Download Protease Inhibitors

AIDS
ΘΕΡΑΠΕΙΑ
Κατευθυντήριες Οδηγίες
ΓΕΩΡΓΙΟΣ ΠΑΝΟΣ
BSc(Biomed.Eng.), CEng, MIET, MD, PhD, DTM&H(Lon),
FRCP
Αν. Καθηγητής Παθολογίας & Λοιμωδών Νοσημάτων
Ιατρική Σχολή Παν/μίου Πατρών
ΠΓΝΠ
RNA Change (Log 10 copies/mL)
1987 AZT
Monotherapy
1997 Combination
Therapy Including
Protease Inhibitors
1994
Two Drug Therapy
0
0
0
-0.5
-0.5
-0.5
-1
-1
-1
-1.5
-1.5
-1.5
-2
-2
-2
-2.5
-2.5
-2.5
-3
-3
-3
Fischl, NEJM, 1987
24 Week Response
Eron, NEJM, 1995
Hammer NEJM, 1996
Gulick, NEJM, 1997
Cameron, Lancet,1998
EuroSIDA, 40th ICAAC 2000
Improved Clinical outcomes: ACTG-320
Percentage of patients (%)
25
AZT (or d4T) + 3TC (n=579)
20
15
IDV + AZT (or d4T) + 3TC (n=577)
-51%
-50%
10
-63%
-49%
-57%
5
-41%
0
AIDS/death
Death
All patients
AIDS/death
Death
BL CD4 cell count <50/mm3
AIDS/death
Death
BL CD4 cell count 51−200/mm3
Hammer et al., NEJM 1997, 337 (11):725
Adapted from Hammer SM, et al. New Engl J Med 1997;337(11):725−733
Reduction in Mortality
Among Persons 25–44 Years Old, USA, 1982–1998
40
Unintentional injury
35
Cancer
30
Heart disease
Suicide
25
HIV infection
20
Homicide
15
Chronic liver disease
Stroke
10
Diabetes
5
0
1982 1984 1986 1988 1990 1992 1994 1996 1998*
Introduction of PIs
National Center for Health Statistics
National Vital Statistics System
* Preliminary 1998 data
Timeline of approved antiretrovirals
Source: ClinicalCareOptions
ARV adherence milestones
TID+
TID
ddC
BD
Delavirdine
OD
ddI EC
Nevirapine
Trizivir
3TC
AZT
ddI
Tenofovir
Combivir
d4T
Atripla
Truvada
ABC
Raltegravir
Kivexa
Efavirenz
Etravirine
FTC
1987 ’88 ’89 ’90 ’91 ’92 ’93 ’94 ’95 ’96 ’97 ’98 ’99 ’00 ’01 ’02 ’03 ’04 ’05 ’06 ’07 ’08 ’09 ’10 ‘11
NRTI
PI
RTV
NNRTI
IDV
Fusion-I
LPV/r
NFV
SQV HG
SQV SG
TPV
APV
ATV
fAPV
DRV
Maraviroc
Fuzeon
CCR5-I
Integrase-I
http://www.fda.gov/oashi/aids/virals.html
Classes of Drugs available for HIV therapy
NRTIs
NNRTIs
Protease Inhibitors
• Abacavir
• Delavirdine
• Atazanavir
• Didanosine
• Efavirenz
• Darunavir
• Emtricitabine
• Nevirapine
• Fos-Amprenavir
• Lamivudine
• Etravirine
• Indinavir
• Stavudine
• Rilpivirine
• Lopinavir
• Tenofovir
• Nelfinavir
• Zidovudine
• Ritonavir
• Saquinavir
• Tipranavir
New Classes
Fusion Inhibitors
• Enfuvirtide (T-20)
R5 Inhibitors
• Maraviroc
Integrase Inhibitors
• Raltegravir
• Elvitegravir
• Dolutegravir
Collated results of HAART studies
The primary driver of virologic
response is regimen potency.
Pill count was not consistently
associated with virologic
responses
Unboosted PI
NNRTI
NRTI
Boosted PI
0
10
20
30
40
50
60
70
80
90
100
% with VL < 50 at week 48
Bartlett JA et al. Abstract 586. 12th CROI 2005
Options for first line HAART
PI-containing
NRTI
+
NRTI
+
PI/r
(DRV/r)
NNRTIcontaining
NRTI
+
NRTI
+
NNRTI
(RPV)
NRTI-saving
PI
+
NNRTI
NRTI
+
NRTI
PI and NNRTIsaving
NRTI and IIs
NRTI
+
NRTI
+
+
NRTI
IIs
Adapted from EACS Guidelines version 8.0 (October 2015
ART CC: Supports Initiating ART at CD4
Threshold of 350 cells/mm3
• Analysis of 15 cohorts from US and Europe (ART Cohort
Collaboration) (N = 24,444)
HR for AIDS or Death*
4.0
Comparison
2.0
1.0
0.5
500
400
300
200
100
CD4 Threshold (cells/mm3)
HR* (95% CI)
1-100 vs 101-200
3.35 (2.99-3.75)
101-200 vs 201-300
2.21 (1.91-2.56)
201-300 vs 301-400
1.34 (1.12-1.61)
251-350 vs 351-450
1.28 (1.04-1.57)
351-450 vs 451-550
0.99 (0.76-1.29)
0
*Adjusted for lead-time and unobserved events.
Sterne J, et al. CROI 2009. Abstract 72LB.
Graphic reproduced with permission for educational use only.
NA-ACCORD: Survival Benefit With
Earlier vs Deferred HAART
Parameter Associated With Risk of Death
Relative Hazard (95% CI)
Deferral of HAART until < 350 cells/mm3 (vs
starting at 350-500 cells/mm3)[1]
1.7
 Female sex
1.1
1.6
 Baseline CD4+ cell count *
< .001
.083
0.9
Deferral of HAART until < 500 cells/mm3
(vs starting at ≥ 500 cells/mm3)[2]
1.6
 Female sex
< .001
.117
1.2
 Older age (per 10 yrs)
1.6
 Baseline CD4+ cell count*
< .001
1.0
1.0
< .001
.290
 Older age (per 10 yrs)
*Per 100 cell/mm3 increase.
0.1
1. Kitahata MM, et al. ICAAC/IDSA 2008. Abstract 896b.
2. Kitahata MM, et al. CROI 2009. Abstract 71.
P Value
.696
2.5
SMART: Immediate Therapy Reduces Risk
of OD, Serious Non-AIDS Events
•
Immediate group experienced substantially fewer events compared with deferred group
–
Excess risk associated with deferring therapy:
5.4 events/100 person-yrs
Event, n
(Rate per 100
Person-Yrs)
Deferred
Arm
(n = 228)
Immediate
Arm
(n = 249)
HR
(DC/VS)
95% CI
P Value
OD/death
15 (4.8)
5 (1.3)
3.5
1.3-9.6
.02
OD only
11 (3.5)
4 (1.1)
3.3
1.0-10.3
.04
Serious nonAIDS events
12 (3.9)
2 (0.5)
7.0
1.6-31.4
.01
Composite
21 (7.0)
6 (1.6)
4.2
1.7-10.4
.002
Emery S, et al. J Infect Dis. 2008;197:1133-1144.
Likelihood of Achieving Normal
CD4+ Cell Count Depends on BL Level
Johns Hopkins HIV Clinical Cohort[1]
BL CD4+ Cell Count
> 350
201-350
< 200
1000
Median CD4+ Cell Count
(cells/mm3)
ATHENA National Cohort[2]
BL CD4+ Cell Count
800
1000
800
600
600
400
400
200
200
0
0
0
1
2
3
4
Yrs on HAART
5
6
< 50
51-200
201-350
0
48
351-500
> 500
96 144 192 240 288 336
Wks From Starting HAART
Moore RD, et al. Clin Infect Dis. 2007;44:441-446. Published by The University of Chicago Press. Copyright © 2009. University of Chicago
Press. All rights reserved. http://www.journals.uchicago.edu/toc/cid/current .
Gras L, et al. J Acquir Immune Defic Syndr. 2007;45:183-192. Reproduced with permission.
Survival of Patients with CD4 Counts ≥ 500 cells/mm3 for
>5 Years is Similar to the General Population
Duration of
Follow-up with CD4 >
500 cells/mm3 (Yrs)
N
Deaths
n
Standardized
Mortality Ratio
(95% CI)
0
1208
37
2.5 (1.8-3.5)
1
1156
29
2.1 (1.4-3.1)
2
1083
26
2.2 (1.4-3.2)
3
1031
22
2.1 (1.3-3.2)
4
967
18
2.1 (1.3-3.4)
5
864
12
1.9 (1.0-3.2)
6
763
2
0.5 (0.1-1.6)
7
610
1
0.5 (0.0-2.6)
Standardized Mortality Ratio = Mortality in HIV-infected patients / Mortality in General
Population
Lewden C, et al. J Acquir Immune Defic Syndr. 2007;46:72–77.
The INSIGHT START Study Group (NEJM 2015)
Initiation of Antiretroviral Therapy in Early
Asymptomatic HIV Infection
• Initiation of ART in HIV(+) adults with CD4>500c/μl
provided net benefits over starting therapy in
HIV(+) patients when CD4 <350c/μl
• The primary composite end point was any serious
AIDS-related event, serious non-AIDS event or
death from any cause
• Primary end point occurred 1.8% in the immediate
initiation group Vs 4.1% in the deferred initiation
group (0.6 Vs 1.38 events per 100 person years)
CURRENT EUROPEAN (EACS)
ANTIRETROVIRAL THERAPY
GUIDELINES (2015)
EACS guidelines, version 8.0 (October 2015)
Retrovirus life cycle
Entry inhibitors
ENF MRV
VCV
Reverse
transcriptase
inhibitors
ZDV NVP
ddI DLV
ddC EFV
d4T 3TC
FTC ABC
TDF
Integrase
inhibitors
GS9137
MK0518
others
Protease
inhibitors
SQV IDV
RTV NFV
FPV LPV
ATV TPV
DRV
Maturation
inhibitor
bevirimat
Treatment of HIV-positive Pregnant Women
Adverse Effects of ARVs & Drug Classes
SWITCHING ANTIRETROVIRAL REGIMENS
I. In Virally Suppressed Patients
II. In Patients with Virological Failure
Virological Failure
ΣΥΜΠΛΗΡΩΜΑΤΙΚΕΣ ΓΝΩΣΕΙΣ
2010 updated score for ART efficacy in
CSF
NRTIS
4
3
2
1
ZDV
ABC
ddI
TDF
FTC
3TC
ddC
d4T
NNRTIs
NVP
DLV
ETV
EVF
PIs
IDV/r
DRV/r
ATV/r
NFV
FPV/r
ATV
RTV
IDV
FPV
SQV/r
LPV/r
Fusion/Entry
Inhibitors
Integrase
inhibitors
SQV
MVC
RAL
ENF
Letendre, S et al. 17th CROI 2010. Abstract 430.