workshop 4: il late-presenter moderatori: g. ippolito, m. moroni discussant: r. iardino overview...
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Workshop 4: “Il late-presenter”Moderatori: G. Ippolito, M. MoroniDiscussant: R. Iardino
Overview epidemiologica e razionale della terapiaA. Lazzarin
Late presenters
= persons who present late to care, because unaware of their HIV positive status
What’s ‘late’?
late in respect of the recommended timing of therapy initiation
Linee guida di terapia antiretrovirale
Clinical category
CD4(cells/mm3)
HIV RNA copies/mL
EACS 2008 DHSS 2009 BHIVA 2008CNA- SIMIT
2010
AIDS-defining or symptoms
Any value Any value Treat Treat Treat Treat
Asymptomatic < 200 Any value Treat Treat Treat Treat
Asymptomatic 200–350 Any value Treat TreatTreat when
pt readyTreat
Asymptomatic 350–500 ≥ 100,000Consider treatment
Individualbasis
Consider trial*
Consider treatment*
Asymptomatic > 350 < 100,000Defer
treatmentIndividual
basisConsider
trialConsider treatment
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 all’arruolamento di linfociti CD4+ <200/mmc o AIDS alla diagnosi
• LP (Late Presenter): pazienti con valore all’arruolamento di linfociti CD4+ <350/mmc o AIDS alla diagnosi
1. Castilla et al. AIDS 2002;16:1945. 2. Delpierre. Eur J Pub Health 2007;18:345. 3. Begovac et al. AIDS Behav 2008;12:S48. 4. Sullivan. BMJ 2005;330:1301. 5. Girardi et al.
JAIDS 2004; 36:951. 6. Wolbers. HIV Med 2008;9:397. 7. Sabin. AIDS 2004;18:2145
Recorded prevalence of late presentation varies across Europe
Country Year of study n Definition %
Spain1 1994–2000 30,778 AIDS < 1 month 28%
France2 1996–2006 6805CD4 < 200 cells/μL, AIDS < 1 year
30%
Croatia3 2004–2006 161CD4 < 200 cells/μL, AIDS, no seroconversion within 5 years
28% of MSM, 59% among
heterosexuals
UK4 2003 977 CD4 < 200 cells/μL 33%
Italy5 1997–1998, 2000 968 CD4 < 200 cells/μL, AIDS 39%
Switzerland6 1998–2007 1915 CD4 < 200 cells/μL 31%
UK7 1996–2002 719 CD4 < 50 cells/μL 15%
Switzerland6 1998–2007 1915 CD4 < 50 cells/μL 10%
Choice of definition complicates measurement of prevalence
26.7%
20.0%
Basis of definition:AIDSCD4Both
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
2000-2002 15,04%2003-2005 11,2%2006-2008 13,8%2009-2010* 17,6%
2000-2002 15,5%2003-2005 18,2%2006-2008 13,5%2009-2010* 11,5%
Prevalenza V LP per area geografica
2000-2002 9,1%2003-2005 3,1%2006-2008 2,6%2009-2010* 1,02%
Persone che scoprono di essere HIV positive alla diagnosi di AIDS
Andamento late presenterdal 2000 al 2010 (giugno)
0%
10%
20%
30%
40%
50%
60%
70%
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010*
V-LP LP
Presentazione tardiva nei pazienti afferenti presso l’Osservatorio Epidemiologico HIV di Modena
2420
25
43
3639
57
4853
0
10
20
30
40
50
60
1992-1997 1998-2003 2004-2009
AP LP<200 LP<350
p=0.25 p=0.19 p=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.
%
Most frequent AIDS-defining illnesses
BHIVA audit: scenario leading to deathn = 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
Un’alta proporzione di decessi in pazienti con HIV è associata la ritardo diagnostico
AIDS alla DiagnosiCD4 alla Diagnosi
Late Presentation (AIDS e/o<350 CD4) 51%Advanced HIV disease (AIDS e/o<200 CD4) 32%
<20032%
200-35020%
351-50020%
>50028%
NO87%
SI13%
Nuove diagnosi di HIV nel Lazio Studio SENDIH 2004-2008
Numero CD4 alla diagnosi
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
HIV in Europe: ‘optimal testing and earlier care’
• ‘Late presenters and the infected not yet diagnosed population’ project2 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 20081
– ‘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)0566. 2. http://www.hiveurope.eu/ [accessed September 2009].
The test and treat strategy
20Source: 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 (1996-2009)
0% 20% 40% 60% 80% 100%
italians(23,092)
foreigners(3,411)
HIV unaware HIV aware
Late diagnosis is common among migrants in Western Europe
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 testHIV test
• fear of disclosure• stigma• political and legal considerationHIV careHIV 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): 102-108
The time between arrival to host country and HIV testing is about 3 years
WELL
Persone che scoprono di essere HIV positive alla diagnosi di AIDS: modalità di esposizionedi esposizione
Conclusioni
Main gaps in advanced naive treatment
1. Late diagnosis of HIV infection2. Under/mis-evaluation of HIV associated
symptoms3. Lack of data on combined treatment of
HIV and associated pathologies
… and superfluos suggestion to observethe indication of guide-lines
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
clinicaloptions.com/hiv
HIV Highlights From Montreal
Abdool Karim SS, et al. CROI 2009. Abstract 36a. Graphic reproduced with permission.
0.70
0.75
0.80
0.85
0.90
0.95
1.00
Su
rviv
al
Months Postrandomization
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Intensive
phase of TB
treatment
Post-TB treatmentContinuationphase of TB
treatment
Early ARTSequential ART
SAPiT: Increased Survival With Concurrent HIV and TB Treatment
Prevalence of Late presenters according to definition in 1,902 patients with new HIV diagnosis at enrollment in Icona
LP non LPAD non AD
AD= AIDS or CD4<=200/cmm
43%, n=821
61%, n=1,168
LP= AIDS or CD4<=350/cmm
AIDS-p non AIDS-p
AIDS presenters
16%, n=296
Separate models with fixed comparator = AIDS-free patients with a CD4 at baseline>350 cells/l (n=734)
Late presenter Adjusted RH* 95% CIp-value
Definition
LP 1.79 0.32-10.030.51
(n=1,168)AD 2.88 0.47-17.49
0.25(n=821)AIDS 7.02 0.98-50.41
0.06(n=296)AD-200 3.10 0.50-19.08
0.22(n=797)LP-350 1.85 0.33-10.43
0.49(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)
04/10/23
Short-term increases may be sufficient to control opportunistic infections
Battegay, Lancet 2006
Distribution of non-AD events according to baseline CD4 counts
0
10
20
30
40
50
60
70
80
Cance
r
Cardio
vasc
ular
diabete
s
ESLDOth
er
VLP
LP
NLP
% o
f ev
ents
VLP = very late presenters = CD4 < 250LP = late presenters = CD4 250-350NLP = non-late presenters = CD4 > 350
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
clinicaloptions.com/hiv
HIV Highlights From Montreal
Early ART Decreases Survival in HIV+ Patients With Cryptococcal Meningitis
Makadzange AT, et al. CROI 2009. 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)
0.00
0.25
0.50
0.75
1.00
0 200 400 600 800Time to Death (in Days)
Delayed ARTEarly ART
P = .028Su
rviv
al
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
Persone che scoprono di essere HIV positive alla diagnosi di AIDS: uso di terapie antiretrovirali e regime terapeutico pre-AIDS
V LP e regime terapeutico iniziale
0
2
4
6
8
10
12
14
2000-2002 2003-2005 2006-2008 2009-2010*
2NRTI+PI 2NRTI+PI/r 2NRTI+NNRTI Altro
%
04/10/23
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
04/10/23
CD4 recovery is greater in patients treated with PI/r and without HCV infection
Castagna, Antiviral Ther 2010;15:165
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
Cost of care after HIV diagnosis, CanadaM
ean
co
st (
C$)
Total Inpatient Outpatient ARV drugs
Gill WJ, Krentz HB. Poster 12C1070. 11th European AIDS Meeting, Madrid, 24-27 October, 2007
25000
<1 year
CD4 < 200
20000
15000
10000
5000
0
CD4 > 200
>1 year <1 year>1 year <1 year>1 year <1 year>1 year
cART in late presenters: features
Pros AIDS/Symptoms
recovery Patients compliance Patients motivations
ConsCons Therapy of associated
pathologies High risk of mortality
or fast progression Patients depression Drug convenience
…….and finally lack of data …….