AIDS: il ruolo del medico e le più attuali
strategie terapeuticheDott. Renato Maserati
Coordinatore Servizi Ambulatoriali e Responsabile Ambulatorio AIDS, Fondazione
IRCCS Policlinico “San Matteo”. Professore a Contratto Facoltà di Medicina
Università di Pavia
Il principio di base della terapia antiretrovirale
E’ il virus, stupido!!!
IMMUNE DESTRUCTION AND HIV: TWO DIFFERENT MODELS
HIV
CD4+ Cells
INFECTION
IMMUNE DESTRUCTION
AIDS
HIV
CD4+ Cells
INFECTION
IMMUNE DESTRUCTION
AIDS
soluble factorscytokinesapoptosisanti MHC Ab
????
Observational data: likelihood of developing AIDS by 3 years after becoming infected with
HIV (untreated patients)
0102030405060708090
100
bDNA>30k
bDNA10K-30K
3K-10K 501-3K >=500
Plasma viral load (copies)
CD4>750CD4 501-750351-500201-350<=200
Mellors jW, Munoz A, Gigorni JV et al Ann. Intern Med 1997
EFV
1987 1991 1992 1994 1995 1996 1997 1998 1999 20001988 1989 1990
NRTI
2001 2002 2003 2004 2005 2006
Fusion Inhibitor
2007 2008 2009
R5 Antagonist
Integrase Inhibitor
NNRTI
Significant Advances Have Been Made in Antiretroviral Therapy
AZT
ETV
CBV
ddI d4T
ddC
3TC
Trizivir
NVP
DLV
TDF
ENF
FTC
Truvada
Atripla
RAL
MVC
ABC
DRV
PI RTV
SQV
APVIDV
LPVNFV ATV
TPV
fAPV
1993
Antiretroviral Agents 1987-2008
U.S. Food and Drug Administration. HIV/AIDS historical time line: 1981-2008.Lexiva [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2008.Intelence [package insert]. Yardley, PA: Tibotec, Inc; 2008.
Il paradigma della ARV Il paradigma della ARV (1985 – 1996)(1985 – 1996)
VOGLIO VIVERE….VOGLIO VIVERE….
- mortalita’ elevata- alto livello di frustrazione nella lotta contro HIV- farmaci con una attivita’ antivirale deludente - basso livello di accettabilita’ della terapia da parte dei pazienti e delle loro associazioni
VOGLIO VIVERE…VOGLIO VIVERE… …BENE!…BENE!
Il paradigma della ARV Il paradigma della ARV (1998 – oggi)(1998 – oggi)
- una buona attivita’ antiretrovirale e’ la norma- comodita’ di assunzione e bassa tossicita’- emergono altre problematiche
“Lipodystrophy Syndrome”
No generally accepted case definition of syndrome(s)
Initial reports suggested clustering of:
– Central fat accumulation/adiposity
– Lipoatrophy/fat wasting
– Dyslipidemia
– Insulin resistance/type 2 diabetes mellitus
Recent cross-sectional epidemiological data question linkage of lipoatrophy and fat accumulation
Fram J Acquir Immune Defic Syndr 2005;40:121-131
Abdominal MRI Scans
Control subject Increased Visceral Fat
HIV Therapies Target Different Stages of the Viral Life Cycle
ss = single-stranded; ds = double-stranded.
Adapted from Agrawal L et al. Curr Pharm Des. 2006;12:2031-2055.
Entry and Fusion Inhibitors
Integrase Inhibitors
Protease InhibitorsReverse Transcriptase Inhibitors
NRTIs NNRTIs
Nucleocapsid
ss RNA
Translation
TranscriptionIntegration
Nucleus
Cytosol
ReverseTranscription
Gp120/gp41CD4
Co-receptor (CCR5, CXCR4)
ds DNA
Mature HIV Virion
HIV Virion
Maturation Inhibitors
Non nucleosidicinhibitors NVP, EFV, DLV No need of activation in the cell
Nucleotidic and nucleosidic inhibitors:
AZT, ddI, ddC, d4T, 3TC, ABC, TDF, FTCNeed phosphorilation before they become active
Reverse transcriptase inhibitors
Guanosine
ABC- MP
CBV-MP
CBV-DP
CBV-TP
ABC
Adenosine Phosphotransferase
Cytosolic Enzyme
Kinase
Kinase
Thymidine
ZDV-MP
ZDV
ZDV-DP
d4T
d4T-MP
d4T-DP
Thymidylate Kinase
NDP Kinase
Thymidine Kinase
ZDV-TP d4T-TP
Cytidine
ddC 3TC FTC
ddC-MP
ddC-DP
3TC-MP
3TC-DP
NDP Kinase
CMP/dCMP Kinase
Deoxycytidine Kinase
ddC-TP 3TC-TP
Adenosine
ddI - MP
ddA-MP
ddA-DP
ddI
5’ Nucleotidase
Adenylate Synthetase& Adenylate Lyase
Adenylate Kinase &PRPP Synthetase
Adenylate Kinase &PRPP Synthetase
ddA-TP
Tenofovir
TFV-MP
Tenofovir DF
Diester Hydrolysis
AMP Kinase
NDP Kinase
TFV-DP
FTC-TP
Phosphorylation of NRTIs and NtRTIs
Attivita’ antiretrovirale e farmacoresistenzaAttivita’ antiretrovirale e farmacoresistenza
p
roba
bilit
à di
sel
ezio
nare
una
mut
azio
ne
aumento della soppressione della replicazione virale
monomono
doppiadoppia
triplatripla
Effects of common NRTI mutations
Mutation EffectsM184V Selected by 3TC, FTC → high-level resistance
Also selected by ABC, rarely ddI and ddC
Low-level resistance to ABC
No major effect on ddI (? beneficial effect)
Hypersusceptibility effects for ZDV, d4T and TDF
TAMs Selected by ZDV and d4T (ddI)
Resistance to ZDV, d4T, ddI, ddC, ABC, TDF
↑ number of TAMs = ↑ NRTI cross-resistance
K65R Selected by TDF, ddI, ABC
Resistance to TDF, ABC, 3TC, ddI, ddC
Uncertain effects on susceptibility to d4T
Hypersusceptibility to ZDV
L74V Selected by ABC, ddI
Resistance to ABC, ddI, ddC
Uncertain effects on susceptibility to TDF
Hypersusceptibility to ZDV
Protease Inhibitors
Protease-substrate complex
•Saquinavir (SGC,HGC)*
•Nelfinavir
•Amprenavir*
•Lopinavir §
•Indinavir*
•Ritonavir
•Fos-Amprenavir*
•Tipranavir*
* May be used with ritonavir as a booster
§ Available only in the boosted form
Is HAART so critical in HIV history?AIDS-related Mortality in the USA
1995 1996 1997 1998 1999 2000 2001Year
Dea
ths
per
100
per
son
-yea
rsT
herap
y with
a PI (%
of p
atient-d
ays)
Deaths
Use of PIs
Palella et al. 8th CROI, 2001
40
35
30
25
20
15
10
5
0
100
75
50
25
0
Lopinavir/r 400/100mg BID
Saquinavir/r 1000/100mg BID
Indinavir/r 800/100mg BID
Nelfinavir 1250mg BID
Amprenavir/r
600/100mg BID
Atazanavir 400mg QDQuestions over data
What PI treatments do we now have?
Non nucleosidicinhibitors NVP, EFV, DLV No need of activation in the cell
Nucleotidic and nucleosidic inhibitors:
AZT, ddI, ddC, d4T, 3TC, ABC, TDF, FTCNeed phosphorilation before they become active
Reverse transcriptase inhibitors
0 10 20 30 40 50 60 70 80 90 100% With VL < 50 at Week 48
Boosted PI
NNRTI
NRTI
Unboosted PI
HAART Studies
Bartlett JA et al. Abstract 586, CROI 2005
Previous analysis emphasized relation b/w pill burden and response
Updated analysis: pill burden less important
Highlights efficacy of boosted-PI and NNRTI regimens
HAART Studies: which one?
Le scelte critiche nella HAART
Quando e come iniziare
Individuare i parametri che predicono il successo e l’insuccesso nel singolo paziente a breve termine
Nel medio-lungo periodo: tollerabilità, tossicità, sequenziabilità
Nel paziente multi-trattato: introduzione di nuovi farmaci, terapie “hold-on”
Co-morbidità: epatopatie croniche, diabete, altro
Ruolo di farmacocinetica, genomica, immunologia
Considerations for Initial Regimen
Initial Treatment
Lifestyle
DosingPill Burden
Toxicity
Short TermLong Term
Drug Interactions
Sequencing
Underlying Conditions
HepatitisCV Disease
Perchè i pazienti interrompono la terapia?
Tossicità58.3%
Non aderenza19.6%
Fallimento virologico 14.1%
Altro8.0%
d’Arminio Monforte et al. AIDS 2000; 14:499–507
Cause di interruzione del primo schema HAART a 45 settimane nella coorte ICONA (n = 862)
Adattato da Munk. CPS Info Pack (suppl). POZ 1998.
Gli eventi avversi come determinanti di non aderenza
% d
i paz
ient
i che
han
no s
alta
to u
na d
ose
pe
r un
par
ticol
are
even
to a
vver
so
0
60
Febb
riG
astra
lgia
Ras
h/ps
oria
siVa
riazi
one
form
a co
rpo
Alte
razi
oni g
usto
Neu
ropa
tia/
form
icol
ioD
iarre
aG
as e
gon
fiore
Fatig
ueEm
icra
nia
Nau
sea
Vom
ito
10
20
30
40
50
0 0
11 13 1415 16 17
26 26
36
57
Adverse Effects of NRTIs* Zidovudine (AZT)- headache, GI intolerance, bone marrow suppression
Abacavir - hypersensitivity reaction
Didanosine (ddI) - GI intolerance, pancreatitis, peripheral neuropathy
Stavudine (d4T) - peripheral neuropathy, pancreatitis, lipoatrophy
Zalcitabine (ddC) - peripheral neuropathy, oral ulcers
Lamivudine (3TC) – rare side effects
Emtricitabine (FTC) – side effects uncommon; hyperpigmentation of palms/soles < 2% (non-Whites)
Tenofovir - headache, GI intolerance, renal insufficiency
*Lactic acidosis is a class effect, most strongly associated with d4T/ddI; 3TC, FTC, and tenofovir are active against HBV. Development of HBV resistance may lead to flare of hepatitis.
Adverse Effects of NNRTIs
Rash, including Stevens-Johnson syndrome with nevirapine
Elevated liver enzymes (nevirapine > efavirenz, delavirdine)
– Incidence of hepatotoxicity highest in women with pre-nevirapine CD4 counts >250 cells/mm3 and men with >400 cells/mm3
Efavirenz - neuropsychiatric, teratogenic in primates (FDA Pregnancy Class D)
Acute Adverse Effects of PIs GI intolerance, diarrhea
Hyperbilirubinemia –atazanavir, indinavir
Hepatotoxicity
Increased bleeding in hemophiliacs
Adverse metabolic effects
– Dyslipidemia
– Insulin resistance
– ? Lipodystrophy/fat redistribution
– Atazanavir has favorable metabolic profile
Adverse Effects of Entry Inhibitors
Enfuvirtide (T-20)
– Injection-site reactions
– Hypersensitivity reaction
– Increased incidence of bacterial pneumonia
Come si sta spostando il “pendolo” della terapia ?
Updated DHHS Guidelines: When to Start Treatment
Clinical Category CD4+ Cell
Count
Plasma
HIV-1 RNA
General Guidelines
AIDS-defining illness or severe symptoms*
Any value Any value Treat
Asymptomatic < 200 Any value Treat
Asymptomatic 200-350 Any value Treatment should be offered following full discussion of pros and cons of treatment.
Asymptomatic > 350 ≥ 100,000 Most clinicians recommend deferring therapy, but some clinicians will treat.
Asymptomatic > 350 < 100,000 Defer therapy
CD4+ Count Prior to Therapy Predicts Progression to AIDS
Johns Hopkins HIV Cohort Analysis of CD4+ cell count response
and disease progression in patients who maintained sustained virologic suppression for up to 6 yrs (N = 280)
Only patients with baseline CD4+ count > 350 cells/mm³ returned to near normal CD4+ cell count levels
Rate of progression to AIDS or death was significantly higher over time in patients with CD4+ count < 200 and CD4+ count 201-350 compared with CD4+ count > 350 cells/mm³
Moore RD, et al. IAC 2006. Abstract THPE0109.
0
100
200
300
400
500
600
700
800
900
0 Yr 1 Yr2 Yr3 Yr 4 Yr 5 Yr 6
CD
4+ c
ells
/mm
³
13%
12%
1.5%†
*% Over 6 years of study† P < .05 compared with CD4+ < 200
% Developing AIDS*
> 350
< 200
201- 350
HAART and Survival Based on Initial CD4+ Cell Count
Modeled data from ART Cohort Collaborative
10,855 patients included 934 progressed to AIDS or
died IDUs excluded from model
Sterne J, et al. CROI 2006. Abstract 525.
Progression and Death According to CD4+ Cell Count (cells/mm3)
< 200 vs 201-350
< 350 vs 351-500
Hazard ratio for AIDS (95% CI)
3.68 (3.01-4.51)
1.52
(1.10-2.10)
Hazard ratio for AIDS or death (95% CI)
2.93 (2.41-3.57)
1.26
(0.94-1.68)
Cumulative Probability of AIDS/Death According to CD4+ Cell Count at Initiation of HAART
Years Since Initiation of HAART
0 1 2 3 4 5
0.00
0.02
0.04
0.06
0.08
0.10
0.12
Pro
bab
ility
of
AID
S o
r D
eath
101-200 cells/mm3
201-350 cells/mm3
351-500 cells/mm3
HOPS CohortPrevalence of Mutations in Persons with Virologic Failure after HIV
Suppression, by CD4 Cell Count at HAART Initiation
Uy J, et al., IAS 2007; WEPEB017.
* p-values are for comparisons between CD4 cell count
ranges at HAART initiation
49 50
28
50
31
43
13
22
11 10
0
50
0
10
20
30
40
50
60
Perc
ent (
%)
0-199 cells/mm³ 200-348 cells/mm³ >350 cells/mm³
Any mutation(n=78)
NRTI mutationAmong NRTI-
exposed (n=77)
NNRTI mutationAmong NNRTI-exposed (n=37)
PI mutationAmong PI-
exposed (n=48)
p=0.076* p=0.007 p=0.051 p=0.103
49 50
28
50
31
43
13
22
11 10
0
50
0
10
20
30
40
50
60
Perc
ent (
%)
0-199 cells/mm³ 200-348 cells/mm³ >350 cells/mm³
Any mutation(n=78)
NRTI mutationAmong NRTI-
exposed (n=77)
NNRTI mutationAmong NNRTI-exposed (n=37)
PI mutationAmong PI-
exposed (n=48)
p=0.076* p=0.007 p=0.051 p=0.103
Any mutation(n=78)
NRTI mutationAmong NRTI-
exposed (n=77)
NNRTI mutationAmong NNRTI-exposed (n=37)
PI mutationAmong PI-
exposed (n=48)
p=0.076* p=0.007 p=0.051 p=0.103 Question: Does initiation of HAART at higher CD4 predispose to drug resistance?
Study Eligibility:
– achieved viral load (VL) <1,000suppression
– later had rebound (>1,000)
– had GT performed
Conclusion:Less resistance observed in all ARV classes when therapy started earlier (CD4 >350)
HOPS: Lipoatrophy and CD4+ Nadir
Lichtenstein K, et al. CROI 2002. Poster 684a (T).
30.8
18.2
17.0
13.2
12.0
3.3
0 25 50
Min CD4+ Max CD4+
> 350 > 350
200-349 > 200
< 200
< 200
< 200
< 200
> 500
350-499
200-349
< 200
Incidence of Lipoatrophy (%)
Factors Associated With Peripheral Neuropathy in HIV
1. Lichtenstein K, et al. IAS 2003. Abstract 729. 2. Lichtenstein K, et al. IAS 2003. Abstract 731.
HIV Insight: Incidence of PNP by Nadir CD4 (N = 7980)[2]
HOPS Cohort: PNP Associated With HAART (N = 2178)[1]
14
12
10
8
6
4
2
0
Year
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
100
80
60
40
20
0
Pa
tie
nts
W
ith
PN
P (
%) P
atie
nts
on
HA
AR
T (%
)
% PNP% on HAART
18
16
14
12
10
8
6
4
2
00-99 100-199 200-349 350-499 ≥ 500
15.5%
11.1%
7.7%
5.1%4.3%
Nadir CD4 Category
P < .0001
Pa
tie
nts
(%
)
Increasing Prevalence of X4- or R5/X4-Tropic Virus at Lower CD4+ Cell Counts
CCR5– Patients with early-stage HIV
disease tend to have pure R5-tropic virus
CXCR4– With advanced disease, X4- or
dual-tropic virus emerges
– Associated with more rapid clinical and immunologic progression
Could CCR5 inhibition select for more virulent X4-tropic virus?
16.0% 16.0% 14.8%
41.9% 40.0%
0
20
40
60
80
> 300
248
Pre
vale
nce
of
X4
or
R5/
X4
(%)
100
201-300
104
101-200
81
51-100
31
< 50
50
CD4+ Cell Count (cells/mm3)
n =
Moyle G, et al. ICAAC 2004. Abstract 1135.
The Case for Earlier Initiation of Therapy
Availability of more potent, easier, and less toxic regimens
Cohort studies showing benefit with earlier therapy
Better response to therapy
Decreased transmission
Preserve R5-tropic virus
Cost-effectiveness
Come scegliere una combinazione HAART iniziale
2006 Guideline Recommendations for Initial HAART Regimen
Recommended Initial Regimens for Antiretroviral-Naive PatientsRecommended Initial Regimens for Antiretroviral-Naive Patients
DHHS Guidelines (May 2006)[1]
NNRTI-based regimen EFV + (3TC or FTC) + (TDF or ZDV)
PI-based regimen LPV/RTV + (3TC or FTC) + ZDV
IAS-USA Guidelines (August 2006)[2]
NNRTI-based regimenEFV*(NVP*)
PI-based regimenLPV/RTV*ATV/RTV*FPV/RTV*SQV/RTV*
*Plus TDF/FTC, ABC/3TC, or ZDV/3TC.
1. DHHS Guidelines. Available at: http://aidsinfo.nih.gov/Guidelines/. Accessed Sept. 15, 2006. . 2. Hammer SM, et al. JAMA. 2006;296:827-843.
Study Follow-up, wks
HIV-1 RNA < 50 c/mL,
%VF, % Any Resistance*,
%
GS 934[1]
EFV + TDF/FTC 144 64 29 68
EFV + ZDV/3TC 144 56 42 76
ACTG 5142[2]
EFV + 2 NRTI 96 89 24 48
LPV/RTV + 2 NRTI 96 77 37 21
KLEAN[3]
FPV/RTV + ABC/3TC 48 66 6 29
LPV/RTV + ABC/3TC 48 65 7 33
Durability of Response to HAART
1. Arribas JR, et al. IAS 2007. Abstract WEPEB029. 2. Riddler S, et al. IAC 2006. Abstract THLB0204. Haubrich RH, et al. HIV Resistance Workshop 2007. Poster 57. 3. Eron J Jr, et al.
Lancet. 2006;368:1238.
*Genotyped patients with virologic failure
% p
atie
nts
wit
h
VL
<50
co
pie
s/m
L a
t w
eek
48
KLEAN: FPV/r vs LPV/r-Naive Virological response
ITT-e: All patients exposed to >1 dose of randomized study medication
66% 65%
89% 88%
n=434 n=444 n=328 n=341
Eron, et al. Lancet 2006; 368 (9534): 476-82.
0
20
40
60
80
100
ITT-e TLOVR Observed
FPV/r
LPV/r
KLEAN: FPV/r vs LPV/r-Naive Grade 3/4 lipid abnormalities
Fasting cholesterol ≥ 300 mg/dL Fasting Triglycerides ≥ 751 mg/dL
11%
9%8% 8%
Eron, et al. Lancet 2006; 368 (9534): 476-82.
(≥ 7.7mmol/l) (≥ 8.4mmol/l)
0
5
10
15
FPV/r
LPV/r
Pat
ien
ts (
%)
ALERT: FPV/r vs ATV/r-Naive Lipid results
FPV/r Baseline
FPV/r Week 24
ATV/r Baseline
ATV/r Week 24Smith K, et al. 46th ICAAC 2006; abstract H-1670a
p < 0.05
0
50
100
150
200
250
Cholesterol LDL HDL TG
n=48 n=38
n=38
n=39
n=48 n=38 n=45 n=39
n=38 n=39
n=48
n=38
n=46 n=39
Med
ian
leve
l (m
g/d
L)
n=46
n=48
1:1 randomization
SQV/r 1000/100 mg bid
+ TDF/FTC
Lopinavir/r 400/100 mg bid
+ TDF/FTC
Prospective, Phase IIIb, randomized, multi-centre, open-label, 2-arm study
N = 337
– 26 North American sites• 8 Canada• 1 Puerto Rico• 17 United States
– 11 French sites
– 1 Thai site
Duration 48 weeks
Inclusion criteria
– Treatment naive– CD4 ≤ 350– HIV RNA > 10,000 copies/ml
Gemini
SQV/r vs LPV/r-Naive
N = 882
– International, open-label trial
Duration: 96 weeks
Inclusion criteria:
– HIV RNA ≥ 5,000 c/mL
– Any CD4 count
Primary efficacy endpoint:VL < 50 c/ml at 48 weeks
Secondary outcomes:
– VL < 50 c/mL at 96 weeks
– VL < 400 c/mL at 48 & 96 weeks
– Safety assessments
Status
– Study start: November 2005
– Fully enrolled
Atazanavir/r300/100 mg qd
+ TDF/FTC
Lopinavir/r 400/100 mg bid
+ TDF/FTC
BMS 138: ATV/r vs. LPV/r + TDF/FTC in ARV-naive patients
1:1 randomization
http://www.clinicaltrials.gov
Metabolic Effects of PIsAgent Lipids Glucose
RTV (full dose) TC/TG insulin resistance
LPV/RTV TC/TG insulin resistance
IDV/RTV TC/TG insulin resistance
NFV LDL/TG, HDL(?) No insulin sensitivity
APV/RTV or FPV/RTV TC/TG No insulin sensitivity
TPV/RTV TC/TG ?
SQV/RTV Little No insulin sensitivity
ATV No No insulin sensitivity
ATV/RTV Little No insulin sensitivity
DRV/RTV ? ?
RTV associated with more pronounced effect on lipids than other PIs
BMS-045: randomized trial of patients with 2 HAART failures
TC HDL-CLDL-C* TG*
*Fasting values.†P < .0001 vs LPV/RTV.
-8†
6
-7
2
-10
1
-4*
30
-15
-5
5
15
25
35
Mea
n C
han
ge
Fro
m
Bas
elin
e to
Wk
48 (
%)
ATV/RTV LPV/RTV
Metabolic Effects of PIs:LPV/RTV vs ATV/RTV
Johnson M, et al. AIDS. 2005;19-685-694.
Il paziente multi-”experienced”
HIV Transmission and the Establishment of HIV Reservoirs
(A)Interactions of HIV envelope glycoproteins, CD4, and CCR5 or CXCR4 coreceptors trigger fusion and entry of HIV.
(B) Outline of the sequence and time course of events involved in viral dissemination.
Fusion inhibitors: T20, (T1249)
•The gp120 subunit binds the CD4 receptor
•Each subunit undergoes a conformational change exposing the region that will bind a transmembrane chemokine receptor
CD4 +chemokine receptors
• Shifts away the steric hindrance of gp 120
• Allows gp 41 to mediate the fusion and entry
DRV/r or TPV/r Versus cPI(s): Week 48: <50 copies/mL With First Use ENF
56%
11% 9%
36%
DRV/r(n = 36)
cPI(s)(n = 35)
TPV/r(n = 123)
cPI(s)(n = 97)
First use of ENF
Pat
ien
ts a
chie
vin
g r
esp
on
se (
%)
20
40
60
80
0
POWER RESIST
Hill A, et al. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract H-1386.
Virologic Response by Number ofDRV-associated Mutations
De Meyer S, et al. 15th International Drug Resistance Workshop; June 13-17, 2006; Sitges, Spain. Poster 73.
50
1(94)
42
2(113)
22
3(58)
10
≥4(41)
42
All(373)
Number of TMC114 mutations(Number of patients)
Pa
tie
nts
wit
h V
LH
IV R
NA
<5
0 c
op
ies
/mL
at
We
ek
24
(%
)
64
0(67)
100
80
40
60
20
0
V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, L89V
8 7 8 8 9 10 IAS-USA PI mutations
ITT analysis (non-completer = failure)
Etravirine: Primary EndpointChange in VL at 48 weeks
Mea
n c
han
ge
in l
og
10 V
L (
±SE
)
Time (weeks)0
0.5
2 4 8 12 16 20 24
0
–0.5
–1.0
–1.5
–2.5
–2.0
32 40 48
–0.14
–0.88, P = 0.018–1.01, P = 0.002
P values versus active control. SE, standard error.
Active control (n = 40)
400 mg bid (n = 80)
800 mg bid (n = 79)
Relevant NNRTI mutations:
K101P, V179E, V179F, Y181I, Y181V, G190S, M230L
Cohen C, et al. 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0061.
Viral Entry Is the First Part of the HIV Life Cycle and Occurs in 3 Stages
Westby M, van der Ryst E. Antivir Chem Chemother. 2005;16:339-354.
FusionCo-receptor BindingAttachment
Co-receptor Usage of HIV-1 Variants: Defining Tropism
X4R5
CCR5 CXCR4CD4
CD4-Expressing Cells CD4-Expressing Cells CD4-Expressing Cells
CD4 memory CD4 naive
D/M
Adapted from Westby M, van der Ryst E. Antivir Chem Chemother. 2005;16:339-354; and Poveda E et al. AIDS. 2006;20:1359-1367.
Primary endpoint at 24 weeks: Mean change from baseline in HIV-1 RNA
MOTIVATE 1 & 2: Trial Design
1076 ARV-experienced patients
MVC 150 mg† BID(n = 426)
MVC 150 mg† QD (n = 414)
Placebo(n = 209)
R5 HIV-1 infection (44% screen failures)HIV-1-RNA ≥5,000 copies/mL
On stable regimen, or no ARVs for ≥4 weeksResistance to and/or ≥6 months’ experience with ≥1 ARV from 3 classes (≥2 for PIs)
2 identical ongoing phase IIb/III studies
Randomized (1:2:2), double-blind, placebo-controlled
OBT = 3-6 ARVs*Stratified by ENF use and HIV-1 RNA < and ≥5 log
*OBT, optimized background therapy (boosting doses of RTV not counted as an ARV).†Pts receiving a PI (except TPV) and/or delavirdine in their OBT received 150 mg of MVC, all others received 300 mg of MVC.
Nelson M, Lalezari J, et al. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstracts 104aLB and 104bLB.
MOTIVATE: Percentage of Patients With Undetectable HIV-1 RNA
MVC QD + OBT (n = 232)MVC BID + OBT (n = 235)
Placebo + OBT (n = 118)
0 4 8 12 16 20 24
20
0
30
40
50
60
70
80
90
100
Time (weeks)2
48.5%42.2%
24.6%
16 20 24
Pat
ien
ts (
%)
0 4 8 12
20
10
0
30
40
50
60
70
80
90
100
Time (weeks)
60.4%54.7%
31.4%
<400 copies/mL <50 copies/mL
P <0.0001*
P <0.0001*P <0.0001*
P = 0.0006*
2
10
HIV-1 RNA value imputed as baseline if missing or if patient discontinued before 24 weeks.*Versus placebo + OBT.Nelson M, et al. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 104aLB.
MERIT: 740 naïve patients randomized to Maraviroc (300 bid) vs EFV (600 OD), both with CBV
VL < 400 copies/mL VL < 50 copies/mL
Pat
ien
ts, %
Pat
ien
ts, %
Time (weeks) Time (weeks)
0
20
40
60
80
100
24 8 16 24 32 40 48 24 8 16 24 32 40 48
70.6%
73.1%69.3%
65.3%
0
20
40
60
80
100
EFV (n = 361) MVC (n = 360)
0 0
Saag M, et al. IAS 2007. Abstract WESS104.
MVC was noninferior to EFV only for < 400 copies/mL endpoint (70.6% vs 73.1%)
CD4+ cell count increases were higher in patients receiving MVC vs EFV (+170 vs +144 cells/mm3)
Recently Approved New or Novel Antiretroviral Agents
Maturevirus
Maraviroc
Entryinhibitors
Reverse transcriptase
inhibitors
EtravirineIntegraseIntegraseinhibitorsinhibitors
RaltegravirRaltegravir
PIs
Darunavir Tipranavir
Percent <400 and <50 Copies/mL(ITT, NC=F)
BENCHMRK 1 & 2
(P<0.001 at Week 16 for all parameters)
Weeks
% o
f P
ati
en
ts <
40
0 C
op
ies
/mL
BENCHMRK 1
Weeks
BENCHMRK 2
RAL <400RAL <50
Placebo <400Placebo <50
Cooper D and Steigbigel R, et al. 14th CROI, Los Angeles, CA, February 25-28, 2007. Absts. 105aLB and 105bLB.
100
80
60
40
20
0
0 2 4 8 12 16 24
100
80
60
40
20
0
0 2 4 8 12 16 24
*Data from GS-9137 125 mg patients after addition of a PI were excluded.
Zolopa A, et al. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstracts 143LB.
Elvitegravir (GS 9137) 125 mg: The Importance of the Regimen
GS-9137 125 mgwith no active drugs in OBT(n = 26)
Mea
n c
han
ge
fro
m b
ase
lin
e in
H
IV R
NA
lo
g1
0 c
op
ies/
mL
Week
GS-9137 125 mgwith ≥1 activeNRTI or first useof T-20 (n = 47)
0 4 8 12 16 20 24
P <0.001
–0.7
–2.1-2
-1
0
The E92Q IN Mutation Reduces Susceptibility to Multiple Integrase
Inhibitors
DrugWild-type
(HXB2)E92Q
E92Q
S147G
E92Q
S147G
H51Y
E92Q
S147G
H51Y
E157Q
S147G H51Y E157Q
GS-9137
EC50, nM1.3 ± 0.3
42.2 ± 11.2
(32.5)
98.6 ± 23.6
(76.0)
208 ± 32.4
(160)
237 ± 61.6
(182)
10.7 ± 1.1
(8.0)
5.1 ± 1.2
(4.0)
3.3 ± 0.4
(2.5)
MK-0518
EC50, nM5.9 ± 0.6
35.3 ±10.5
(6.0)
45.6 ± 13.7
(7.7)
37.8 ± 6.0
(6.4)
33.7 ± 9.0
(5.7)N/D N/D N/D
L-870,810
EC50, nM0.6 ± 0.2
7.1 ± 1.1
(11.8)
16.6 ± 4.3
(27.7)
13.0 ± 1.5
(21.7)
20.0 ± 4.1
(33.3)N/D N/D N/D
Fold changes: blue: FC <2.5; Yellow: FC ≥2.5 -10; Orange: FC >10.Mean EC50 and standard deviation of n = 3 experiments; N/D, not determined.
EC50 and Fold Change (FC, Relative to Wild-type, HXB2) in Susceptibility to INIs and Control ARV Drugs of IN Site-directed Mutant HIV-1
Jones, et al. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstracts 627.
Ingresso di nuovi strumenti di diagnosi e monitoraggio
Potential HLA-B*5701 Screening Implications
Blackn = 100
HLA-B*5701 test
2positive
98negative
Whiten = 100
HLA-B*5701 test
94negative
6positive
Do not treat with ABC
Do not treat with ABC
Appropriate totreat with ABC
Test 100 black patients:
Treat 98 patients at low risk for ABC HSR
Prevent 1 ABC HSR event
Exclude ABC unnecessarily in 1 patient
Test 100 white patients:
Treat 94 patients at low risk for ABC HSR
Prevent 4 ABC HSR events
Exclude ABC unnecessarily in 2 patients
Example shown is based on PPV derived from PREDICT-1 and SHAPE data.
Saag M, et al. IAS 2007. Abstract WEAB305.
Linee guida sull’impiego della farmacocinetica in diverse nazioni
UK BHIVA 2005
Spain 2005
Germany Austria
2004
France 2002
USA DHHS 2006
Unselected, routine
Treatment failure C B B C
Interactions B C B B C
Liver impairment B C B B C
Children B B C
Pregnancy B C
Malabsorption B B C
Once-daily C B C
Toxicity B / C C B B C
Adherence C
CB recommended consider
Utilita’ del TDM (1)
Spesso il dato che si ottiene dal TDM rientra nel “range terapeutico indicato dal laboratorio e/o dalla letteratura
Se il livello è “normale”..
– Vengono escluse interazioni significative
– Bisogna cercare una spiegazione alternativa a fenomeni di tossicità o fallimento
Utilita’ del TDM (2)
PROBLEMA / SITUAZIONE
– Terapia efficace
– Fallimento
– Tossicità
– Aderenza
– Coinfezione HCV o HBV
– Interazioni
– Pz. speciali
COSA AGGIUNGE TDM?
livello ancora basso?spiega e/o previenepreviene? dose?misura oggettivaIndividualizzazione; dose?accerta, ottimizzaindividualizza in gravide,
bambini, insuff. organo
Final Consideration on PK and ARVs
The management of HIV/AIDS patients is centered on optimizing their drug regimen. What do you think is a better correlate with clinical
outcomes?
Drug concentration
Time (hours)12 24
?
ADERENZA
Factors Affecting Adherence
Important to recognize factors that influence adherence However, physicians’ ability to identify patients who will or will not be
adherent is limited
Race, sex, and socioeconomic status are not independent risk factors for nonadherence
Factors associated with
increased adherence
Patient belief in HAART
Physician experience
Social supports
Regular office visits
Factors associated with
nonadherence
Active injection-drug use
Active alcohol abuse
Active psychiatric disease (especially depression)
Younger age
Chaotic lifestyle
Low functional literacy
Why Do Patients Miss Doses?
0 10 20 30 40 50 60
52Too busy/simply forgot46Away from home
45Change in daily routine27Felt depressed/overwhelmed
20Took drug holiday/medication break20Ran out of medication
19Too many pills19Worried about becoming 'immune'
18Felt drug was too toxic17Wanted to avoid side effects17Didn't want others to notice
16Reminder of HIV infection14Confused about dosage direction
13Didn't think it was improving health10To make it last longer9Were told the medicine is no good
Reasons given for missing
antiretroviral doses(structured questionnaire)
POSSIBLE INTERVENTIONS
Simplify dosing schedule
Decrease pill burden
Other
%
Gifford et al. JAIDS 2000;23:386–395.
Patient Preferences in Antiretroviral Regimens
4 most important regimen issues for patients
– Total number of pills per day
– Dosing frequency
– Dietary restrictions
– Side effects The ideal regimen from a patient perspective:
– 2 or fewer small pills per day
– Dosed all together, once daily
– No dietary restrictions
– No adverse effects
Moyle et al. 6th Intl Congress on Drug Ther in HIV Inf 2002. Abstract 99.
Fewer Patients Forget to Take QD Regimens
0
Pat
ien
ts F
org
etti
ng
to
T
ake
HA
AR
T (
%)
7166 63
40
10
20
30
40
50
60
70
80
TID+ TID BID QD
• Forgetting rates reported by 438 of 504 patients in standardized interviews• Patients answered the APPT-1 pan-European survey
Moyle G. Int J STD AIDS. 2003;14(Suppl 1):34-36.
All at onceDivided and taken twice-a-day
Pat
ien
ts p
refe
rrin
g
sch
edu
le (
%)
> 8 pills 8 pills 6 pills6 pills 4 pills4 pills 3 pills
31
69
38
62 59
41
8484
16
9393
7
0102030405060708090
100
Dosing Preferences By Pill Burden
“If you were to take a certain number of pills each day, how would you prefer them to be administered?”
You and your patient decided “it’s time to start”
Initial treatment
Clinical conditions at baseline
Available drugsDrug drug interactions
Co-morbidity
Treatment schedule
Future options
Resistance pattern at baseline
Patient’s expectations on the outcome
Short term side effects
Pill burden
Long term side effects
PK
General Principles of Client-Centered Counselling
The focus of counselling should be client’s concerns and interest explore the personal meaning that a client gives to issues
Context is important assess the physical and emotional circumstances under which HIV risk behaviors take place
Individualize sessions Impact of counselling will be enhanced when based on specific needs and unique situations of individual clients
modified from: Ed Wolf, UCSF Enhanced Counselling Skills Training: The single Session Risk Assessment and Test Disclosure, September 2003
General Principles of Client-Centered Counselling
Take a neutral stance maintain a nonjudgmental manner when discussing sexual practices, substance abuse and other personal issues
Remember you limits information alone does not lead to behavior changes, that are a complex process requiring interventions based on client’s personal circumstances.
modified from: Ed Wolf, UCSF Enhanced Counselling Skills Training: The single Session Risk Assessment and Test Disclosure, September 2003