Transcript Popular Links - UNC School of Medicine

What’s New in Antiretroviral
Therapy??
Joe Eron
UNC School of Medicine
DHHS Guidelines, March 2012:
What to Start
Preferred Regimens
NNRTI based
 EFV/TDF/FTC
Boosted PI based
 ATV/r + TDF/FTC
 DRV/r + TDF/FTC
INSTI based
 RAL + TDF/FTC
Alternative Regimens
NNRTI based
 EFV + ABC/3TC
 RPV/TDF/FTC or RPV + ABC/3TC
Boosted PI based




INSTI based
 RAL + ABC/3TC
ATV/r + ABC/3TC
DRV/r + ABC/3TC
FPV/r + (ABC/3TC or TDF/FTC)
LPV/r + (ABC/3TC or TDF/FTC)
DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 27, 2012
IAS-USA Guidelines, July 2012:
What to Start
Recommended Regimens
NNRTI based
 EFV/TDF/FTC or EFV + ABC/3TC*
Boosted PI based
 ATV/r + (TDF/FTC or ABC/3TC*)
 DRV/r + TDF/FTC
INSTI based
 RAL + TDF/FTC
Alternative Regimens‡
NNRTI based
 NVP + (TDF/FTC or ABC/3TC*)
 RPV/TDF/FTC or RPV + ABC/3TC*
Boosted PI based
 DRV/r + ABC/3TC
 LPV/r + (TDF/FTC or ABC/3TC*)
INSTI based
 RAL + ABC/3TC*
 EVG/COBI/TDF/FTC
*HLA-B*5701 screening recommended before ABC administration to reduce risk of HSR..
Consider avoiding use of ABC or LPV/r for pts with or at high risk of CV disease.
‡ZDV/3TC is alternative NRTI component of NNRTI-, PI/r-, and RAL-based regimens, but toxicity profile of ZDV reduces its utility.
Thompson MA, et al. JAMA. 2012;308:387-402
ECHO, THRIVE:
Rilpivirine vs EFV in ART-Naïve Patients:
Viral Load <50, 96 Week ITT-TLOVR Data
RPV 25mg qd (N=686)
RPV
Cohen C, et al. J Acquir Immune Defic Syndr. 2012
ECHO/THRIVE: RPV vs EFV:
96 Week Results by Baseline VL
Responders
RPV
4.0 (–1.7, 9.7)
84
80
-5.2 (-12, 1.5)
70
EFV
75
Non responders
Discontinued due
to other reasons†
Discontinued
due to AE/death
VFeff
≤100K
>100K
• RPV: More virologic failures and NNRTI/NRTI resistance; cross-resistance with ETR
(138K mutation)
• EFV: More adverse effects (rash, CNS side effects), greater increase in lipids
Cohen C, et al. J Acquir Immune Defic Syndr. 2012
Switching From TDF/FTC/EFV to
TDF/FTC/RPV in Suppressed Pts
Single-arm study of 50 pts
virologically suppressed on
TDF/FTC/EFV as first regimen for
≥ 3 mos
– No known resistance mutations to
study meds
– Desiring to switch to
TDF/FTC/RPV for intolerance of
regimen
•
100% maintained VL < 50 at Wk
12 after switch (1o endpoint)
•
•
Mean Concentration (ng/mL)
•
No events leading to
discontinuation after switch
RPV mean Ctrough within target
range by 2 weeks
Plasma Concentrations of RPV (Ctrough)
or EFV (any time)
2000
1600
EFV concentration
1200
RPV Ctrough
800
RPV mean Ctrough in ECHO/THRIVE
400
120
80
40
0
0
2
4
6
8
Weeks After Switch
Mills A, et al. ICAAC 2011. Abstract H2-794c.
10
12
SPIRIT: Switch to RPV/TDF/FTC From
Boosted-PI Regimens in Suppressed Pts
• Multicenter, randomized, open-label switch study
– 1o endpoint: maintenance of VL < 50 c/mL at Wk 24
(FDA snapshot analysis)
Wk 24
Primary endpoint
Randomized 2:1
Pts with VL < 50 on
stable PI/r + 2 NRTIs
for ≥ 6 mos, no
previous NNRTI use
(N = 476)
Wk 48
RPV/TDF/FTC
(n = 317)
PI/r* + 2 NRTIs
(n = 159)
*PIs: ATV/r, 37%; LPV/r, 33%; DRV/r, 20%; FPV/r, 8%; SQV/r, 2%.
Palella F, et al. AIDS 2012. Abstract TUAB0104.
(n = 159) RPV/TDF/FTC
SPIRIT: Switch to RPV/TDF/FTC From
Boosted-PI Regimens in Suppressed Pts
Switch to RPV/TDF/FTC noninferior
to maintaining boosted-PI regimen
at Wk 24
– 93.7% vs 89.9% with VL < 50
– Noninferior regardless of
pretreatment VL stratum
•
•
17/17 with baseline K103N
maintained suppression after
switch
Sig. reductions in TC, LDL, TG,
HDL, TC:HDL ratio (P < .001) and
in 10-yr Framingham score
(P = .001) at Wk 24 with switch
VL< 50 at Wk 24
RPV/TDF/FTC
Pts With VL < 50 c/mL (%)
•
100
Boosted PI
Δ 3.8%
(-1.6 to 9.1)
Δ 5.9%
(-1.4 to 12.9)
Δ 3.2%
(-4.8 to 11.3)
93.7
95.0
95.5
92.3
128/
134
48/
52
89.9
89.2
80
60
40
20
0
n = 317 159
Overall
152/
160
83/
93
< 100K
≥ 100K
Baseline VL (When Naive)*
*Excludes 23 RPV and 14 boosted PI pts lacking baseline
VL while ARV naive .
Palella F, et al. AIDS 2012. Abstract TUAB0104.
GS 102: TDF/FTC/EVG/COBI (“Quad”) vs.
TDF/FTC/EFV: Study Design
n=350
Quad QD
ART- naive
Any CD4 count
(N = 700 planned)
• Randomized 1:1
• Stratification by VL (>100,000)
• Conducted in US
EFV/FTC/TDF QHS
Placebo
n=350
EFV/FTC/TDF QHS
Quad Placebo QD
Week 48
1o Endpoint: Proportion with VL< 50 at Week 48
– FDA snapshot analysis (ITT), 12% noninferiority margin
Sax P, et al. CROI 2012
Week 192
GS 103: TDF/FTC/EVG/COBI (“Quad”) vs.
TDF/FTC + ATV/r: Study Design
(n=350)
Quad QD
ART naive
(N = 700 planned)
•International
•Randomized 1:1
•Stratification by VL
(>100,000)
ATV/r + FTC/TDF Placebo
QD
(n=350)
ATV/r + FTC/TDF QD
Quad Placebo QD
Week 48
1o Endpoint: Proportion with VL < 50 at Week 48
– FDA snapshot analysis, 12% non-inferiority margin
DeJesus E, et al. CROI 2012
Week 192
GS 102: “Quad” vs. TDF/FTC/EFV
1o Endpoint: VL <50 at 48 weeks
Quad non-inferior to EFV/FTC/TDF at Week 48
95% CI for Difference
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
88%
Favors
EFV/FTC/TDF
84%
3.6
-1.6
7% 7%
Virologic
Success
Sax P, et al. CROI 2012
5%
8.8
9%
Virologic Non- No W48 Data
Suppression
Quad
Favors
Quad
EFV/FTC/TDF
-12%
0
12%
GS 103: “Quad” vs. TDF/FTC + ATV/r
1o Endpoint: VL < 50 at 48 weeks
QUAD non-inferior to ATV/r + FTC/TDF
95% CI for Difference
Favors
Favors
ATV/r + FTC/TDF Quad
3.0
-1.9
-12%
DeJesus E, et al. CROI 2012
0
7.8
12%
GS 102: “Quad” vs. TDF/FTC/EFV
Drug resistance through week 48
Quad
(n=348)
EFV/FTC/TDF
(n=352)
Subjects Analyzed for Resistance*, n (%)
14 (4)
17 (5)
Subjects with Resistance to ARV Regimen, n (%)
8 (2)
8 (2)
Any Primary Integrase-R, n
7
E92Q
7
T66I
1
Q148R
1
N155H
1
Any Primary NNRTI-R n
8
K103N
7
V108I
2
Y188Y/F/H/L
1
G190A
1
Any Primary NRTI-R, n
8
2
M184V/I
8
2
K65R
3
2
*Subjects who experienced either suboptimal virologic response (two consecutive visits with HIV-1 RNA ≥50 c/mL and <1 log10
Sax
P, etbaseline
al. CROI
2012
below
after
Week 8), virologic rebound (two consecutive visits with HIV-1 RNA either ≥400 c/mL after achieving HIV1 RNA <50, or >1 log10 increase from nadir), or had HIV-1 RNA ≥400 c/mL at their last visit.
GS 103: “Quad” vs. TDF/FTC + ATV/r:
Drug resistance through week 48
Quad
(n=353)
ATV/r + FTC/TDF
(n=355)
Subjects Analyzed for Resistancea, n (%)
12 (3)
8 (2)
Subjects with Resistance to ARV Regimen, n (%)
5 (1)
0
4
-
Any Primary Integrase-R, n
E92Q
1
-
T66I
1
-
Q148R
2
-
N155H
2
-
Any Primary PI-R, n
-
0
Any Primary NRTI-R, n
4
0
DeJesus E, et al. CROI 2012
M184V/I
4
K65R
1
GS 102: “Quad” vs. TDF/FTC/EFV
Median Change in Serum Creatinine
Change from BL in Serum Creatinine (mg/dL)
(IQR)
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
-0.05
-0.10
BL 2 4
8
12
16
24
32
40
48
Week
Quad (n=):
348 341 345
EFV/FTC/TDF (n=):
352 340
345
340
337
336
335
327
328
323
323
317
320
313
320
309
307
Median change at Week 48: 0.14 mg/dL vs. 0.01 mg/dL (Quad vs. EFV/FTC/TDF group, p<0.001)
Sax P, et al. CROI 2012
“Quad” Conclusions
• Non-inferior to TDF/FTC/EFV and TDF/FTC + ATV/r,
overall and at all CD4 and VL strata
• More nausea than EFV; same as ATV/r
• Less CNS effects than EFV; less jaundice than ATV/r
• Better lipid profiles than comparators (esp. TG)
• Better CD4 response than EFV; more rapid VL response
than comparators
• Cobicistat increases serum creatinine by ~0.12-0.14
mg/dL due to inhibition of creatinine excretion
– Quad not recommended if creatinine clearance <70
– Discontinue if creatinine clearance <50
GS 114: Cobicistat-Boosted vs RTVBoosted ATV in ART-Naïve Patients
• Randomized, multicenter, placebo-controlled phase III trial
– 1o endpoint: VL < 50 c/mL at Wk 48 (FDA snapshot analysis)
Stratification by VL ≤ vs >
100,000 copies/mL
ART-naïve pts,
VL ≥ 5000,
eGFR ≥ 70 mL/min
(N = 692)
Gallant J, et al. IAC 2012. Abstract TUAB0103.
Wk 48
Primary endpoint
ATV/COBI* + TDF/FTC
(n = 344)
ATV/r + TDF/FTC
(n = 348)
Wk 96
GS 114: Cobicistat-Boosted vs RTVBoosted ATV in ART-Naïve Patients
VL < 50 at Wk 48 (Snapshot Analysis)
Δ-2.2%
(-7.4 to 3.0)
100
85
87
ATV/COBI
P = NS
88
84
ATV/r
P = NS
86
86
P = NS
90 90
81
Patients (%)
80
85
60
40
20
0
n = 344 348
Overall
•
•
P = NS
179/ 181/
212 205
114/ 123/
132 143
156/ 164/
174 183
Baseline
VL ≤ 100K
Baseline
VL > 100K
Baseline
CD4+ ≤ 350
137/ 140/
170 165
Baseline
CD4+ > 350
CD4 count gain: +213 with ATV/COBI vs +219 with ATV/r
Among 24 pts with suboptimal virologic response and genotype: no primary
PI or TDF resistance; M184V/I in 2 pts in COBI arm, 0 in RTV arm
Gallant J, et al. IAC 2012. Abstract TUAB0103.
SPRING-2: Dolutegravir vs Raltegravir
in ART-Naive Pts at 48 Wks
• Randomized, double-blind, placebo-controlled phase III trial
– 1o endpoint: VL < 50 at Wk 48 (FDA snapshot analysis)
Stratified by screening VL
(≤ vs > 100,000)
and NRTI backbone
ART-naive pts,
VL ≥ 1000
(N = 822)
Wk 48
Primary endpoint
DTG 50 mg QD + 2 NRTIs*
(n = 411)
RAL 400 mg BID + 2 NRTIs*
(n = 411)
*Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC.
Raffi F, et al. IAC 2012. Abstract THLBB04.
Wk 96
SPRING-2: Dolutegravir Noninferior
to Raltegravir at 48 Wks
Pts With VL < 50 c/mL (%)
100
88%
80
85%
DTG 50 mg QD (n = 411)
RAL 400 mg BID (n = 411)
60
• CD4 gain of +230 from BL in both arms
• No significant differences by baseline VL or NRTI backbone
 Per protocol response: 90% (DTG) vs 88% (RAL) by snapshot
analysis Δ 1.6% (95% CI: -2.7% to 5.9%)
40
20
0
Δ 2.5% (95% CI: -2.2% to 7.1%)
BL
4
8
12
16
24
Wk
Raffi F, et al. IAC 2012. Abstract THLBB04.
32
40
48
SPRING-2:
Safety and Resistance
•
Less confirmed virologic failure at or after Wk 24 with DTG vs RAL (5% vs 7%)
Patients
DTG 50 mg QD
(n = 411)
RAL 400 mg BID
(n = 411)
20
28
0/8
0/12
1/18
4/19
Subjects with virologic failure, n
Resistance, n/N
 INSTI resistance mutations
 NRTI resistance mutations
 DTG had favorable safety profile, comparable to RAL
– Few AEs necessitating discontinuation (2% in each arm)
– Greater increase in creatinine with DTG vs RAL (+0.139 vs +0.053 mg/dL)
– DTG increases serum creatinine by inhibiting renal creatinine secretion but does not affect
actual GFR[2]
– No premature discontinuation for renal events
1. Raffi F, et al. IAC 2012. Abstract THLBB04. 2. Koteff J, et al. ICAAC 2011. Abstract A1-1728.
SINGLE: Study Design
HIV + ART-naive
DTG 50 mg plus ABC/3TC FDC QD
+ ATRIPLA (ATR) placebo
VL ≥1000 c/mL
HLA-B*5701 negative
Creatinine clearance >50 mL/min
Stratified by: Baseline plasma
HIV-1 RNA and CD4 cell count
ATRIPLA QD + DTG plus ABC/3TC FDC
placebo
Randomization
Week 48
primary analysis
Week 96
Primary endpoint:
Proportion with HIV-1 RNA <50 c/mL at Week 48, FDA snapshot analysis
– 10% noninferiority margin with prespecified tests for superiority
Secondary endpoints:
– Tolerability, long-term safety, immunologic, health outcome, and viral
resistance
23
Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b
Proportion (95% CI) of Subjects
<50 c/mL (FDA Snapshot)
100
DTG + ABC/3TC: 88%
Proportion of Subjects
<50 c/mL HIV-1 RNA, %
90
80
70
ATR: 81%
60
Week 48 difference in response (95% CI):
+7.4% (+2.5% to +12.3%); P=0.003
50
40
30
20
DTG 50 mg + ABC/3TC QD
10
ATRIPLA (ATR) QD
0
BL 2
4
8
12
16
24
32
40
48
Week
•
•
DTG 50 mg + ABC/3TC QD was statistically superior to ATRIPLA at Week 48 (primary endpoint)
Subjects receiving DTG + ABC/3TC achieved virologic suppression faster than ATRIPLA, median
time to HIV-1 RNA <50 c/mL of 28 days (DTG + ABC/3TC) vs 84 days (ATRIPLA), P<0.0001
26
Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b
Supportive Efficacy Analyses
DTG 50 mg
+ ABC/3TC QD
(n=414)
Atripla QD
(n=419)
Difference in
proportion (95% CI)
(DTG–Atripla)
81%
8.7 (3.9, 13.4)
Proportion of responders
Per protocol analysis
(<50 c/mL; “snapshot”)
90%
Estimated proportion without failure by Week 48
Treatment-related
discontinuation=failure (TRDF)
94%
87%
7.7 (3.6, 11.7)
Efficacy-related
discontinuation=failure (ERDF)
95%
95%
0.2 (-2.9, 3.3)
TRDF=PDVF or withdrawal due to drug-related adverse event, safety stopping criteria, or lack of efficacy.
ERDF=PDVF or withdrawal due to lack of efficacy.
28
Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b
Snapshot of Primary Outcome
at Week 48 by Strata
DTG 50 mg
+ ABC/3TC QD
(n=414) (%)
Atripla QD
(n=419) (%)
Difference in
proportion (95% CI)
(DTG–ATR)
Number of responders/
total assessed
Baseline plasma HIV-1 RNA
≤100,000 c/mL
253/280 (90)
238/288 (83)
7.7 (2.1, 13.3)
>100,000 c/mL
111/134 (83)
100/131 (76)
6.5 (-3.2, 16.2)
P=0.831*
CD4 Cell Count
>200 cells/mm3
319/357 (89)
290/357 (81)
8.1 (3.0, 13.3)
≤200 cells/mm3
45/57 (79)
48/62 (77)
1.5 (-13.3, 16.4)
P=0.414*
* Test for homogeneity: P value confirms that there is no evidence of heterogeneity in treatment difference
across the baseline stratification factors.
29
Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b
Adjusted Mean Change From Baseline
CD4+ Cell Count (cells/mm3)
Absolute Change From Baseline in CD4+ Cell
Count: Repeated Measures Mixed Model Analysis
DTG + ABC/3TC
267 cells/mm3
300
250
200
ATR
208 cells/mm3
150
Week 48 difference in response (95% CI):
59 (33-84); P<0.001
100
50
ATRIPLA QD
DTG 50 mg + ABC/3TC QD
0
4
8
12
16
24
Week
32
40
48
Significant at prespecified level of 4%
30
Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b
Virology: Resistance
DTG 50 mg
+ ABC/3TC QD
(n=414)
ATRIPLA QD
(n=419)
18 (4%)
17 (4%)
PDVF genotypic population
11
9
PDVF genotypic (RT results at baseline and PDVF)
9
9
0
1 (K65R)
NNRTI tmt-emergent major mutations
0
4 (K101E,
K103N,
G190A)*
PDVF genotypic (IN results at baseline and PDVF)
7
7
0**
0
Subjects with PDVF
NRTI tmt-emergent major mutations
INI-r tmt-emergent major substitution
* n=1 with K101E; n=1 with K103N; n=1 with G190A; n=1 with K103N+G190A.
** E157Q/P polymorphism detected with no significant change in IN phenotypic susceptibility.
32
Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b
PI News
• Coming soon:
– DRV 800 mg tab
– DRV/COBI and ATV/COBI coformulations
• Coming later:
– DRV/COBI/GS7340/COBI coformulation
• Fully enrolled:
– ACTG ARENT: DRV/r vs. ATV/r vs. RAL comparison
Single tablet regimens
PROS
TDF/FTC/EFV
• PK
forgiving of missed doses
TDF/FTC/RPV
•Better
TDF/FTC/
EVG/COBI
•Non-inferior
tolerated than EFV
to TDF/FTC/ EFV
•Better tolerated than EFV
CONS
• CNS
side effects
• Teratogenicity
• Resistance with interruption
• Rash
• More lipid effects than others
•Less
effective at high VL?
•Less forgiving of non-adherence
•More resistance with failure, including
ETR cross-resistance
•Food requirement
•No PPI, caution with H2 blockers
•COBI
drug interactions
•COBI effect on eGFR
Single tablet regimens
PROS
forgiving of missed doses
CONS
TDF/FTC/EFV
• PK
TDF/FTC/RPV
•Better
TDF/FTC/
EVG/COBI
•Non-inferior
to TDF/FTC/ EFV
•Better tolerated than EFV
•COBI
ABC/3TC/DTG
•Only
•ABC
tolerated than EFV
non-TDF-based STR
•Superior to TDF/FTC/EFV due
to better tolerability
• CNS
side effects
• Teratogenicity
• Resistance with interruption
• Rash
• More lipid effects than others
•Less
effective at high VL?
•Less forgiving of non-adherence
•More resistance with failure, including
ETR cross-resistance
•Food requirement
•No PPI, caution with H2 blockers
drug interactions
•COBI effect on eGFR
issues
Why use multiple tablet regimens?
 Boosted PI + 2 NRTIs:
– Lack of resistance with failure. Ideal for patients
with unreliable adherence.
– Preferred in pregnancy
 RAL + 2 NRTIs:
– Superior to EFV at 4 & 5 years.
– Few drug interactions. Ideal for patients needing
HCV therapy
 ABC/3TC + 3rd agent:
– Patients with kidney disease
Choice of ART:
Special populations and scenarios
• Pregnancy or likelihood of pregnancy
•
•
•
•
Avoid EFV (1st trimester)
No data on newer agents (RPV, EVG/COBI)
NRTIs: AZT/3TC, TDF/FTC
PIs: LPV/r, ATV/r
• HCV coinfection
• RAL: can be used with telaprevir, boceprevir
• ATV: can be used with telaprevir
• EFV: requires higher dose telaprevir
• HBV coinfection
• TDF/FTC-based regimen if possible
Choice of ART:
Special populations and scenarios
• Chronic kidney disease
• Avoid TDF (and ATV, LPV/r?)
• Pre-existing osteoporosis/osteopenia
• Avoid TDF
• Need for urgent ART without resistance data
(primary HIV, acute OI)
• Boosted PI-based regimen
• Transmitted resistance
• Depends on mutations
• PI-based regimen preferred for NRTI resistance
ART: New formulations
 3 single-tablet regimens now available;
2 more in development:
– DTG/ABC/3TC
– DRV/COBI/GS7340/FTC/
 Other new formulations planned:
– DRV 800 mg tab
– ATV/COBI
– DRV/COBI
– EVG/COBI
– GS7340/FTC