a consensus definition of “late presentation” jose m gatell

A consensus definition of “late presentation”

Jose M Gatell


1. The need2. The outcome3. The rationale4. The process5. The implementation and its

consequences6. How to keep it updated


1. The need

A concept frequently used and applied for a wide range of purposes

Substantial variability

Consensus that “the later” the worse for individuals and for public health and also more costly

Late presentation in Europe

Many definitions reportedTime until first ADE Country and year

< 1 year European survey, 2006

< 6 months England, 2006France, 1998Italy, 2005

< 3 months Sweden, 2005England, 2000France, 2004, 2007Italy, 2000Poland, 2006

< 8 weeks Spain, 2002Denmark, 2005

< 1 month England, 2001Italy, 2003

Concurrent AIDS Poland, 2006England, 2006France, 2000

Adler et al. AIDS Care 2008:1

Summary of definitions used in trials identified in a

literature search carried out in 2007

CD4 count Country and year

CD4 < 350 England, 2000

CD4 < 200 UK 2000, 2005, 2006

France 2006, 2007

Italy, 2004

CD4 < 50

Spain, 2005

UK 2004


Effect of choice of definition

26.7%

20.0%

Basis of definition:AIDS CD4Both

15.0%

14.0%

16.0%

14.1%

8.9%

30.0%

31.0%34.0%

• New patients presenting late (%)

• Survey carried out in September 2007

38.0%

• Belarus, Estonia, Moldova, Portugal, Slovakia, and Slovenia did not report prevalence

• Belgium, Cyprus, Finland, Ireland, Latvia, Lithuania, Luxemburg, Romania, Sweden did not respond to survey

Adler et al. AIDS Care 2008:1


BHIVA audit: scenario leading to death

Adapted from Lucas. Clin Med 2008;8:250

6.5

2.1

0

0.3

0.3

1.8

2.8

3.4

4.7

6.7

15.8

24

31.8

0 10 20 30 40

Not known/not stated

Other

Treatment delayed/ineligible for NHS

Died in community without seeking care

Unable to take treatment – toxicity/intolerance

Successful treatment but suffered catastrophic event

MDR HIV, run out of options

HIV +ve, irregular care, re-presented too late

Chose not to receive treatment

Treatment ineffective due to poor adherence

Under care but had untreatable complication

Diagnosed too late for effective treatment

Death not directly related to HIV

Percentage of deaths

n = 387 deaths between October 2004 and September 2005

Inci

denc

e pe

r 10

00 P

YF

U (

95%

CI)

Current CD4 count (/mm3)

AIDS defining illnessNon-AIDS defining illness

<50 51-100 101-200 201-350 351-500 501-700 >700

Incidence of AIDS-defining & Non-AIDS defining illness and current CD4 count

1

10

100

1000

EuroSIDA: Mocroft et al, CROI 2009


Prognosis from starting ART according to pre-therapy CD4 cell counts and HIV-RNA levels

ART CC. Egger et al, Lancet. 2002

CD4 Cell Count (cells/µL)P

rob

abili

ty o

f A

IDS

or

Dea

th (

%)

Years From Starting ART

0-49

50-99

>350

100-199

200-349

0 1 2 30

5

10

15

20

25

Deirdre et al JID, 2008


Cost of late presentation in Canada

• Based on data from 241 patients

• Estimated excess cost of late presentation, after adjusting for patient characteristics: CAN$9,723

• Difference in total costs largely attributable to differences in HIV-related hospital care costs (15 times higher for late presenters)

18488

8455

0

4000

8000

12000

16000

20000

Latepresenters

Non-latepresentersM

ea

n a

nn

ua

l c

os

ts, y

ea

r a

fte

r d

iag

no

sis

(C

AN

$)

Adapted from Krentz et al. HIV Med 2004;5:93CD

4 co

un

t <

200

cel

ls/m

l at

pre

sen

tati

on


2. The outcome…

Is a definition intended (and hopefully valid) for identifying patients at particularly raised risk of clinical disease progression, improving surveillance and for satisfying public health needs.

Responds to the need of a common European definition for late presentation

2. The outcome…

Late presentation: < 350 CD4´s or an AIDS event

Advanced HIV disease: A late presenter with < 200 CD4´s or an AIDS event

> 350 CD4´s (50%)


< 350 CD4´s (50%)

2. The outcome…


Advanced HIV disease: A late presenter with < 200 CD4´s


It is recommended to measure CD4´s twice. If done both should be below 350

Pay attention to conditions associated with transient artificially low CD4 counts such as pregnancy, concomitant infections, or myelosuppressive therapy

2. The outcome… (from earlier group discussion)


Advanced HIV disease: A late presenter with < 200 CD4´s


Presentation is different than diagnosis

Presentation to a facility able to monitor the evolution of infection and to prescribe treatment if considered necessary

CD4 levels for naive patients (approximately 300 per year)

0

10

20

30

40

50

60

70

80

90

100

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Year

%

>350

250-350

<200


Late presentation in Italy

0

200

400

600

800

1992-1996 1997-2001 2002-2006

CD

4 c

ou

nt

(ce

lls

/mm

3)

85th percentile

75th percentile

50th percentile

25th percentile

15th percentile

Estimated adjusted CD4+ cell count percentiles at HIV diagnosis in Modena (Italy) between 1992 and 2006. Estimates were obtained by fitting a simultaneous quantile regression model for the percentiles in the graph, adjusted for: sex, age at diagnosis, country of birth, exposure category, and years of diagnosis.

Despite improvements in diagnosis and treatment, > 25% of patients still present with CD4 < 200/μL and > 50% with < 350

Adapted from Borghi et al. J Acquir Immune Defic Syndr 2008;49:282Lat

e p

rese

nte

rs h

ad C

D4

< 2

00 c

ells

/μL

or

AID

S w

ith

in 3

mo

nth

s


1. The need2. The outcome3. The rationale4. The process5. The implementations and its


Inci

denc

e pe

r 10

00 P

YF

U (

95%

CI)

Current CD4 count (/mm3)


<50 51-100 101-200 201-350 351-500 501-700 >700

Incidence of AIDS-defining & Non-AIDS defining illness and current CD4 count

1

10

100

1000

EuroSIDA: Mocroft et al, CROI 2009


Lancet 2009

HIV-1 infected adults with CD4 cell count > 500/mm3 on long-term ARV therapy reach same

mortality rates as the general population

• Standardized mortality ratio (SMR) in 2435 HIV-infected adults, according to cumulated time spent with CD4 cell count between 350 and 499 /mm3 and > 500 /mm3, after the time of truncation $

Lewden C, Chêne G, Morlat P, Raffi F, Dupon M, Dellamonica P, et al. JAIDS 2007, Sept.

SMR(CI)

8

7

6

5

4

3

2

1

00 1 2 3 4 5 6 7 8

Time of truncation after initiation of cART (years)

§ truncation : the time period taken into account starts 1, 2, 3, … years after initiation of cART

CD4 : 350 to 499/mm3

CD4 > 500/mm3

ANRS CO8 APROCO-COPILOTE and ANRS CO3 AQUITAINE cohorts, 1997-2005

Gras et al.

CD4+ T cells/mm3 at

baseline*

CD4+ T cells/mm3 at last determination*

Total <200 200-349 350-499 >=500

<200 91 (31) 94 (32) 62 (21) 48 (16) 295

200-349 15

(8.5)28 (16) 39 (22) 94 (53.5) 176

350-499 2 (2) 4 (3) 21 (19) 85 (76) 112

>=500 0 (0) 2 (4) 5 (9) 47 (87) 54

Total 108 (17)

128 (20) 127 (20) 274 (43) 637

Classification of the patients according to baseline and last determination of CD4+ T cells after a median f/u 3 years

*Number of patients (%); García F, et al. J AIDS. 2004. *Number of patients (%); García F, et al. J AIDS. 2004.


4. The process…. Initiated by

involved clinicians, patient group representatives, public health workers and other stakeholders in the field of HIV


5. The implementations and its consequences

- Make the problem “visible”- Be used to report surveillance data and

compare between countries- Identify risk factors in a common way- Be used to monitor the evolution by

official bodies or academic organizations (COHERE: 31 cohorts from 10 European countries)

- Quality control marker for public health policies and academic initiatives (like “HIV in Europe”) promoting earlier diagnosis


5. The implementation and its consequences (from eralier group discussion)

- Publication of a brief position paper focusing exclusively on the definition, the rational behind it and tis potential consequences apart from a general report of the whole meeting

- Make it available to editors of main journals and suggest they request authors of papers on “late presentation” to perform and report at least a subanalysis using the definition


Who is likely to present late?

• Heterosexuals• Older patients• Migrants

• Intravenous drug users are– Less likely to be diagnosed late– More likely to experience a delay in presenting for clinical care

once diagnosed– More likely to be lost to follow-up

This slide represents the expert opinion of the Scientific Committee (Yazdan Yazdanpanah, Joep Lange and Jan Gerstoft), March 2009


1. The need2. The outcome3. The rationale4. The process5. The consequences6. How to keep it updated


6. How to keep it updated

The definition mainly reflect most common current recommendations on when to start cART. If guidelines change the definition will be reviewed and may also change (although not automatically)

a consensus definition of “late presentation” jose m gatell

Documents

aids cd4

aids care

late chose

aids behav

year cd4

gatell slide

costly slide

cd4 countcountry