI ]
Model 1: cumulative exposure only
Abacavir, cumul expo
410
127
1.05 ( )
0.97 ( )
Didanosine, cumul expo
691
186
1.02 (0.95 – 1.09)
0.91 (0.82 – 1.01)
Lamivudine, cumul expo
1043
269
1.06 (1.00 – 1.13)
0.96 (0.86 – 1.08)
Stavudine, cumul expo
718
199
1.09 (1.02 – 1.16)
1.11 (0.99 – 1.24)
Tenofovir, cumul expo
238 65
1.19 (0.99 – 1.44)
1.01 (0.79 – 1.30)
Zalcitabine, cumul expo
314 92
1.08 (0.94 – 1.24)
0.99 (0.82 – 1.21)
Zidovudine, cumul expo
998
256
1.03 (0.98 – 1.08)
1.09 (1.00 – 1.19)
The impact of cardiovascular risk factors on the
likelihood of receiving tenofovir and abacavir is big
Adjusted for hypertension, smoking, family history of premature CAD, use of cocaine and/or IV drug use, plasma HIV-1 RNA level, CD4/CD8 cells ratio, exposure to emtricitabine, atazanavir, ritonavir and tipranavir

6. Model 1: cumulative exposure only No such impact for NNRTIs and PIs
Exposure to NNRTIs and PIs and risk of MI, FHDH study N
exposed
cases
Univariate model
OR [ 95% CI ]
Model 1: cumulative exposure only
NNRTI
Efavirenz, cumul expo
404
109
1.00 (0.90 – 1.10)
1.01 (0.87 – 1.16)
Nevirapine, cumul expo
380
111
1.01 (0.88 – 1.15) PI
Ampr/fos+/-r cumul expo
117 46
1.41 (1.17 – 1.69)
1.57 (1.24– 2.00)
Indinavir+/-r, cumul expo
497
146
1.10 (1.01 – 1.19)
1.07 (0.95 – 1.21)
Lopinavir/r, cumul expo
290 94
1.35 (1.17 – 1.55)
1.37 (1.13 – 1.65)
Nelfinavir, cumul expo
453
131
1.08 (0.98 – 1.19)
1.09 (0.96 – 1.25)
Saqui+/-r, cumul expo
324 92
1.02 (0.91 – 1.13)
0.94 (0.81 – 1.09)
No such impact for NNRTIs and PIs
Adjusted for hypertension, smoking, family history of premature CAD, use of cocaine and/or IV drug use, plasma HIV-1 RNA level, CD4/CD8 cells ratio, exposure to emtricitabine, atazanavir, ritonavir and tipranavir

7. Conclusion Can the results be extrapolated to naive patients?
Without DAD, we would have found nothing
In France, the confounders played a higher role on the prescription of NRTIs, in particular tenofovir and abacavir, than on the prescription of NNRTIs or of PIs
If true also in other countries, the results of the different studies will be more likely to be concordant for NNRTIs and for PIs and discordant for NRTIs
Results of observational studies will be more robust for NNRTIs and PIs than for NRTIs

8. Risks and relationship between HIV viremia and myocardial infarction
Chapter 2
Risks and relationship between HIV viremia and myocardial infarction

9. Rates per thousand person years
Observed and predicted rates of myocardial infarction by duration of CART 8 7
Observed
rates 6 5
Rates per thousand person years
Best
estimate of
predicted
rates 4 3 2 1
None
< 1 year
1-2 years
2-3 years
3-4 years
4+ years
Duration of CART
Adapted from Law et al, HIV Med 2006.

10. HIV RNA and risk of serious non-AIDS events: Smart CROI 2008 – A, Phillips (plenary presentation)
All serious non-AIDS
Non-AIDS malignancy
Renal
CVD
Liver
Other non-AIDS death
0,2
0,5
1,0
1,5
Adjusted hazard ratio < 400 vs, > 400 copies/mL
Adjusted for age, gender, prior AIDS, hep B/C, smoking, latest CD4 count
SMART, unpublished

11. Adapted from Marin et al. AIDS (in press)
Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy
HIV RNA level and risk of death from cardiovascular disease (n=36)
Variables Adj* Hazards Ratio % CI p-value
Latest CD4 cell count (/µl)
vs. ≥ ( )
vs. ≥ ( )
<50 vs. ≥ ( )
Latest HIV RNA (log10/ml)
≥5 vs. < ( )
*Adjusted for age, sex, exposure category, Hepatitis C serostatus, first line cART
The risk of death from a cardiovascular cause was associated with HIV RNA level
Adapted from Marin et al. AIDS (in press)

12. Risk factors of MI in HIV infected patients apart from treatment
FHDH ANRS CO4
N exposed
1151
N exposed cases
278
OR [95% CI ]
Cardiovascular risk factors*
173 5 1
1 or 2
710
166
16.8 (5.9 – 48.4)
3 or more
268
107
49.4 (16.4 – 149,0)
Plasma HIV-1 RNA
<= 50 copies/ml
573
121
> 50 copies/ml
578
157
1.6 (1,1 – 2,1)
CD4 / CD8 ratio
>= 1
135 19
< 1
1016
259
1,8 (1,0 – 3,0)
*man more than 50 years or woman more than 60 years, current smoker or smoking cessation < 3years, family history of premature coronary arterial disease, hypertension, hypercholesterolemia, diabetes and cocaine and/or intravenous drug use

13. Conclusion
The traditional cardiovascular risk factors, including cocaine and IV drug use, are very strong risk factors of MI in HIV-1 infected patients
The role of HIV parameters must also be accounted for
Plasma HIV-1 RNA (positive impact of cART)
CD4/CD8 ratio
Activation?
Inflammation?
No role of CD4 cell count?