Nuove strategie e nuovi approcci terapeutici nel trattamento dell’infezione da HIV

Giuliano RizzardiniOspedale L. Sacco

Milano

Alcuni obiettivi raggiunti, le sfide aperte ed i dati utili nella gestione dei pazienti complessi

Gli strumenti del futuro prossimoUno 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

From S Deeks, MD, at Chicago, IL: April 19, 2010, IAS–USA.

HIV infection may result in accelerated immunologic aging

Desai and Landay, Current HIV/AIDS Reports 2010From SG Deeks, MD, at Atlanta, GA: March 2, 2010, IAS–USA.

START study: Piu’ di 4000 naive con CD4 >500 cellule/ul - Pazienti randomizzati a iniziare la terapia subito o ad attendere il raggiungimento della soglia di 350/ul-Follow-up per i seguenti eventi:

- Eventi severi AIDS definenti- eventi clinici non AIDS definenti- decesso

-Arruolamento in corso, risultati attesi entro il 2015.

Clinical category

CD4cells/mm3 DHHS 091 IAS-USA 102 EACS 093 ITA 104

AIDS-defining or symptoms Any value Treat (AI) Treat (AI) Treat Treat (AI)

NAD diseases, HBV, pregnancy

Any value Treat (AI/III) Treat (BII/AI)

Treat or consider

only if CD4 <500/mm3

Treat (AI-II/BII)#

Asymptomatic <350 Treat (AI) Treat (AI) Treat Treat (AI)

Asymptomatic 350–500 Treat (A/BII) Treat (AII)

Treat or consider only on

individual basis§

Treat all (BII) or on

individual basis^ (AII/BIII)

Asymptomatic >500Treat as

moderate or optional*

Consider treatment

(CIII)°

Generally defer

Generally defer (CII)

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-basedregimen 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 middle-income 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



0 20 40 60 80 100

Castle

Klean

5142

Startmrk

Artemis

Proportion of subjects with VL<50 copies at w 96 in RCTs in naives

DarunavirRaltegravirEfavirenzFosamprenavirKaletraAtazanavir/ r

§§

§ difference confirmed in High VL subgroup§ difference confirmed in High VL subgroup*superiority*superiority

**

RegimeRegime % paz <50 % paz <50 copie a 48 copie a 48 settimanesettimane

% di paz < % di paz < 50 copie a 50 copie a 96 96 settimanesettimane

CommentiCommenti

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

DRV/r +OBR 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

MVC + OBR 46% (vs17% pl)

In pazienti con virus CCR% tropico (50% dei pazienti expd)

ETV+ OBR 61% (vs 41%) 57% (vs 36%) DUET: DRV+NRTI+ placebo o ETV con o senza ENF

RAL+OBR 57% (vs 26%) Benchmrk. Alta potenza e rapidità di discesa della viremia ma relativamente bassa barr genetica

RegimeRegime % paz <50 % paz <50 copie a 24 copie a 24 settimanesettimane

% di paz < % di paz < 50 copie a 50 copie a 48settiman48settimanee

CommentiCommenti

DRV/r, ETV, RALDRV/r, ETV, RAL 90%90% 86%86%

MVC, ETV RAL 92% Studio su 28 pazienti. Potenziali problemi su DDI

ELV/rELV/r 50 mg non inferiore a DRV/r o 50 mg non inferiore a DRV/r o TPV/r, 125 mg superiore a 24 e 48 TPV/r, 125 mg superiore a 24 e 48 settimane.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 drugsPI (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 3-

8), 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




• 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

Dinisio PNAS 09, McMahon CID 10; Gandhi IAS 09From S Deeks, MD, at Chicago, IL: April 19, 2010, IAS–USA.

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

Persistent HIV expression•Replication competent?•Immune disfunction?

Latently infected cells

InflammationHomeostatic 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

Richman et al, Science, 2009From S Deeks, MD, at Chicago, IL: April 19, 2010, IAS–USA.


– 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

Eradication Strategies


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


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


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

~ 1.5 million compounds (MRL Library)

~ Confirmed 104 compounds (not known HDACIs)

~ 92 compounds that did not activate T-cell

~ 83 compounds with potential novel mechanism of

LTR-LTR-Gal HTSGal HTS

NFAT-BLA Jurkat cell assayNFAT-BLA Jurkat cell assay

HDAC activity assay (novel HDACIs)HDAC activity assay (novel HDACIs)

ToxicityToxicityChemical attractivenessChemical attractivenessFurther chacterization eg ACH-2, J1.1, primary cells, ex vivoFurther chacterization eg ACH-2, J1.1, primary cells, ex vivo

Non-mechanism based screening can identify novel HIV-1 activators

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

01-13-RTG-2010-IT-4769-AV

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.

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Nuove strategie e nuovi approcci terapeutici nel trattamento dell’infezione da HIV