introductory talk
DESCRIPTION
Introductory talk. D Costagliola. Chapter 1. THE CURRENT DEBATE ON ABACAVIR. All or majority of patients antiretroviral-experienced at ABC initiation. All or majority of patients antiretroviral naive at ABC inclusion. - PowerPoint PPT PresentationTRANSCRIPT
INTRODUCTORY TALK
D Costagliola
Chapter 1
THE CURRENT DEBATE ON ABACAVIR
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 studyProspective, MI retrospectively
validatedYes
1st yr of exposure
SMART[3] (N of MI = 19)RCT, observational
analysesProspective, predefined Yes
STEAL[4] (N of MI = 3 ) RCT Prospective Yes
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
No
HEAT[7]
(N of MI = 0 )RCT Prospective No
All or majority of patients antiretroviral-experienced at ABC initiation
All or majority of patients antiretroviral naive at ABC inclusion
Summary of studies on the association between exposure to abacavir the risk of myocardial infarction
Adapted from: 1. Lundgren JD, et al. CROI 2009. Abstract 44LB; 2. Lang S, et al. CROI 2009. Abstract 43LB; 3. SMART. AIDS. 2008;22:F17-F24; 4. Carr A, et al. CROI 2009. Abstract 576; 5. Cutrell A, et al. IAC 2008. Abstract WEAB0106; 6. Benson C, et al. CROI 2009. Abstract 721; 7. McComsey G, et al. CROI 2009. Abstract 732.
Can we extrapolate the results to naive patients?
Exposure to abacavir and other NRTIsand risk of MI, FHDH Study
N exposed
N exposed
cases
Univariate model
OR [ 95% CI ]
Model 1: cumulative exposure only
OR [ 95% CI ]
Abacavir, cumul expo 410 127 1.05 (0.96 - 1.15) 0.97 (0.86 - 1.10)
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)
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
This is different from D:A:D
Without D:A:D, we would have found no association
Exposure to abacavir and other NRTIsand risk of MI, FHDH Study
N exposed
N exposed
cases
Univariate model
OR [ 95% CI ]
Model 1: cumulative exposure only
OR [ 95% CI ]
Abacavir, cumul expo 410 127 1.05 (0.96 - 1.15) 0.97 (0.86 - 1.10)
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)
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
The impact of cardiovascular risk factors on the likelihood of receiving tenofovir and abacavir is big
Exposure to NNRTIs and PIs and risk of MI, FHDH study
Nexposed
Nexposed
cases
Univariate model
OR [ 95% CI ]
Model 1: cumulative exposure only
OR [ 95% CI ]
NNRTI
Efavirenz, cumul expo 404 109 1.00 (0.90 – 1.10) 1.01 (0.87 – 1.16)
Nevirapine, cumul expo 380 111 1.00 (0.90 – 1.10) 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)
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
No such impact for NNRTIs and PIs
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
Chapter 2
Risks and relationship between HIV viremia and
myocardial infarction
Observed and predicted rates of myocardial infarction by duration of CART
Adapted from Law et al, HIV Med 2006.
0
1
2
3
4
5
6
7
8
Duration of CART
Rat
es
per
thou
san
d p
erso
n ye
ars
< 1 year 1-2 years 2-3 years 3-4 years 4+ years
Observedrates
None
Bestestimate of predicted rates
Renal
Liver
All serious non-AIDS
HIV RNA and risk of serious non-AIDS events: Smart CROI 2008 – A, Phillips (plenary presentation)
CVD
Non-AIDS malignancy
Other non-AIDS death
Adjusted for age, gender, prior AIDS, hep B/C, smoking, latest CD4 count
SMART, unpublished
Adjusted hazard ratio < 400 vs, > 400 copies/mL
1,0 1,50,50,2
Latest CD4 cell count (/µl) 0.14
349-200 vs. ≥350 1.15 (0.51-2.63)
199-50 vs. ≥350 0.89 (0.28-2.82)
<50 vs. ≥350 4.15 (1.14-15.17)
Latest HIV RNA (log10/ml)
≥5 vs. <5 3.86 (1.57-9.51) 0.003
*Adjusted for age, sex, exposure category, Hepatitis C serostatus, first line cART
Variables Adj* Hazards Ratio 95% CI p-value
HIV RNA level and risk of death from cardiovascular disease (n=36)
Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy
The risk of death from a cardiovascular cause was associated with HIV RNA level
Adapted from Marin et al. AIDS (in press)
Risk factors of MI in HIV infected patients apart from treatment
N exposed1151
N exposed cases278
OR [95% CI ]
Cardiovascular risk factors*
0 173 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 1
> 50 copies/ml 578 157 1.6 (1,1 – 2,1)
CD4 / CD8 ratio
>= 1 135 19 1
< 1 1016 259 1,8 (1,0 – 3,0)
FHDH ANRS CO4
*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
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?