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Workshop 4: Il late-presenter Moderatori: G. Ippolito, M. Moroni Discussant: R. Iardino Overview epidemiologica e razionale della terapia A. Lazzarin.

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Presentation on theme: "Workshop 4: Il late-presenter Moderatori: G. Ippolito, M. Moroni Discussant: R. Iardino Overview epidemiologica e razionale della terapia A. Lazzarin."— Presentation transcript:

1 Workshop 4: Il late-presenter Moderatori: G. Ippolito, M. Moroni Discussant: R. Iardino Overview epidemiologica e razionale della terapia A. Lazzarin

2 Overwiev epidemiologica e razionale della terapia Prof. Adriano Lazzarin Università Vita-Salute San Raffaele, Milano Roma, dicembre 2010 Guidelines and Clinical Expertise

3 Late presenters = persons who present late to care, because unaware of their HIV positive status Whats late? late in respect of the recommended timing of therapy initiation

4 Linee guida di terapia antiretrovirale Clinical category CD4 (cells/mm 3 ) HIV RNA copies/mL EACS 2008DHSS 2009BHIVA 2008 CNA- SIMIT 2010 AIDS-defining or symptoms Any value Treat Asymptomatic< 200Any valueTreat Asymptomatic200–350Any valueTreat Treat when pt ready Treat Asymptomatic350– ,000 Consider treatment Individual basis Consider trial* Consider treatment* Asymptomatic> 350< 100,000 Defer treatment Individual basis Consider trial Consider treatment


6 Late Presenter: Definizioni Recentemente nel corso della Conferenza HIV in Europe a Stoccolma è stato proposto di definire come Late Presenter i pazienti con valore di CD4 < 350/mmc V-LP (Very Late Presenter): pazienti con valore allarruolamento di linfociti CD4+ <200/mmc o AIDS alla diagnosi LP (Late Presenter): pazienti con valore allarruolamento di linfociti CD4+ <350/mmc o AIDS alla diagnosi

7 1. Castilla et al. AIDS 2002;16: Delpierre. Eur J Pub Health 2007;18: Begovac et al. AIDS Behav 2008;12:S Sullivan. BMJ 2005;330: Girardi et al. JAIDS 2004; 36: Wolbers. HIV Med 2008;9: Sabin. AIDS 2004;18:2145 Recorded prevalence of late presentation varies across Europe CountryYear of studynDefinition% Spain –200030,778AIDS < 1 month28% France – CD4 < 200 cells/μL, AIDS < 1 year 30% Croatia – CD4 < 200 cells/μL, AIDS, no seroconversion within 5 years 28% of MSM, 59% among heterosexuals UK CD4 < 200 cells/μL33% Italy – 1998, CD4 < 200 cells/μL, AIDS39% Switzerland – CD4 < 200 cells/μL31% UK – CD4 < 50 cells/μL15% Switzerland – CD4 < 50 cells/μL10%

8 Choice of definition complicates measurement of prevalence 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 % 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

9 ,04% ,2% ,8% * 17,6% ,5% ,2% ,5% * 11,5% Prevalenza V LP per area geografica ,1% ,1% ,6% * 1,02%

10 Persone che scoprono di essere HIV positive alla diagnosi di AIDS

11 Andamento late presenter dal 2000 al 2010 (giugno)

12 Presentazione tardiva nei pazienti afferenti presso lOsservatorio Epidemiologico HIV di Modena p=0.25p=0.19p=0.06 La percentuale di persone AIDS presenters o con compromissione dello stato immunitario (LP 200 o LP 350) non hanno subito modificazioni significative nei periodi osservati. %

13 Most frequent AIDS-defining illnesses

14 BHIVA audit: scenario leading to death n = 387 deaths between October 2004 and September 2005 Lucas SB. 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 Unalta proporzione di decessi in pazienti con HIV è associata la ritardo diagnostico

15 AIDS alla Diagnosi CD4 alla Diagnosi Late Presentation (AIDS e/o<350 CD4) 51% Advanced HIV disease (AIDS e/o<200 CD4) 32% Nuove diagnosi di HIV nel Lazio Studio SENDIH

16 Numero CD4 alla diagnosi

17 In Summary By current definitions, many patients with HIV infection still present late Late presentation is associated with increased morbidity, mortality, and healthcare resource use, and may lead to increased disease transmission Guidelines are shifting towards earlier treatment Further strategies to encourage and facilitate earlier diagnosis and treatment are needed

18 HIV in Europe: optimal testing and earlier care Late presenters and the infected not yet diagnosed population project 2 to –Study the epidemiology for persons presenting late with HIV over time, compared with those presenting early for care –Develop methodologies that are able to estimate the size of the undiagnosed yet infected pool of persons European Parliament resolution 20 November –ensure accurate monitoring and surveillance by the European Centre for Disease Prevention and Control, including more precise estimates (size, characteristics, etc.) of the undiagnosed population A common definition would support these goals 1. European Parliament resolution of 20 November 2008 on HIV/AIDS: early diagnosis and early care. P6_TA(2008) [accessed September 2009].

19 The test and treat strategy

20 20 Source: Not Ist Super Sanità, 2010; 23(4 suppl. 1) Proportion of AIDS cases who were unaware of their HIV infection at the time of AIDS diagnosis in Italy ( ) Late diagnosis is common among migrants in Western Europe

21 21 ARRIVE IN HOST COUNTRY Paucity of information on HIV (including risk, prevention and treatment options) Informal networks / Word-of-mouth Lack of perceived risk of HIV Lack of perceived benefit in knowing HIV status (e.g. treatment options, eligibility to care) UNWELL Priorities: family Housing Visa/permit of stay Money/empolyment Pregnant Antenatal services HIV test fear of disclosure stigma political and legal consideration HIV care GP/Emergency/Hospital/TB clinic/ Migrants services Referral for an HIV test Institutional barriers (e.g. appointment system) Stigma Immigration concerns Source: Burns FM et al. AIDS care, 2007; 19(1): The time between arrival to host country and HIV testing is about 3 years WELL

22 di esposizione Persone che scoprono di essere HIV positive alla diagnosi di AIDS: modalità di esposizione

23 Conclusioni



26 Main gaps in advanced naive treatment 1.Late diagnosis of HIV infection 2.Under/mis-evaluation of HIV associated symptoms 3.Lack of data on combined treatment of HIV and associated pathologies … and superfluos suggestion to observe the indication of guide-lines

27 Limit of SOC in AIDS-presenters: main concerns Waiting time for resistance and loss of CD4 PI friendly treatment combination for EKS Short term side effects (rash) and PI-DDI with anti-TB therapy THE cART EFFICACY WORST ENEMIES Time Tumours Toxicity

28 HIV Highlights From Montreal Abdool Karim SS, et al. CROI Abstract 36a. Graphic reproduced with permission Survival Months Postrandomization Intensive phase of TB treatment Post-TB treatment Continuation phase of TB treatment Early ART Sequential ART SAPiT: Increased Survival With Concurrent HIV and TB Treatment

29 Prevalence of Late presenters according to definition in 1,902 patients with new HIV diagnosis at enrollment in Icona AD= AIDS or CD4<=200/cmm 43%, n=821 61%, n=1,168 LP= AIDS or CD4<=350/cmm AIDS presenters 16%, n=296

30 Separate models with fixed comparator = AIDS-free patients with a CD4 at baseline>350 cells/ l (n=734) Late presenterAdjusted RH* 95% CIp-value Definition LP (n=1,168) AD (n=821) AIDS (n=296) AD (n=797) LP (n=1,154) *Adjusted for: age, gender, mode of HIV transmission, calendar year at baseline, hepatitis co-infection, nationality viral load and whether previously started ART Long term risk of death associated with being LP (Cox regression model)

31 2/6/2014 Short-term increases may be sufficient to control opportunistic infections Battegay, Lancet 2006

32 Distribution of non-AD events according to baseline CD4 counts % of events VLP = very late presenters = CD4 < 250 LP = late presenters = CD NLP = non-late presenters = CD4 > 350

33 HIV therapy principal goals in advanced naive/AIDS presenters 1.AIDS reversion (in symptomatic patients) 2.Rapid HIV/RNA decay 3.Fast immunerecovery 4.Block of reservoir replenishment 5.Avoid short term toxicity

34 HIV Highlights From Montreal Early ART Decreases Survival in HIV+ Patients With Cryptococcal Meningitis Makadzange AT, et al. CROI Abstract 36cLB. Graphic reproduced with permission. HIV-infected African patients diagnosed with cryptococcal meningitis randomized to receive 10 wks of fluconazole 800 mg QD + ART (n = 26) or fluconazole alone (n = 28) –After 10 wks, all patients received fluconazole 200 mg QD + ART After 2 yrs of follow-up: 23 deaths in early ART group (87% mortality rate) vs 9 deaths in delayed ART group (37% mortality rate) (P =.002) Median survival, early ART vs delayed ART: 35 vs 274 days (P =.028) Time to Death (in Days) Delayed ART Early ART P =.028 Survival

35 Advanced HIV disease with low CD4 T cells count and high pathogen endemicity are well-known risk factors for IRIS Battegay M et al. J. Antimicrob. Chemother. 2008;62:41-44

36 Persone che scoprono di essere HIV positive alla diagnosi di AIDS: uso di terapie antiretrovirali e regime terapeutico pre-AIDS

37 V LP e regime terapeutico iniziale %

38 2/6/2014 Poor Initial CD4+ Recovery With Antiretroviral Therapy Prolongs Immune Depletion and Increases Risk for AIDS and Non-AIDS Diseases Baker at al., JAIDS 2008;48:541

39 2/6/2014 CD4 recovery is greater in patients treated with PI/r and without HCV infection Castagna, Antiviral Ther 2010;15:165

40 The new classes of drugs could help us to ameliorate results of therapy in AIDS presenters or advanced naive patients? Consider Rapid decay of viral load Short term tolerability Good DDI More evident immunereconstitution




44 Cost of care after HIV diagnosis, Canada Mean cost (C$) TotalInpatientOutpatientARV drugs Gill WJ, Krentz HB. Poster 12C th European AIDS Meeting, Madrid, October, <1 year CD4 < CD4 > 200 >1 year<1 year>1 year<1 year>1 year<1 year>1 year

45 cART in late presenters: features Pros AIDS/Symptoms recovery Patients compliance Patients motivationsCons Therapy of associated pathologies High risk of mortality or fast progression Patients depression Drug convenience …….and finally lack of data …….


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