Αντιρετροϊκή αγωγή
2014 : Υπέρ και κατά
Αναστολείς ιντεγκράσης
Ν. Τσόγκας
Παθολόγος – Λοιμωξιολόγος, ΜΕΛ ΕΕΣ
HIV Viral Life Cycle
Maturation
Budding
Uncoating
Attachment
fusion
Integration
Assembly
Reverse
transcription
Transcription,
translation
HIV Viral Life Cycle
Currently available integrase inhibitors
Raltegravir (approved 10/07)
Elvitegravir* (approved 8/12)
Dolutegravir (approved 8/13)
*Currently available only as part of a coformulated single-tablet regimen.
Maturation
Attachment
fusion
Budding
Uncoating
Integrase
inhibitors
Assembly
Reverse
transcription
Transcription,
translation
Registrational Treatment-Naive Clinical Trials: Historical Data*
HIV RNA <50 c/mL at Week 48
*This slide depicts data from multiple studies published from 2004-2014. Not all regimens have been compared head-to-head in a clinical trial
GS-103 STRIBILD (n=353)
SPRING-2 DTG (n=242)
GS-102 STRIBILD (n=348)
SINGLE DTG (n=414)
GS-103 ATV + RTV (n=355)
STaR RPV (n=394)
SPRING-2 DTG (n=169)
STARTMRK RAL (n=281)
GS-102 ATRIPLA (n=352)
ARTEMIS DRV + RTV (n=343)
ECHO/THRIVE RPV (n=550)
ECHO/THRIVE EFV (n=546)
STaR EFV (n=392)
STARTMRK EFV (n=282)
GS 934 EFV (n=244)
ARTEMIS LPV/r (n=346)
CASTLE ATV + RTV (n=440)
ABT 730 LPV/r qd (n=333)
CASTLE LPV/r (n=443)
ABT 730 LPV/r bid (n=331)
GS-903 EFV (n=299)
ASSERT EFV (n=193)
HEAT LPV/r (n=343)
HEAT LPV/r (n=345)
ASSERT EFV (n=192)
0
90
89
88
88
87
86
86
86
84
84
83
82
82
82
80
78
78
77
76
76
76
NRTI Backbone
TVD
3TC/ABC
71
68
67
59
10
20
30
40
50
60
70
80
Proportion with HIV-1 RNA <50 copies/mL at Week 48, %
90
100
RECOMMENDED INITIAL REGIMENS
DHHS1
IAS-USA2
EACS3
(Dept. of Health and Human Services)
2013/2014
(International Antiviral Society USA
Panel)
(European AIDS Clinical Society)
2014
2014
NNRTI-based therapy
EFV/TDF/FTC
EFV +TDF/FTC or ABC/3TC*
EFV + TDF/FTC or ABC/3TC**
RPV/TDF/FTCa
(only if HIV-1 RNA <100,000 c/mL)
RPV/TDF/FTC if HIV-1 RNA
<100,000 c/mL)
RPV (only if HIV-1 RNA <100,000 c/mL) +
TDF/FTC or ABC/3TC***
ATV/r + TDF/FTC
ATV/r plus ABC/3TCa
for patients who are HLA-B*5701 negative
ATV/r + TDF/FTC or ABC/3TC*
ATV/r + TDF/FTC or ABC/3TC**
DRV/r + TDF/FTC
DRV/r + TDF/FTC
DRV/r + TDF/FTC or ABC/3TC**
RAL + TDF/FTC
RAL+ABC/3TC (alternative)
EVG/c/TDF/FTC
RAL +TDF/FTC
RAL+ABC/3TC (alternative)
RAL + TDF/FTC or ABC/3TC**
EVG/c/TDF/FTC
EVG/cobi/TDF/FTC
DTG + ABC/3TC or TDF/FTC
DTG + ABC/3TC or TDF/FTC
Ritonavir-boosted PI-based therapy
INI-based therapy
*ABC/3TC
only to be used in HLA-B*5701 negative patients with baseline plasma HIV-1 RNA <100,000 c/mL
**ABC contra-indicated if HLA-B*5701 positive. Even if HLA-B*5701 negative, counselling on HSR risk still mandatory.
ABC should be used with caution in patients with a high CVD risk and/or patients with a VL > than 100,000 c/mL.
***RPV: only if VL <100 000 c/mL; PPI contraindicated, H2 antagonists to be taken 12h before or 4h after RPV.
1. DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, October 2013
2. Thompson MA, et al. JAMA 2014;312 (4):410–425 3. EACS Guidelines Version 7.02, June 2014
Σύνοψη κύριων χαρακτηριστικών των INSTIs
RALTEGRAVIR
EU status (Rx naïve)
Approved
ELVITEGRAVIR/c
DOLUTEGRAVIR
Approved
Approved
Dosing
400mg BD
In single tablet OD
with TDF/FTC/c
50mg OD, Single tab
with ABV/3TC soon
Food
Regardless
With food
Regardless
CYP3A, induces 2C9
/c inhibits 3A & 2D6, Pgp, BCRP, OAT1,
MATE1 – (not same as
Elvitegravir and
ritonavir)
UGT1A1 > CYP3A.
Substrate of UGT1A3,
UGT1A9, BCRP, and
P-gp in vitro
High via P-gp, CYP
and MATE1
Moderate via CYP3A,
P-gp, OCT2
Raised creatinine via
MATE1 inhibition
Raised creatinine via
OCT2 inhibition
Few
Few
Metabolism
DDIs
Renal effect
Data on women, age
>50yrs, low CD4/ &
high
VL
6
UGT1A
Low
Nil
Some
Package Insert: raltegravir, elvitegravir/cobi/, dolutegravir
Δεδομένα μελετών από τη χρήση
αναστολέων ιντεγκράσης σε
πρωτοθεραπεύομενους (naive) ασθενείς
Efficacy and Tolerability of
Atazanavir, Raltegravir, or Darunavir
with FTC/TDF:
Landovitz RJ, Ribaudo HJ, Ofotokun I, Wang H, Baugh BP, Leavitt RY,
Rooney JF, Seekins D, Currier JS, and Lennox JL for the A5257 Study Team
Adapted from Landovitz RJ, et al. CROI 2014; oral presentation 85; Available from: http://www.natap.org/2014/CROI/croi_30.htm (accessed March 2014).
Σχεδιασμός ACTG-5257
Ασθενείς με HIV λοίμωξη, ≥18 ετών, χωρίς προηγούμενη ART,
VL ≥1000 αντίγραφα/mL σε κέντρα των ΗΠΑ (N=1809)
Τυχαιοποίηση 1:1:1 σε ανοικτή θεραπεία
Διαστρωμάτωση με βάση το αρχικό επίπεδο HIV-1 RNA
(≥ έναντι < 100.000 αντίγραφα/mL), συμμετοχή στη
μεταβολική υπομελέτη A5260s, καρδιαγγειακός κίνδυνος
ATV 300 mg QD + RTV 100mg QD
+ FTC/TDF 200/300 mg QD
RAL 400 mg BID +
FTC/TDF 200/300 mg QD
DRV 800 mg QD + RTV 100 mg QD
+ FTC/TDF 200/300 mg QD
Ολοκλήρωση της μελέτης 96 εβδομάδες μετά την ένταξη του τελευταίου
συμμετέχοντα
Η παρακολούθηση συνεχίστηκε για 96 εβδομάδες μετά την τυχαιοποίηση του
τελευταίου ασθενούς (εύρος 2-4 έτη)
ACTG 5257 : Συνολικά αποτελέσματα στις 96 εβδ
Virologic Failure
Tolerability Failure
Regimens equivalent
in time to VF
Significantly greater
incidence of treatment
failure with ATV/RTV vs
RAL or DRV/RTV
–
ATV/RTV vs RAL
3.4% (-0.7 to 7.4)
Favors RAL
ATV/RTV vs RAL
13% (9.4-16.0)
DRV/RTV vs RAL
5.6% (1.3 -9.9)
DRV/RTV vs RAL
3.6% (1.4-5.8)
0
10 20
Considering both
efficacy and tolerability,
RAL superior to either
boosted PI
DRV/RTV superior to
ATV/RTV
Favors RAL
ATVRTV vs RAL
15% (10-20)
Favors RAL
DRV/RTV vs RAL
7.5% (3.2-12.0)
Favors DRV/RTV
ATV/RTV vs DRV/RTV
7.5% (2.3-13.0)
Favors DRV/RTV
ATV/RTV vs DRV/RTV
9.2% (5.5-13.0)
ATV/RTV vs DRV/RTV
-2.2% (-6.7 to 2.3)
-10
In part due to high
proportion of pts with
hyperbilirubinemia
Composite Endpoint
-10
0
10 20
-10
0
Difference in 96-Wk Cumulative Incidence (97.5% CI)
Landovitz R, et al. CROI 2014. Abstract 85..
10 20
STARTMRK: Raltegravir vs Efavirenz in TreatmentNaive Patients
Randomized, double-blind (through 5 yrs), placebo-controlled, phase III trial
Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48
Stratified by HIV-1 RNA (> vs ≤ 50,000 copies/mL)
and viral hepatitis status
HIV-infected, treatment-naive
patients with HIV-1 RNA
> 5000 copies/mL and
no resistance to EFV,
TDF, or FTC
(N = 563)
Lennox J, et al. Lancet. 2009;374:796-806.
Raltegravir 400 mg BID + TDF/FTC
(n = 281)
Efavirenz 600 mg QHS + TDF/FTC
(n = 282)
STARTMRK: RAL vs EFV in Treatment-Naive
Patients: 5-Yr Final Report
HIV-1 RNA < 50 c/mL (% )
RAL noninferior to EFV in HIV-1 RNA < 50 c/mL at Wk 48
(primary endpoint; ITT, NC = F analysis); superior from Wk 192
100
86
80
81
82
75
76
71
69
67
61
79
60
∆: +9.5% (95% CI: 1.7% to 17.3%;
noninferiority P < .001)
40
20
0
0 12
24
48
Pts at Risk, n
RAL
281 276 279 280
EFV
282 282 282 281
72
96
120
Wks
144
168
192
216
240
281
282
281
282
277
281
280
281
281
282
281
282
277
282
279
279
Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;63:77-85.
STARTMRK: RAL vs EFV in Treatment-Naive
Patients: 5-Yr Final Report
Efficacy as good as or better
than EFV in all baseline
subgroups tested
CD4+ cell count at Wk 240:
+374 (RAL) vs +312 (EFV)
RAL associated with
– Fewer CNS adverse events
(39.1% vs 64.2%; P < .001)
VF and Resistance at Wk 240
RAL
(n = 281)
EFV
(n = 282)
55 (19.6)
59 (20.9)
Resistance data
available, n
23
20
INSTI or NNRTI
mutations only, n
1
7
NRTI mutations only, n
3
2
NRTI + (RAL or EFV)
resistance mutations, n
3
3
VF, n (%)
– Fewer drug-related clinical
adverse events (52.0% vs
80.1%; P < .001)
– Fewer discontinuations due to
adverse events (5% vs 9%)
Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;63:77-85 plus Supplemental Digital Content.
QDMRK: RAL QD Inferior to RAL BID at Wk 48 in
Treatment-Naive Patients
Randomized, noninferiority phase III
trial of RAL 800 mg QD (n = 382) vs
RAL 400 mg BID (n = 389), both with
TDF/FTC[1]
RAL QD inferior to RAL BID at Wk 48 in
ITT (NC = F) analysis
Lower RAL trough levels associated
with higher risk of failure in QD arm but
not in BID arm
HIV-1 RNA < 50 c/mL
(NC = F)
100
83
89
80
∆: -5.7
(95% CI: -10.7 to -0.83;
P for noninferiority = .044)
60
40
RAL 800 mg
QD (n = 382)
20
RAL 400 mg
BID (n = 389)
0
318/
382
343/
389
Wk 48
More resistance at failure in QD arm
Parameter, n
RAL QD
(n = 382)
RAL BID
(n = 388)
Pts with VF* and
HIV-1 RNA > 400 c/mL
30
16
Resistance data available
27
11
FTC resistance only
11
2
Integrase inhibitor and FTC
resistance
9
2
No evidence of resistance
7
7
*Failure included both failure to suppress and rebounders.
Most patients with VF and RAL resistance had
≥ 2 mutations associated with resistance to RAL.
PK studies of 2 new RAL formulations
administered as 1200-mg once daily
showed promise in healthy patients[2]
1. Eron J, et al. Lancet Infect Dis. 2011;11:907-915. 2. Krishna R, et al. EACS 2013, Abstract PE10/17.
Elvitegravir/Cobicistat vs EFV or ATV/RTV +
TDF/FTC in Treatment-Naive Pts
Randomized, double-blind, active-controlled phase III studies
Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48
EVG/COBI/TDF/FTC QD
(n = 348)
Study 102[1]
(N = 700)
Treatment naive;
HIV-1 RNA ≥ 5000 copies/mL;
any CD4+ cell count;
susceptible to TDF, FTC, and EFV, or ATV;
eGFR ≥ 70 mL/min
Study 103[2]
(N = 708)
EFV/FTC/TDF QD
(n = 352)
EVG/COBI/TDF/FTC QD
(n = 353)
ATV/RTV + TDF/FTC QD
(n = 355)
1. Sax P, et al. Lancet. 2012;379:2439-2448. 2. DeJesus E, et al. Lancet. 2012;379:2429-2438.
EVG/COBI/TDF/FTC Noninferior to EFV/TDF/FTC
Through Wk 144
EVG/COBI/TDF/FTC
(n = 348)
Δ: 3.6%
(-1.6 to 8.8)
HIV-1 RNA < 50 copies/mL (%)
100
88 84
80
EFV/TDF/FTC
(n = 352)
Δ: 2.7%
(-2.9 to 8.3)
84
82
– Results consistent across
subgroups: BL HIV-1 RNA,
CD4+ cell count, age, sex, race
Δ: 4.9%
(1.3 to 11.1)
80
75
– Treatment-related study d/c: 6% in
EVG/COBI arm vs 7% in EFV arm
at Wk 144
60
40
20
0
Wk 48
Wk 96
Wk 144
EVG/COBI arm noninferior to EFV
arm at Wk 48 primary endpoint[1]
and through Wk 144[2,3]
VF: 7% in EVG/COBI arm and 10%
in EFV arm at Wk 144
Similar CD4+ cell count increase at
Wk 144:
– +321 cells/mm3 (EVG/COBI) vs
+300 cells/mm3 (EFV)
1. Sax PE, et al. Lancet. 2012;379:2439-2448. 2. Zolopa A, et al. J Acquir Immune Defic Syndr. 2013;63:96100. 3. Wohl D, et al. ICAAC 2013. Abstract H-672a.
EVG/COBI/TDF/FTC Noninferior to ATV/RTV +
TDF/FTC Through Wk 144
EVG/COBI/TDF/FTC
(n = 353)
Δ: 3.0%
(-1.9 to 7.8)
HIV-1 RNA < 50 copies/mL (%)
100
90 87
80
ATV/RTV + TDF/FTC
(n = 355)
Δ: 1.1%
(-4.5 to 6.7)
83
82
– Results consistent across subgroups:
BL HIV-1 RNA, CD4+ count,
adherence, age, sex, race
Δ: 3.1%
(-3.2 to 9.4)
78 75
Treatment-related study d/c:
6% in EVG/COBI arm vs
9% in ATV/RTV arm at Wk 144
VF: 8% in EVG/COBI arm vs
7% in ATV/RTV arm at Wk 144
Similar CD4+ cell count increase at
Wk 144: +280 cells/mm3 (EVG/COBI)
vs +293 cells/mm3 (ATV/RTV)
60
40
20
0
Wk 48
Wk 96
Wk 144
EVG/COBI arm noninferior to
ATV/RTV arm at Wk 48 primary
endpoint[1] and through Wk 144[2,3]
1. De Jesus E, et al. Lancet. 2012;379:2429-2438. 2. Rockstroh J, et al. J Acquir Immune Defic Syndr.
2013;62:483-486. 3. Clumeck N, et al. EACS 2013. Abstract LBPS7/2.
EVG/COBI/TDF/FTC Adverse Events Summary
EVG/COBI vs EFV: fewer CNS, rash events; smaller increase in
TC, HDL-C, and LDL-C (but similar increase in TC:HDL ratio),
similar TG increase; more nausea[1]
EVG/COBI vs ATV/RTV: less jaundice; similar increase in TC,
HDL-C, and LDL-C; smaller TG increase[2]
Small, rapid increase in serum creatinine related to inhibition of
tubular secretion of creatinine by COBI
– 0.14 ± 0.13 mg/dL at Wk 48; most change occurs by Wk 2[3]
4 pts (0.6% of total) developed tubulopathy, likely from TDF[3]
1. Sax P, et al. Lancet. 2012;379:2439-2448. 2. DeJesus E, et al. Lancet. 2012;379:2429-2438. 3.
TDF/FTC/EVG/COBI [package insert].
EVG/COBI/TDF/FTC Resistance Summary
EVG/COBI vs EFV through
Wk 144[1-3]
EVG/COBI
(n = 348)
EVG/COBI vs ATV/RTV
through Wk 144[4-6]
EFV
(n = 352)
EVG/COBI
(n = 353)
ATV/RTV
(n = 355)
Wk
48
96
144
48
96
144
Wk
48
96
144
48
96
144
Resistance
at VF, n
8
+2
+0
8
+2
+4
Resistance
at VF, n
5
+1
+2
0
+0
+2
INSTI
RAMs, n
7
+2
+0
INSTI
RAMS, n
4
0
+1
0
+0
+0
0
0
+2
NNRTI
RAMs, n
NRTI
RAMs, n
8
8
+2
+0
2
+2
+1
+4
+1
PI RAMs, n
NRTI
RAMs, n
3
+1
+2
1. Sax PE, et al. Lancet. 2012;379:2439-2448. 2. Zolopa A, et al. J Acquir Immune Defic Syndr. 2013;63:96-100. 3. Wohl D,
et al. ICAAC 2013. Abstract H-672a. 4. De Jesus E, et al. Lancet. 2012;379:2429-2438. 5. Rockstroh J, et al. J Acquir
Immune Defic Syndr. 2013;62:483-486.
6. Clumeck N, et al. EACS 2013. Abstract LBPS7/2
Dolutegravir vs Currently “Preferred” Regimens in
Treatment-Naive Pts
Randomized, noninferiority phase III studies
Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48
SPRING-2[1]
(active controlled)
SINGLE[2]
(placebo controlled)
FLAMINGO[3]
(open label)
ART-naive pts
VL ≥ 1000 c/mL
(N = 822)
ART-naive pts
VL ≥ 1000 c/mL
HLA-B*5701-neg
CrCL > 50 mL/min
(N = 833)
ART-naive pts
VL ≥ 1000 c/mL
(N = 484)
DTG 50 mg QD + 2 NRTIs*
(n = 411)
RAL 400 mg BID + 2 NRTIs*
(n = 411)
DTG 50 mg QD + ABC/3TC QD
(n = 414)
EFV/TDF/FTC QD
(n = 419)
DTG 50 mg QD + 2 NRTIs*
(n = 242)
DRV/RTV 800/100 mg QD + 2 NRTIs*
(n = 242)
*Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC.
1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818.
al. ICAAC 2013. Abstract H1464a.
3. Feinberg J, et
SPRING-2: DTG vs RAL + 2 NRTIs in Naive Patients
DTG 50 mg QD
(n = 411)
HIV-1 RNA < 50 copies/mL (% )
100
Δ: 2.5%
(-2.2% to 7.1%)
88
85
80
RAL 400 mg BID
(n = 411)
DTG noninferior to RAL at both Wk
48 primary endpoint[1] and Wk 96[2]
Δ: 4.4%
(-1.1% to 10.0%)
Treatment-related study d/c:
2% in each arm at Wk 96
VF at Wk 96[2]: 5% (22/411) in DTG
arm and 7% (29/411) in
RAL arm
Similar CD4+ cell count increase at
Wk 96:
81
76
60
40
– +276 cells/mm3 (DTG) vs
20
0
361/
411
351/
411
Wk 48
333/
411
314/
411
+264 cells/mm3 (RAL)
Wk 96
1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Raffi F, et al. IAS 2013. Abstract TULBPE17.
HIV-1 RNA < 50 c/mL at Wk 48 (% )
SINGLE: DTG + ABC/3TC vs EFV/TDF/FTC in Naive
Patients at Wk 48
100
Δ +7.4%
(95% CI +2.5% to +12.3%; P = .003)
88
Treatment-related study d/c:
2% in DTG arm vs 10% in EFV arm
VF at Wk 48: 4% (18/414) in DTG
arm and 4% (17/419) in EFV arm
CD4+ cell count increase at
Wk 48 greater with DTG:
81
80
60
40
20
0
364/
414
340/
419
DTG 50 mg +
ABC/3TC QD
EFV/TDF/
FTC QD
Walmsley S, et al. N Engl J Med. 2013;369:1807-1818.
DTG superior to EFV at Wk 48
primary efficacy endpoint
– +267 cells/mm3 (DTG) vs +208
cells/mm3 (EFV)
(P < .001)
HIV-1 RNA < 50 c/mL at Wk 48 (% )
FLAMINGO: DTG vs DRV/RTV + 2 NRTIs in Naive
Patients at Wk 48
Δ +7.1%
(95% CI: +0.9% to +13.2%; P = .025)
100
90
83
80
60
– Treatment-related study d/c:
2% in DTG arm vs 4% in
DRV/RTV arm
VF at Wk 48: < 1% (n = 2) in
each arm
40
Similar CD4+ cell count
increase at Wk 48:
20
0
DTG superior to DRV/RTV at
Wk 48 primary efficacy endpoint
217/
242
200/
242
DTG 50 mg
QD + NRTIs
DRV/RTV
800/100 mg QD
+ NRTIs
Feinberg J, et al. ICAAC 2013. Abstract H1464a.
– +210 cells/mm³ in each arm
Virologic Suppression at Wk 48 by Baseline HIV-1
RNA
STARTMRK[1]
SPRING-2[4]
Difference, % (RAL-EFV) and 95% CI
Difference, % (DTG-RAL) and 95% CI
In favor of EFV
≤ 100,000 c/mL
> 100,000 c/mL
-20
-10
In favor of RAL
≤ 100,000 c/mL
> 100,000 c/mL
In favor of RAL
0
10
20
30
-20
-10
Difference, % (EVG/COBI-EFV) and 95% CI
-15 -10 -5
In favor of EVG/COBI
0
5
10 15
In favor of EVG/COBI
0
5
20
30
In favor of DTG
In favor of EFV
≤ 100,000 c/mL
> 100,000 c/mL
-20
-10
0
10
20
30
FLAMINGO[5]
Difference, % (EVG/COBI-ATV/RTV) and 95% CI
-15 -10 -5
10
Difference, % (DTG-EFV) and 95% CI
Study 103[3]
In favor of ATV/RTV
≤ 100,000 c/mL
> 100,000 c/mL
0
SINGLE[4]
Study 102[2]
In favor of EFV
≤ 100,000 c/mL
> 100,000 c/mL
In favor of DTG
10 15
Difference , % (DTG-DRV/RTV) and 95% CI
In favor of DRV/RTV
≤ 100,000 c/mL
> 100,000 c/mL
-20
-10
In favor of DTG
0
10
20
30
1. Lennox J, et al. Lancet. 2009;374:796-806. 2. Sax PE, et al. Lancet. 2012;379:2439-2448. 3. DeJesus E, et al. Lancet. 2012;379:24292438. 4. Brinson C, et al. CROI 2013. Abstract 554. 5. Feinberg J, et al. ICAAC 2013. Abstract H1464a.
40
Similar Efficacy of INSTIs (RAL or DTG) + ABC/3TC
or TDF/FTC, Even for High BL VL
HIV-1 RNA < 50 c/mL at Wk 48 by
FDA Snapshot Analysis (%)
In SPRING-2, similar efficacy with ABC/3TC or TDF/FTC + RAL or
DTG, including with high BL HIV-1 RNA*
ABC/3TC
100
88
91
TDF/FTC
81
86
82
76
72
64
80
60
40
20
n/
N=
0
225/
257
306/
335
< 100k
36/
42
72/
88
100K - < 250K
13/
16
29/
38
250K - 500K
Baseline HIV-1 RNA (c/mL)
*Pooled data from both INSTIs.
Eron J, et al. Glasgow 2012. Abstract P204.
13/
18
18/
28
> 500K
Dolutegravir: Adverse Events Summary
DTG vs RAL[1,2]
– Adverse events similar
between arms
DTG vs EFV[3]
– CNS events and rash more
common with EFV; insomnia
more frequent with DTG
DTG vs DRV/RTV[4]
– More diarrhea with DRV/RTV;
more headache with DTG
DTG associated with small,
rapid increase in serum
creatinine in first 4 wks of tx that
remained stable through Wk 48
(mean change from baseline:
+0.11 mg/dL; range: -0.60 to
0.62 mg/dL)[5]
– Rise in creatinine related to
inhibition of tubular secretion of
creatinine by DTG
– No drug-related
discontinuations due to renal
adverse events
1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Raffi F, et al. IAS 2013. Abstract TULBPE17.
3. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. 4. Feinberg J, et al. ICAAC 2013. Abstract H1464a. 5.
Dolutegravir [package insert].
Resistance Summary
DTG vs RAL[1,2]
– 0 pts with resistance in DTG arm
– 1 pt with INSTI-R and 4 pts with NRTI-R with RAL at Wk 48; no
additional resistance by Wk 96
DTG vs EFV[3]
– 0 pts with resistance in DTG arm
– 1 pt with NRTI and 4 with NNRTI resistance in EFV arm
DTG vs DRV/RTV[4]
– No pts with resistance in either arm
1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Raffi F, et al. IAS 2013. Abstract TULBPE17. 3. Walmsley S, et al. N Engl J
Med. 2013;369:1807-1818. 4. Feinberg J, et al. ICAAC 2013. Abstract H1464a.
Aλληλεπιδράσεις INSTIs με άλλα αντιρετροϊκά
Raltegravir
Elvitegravir
(with TDF/FTC/c)
Dolutegravir
Etravirine
Should not be used without
coadministration of
atazanavir/r, darunavir/r or
lopinavir/r
Efavirenz
Dose adjustment to 50mg BID
Nevirapine
No dose
adjustment
As a complete regimen,
should not be
administered with other
ARV
Fosamprenavir/r ;
Should be avoided
Dose adjustment to 50mg BID
Tipranavir/r
Other ARV
29
Package Insert: raltegravir, elvitegravir/cobi/, dolutegravir
Limited data
Drug–Drug Interactions With Integrase Inhibitors
and Key Drugs
RAL[1,2]
Rifampin
Aluminum- or
magnesiumcontaining
antacids
EVG/COBI[1]
Antacids
Benzodiazepines
Beta blockers
Calcium channel
blockers
Erectile dysfunction
drugs
Inhaled/injectable
corticosteroids
MVC
OCPs (norgestimate)
Rifampin
Statins
DTG[3]
EFV
ETR
FPV/RTV
Medications containing
polyvalent cations (Ca++,
Mg++), including
laxatives, antacids
Metformin
Rifampin
TPV/RTV
1. DHHS Adult Guidelines. February 2013. 2. Raltegravir [package insert]. 3. Dolutegravir [package insert].
Δεδομένα από μελέτες τροποποίησης
(Switch Studies) αντιρετροϊκών σχημάτων
με τη χρήση αναστολέων ιντεγκράσης
Switching Virologically Suppressed Patients to RAL
SWITCHMRK-1 and -2[1]
– Switching to RAL inferior to remaining on LPV/RTV-based regimen in pts with
HIV-1 RNA < 50 c/mL for > 3 mos, particularly among those with previous VF
– TC, non–HDL-C, and TG improved in switch pts
SPIRAL[2]
– Switching from any boosted PI to RAL noninferior to remaining on boosted PIbased regimens through Wk 48 in pts with HIV-1 RNA < 50 c/mL for ≥ 6 mos
Switching to RAL significantly improved lipids and TC:HDL-C ratio
EASIER/ANRS 138[3]
– Switch from ENF to RAL regimens maintained virologic suppression through Wk 48
in patients with multidrug resistance and HIV-1 RNA < 400 c/mL for ≥ 3 mos
1. Eron J, et al. Lancet. 2010;375:396-407. 2. Martinez E, et al. AIDS. 2010;24:1697-1707.
3. Gallien S, et al. J Antimicrob Chemother. 2011;66:2099-2106.
Study 123: Switch From RAL + TDF/FTC to
EVG/COBI/TDF/FTC
Open-label, multicenter, 48-wk pilot study of switch from RAL + TDF/FTC to
EVG/COBI/TDF/FTC in pts with HIV-1 RNA < 50 c/mL for 6 mos (N = 48)
Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 12 postswitch
Secondary endpoints: Safety and tolerability by Wk 24 and Wk 48
HIV-1 RNA < 50 c/mL at Wk 24 and Wk 48 postswitch
All subjects maintained virologic
suppression at Wks 12 and 24
– 38/38 subjects who reached
Wk 48 at time of report also
suppressed
TC and LDL-C improved;
no renal AEs
Crofoot G, et al. IAS 2013. Abstract TUPE283.
HIV-1 RNA < 50 c/mL (%)
100
80
60
40
20
0
48/48
48/48
38/38*
Wk 12
Wk 24
Wk 48
Study 0115 (STRATEGY PI)
Study Design
Multicenter, randomized, open-label, 96-week study
n =293
STRATEGY-PI
PI + RTV + TVD
•
•
•
•
•
STB
2:1
HIV-1 RNA <50 c/mL for ≥6 months
≤ 2 prior ARV regimens
No resistance to FTC or TDF
No history of virologic failure
eGFRCG ≥70 mL/min
n =140
PI + RTV + TVD
Week 48
Week 96
Primary endpoint:
HIV-1 RNA <50 c/mL at Week 48 by Snapshot (noninferiority margin of
12%). If noninferiority is established, then superiority will be tested.
Secondary endpoint:
Safety and tolerability at Week 48 & 96
Other endpoints:
Patient-reported outcomes*
*HIV-specific, health-related quality of life questionnaires: HIV Symptom Index, HIV Treatment Satisfaction
Arribas J, et al. CROI 2014. Boston, MA #551LB
Arribas J, et al. Lancet Inf ect Dis. 2014;14:581-589
Study 0115 (STRATEGY PI)
Enrollment and Antiretroviral History
Reasons for enrollment and ART history
At screening (n =433), %
Reasons subject choose to enroll in study*
Desire to simplify current regimen
86
Concerned about long-term side effects of current regimen
12
Have trouble taking current regimen on a regular basis
3
Have trouble tolerating current regimen well due to side effects
3
Protease inhibitor use
Atazanavir
40
Darunavir
40
Lopinavir
17
Fosamprenavir
3
Saquinavir
Prior regimen(s)
On 1st antiretroviral regimen
On 2nd antiretroviral regimen
<1
On > 2 prior regimens
2
*Subject can prov ide more than one reasons f or enrollment in study
Arribas J, et al. CROI 2014. Boston, MA #551LB
Arribas J, et al. Lancet Inf ect Dis. 2014;14:581-589
79
19
100
90
94%
E/C/F/TDF
STB (n=290)
(n=290)
PI + RTV + FTC/TDF (n=139)
87%
95% CI for Difference
80
Favors Favors
PI + RTV + TVD STB
Subjects, %
70
60
50
6.7
40
30
0.4
20
10
6%
<1% 1%
0
Virologic Success
W48
Virologic Failure
W48
12%
-12%
No Virologic Data
W48
0
ΔWeek 48
(mean)
P-value
(Δ W48 - BL)
STB
603
+40
<0.001
PI + RTV + TVD
625
+32
=0.025
Arribas J, et al. CROI 2014. Boston, MA #551LB
Arribas J, et al. Lancet Inf ect Dis. 2014;14:581-589
12%
Prespecified sequential testing
Statistical superiority (P = 0.025)
Baseline
(mean)
CD4 Cell Count (cells/mm3)
13.7
Study 0115 (STRATEGY PI) – Week 48
Virologic Success and Difference By Subgroups
STB
E/C/F/TDF
Favors PI + RTV + TVD
PI + RTV + FTC/TDF
Favors STB
Overall
Age <40 years
Age ≥40 years
Male
Female
White
Non-White
Atazanavir
Darunavir
Lopinavir
One regimen
Two regimens
0
20
40
60
80
100
-50 -40 -30 -20 -10
0
10 20 30 40 50
Virologic success (%)
Difference (%)
Arribas J, et al. CROI 2014. Boston, MA #551LB
Arribas J, et al. Lancet Inf ect Dis. 2014;14:581-589
Study 0115 (STRATEGY PI) – Week 48
Adverse Events (≥5%) in Either Treatment Arm
STB
(n =293)
PI + RTV + TVD
(n =140)
Nasopharyngitis
12
10
Upper respiratory infection
8
4
Diarrhea
7
8
Nausea
7
3
Headache
6
6
Back pain
5
1
Anxiety
6
4
Cough
5
3
Depression
4
6
Insomnia
3
5
Adverse events*, %
*Treatment-emergent adv erse events occurring in ≥5% of subjects in either treatment arm
Adverse events consistent with known safety profile of STB
Arribas J, et al. CROI 2014. Boston, MA #551LB
Arribas J, et al. Lancet Inf ect Dis. 2014;14:581-589
Study 0115 (STRATEGY PI) – Week 48
Change From Baseline in Fasting Lipids by Subgroup
ATV + RTV Subgroup
Median change from baseline at Week 48,
Q1, Q3 (mg/dL)
STB
Atazanavir
TC
LDL
TG
P=0.11
P=0.20
P=0.01
-5
-15
HDL
TC
LDL
P=0.12
P=0.43
P=0.56
4
3
-3
0
-2
-2
-12
-25
STB
Lopinavir
TG
HDL
TC
LDL
TG
HDL
P=0.32
P=0.03
P=0.002
P=0.16
P=0.003
P=0.016
15
5
LPV/r Subgroup
Darunavir
STB
15
15
5
DRV + RTV Subgroup
15
0 0
3
0 0
-5
0
-1
-5
-2
-5
-15
-25
-11
-9
-15
-13
-25
-25
-35
-35
-35
-45
-45
-45
-46
-55
-55
-55
Changes from baseline in total cholesterol/HDL ratios were not statistically significant.
HDL, high density lipoprotein cholesterol; LDL, low density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides
Arribas J, et al. CROI 2014. Boston, MA #551LB
Arribas J, et al. Lancet Inf ect Dis. 2014;14:581-589
5
2
5
Study 0121 (STRATEGY NNRTI)
Study Design
Multicenter, randomized, open-label, 96-week study
n =291
STRATEGY-NNRTI
NNRTI + TVD
•
•
•
•
•
STB
2:1
HIV-1 RNA <50 c/mL for ≥6 months
≤ 2 prior ARV regimens
No resistance to FTC or TDF
No history of virologic failure
eGFRCG ≥70 mL/min
n =143
NNRTI + TVD
Week 48
Week 96
Primary endpoint:
HIV-1 RNA <50 c/mL at Week 48 by Snapshot (noninferiority margin of
12%). If noninferiority established, test for superiority
Secondary endpoint:
Safety and tolerability at Weeks 48 & 96
Other endpoints:
Patient-reported outcomes*
*Expanded HIV Sy mptom Index and HIV Treatment Satisfaction questionnaires
Pozniak A, et al. CROI 2014. Boston, MA. #553LB
Pozniak A, et al. Lancet Inf ect Dis. 2014;14:590-599
Study 0121 (STRATEGY NNRTI)
Reasons for Enrollment and ART History
Reasons for enrollment and ART history
Reasons subject choose to enroll in study*
Desire to simplify current regimen†
Concerned about long-term side effects of current regimen
Have trouble tolerating current regimen well due to side effects
Have trouble taking current regimen on a regular basis
NNRTI use‡
Efavirenz§
Nevirapine
Rilpivirineδ
On 1st antiretroviral regimen
On 2nd antiretroviral regimen
On > 2nd antiretroviral regimen
*Subjects can prov ide more than one reasons for enrollment in study.
† “Simplif y” was def ined by the subject and may have other meanings beside number of pills and/or dosing frequency.
‡ <1% of subjects were on etrav irine at screening.
74% of subjects were on Atripla
δ4% of subjects were on Complera
§
Pozniak A, et al. CROI 2014. Boston, MA. #553LB
Pozniak A, et al. Lancet Inf ect Dis. 2014;14:590-599
At screening (n=434), %
48
20
14
5
78
17
4
91
9
<1
Study 0121 (STRATEGY NNRTI) – Week 48
Primary Endpoint: HIV-1 RNA < 50 c/mL: Week 48
100
90
93%
E/C/F/TDF
(n=290)
STB
(n=290)
NNRTI + FTC/TDF (n=143)
88%
Subjects, %
80
95% CI for Difference
70
Favors Favors
NNRTI + TVD STB
60
50
40
30
20
10
1% <1%
0
Virologic Success
W48
Virologic Failure
W48
6%
-0.5
11%
No Virologic Data
W48
-12%
0
Baseline
(mean)
ΔWeek 48
(mean)
P value
(Δ W48 - BL)
STB
586
+56
<0.001
NNRTI + TVD
593
+58
<0.001
CD4 Cell Count (cells/mm3)
Pozniak A, et al. CROI 2014. Boston, MA. #553LB
Pozniak A, et al. Lancet Inf ect Dis. 2014;14:590-599
5.3
12.0
12%
Study 0121 (STRATEGY NNRTI) – Week 48
Virologic Success and Difference By Subgroups
STB
E/C/F/TDF
Favors NNRTI + TVD Favors STB
NNRTI + FTC/TDF
Overall
Age <40 years
Age ≥40 years
Male
Female
White
Non-White
Efavirenz
Non-Efavirenz
One regimen
Two regimens
0
20
40
60
80
100
-50 -40 -30 -20 -10 0
10 20 30 40 50
Virologic success (%)
Difference (%)
Pozniak A, et al. CROI 2014. Boston, MA. #553LB
Pozniak A, et al. Lancet Inf ect Dis. 2014;14:590-599
Study 0121 (STRATEGY NNRTI) – Week 48
Adverse Events (≥5%) in Either Treatment Arm
STB
(n =291)
NNRTI + TVD
(n =143)
Upper respiratory infection
10
7
Headache*
10
3
Nasopharyngitis
9
10
Diarrhea
8
7
Nausea*
8
3
Cough
7
2
Insomnia
6
5
Fatigue
5
1
Arthralgia
5
3
Adverse events,%
Treatment-emergent adv erse events occurring in ≥5% of subjects in either treatment arm
* Percentage dif f erence of ≥5% between groups. Statistical significance have not been examined.
Adverse events consistent with known safety profile of STB
Pozniak A, et al. CROI 2014. Boston, MA. #553LB
Pozniak A, et al. Lancet Inf ect Dis. 2014;14:590-599
Study 0121 (STRATEGY NNRTI) – Week 48
Change From Baseline in Fasting Lipids in Overall and EFV
Subgroup
Efavirenz Subgroup
Overall
Total-c
Median changes from baseline
(mg/dL)
10
P =0.071
LDL-c
P =0.082
TG
P =0.57
HDL-c
10
P =0.001
Total-c
P =0.010
LDL-c
P =0.001
2
P =0.008
3
1 1
1
1
0
0
P =0.48
HDL-c
5
5
5
TG
0
0
-1
-2
-5
-5
-3
-10
-3
-4
STB (n =271)
NNRTI + TVD (n =127)
-10
-5
-8
STB (n =214)
ATR (n =92)
P values for all comparisons between treatment groups using ANOVA
were not significant except for TG (p <0.001)
Median BL
Values (mg/dL)
189 186
119 115
112 101
53 51
Small decrease from baseline at Week 48 in HDL-c after
switching to STB
189 186
120 115
114 107
Small decreases from baseline in total, LDL, and HDL
cholesterols at Week 48 in EFV switches
Changes from baseline in total cholesterol/HDL ratios were not statistically significant.
Pozniak A, et al. CROI 2014. Boston, MA. #553LB
Pozniak A, et al. Lancet Inf ect Dis. 2014;14:590-599
52 51
Δεδομένα μελετών από τη χρήση
αναστολέων ιντεγκράσης σε
προθεραπευμένους
(treatment-experienced) ασθενείς
TRIO Study (ANRS 139): RAL + ETR + DRV/RTV in
Treatment-Experienced Pts
Multicenter phase II study of DRV/RTV + ETR + RAL (N = 103); addition of
NRTIs, ENF at discretion of physician
– Inclusion criteria: susceptibility to DRV and ETR based on ≤ 3 DRV and
≤ 3 ETR RAMs, respectively
– 59% of pts had < 1 active agent in OBR, as assessed by GSS
86% of pts reached HIV-1 RNA < 50 c/mL at Wk 48 (95% CI: 79% to 93%)[1]
Of 100 pts entering extension trial through Wk 96, 88% achieved HIV-1 RNA
< 50 c/mL (95% CI: 82% to 94%)[2]
Median CD4+ cell count change: +150 cells/mm3
4 tx-related grade 3/4 AEs reported before Wk 48: recurrent epidermal
necrolysis (n = 1) (study d/c); nephrolithiasis (n = 1); lipodystrophia (n = 1);
muscle spasm (n = 1)
No further events between Wks 48 and 96
1. Yazdanpanah Y, et al Clin Infect Dis. 2009;49:1441-1449.
2. Fagard C, et al. Acquir Immune Defic Syndr. 2012;59:489-493.
Study 145: Elvitegravir vs Raltegravir in TreatmentExperienced Patients
Randomized, placebo-controlled phase III study
Wk 48
HIV-infected pts,
HIV-1 RNA ≥ 1000
copies/mL,
resistance or 6 mos of
exposure to ≥ 2
antiretroviral classes
(N = 702)
Elvitegravir 150 mg (or 85 mg) QD* +
Boosted PI‡ + Third Agent§
(n = 351)
Raltegravir 400 mg BID +
Boosted PI‡ + Third Agent§
(n = 351)
*EVG currently unavailable as single agent.
†EVG dose reduced to 85 mg QD for pts receiving ATV/RTV or LPV/RTV as part of background regimen.
‡Background regimen to include fully active RTV-boosted PI, selected using resistance testing.
§Selected from ENF, ETR, MVC, or NRTI. Option of also adding FTC or 3TC for pts with M184V/I.
Molina J, et al. Lancet Infect Dis. 2012;12:27-35.
Wk 96
Study 145: EVG Noninferior to RAL at Wks 48 and 96
Subjects (% )
100
EVG (n = 351)
RAL (n = 351)
80
60
40
20
0
Similar incidence of resistance
at VF with EVG vs RAL
– Integrase resistance: 6.6% vs
7.4%
59 58
48 45
29
26
26 26
22 23
19 19
– OBR resistance: 7.4% vs 7.1%
Both regimens well tolerated
Wk 48 Wk 96 Wk 48 Wk 96 Wk 48 Wk 96
Virologic Virologic
Response Failure*
Other
– Higher rates of diarrhea with
EVG at Wks 48 and 96
– Discontinuations: 3% vs 4%
*VF includes never suppressed, rebound, switch of BR, and
d/c due to lack of efficacy.
Others include death, discontinuation due to AE,
investigator’s discretion, lost to follow-up, pregnancy, protocol
violation, subject noncompliance, withdrawal of consent.
Elion R, et al. J Acquir Immune Defic Syndr. 2013;63:494-497.
SAILING: Dolutegravir vs Raltegravir in
ART-Exp’d, Integrase Inhibitor–Naive Pts
Randomized, double-blind, noninferiority, phase III study
Stratified by number of fully active background
agents, use of DRV, screening HIV-1 RNA
(≤ vs > 50,000 copies/mL)
Treatment-experienced,
integrase inhibitor–naive
patients with HIV-1 RNA
> 400 copies/mL and
≥ 2 class resistance
(N = 715)
Dolutegravir 50 mg QD
+ Raltegravir placebo + OBR*
(n = 354)
Raltegravir 400 mg BID
+ Dolutegravir placebo + OBR*
(n = 361)
*OBR comprising at least 1 and no more than 2 active agents.
Cahn P, et al. Lancet. 2013;382:700-708.
Wk 48
SAILING: Superior Rate of Virologic Suppression With DTG
vs RAL at Wk 48
Lower incidence of resistance
at VF with DTG vs RAL
100
Subjects (% )
80
Δ: 7.4% (95% CI: 0.7-14.2;
P = .03)
DTG + OBR (n = 354)
RAL + OBR (n = 361)
71
64
60
28
20
– Grades 2-4: 8% vs 9%
9 9
0
– OBR resistance: 1% (4/354) vs
3% (12/361)
Both regimens well tolerated
with similar AE profiles
40
20
– Integrase resistance: 1%
(4/354) vs 5% (17/361);
P = .003
Virologic Virologic
No Wk
Success Nonresponse 48 Data
Cahn P, et al. Lancet. 2013;382:700-708.
– Discontinuations: 3% vs 4%
No difference in outcome
between study arms when
combined with fully active
DRV/RTV
VIKING-3: Dolutegravir After Failure of Integrase Inhibitor–
Based Regimen
Phase III single-arm trial
Pts with HIV-1 RNA
≥ 500 c/mL, RAL and/or
EVG resistance, and
resistance to ≥ 2 other
antiretroviral classes*
(N = 183)
Day 8
Wk 24
Wk 48
Dolutegravir 50
mg BID +
Continue Failing
Regimen
Dolutegravir 50 mg BID +
Optimized Background Regimen With
Overall Susceptibility Score ≥ 1
(ie, ≥ 1 active drug)
Functional
Monotherapy
Optimized Therapy
Mean HIV-1 RNA change from baseline to Day 8
– Overall: -1.4 log10 copies/mL (P < .001)
– No primary integrase resistance mutations at BL: -1.6 log10 copies/mL
– Q148 + ≤ 1 secondary integrase resistance mutation: -1.1 log10 copies/mL
– Q148 + ≥ 2 secondary integrase resistance mutations: -1.0 log10 copies/mL
*Detected at screening or based on historical evidence.
Nichols G, et al. Glasgow 2012. Abstract O232.
VIKING-3: Efficacy of DTG in
INSTI-Experienced Pts at Wk 48
24-wk data on full cohort
(N = 183) and 48-wk data on
first 114 pts
Outcome, n (% )
HIV-1 RNA < 50 c/mL at
Wk 24 (snapshot, ITT-E)
Response rates affected
by baseline INSTI resistance
but not overall susceptibility
score of background regimen
HIV-1 RNA < 50 c/mL at Wk 24
by INSTI Mutation(s), n/N (% )
Wk 24
Wk 48
(n = 183) (n = 114)
126 (69)
64 (56)
Virologic nonresponse
50 (27)
44 (39)
d/c due to AE or death
5 (3)
5 (4)
Overall Susceptibility Score
0
1
≥2
Total
No Q148
4/4 (100)
35/40 (83)
57/70 (76)
96/114 (79)
Q148 + 1
2/2 (100)
8/12 (67)
10/17 (59)
20/31 (65)
Q148 + ≥ 2
1/2 (50)
2/11 (18)
1/3 (33)
4/16 (25)
Nichols G, et al. IAS 2013. Abstract TULBPE19.
Raltegravir Summary:
Advantages and Disadvantages
Advantages
Disadvantages
INSTI with longest track record of
safety and efficacy—approved in
2007
Noninferior to EFV in initial therapy
at Wk 48 (superior from Wk 192
through Yr 5 final analysis)
Fewer CNS adverse effects, less
rash, and better lipids than EFV
Few drug–drug interactions
No food effect
Conflicting data on efficacy in switch
strategies
Integral part of many regimens in
treatment-experienced pts
Twice-daily dosing
No FDC available or planned
Rare CNS, cutaneous, and musclerelated adverse effects
Inferior to DTG in treatmentexperienced patients
Risk of resistance at VF, especially in
treatment-experienced pts
When VF failure occurs with
resistance, 2-class resistance is
common
Elvitegravir Summary:
Advantages and Disadvantages
Advantages
Disadvantages
Only INSTI currently available as a
1-pill once-daily regimen
Noninferior to EFV and ATV/RTV in
initial therapy
Maintains antiviral activity as well as
comparators across HIV-1 RNA and
CD4+ cell count strata
Fewer CNS adverse effects, less
rash, and better lipids than EFV
Less jaundice than ATV/RTV
Appears to be effective switch
regimen for patients on first-line RAL
Noninferior to RAL in treatmentexperienced patients
Not recommended for patients with
eGFR < 70 mL/min
Must be taken with food
Cobicistat inhibits tubular secretion of
creatinine, increasing Cr levels
More nausea than EFV
Risk of resistance at VF, especially in
treatment-experienced patients
When VF occurs with resistance,
2-class resistance is common
Many COBI-related drug–drug
interactions
Currently only available in FDC,
limiting regimen flexibility
Dolutegravir Summary:
Advantages and Disadvantages
Advantages
Disadvantages
Once-daily administration
Small mg dose and tablet size
Noninferior to RAL and superior to
EFV and DRV/RTV
Maintains comparable or better
virologic activity to EFV, RAL,
DRV/RTV across low and high HIV1 RNA
Fewer CNS and rash events vs EFV
When VF occurs, no integrase
resistance mutations as yet detected
in treatment-naive patients
Few drug–drug interactions
Can be taken with or without food
Not yet available as part of FDC
Inhibits tubular secretion of
creatinine, increasing Cr levels
Relatively little clinical experience
compared with RAL (especially) and
EVG
Συμπεράσματα
Ενώ υπάρχουν αρκετές επιλογές στην έναρξη θεραπείας, η
ανάλυση των δεδομένων ευνοεί τη χρήση των αναστολέων
ιντεγκράσης για τους περισσότερους πρωτοθεραπεύομενους
ασθενείς λόγω:
– Υψηλής δραστικότητας, καλής ανοχής, απουσίας σημαντικών
διαταραχών των λιπιδίων
– Χαμηλής μεταδιδόμενης αντοχής
– Λίγων αλληλεπιδράσεων με φάρμακα (RAL, DTG)
– Χαμηλής αντοχής, ειδικά με DTG
– Απλού δοσολογικού σχήματος (DTG, EVG)
Study 0121 and 0115 (STRATEGY PI and NNRTI) – Week 48
Συμπεράσματα
Η τροποποίηση σε STB από PI+RTV+TVD ή NNRTI+TVD
μετά από 48 εβδομάδες:
STB μη-κατώτερο στη διατήρηση της ιολογικής καταστολής
– 94% STB (στατιστικά ανώτερο) vs. 87% PI+RTV+TVD
– 93% STB vs. 88% NNRTI+TVD
Δεν παρατηρήθηκε αντοχή μετά την τροποποίηση σε STB
STB καλά ανεκτό, με τις αναμενόμενες ανεπιθύμητες ενέργειες (ΑΕ)
– Διακοπές αγωγής λόγω ΑΕ, σπάνιες
– Ιδια ποσοστά ΑΕ μεταξύ STB και PI+RTV+TVD, ενώ αναφέρθηκαν
υψηλότερα ποσοστά κεφαλαλγίας και ναυτίας στην ομάδα του STB σε
σύγκριση με την ομάδα των NNRTI+TVD
– Ποσοστό διάρροιας και μετεωρισμού χαμηλότερο στην ομάδα του STB
μετά την τροποποίηση από PI+RTV+TVD, ενώ χαμηλότερο ποσοστό
νευροψυχιατρικών συμπτωμάτων στην ομάδα του STB σε σύγκριση με
την ομάδα του EFV
– Μικρές μη-επιδεινούμενες αλλαγές σε SCr και eGFR, λόγω της
γνωστής αναστολής των MATE-1 μεταβιβαστών από το cobicistat
Mills A, et al. IAC 2014. Melbourne, Australia. #WEPE092
Συμπεράσματα
INSTI κατάλληλοι για αρκετούς προθεραπευμένους ασθενείς
– Για ΙNSTI-naive ασθενείς, όλοι οι INSTI είναι κατάλληλοι
– DTG ανώτερο από το RAL, EVG μη κατώτερο από το RAL
– Για INSTI προθεραπευμένους ασθενείς, DTG ανώτερο του RAL
– Διασταυρούμενη αντοχή ανάμεσα σε EVG και RAL
Δυσκολία στη χρήση EVG λόγω της ύπαρξης μόνο ως FDC, έλλειψη
δεδομένων για συγχορήγηση με άλλα ARV
Μεγαλύτερη κλινική εμπειρία και περισσότερα δεδομένα έχει το RAL
ως μέρος του νέου αντιρετροϊκού σχήματος για ασθενείς που έχουν
λάβει σχήματα με NRTI, NNRTI, PI
DTG πιθανά αποτελεί μια καινούρια επιλογή για INSTI
προθεραπευμένους ασθενείς, αλλά απαιτεί χορήγηση δις ημερησίως
σε ανίχνευση INSTI αντοχής