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

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 …….