Transcript to Dr. Gallant`s slides.

ART Update
Joel Gallant, MD, MPH
Johns Hopkins University School of Medicine
When to Start
When to Start:
DHHS Guidelines 02/12/2013
ART recommended for all HIV+ individuals to reduce risk of disease
progression. Strength and evidence for recommendation vary by pretreatment CD4 count:
• CD4 ≤ 350
• CD4 350-500
• CD4 >500
AI
AII
BIII
ART recommended for HIV-infected individuals for prevention of HIV
transmission. Strength and evidence for recommendation vary by
transmission risk:
• Perinatal transmission
• Heterosexual transmission
• All other risk groups
US DHHS Guidelines, February 2013.
AI
AI
AIII
When to Start
IAS-USA Guidelines, July 2012
ART recommended and should be offered regardless of CD4
count. Strength of recommendation varies based on CD4 count:
Clinical Condition and/or
CD4 Count
Recommendations
• CD4 ≤500
• CD4 >500
AIa
BIII
•
•
•
•
•
•
AIa
AIIa
AIIa
CIII
BIIa
BIII
Pregnancy
HIV-associated nephropathy
HBV coinfection
HCV coinfection
Age >60
Acute phase of primary infection
MA, et al.
JAMA2011.
2012;308:387-402
USThompson
DHHS Guidelines,
January
Why abandon CD4 thresholds?
• Observational data showing improved survival
and/or lack of harm
• Association between copy-year viremia and
morbidity and mortality
• Presumed benefit of reducing inflammation and
immune activation
• Minimal incremental difference between treating
everyone vs. treating a CD4 of 500
• Prevention
Frequent CD4 Count Monitoring Not
Necessary for Patients With CD4 > 300

Retrospective review of VA lab
database of > 25,000 paired VL and
CD4 counts from 1821 unique pts
(1998 -2011)

Eligible pts had “sequences”:
consecutive VL/CD4 pairs with
– VL < 200

Virologically suppressed pts with
CD4 > 300 extremely unlikely to have
CD4 count dip < 200
Probability of Maintaining CD4 >200
During Viral Suppression
1.00
– %CD4 >14
Probability
– CD4 count > 200
≥ 350
300-349
250-299
200-249
0.90
DHHS Guidelines:
0.80
– < 390 days between CD4 counts
“In clinically stable patients with suppressed
viral load,
0.70
 Analysis
of pts with
sequences
CD4
count
can
be monitored every
6–12 months”
0.60
(n = 846) who experienced CD4
“dips” < 200 during periods of
virologic suppression (n = 61)
Gale H, et al. AIDS 2012. Abstract WEPDB0101.
0.50
0
1 2 3 4 5 6
Viral Suppression, Yrs
The Initial Regimen
DHHS Guidelines, Febuary 2013:
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 (VL <100,000)
Boosted PI based




INSTI based
 RAL + ABC/3TC
 EVG/COBI/FTC/TDF(eGFR >70)
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. February 2013
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
NNRTIs
NNRTIs
NNRTI
Abb.
Brand Name(s)
Comments
Nevirapine
NVP
Viramune, Viramune XR
Women: CD4<250
Men: CD4 <400
Delavirdine
DLV
Rescriptor
Rarely used
Efavirenz
EFV
Sustiva (Atripla)
Preferred NNRTI
for initial therapy
Etravirine
ETR
Intelence
ART-experienced
patients
Rilpivirine
RPV
Edurant (Complera)
VL <100,000; no
PPIs/H2 blockers;
with meal
ECHO/THRIVE:
Viral Load <50, 96 Week ITT-TLOVR Data
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
STaR: RPV/TDF/FTC vs. EFV/TDF/FTC
Week 48FDA Snapshot Analysis – ITT Population
RPV/FTC/TDF non-inferior to EFV/FTC/TDF
Proportion of Subjects, %
95% CI for Difference
RPV/FTC/TDF
EFV/FTC/TDF
Favors
EFV/FTC/TDF
Favors
RPV/FTC/TDF
-1.1
4.1
9.2
p=0.12
338/
394
320/
392
32/394 22/392
24/394 50/392
-12%
0
(VL<50 c/mL)
CD4 change: RPV/FTC/TDF +200 vs EFV/FTC/TDF +191 (p=0.34)
Cohen C, et al. 11th Int’l Conf on Drug Therapy in HIV Infection, Glasgow, 2012
12%
STaR: RPV/TDF/FTC vs. EFV/TDF/F
Virologic Suppression by Baseline Viral Load
2%
231/
260
1%
204/
250
8%
0%
81/
98
96/
117
19% 4%
26/
36
*
20/
25
*
Baseline VL c/mL
* Post hoc analyses; analyses for non-inferiority only pre-specified for ≤100,000 c/mL and >100,000 c/mL
Cohen C, et al. 11th Int’l Conf on Drug Therapy in HIV Infection, Glasgow, 2012
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.
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
Mills A, et al. ICAAC 2011. Abstract H2-794c.
Percent with VL <50 at 12
weeks
100%
VL <50
Integrase Inhibitors
Integrase Inhibitors
INSTI
Abb.
Brand Name(s)
Comments
Raltegravir
RAL
Isentress
Twice daily
Elvitegravir
EVG
Stribild
(EVG/COBI/TDF/FTC)
Once-daily boosted
Coformulation only
Dolutegravir
DVG
?
Once-daily
unboosted; coming
soon
STARTMRK: Final 5-Yr Phase III Results of
Efavirenz vs Raltegravir in Naive Pts

Double-blind phase III trial of EFV vs
RAL, with TDF/FTC, in ART-naïve pts
Pts With VL < 50 c/mL (%)
100
86
81
80
82
75
76
69
67
71
RAL noninferior at Wk 48 1o endpoint

RAL superior to EFV at 192-240 wks
by VL < 50 (ITT, NC = F analysis)

CD4 gain: +374 (RAL) vs +312 (EFV)

Consistent virologic and immunologic
effects by subgroup (e.g., baseline
CD4/VL, age, sex, race, etc.)

Low levels of resistance among
patients with VF and VL
> 400 in both arms
79
60
61
40
20

RAL
Wk 240 ∆ = +9.5 (95% CI, 1.7-17.3)
Noninferiority P < .001
EFV
–
0
0 12 24
Pts, n
48
72
96
120 144 168 192 216
Wks
240
281 278 279
280
281
281
277
280
281
281
277
282 282 282
281
282
282
281
281
282
282
282
279
279
Rockstroh JK, et al. J Acquir Immune Defic Syndr 2013
RAL, n = 7; EFV, n = 12

Fewer drug-related AEs in RAL arm

Smaller increases in TC, HDL-C, LDLC, and TG levels with RAL vs EFV
GS 102: EVG/COBI/TDF/FTC vs.
TDF/FTC/EFV: VL <50
EFV/TDF/FTC (n=352)
Percentage of subjects (%)
“Quad” (n=348)
95% CI for Difference
Favors EFV/TDF/FTC Favors Quad
W48
3.6%
-1.6%
8.8%
2.7%
W96
-12%
Virologic Success
Virologic
Nonsuppression
Zolopa A, et al. J Acquir Immune Defic Syndr 2013.
No data at W48
(or 96)
-2.9%
8.3%
0
12%
GS 102: Common Neuropsychiatric AEs
“Quad” (n=348)
Dizziness
Patients with AE (%)
Abnormal Dreams
EFV/TDF/FTC (n=352)
Weeks
Incidence (bar) and Prevalence (line)
Zolopa A, et al. J Acquir Immune Defic Syndr 2013.
Weeks
GS 102: Changes in serum creatinine
Discontinuation due to renal A/Es
EVG/COBI/TDF/FTC
1.4%
0.4
EFV/TDF/FTC
0%
2.0%
0%
0.3
20
0.2
0.14
0.13
10
0.1
0.0
0.01
-0.1
0.01
STB
-10
ATR
-0.2
BL
0
24
48
72
96
Week
STB (n=)
348
328
320
305
298
ATR (n=)
352
317
307
302
295
Zolopa A, et al. J Acquir Immune Defic Syndr 2013.
(mmol/L)
Change in Cr (mg/dL),
Median [IQR]
30
GS 102: Drug Resistance Through Week 96
“Quad”
(n=348)
EFV/TDF/FTC
(n=352)
BL-Week 48
BL-Week 96
BL-Week 48
BL-Week 96
14 (4%)
17 (5%)
17 (5%)
23 (7%)
8 (2%)
10 (3%)
8 (2%)
10 (3%)
7
9
-
-
Any Primary NNRTI-R, n
-
-
8
10
Any Primary NRTI-R, n
8
10
2
3
Subjects Analyzed for
Resistance*, n (%)
Subjects with Resistance to
ARV Regimen, n (%)
Any Primary INSTI-R, n
*Subjects
who experienced either suboptimal virologic response (VL ≥50 c/mL and <1 log 10 below baseline at Week 8 and
confirmed at the subsequent visit), virologic rebound (two consecutive visits with VL either ≥400 c/mL after achieving VL <50, or
>1 log10 increase from nadir), or had VL ≥400 c/mL at Week 48, Week 96, or their last visit (at or after Week 8).
Zolopa A, et al. J Acquir Immune Defic Syndr 2013.
GS 103: EVG/COBI/TDF/FTC vs.
TDF/FTC + ATV/r: VL <50
EVG/COBI/FTC/TDF (n=353)
ATV/r + FTC/TDF (n=355)
Percentage of subjects (%)
95% CI for Difference
Favors EVG/COBI/FTC/TDF
Favors ATV/r + FTC/TDF
2.7
W48
-2.1
7.5
1
1.1
W96
6.7
-4.5
-12%
Virologic Success Virologic Non
suppression
No data at
W48 (or 96)
Figure 1: Efficacy (Snapshot Analysis) through Week 48 (Primary) and Week 96 (Secondary)
Rockstroh JK, et al. J Acquir Immune Defic Syndr 2013.
0
12%
Change from Baseline in Serum Creatinine (mg/dL)
GS 103: Changes in Serum Creatinine
0.28
0.24
0.20
0.16
0.12
0.08
0.04
0.0
-0.04
-0.08
BL 2 4
8
12
16
24
32
40
48
Week
QUAD (n=):
353 346 344
ATV/r +FTC/TDF (n=): 355 344
344
342
340
339
337
335
334
332
325
329
324
323
Median change W48: 0.12 mg/dL vs. 0.08 mg/dL (Quad vs. ATV/r + FTC/TDF group, p<0.001)
DeJesus E, et al. Lancet 2012;379:2429-38
323
316
314
GS 103: 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
M184V/I
4
K65R
1
DeJesus E, et al. Lancet 2012;379:2429-38
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: Dolutegravir + ABC/3TC vs.
EFV/TDF/FTC
100
DTG+ABC/3TC: 88%
Proportion (%) with <50 c/mL
90
80
EFV/TDF/FTC: 81%
70
WK 48 difference in response (95% CI):
+7.4% (+2.5% to +12.3%); p=0.003
60
50
40
30
20
10
DTG 50 mg + ABC/3TC QD
EFV/TDF/FTC QD
0
BL 2
4
8
12
16
24
32
40
48
Week
● DTG +ABC/3TC QD superior to EFV/TDF/FTC at Wk 48 (1o endpoint)
● Subjects receiving DTG +ABC/3TC achieved faster suppression than EFV/TDF/FTC, med. time to
FL <50 c/mL of 28 vs 84 days, P<0.0001
Walmsley S, et al. 52nd ICAAC. 9-12 Sept 2012. Abstract H-556b.
SINGLE: DTG + ABC/3TC vs. EFV/TDF/FTC:
Disposition
DTG 50 mg +ABC/3TC
n=411
n (%)
EFV/TDF/FTC
(N=419)
n (%)
364 (88)
338 (81)
21 (5)
26 (6)
Data in window not <50 c/mL
6 (1)
5 (1)
Discontinued for lack of efficacy
7(2)
9 (2)
Discontinued for other reason while not <50 c/mL
8 (2)
12 (3)
29 (7)
55 (13)
Discontinued because of AE or death*
9 (2)
40 (10)
Discontinued for other reasons
20 (5)
14 (3)
0
1 (<1)
Outcome (snapshot) at Week 48
Virologic success
Virologic nonresponse
No virologic data at Week 48
Missing data during window but on study
*Deaths: n=2, both on EFV/TDF/FTC: n=1 primary cause of death (sepsis) judged unrelated to study drug but
complicated by renal failure judged possibly related to EFV/TDF/FTC; n=1 not related to EFV/TDF/FTC (pneumonia).
Walmsley S, et al. 52nd ICAAC. 9-12 Sept 2012. Abstract H-556b.
SINGLE: DTG + ABC/3TC vs. EFV/TDF/FTC:
Resistance
DTG 50mg
+ABC/3TC
(N=414)
EFV/TDF/FTC
(N=419)
18 (4%)
17 (4%)
PDVF genotypic population
11
9
PDVF Genotypic (RT Results at Baseline and PDVF)
NRTI tmt-emergent major mutations
NNRTI tmt-emergent major mutations
9
0
0
PDVF Genotypic (IN Results at Baseline and PDVF)
INI-r tmt-emergent major substitution
7
0**
9
1(K65R)
4 (K101E,
K103N, G190A)*
7
0
Subjects with PDVF
* n=1 with K101E, n=1 with K103N, n=1 with G190A and n=1 with K103N+G190A
**E157Q/P polymorphism detected with no significant change in IN phenotypic susceptibility
Walmsley S, et al. 52nd ICAAC. 9-12 Sept 2012. Abstract H-556b.
PIs
PIs
PI
Abb.
Brand Name(s)
Comments
Saquinavir
SQV
Invirase
Rarely used
Indinavir
IDV
Crixivan
Rarely used
Ritonavir
RTV
Norvir
Used only as booster
Nelfinavir
NFV
Viracept
Rarely used
Lopinavir/RTV
LPV/r
Kaletra
Only coformulated PI;
Once or twice daily
Higher RTV dose than others
Fosamprenavir
FPV
Lexiva
Infrequently used
Atazanavir
ATV
Reyataz
Once-daily boosted;
Unboosted OK without TDF
Jaundice; caution with PPIs
Tipranavir
TPV
Aptivus
Rarely used; ART-experienced
with TPV susceptibility and DRV
resistance
Darunavir
DRV
Prezista
Once-daily in most cases;
Twice daily if DRV mutations
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. J Infect Dis 2013.
ATV/COBI vs ATV/r: Changes in
Serum Creatinine and eGFR
•
COBI  serum creatinine and  eGFR by inhibiting renal creatinine secretion[1]
•
COBI does not affect actual GFR[2]
Change in Serum Creatinine, Median (IQR)
0.4
Change in eGFR, Median (IQR)
0
ATV/COBI
ATV/r
-10
mL/min
mg/dL
0.3
0.2
-20
0.1
-30
0.0
-40
BL
8
16
24
Wk
32
40
48
ATV/COBI
ATV/r
BL
8
16
24
Wk
32
•
6 pts in COBI arm and 5 in RTV arm D/C’d therapy due to renal abnormalities[3]
•
Higher proportion with hyperbilirubinemia with COBI but discontinuations similar by arm
•
5 of 6 in COBI arm vs 2 of 5 in RTV arm with proximal tubulopathy discontinued therapy
40
1. Lepist EI, et al. ICAAC 2011. Abstract A1-1724. 2. German P, et al. J Acquir Immune Defic Syndr. 2012;[Epub
ahead of print]. 3. Gallant J, et al. J Infect Dis 2013.
48
PI News
• Coming soon?
– DRV/COBI and ATV/COBI coformulations
• Coming later?
– DRV/COBI/FTC/TAF (“D/C/F/TAF”) coformulation
• Awaiting results:
– ACTG ARENT: DRV/r vs. ATV/r vs. RAL comparison
HIV Entry Inhibitors
CD4
Binding
BMS-663068
Coreceptor
Binding
Enfuvirtide
gp41
Ibalizumab
gp120
V3 loop
CCR5 antagonists
CD4
Cell
Membrane
Virus-Cell
Fusion
CCR5/CXCR4
(R5/X4)
Entry Inhibitors
Entry Inhibitor Abb.
Brand Name(s)
Comments
Enfuvirtide
ENF,
T20
Fuzeon
Fusion inhibitor; rarely used;
twice-daily injections with
injection site reactions
Maraviroc
MVC
Selzentry
CCR5 antagonist; pre-treatment
tropism testing required
New Entry Inhibitors
 Cenicriviroc (TBR-652): CCR5 antagonist with anti-CCR2
properties (anti-inflammatory)
 BMS-663068: CD4 attachment inhibitor
 Ibalizumab (TNX-355): Anti-CD4 monoclonal antibody;
once weekly IV dosing
NRTIs
NRTIs
NRTI
Abb.
Brand Name(s)
Comments
Zidovudine
AZT,
ZDV
Retrovir (Combivir,
Trizivir), generic
Rarely used
Didanosine
ddI
Videx, Videx EC, generic
Rarely used
Stavudine
d4T
Zerit, generic
Rarely used
Lamivudine
3TC
Epivir (Combivir, Trizivir,
Epzicom), generic
Typically used in
combination with AZT or
ABC
Abacavir
ABC
Ziagen (Epzicom)
Prescreen with HLA B*5701
Tenofovir DF
TDF
Viread (Truvada, Atripla,
Complera, Stribild)
Monitor kidney function
Emtricitabine
FTC
Emtriva (Truvada, Atripla,
Complera, Stribild)
Typically used in
combination with TDF
ACTG 5202: Time to Virologic Failure by
Baseline Viral Load and CD4 Count
ABC/3TC
TDF/FTC
1.0
0.8
0.6
0.4
CD4<50, RNA≥100K (n=98, 35 VF)
CD4<50, RNA<100K (n=78, 23 VF)
CD4 50 to <200, RNA≥100K (n=80, 19 VF)
CD4 50 to <200, RNA<100K (n=153, 10 VF)
CD4 200 to <350, RNA≥100K (n=39, 6 VF)
CD4 200 to <350, RNA<100K (n=273, 28 VF)
CD4≥350, RNA≥100K (n=23, 5 VF)
CD4≥350, RNA<100K (n=184, 29 VF)
0.2
0.0
Probability of Remaining free of
Virologic Failure
Probability of Remaining free of
Virologic Failure
1.0
0.8
0.6
0.4
CD4<50, RNA≥100K (n=80, 6 VF)
CD4<50, RNA<100K (n=83, 17 VF)
CD4 50 to <200, RNA≥100K (n=70, 9 VF)
CD4 50 to <200, RNA<100K (n=158, 19 VF)
CD4 200 to <350, RNA≥100K (n=55, 8 VF)
CD4 200 to <350, RNA<100K (n=289, 29 VF)
CD4≥350, RNA≥100K (n=20, 2 VF)
CD4≥350, RNA<100K (n=173, 24 VF)
0.2
0.0
0
24
48
72
96 120 144 168 192 216
Weeks from Randomization
Grant P, et al. CROI 2011. Abstract 535.
0
24
48
72
96 120 144 168 192 216
Weeks from Randomization
Abacavir and MI Risk:
Recent published studies
Reference
Study Design
Increased risk?
Choi, AIDS 2011, VA
Observational
Yes
Bedimo, CID 2011, VA
Observational
No
Durand, J AIDS 2011, Montreal
Observational
Yes
Cohort from RCTs
No
Met-analysis
No
Ribaudo, CID 2011, ACTG
Cruciani, AIDS 2011
“How difficult it is to find a consensus can be exemplifiedby
the fact that even identical data sources (Veterans Health
Administration) analyzed by different investigators can lead
to conflicting results …”
Georg Behrens, AIDS 2011;2043-2045.
Paul Sax
Abacavir and MI Risk
• Conflicting data from observational and
prospective studies
• Proposed pathogenic models:
– Inflammation
– Increased platelet reactivity/adhesion
– Impaired flow-mediated dilatation
– Atherogenic lipid profile
• Guidelines: “use with caution” in patients
with high CV risk
DHHS Guidelines, October 14, 2011
VA Study: TDF and risk of kidney
disease
• 10,841 HIV+ pts at VA
• Time to first occurrence of 1) proteinuria 2) rapid decline
in kidney function and 3) CKD (eGFR rate < 60 )
• Each year of exposure to TDF associated with:
– 34% increased risk of proteinuria (p < 0.0001)
– 11% increased risk of rapid decline (p = 0.0033)
– 33% increased risk of CKD (p < 0.0001).
• Pre-existing renal risk factors did not appear to worsen
the effects of tenofovir.
Scherzer R, et al. AIDS 2012 [Epub ahead of print]
Switch to TDF increases bone turnover
and reduces bone mineral density
Subjects on AZT/3TC (n=54) randomized to
continue or switch to TDF/FTC
Randomization group
Continue AZT/3TC
Switch to TDF/FTC
BMD
Med. (IQR)
Within group
p-value
Med. (IQR)
Within group
p-value
Between
group p-value
Femoral neck
1.36
(-3.26, 1.63)
0.74
-1.52
(-3.04, 0.22)
0.16
0.48
Lumbar spine
-0.18
(-2.35, 1.85)
0.91
-2.04
(03.28, -0.40)
0.01
0.03
Markers of bone formation and bone resorption also
increased in TDF/FTC group
Cotter A, et al. Abstract 125LB, CROI 2012
Switching from TDF to RAL
improves BMD
Bloch, 2012
Tenofovir alafenamide fumarate (TAF):
Tenofovir pro-drug with greater antiviral activity than TDF
Dosing
Median VL Change
(log10c/mL)
0.5
Placebo (n = 7)
TDF 300 mg (n = 6)
TAF 8 mg (n = 9)
TAF 25 mg (n = 8)
TAF 40 mg (n = 8)
0.0
-0.5
-1.0
-1.5
-2.0
0
10
20
Day
• Higher intracellular tenofovir diphosphate levels and lower
circulating plasma tenofovir levels with TAF vs TDF
Ruane PJ, et al. CROI 2012. Abstract 103.
GS-US-292-0101: E/C/F/TDF vs. E/C/F/TAF
Phase 2 Study Design
Randomized, placebo-controlled, double-blind study
Treatment Arm 1 (n=100)
E/C/F/TAF QD
ART-naive
subjects (n=150)
E/C/F/TDF Placebo QD
Week 48
Randomized 2:1
Stratification by
VL >/≤100,000
Treatment Arm 2 (n=50)
E/C/F/TDF QD
E/C/F/TAF Placebo QD
Primary endpoint
--Proportion with VL < 50 at
Week 24 (Snapshot)
Zolopa, et al., CROI 2013;# 99LB
GS-US-292-0101: Virologic
Response (M=F, ITT), week 24
100
E/C/F/TDF 89.7%
% Subjects with VL <50 (M=F, ITT)
90
80
E/C/F/TAF 87.5%
70
60
50
E/C/F/TAF (n=112)
40
30
E/C/F/TDF (n=58)
20
10
0
2
4
8
12
16
24
Time (Weeks)
 Mean change from baseline CD4 count:
– E/C/F/TAF, +163
– STB, +177 (p = 0.76)
Zolopa, et al., CROI 2013; Paper # 99LB
GS-US-292-101: Median Change in
Serum Creatinine through Week 24
E/C/F/TAF
STB
Median (Q1, Q3) change from
baseline Serum Creatinine (mg/dL)
0.2
0.09 0.11
0.1
0.10
0.08
0.12
p = 0.02
0.08
0.06
0.06 0.05
0.0
0.12
0.07
0.08
-0.1
-0.2
0
12
24
Time (Weeks)
 Change in serum creatinine at Week 24
– E/C/F/TAF: 0.07 mg/dL
– E/C/F/TDF: 0.12 mg/dL (p=0.02)
Zolopa, et al., CROI 2013; Paper # 99LB
GS-US-292-102: Percent Change in Bone
Mineral Density (DEXA) at Week 24
HIP
2
0
- 0.8
p = 0.002
-2
- 2.5
0
12
Time (Weeks)
24
Mean % change in BMD
Mean % change in BMD
SPINE
2
- 0.3
0
p < 0.001
- 2.0
-2
0
12
Time (Weeks)
24
 Proportion of subjects with no decrease in BMD
– Spine: E/C/F/TAF, 38%; E/C/F/TDF, 12%
– Hip: E/C/F/TAF, 41%; E/C/F/TDF: 23%
Zolopa, et al., CROI 2013; Paper # 99LB
Single tablet regimens
PROS
forgiving of missed doses
CONS
TDF/FTC/EFV
• PK
TDF/FTC/RPV
•Better
tolerated than EFV
•Good switch data
•Recommended
TDF/FTC/
EVG/COBI
•Non-inferior
•COBI
to TDF/FTC/ EFV
•Better tolerated than EFV
• CNS
side effects
• Teratogenicity
• Resistance with interruption
• Rash
• More lipid effects than others
only if VL <100,000
•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
Single tablet regimens
PROS
forgiving of missed doses
CONS
TDF/FTC/EFV
• PK
TDF/FTC/RPV
•Better
tolerated than EFV
•Good switch data
•Recommended
TDF/FTC/
EVG/COBI
•Non-inferior
to TDF/FTC/ EFV
•Better tolerated than EFV
•COBI
ABC/3TC/DTG
•Only
•Possible
non-TDF-based STR
•Superior to TDF/FTC/EFV
(better tolerability)
• CNS
side effects
• Teratogenicity
• Resistance with interruption
• Rash
• More lipid effects than others
only if VL <100,000
•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
increased risk of MI with ABC
Why prescribe more than one tablet
in 2013?
 Boosted PI + 2 NRTIs:
– Patients with unreliable adherence
– Transmitted resistance
– Pregnancy
 RAL + 2 NRTIs:
– Few drug interactions
 ABC/3TC + 3rd agent:
– Kidney, bone disease
 NRTI-sparing regimens:
– Contrainidications to NRTIs
– Baseline NRTI resistance
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
ART: New formulations
 3 single-tablet regimens now available
 3 more in development:
– DTG/ABC/3TC
– EVG/COBI/FTC/TAF (“E/C/F/TAF”)
– DRV/COBI/FTC/TAF (“D/C/F/TAF”)
 Other possible coformulations:
– ATV/COBI
– DRV/COBI
– EVG/COBI
– TAF/FTC
Treatment-Experienced Patients
Elvitegravir Comparable to Raltegravir in
ART- Experienced Patients at Wk 96
100
 CD4 gain: +205 (EVG) vs +198
(RAL) at Wk 96
VL< 50 c/mL
(ITT, TLOVR)
EVG (n = 351)
RAL (n = 351)
Patients, %
80
60
59 58
48 45
 Similar rates of AEs overall
40
22 23
20
26
29
26 26
19 19
0
W48 W96 W48 W96 W48 W96
Virologic
Response
 Similar rates of treatmentemergent integrase resistance
in each arm (7%)
Virologic
Failure
– More diarrhea with EVG vs
RAL (13% vs 8%)
– More liver-related AEs with
RAL (1.7% vs 0.8%)
Others
Elion R, et al. International AIDS Conference 2012. Abstract TUAB105.
SAILING: Superior Virologic Suppression
With DTG vs RAL at 24 Wks
100
80
VL < 50 c/mL (%)
 Lower incidence of integrase
resistance at VF with DTG
Dolutegravir + OBR
Raltegravir + OBR
79%
70%
60
– < 2-fold change in IC50 for
both DTG and RAL
Week 24 adjusted difference
in response (95% CI):
+9.7 in favor of DTG
(3.1%, 15.9%); P = .003
40
20
– Y143, Q148, and/or N155 at VF
in 9 RAL pts; consistent with
previous studies
0
BL
4
8
12
Week
16
Pozniak A, et al. CROI 2013. Abstract 179LB.
– R263K at VF in 2 DTG pts; first
report of treatment-emergent
resistance on DTG
24
– High-level resistance to RAL
 Both regimens well tolerated
with similar AE profiles
SECOND-LINE: Treatment options after
failure of NNRTI + 2 NRTIs
 541 patients failing initial therapy randomized to:
– LPV/r + 2-3 NRTIs selected by genotype
– LPV/r + RAL
LPV/r +
NRTs
(N=271)
LPVr + RAL
(N=270)
P
VL <200
219 (81%)
223 (83%)
0.59
VL <50
191 (70%)
192 (71%)
0.56
114
150
0.01
CD4
increase
Boyd M, et al. CROI 2013. Abstract 180 LB
ACTG OPTIONS: Are NRTIs necessary
in treatment-experienced patients?
– 360 pts failing ART w/ NRTI, NNRTI, and PI resistance
or experience
– Regimen chosen based on review of ART history,
resistance, and tropism
– PSS >2 required
– Randomized to omit or include NRTIs
Omit NRTIs
N=179
Include NRTIs
N=181
Regimen failure through wk 48
53 (30%)
48 (26%)
VL <50 at wk 48
64%
68%
Severe signs/Sx or lab abnormality
67 (38%)
65 (35%)
– NRTIs not necessary if >2 active drugs included in
regimen
Tashima K, et al. CROI 2013. Abstract 153LB