(SQV/r) bid vs lopinavir/r

AIDS: il ruolo del medico e le più attuali
strategie terapeutiche
Dott. 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
INFECTION
CD4+ Cells
HIV
INFECTION
CD4+ Cells
IMMUNE DESTRUCTION
IMMUNE DESTRUCTION
AIDS
AIDS
soluble factors
cytokines
apoptosis
anti MHC Ab
????
Observational data: likelihood of developing AIDS
by 3 years after becoming infected with HIV
(untreated patients)
100
90
80
70
60
50
40
30
20
10
0
CD4>750
CD4 501-750
351-500
201-350
<=200
bDNA
>30k
bDNA 3K-10K 501-3K >=500
10K30K
Plasma viral load (copies)
Mellors jW, Munoz A, Gigorni JV et al Ann. Intern Med 1997
Il paradigma della ARV
(1985 – 1996)
- 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….
Il paradigma della ARV
(1998 – oggi)
- una buona attivita’ antiretrovirale e’ la norma
- comodita’ di assunzione e bassa tossicita’
- emergono altre problematiche
VOGLIO VIVERE… …BENE!
“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
Reverse transcriptase inhibitors
Nucleotidic and nucleosidic
inhibitors:
AZT, ddI, ddC, d4T, 3TC,
ABC, TDF, FTC
Need phosphorilation before
they become active
Non nucleosidic
inhibitors
NVP, EFV, DLV
No need of activation in
the cell
Phosphorylation of NRTIs and NtRTIs
Thymidine
d4T
ZDV
Thymidine Kinase
ZDV-MP
d4T-MP
Thymidylate Kinase
ZDV-DP
d4T-DP
NDP Kinase
ZDV-TP d4T-TP
Cytidine
Guanosine
ddC 3TC FTC
ABC
ddI
Tenofovir DF
Deoxycytidine Kinase
Adenosine
Phosphotransferase
5’ Nucleotidase
Diester Hydrolysis
ABC- MP
ddI - MP
Tenofovir
ddC-MP
3TC-MP
Adenosine
Adenylate Synthetase
Cytosolic Enzyme & Adenylate Lyase
AMP Kinase
CMP/dCMP Kinase
ddC-DP
3TC-DP
NDP Kinase
CBV-MP
ddA-MP
TFV-MP
Kinase
Adenylate Kinase &
PRPP Synthetase
NDP Kinase
CBV-DP
ddA-DP
TFV-DP
Kinase
Adenylate Kinase &
PRPP Synthetase
CBV-TP
ddA-TP
ddC-TP 3TC-TP
FTC-TP
probabilità di selezionare una mutazione
Attivita’ antiretrovirale e farmacoresistenza
doppia
mono
tripla
aumento della soppressione della replicazione virale
Effects of common NRTI mutations
Mutation
M184V
TAMs
K65R
L74V
Effects
















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
Selected by ZDV and d4T (ddI)
Resistance to ZDV, d4T, ddI, ddC, ABC, TDF
↑ number of TAMs = ↑ NRTI cross-resistance
Selected by TDF, ddI, ABC
Resistance to TDF, ABC, 3TC, ddI, ddC
Uncertain effects on susceptibility to d4T
Hypersusceptibility to ZDV
Selected by ABC, ddI
Resistance to ABC, ddI, ddC
Uncertain effects on susceptibility to TDF
Hypersusceptibility to ZDV
Protease Inhibitors
•Saquinavir (SGC,HGC)*
•Nelfinavir
•Amprenavir*
•Lopinavir §
•Indinavir*
•Ritonavir
•Fos-Amprenavir*
•Tipranavir*
* May be used with ritonavir as a
booster
Protease-substrate complex
§ Available only in the boosted
form
Is HAART so critical in HIV history?
AIDS-related Mortality in the USA
Deaths per 100 person-years
35
100
Deaths
30
75
25
20
50
15
10
5
25
Use of PIs
0
1995
0
1996
1997
1998
Year
1999
2000
Therapy with a PI (% of patient-days)
40
2001
Palella et al. 8th CROI, 2001
What PI treatments do we now have?
Atazanavir
Questions over data
400mg QD
Lopinavir/r
400/100mg BID
Saquinavir/r
1000/100mg BID
Indinavir/r
800/100mg BID
Nelfinavir
1250mg BID
Amprenavir/r
600/100mg BID
Reverse transcriptase inhibitors
Nucleotidic and nucleosidic
inhibitors:
AZT, ddI, ddC, d4T, 3TC,
ABC, TDF, FTC
Need phosphorilation before
they become active
Non nucleosidic
inhibitors
NVP, EFV, DLV
No need of activation in
the cell
HAART Studies
 Previous analysis emphasized
relation b/w pill burden and
response
 Updated analysis: pill burden less
important
 Highlights efficacy of boosted-PI
and NNRTI regimens
Unboosted PI
NNRTI
NRTI
Boosted PI
0
10
20
30
40
50
60
% With VL < 50 at Week 48
Bartlett JA et al. Abstract 586, CROI 2005
70
80
90
100
HAART Studies: which one?
Le scelte critiche nella HAART


Quando e come iniziare

Nel medio-lungo periodo: tollerabilità, tossicità,
sequenziabilità

Nel paziente multi-trattato: introduzione di nuovi
farmaci, terapie “hold-on”

Co-morbidità: epatopatie croniche, diabete, altro
Individuare i parametri che predicono il successo e
l’insuccesso nel singolo paziente a breve termine
 Ruolo di farmacocinetica, genomica, immunologia
Considerations for Initial Regimen
Underlying
Conditions
Lifestyle
Dosing
Pill Burden
Hepatitis
CV Disease
Initial
Treatment
Drug
Interactions
Sequencing
Toxicity
Short Term
Long Term
Perchè i pazienti interrompono
la terapia?
Cause di interruzione del primo schema HAART
a 45 settimane nella coorte ICONA (n = 862)
Tossicità
58.3%
Fallimento
virologico 14.1%
Non aderenza
19.6%
Altro
8.0%
d’Arminio Monforte et al. AIDS 2000; 14:499–507
% di pazienti che hanno saltato una dose
per un particolare evento avverso
Gli eventi avversi come determinanti di
non aderenza
57
60
50
36
40
26
30
20
11
10
0
0
13
14
15
16
26
17
0
Adattato da Munk. CPS Info Pack (suppl). POZ 1998.
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
Plasma
Count
HIV-1 RNA
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
AIDS-defining illness
or severe
symptoms*
General Guidelines
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 201350 compared with CD4+ count
> 350 cells/mm³
900
800
> 350
600
201- 350
500
12%
13%
400
300
< 200
200
100
0
0
Yr 1 Yr2 Yr3 Yr 4 Yr 5 Yr 6
*% Over 6 years of study
† P < .05 compared with CD4+ < 200
Moore RD, et al. IAC 2006. Abstract THPE0109.
1.5%†
700
CD4+ cells/mm³


%
Developing
AIDS*
HAART and Survival Based on Initial
CD4+ Cell Count



Cohort Collaborative
10,855 patients included
934 progressed to AIDS or
died
IDUs excluded from model
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
Probability of AIDS or Death
 Modeled data from ART
101-200 cells/mm3
201-350 cells/mm3
351-500 cells/mm3
0.12
0.10
0.08
0.06
0.04
0.02
0.00
0
1
2
3
4
Years Since Initiation of HAART
Sterne J, et al. CROI 2006. Abstract 525.
5
HOPS Cohort
Prevalence of Mutations in Persons with Virologic Failure after HIV
Suppression, by CD4 Cell Count at HAART Initiation
 Question:
Does initiation of
HAART at higher CD4
predispose to drug resistance?
–
–
<1,000suppression
later had rebound (>1,000)
had GT performed
 Conclusion:
Less resistance observed in
all ARV classes when
therapy started earlier (CD4
>350)
Uy J, et al., IAS 2007; WEPEB017.
50
Percent (%)
 Study Eligibility:
– achieved viral load (VL)
60
p=0.076*
50 50
p=0.007
p=0.051
p=0.103
50
49
43
40
31
30
28
22
20
11
10
10
13
0
0
Any mutation
(n=78)
0-199 cells/mm³
NRTI mutation NNRTI mutation
PI mutation
Among NRTI- Among NNRTIAmong PIexposed (n=77) exposed (n=37) exposed (n=48)
200-348 cells/mm³
>350 cells/mm³
* p-values are for comparisons between CD4 cell count
ranges at HAART initiation
HOPS: Lipoatrophy and CD4+ Nadir
Min CD4+
Max CD4+
> 350
> 350
200-349
> 200
< 200
> 500
< 200
350-499
< 200
200-349
< 200
< 200
3.3
12.0
13.2
17.0
18.2
30.8
0
25
Incidence of Lipoatrophy (%)
Lichtenstein K, et al. CROI 2002. Poster 684a (T).
50
Factors Associated With Peripheral
Neuropathy in HIV
HOPS Cohort: PNP Associated
With HAART (N = 2178)[1]
% PNP
% on HAART
100
10
80
8
60
6
40
4
20
2
0
0
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
Year
1. Lichtenstein K, et al. IAS 2003. Abstract 729.
2. Lichtenstein K, et al. IAS 2003. Abstract 731.
16
Patients on HAART (%)
12
18
P < .0001
15.5%
14
Patients (%)
14
Patients With PNP (%)
HIV Insight: Incidence of PNP by
Nadir CD4 (N = 7980)[2]
11.1%
12
10
7.7%
8
5.1%
6
4.3%
4
2
0
0-99
100-199
200-349
350-499
Nadir CD4 Category
≥ 500
Increasing Prevalence of X4- or R5/X4Tropic Virus at Lower CD4+ Cell Counts

CCR5
– Patients with early-stage HIV
disease tend to have pure R5tropic 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 X4tropic virus?
100
Prevalence of X4 or R5/X4 (%)

80
60
41.9%
40.0%
51-100
< 50
40
20
16.0%
16.0%
14.8%
0
> 300
201-300 101-200
CD4+ Cell Count (cells/mm3)
n=
Moyle G, et al. ICAAC 2004. Abstract 1135.
248
104
81
31
50
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 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 regimen
PI-based regimen
EFV*
(NVP*)
LPV/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.
Durability of Response to HAART
Followup, wks
HIV-1 RNA
< 50 c/mL,
%
VF, %
Any Resistance*,
%
 EFV + TDF/FTC
144
64
29
68
 EFV + ZDV/3TC
144
56
42
76
 EFV + 2 NRTI
96
89
24
48
 LPV/RTV + 2 NRTI
96
77
37
21
 FPV/RTV + ABC/3TC
48
66
6
29
 LPV/RTV + ABC/3TC
48
65
7
33
Study
GS 934[1]
ACTG 5142[2]
KLEAN[3]
*Genotyped patients with virologic failure
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.
% patients with
VL<50 copies/mL at week 48
KLEAN: FPV/r vs LPV/r-Naive
Virological response
100
FPV/r
89%
80
60
66%
88%
65%
40
20
0
n=434 n=444
n=328 n=341
ITT-e TLOVR
Observed
ITT-e: All patients exposed to >1 dose of randomized study medication
Eron, et al. Lancet 2006; 368 (9534): 476-82.
LPV/r
KLEAN: FPV/r vs LPV/r-Naive
Grade 3/4 lipid abnormalities
15
FPV/r
Patients (%)
LPV/r
10
11%
9%
8%
8%
5
0
Fasting cholesterol ≥ 300 mg/dL
Fasting Triglycerides ≥ 751 mg/dL
(≥ 7.7mmol/l)
(≥ 8.4mmol/l)
Eron, et al. Lancet 2006; 368 (9534): 476-82.
ALERT: FPV/r vs ATV/r-Naive
Lipid results
Median level (mg/dL)
250
200
150
n=39
n=48 n=38
p < 0.05
n=38
n=38
n=46 n=39
n=48 n=38
100
n=48
n=45 n=39
n=46
50
n=48 n=38
n=39
0
Cholesterol
LDL
Smith K, et al. 46th ICAAC 2006; abstract H-1670a
HDL
TG
FPV/r Baseline
ATV/r Baseline
FPV/r Week 24
ATV/r Week 24
Gemini
SQV/r vs LPV/r-Naive

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
SQV/r
1000/100 mg bid
+ TDF/FTC
1:1 randomization
Lopinavir/r
400/100 mg bid
+ TDF/FTC
BMS 138: ATV/r vs. LPV/r + TDF/FTC
in ARV-naive patients

N = 882
– International, open-label trial


Duration: 96 weeks
–
–
HIV RNA ≥ 5,000 c/mL
Any CD4 count

Primary efficacy endpoint:
VL < 50 c/ml at 48 weeks

Secondary outcomes:

Atazanavir/r
300/100 mg qd
+ TDF/FTC
Inclusion criteria:
–
–
–
VL < 50 c/mL at 96 weeks
–
Fully enrolled
1:1 randomization
VL < 400 c/mL at 48 & 96 weeks
Lopinavir/r
400/100 mg bid
+ TDF/FTC
Safety assessments
Status
– Study start: November 2005
http://www.clinicaltrials.gov
Metabolic Effects of PIs
Agent
Lipids
Glucose
  TC/TG
 insulin resistance
LPV/RTV
 TC/TG
 insulin resistance
IDV/RTV
 TC/TG
 insulin resistance
 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
No 
No  insulin sensitivity
ATV/RTV
Little 
No  insulin sensitivity
DRV/RTV
?
?
RTV (full dose)
NFV
ATV

RTV associated with more pronounced effect on lipids than other PIs
Metabolic Effects of PIs:
LPV/RTV vs ATV/RTV

BMS-045: randomized trial of patients with 2 HAART
failures
ATV/RTV
Mean Change From
Baseline to Wk 48 (%)
TC
LPV/RTV
LDL-C*
HDL-C
TG*
35
30
25
15
6
5
2
1
-5
-8†
-15
-10
-7
*Fasting
-4*
values.
†P < .0001 vs LPV/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
Patients achieving response (%)
DRV/r or TPV/r Versus cPI(s):
Week 48: <50 copies/mL With First Use ENF
80
60
POWER
RESIST
56%
40
36%
20
11%
9%
0
DRV/r
cPI(s)
TPV/r
cPI(s)
(n = 36)
(n = 35)
(n = 123)
(n = 97)
First use of ENF
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 of
DRV-associated Mutations
V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, L89V
Patients with VL
HIV RNA <50 copies/mL at
Week 24 (%)
100
80
64
60
50
42
42
40
22
20
0
IAS-USA PI mutations
10
0
(67)
1
(94)
2
(113)
3
(58)
≥4
(41)
All
(373)
7
8
8
9
10
8
Number of TMC114 mutations
(Number of patients)
De Meyer S, et al. 15th International Drug Resistance Workshop; June 13-17, 2006; Sitges, Spain. Poster 73.
Etravirine: Primary Endpoint
Change in VL at 48 weeks
0.5
Mean change in log10 VL (±SE)
ITT analysis (non-completer = failure)
0
–0.14
–0.5
–0.88, P = 0.018
–1.01, P = 0.002
–1.0
P values versus active control.
SE, standard error.
–1.5
Relevant NNRTI mutations:
Active control (n = 40)
–2.0
K101P, V179E, V179F,
Y181I, Y181V, G190S,
M230L
–2.5
0 2 4
8
12
16
20
24
32
400 mg bid (n = 80)
800 mg bid (n = 79)
40
Time (weeks)
Cohen C, et al. 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0061.
48
Viral Entry Is the First Part of the HIV Life Cycle and Occurs
in 3 Stages
Attachment
Co-receptor Binding
Westby M, van der Ryst E. Antivir Chem Chemother. 2005;16:339-354.
Fusion
Co-receptor Usage of HIV-1 Variants: Defining Tropism
D/M
R5
X4
CD4
CCR5
CD4-Expressing Cells
CXCR4
CD4-Expressing Cells
CD4 memory
CD4-Expressing Cells
CD4 naive
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.
MOTIVATE 1 & 2: Trial Design
2 identical ongoing phase IIb/III studies
Randomized (1:2:2), double-blind, placebo-controlled
1076 ARV-experienced patients
R5 HIV-1 infection (44% screen failures)
HIV-1-RNA ≥5,000 copies/mL
On stable regimen, or no ARVs for ≥4 weeks
Resistance to and/or ≥6 months’ experience with ≥1 ARV from 3 classes (≥2 for PIs)
OBT = 3-6 ARVs*
Stratified by ENF use and HIV-1 RNA < and ≥5 log
Placebo
(n = 209)
MVC 150 mg† QD
(n = 414)
MVC 150 mg† BID
(n = 426)
Primary endpoint at 24 weeks:
Mean change from baseline in HIV-1 RNA
*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
100
100
90
90
<400 copies/mL
80
Patients (%)
70
<50 copies/mL
80
70
P <0.0001*
60.4%
54.7%
60
50
MVC BID + OBT (n = 235)
MVC QD + OBT (n = 232)
Placebo + OBT (n = 118)
P <0.0001*
40
60
P <0.0001*
50
40
31.4%
30
20
10
10
0
0
0 2 4
8
12
16
Time (weeks)
20
24
P = 0.0006*
30
20
48.5%
42.2%
24.6%
0 2 4
8
12
16
Time (weeks)
20
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.
24
MERIT: 740 naïve patients randomized to Maraviroc (300
bid) vs EFV (600 OD), both with CBV
MVC (n = 360)
EFV (n = 361)
100
VL < 400 copies/mL
80
73.1%
60
70.6%
40
VL < 50 copies/mL
80
69.3%
60
65.3%
40
20
20
0
Patients, %
Patients, %
100
0 24 8
16
24
32
Time (weeks)
40
48
0
024 8
16
24
32
Time (weeks)
40
48

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)
Saag M, et al. IAS 2007. Abstract WESS104.
Recently Approved New or Novel
Antiretroviral Agents
Mature
virus
PIs
Entry
inhibitors
Darunavir
Tipranavir
Reverse
transcriptase
inhibitors
Maraviroc
Etravirine
Integrase
inhibitors
Raltegravir
BENCHMRK 1 & 2
Percent <400 and <50 Copies/mL
(ITT, NC=F)
RAL <400
RAL <50
Placebo <400
Placebo <50
BENCHMRK 2
% of Patients <400 Copies/mL
BENCHMRK 1
100
100
80
80
60
60
40
40
20
20
0
0
0
2
4
8
12
16
24
0
2
Weeks
(P<0.001 at Week 16 for all parameters)
Cooper D and Steigbigel R, et al. 14th CROI, Los Angeles, CA, February 25-28, 2007. Absts. 105aLB and 105bLB.
4
8
12
Weeks
16
24
Elvitegravir (GS 9137) 125 mg:
The Importance of the Regimen
Mean change from baseline in
HIV RNA log10 copies/mL
0
–0.7
-1
P <0.001
–2.1
-2
0
4
8
12
Week
16
20
*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.
24
GS-9137 125 mg
with no active
drugs in OBT
(n = 26)
GS-9137 125 mg
with ≥1 active
NRTI or first use
of T-20 (n = 47)
The E92Q IN Mutation Reduces
Susceptibility to Multiple Integrase
Inhibitors
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
Drug
GS-9137
EC50, nM
MK-0518
EC50, nM
L-870,810
EC50, nM
E92Q
S147G
H51Y
E157Q
S147G
H51Y
E157Q
Wild-type
(HXB2)
E92Q
E92Q
S147G
E92Q
S147G
H51Y
1.3 ± 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)
5.9 ± 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
0.6 ± 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.
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
Example shown is based on PPV derived from PREDICT-1 and SHAPE data.
Black
n = 100
White
n = 100
HLA-B*5701 test
HLA-B*5701 test
2
positive
98
negative
Appropriate to
treat with ABC
94
negative
Do not treat
with ABC
6
positive
Do not treat
with ABC
Test 100 black patients:
Test 100 white patients:
 Treat 98 patients at low risk for ABC HSR
 Treat 94 patients at low risk for ABC HSR
 Prevent 1 ABC HSR event
 Prevent 4 ABC HSR events
 Exclude ABC unnecessarily in 1 patient
 Exclude ABC unnecessarily in 2 patients
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
B
B
C
Unselected, routine
Treatment failure
C
Interactions
B
C
B
B
C
Liver impairment
B
C
B
B
C
Children
B
B
C
Pregnancy
B
Malabsorption
B
Once-daily
C
Toxicity
B/C
Adherence
C
B
C
B
C
B
C
B
C
C
B
recommended
C
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 previene
previene?  dose?
misura oggettiva
Individualizzazione;  dose?
accerta, ottimizza
individualizza 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
?
12
Time (hours)
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
Factors associated with
nonadherence
 Patient belief in HAART
 Physician experience
 Social supports
 Regular office visits
 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
Too busy/simply forgot
Away from home
Change in daily routine
Felt depressed/overwhelmed
Took drug holiday/medication break
Ran out of medication
Too many pills
Worried about becoming 'immune'
Felt drug was too toxic
Wanted to avoid side effects
Didn't want others to notice
Reminder of HIV infection
Confused about dosage direction
Didn't think it was improving health
To make it last longer
Were told the medicine is no good
Gifford et al. JAIDS 2000;23:386–395.
10
20
30
40
50
60
52
46
45
27
20
20
19
19
18
17
17
16
14
13
10
9
Reasons given
for missing
antiretroviral doses
(structured questionnaire)
POSSIBLE INTERVENTIONS
Simplify dosing schedule
Decrease pill burden
Other
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
Patients Forgetting to
Take HAART (%)
Fewer Patients Forget to Take
QD Regimens
80
70
60
50
40
30
20
10
0
71
66
63
40
TID+
TID
BID
QD
• Forgetting rates reported by 438 of 504 patients in standardized interviews
• Patients answered the APPT-1 pan-European survey
Moyle et al. 6th Intl Congress on Drug Ther in HIV Inf 2002. Abstract 99.
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?”
Patients preferring
schedule (%)
100
90
80
70
60
50
40
30
20
10
0
All at once
Divided and taken twice-a-day
69
31
62
38
93
84
59
41
16
7
> 8 pills
8 pills
Moyle G. Int J STD AIDS. 2003;14(Suppl 1):34-36.
6 pills
4 pills
3 pills
You and your patient decided “it’s time
to start”
Treatment
schedule
Short term side
effects
Co-morbidity
Long term side effects
PK
Initial treatment
Drug drug
interactions
Available drugs
Patient’s
expectations
on the
Pill burden
outcome
Future options
Clinical conditions at
baseline
Resistance pattern at
baseline
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