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

3. 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

4. Linee guida di terapia antiretrovirale
Clinical category
CD4 (cells/mm3)
HIV RNA copies/mL
EACS 2008
DHSS 2009
BHIVA 2008
CNA- SIMIT 2010
AIDS-defining or symptoms
Any value
Treat
Asymptomatic
< 200
200–350
Treat when pt ready
350–500
≥ 100,000
Consider treatment
Individual
basis
Consider trial*
Consider treatment*
> 350
< 100,000
Defer treatment
Individual basis
Consider trial

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 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

7. 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
6805
CD4 < 200 cells/μL, AIDS < 1 year
30%
Croatia3
2004–2006
161
CD4 < 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
31%
UK7
1996–2002
719
CD4 < 50 cells/μL
15%
10%
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 7 7

8. Choice of definition complicates measurement of prevalence
Basis of definition:
AIDS CD4
Both
14.0%
34.0%
New patients presenting late (%)
Survey carried out in September 2007
31.0%
8.9%
30.0%
15.0%
16.0%
26.7%
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
20.0%
38.0%
14.1%
Adler et al. AIDS Care 2008:1 8

9. Prevalenza V LP per area geografica 2000-2002 15,04% 2003-2005 11,2%
,04%
,2%
,8%
* 17,6%
,5%
,2%
,5%
* 11,5%
,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 l’Osservatorio Epidemiologico HIV di Modena%
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.
p=0.25
p=0.19
p=0.06

13. Most frequent AIDS-defining illnesses

14. Un’alta proporzione di decessi in pazienti
con HIV è associata la ritardo diagnostico
BHIVA audit: scenario leading to death n = 387 deaths between October 2004 and September 2005
Death not directly related to HIV
Diagnosed too late for effective treatment
Under care but had untreatable complication
Treatment ineffective due to poor adherence
Chose not to receive treatment
HIV+ve, irregular care, re-presented too late
MDR HIV, run out of options
Successful treatment but suffered catastrophic event
Unable to take treatment – toxicity/intolerance
Died in community without seeking care
Treatment delayed/ineligible for NHS
Other
Not known/not stated
Percentage of deaths
Lucas SB. Clin Med 2008;8:250 14 14

15. Nuove diagnosi di HIV nel Lazio Studio SENDIH 2004-2008
CD4 alla Diagnosi
AIDS alla Diagnosi
Late Presentation (AIDS e/o<350 CD4) 51%
Advanced HIV disease (AIDS e/o<200 CD4) 32%

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’ 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) [accessed September 2009]. 18

19. The test and treat strategy

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

21. GP/Emergency/Hospital/TB clinic/ Migrants services
The time between arrival to host country and HIV testing is about 3 years
ARRIVE IN HOST COUNTRY
WELL
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)
Pregnant
Priorities:
family
Housing
Visa/permit of stay
Money/empolyment
Antenatal services
HIV test
Institutional barriers (e.g.
appointment system)
Stigma
Immigration concerns
UNWELL
fear of disclosure
stigma
political and legal
consideration
GP/Emergency/Hospital/TB clinic/ Migrants services
HIV care
Referral for an HIV test 21
Source: Burns FM et al. AIDS care, 2007; 19(1): 21

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

23. Conclusioni

26. Main gaps in advanced naive treatment
Late diagnosis of HIV infection
Under/mis-evaluation of HIV associated symptoms
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
THE cART EFFICACY WORST ENEMIES
Time Tumours Toxicity
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

28. SAPiT: Increased Survival With Concurrent HIV and TB Treatment
1.00
Early ART
Sequential ART
0.95
0.90
Survival
0.85
0.80
ART, antiretroviral therapy; SAPiT, Starting Antiretrovirals at Three Points in Tuberculosis; TB, tuberculosis.
The curves shown on this slide describe survival during the course of intensive, continuous, and post‑TB treatment. The orange line represents patients who started antiretrovirals after completing TB therapy. It is clear that the survival curves of patients who received early vs sequential antiretroviral therapy diverged, but the divergence was greatest following completion of TB therapy. It is interesting that most of the survival difference between the 2 treatment groups seemed to occur somewhat late. As mentioned earlier, data assessing whether there is a survival difference between patients treated with antiretrovirals during the intensive phase vs the continuous phase of TB therapy are awaited.
Intensive phase of TB treatment
0.75
Continuation phase of TB treatment
Post-TB treatment
0.70 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Months Postrandomization
Abdool Karim SS, et al. CROI Abstract 36a. Graphic reproduced with permission. 28

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
LP= AIDS or CD4<=350/cmm
43%, n=821
61%, n=1,168
AIDS presenters
16%, n=296

30. Long term risk of death associated with being LP (Cox regression model)
Separate models with fixed comparator =
AIDS-free patients with a CD4 at baseline>350 cells/l (n=734)
Late presenter Adjusted RH* 95% CI p-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

31. Short-term increases may be sufficient to control opportunistic infections
Battegay, Lancet 2006
3/27/2017

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
AIDS reversion (in symptomatic patients)
Rapid HIV/RNA decay
Fast immunerecovery
Block of reservoir replenishment
Avoid short term toxicity

34. Early ART Decreases Survival in HIV+ Patients With Cryptococcal Meningitis
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
1.00
Delayed ART
0.75
Early ART
Survival
0.50
0.25
P = .028
0.00
200
400
600
800
ART, antiretroviral therapy; QD, once daily.
This slide depicts the results of a similar study in HIV-infected patients with cryptococcal meningitis in Africa, where the standard of care is not amphotericin B and flucytosine as in the developed world but rather is fluconazole because of resource limitations. Mortality in HIV-infected patients with cryptococcal meningitis in this region is considerably higher than in developed nations. This may be partly because of the lack of amphotericin B and flucytosine therapy and partly because patients are presenting and being diagnosed later and receiving less supportive care during the course of therapy.
This study included 54 HIV-infected patients, a relatively small number, who were diagnosed with cryptococcal meningitis and were randomized to receive an initial 10 weeks of fluconazole at 800 mg daily either with or without antiretroviral therapy. Treatment was initiated within the first several days of diagnosis and after 10 weeks of randomized treatment, all patients received fluconazole plus antiretroviral therapy. The curves on this slide reveal that there was a markedly increased risk of mortality, reaching 87% after 2 years of follow-up, among patients who received antiretroviral therapy within the first few days of starting fluconazole vs those who deferred HIV-1 treatment for 10 weeks. This was a dramatic finding: Mortality was high in both groups but much higher in those who started antiretroviral therapy earlier.
The presenter speculated on the explanations for this outcome. It is certainly conceivable that early antiretroviral therapy was associated with an increased incidence of IRIS and that the mortality may have been even higher in this setting because of the inability to manage complications such as increased intracranial hypertension. However, the investigators were not able to specify how many patients died with IRIS. Other possibilities included unexpected drug‑drug interactions since patients in this study received a regimen, which included nevirapine and fluconazole, that has been shown to increase nevirapine levels.
Although the reason for the outcome of this study is not clear, it appears that initiation of antiretroviral therapy within the first few days of treating cryptococcal meningitis with fluconazole is associated with a markedly increased risk of mortality.
Time to Death (in Days)
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)
Makadzange AT, et al. CROI Abstract 36cLB. Graphic reproduced with permission. 34

35. Advanced HIV disease with low CD4 T cells count and
high pathogen endemicity are well-known risk factors for IRIS
Advanced HIV disease with low CD4 T cells count and high pathogen endemicity are well-known risk factors for IRIS. Due to very low CD4 T cell counts, CD4- and/or CD8-mediated cellular immune responses are likely to be strongly impaired and defence inflammatory reactions may not develop. Consequently, the threshold for clinically manifested disease is not crossed. Following ART initiation, viral load rapidly decreases and cellular immune functions improve within days or weeks, leading to an increased pathogen-specific immunity, which becomes apparent as an inflammatory reaction. Of course, such a reaction is recognizable only if a pathogen is present.
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. 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
3/27/2017

39. CD4 recovery is greater in patients treated with PI/r and without HCV infection
Castagna, Antiviral Ther 2010;15:165
3/27/2017

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
25000
20000
Mean cost (C$)
15000
CD4 < 200
CD4 > 200
10000
In questa diapositiva, che si riferisce ad uno studio canadese, sono riportati i costi dei diversi tipi di attività assistenziale per i pazienti stratificati a seconda di un numero di CD4 superiore (barre verdi) o inferiore (barre azzurre) a 200.
In generale, in tutti i casi, i bassi livelli di CD4 coincidono con costi più elevati.
5000
<1 year
>1 year
<1 year
>1 year
<1 year
>1 year
<1 year
>1 year
Total
Inpatient
Outpatient
ARV drugs
Gill WJ, Krentz HB. Poster 12C th European AIDS Meeting, Madrid, October, 2007 44

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