Giuliano Rizzardini
Ospedale L. Sacco
Milano
 Alcuni obiettivi raggiunti, le sfide aperte
ed i dati utili nella gestione dei pazienti
complessi
 Gli strumenti del futuro prossimo
 Uno sguardo sul futuro “remoto”
 Alcuni obiettivi raggiunti, le sfide aperte
ed i dati utili nella gestione dei pazienti
complessi
 Gli strumenti del futuro prossimo
 Uno sguardo sul futuro “remoto”
 Oggi, un regime ART efficace puo’ essere tanto
semplice da essere una sola pillola da assumere
prima di dormire.
 L’utilizzo della terapia antiretrovirale nei paesi in
via di sviluppo si è espanso dopo il 2000 che si
stima che attualmente vi siano più di 5 milioni di
soggetti HIV infetti nei paesi a risorse limitate
che assumono la ART con un beneficio clinico
simile a quello dei paesi occidentali.
 L’aspettativa di vita di una persona HIV positiva
trattata in modo appropriato è aumentata da
10.5 anni nel 1996 a 22.5 anni nel 2005, ed è ora
vicina a quella della popolazione generale
 Aderenza, tossicità, interazioni farmacologiche e
resistenza rimangono un problema,specialmente
in popolazioni svantaggiate
 Alcuni gruppi di pazienti, inclusi i TD, non hanno
fino ad ora beneficiato appieno della ART a causa
di numerosi fattori concomitanti (accesso alle
cure, aderenza, coinfezioni e comorbidità,
problemi psichiatrici)
 Dopo 20 anni di ART, alcune domande rimangono
ancora aperte:
 Quando e come iniziare la terapia?
 Quando e come cambiare la terapia?
 Quali strategie per prevenire le resistenze?
 Untreated HIV disease is associated with increased T cell
activation/inflammation and these markers predict disease
 Treatment dramatically reduces but does not normalize
levels inflammation
 Inflammation on HAART predicts disease
 The degree of residual inflammation during HAART is
determined in part by CD4 nadir (strong effect < 200, less
clear effect > 350)
From SG. Deeks, MD, at Atlanta, GA: March 2, 2010, IAS–USA
HIV infection may result in accelerated immunologic aging
From
Deeks, MD,
MD, at
at Chicago,
Atlanta, GA:
March
2,2010,
2010,IAS–USA.
IAS–USA.
FromSG
S Deeks,
IL: April
19,
Desai and Landay, Current HIV/AIDS Reports 2010
Clinical
CD4di 4000 naive1 con CD4 >500
START
study: Piu’
cellule/ul
DHHS 09
IAS-USA 102
EACS 093
ITA 104
3
category
cells/mm
- Pazienti randomizzati a iniziare la terapia subito o ad attendere il
AIDS-defining
raggiungimento
della
di (AI)
350/ul Treat (AI)
Any
valuesoglia
Treat
Treat
Treat (AI)
or symptoms
-Follow-up per i seguenti eventi:
Treat or
- Eventi severi AIDS definenti
NAD diseases,
consider
HBV, - eventi clinici
Any value
Treatdefinenti
(AI/III)
Treat (BII/AI)
Treat (AI-II/BII)#
non AIDS
only if CD4
pregnancy
- decesso
<500/mm3
-Arruolamento in corso, risultati attesi entro il 2015.
Asymptomatic
Asymptomatic
Asymptomatic
<350
Treat (AI)
Treat (AI)
Treat
Treat (AI)
Treat all (BII)
or on
individual
basis^ (AII/BIII)
Generally
defer (CII)
350–500
Treat (A/BII)
Treat (AII)
Treat or
consider
only on
individual
basis§
>500
Treat as
moderate or
optional*
Consider
treatment
(CIII)°
Generally
defer
PLOS one Jun 2010
Half (50%) of individuals who initiated
therapy discontinuedor changed their initial
regimen within the first2 years.
Individuals initiating using an NNRTI-based
regimen were more likely to achieve virologic
suppression(HIV-1 RNA 500 copies/ml) than
those initiating using a boosted protease
inhibitor-based regimen
THE latest dispatch from the war on
AIDS brings good news. At 5.25m, the
number of people in poor and middleincome countries who were being
treated for HIV infection at the end of
2009 was up 30% from the end of
2008. Eight countries achieved coverage
of 80% or better and 21 others covered
more than half of those in need. Though
the new figure still represents only
about a third of those who could
benefit, the rate of increase is
impressive. The news is doubly
welcome, too, because it is now
agreed that treatment, which has
the effect of making people less
infective, is an important way of
stopping the spread of HIV as well
as being desirable in its own right.
Sep 2010
 Alcuni obiettivi raggiunti, le sfide aperte
ed i dati utili nella gestione dei pazienti
complessi
 Gli strumenti del futuro prossimo
 Uno sguardo sul futuro “remoto”
Proportion of subjects with VL<50 copies at
w 96 in RCTs in naives
*
Artemis
Darunavir
Startmrk
§
5142
Raltegravir
Efavirenz
Fosamprenavir
Klean
Kaletra
Atazanavir/r
Castle
0
20
40
60
80
100
§ difference confirmed in High VL subgroup
*superiority
Regime
% paz <50
copie a 48
settimane
% di paz <
50 copie a
96
settimane
Commenti
ENF + OBR
18%
16%
Ridotto numero di farmaci attivi nell’
OBR, eff collaterali e poca
maneggevolezza
TPV/r + OBR
21%* (vs
14% di PI/r)
20%
* 28% in pazienti con terapia
contenente ENF, 21% senza ENF:
Problemi con doppia dose booster
39%(vs 9%
PI/r)*
* Studi Power 1 e 2 vs PI/r, Power 3
single arm 42% <50 copie; alta
barriera genetica. In naive anche QD
DRV/r +OBR
MVC + OBR
46% (vs17%
pl)
ETV+ OBR
61% (vs
41%)
RAL+OBR
In pazienti con virus CCR% tropico
(50% dei pazienti expd)
57% (vs
36%)
DUET: DRV+NRTI+ placebo o ETV
con o senza ENF
57% (vs
26%)
Benchmrk. Alta potenza e rapidità di
discesa della viremia ma
relativamente bassa barr genetica
Regime
% paz <50
copie a 24
settimane
% di paz <
50 copie a
48settiman
e
DRV/r, ETV, RAL
90%
86%
MVC, ETV RAL
ELV/r
92%
Commenti
Studio su 28 pazienti. Potenziali
problemi su DDI
50 mg non inferiore a DRV/r o
TPV/r, 125 mg superiore a 24 e 48
settimane.
 Prospective observational cohort of multi
experieced patients with very limited options
starting a NUC sparing dual therapy including
RAL+ 3 rd agent
 3 rd agent choice based on historical mutations
pattern and last genotype at failure
 Patients must be failing their current treatment to
be included
 Data on VL, biochemistry, CD4 cells count
collected and descriptive analysis performed
 26 patients included in the analysis
 Minimum follow-up: 70 weeks
 Co- administered drugs
 PI (DRV/r =18, LPV/r= 1, ATV/r= 4, ATV= 1)
 NNRTI (EFV = 2).
 Median HIV-1 RNA 4.65 log10, (range 3,01 – 5,66)
 Median CD4+ cell count 352 cells/mm3 (range: 24 –
1064).
 Patients had been exposed to a median of 8 previous
antiretroviral regimens (range 5-12).
 Median number of NRTI associated mutations: 6 (range 38), for NNRTI was 1 (range 1-4) and for PIs was 6 (range
0-13).
 Patients were never fully-resistant to the chosen PIs or
NNRTI (GSS = 0.5-1).
 In the subgroup of 24 PI-treated patients, 17 had at least
one major IAS protease mutation (median 3, range 1-5),
and 11 at least one relevant darunavir (DRV) -mutation
 At week 24 all patients (100%) reached an HIV RNA
load of <50 copies/ml and maintained viral suppression
until week 70 and for the entire observation period for
those followed longer.
 Two subjects experienced a transient ‘blip’ in virus (127
and 113 RNA copies/mL, respectively) and re-suppressed
promptly
 At week 4, 21/26 patients (80,7%) reached full viral
suppression (< 50 copies HIV-1 RNA/mL).
 The mean CD4+ cell count increased from 352/mm3
(range 24 – 1064 cells/) to 529/mm3 at week 70 (range
187-1106) (p <0.001).
 Switch da PI a RAL: bene nello studio SPIRAL,
attenzione all’efficacia del backbone (Switchmrk)
 NUC Sparing regimens (RAL+PI): numerose
segnalazioni di successo terapeutico, no all’uso di
RAL+ATV senza booster (DDI)
 Monoterapie: per molti, ma non per tutti (risultati
discordanti per LPV/r e ATV/r), incoraggianti i
risultati su DRV/r negli studi MONET e MONOI
 Alcuni obiettivi raggiunti, le sfide aperte
ed i dati utili nella gestione dei pazienti
complessi
 Gli strumenti del futuro prossimo
 Uno sguardo sul futuro “remoto”
• Complete eradication of all replication competent
virus (“sterilizing cure”)
– Is this remotely possible?
– How can this be proven?
• Long-term health in absence of therapy (“functional
cure”)
– Cancer model (remission)
– Definition: no readily detectable virus in absence
of therapy for prolonged periods
– Natural model: “elite” controllers
From S Deeks, MD, at Chicago, IL: April 19, 2010, IAS–USA.
From S Deeks, MD, at Chicago, IL: April 19, 2010, IAS–USA.
Dinisio PNAS 09, McMahon CID 10; Gandhi IAS 09
 In most (but not all) studies, treatment intensification is not
associated with measurable changes in plasma HIV RNA
levels, immune activation, or HIV-specific responses
 Dinoso PNAS 09; Gandhi IAS 09; McMahon CID 10;
Hatano CROI 10
 In other studies using more precise measures of replication,
an effect of intensification may be evident, but this does not
affect plasma HIV RNA levels
 Buzon, CROI 10, Yukl CROI 10
 Ongoing viral replication is not likely to be a major cause of
persistent viremia, but it is possible that low-level virus
replication persists and that this virus will remain a barrier to
eradication
Residual replication
•Sanctuaries; drug penetration
•Efficacy, cell type differences
Latently infected cells
Persistent HIV expression
•Replication competent?
•Immune disfunction?
Inflammation
Homeostatic Proliferation
These are not mutually exclusive mechanisms; will multiple approaches be required?
Can HIV be Purged from Latent Reservoir?
Increased DNA
transcription direclty
(HDAC inhibitors,
including SAHA) vs.
indirectly (IL2, OKT3)
under fully suppressive
HAART
BMT (CCR5), gene
therapy, HIV vaccine
From S Deeks, MD, at Chicago, IL: April 19, 2010, IAS–USA.
Richman et al, Science, 2009
Eradication Strategies
– Stimulate HIV expression from latently infected cells
• HDAC and other approaches to remodel chromatin
• Specific HIV induction
• Immune modulators
– Target infected cells with low level replication
• Inhibit cellular activation
• Direct cytotoxic therapy
• Gene therapy approaches
– Transplantation approaches
• Replacement of bone marrow with HIV resistant donor
– Heller et al., 2009
• NOT widely applicable
– ARV discontinuation
– Clinical success will require surveillance
From S Deeks, MD, at Chicago, IL: April 19, 2010, IAS–USA.
Eradication Studies (1st Generation)
• HDAC inhibitors and other activations of DNA transcription
– Valproic acid failed to accelerate HIV decay (Lerman
Lancet 05; Siliciano JID 07)
– Suberoylanilide hydroxamic acid (SAHA) (Contreras JBC
09)
– Prostratin (Korin JV 02)
• T cell activation
– IL-2 failed to accelerate viral decay (Chun JEM 98,
Lafeuilade JAIDS 01, others)
– OKT3 (anti-CD3 antibody) (Kulkosky JID 02, Van Praag
J Clin Imm 01) failed to accelerate decay, and caused
significant toxicity
From S Deeks, MD, at Chicago, IL: April 19, 2010, IAS–USA.
Eradication Studies (2nd Generation)
• Gene therapy approaches
– Gene modified HIV specific T cells (Deeks
Molecular Med 02)
– CCR5 excision (Sangamo)
– Anti-sense methods (VIRxSYS)
• Practical concerns regarding gene therapy
– Stem cell versus T cell therapies
– Partial versus full ablation
– Bone marrow transplant
• Therapeutic vaccines
From S Deeks, MD, at Chicago, IL: April 19, 2010, IAS–USA.
Potential HIV-1 Latency
Activation Therapies
• Histone deacetylase (HDAC) inhibitors
– Class I-selective: SAHA, others (MRL)
– Non-selective: Trichostatin A (TSA), valproic acid (VPA)
• NF-kB activators
– Prostratin, PMA, TNF
• Akt/HEXIM-1 modulators
– Hexamethylbisacetamide (HMBA)
• Histone methyltransferase (HMT) inhibitors
– DZNep: targets Ezh2 (trimethylates H3-K27/H4-K20)
– Chaetocin: targets su(var)3-9 (methylates H3-K9)
• Jak/Stat pathway
– IL-7
From S Deeks, MD, at Chicago, IL: April 19, 2010, IAS–USA.
Non-mechanism based screening can
identify novel HIV-1 activators
~ 1.5 million compounds (MRL Library)
LTR-bGal HTS
~ Confirmed 104 compounds (not known HDACIs)
NFAT-BLA Jurkat cell assay
~ 92 compounds that did not activate T-cell
HDAC activity assay (novel HDACIs)
~ 83 compounds with potential novel mechanism of
Toxicity
Chemical attractiveness
Further chacterization eg ACH-2, J1.1, primary cells, ex vivo
 The need for new antiretroviral medications that are effective against drug
resistant HIV variants:
 Silencing RNA screens are being used to identify host-cell factors important
during the HIV replication cycle. These cellular factors could be ideal targets for
future HIV drugs. As opposed to targeting viral genes, cellular factors are more
stable and thus, less likely to engender drug resistance.

Optimal time to initiate antiretroviral therapy:
 Starting an antiretroviral regimen while the CD4 count is relatively high is costly
and potentially leads to a large number of adverse drug effects from the lifelong
therapy. By contrast, beginning treatment when the CD4 count is low leads to an
unacceptable risk for opportunistic infections. Assays for specific genetic
markers may help discriminate patients who should have antiretroviral therapy
started early rather than later in infection.
 Controlling HIV replication without lifelong antiretroviral therapy:
 Currently, patients must strictly adhere to a lifelong antiretroviral regimen to
control HIV replication. Newer strategies aimed at blocking the expression of a
functional CCR5 receptor and/or excising the integrated HIV proviral genome
may lead to the control of HIV replication in the absence of antiretroviral drugs
HIV Ther Jul 010
Disclaimer
Servizio scientifico offerto alla Classe Medica da MSD
Italia S.r.l.
Questa pubblicazione riflette i punti di vista e le
esperienze dell’autore [o degli autori] e non
necessariamente quelli della MSD Italia S.r.l.
Ogni farmaco menzionato deve essere usato in
accordo con il relativo riassunto delle caratteristiche
del prodotto fornito dalla ditta produttrice.
01-13-RTG-2010-IT-4769-AV