EuroSIDA: what does the numbers tell us Jens D' Lundgren, M'D' Professor University of Copenhagen Di

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EuroSIDA what does the numbers tell us?Jens
D. Lundgren, M.D.Professor University of
CopenhagenDirector - Copenhagen HIV Programme
(www.cphiv.dk)
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(No Transcript)
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The EuroSIDA study
Cohort VII November 2005, n2500
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Changing population CD4 lymphocyte count in
EuroSIDA
CD4 count during period (/mm3)
EuroSIDA, 2003
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Incidence of AIDS or death 1994-2004
Test for trend 0.82 (0.81 0.83) p lt 0.0001
Incidence per 100 PYFU (95 CI)
Calendar year of follow-up
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At what CD4 count to start ART ?
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Risk of disease progression andcurrent CD4
lymphocyte cell count
300 250 200
150 100 50 0

EuroSIDA
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Incidence of opportunistic infections for various
CD4 cell count strata Traditionally believed
thresholds value indicated
EuroSIDA Podlekareva et al, JID 2006
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The risk of opportunistic disease or death
gradual decrease by higher current CD4 cell
count in SMART


Current CD4 count (cells/µL)
plt0.05 (DC/VS)
SMART study group Lundgren et al, XVI IAC,
Toronto, 2006
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Predicted 6-Month Risk of AIDS
Predicted Risk at Current CD4 Cell Count
CASCADE study group Phillips, et al. AIDS. 2004
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Discontinuation of Secondary PCPDisease-Specific
Prophylaxis After Immunological Recovery
Start of ART
Discontinuationof SecondaryProphylaxis

• Persons 325
• Median follow-up time 13.2 months (7.0-19.0)
• Person-years of follow-up 374.5
• Recurrent PCP 0
• Incidence 0 (0-1.23) per 100 person-years

600
400
CD4 Count
8
7
12
11
200
0
24
0
12
0
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Diagnosis ofPneumocystis pneumonia
(End of StudyPeriod)
Month
Ledergerber. NEJM 2001.
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Incidence of relapse after discontinuation of
maintenance prophylaxis following immunological
recovery

• Disease Events PYFU Rate (95 CI)
• per 100 PYFU
• CMV 2 370 0.54 (0.07 1.95)
• MAC 2 222 0.90 (0.11 3.25)
• Toxo 1 119 0.84 (0.02 4.68)
• Crypto 0 70 0.0 (0.0 5.27)

Kirk et al, Ann Intern Med 2002137 239-250
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Rate of AIDS after start of ART according to
baseline CD4 count
CD4 count (95 CI)
100
0-49
50
50-199
200-349
350-499
500
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Rate of AIDS (per year) note log scale
5
1
0
.5
1
1.5
2
Years from start of HAART
ART-CC 2004
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Incidence of AIDS-Defining EventsAfter
Initiation of ART
ART-CC dArminio Monforte, et al. Arch Intern
Med. 2005
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Relative contribution of different AIDS defining
diseases
N 500 496
384 192 95
Adapted from Mocroft et al, Lancet 2000
356291-296
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Incidence of KS, NHL and other AIDS defining
illnesses 1994-2003
Test for trend (poisson regression) 0.61, 95 CI
(0.57 0.65) p lt 0.0001 0.74, 95 CI (0.70
0.78) p lt 0.0001 0.61, 95 CI (0.59 0.62) p lt
0.0001
Incidence (per 1000 PYFU)
Adapted from Mocroft et al, Cancer
20041002644-2654
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Incidence of NHL Calendar date of starting cART
and time from cART
P0.027
P0.004
From Kirk et al, Blood 2001, 983406-3412
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Immune restoration diseaseClinical
deterioration after initiation of ART

• Definition
• Worsening symptoms of inflammation
• Temporally association with initiating ART
• Atypical symptoms not explained by newly acquired
  infection
• gt 1 log10 HIV-RNA
• Risk factors
• Opportunistic disease prior to commencing ART
• Signs of ongoing unidentified infection (i.e.
  anaemia, CRP elevation, weight loss)
• Low CD4 count
• Remains undefined with delay of ART reduce risk
  of IRD
• Risk of fatal outcome presumably minimal is
  appropriately managed (specific antiinfective and
  antiinflammatory medication)

Robertson et al CID 2006 Shelburne et al AIDS
2005
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Restoration of pathogen-specific immune responses
by antiretroviral therapy
Restored pathogen-specific immune responses
Protective Regression or prevention of disease
caused by opportunistic pathogens
Immunopathological Immune restoration disease
French MA et al, AIDS 2004181615
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Once ART has been initiated Who are the patients
at risk of clinical disease progression ? Who do
we need to monitor more frequently ?
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Components of EuroSIDA risk score to predict
short-term risk of clinical disease progression
Mocroft et al, IAC, Toronto, 2006
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An example

• 30 year old patient
• started cART from ARV naïve
• current CD4 count 400/mm3, viral load 50
  copies/ml
• Currently BMI of 22 and mild anaemia
• CD4 slope increased by 15/mm3 over the past 3
  months
• currently taking cART
• EuroSIDArisk score1.16
• 0 (CD4 component) 0 (viral load component)
  0.78 (mild anaemia) 0 (BMI component)
  0.02430 (age) 0 (CD4 slope component) 0 (on
  cART) 0 (ARV experienced)

Mocroft et al, IAC, Toronto, 2006
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Incidence of new AIDS/death stratified by current
EuroSIDA risk-score teaching and validation
cohort results
EuroSIDA
SHCS
Incidence rate (95 confidence interval)
Current score
One unit increase 2.70 (2.84) times higher
incidence of clinical progression
Mocroft et al, IAC, Toronto, 2006
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Does immunodeficiency aggravate other pathologies
than opportunistic infections?
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Causes of death in DAD 2000-2004 percentage /
year
Total deaths 1248

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Severe Complications Endpoint and Components
No. of Patients with Events
Relative Risk (95 CI)
Subgroups
1.5
Severe Complications 114
1.4
CVD, Liver, or Renal Deaths 31
1.5
Non-Fatal CVD events 63
1.4
Non-Fatal Liver events 14
2.5
Non-Fatal Renal events 7
gt
Favors VS ?
El-Sadr et al, CROI 2006, oral 106LB
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Death rate by latest CD4 count for combined
outcome MI, Stroke, Other cardiovascular
disease, Other heart disease (not DAD
endpoint), Chronic viral hepatitis, Lactic
acidosis, Complications due to diabetes mellitus,
Renal failure, Liver failure, Pancreatitis.
CD4 count P-yrs No. deaths Rate  (/1000
pyrs) lt50 1,296.0 29 22.4 50- 1,367.3
21 15.4 100- 4,821.8 55 11.4 200- 11,519
.5 78 6.8 350- 12,839.2 31
2.4 500- 24,722.1 53 2.1
DAD Weber R et al CROI 2005
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Deaths in DADMultivariable relationships with
death ratelatest CD4 count
Latest CD4 count
lt50
50-99
100-199
All-cause mortality
200-349
350-499
gt500
lt50
50-99
100-199
200-349
350-499
Liver-related mortality
gt500
DAD study Weber et al, Arch Intern Med 2006
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Non-AIDS malignancy-related deaths according to
latest CD4 count in DAD
CD4 count Number PY Rate (95 CI) Rate ratio
(95 CI) per 1000 PY lt50 9 1657 5.4
(2.5-10.3) 23.5 (9.4-58.7) 50- 9 1711 5.3
(2.4-10.0) 15.4 (6.6-36.2) 100- 33 6044 5.5
(3.6-7.3) 11.4 (6.1-21.4) 200- 26 15421 1.7
(1.0-2.3) 3.7 (1.9-6.9) 350- 8 17578 0.5
(0.2-0.9) 1.0 (0.4-2.4) 500- 15 34370 0.4
(0.2-0.7) 1.00
Adjusted for HIV RNA, age, cohort, race and
smoking status
Weber et al CROI 2005 poster 595
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Immunodeficiency appears to worsen course of
several other pathologies than those
traditionally though to be aggrevated
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Does ART aggrevate risk of liver-related disease
?
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AIDS and Death rates by HBV status
Deaths Person Rate IRR p -
years New AIDS event HBV ve 759 22,587
3.4 1 HBV ve 75 2,267
3.3 0.86 0.35 All deaths HBV ve 647 25,136
2.6 1 HBV ve 95 2,556 3.7 1.54
0.0010 Liver-related death HBV ve 53 25,136
0.2 1 HBV ve 18 2,566
0.7 3.31 lt0.0001
multivariate, adjusted for latest CD4, VL,
starting cART as a time-dependant covariate,
exposure group, gender, ethnic origin, region of
Europe, date of enrolment, age, diagnosis of AIDS
and hepatitis C status
Konopnicki et al, AIDS 2005 19593-601
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Relationship between duration of cART and death
from liver-related disease
12 increased risk of death from LRD per years
additional exposure (95 CI 4 20), p0.022
Incidence rate ratio (95 CI)
lt0.0001 0.0015 0.0039
0.0082 0.72
0.77
Unadjusted
Adjusted
Duration of cART
Adjusted for exposure group and CD4, diagnosis of
AIDS, HBV and HCV status and starting lamivudine
as time-updated values
Mocroft et al, AIDS 2005 192117-2125
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Relationship between combination antiretroviral
therapy per year of exposure and liver-related
deaths
DAD study Weber et al, Arch Intern Med, 2006
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How drug resistant HIV affect predictive role of
CD4 and HIV-RNA level ?
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PLATO CD4-Slopes in Patients with Stable Viral
Load Compared to Patients Off-Treatment
PLATO Ledergerber et al, Lancet, 2004
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CD4 slope in triple class failures on stable ART
Use of Hydroxyurea Use of NNRTI Use of
boosted PI (y/n) of drugs (/1
additional) Current VL (/log10 higher) Age (per
10 year older)
Change (95 CI) in CD4 count slope
cells/?L per year
Uni- and multivariable Poisson model
Also adjusted for HIV transmission,
gender, and current CD4 count
PLATO study group, Ledergerber et al, Lancet, 2004
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Mortality rate in patients with 3-class resistant
HIV The lack of independent influence of latest
HIV-RNA
66 of subjects died from HIV
PLATO Ledergerber et al, Lancet, 2004
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Does ART affect the risk of coronary heart
disease ?
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Myocardial infarction DAD study
Risk of MI by antiretroviral duration and type
Friis-Møller et al, 13th CROI 2006
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Myocardial infarction DAD study
Risk of MI traditional risk factors
Adjusted relative rate of myocardial infarction
(95 CI) Uni- and multivariable Poisson model
El-Sadr et al, 12th CROI 2005
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Long-Term Studies

• Short-term studies
• impact on drug approval and availability
• do not inform long-term outcomes or side effects
• careful to extrapolate to populations not studies
• Some things you can count dont matter
• Some things that matter you cant count
• A. Einstein

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The ultimate argument for the need of
observational studies in areas with access to ART

HAART
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The EuroSIDA Study Group (national coordinators
in parenthesis). Argentina (M Losso), A Duran.
Austria (N Vetter). Belarus (I Karpov), A
Vassilenko, Belgium (N Clumeck) S De Wit, B
Poll, R Colebunders, Czech Republic (L Machala),
D Sedlacek. Denmark (J Nielsen) J Lundgren, T
Benfield, O Kirk, J Gerstoft, T Katzenstein, A-B
E Hansen, P Skinhøj, C Pedersen. Estonia (K
Zilmer). France (C Katlama), J-P Viard, P-M
Girard, T Saint-Marc, P Vanhems, C Pradier, F
Dabis. Germany M Dietrich, C Manegold, J van
Lunzen, H-J Stellbrink, S Staszewski, M Bickel,
F-D Goebel, G Fätkenheuer, J Rockstroh, R
Schmidt. Greece (J Kosmidis) P Gargalianos, G
Xylomenos, J Perdios, G Panos, A Filandras, E
Karabatsaki. Hungary (D Banhegyi). Ireland (F
Mulcahy). Israel (I Yust) D Turner, M Burke, S
Pollack, G Hassoun, Z Sthoeger, S Mallan. Italy
(A Chiesi) R Esposito, I Mazeu, C Arici, R
Pristera, F. Mazzotta, A Gabbuti, M Lichtner, A
Chirianni, E Montesarchio, AD Cotugno, Antonucci,
F Iacomi, Narciso, Zaccarelli, A Lazzarin, R
Finazzi, A D'Arminio Monforte. Latvia (L
Viksna). Lithuania (S Chaplinskas). Luxembourg
(R Hemmer), T Staub..Netherlands (P Reiss)
Norway (J Bruun) A Maeland, V Ormaasen .Poland
(B Knysz) J Gasiorowski, A Horban, D Prokopowicz,
A Wiercinska-Drapalo, A Boron-Kaczmarska, M
Pynka,M Beniowski, E Mularska, H Trocha.
Portugal (F Antunes) E Valadas, K Mansinho, F
Maltez. Romania (D Duiculescu), A
Streinu-Cercel. Russia E Vinogradova, A
Rakhmanova. Serbia Montenegro (D
Jevtovic).Slovakia (M Mokrá) D Staneková.
Spain (J González-Lahoz) M Sánchez-Conde, T
García-Benayas, L Martin-Carbonero, V Soriano, B
Clotet, A Jou, J Conejero, C Tural, JM Gatell, JM
Miró, P Domingo, MGutierrez, G Mateo, MA Sambeat.
Sweden (A Blaxhult), A Karlsson, P Pehrson.
Switzerland (B Ledergerber) R Weber, P
Francioli, A Telenti, B Hirschel, V
Soravia-Dunand, H Furrer. Ukraine (E Kravchenko)
N Chentsova. United Kingdom (S Barton), AM
Johnson, D Mercey, A Phillips, MA Johnson, A
Mocroft, M Murphy, J Weber, G Scullard, M Fisher,
R Brettle.Virology group B Clotet (Central
Coordinators), L Ruiz Steering Committee  F
Antunes, B Clotet, D Duiculescu, J Gatell, B
Gazzard, A Horban, Karlsson, C Katlama, B
Ledergerber (Chair), A DArminio Montforte, A
Phillips, A Rakhmanova, P Reiss (Vice-Chair), J
Rockstroh Coordinating Centre Staff J Lundgren
(project leader), I Gjørup, O Kirk, A Mocroft, N
Friis-Møller, A Cozzi-Lepri, W Bannister, M
Ellefson, A Borch, D Podlekareva, C Holkmann
Olsen, J Kjær