Introductory talk

1
Introductory talk

• D Costagliola

2
Chapter 1

• THE CURRENT DEBATE ON ABACAVIR

3
Summary of studies on the association between
exposure to abacavir the risk of myocardial
infarction
Study Design CV Events Effect of ABC?
DAD1 (N of MI 580) Observational cohort Prospective, predefined Yes
FHDH2 (N of MI 289) Case control study Prospective, MI retrospectively validated Yes 1st yr of exposure
SMART3 (N of MI 19) RCT, observational analyses Prospective, predefined Yes
STEAL4 (N of MI 3 ) RCT Prospective Yes
GSK analysis5(N of MI 11 ) 12 RCTs Retrospective database search No
ALLRT ACTG A50016(N of MI 27 ) 5 RCTs Retrospective by 2 independent reviewers No
HEAT7(N of MI 0 ) RCT Prospective No
Can we extrapolate the results to naive patients?
Adapted from 1. Lundgren JD, et al. CROI 2009.
Abstract 44LB 2. Lang S, et al. CROI 2009.
Abstract 43LB 3. SMART. AIDS. 200822F17-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.
4
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)
This is different from DAD
Without DAD, 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 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)
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
Exposure to NNRTIs and PIs and risk of MI, FHDH
study
N exposed N exposed cases Univariate model OR 95 CI Model 1 cumulative exposure only OR 95 CI
NNRTI 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 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
Chapter 2

• Risks and relationship between HIV viremia and
  myocardial infarction

9
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
0
lt 1 year
1-2 years
2-3 years
3-4 years
4 years
None
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
1,0
1,5
0,5
0,2
Adjusted hazard ratio lt 400 vs, gt 400
copies/mL
Adjusted for age, gender, prior AIDS, hep B/C,
smoking, latest CD4 count
SMART, unpublished
11
Non-AIDS-defining deaths and immunodeficiency in
the era of combination antiretroviral therapy
HIV RNA level and risk of death from
cardiovascular disease (n36)
Variables Adj Hazards Ratio 95 CI
p-value
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)
lt50 vs. 350 4.15 (1.14-15.17) Latest HIV RNA
(log10/ml) 5 vs. lt5 3.86 (1.57-9.51)
0.003
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 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 Plasma HIV-1 RNA
lt 50 copies/ml 573 121 1
gt 50 copies/ml 578 157 1.6 (1,1 2,1)
CD4 / CD8 ratio CD4 / CD8 ratio
gt 1 135 19 1
lt 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 lt
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?