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Boosted Protease Inhibitors: Current and Future Role in HIV Therapy
This activity is supported by an independent educational grant from Janssen Therapeutics
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Faculty and Disclosure Information
Sally Hodder, MDProfessor of Medicine Rutgers, New Jersey Medical SchoolNewark, New Jersey
Sally Hodder, MD, has disclosed that she has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck; has received funds for research support from Bristol-Myers Squibb, Gilead Sciences, Janssen, and ViiV; and her spouse has ownership interest in Merck.
Boosted Protease Inhibitors: Current and Future Role in HIV Therapy
Boosted Regimens: An Introduction
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60,000
AIDS-Related Mortality and Advent of PIs
Introduction of PI-containing triple ART
80,000
70,000
50,000
40,000
30,000
20,000
10,000
0
Dea
ths
(n)
Yr of Death
19
85
19
86
19
87
19
88
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20
09
20
10
CDC.gov. Epidemiology of HIV infection.
clinicaloptions.com/hivBoosted Protease Inhibitors: Current and Future Role in HIV Therapy
Milestones in the Evolution of the PI Class
PAST PRESENT(Not-too-distant)
FUTURE
Many pills per day Multiple doses necessary
Improved tolerabilitySome boosted
1 pill per day (+ RTV & NRTIs)Boosting gold standard
Manageable toxicity
More coformulations Single-tablet regimens
High toxicity
Once-daily dosingCoformulation
Some treatment-limiting toxicity
SQVRTVIDV
APVNFV
FPV/RTVLPV/RTV
ATVATV/RTVDRV/RTV
ATV/COBIDRV/COBI
DRV/COBI/TAF/FTC
SQV/RTVIDV/RTV
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Ritonavir-Boosted PIs
PIs traditionally coupled with RTV (100-400 mg QD) as a pharmacologic booster
RTV inhibits CYP3A4 in the liver, increasing PI exposure and half-life[1]
Boosting allows less frequent PI administration and lower daily dose
RTV associated with diarrhea and nausea, increased lipids, many drug–drug interactions[2]
Mea
n P
lasm
a C
on
cen
trat
ion
(S
D)
at S
tea
dy
Sta
te (
ng
/mL
)[3]
Hrs0 4 8 12 16 20 24
ATV 400 mg QD
ATV/RTV 300/100 mg QD
0
10
100
1000
10,000
Median wild-type EC90 = 14 ng/mL
1. Merry C, et al. AIDS 1997;11:F29-F33. 2. Ritonavir [package insert]. 3. Atazanavir [package insert].
Pharmacologic Boosting of ATV by RTV
clinicaloptions.com/hivBoosted Protease Inhibitors: Current and Future Role in HIV Therapy
Key Drug–Drug Interactions With RTV
Exposures Increase With RTV
Maraviroc Antiarrythmics Anticancer agents Anticonvulsants (some) Antidepressants (some) Beta-blockers Calcium channel blockers Colchicine Digoxin Erectile dysfunction drugs Glucocorticoids Methamphetamine Rifabutin Sedatives/hypnotics Statins (some)
Exposures Decrease With RTV
Anticonvulsants (some) Antidepressants (some) Bupropion Ethinyl estradiol Methadone Theophylline Rifampin
Ritonavir [package insert].
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Cobicistat: A New Boosting Agent
Small molecule with no HIV activity
Similar from BL in fasting TC and TGs compared with RTV when boosting same agent[1]
Inhibitor of and metabolized by CYP3A4; many drug–drug interactions[2,3]
Modest, rapid increase in serum Cr due to inhibition of tubular secretion[3]
– Not associated with any change in actual GFR
– Other drugs (including certain ARVs) have similar effect[4,5]
1. Gallant JE, et al. J Infect Dis. 2013;208:32-39. 2. DHHS Guidelines. May 2014. 3. TDF/FTC/EVG/COBI [package insert]. 4. Rilpivirine [package insert]. 5. Dolutegravir [package insert].
clinicaloptions.com/hivBoosted Protease Inhibitors: Current and Future Role in HIV Therapy
8000
DRV/COBI FDC Bioequivalent to DRV + RTV and to DRV + COBI PK analyses in healthy subjects
DRV Concentration When DRV and COBI Administered as Single Agents
or as Coformulation[2]
DRV Concentration When Administered as DRV + RTV or as DRV/COBI Coformulation[1]
1. Kakuda TN, et al. Clin Pharmacol. 2012. Abstract O_20. 2. Kakuda TN, et al. IAS 2013. Abstract MOPE029.
HrsPla
sma
Co
nce
ntr
atio
n o
f D
RV
(n
g/m
L;
Mea
n ±
SD
)
Hrs
DRV/RTV 800/100 mg QD as single agents (n = 32)DRV/COBI 800/150 mg QD as FDC (n = 33)DRV/COBI 800/150 mg QD as FDC (n = 33)
Single agents; fed (n = 38)FDC; fed (n = 40)Single agents; fasted (n = 72)FDC; fasted (n = 74)
6000
4000
2000
0240 6 12 18
8000
6000
4000
2000
00 4 8 12 16 20 24
clinicaloptions.com/hivBoosted Protease Inhibitors: Current and Future Role in HIV Therapy
Key Drug–Drug Interactions With COBI
Exposure Increased With COBIAntacids
Antiarrythmics
Benzodiazepines
Beta-blockers
Calcium channel blockers
Erectile dysfunction drugs
Inhaled/injectable corticosteroids
OCPs (norgestimate)
Statins
Increase COBI Exposure
Azole antifungals
Clarithromycin
Decrease COBI Exposure
Rifabutin
Carbamazepine
Phenytoin
DHHS Adult Guidelines. May 2014.
No interaction between COBI and methadone
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Creatinine Changes With Cobicistat and Ritonavir
Interpretation of changes in renal function may be problematic when using coformulations of COBI and TDF[1]
Coformulated drugs containing COBI should not be initiated in patients with estimated CrCl < 70 mL/min or used with other nephrotoxic drugs[2,3]
1. Gallant J, et al. J Infect Dis. 2013;208:32-39. 2. TDF/FTC/EVG/COBI [package insert]. 3. DHHS Guidelines. May 2014.
Ch
ang
e i
n C
reat
inin
e L
evel
, M
edia
n m
g/d
L (
IQR
)
Wks
0
-0.1
0.1
0.2
0.4
0.3
-0.2BL 12 24 36 48
COBIRTV
Boosted PIs in Treatment-Naive Patients,
Including Acute HIV Infection
clinicaloptions.com/hivBoosted Protease Inhibitors: Current and Future Role in HIV Therapy
Zolopa AR, et al. PLoS One. 2009;4:e5575.
ACTG 5164: Immediate vs Deferred ART for Acute OI
Total
PCP
Bacterial Infection
Other Ol
Fungal
Crypto
Mycobacterial
> 1 Ol
CD4+ < 50
CD4+ ≥ 50
0 0.25 0.5 20.08.02.51.0
54
28
11
42
12
8
8
30
39
15
282
181
41
194
52
41
18
148
196
86
# Events # Total
Log OR of Death/AIDS Progression
Favors Early ART Favors Deferred ART
clinicaloptions.com/hivBoosted Protease Inhibitors: Current and Future Role in HIV Therapy
Transmitted HIV Drug Resistance in MSM in 11 Jurisdictions, 2008-2011 Genotypic analysis of pol sequences of samples from 10,894 newly
diagnosed MSM pts in CDC National HIV-1 Surveillance System
Bañez Ocfemia MC, et al. CROI 2014. Abstract 579.
All cases with sequencesCases classified as recent infections (n = 3083)Cases classified as long-standing infections (n = 7810)
0
4
Transmitted Drug Resistance Mutations
1 or more
20
8
12
16
NNRTI NRTI PI
17.4
9.0
6.6
4.6
18.8
10.9
6.5
4.7
8.36.7
4.5
16.8
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DHHS Guidelines: Boosted PIs in Recommended Regimens
If initiating ART in a pt with acute/early HIV before resistance test results are available, use a boosted PI plus NRTIs due to slow emergence of PI resistance and uncommon transmitted resistance
DHHS Guidelines. May 2014.
For All Pts, Regardless of BL VL or CD4+ Count
Only for Pts With Pre-ART VL < 100,000 c/mL
NNRTI EFV/TDF/FTC EFV + ABC/3TC* RPV/TDF/FTC
Boosted PI ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC
ATV/RTV + ABC/3TC*
INSTI
RAL + TDF/FTC EVG/COBI/TDF/FTC DTG + ABC/3TC* DTG + TDF/FTC
*Only for pts who are HLA-B*5701 negative. Only for those with CD4+ cell counts > 200 cells/mm3.
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Key Considerations in Choosing RTV-Boosted PIs in First-line ART
Advantages Disadvantages
Potent activity; low rates of transmitted PI resistance
CD4+ cell count increase generally greater than with EFV
Resistance to PI rare at virologic failure
Low risk of NRTI resistance with boosted PI failure
Options (including PIs) retained for future use
Metabolic complications due to some PIs and/or low-dose RTV
GI intolerance due to some PIs and/or low-dose RTV
Potential drug–drug interactions (CYP450)
LPV/RTV currently* only coformulated PI (others in advanced development)
Current boosted PI regimens are more pills (3) than some other options
No single-tablet regimen using current preferred PIs currently* available
*Current as of July 2014
Key Clinical Data on Atazanavir/Ritonavir and
Darunavir/Ritonavir in Treatment-Naive Patients
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Atazanavir/Ritonavir Comparative Studies in Treatment-Naive Pts Randomized, noninferiority phase III studies
Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48
ART-naive ptsVL ≥ 5000 c/mL
(N = 883)
ATV/RTV + TDF/FTC (n = 440)
LPV/RTV BID* + TDF/FTC (n = 443)
*SGC until Wk 48.
ART-naive ptsVL ≥ 1000 c/mL
(N = 1857)
ATV/RTV + ABC/3TC (n = 463)
EFV + TDF/FTC (n = 464)
CASTLE[1]
(open label)
ACTG 5202[2]
(third agent, open label; NRTIs prematurely unblinded)
ATV/RTV + TDF/FTC (n = 355)
EVG/COBI/TDF/FTC (n = 353)
ART-naive ptsVL ≥ 5000 c/mL
eGFR ≥ 70 mL/min(N = 708)
GS-103[3]
(placebo controlled)
1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Daar E, et al. Ann Intern Med. 2011;154:445-456. 3. De Jesus E, et al. Lancet. 2012;379:2429-2438.
ATV/RTV + TDF/FTC (n = 465)
EFV + ABC/3TC (n = 465)
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CASTLE: ATV/RTV vs LPV/RTV in Naive Pts Through 96 Wks
ATV/RTV noninferior to LPV/RTV at Wk 48[1]; superior at Wk 96[2]
– Results consistent across BL HIV-1 RNA, CD4+ cell count, subgroups
VF in 7% of each arm by Wk 96
– 1 pt in ATV/RTV arm with major PI mutation at Wk 96 vs 0 in LPV/RTV arm; NRTI resistance in 7 vs 10, respectively
Treatment-related study d/c: 3% in each arm at Wk 96
Similar CD4+ cell count increase: +268 (ATV/RTV) vs +290 (LPV/RTV) at Wk 96
0
20
40
60
80
100
Wk 96
6874
Wk 48
7678
1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Molina JM, et al. J Acquir Immune Defic Syndr. 2010;53:323-332.
Δ 1.7% (-3.8 to 7.1)
P = NS
LPV/RTV = TDF/FTC (n = 443)
ATV/RTV + TDF/FTC (n = 440)
Δ 6.1% (0.3 to 12.0)
P < .05
343/440
338/443
327/440
302/443n/N =
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A5202: Efficacy With ATV/RTV vs EFV
Similar time to VF with ATV/RTV vs EFV, whether with TDF/FTC or ABC/3TC
Time to safety (P = .048) and tolerability (P < .001) endpoints shorter with EFV when paired with ABC/3TC but not when with TDF/FTC
Similar CD4+ count increase with ATV/RTV vs EFV when paired with ABC/3TC (+250 vs +251) but greater when paired with TDF/FTC (+252 vs +221)
Less resistance at VF with ATV/RTV vs EFV
Daar ES, et al. Ann Intern Med. 2011;154:445-456. Sax PE, et al. J Infect Dis. 2011;204:1191-1201.
EFV + TDF/FTC (57 events)ATV/RTV + TDF/FTC (57 events)EFV + ABC/3TC (72 events)ATV/RTV + ABC/3TC (83 events)
*Interim analysis showed time to VF shorter with ABC/3TC in pts with BL VL > 100,000 c/mL
0 4 16 36 8460 108 156132 180
1.0
0.8
0.6
0
0.2
0.4
8 24 48 72 96 144 168120
Wks From Randomization
Cu
mu
lati
ve P
rob
abili
ty o
f V
F
Resistance at Wk 96
Pts With Resistance, n
EFV Arms ATV/RTV Arms
NRTI 36 16
NNRTI 68 1
NRTI + NNRTI 36 0
PI resistance 0 1
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EVG/COBI/TDF/FTC Noninferior to ATV/RTV + TDF/FTC Through Wk 144
EVG/COBI arm noninferior to ATV/RTV arm at Wk 48 primary endpoint[1] and through Wk 144[2,3]
– Results consistent across subgroups: BL HIV-1 RNA, CD4+ count, adherence, age, sex, race
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 vs7% in ATV/RTV arm at Wk 144
– 8 pts with resistance (NRTI + INSTI) in EVG/COBI arm vs 2 (PI only) in ATV/RTV arm at Wk 144
Similar CD4+ count increase at Wk 144: +280 (EVG/COBI) vs +293 (ATV/RTV)
1. DeJesus 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 (n = 353)
ATV/RTV + TDF/FTC (n = 355)
Δ 3.0% (-1.9 to 7.8) Δ 1.1%
(-4.5 to 6.7)
Wk 48 Wk 144
78 75
0
20
40
60
80
10090 87
Δ 3.1% (-3.2 to 9.4)
8382
Wk 96
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Lipid Changes From BL to Wk 48
This slide is an illustration only and not meant to be a cross-study comparison.
10 81111
568
23
P = .006
ATV/RTVEVG/COBI
Study 103[3]
EFV + TDF/FTCATV/RTV + TDF/FTC
P < .001
ACTG 5202[2]
P < .0001
ATV/RTVLPV/RTV
17
38
1117
2732 14
58
P < .0001
CASTLE[1]
TC LDL HDL TG
Me
dia
n C
ha
ng
e
(mg
/dL
)
0
10
20
30
40
50
60
70
TC LDL HDL TG
Me
dia
n C
ha
ng
e
(mg
/dL
)
0
10
20
30
40
50
60
70
TC LDL HDL TG
Me
dia
n C
ha
ng
e
(mg
/dL
)
0
10
20
30
40
50
60
70
22
10
40
1512
2113
24
1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Daar E, et al. Ann Intern Med. 2011;154:445-456.. 3. De Jesus E, et al. Lancet. 2012;379:2429-2438.
10 82
514
813
29
EFV + ABC/3TCATV/RTV + ABC/3TC
P < .001P < .001
P < .001
P < .001
P = .002
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ATV/RTV Adverse Events Summary
ATV/RTV vs LPV/RTV[1,2]:
– More rash
ATV/RTV vs EFV[3]:
– Decrease in CrCl (with TDF/FTC) vs increase with EFV; fewer CNS events
– Substudy[4]: greater loss in spine (not hip) BMD
All studies:
– More jaundice and hyperbilirubinemia
– Overall low rate (5% to 9%) of moderate to severe jaundice/scleral icterus in clinical studies of ATV/RTV[5]
1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Molina JM, et al. J Acquir Immune Defic Syndr. 2010;53:323-332. 3. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 4. McComsey G, et al. J Infect Dis. 2011;203:1791-1801. 5. Atazanavir [package insert].
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ACTG 5202 Substudy: Loss of Bone With EFV vs ATV/RTV Initiation
Change in Spine BMD Change in Hip BMD
McComsey G, et al. J Infect Dis. 2011;203:1791-1801.
0
-5
-1
-2
-3
-4
1920 24 48 96 144
Visit Wk From Randomization
EFVATV/RTV
133125
117116
109102
10791
8681
5848
P = .035
EFVATV/RTV
0
-5
-1
-2
-3
-4
1920 24 48 96 144
Visit Wk From Randomization
EFVATV/RTV
131123
114114
107101
10590
8180
5948
P = .61
Ch
ang
e F
rom
BL
(%
)
Ch
ang
e F
rom
BL
(%
)
clinicaloptions.com/hivBoosted Protease Inhibitors: Current and Future Role in HIV Therapy
DRV/RTV Comparative Studies in Treatment-Naive Pts Randomized, noninferiority phase III studies
Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48
ART-naive ptsVL ≥ 5000 c/mL
(N = 689)
DRV/RTV + TDF/FTC (n = 343)
LPV/RTV QD or BID + TDF/FTC (n = 346)
*Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC.
ARTEMIS[1,2]
(open label)
DTG + 2 NRTIs*(n = 242)
DRV/RTV + 2 NRTIs*(n = 242)ART-naive pts
VL ≥ 1000 c/mL(N = 484)
FLAMINGO[3]
(open label)
1. Ortiz R, et al. AIDS. 2008;22:1389-1397. 2. Mills A, et al. AIDS. 2009;23:1679-1688. 3. Clotet B, et al. Lancet. 2014;[Epub ahead of print].
No phase III clinical trial comparison with EFV
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ARTEMIS: DRV/RTV vs LPV/RTV in Naive Pts Through 96 Weeks
DRV/RTV noninferior to LPV/RTV at Wk 48; superior at Wk 96
– Efficacy results better in DRV/RTV arm among those with BL VL > 100K (P = .023) c/mL and CD4+ < 200 (P = .009)
VF in 1% of DRV/RTV arm vs 2% of LPV/RTV by Wk 96
– No major PI mutations in either arm at Wk 96; NRTI mutations in 2 pts in DRV/RTV arm vs 5 in LPV/RTV arm
Treatment-related study d/c: 4% in DRV/RTV arm vs 9% in LPV/RTV arm at Wk 96
CD4+ count increase at Wk 96: +171 (DRV/RTV) vs +188 (LPV/RTV)
Significantly smaller mean change in TC and TG at Wk 48 with DRV/RTV
0
20
40
60
80
100
717978
84
Wk 48[1] Wk 96[2]
1. Ortiz R, et al. AIDS. 2008;22:1389-1397. 2. Mills A, et al. AIDS. 2009;23:1679-1688.
LPV/RTV + TDF/FTC (n = 346)
DRV/RTV + TDF/FTC (n = 343)
Δ 8.4% (1.9-14.8)
P < .001 noninferiorityP < .012 superiority
Δ 5.6% (-0.1 to 11.0)
P < .001 noninferiority
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FLAMINGO: DTG vs DRV/RTV + 2 NRTIs in Naive Patients at Wk 48
DTG superior to DRV/RTV at Wk 48 primary efficacy endpoint
– Efficacy results better in DTG arm among pts with BL VL > 100K
VF < 1% (n = 2) in each arm at Wk 48
– No pts with resistance in either arm at Wk 48
Treatment-related study d/c: 2% in DTG arm vs 4% in DRV/RTV arm
Same CD4+ cell count increase at Wk 48: +210 cells/mm³ in each arm
Mean increase in fasting LDL-C at Wk 48 significantly lower in DTG arm than DRV/RTV arm (P < .0001)
HIV
-1 R
NA
< 5
0 c/
mL
at
Wk
48 (
%)
9083
Δ +7.1%(0.9-13.2; P = .025)
Clotet B, et al. Lancet. 2014;[Epub ahead of print].
DTG 50 mg QD + NRTIs
DRV/RTV 800/100 mg QD
+ NRTIs
217/242
200/242
0
20
40
60
80
100
clinicaloptions.com/hivBoosted Protease Inhibitors: Current and Future Role in HIV Therapy
DRV/RTV Adverse Events Summary
DRV/RTV vs LPV/RTV[1]
– At Wk 96, significantly more diarrhea with LPV/RTV; more rash in DRV/RTV arm (3% vs 1%, not significant)
DRV/RTV vs DTG[2]
– More diarrhea with DRV/RTV; more headache with DTG
– Small, rapid increase in serum creatinine in first 4 wks of treatment with DTG related to inhibition of tubular secretion of creatinine by DTG
1. Mills A, et al. AIDS. 2009;23:1679-1688. 2. Clotet B, et al. Lancet. 2014;[Epub ahead of print].
Key Drug–Drug Interactions With ATV/RTV and DRV/RTV
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Drug–Drug Interactions With First-line Boosted PIs and Lipid-Lowering Therapy
Antiretroviral Contraindicated Titrate Dose No Dose Adjustment
ATV/RTVLovastatin
SimvastatinAtorvastatinRosuvastatin
Pitavastatin
DRV/RTVLovastatin
Simvastatin
AtorvastatinPravastatin
RosuvastatinPitavastatin
DHHS Adult Guidelines. May 2014.
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First-line Boosted PI Drug–Drug Interactions With OCPsAntiretroviral Effect on OCP Dosing Recommendation
ATV/RTV[1,2] Ethinyl estradiol AUC 19%Norgestimate AUC 85%
OCP should contain ≥ 35 mcg ethinyl estradiol
DRV/RTV[1,2] Ethinyl estradiol AUC 44%Norethindrone AUC 14%
Additional methods of contraception recommended
1. DHHS Adult Guidelines. May 2014. 2. DHHS Perinatal Guidelines. March 2014.
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First-line Boosted PI Drug–Drug Interactions With Acid-Reducing Agents
ARV Antacids H2-Receptor AntagonistsProton Pump
Inhibitors
ATV/RTV
Give ATV ≥ 2 hrs before or
1 hr after antacids orbuffered medications
Give ATV/RTV simultaneously with and/or ≥ 10 hrs after the H2-receptor antagonist
If using TDF and H2-receptor antagonist in ART-experienced pts, use ATV/RTV 400/100 mg
Use dose equivalent of famotidine ≤ 40 mg BID in ART-naive pts or ≤ 20 mg BID in ART-experienced pts
PPIs should be administered at least12 hrs before ATV/RTV
PPIs not recommended in PI-experienced pts
Use dose equivalent of omeprazole ≤ 20 mg daily in PI-naive pts
DRV/RTVNo clinically relevant
interactionsNo clinically relevant
interactionsNo clinically relevant
interactions
DHHS Adult Guidelines. May 2014.
ACTG 5257: Comparison ofATV/RTV vs RAL vs DRV/RTV
in First-line Therapy
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ACTG 5257: Open-Label ATV/RTV vs RAL vs DRV/RTV in First-line ART
Primary endpoints
– VF: time to HIV-1 RNA > 1000 c/mL (at Wk 16 or before Wk 24) or > 200 c/mL (at or after Wk 24)
– TF: time to discontinuation of randomized component for toxicity
Composite endpoint: the earlier occurrence of either VF or TF in a given participant
Switch of regimens allowed for tolerabilityLandovitz R, et al. CROI 2014. Abstract 85.
ART-naive patients with HIV-1 RNA ≥ 1000 c/mL
(N = 1809)
ATV/RTV 300/100 mg QD +TDF/FTC(n = 605)
RAL 400 mg BID +TDF/FTC(n = 603)
Stratified by HIV-1 RNA < or ≥ 100,000 c/mL, participation in
metabolic substudy, CV risk
DRV/RTV 800/100 mg QD +TDF/FTC(n = 601)
Wk 96 after last patient enrolled
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ACTG 5257: Primary Endpoint Analyses at Wk 96
Regimens equivalent in time to VF
Landovitz R, et al. CROI 2014. Abstract 85. Reproduced with permission.
Significantly greater incidence of treatment failure with ATV/RTV vs RAL or DRV/RTV
– In part due to high proportion of pts with hyperbilirubinemia
Considering both efficacy and tolerability, RAL superior to either boosted PI
DRV/RTV superior to ATV/RTV
Virologic Failure Tolerability Failure Composite Endpoint
Difference in 96-Wk Cumulative Incidence (97.5% CI)
0-10 10 20
ATV/RTV vs RAL3.4% (-0.7 to 7.4)
DRV/RTV vs RAL5.6% (1.3-9.9)
ATV/RTV vs DRV/RTV-2.2% (-6.7 to 2.3)
ATV/RTV vs DRV/RTV9.2% (5.5-13.0)
0-10 10 20
ATV/RTV vs RAL13% (9.4-16.0)
DRV/RTV vs RAL3.6% (1.4-5.8)
Favors RAL
Favors DRV/RTV
0-10 10 20
ATV/RTV vs RAL15% (10-20)
DRV/RTV vs RAL7.5% (3.2-12.0)
ATV/RTV vs DRV/RTV7.5% (2.3-13.0)
Favors RAL
Favors DRV/RTV
Favors RAL
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89%
ACTG 5257: Virologic Efficacy
In ITT analysis with ART changes allowed (per protocol), regimens similar in virologic efficacy at Wk 96 and through Wk 144
In ITT analysis when change = failure (Snapshot), RAL superior to both boosted PIs at Wk 96 and DRV/RTV superior to ATV/RTV at Wks 96 and 144
Mean change in CD4+ count across arms– ATV/RTV (+284); RAL (+288)
DRV/RTV (+256) cells/mm3
1.0
Pro
po
rtio
n W
ith
HIV
-1 R
NA
≤ 5
0 c
/mL
0.8
0.6
0.4
0.2
0
ITT, Regardless of ART Change
0 24 48 64 80 96 120 144
1.0
0.8
0.6
0.4
0.2
0
ITT, NC = Failure (Snapshot)
RALDRV/RTVATV/RTV
Study Wk
0 24 48 64 80 96 120 144
88%
94%
63%73%80%
RALDRV/RTVATV/RTV
Landovitz R, et al. CROI 2014. Abstract 85. Reproduced with permission.
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ACTG 5257: Resistance
VF with drug resistance occurred more often in patients initially assigned to RAL[1]
– 3% randomized to RAL had ≥ 1 resistance mutation and 1.8% had INSTI mutations
– 1.5% randomized to ATV/RTV and < 1% randomized to DRV/RTV developed resistance
– No major PI mutations observed
1. Landovitz R, et al. CROI 2014. Abstract 85.
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ACTG 5257: Mean Change From BL in Fasting Lipids
30
20
10
00 24 48 96 144
15
10
5
0
-50 24 48 96 144
0 24 48 96 144
0 24 48 96 144
10.0
7.5
5.0
2.5
0
40
20
0
-20
Study Wk
Ch
ang
e (
mg
/dL
)
Fasting TC
Study Wk
Fasting LDL-C
Study Wk
Fasting TG
Study Wk
Fasting HDL-C
ATV/RTV RAL DRV/RTV
Ofotokun I, et al. CROI 2014. Abstract 746.
Ch
ang
e (
mg
/dL
)
Ch
ang
e (
mg
/dL
)
Ch
ang
e (
mg
/dL
)
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ACTG 5257: Loss of BMD With First-line Boosted PI vs RAL All arms associated with
significant loss of BMD through Wk 96 (P < .001)
At hip and spine, similar loss of BMD in the PI arms
– Significantly greater loss in the combined PI arms than in the RAL arm
ATV/RTV RALDRV/RTVCombined PI arms
-5
-4
0
-3
-2
-1
-3.9-3.4
-3.7
-2.4
-1.8
-4.0-3.8
-3.6
P = .36
Total Hip Total Spine
P = .005
P = .42
P < .001
Brown T, et al. CROI 2014. Abstract 779LB. Reproduced with permission.
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PI Resistance Rare at VF in First-line Studies of Boosted PIsStudy n PI Wk Genotypes Major PI Mutations
CASTLE[1] 440443
ATV/RTVLPV/RTV
962626
10
ACTG 5202[2] 463465
ATV/RTV 968357
10
Study 103[3] 355 ATV/RTV 144 NR 0
ARTEMIS[4] 343346
DRV/RTVLPV/RTV
963146
00
FLAMINGO[5] 242 DRV/RTV 48 NR 0
ACTG 5257[6] 605601
ATV/RTVDRV/RTV
967599
00
1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Daar ES, et al. Ann Intern Med. 2011;154:445-456.3. Clumeck N, et al. EACS 2013. Abstract LBPS7/2. 4. Mills A, et al. AIDS. 2009;23:1679-1688. 5. Clotet B, et al. Lancet. 2014;[Epub ahead of print]. 6. Landovitz R, et al. CROI 2014. Abstract 85.
Among 4303 pts in these trials, only 2 pts developed major PI mutations at initial VF
Special Considerations: Boosted PIs in Pregnancy and
First Failure
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Antiretroviral Agents and Pregnancy
Guideline Categorization
NRTI NNRTI PIEntry
InhibitorINSTI
Fusion Inhibitor
Preferred
ABC/3TC*TDF/FTC or
3TC ZDV/3TC‡
EFV§ LPV/RTV¶
ATV/RTV
Alternative NVP‖ DRV/RTVSQV/RTV**
RAL
Insufficient data RPV FPV/RTV MVCDTG
EVG/COBI
Not recommended‡‡
ABC/3TC/ZDVd4Tddl
ETR
IDV/RTVNFVRTVTPV
T20
DHHS Perinatal Guidelines. March 2014.
*Should not be used in pts who are HLA-B*5701 positive. TDF combinations should be used with caution in pts with renal insufficiency. ‡Most experience for use in pregnancy but potential for hematologic toxicity. §After first 8 wks of pregnancy. Preferred when potential for drug–drug interactions with PI a problem. ¶Once-daily administration not recommended for pregnant pts. ‖Use with caution in pts with CD4+ counts > 250 cells/mm3 due to potential for liver toxicity; use with caution with ABC since both associated with potential for HSR. **Baseline EKG recommended; contraindicated in pts with preexisting cardiac condition. Limited data on use in pregnancy, but may be considered when drug–drug interactions with PI regimens are a concern. ‡‡Because of toxicity, lower rates of virologic suppression or lack of data in naive pts.
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Antiretroviral Pregnancy Registry: Birth Defects With First Trimester Exposure Enrolls ~ 1300 women exposed
to ART each yr (80% US)
18,488 live births with follow-up data through July 2013
– 7790 with first trimester exposure
Overall birth defect prevalence comparable to CDC population–based surveillance data: 2.9 per 100 live births vs 2.7
Commonly used PIs not associated with increased birth defect rate
Antiretroviral Pregnancy Registry. Interim Report. December 2013.
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PI-Based ART and Preterm Delivery
Mma Bana (study of HAART for PMTCT, N = 530)
– PI-based HAART (ZDV/3TC + LPV/RTV) associated with 2-fold higher rate of preterm delivery than triple-NRTI HAART, but no increase in infant morbidity or mortality through 6 mos of life[1]
Retrospective US analysis
– Among 161 HIV-infected women in US with singleton pregnancies (n = 53 on PI-based ART, 84 on non–PI-based ART, 6 on no ART), no association between PI and premature birth or low birth weight[2]
1. Powis K, et al. J Infect Dis. 2011;204 :506-514. 2. Dola CP, et al. J Perinat Med. 2011;40:51-55.
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ACTG 5202: Efficacy and Tolerability by Sex With EFV and ATV/RTV Of 1857 pts, 322 were women
Women on ATV/RTV arm had a higher risk of VF with either NRTI backbone
ATV/RTV and EFV did not differ significantly by sex in safety and tolerability measures
Women on ABC/3TC had a significantly higher (32%) safety risk compared with men
With TDF/FTC, the safety risk was 20% larger for women compared with men (not statistically significant)
Self-reported adherence similar between sexes
Smith K, et al. Clin Infect Dis. 2014;58:555-563.
VF(all)VF (univariate)
ATV/RTVEFV
VF (multivariate)ATV/RTVEFV
Grade 3/4 Safety (all)Grade 3/4 Safety (univariate)
ATV/RTVEFV
Tolerability (all)Tolerability (univariate)
ATV/RTVEFV
1.05 (0.70-1.58)
1.70 (1.01-2.87)0.63 (0.33-1.20)
1.72 (0.99-2.99)0.51 (0.25-1.02)1.32 (1.03-1.70)
1.44 (0.98-2.10)1.20 (0.86-1.68)0.86 (0.64-1.16)
0.85 (0.52-1.37)0.82 (0.57-1.19)
.017
.006
.035.49
.31
.92
Women vs Men P Value
Men at Higher Risk Women at Higher Risk0.17 1.00 6.00
HR (95% CI) With ABC/3TC
VF (all)VF (univariate)
ATV/RTVEFV
VF (multivariate)ATV/RTVEFV
Grade 3/4 Safety (all)Grade 3/4 Safety (univariate)
ATV/RTVEFV
Tolerability (all)Tolerability (univariate)
ATV/RTVEFV
1.74 (1.13-2.69)
2.69 (1.54-4.70)1.00 (0.49-2.05)
2.36 (1.30-4.26)0.88 (0.42-1.84)
1.20 (0.88-1.62)
1.38 (0.91-2.08)1.03 (0.66-1.61)1.11 (0.81-1.52)
1.17 (0.75-1.83)1.07 (0.68-1.67)
.028
.034
.26
.35
.51
.78
P Value
Men at Higher Risk Women at Higher Risk0.17 1.00 6.00
HR (95% CI) TDF/FTC
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SECOND-Line: Boosted PI ART After First-line VF on an NNRTI-Based Regimen Randomized, multinational, open-label noninferiority phase IIIb/IV trial
Primary endpoint: HIV-1 RNA < 200 copies/mL at Wk 48
LPV/RTV + RAL (n = 270)
LPV/RTV + 2-3 NRTIs* (n = 271)
HIV-infected ptswith VF on first-line regimen of NNRTI +
2 NRTIs(N = 541)
Δ -1.8% (-4.7 to 8.3)
HIV
-1 R
NA
< 2
00 c
/mL
at
Wk
48 (
%)
83 81
223 2190
20
40
60
80
100
n =
*77% received 2 NRTIs; 23% received 3 NRTIs. Most common NRTIs: TDF, 81%; FTC/3TC, 87%; ZDV, 45%
Wk 48 Wk 96
Boyd MA, et al. Lancet. 2013;381:2091-2099.
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In Pts With Isolated M184V, (3TC or FTC) + NRTI + bPI Sufficient for Suppression Retrospective analysis of pts
with M184V mutation in British Columbia HIV Drug Treatment Program, 2000-2006
Pts categorized by regimen after identification of M184V
– 3TC or FTC + NRTI + bPI (n = 48)
– 3TC or FTC + NRTI + bPI + another ART agent (n = 25)
– 3TC/FTC-sparing: 2 NRTIs + bPI ± another ART agent (n = 44)
Neither failed regimen nor subsequent regimen associated with time to HIV-1 RNA suppression
Factor Associated With Virologic Suppression
HR (95% CI)
IDU history 0.37 (0.24-0.59)
Regimen failed at M184V detection
NNRTI based Reference
bPI based 0.77 (0.42-1.41)
Other 1.37 (0.83-2.26)
Subsequent regimen
(3TC or FTC) + NRTI + bPI Reference
(3TC or FTC) + NRTI + bPI + additional active agent(s)
1.09 (0.60-1.96)
(3TC or FTC)-sparing: 2 NRTIs + bPI ± additional agents
0.61 (0.37-1.03)
≥ 95% adherence 6 mos after study start, %
2.40 (1.31-4.43)
Hull M, et al. ICAAC 2009. Abstract H-916.
Summary and Future Directions:Potential for New Coformulations
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ATV/COBI + TDF/FTC Noninferior to ATV/RTV + TDF/FTC Through Wk 48 Randomized, double-blind, phase III trial in ART-naive patients
– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48
Gallant JE, et al. J Infect Dis. 2013;208:32-39.
ART-naive pts, HIV-1 RNA
≥ 5000 c/mL, eGFR ≥ 70
mL/min(N = 692)
TDF/FTC + ATV/COBI(n = 344)
TDF/FTC + ATV/RTV(n = 348)
Wk 48Wk 24 ATV/COBIATV/RTV
Δ -2.2% (-7.4 to 3.0)
Virologic Success*
Virologic Failure
Pat
ien
ts (
%)
85 87
293 3040
20
40
60
80
100
5.8 4.09.0 8.6
6
20 14
No Data
n = 31 30
*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithmDiscontinued for AE, death, or missing data.
Coformulation of ATV and COBI being considered for approval by FDA
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Ongoing Studies of COBI-Boosted DRV Plus 2 NRTIs Phase IIIb study in tx-naive tx-exp’d
pts with no DRV RAMs[1]
– Primary endpoint: grade 3 or grade 4 AEs by Wk 24
– Secondary endpoints: HIV-1 RNA at Wk 24 and Wk 48
Randomized, double-blind phase II trial[2]
– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 24
Pts with HIV-1 RNA≥ 500; naive or on stable ART for 12
wks and sensitive to 2 NRTIs with no
DRV RAMS(N = 300)
DRV + COBI + 2 NRTIs
Wk 48
1. ClinicalTrials.gov. NCT01440569. 2. ClinicalTrials.gov. NCT01565850.
ART-naive pts, HIV-1 RNA
≥ 5000 c/mL,
eGFR ≥ 70 mL/min(N = 150)
DRV/COBI/TAF/FTC QD
(n = 75)
DRV/COBI + TDF/FTC(n = 75)
Wk 48Wk 24
Wk 24
Coformulation of DRV and COBI being considered for approval by FDA
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Boosted Atazanavir: Advantages and Disadvantages
Advantages Disadvantages
Efficacy comparable to EFV at Wk 96[1]
Favorable lipid profile[2,3]
Low risk of resistance at failure[1-3]
Pill burden similar to DRV/RTV—lowest among boosted PIs
Can be given unboosted Once-daily dose requires only RTV
100 mg/day Currently being studied as
coformulated boosted PI with cobicistat[4]
Higher rates of treatment failure than DRV/RTV and RAL in ACTG 5257 due to tolerability[5]
Associated with increase in unconjugated bilirubin and scleral icterus in 4% to 9% of patients[6]
Absorption impaired with acid-reducing agents[6]
Food requirement for dosing[6]
No plans for single-tablet regimen
1. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 2. Molina JM, et al. Lancet. 2008;372:646-655. 3. Molina JM, et al. J Acquir Immune Defic Syndr. 2010;53:323-332. 4. Gallant JE, et al. J Infect Dis. 2013;208:32-39. 5. Landovitz R, et al. CROI 2014. Abstract 85. 6. Atazanavir [package insert].
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Boosted Darunavir: Advantages and Disadvantages
Advantages Disadvantages
Favorable lipid profile[1,2]
Low risk of resistance at failure[1,2]
Pill burden similar to ATV/RTV—lowest among boosted PIs
Lower risk of treatment failure than ATV/RTV in ACTG 5257[3]
Once-daily dose requires only RTV 100 mg/day[5]
Currently being studied as coformulated boosted PI with cobicistat and single-tablet regimen
Rash in ~ 6% of patients; use with caution in patients with sulfa allergy[4]
Inferior to DTG in Flamingo study[5]
Cannot be given unboosted
1 Ortiz R, et al. AIDS. 2008;22:1389-1397. 2. Mills AM, et al. AIDS. 2009;23:1679-1688. 3. Landovitz R, et al. CROI 2014. Abstract 85. 4. Darunavir [package insert]. 5. Clotet B, et al. Lancet. 2014;[Epub ahead of print].
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Conclusions
Boosted PIs appropriate for many ART-naive and treatment-experienced patients
Long history of clinical experience with this class
Low prevalence of transmitted resistance
High levels of virologic suppression in first-line therapy
No major PI resistance at initial VF in many clinical trials
Newer preferred PIs have improved metabolic profile
Ritonavir and cobicistat associated with many drug–drug interactions
Newer booster, cobicistat, may offer new opportunities for coformulation with a concomitant decrease in pill burden
Go Online for More Educational Content on Boosted Protease
Inhibitors!Interactive Virtual Presentation featuring streaming narration of these slides and case studies illustrating the use of boosted protease inhibitors across the treatment spectrum by expert faculty Sally Hodder, MD
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