Sergio Lo Caputo
Malattie Infettive
Azienda Sanitaria Firenze
Roma, 9 maggio 2014
Seminario Nadir 2014 - Iniziativa resa possibile grazie al supporto di Gilead Sciences
Antiretroviral therapy history
Durability
Effectiveness
Sustainability
Efficacy
Early
80s
Late
80s
Early
90s
Mid
90s
Late
90s
Early
00s
Late
00s
Available Antiretrovirals 2014
NRTIs
NNRTIs
Protease Inhibitors
New Classes
• Abacavir
• Efavirenz
• Atazanavir
Fusion Inhibitors
• Didanosine
• Nevirapine
• Darunavir
• Enfuvirtide
• Emtricitabine
• Etravirine
• Fos-Amprenavir
• Lamivudine
• Rilpivirine
• Indinavir
R5 Inhibitors
• Stavudine
• Lopinavir
• Maraviroc
• Tenofovir
• Nelfinavir
• Zidovudine
• Ritonavir
Fixed-dose Combinations
AZT/3TC
ABC/3TC
TDF/FTC
AZT/3TC/ABC
TDF/FTC/EFV
TDF/FTC/RPV
TDF/FTC/ELV/COB
Integrase Inhibitors
• Saquinavir
• Raltegravir
• Tipranavir
• Elvitegravir
• Dolutegravir (2014)
www.emea.europa.eu
Proportion of ART classes in first line regimens according to
calendar period of starting (NRTIs not considered)
100%
90%
88.5%
80%
70%
62.3%
60%
53.0%
50%
46.7%
55.3%
52.3%
47.3%
55.6%
PI
NNRTI
36.5%
40%
37.3%
34.8%
RAL
30%
20%
Other
11.4%
8,2%
10%
0.1%
0.3%
0.3%
0.7%
4,1%
1997-1999
n=2653
2000-2002
n=1028
2003-2005
n=721
2006-2008
n=707
2009-2010
n=972
0%
2011-2013
n=2321
for 2013, 10 months
Proportion of patients with a HIV-RNA<=80 copies/mL at 12
months from starting their first ART by calendar year of
initiation
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
Il limite delle cART attualmente disponibili consiste
nell’impossibilità di ottenere l’eradicazione dell’infezione:
trattamento deve quindi essere continuato a tempo indefinito e
nel corso degli anni è possibile/probabile che insorgano sia
problemi di aderenza, sia di tossicità; inoltre, è
possibile/probabile che si renda necessario introdurre terapie
concomitanti per co-morbilità (con conseguente maggior
rischio di interazioni farmacologiche) e che si renda
necessario modificare la cART per prevenire danni d’organo o
anche solo per evitare che i farmaci antiretrovirali aggiungano
danno alle inevitabili conseguenze dell’invecchiamento.
Cosa spinge il medico
a semplificare una
terapia antiretrovirale
?
Quali sono le richieste e le
necessità del paziente
che assume una terapia per
tutta la vita ?
Reasons to Switch Antiretrovirals in
Patients on a Suppressive Regimen

Simplification/convenience
 Reduce pill burden, dosing frequency, or
avoid other specific dosing requirements

Tolerability/toxicity
 Improve short-term tolerability, reduce risk of
long-term complications
Drug-drug interactions
 Costs

Principali cause di switch in corso di
soppressione virologica










Documentata tossicità;
- Presenza di effetti collaterali;
- Prevenzione di tossicità a lungo termine (pre-emptive
switch);
- Terapia in atto che possa aggravare comorbosità presenti;
- Interazioni con altri farmaci;
- Necessità di cura di altre infezioni (TB, HBV, HCV, ecc.);
- Necessità di migliorare l’aderenza alla terapia del paziente;
- Pianificazione di gravidanza;
- Richiesta del paziente;
- Regime in atto non più raccomandato
Reason for change drug
during VL <50 copies/ml
%
S. Lo Caputo et al IWOOD 2013
Ottimizzazione
Il termine ottimizzazione della cART è utilizzato per indicare strategie
finalizzate al miglior risultato possibile, attraverso switch terapeutici anche
differenti fra loro e con scopi e razionali diversi, ma sempre in condizioni di
soppressione virologica (HIV-RNA < 50 copie/mL).
Ottimizzazione della cART non significa necessariamente riduzione del
numero di compresse o dosi.
Sono immaginabili tre principali modalità di ottimizzazione:
• Riduzione del numero di farmaci antiretrovirali;
• Riduzione del numero di dosi/somministrazioni e di compresse
giornaliere, ma sempre ricorrendo ad uno schema di triplice terapia
Ottimizzazione - Monoterapia
Randomised Controlled Trial of a PI
Monotherapy Switch Strategy for Long-term
HIV Management (The PIVOT Trial)
P-550LB
The Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT)
Trial was a 5-year prospective, randomised, controlled, open-label strategy trial
performed in 43 centres in the United Kingdom.
Primary outcome: loss of future
drug options, defined as new
intermediate/high level resistance
to ≥1 drug to which the patient’s
virus was considered to be
sensitive at trial entry
Secondary outcomes: included
serious disease complications
(AIDS, serious non-AIDS, allcause death), total grade 3/4
adverse events and
neurocognitive function change
Results
We randomised 587 patients who were followed for a median
(maximum) of 44 (59) months; 2.7% withdrew or were lost-to follow
up (Fig 2). In PIm, 80% selected DRV/r, 14% LPV/r, 7% other PI/r at
randomisation.
VL rebound was much more common in Pim, but all rebounds on PIm
re-suppressed either spontaneously or with NRTI reintroduction.
Sequences were obtained in 83% of confirmed VL rebounds. Few new
resistance mutations were seen in either arm .
PIm was non-inferior on the primary outcome of loss of future drug
options and had fewer Grade 3/4 adverse events.
In Which Setting(s) Can Boosted PI
Monotherapy Be Regarded as Safe?







In virologically suppressed patients (either on PI- or NNRTI-based
regimens)
No history of PI failure
No previous HIV-related encephalopathy
Absence of HBV coinfection (or other conditions in which NRTIs are
essential for therapy)
Patients able to tolerate low-dose RTV
Patients with history of optimal adherence
Nadir CD4+ cell count > 100 cells/mm³[1-3] or HIV-1 RNA < 105
copies/mL[4]
Low number of patients eligible for PI/r monotherapy
1. Pulido F, et al. Antivir Ther. 2009;14:195-201. 2. Campo R, et al. CROI 2007. Abstract 514 .
3. Gutmann C, et al. AIDS. 2010;24:2347-2354. 4. Katlama C, et al. AIDS. 2010;24:2365-2374.
Ottimizzazione (CNA-SIMIT 2013)
Duplice terapia
Riduzione del numero di dosi/somministrazioni
e di compresse giornaliere
STR
SingleTablet Regimen
Atripla
(TDF/FTC/EFV)
Eviplera
(TDF/FTC/RPV)
Stribild
(TDF/FTC/ELV/COB)
LifeLink Database
Complete Non-Adherence to ART Regimens
Retrospective analysis of US healthcare claims for commercially insured population (n=4,588)
receiving 2 NRTIs plus NNRTI or PI or INSTI based ART (2009 – 2011)
Percentage of Days
• Complete non-adherence was relatively similar across regimens
10%
Raltegravir
n=522
12%
8%
Boosted PI
n=1,601
Cohen19C, et al. ICAAC 2012; San Francisco, CA. #H-211
NNRTI
n=657
10%
STR
n=1,751
Complete
Non-adherence
LifeLink Database
Partial and Complete
Non-Adherence to ART Regimens
Retrospective analysis of US healthcare claims for commercially insured population (n=4,588)
receiving 2 NRTIs plus NNRTI or PI or INSTI based ART (2009 – 2011)
30%
Percentage of Days
p<0.0001
21%
20%
20%
p<0.0001
p<0.0001
11%
8%
• STR patients had
significantly more
days with a
complete regimen
15%
7%
10%
10%
Partial Adherence
10%
0%
Raltegravir
n=522
12%
8%
Boosted PI
n=1,601
Cohen20C, et al. ICAAC 2012; San Francisco, CA. #H-211
NNRTI
n=657
10%
STR
n=1,751
Complete
Non-adherence
LifeLink Database
Association of Adherence and Hospitalization Rate
Adjusted Hospitalization Rate, % Patients
Among non-STR cohorts, patients who were completely and partially non-adherent were
significantly more likely to be hospitalized vs. those only completely non adherent
25%
20%
Complete Non-adherence only
OR: 1.43
p<0.0001
OR: 1.54
p<0.0001
Complete and Partial Non Adherence*
OR: 1.50
p<0.0001
16.0%
15%
10%
15.4%
14.6%
10.2%
10.4%
10.3%
10.4%
5%
0%
N/A
Raltegravir
n=522
Boosted PI
n=1,601
NNRTI
n=657
Hospitalization rate adjusted for differences between groups including complete non-adherence, treatment status
at index, age, geographic location, plan and types.
* Partial Adherence: Patients with at least 5% of days with either no NRTIs or no 3rd agents.
Cohen21C, et al. ICAAC 2012; San Francisco, CA. #H-211
STR
n=1,751
Current and Future STR Options
for ARV-Naïve Patients
Current



ATRIPLA (1550 mg)
EVIPLERA (1150 mg)
STRIBILD (1350mg)
QUAD1
ATRIPLA2
Future



DRV/COBI/FTC/TAF (1550 mg)
EVG/COBI/FTC/TAF (1050 mg)
ABC/3TC/DLV
TAF = tenofovir alafenamide; investigational
tenofovir prodrug (GS-7340)
22
EVIPLERA3
EVG/COBI/FTC/TAF
DRV/COBI/FTC/TAF
1. German P, et al. JAIDS 2010;55:323–329
2. Mathias AA, et al. JAIDS;2007;46(2):167-73
3. Mathias AA, et al. IAC 2010; Vienna. THLBPE17
STR per quale paziente?
I due nuovi STR hanno ampliato di
molto la possibilità di usufruire di un
intero regime in unica compressa
 Naive: sia pazienti a bassa carica virale
che ad alta viremia
 Switch: pazienti con buona tollerabilità al
TDF/FTC e sensibilità a RPV e ELV
 Importanza dei dati sulla pregressa
storia terapeutica (genotipo storico)

2012
Main differences SPIRAL vs.
SWITCHMRK 1&2 Studies
SPIRAL
SWITCHMRK 1&2
N
273
702
Design
Open
Double-blind, doub dummy
PI/r
Any (44% LPV/r)
LPV/r
Time on VL<50 c/mL
>6 months
> 3 months
Prior virol failure
38%
33.5%
Median CD4 cells, BL
516 cells
445 cells
Median Time Undetec. VL
73 (39–106) months
unknown
Improvement in LDL-Chol
Yes
No
% with VL < 50 c/mL
RAL 96.9%, PI/r 95.1% (48 w)
RAL 84.4%, LPV/r 90.6% (24 w)
Increased RAL failure with
prior VF and not being on the
1st ART
NO
YES
?
Need to avoid drug-drug interactions
ATV/r
DRV/r
LPV/r
EFV
ETV
NVP
RPV
MVC
RAL
atorvastatin
↑
↑
↑490%
↓43%
↓37%
↓
↔
↔
↔
rosuvastatin
↑213%
↑48%
↑107%
↔
↑
↔
↔
↔
↔
simvastatin
↑
↑
↑
↓68%
↓
↓
↔
↔
↔
amlodipine
↑3
↑
↑3
↓
↓
↓
↔
↔
↔
↑or ↓
↓
↓
↑or ↓
↑
↑or ↓
↔
↔
↔
diazepam
↑
↑
↑
↓
↑
↓
↔
↔
↔
citalopram
↑3
↑
↑3
↓
↓
↓
↔
↔
↔
mirtazapine
↑
↑
↑
↓
↓
↓
↔
↔
↔
D35%
↓32%D44%
↓45%D34%
↓19%E20%
↑10%D23%
↓E
E
E
↔
clarithromycin
↑3
↑
↑3
↓
↓E
↓
E
E
↔
fluconazole
↔
↔
↔
↔
E86%
E100%
E
↔
↔
itraconazole
↑E
↑E
↑E
↓
↓E
↓61%
E
E
↔
rifabutin
↑
↑E50%
↑
↓
D37%
↑17%
D
*
↔
rifampicin
D72%
D
D
D26%
D
D58%
D80%
D
D40%
telaprevir
↓20%E17%
↓35%D40%
↓54%
↓26%D7%
↓16%
↓?
↓5%E
E
E31%
antacids
D
↔
↔
↔
↔
↔
D
↔
D
PPIs
D
↔
↔
↔
↔
↔
D
↔
E
H2 blockers
D
↔
↔
↔
↔
↔
D
↔
E
ergot derivatives
↑
↑
↑
↑
↑
↓
E
↔
↔
↓2,3
↓16%
↓53%3
↓52%
↑6%
↓≈50%
↓16%
↔
↔
sildenafil (erec. dys.)
↑
↑
↑
↓
↓37%
↓
↔
↔
↔
St John's wort
D
D
D
D
D
D
D
D
↔
warfarin
boceprevir
methadone
Cortesía de Catia Marzolini (EACS guidelines, 2013 update)
Drug–Drug Interactions With AcidReducing Medications and Newer ARVs
ARV
Antacids
H2-Receptor Antagonists
Proton Pump
Inhibitors
Give antacids at least
2 hrs before or at
least 4 hrs after RPV
Give H2-receptor
antagonists at least 12 hrs
before or at least 4 hrs
after RPV
Contraindicated
EVG/COBI
TDF/FTC[1]
Separate EVG/COBI/
FTC/TDF and antacid
administration by > 2 hrs
No clinically relevant
interactions
No clinically relevant
interactions
DTG[2]
DTG should be given
2 hrs before or 6 hrs after
taking medications
containing polyvalent
cations
RPV[1]
1. DHHS Adult Guidelines. February 2013. 2. Dolutegravir [package insert].
No clinically relevant
interactions
Semplificazione e farmaci generici
Semplificazione:
per molti ma non per tutti
Punti chiave nella scelta di un
regime di semplificazione da
parte del medico
Conoscenza della storia terapeutica
 Importanza dei test di resistenze (genotipo storico)
 Prevenire e/o trattare eventuali Co-morbilità
 Interazioni farmacologiche
 Comprendere l’evoluzione della cART
 Comprendere/conoscere il paziente
 Garantire eventuali altre opzioni terapeutiche
 Garantire la soppressione virologica

Simplified Treatment Approaches
Miglioramento della qualità della vita del
paziente
 Successo più duraturo nel tempo
 Ampliamento delle scelte terapeutiche in
base alle caratteristiche del paziente

Seminario Nadir 2014 - Iniziativa resa possibile grazie al supporto di Gilead Sciences