1. A consensus definition of “late presentation” Jose M Gatell

2. A consensus definition of “late presentation” 1.The need 2.The outcome 3.The rationale 4.The process 5.The implementation and its consequences 6.How to keep it updated

3. A consensus definition of “late presentation” 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

4. Late presentation in Europe 1. Castilla et al. AIDS 2002;16:1945. 2. Delpierre C. Eur J Pub Health 2007;18:345. 3. Begovac et al. AIDS Behav 2008;12:S48. 4. Sullivan AK. BMJ 2005;330:1301. 5. Girardi et al. JAIDS 2004; 36:951. 6. Wolbers M. HIV Med 2008;9:397. 7. Sabin CA. AIDS 2004;18:2145 Late presentation in Europe CountryYear of studynDefinition% Spain 1 1994–200030,778AIDS < 1 month28% France 2 1996–20066805 CD4 < 200 cells/μL, AIDS < 1 year 30% Croatia 3 2004 – 2006 161 CD4 < 200 cells/μL, AIDS, no seroconversion within 5 years 28% of MSM, 59% among heterosexuals UK 4 2003977CD4 < 200 cells/μL33% Italy 5 1997 – 1998, 2000 968CD4 < 200 cells/μL, AIDS39% Switzerland 6 1998–20071915CD4 < 200 cells/μL31% UK 7 1996–2002719CD4 < 50 cells/μL15% Switzerland 6 1998–20071915CD4 < 50 cells/μL10%

5. Late presentation in Europe Many definitions reported Time until first ADECountry and year < 1 yearEuropean survey, 2006 < 6 monthsEngland, 2006 France, 1998 Italy, 2005 < 3 monthsSweden, 2005 England, 2000 France, 2004, 2007 Italy, 2000 Poland, 2006 < 8 weeksSpain, 2002 Denmark, 2005 < 1 monthEngland, 2001 Italy, 2003 Concurrent AIDSPoland, 2006 England, 2006 France, 2000 Adler et al. AIDS Care 2008:1 Summary of definitions used in trials identified in a literature search carried out in 2007 CD4 countCountry and year CD4 < 350England, 2000 CD4 < 200UK 2000, 2005, 2006 France 2006, 2007 Italy, 2004 CD4 < 50 Spain, 2005 UK 2004

6. Late presentation in different areas CountryAuthor, yearDefinitionPrevalence AustraliaHocking, 2004<8 weeks from diagnosis to AIDS event 249/1021 (24%) SpainCastilla, 2002HIV+ve test in same/preceding month as AIDS event 8499/30778 (28%) ScotlandManavi, 2004CD4 <200 cells/mm 3 249/1021 (24%) CanadaKrentz, 2004CD4 <200 cells/mm 3 93/241 (39%) USKlein, 2003CD4 <200 cells/mm 3 167/388 (43%) ItalyGirardi, 2004CD4 <200 cells/mm 3 or AIDS in preceding month 379/968 (39%)

7. Late presentation in Europe Effect of choice of definition 26.7% 20.0% Basis of definition: AIDS CD4 Both 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

8. Late presentation in Europe BHIVA audit: scenario leading to death Adapted from Lucas. Clin Med 2008;8:250 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

9. Incidence per 1000 PYFU (95% CI) Current CD4 count (/mm 3 ) AIDS defining illness Non-AIDS defining illness 700 Incidence of AIDS-defining & Non-AIDS defining illness and current CD4 count EuroSIDA: Mocroft et al, CROI 2009 AIDS defining illness Non-AIDS defining illness

10. 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) Probability of AIDS or Death (%) Years From Starting ART 0-49 50-99 >350 100-199 200-349 0123 0 5 10 15 20 25

11. Deirdre et al JID, 2008

12. Late presentation in Europe 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) Adapted from Krentz et al. HIV Med 2004;5:93 CD4 count < 200 cells/ml at presentation

13. A consensus definition of “late presentation” 1.The need 2.The outcome 3.The rationale 4.The process 5.The implementation and its consequences 6.How to keep it updated

14. A consensus definition of “late presentation” 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

15. 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%) A consensus definition of “late presentation” < 350 CD4´s (50%)

16. 2. The outcome… Late presentation: < 350 CD4´s or an AIDS event Advanced HIV disease: A late presenter with < 200 CD4´s A consensus definition of “late presentation” 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

17. 2. The outcome… (from earlier group discussion) Late presentation: < 350 CD4´s or an AIDS event Advanced HIV disease: A late presenter with < 200 CD4´s A consensus definition of “late presentation” Presentation is different than diagnosis Presentation to a facility able to monitor the evolution of infection and to prescribe treatment if considered necessary

19. Late presentation in Europe Late presentation in Italy 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 50% with < 350 Adapted from Borghi et al. J Acquir Immune Defic Syndr 2008;49:282 Late presenters had CD4 < 200 cells/μL or AIDS within 3 months

20. A consensus definition of “late presentation” 1.The need 2.The outcome 3.The rationale 4.The process 5.The implementations and its consequences 6.How to keep it updated

21. Incidence per 1000 PYFU (95% CI) Current CD4 count (/mm 3 ) AIDS defining illness Non-AIDS defining illness 700 Incidence of AIDS-defining & Non-AIDS defining illness and current CD4 count EuroSIDA: Mocroft et al, CROI 2009 AIDS defining illness Non-AIDS defining illness

22. Serious non-AIDS events and latest CD4 (adjusted hazard ratio /100 cells/mm 3 higher) 0.91.01.20.80.70.61.5 SMART FIRST DAD Number Includes of events non-fatal 14Yes 27No 18Yes 0.50.4 Adjusted hazard ratio (iii) Renal disease / death 0.9 1.0 CASCADE SMART FIRST DAD 1.11.21.30.80.7 0.6 1.4 1.5 1.6 Number Includes of events non -fatal 24Yes 855Yes 36No 145Yes (iv) Cardiovascular disease / death Adjusted hazard ratio 0.9 1.0 (i) Liver disease / death 1.11.2 1.3 0.80.7 0.61.41.51.6 CASCADE SMART FIRST DAD Number Includes of events non-fatal 14Yes 301No 46No 25Yes Adjusted hazard ratio 0.9 1.01.11.21.30.80.7 0.6 1.41.51.6 CASCADE SMART FIRST DAD Number Includes of events non - fatal 32Yes 255No 46No 49Yes Adjusted hazard ratio - (ii) Non-AIDS cancer / death Adapted from Phillips AN et al. AIDS 2008;22:2409–18.

23. Lancet 2009

26. Gras et al.

27. CD4+ T cells/mm 3 at baseline* CD4+ T cells/mm 3 at last determination* Total <200200-349350-499>=500 <20091 (31)94 (32)62 (21)48 (16)295 200-349 15 (8.5) 28 (16)39 (22)94 (53.5)176 350-4992 (2)4 (3)21 (19)85 (76)112 >=5000 (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.

28. A consensus definition of “late presentation” 1.The need 2.The outcome 3.The rationale 4.The process 5.The implementation and its consequences 6.How to keep it updated

29. A consensus definition of “late presentation” 4. The process…. Initiated by involved clinicians, patient group representatives, public health workers and other stakeholders in the field of HIV

30. A consensus definition of “late presentation” 1.The need 2.The outcome 3.The rationale 4.The process 5.The implementation and its consequences 6.How to keep it updated

31. A consensus definition of “late presentation” 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

32. A consensus definition of “late presentation” 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

33. Late presentation in Europe Groups at risk of late presentation UK 1 National survey France 2 National survey Italy 3 Centres in Modena Spain 4 National survey CD4 < 200 cells/μL within 3 months of diagnosis AIDS or CD4 < 200 cells/μL at enrolment AIDS < 1 month after HIV diagnosis Older patients – 52.1% of those aged > 60 years 56.3% of those aged > 50 years 62.0% of those aged > 45 years Migrants – 35.4% of migrant women, 47.2% of migrant men 34.5%68.7% of those from developing countries IDUs30%38.7%33.1%17.6% Females36% – 25.9%32.0% Who is likely to present late? 1. HPA. HIV in the United Kingdom: 2008 Report. 2. Lanoy et al. Antiviral Therapy 2007;12:89. 3. Girardi et al. JAIDS 2004;36:951. 4. Castilla et al. AIDS 2002;16:1945

34. Late presentation in Europe 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

35. A consensus definition of “late presentation” 1.The need 2.The outcome 3.The rationale 4.The process 5.The consequences 6.How to keep it updated

36. A consensus definition of “late presentation” 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)