Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients.2014

Evolving Switch Strategies for
Virologically Suppressed
HIV-Infected Patients
This activity is supported by an independent educational
grant from Gilead Sciences.

Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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Program Director
David A. Wohl, MD
Associate Professor of Medicine
School of Medicine
Site Leader, AIDS Clinical Trials Unit-Chapel Hill
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Co-Director for HIV Services
North Carolina Department of Correction
Raleigh, North Carolina
David A. Wohl, MD, has disclosed that he has received consulting
fees from Gilead Sciences and Janssen and funds for research
support from Gilead Sciences, Merck, and ViiV.

Other Faculty Who Contributed to This
Program
Oluwatoyin Adeyemi, MD
Associate Professor of
Medicine
Department of Internal
Medicine/Infectious Diseases
Rush University Medical Center
Attending Physician, Infectious
Diseases
Co-Director, Hepatitis Clinic
Ruth Rothstein CORE Center
and Stroger Hospital
Cook County Health and
Hospital System
Chicago, Illinois
José R. Arribas, MD
Research Director (HIV and
Infectious Diseases)
Hospital La Paz. IdiPAZ.
Madrid, Spain

Other Faculty Who Contributed to This
Program
Joseph J. Eron, Jr., MD
Professor of Medicine and
Epidemiology
University of North Carolina
School of Medicine
Director, AIDS Clinical Trials
Unit
University of North Carolina
Chapel Hill, North Carolina
Anton L. Pozniak, MD,
FRCP
Consultant Physician
Director of HIV Services
Department of HIV and
Genitourinary Medicine
Chelsea and Westminster
Hospital NHS Trust
London, United Kingdom

Faculty Disclosures
Oluwatoyin Adeyemi, MD, has disclosed that she has received consulting fees
from Bristol-Myers Squibb and Gilead Sciences.
José R.Arribas, MD, has disclosed that he has received consulting fees from
AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Tobira, and
ViiV.
Joseph J. Eron, Jr., MD, has disclosed that he has received consulting fees from
AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Merck,
Tibotec/Janssen, and Tobira; has received funds for research support paid to the
University of North Carolina from GlaxoSmithKline/ViiV; and has served on a data
and safety monitoring board for Vertex.
Anton L. Pozniak, MD, FRCP, has disclosed that he has received consulting
fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Merck, Tobira, and
ViiV; has received fees for non-CME/CE services received directly from a
commercial interest or their agents (eg, speaker bureaus) from Gilead Sciences;
and has received funds for research support from Bristol-Myers Squibb, Gilead
Sciences, and ViiV.

Background on
Switching Strategies

Why Switch ART in Virologically
Suppressed Patients?
 Convenience
– Reduce pill count/dosing frequency
– Adjust food restrictions
 Tolerability
– Eliminate/reduce adverse effects
 Drug–drug interactions
– Avoid deleterious interactions with non-HIV medications
 Pregnancy
– Reduce risk of teratogenicity
– Achieve adequate drug levels
 Cost
– To patient (copays)
– To healthcare system (generics, competitive pricing, discounts)
DHHS. Adult antiretroviral guidelines, May 2014.

DHHS ART Treatment Guidelines 2014
DHHS. Adult antiretroviral guidelines, May 2014.

Why Switch ART in Virologically
Suppressed Patients?
 Potential drawbacks
– Exposure to new agents risks new toxicities
– If any previous resistance or history of resistance, switching
even if undetectable can be an issue
– Inability to adjust dose of a component if necessary when
switching to a fixed-dose formulation
– Potential for pharmacy/patient error
– Can be more expensive
– “If it ain’t broke, don’t fix it”

Principles of ART Switch
 Maintain viral suppression (do no harm or don’t mess up)
 Need to know beforehand
– Previous ART history
– Previously demonstrated or possible/probable ARV resistance based on
history
– Drug-resistant virus remains archived in latently infected cells and does not
disappear even if not detected by resistance tests
– Likelihood of patient adherence to new regimen and its requirements
– Patient acceptance of any new potential adverse effects
– Other mediations for potential DDIs
– Affordability
 Use available evidence to guide switch decisions

STRATEGY-NNRTI: Switch to
EVG/COBI/TDF/FTC in Suppressed Pts
 Randomized, open-label switch study in pts virologically suppressed on an
NNRTI + TDF/FTC regimen for ≥ 6 mos
 Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48
HIV-1 RNA < 50 c/mL,
£ 2 previous regimens, no
resistance to FTC or TDF
and CrCl ≥ 70 mL/min
(N = 434)
Switch to EVG/COBI/TDF/FTC QD
(n = 291)
Remain on NNRTI + TDF/FTC
(n = 143)
*Pts with previous VF ineligible.
Pozniak A, et al. CROI 2014. Abstract 553LB.

STRATEGY-NNRTI: Change to EVG/COBI
Noninferior to Stable NNRTIs at Wk 48
 Regimens: EFV, 78%; NVP, 17%;
RPV, 4%; ETR, < 1%; 74% on
EFV/TDF/FTC; 91% on first
regimen
 Results similar across all baseline
virologic and demographic
subgroups
 3 pts with VF in EVG/COBI arm
and 1 in NNRTI arm
– No pts with resistance in either arm
 5 in the switch arm and 1 in the
NNRTI arm discontinued due to
adverse event
Patients (%)
Δ +5.3%
(95% CI: -0.5 to +12)
93 88
EVG/COBI/TDF/FTC
(n = 290)
Stable NNRTIs
(n = 143)
100
80
60
40
20
0
13
< 1
1
6
11
271 126 16 16
Virologic
Success*
Virologic
Nonresponse
No Data
n =
*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm
Discontinued for AE, death, or missing data.
Pozniak A, et al. CROI 2014. Abstract 553LB. Reproduced with permission.

STRATEGY-NNRTI: Outcomes in Patients
Switching from EFV-based Therapy
Subject Reporting Symptoms (%)
HIV Symptom Index
Vivid Dreams Insomnia Anxiety Dizziness
100
61
136
224
Baseline
EVG/COBI/TDF/FTC
NNRTI + TDF/FTC
64 64
53
48 47 46
* †
35
75
212
65
101
56
87
119
224
†
40
84
209
48
100
41
87
103
222
71
208
40
100
34
87
Wk 48
EVG/COBI/TDF/FTC
NNRTI + TDF/FTC
90
225
*
49
211
37
99
32
87
BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48
70
60
50
40
30
20
10
0
 Subjects who switched to EVG/COBI/TDF/FTC from EFV + TDF/FTC had
– Lower rates of neuropsychiatric symptoms at Wk 48 compared with baseline
– Higher treatment satisfaction scores at Wk 24 (mean: 21 vs 14; P < .001)‡
*P < .001, †P < .01 (comparison with baseline within treatment group). Decreases noted at Wk 4 & sustained through Wk 48.
P < .001, vivid dreams & P < .01, dizziness (comparison of changes from baseline at Wk 48 between treatment group).
‡HIV Treatment Satisfaction questionnaire, score range: -30 to 30.
Pozniak A, et al. Lancet Infect Dis. 2014;14:590-599.
34
40 39 40 37 37
23

Increased Risk of Suicidality Associated
With EFV as First-Line ART
 Randomization to EFV-based initial ART associated with 2-fold increase in
hazard of suicidality* vs EFV-free ART among patients in 4 ACTG studies
(A5095, A5142, A5175, A5202)
Overall
Study
A5095
A5142
A5175
A5202
Region
US
Multinational
47/5817
6/739
8/1001
13/1763
20/2315
39/4346
8/1471
(8.08)
(8.12)
(7.99)
(7.38)
(8.64)
(8.97)
(5.44)
15/4099
1/364
2/510
2/889
10/2336
13/3354
2/745
*Composite of suicide, suicide attempt, and suicidal ideation.
Mollan K, et al. Ann Intern Med. 2014;161:1-10.
(3.66)
(2.75)
(3.92)
(2.25)
(4.28)
(3.88)
(2.68)
2.28 (1.27-4.10)
3.00 (0.36-24.88)
2.04 (0.43-9.62)
3.28 (0.74-14.52)
2.02 (0.94-4.31)
2.32 (1.23-4.38)
2.02 (0.43-9.53)
.006*
.94
.87
Events/PYs (IR per 1000 PYs)
EFV EFV Free HR (95% CI) P Value
0.02 1.00 50.00
Increased Suicidality With EFV-Free Increased Suicidality With EFV

SPIRIT: Switch to RPV/TDF/FTC From
Boosted PI Regimens in Suppressed Pts
 Multicenter, randomized, open-label switch study
– Primary endpoint: maintenance of HIV-1 RNA < 50 copies/mL at
Wk 24 (FDA Snapshot algorithm)
Pts with HIV-1 RNA
< 50 copies/mL on
stable RTV-boosted
PI + 2 NRTIs for
≥ 6 mos, no previous
NNRTI use
(N = 476)
Switch to RPV/TDF/FTC
(n = 317)
Continue
RTV-Boosted PI* +
2 NRTIs
(n = 159)
Wk 48
Wk 24
Primary endpoint
Switch to RPV/TDF/FTC
(n = 159)
*PIs: ATV/RTV, 37%; LPV/RTV, 33%; DRV/RTV, 20%; FPV/RTV, 8%; SQV/RTV, 2%.
Palella F, et al. AIDS. 2014;28:335-344.
Continue RPV/TDF/FTC
(n = 317)

SPIRIT: Virologic Suppression at Wk 24
and Wk 48
 Switch to RPV/TDF/FTC noninferior to continuing boosted-PI regimen at Wk 24
 23/24 pts with preexisting K103N maintained virologic suppression at Wk 24
FDA Snapshot at Wk 24
(immediate switch, Day 1 - Wk 24)
(delayed, Day 1 - Wk 24)
(delayed switch, Wk 24 - Wk 48)
FDA Snapshot at Wk 48
RPV/TDF/FTC
(immediate switch,
Day 1 - Wk 48)
100
80
(%)
Subjects 60
40
20
0
Virologic
Suppression
Palella F, et al. AIDS. 2014;28:335-344. Virologic
Failure
No Data
93.7 89.9 92.1
RPV/TDF/FTC
bPI + 2 NRTIs
RPV/TDF/FTC
0.9 5 1.3 5.4 5 6.6
100
80
60
40
20
0
Virologic
Suppression
Virologic
Failure
No Data
89.3
2.5
8.2

SPIRIT: Pretreatment HIV-1 RNA and
Outcomes
RPV/TDF/FTC PI/RTV + 2 NRTIs
95.0
89.2
95.5 92.3
152/160 83/93 128/134 48/52
Pretreatment HIV-1 RNA, copies/mL
100
80
60
40
20
Palella F, et al. IAC 2012. Abstract TUAB0104.
95% CI for Difference
Favors
PI/RTV + 2 NRTIs
≥ 100K
Favors
RPV/TDF/FTC
-4.8 3.2 11.3
-1.4 5.8 12.9
-12 0 +12
0
< 100K ≥ 100K
< 100K
HIV-1 RNA < 50 c/mL at Wk 24, (%)

SPIRIT: Change in Fasting Lipids From
Baseline at Wks 24 and 48
 Significant reductions in TC, LDL, TG, HDL, TC:HDL ratio at Wk
24 among RPV/TDF/FTC switch pts
-0.03
Palella F, et al. AIDS. 2014;28:335-344. Mean Changes From
Baseline (mmol/L)
0
-0.2
-0.4
-0.6
-0.8
-1.0
TC LDL TG HDL
-0.03
0.1
TC:HDL ratio
RPV/TDF/FTC (immediate, Day 1 - Wk 24)
RPV/TDF/FTC (delayed, Wk 24 - Wk 48)
bRTV + 2 NRTIs (Days 1 - Wk 24)
RPV/TDF/FTC (immediate, Day 1 - Wk 48)
-0.65
-0.41
-0.62
-0.65
-36
-0.41
-0.60
-0.72
-0.90
-0.1
-0.05 -0.05
0
0.03
Mean Change
0
-0.1
-0.2
-0.3
-0.4
-0.5
-0.27
-0.43
-0.35
0.08

STRATEGY-NNRTI: Lipid Effects of
Switching From NNRTI to EVG/C/TDF/FTC
 Small decrease in HDL-C from baseline to Wk 48 in patients who switched
from EFV-based regimen to EVG/COBI/TDF/FTC
 No statistically significant change in total-C:HDL ratio
Median Change From
Baseline (mmol/L)
1.0
0.4
0.2
0
-0.2
-0.4
-0.6
-1.0
Total-C LDL-C TG HDL-C
-0.13 vs 0.0
P = .082 P = .570 P = .001
Pozniak A, et al. Lancet Infect Dis. 2014;14:590-599.
EVG/COBI/TDF/FTC (n = 260)
NNRTI + TDF/FTC (n = 120)
0.8
0.6
-0.8
P = .071
-0.03 vs 0.05 -0.06 vs -0.05 -0.08 vs 0

D:A:D: ABC Remains Associated With
Elevated Risk of MI
 Update of analysis of ABC and
risk of acute MI in pts with low,
medium, and high CVD risk
 After initial D:A:D report in March
2008, decline in ABC initiations in
pts with higher CVD risk
35
30
25
20
15
10
5
0
Adjusted Relative Rate of MI
in Pts Currently Receiving ABC
Overall Pre-3/08 Post-3/08
1.98
(1.72-2.29)
Low CVD risk
Moderate CVD risk
High CVD risk
CVD risk unknown
Total cohort
Patients on ABC by CVD Risk
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
Patients (%)
5432
1
0.7
Sabin C, et al. CROI 2014. Abstract 747LB. Reproduced with permission.
1.97
(1.68-2.33)
1.97
(1.43-2.72)

ACTG 5202: Change in Lipid Fractions
Total
Cholesterol
LDL HDL Triglycerides
ATV/RTV + ABC/3TC
EFV + ABC/3TC
n = 326 290 326 300 303 270 310 281 322 288 324 299 325 289 324 300
Daar E, et al. CROI 2010. Abstract 59LB.
ATV/RTV + TDF/FTC
EFV + TDF/FTC
45
40
35
30
25
20
15
10
5
0

Is There a Role for
NRTI-Sparing Regimens?

EuroSIDA Study: Risk for Chronic Kidney
Disease
 Analysis of patients with ≥ 3 creatinine measurements and weight
– 6843 patients with 21,482 person-yrs of follow-up
 Definition of CKD (eGFR by Cockcroft-Gault)
– If baseline eGFR ≥ 60 mL/min, fall to < 60 mL/min
– If baseline eGFR < 60 mL/min, fall by 25%
 225 patients (3.3%) progressed to CKD
Cumulative Exposure to
ARVs and Risk of CKD
Kirk O, et al. AIDS. 2010;24:1667-1678.
Multivariate Analysis
IRR/Yr 95% CI P Value
Tenofovir 1.16 1.06-1.25 < .0001
Indinavir 1.12 1.06-1.18 < .0001
Atazanavir 1.21 1.09-1.34 .0003
Lopinavir/ritonavir 1.08 1.01-1.16 .030

ARV Discontinuation According to Current
eGFR in D:A:D
4
2
1
0.5
Discontinuation
IRR (95% CI)
< 60
Tenofovir
> 90
80.1-90
70.1-80
60.1-70
Current eGFR, mL/min
Lopinavir/RTV
70.1-80
60.1-70
Ryom L ,et al. J Infect Dis. 2013;207:1359-1369.
Univariate
Multivariate
Atazanavir/RTV
4
2
1
0.5
> 90
80.1-90
70.1-80
60.1-70
< 60
4
2
1
0.5 Discontinuation
IRR (95% CI)
> 90
80.1-90
< 60
4
2
1
0.5
> 90
80.1-90
70.1-80
60.1-70
< 60
Abacavir

Atazanavir Nephrolithiasis
 Renal calculi in which the ATV content was 41% to 49% by weight[1]
 Chelsea and Westminster Hospital comparison[2] of rate of
development of renal stones in ATV/RTV recipients (n = 1206) vs
combined group of EFV, LPV/RTV, or DRV/RTV recipients (n = 4449):
̶ 7.3/1000 PYs (95% CI: 4.7-10.8) vs 1.9/1000 PYs (95% CI: 1.2-2.8),
respectively (P < .001)
1. Anderson P, et al. AIDS. 2007;21:1060-1062. 2. Rockwood N, et al. AIDS. 2011:25:1671-
1673.

Switching to Boosted PI Monotherapy
Regimen Switch to Clinical Trial
1]
Lopinavir/ritonavir BID
Lopinavir/ritonavir BID
OK pilot[2-3]
+ 2 NRTIs
monotherapy
OK04[ACA-ARGE-04-001[4]
Atazanavir/ritonavir
+ 2 NRTIs
Atazanavir/ritonavir
monotherapy
ACTG 5201[5]
ATARITMO[6]
OREY[7]
Boosted PI or NNRTI
+ 2 NRTIs
Darunavir/ritonavir QD
monotherapy MONET[8]
Boosted PI or NNRTI
+ 2 NRTIs
Darunavir/ritonavir QD
monotherapy MONET[8]
Darunavir/ritonavir BID
+ 2 NRTIs
Darunavir/ritonavir BID
monotherapy MONOI[9]
PI or NNRTI + 2 NRTIs PI monotherapy PIVOT[10]
Monotherapy with a boosted PI is not recommended in the DHHS guidelines[11]
1. Escobar I, et al. Enferm Infecc Microbiol Clin. 2006;24:490-494. 2. Arribas JR, et al. J Acquir Immune Defic Syndr.
2005;40:280-287. 3. Arribas JR, et al. J Acquir Immune Defic Syndr. 2008;47:74-78. 4. Cahn P, et al. PLoS One
2011;6:23726. 5. Wilkin TJ, et al. J Infect Dis. 2009;199:866-871. 6. Vernazza P, et al. AIDS. 2007;21:1309-1315.
7. Pulido F, et al EAC 2009. Abstract PS4/6. 8. Arribas JR, et al. AIDS. 2010;24:223-230. 9. Katlama C, et al. AIDS.
2010;24:2365-2374. 10. Paton N, et al. CROI 2014. Abstract 550LB. 11. DHHS antiretroviral guidelines, May 2014.

GARDEL: Dual ART With LPV/RTV + 3TC
vs Triple ART With LPV/RTV + 2 NRTIs
 Randomized, open-label, phase III, noninferiority trial
 Primary endpoint: HIV-1 RNA < 50 copies/mL (ITT-e, FDA Snapshot algorithm)
ART-naive patients with
HIV-1 RNA > 1000 c/mL;
no NRTI/PI resistance;
HBsAg negative
(N = 426)
LPV/RTV 400/100 mg BID +
3TC 150 mg BID
(n = 217)
3TC or FTC + investigator-selected NRTI in FDC*
(n = 209)
Wk 48
primary analysis
Stratified by HIV-1 RNA
(≤ vs > 100,000 copies/mL)
Wk 24
interim analysis
*ZDV/3TC: 54%; TDF/FTC: 37%; ABC/3TC: 9%
Cahn P, et al. EACS 2013. Abstract LBPS7/6. Reproduced with permission.

GARDEL: Dual ART Noninferior to
Triple ART at Wk 48
 CD4+ cell count increase
– +227 with dual ART vs
+217 with triple ART
 Grade 2/3 AEs more frequent
in triple-ART arm (88 vs 65
events)
 Hyperlipidemia more common
in dual-ART arm (23 vs 16 pts)
 Lab abnormalities similar
 VF in 22 pts, of whom 2 had
resistance (M184V)
– Both on dual ART
100
Patients (%)
Δ 4.6
(95% CI: -2.2 to 11.8;
P = .171)
88.3 83.7
Dual ART (n = 214)
Triple ART (n = 202)
80
60
40
20
0 189 169
4.7 5.9 0.9 4.9
n = 10 12 2
Virologic
Success*
Virologic
Non-response
10 13 11
D/C Due
to AE or
Death
6.1 5.4
D/C for
Other
Reasons
*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm.
Cahn P, et al. EACS 2013. Abstract LBPS7/6.

SECOND-LINE : LPV/RTV + NRTIs vs
LPV/RTV + RAL for Pts With First-Line VF
 Randomized, open-label, phase IIIb/IV, noninferiority study
 Primary endpoint: Proportion of pts with HIV-1 RNA < 200 copies/mL at Wk 48
in mITT population, with noninferiority margin of 12%
HIV-infected pts (n = 271)
Boyd MA, et al. Lancet. 2013;381:2091-2099.
2-3 NRTIs QD or BID
2-3 NRTIs QD or BID
(n = 271)
with virologic failure on
first-line regimen of
2 NRTIs + NNRTI
(N = 541)
Wk 48
Raltegravir 400 mg BID
Raltegravir 400 mg BID
(n = 270)
(n = 270)
Stratified by baseline HIV-1 RNA
(≤ or > 100,000 copies/mL)

SECOND-LINE: Noninferiority of
LPV/RTV + RAL vs LPV/RTV + NRTIs
100
80
40
20
0
LPV/RTV + RAL
LPV/RTV + 2-3 NRTIs
Wk
60
0 12 24 36 48
HIV-1 RNA < 200 c/mL (%)
82.6
80.8
P = .59
Humphries A, et al. CROI 2013. Abstract 180LB. Graphic used with permission.

EARNEST: Second-line LPV/RTV-Based
ART After Initial NNRTI Failure
 Randomized, controlled, open-label phase III trial
 At baseline (medians): HIV-1 RNA 69,782 copies/mL; CD4+ cell count
71 cells/mm3; on ART for 4 yrs
HIV-infected adults and
adolescents on first-line
NNRTI-based ART
> 12 mos, > 90%
adherence in previous mo,
treatment failure by WHO
(2010) criteria*
(N = 1277)
*Including clinical, CD4+ cell count (HIV-1 RNA confirmed), or virologic criteria.
†Selected by physician according to local standard of care.
Paton N, et al. IAS 2013. Abstract WELBB02.
LPV/RTV + 2-3 NRTIs†
(n = 426)
LPV/RTV + RAL
(n = 433)
LPV/RTV + RAL
(n = 418)
Wk 12 Wk 144
LPV/RTV Monotherapy
(n = 418)

EARNEST: Clinical Outcomes at Wk 96
100
80
60
40
20
0
60 64
56
Good Disease
Control*
86 86
61
HIV-1 RNA
< 400 copies/mL
PI/NRTI
PI/RAL
PI mono
74 73
44
HIV-1 RNA
< 50 copies/mL
Patients (%)
*“Good disease control” at Wk 96 defined as pt alive, no new WHO4 events from Wks 0-96, and CD4+
cell count > 250 cells/mm3, and HIV-1 RNA < 10,000 copies/mL or > 10,000 copies/mL without PI
resistance mutations.
Paton N, et al. IAS 2013. Abstract WELBB02.

PROGRESS: LPV/RTV + RAL vs
LPV/RTV + TDF/FTC in Tx-Naive Pts
 Randomized, open-label, 96-week pilot study
 Primary endpoint: HIV-1 RNA < 40 copies/mL at Wk 48, by FDA ITT TLOVR analysis
 Criteria for noninferiority of raltegravir vs NRTI regimen met if 95% CI for estimated
RAL 400 mg BID
(n = 101)
TDF/FTC 300/200 mg QD
(n = 105)
HIV-infected,
treatment-naive
patients with HIV-1
RNA > 1000
copies/mL
(N = 206)
Week 96
Week 48:
Primary Endpoint
difference between arms within -20% margin
 Further noninferiority test conducted with -12% margin if initial criteria met
Reynes J, et al. AIDS Res Hum Retroviruses. 2013;29:256-265.

PROGRESS: LPV/RTV + RAL Noninferior
to LPV/RTV + TDF/FTC at Wk 48
 First-line LPV/RTV + RAL associated with similar, low risk of virologic failure at Wk 48
vs LPV/RTV + TDF/FTC
 AE profiles generally similar and toxicity-related discontinuation rates low in both arms
– Mean increase in total cholesterol, triglycerides, HDL cholesterol at Wk 48 vs baseline
significantly greater in LPV/RTV + RAL arm
 No new LPV resistance mutations emerged in either arm
Outcomes at Wk 48 LPV/RTV + RAL
(n = 101)
LPV/RTV + TDF/FTC
(n = 105)
HIV-1 RNA < 40 copies/mL
(ITT TLOVR), % 83.2 84.8
Mean CD4+ cell count change
from BL, cells/mm3 +215 +245
Reynes J, et al. AIDS Res Hum Retroviruses. 2013;29:256-265.

NEAT-001/ANRS 143: DRV/RTV + RAL vs
DRV/RTV + TDF/FTC in Naive Pts
 Randomized, open-label phase III study
 Primary endpoint
– Virologic: change of treatment before Wk 32 because of insufficient
response or HIV-1 RNA ≥ 50 c/mL at Wk 32 or beyond
– Clinical: death, any new AIDS-defining event, any new non-AIDS event
ART-naive pts with
HIV-1 RNA > 1000 c/mL
CD4+ cell count
≤ 500 cells/mm3
(N = 805)
DRV/RTV 800/100 mg QD + RAL 400 mg BID
Raffi F, et al. Lancet. 2014. [Epub ahead of print].
(n = 401)
Wk 96
DRV/RTV 800/100 mg QD + TDF/FTC 300/200 mg QD
(n = 404)

NEAT: RAL + DRV/RTV Noninferior to
TDF/FTC + DRV/RTV at 96 Wks
Primary Endpoint at Wk 96:
Adjusted Difference Estimate (95% CI)
Overall N = 805
BL HIV-1 RNA
< 100,000 c/mL
n = 530
≥ 100,000 c/mL
n = 275
BL CD4+ cell count
< 200/mm3
≥ 200/mm3
n = 123
n = 682
RAL - TDF/FTC
-10 0 10 20 30
Raffi F, et al. Lancet. 2014. [Epub ahead of print].
RAL TDF/FTC
17.8 13.8
7.4
36.8
7.3
27.3 (P = .10)
43.2
13.7
20.9
12.3
(P = .01)

LATTE: GSK1265744 as Part of ART in
Naive Pts: Results of 24-Wk Induction
 GSK1265744 (744), DTG analogue with long half-life, oral or injectable formulations
 Randomized, dose-ranging phase IIb study of oral formulation
 Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48
744 10 mg QD + RPV 25 mg QD
744 10 mg QD + 2 NRTIs
(n = 60)
744 30 mg QD + 2 NRTIs
(n = 60)
744 60 mg QD + 2 NRTIs
(n = 61)
*Pts with HIV-1 RNA < 50 c/mL at Wk 24 continued to maintenance
phase.
TDF/FTC or ABC/3TC.
ART-naive pts,
HIV-1 RNA
> 1000 c/mL
(N = 243)
EFV 600 mg QD + 2 NRTIs QD
(n = 62)
Margolis D, et al. EACS 2013. Abstract PS7/1. Margolis D, et al. CROI 2014. Abstract 91LB.
Wk 48
primary analysis Stratified by HIV-1 RNA
(≤ vs > 100,000 c/mL) and NRTI Wk 24
Induction Phase* Maintenance Phase

LATTE: Virologic Success During
Induction and Maintenance Phases
HIV-1 RNA < 50 c/mL by
Snapshot Algorithm (%)
100
80
60
40
20
Induction Phase Maintenance Phase
0
BL 2 4 8 12 16 24
Wks
 2 pts with PDVF during maintenance; both with INSTI mutations at BL
Margolis D, et al. EACS 2013. Abstract PS7/1. Margolis D, et al. CROI 2014. Abstract 91LB
96%
94%
92%
91%
GSK1265744 10 mg (n = 60)
GSK1265744 30 mg (n = 60)
GSK1265744 60 mg (n = 61)
EFV 600 mg (n = 62)
26 28 32 36 40 48

ASSURE: Simplification to ABC/3TC + ATV
From TDF/FTC + ATV/RTV
Switch to ABC/3TC + ATV
(n = 199)
Continue TDF/FTC + ATV/RTV
(n = 97)
Patients with HIV-1 RNA
< 75 c/mL after ≥ 6
months' treatment with
TDF/FTC + ATV/RTV as
last regimen and eCrCL
≥ 50 mL/min
(N = 296)
Primary endpoint: % with HIV-1 RNA < 50 c/mL at Wk 24 by the TLOVR algorithm
Wohl DA, et al. PLoS One. 2014;9:e96187.
Wk 24 Wk 48

ASSURE: Treatment Outcomes Through
48 Wks
1.0
0.8
0.6
0.4
0.2
0
Proportion of Subjects With
HIV-1 RNA < 50 c/mL
TDF/FTC + ATV/RTV
ABC/3TC + ATV
BL 2 4 12 24 36 48
Study Wk
 ABC/3TC + ATV noninferior to TDF/FTC + ATV/RTV based on a 12% margin
 Adjusted treatment difference: 0.33% (95% CI: -7.97%, 8.64%)

ASSURE: Urine β2-Microglobulin:
Creatinine Ratio
 Significant decline in urine β-microglobulin creatinine ratio (P < .001) in the ABC/3TC +
2ATV arm, but no significant change (P = .871) in the TDF/FTC + ATV/RTV arm
– Significant difference (P < .001) between groups
Urine β2-Microglobulin/Creatinine Ratio at Wk 24
ABC/3TC
+ ATV
(n = 139)
TDF/FTC +
ATV/RTV
(n = 77)
400
300
200
100
0
Geometric mean (μg/g)
P < .001
P = .871
Baseline
Wk 24

Simeprevir and Darunavir/Ritonavir:
Day 7 PK Alone and in Combination
Simeprevir Darunavir Ritonavir
6000
5000
4000
3000
2000
1000
0
0 4 8 12 16 20 24
Hrs
Plasma Concentration
of SIM (ng/mL), Day 7
of DRV (ng/mL), Day 7
SIM 150 mg QD for 7 days (n = 21)
SIM 50 mg QD + DRV/RTV
800/100 mg QD for 7 days (n = 25)
10000
8000
6000
4000
2000
0
0 4 8 12 16 20 24
Hrs
DRV/RTV 800/100 mg QD
for 7 days (n = 23)
DRV/RTV 800/100 mg QD +
 SIM exposure 2.6-fold higher when coadministered with DRV/RTV vs SIM alone
 When coadministered with SIM, DRV exposure increased 18% and RTV exposure
increased 32%
Ouwerkerk-Mahadevan S, et al. IDWeek 2012. Abstract 36620.
10000
8000
6000
4000
2000
0
0 4 8 12 16 20 24
Hrs
of RTV (ng/mL), Day 7
DRV/RTV 800/100 mg QD
for 7 days (n = 23)

Simeprevir and Rilpivirine:
Simeprevir
1000
250
200
150
100
0
0 4 8 12 16 20 24
RPV 25 mg QD for 11 days (n = 23)
 No clinically relevant interactions observed between RPV and SIM
 No relevant differences in incidence of AEs observed with SIM alone vs
coadministration of SIM and RPV
Rilpivirine
4000
3000
2000
0
0 4 8 12 16 20 24
urs
SIM 150 mg QD + RPV 25 mg QD for 11 days (n = 21)
Hrs
of RPV (ng/mL), Day 7
50

Simeprevir and Raltegravir:
Simeprevir Raltegravir
3500
3000
2500
2000
1500
1000
500
0
0 4 8 12 16 20 24
Hours
Plasma concentration
Simeprevir (150 mg qd) for 7 days ( n = 24)
3000
2500
2000
1500
RAL (400 mg bid) for 7 days ( n = 24)
Simeprevir (150mg qd) + RAL (400 mg bid) for 7 days ( n = 23)
 No clinically relevant interactions were observed between RAL and SIM
 No relevant differences in incidence of AEs observed with SIM alone vs
coadministration of SIM and RAL
0
0 2 4 6 8 10 12
Hours
Plasma concentration
of RAL (ng/mL), Day 7
1000
500

Considering Switching
Due to Drug-Drug Interactions

SPIRAL: Switch From RTV-Boosted PIs to
RAL in Virologically Suppressed Patients
 Randomized, open-label, multicenter study
 Median duration of virologic suppression before switch: 6.6 yrs
Switch Boosted PI to RAL 400 mg BID
+ maintain other BL antiretroviral agents
(n = 139)
Continue Boosted PI-Based Regimen*
(n = 134)
Patients on stable
RTV-boosted PI therapy,
HIV-1 RNA < 50
copies/mL for ≥ 6 mos
(N = 273)
Wk 48
Stratified by use of lipid-lowering
agents (yes vs no)
*LPV/RTV: 44%; ATV/RTV: 35%; other: 21%.
Martinez E, et al. AIDS. 2010;24:1697-1707.

SPIRAL: Switch to RAL Noninferior to
Maintaining Boosted PI Regimens
Free of Treatment Failure at Wk 48
100
80
60
40
20
0
(ITT, Switch = Failure)
89.2 86.6
Switch to
RAL
Continue
PI/RTV
Patients With VF RAL
(n = 4)
PI/RTV
(n = 6)
Prior VF 1 3
Prior suboptimal ART 2 3
Prior resistance mutations 1 5
Resistance test at VF 1 4
 Mutations 0 3 (PR, RT)
Martinez E, et al. AIDS. 2010;24:1697-1707.
Mean Change
From Baseline
to Wk 48, %
Switch
to RAL
Continue
PI/RTV P Value
Triglycerides -22.1 +4.7 < .0001
TC -11.2 +1.8 < .0001
LDL-C -6.5 +3.0 < .001
HDL-C -3.2 +5.8 < .0001
Total to HDL-C
ratio -4.9 -1.3 < .05

SWITCHMRK: Switch to RAL from
LPV/RTV in Pts With Viral Suppression
HIV-infected patients with
viral suppression on
LPV/RTV-based ART
for ≥ 3 mos
(N = 702)
(SWITCHMRK 1: 348
SWITCHMRK 2: 354)
Switch to Raltegravir 400 mg BID
+ other BL antiretroviral agents*
(SWITCHMRK 1: n = 174
SWITCHMRK 2: n = 176)
Continue Lopinavir/Ritonavir 200 mg/50 mg BID
+ other BL antiretroviral agents*
(SWITCHMRK 1: n = 174
SWITCHMRK 2: n = 178)
Stratified by duration of LPV/RTV use
(≤ 1 yr vs > 1 yr), age, race, sex,
region, hepatitis B and C Wk 12 lipid
analysis
Wk 24 efficacy
analysis
*All patients continued background regimen including ≥ 2 NRTIs.
Eron JJ, et al. Lancet. 2010;375:396-407.

SWITCHMRK: Main Findings
 RAL did not meet efficacy noninferiority criteria vs continued LPV/RTV
at Wk 24; study terminated
– However, comparable efficacy between arms among patients receiving
LPV/RTV as first regimen at study entry
Outcome
SWITCHMRK1 SWITCHMRK 2
RAL
LPV/RTV
RAL
(n = 174)
(n = 174)
(n = 176)
LPV/RTV
(n = 178)
All patients
 HIV-1 RNA < 50 copies/mL at Wk 24, % 80.8 87.4 88.0 93.8
 Treatment difference, % (95% CI) -6.6 (-14.4 to 1.2) -5.8 (-12.2 to 0.2)
Patients receiving LPV/RTV as first regimen

SWITCHMRK: Main Findings
 Inferior efficacy of RAL appeared driven by higher failure rate among
patients with previous virologic failure
Outcome
SWITCHMRK1 SWITCHMRK 2
RAL
LPV/RTV
RAL
(n = 174)
(n = 174)
(n = 176)
LPV/RTV (n
= 178)
Patients without previous virologic failure
Patients with previous virologic failure
 Treatment difference, % (95% CI) -17.3 (-33.0 to -2.5) -14.2 (-26.5 to -2.6)

STRATEGY-PI: Switch to
EVG/COBI/TDF/FTC in Suppressed Pts
 Randomized, open-label switch study in pts virologically suppressed
on a boosted PI–based regimen (both with TDF/FTC) for ≥ 6 mos
 Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48
HIV-1 RNA < 50 c/mL,
£ 2 previous regimens, no
resistance to FTC or TDF
and CrCl ≥ 70 mL/min
(N = 433)
Switch to EVG/COBI/TDF/FTC QD
(n = 293)
Remain on Boosted PI + TDF/FTC
(n = 140)
*Pts with previous VF ineligible.
Arribas J, et al. CROI 2014. Abstract 551LB.

STRATEGY-PI: Change to EVG/COBI
Better Than Maintaining bPIs at Wk 48
 Regimens: ATV, 40%; DRV, 40%;
LPV, 17%; FPV, 3%; SQV, < 1%;
79% on first regimen
 Results similar across all baseline
virologic and demographic
subgroups
Δ +6.7%
(95% CI: 0.4-13.7)
100
80
 Lipids in switch pts
– ¯ TGs vs all bPIs
– ¯ TC, TG, HDL-C vs LPV/RTV
– HDL-C vs DRV/RTV Patients (%)
 2 pts with VF in each arm but no
pts with resistance in either arm
 5 in the switch arm and 2 in the
boosted PI arm discontinued due to
adverse event
94 87
EVG/COBI/TDF/FTC
(n = 290)
Stable boosted PIs
(n = 139)
60
40
20
0
< 1
2
12
6
12
272 121 16 16
Virologic
Success*
Virologic
Nonresponse
No Data
n =
*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm
Discontinued for AE, death, or missing data.
Arribas J, et al. CROI 2014. Abstract 551LB.

Considerations for
HBV Coinfection

ACTG 5257: Open-Label ATV/RTV vs RAL
vs DRV/RTV in First-line ART
ART-naive patients
with HIV-1 RNA
≥ 1000 c/mL
(N = 1809)
 Primary endpoints
– Virologic failure: time to HIV-1 RNA > 1000 c/mL (at Wk 16 or before Wk 24) or > 200 c/mL
(at or after Wk 24)
– Tolerability failure: 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 tolerability
Landovitz R, et al. CROI 2014. Abstract 85.
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
TDF/FTC
(n = 601)
Wk 96 after last
patient enrolled

ITT, Regardless of ART Change
94%
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
 Similar mean change in CD4+
count across arms
– ATV/RTV (+284); RAL (+288)
DRV/RTV (+256) cells/mm3
1.0 Proportion With HIV-1 RNA ≤ 50 c/mL
0.8
0.6
0.4
0.2
0
88%
0 24 48 64 80 96 120 144
1.0
0.8
0.6
0.4
0.2
0
ITT, NC = Failure (Snapshot)
80%
73%
63%
0 24 48 64 80 96 120 144
Landovitz R, et al. CROI 2014. Abstract 85. Reproduced with permission.
RAL
DRV/RTV
ATV/RTV
Study Wk
RAL
DRV/RTV
ATV/RTV

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)
 Total body BMD loss
significantly greater with
ATV/RTV than either
DRV/RTV or RAL
 At hip and spine, similar
loss of BMD in the PI arms
Total Hip Total Spine Total Body
P = .72
P = .004
– Significantly greater loss
in the combined PI arms
than in the RAL arm
ATV/RTV
RAL
DRV/RTV
Combined PI arms
0
-1
-2
-3
-4
-5
-3.9
-1.7
-3.4
-2.9
-3.7
-2.4
-1.8
-4.0
-3.8
-3.6
-1.6
P = .36
P = .005
P = .42
P < .001
P = .001
Brown T, et al. CROI 2014. Abstract 779LB. Reproduced with permission.

TROP Study: Improvements in Bone
Density With TDF to RAL Switch
 Multicenter, open-label,
nonrandomized study
– 37 pts (97% male; mean
age: 49 yrs) suppressed on
TDF/FTC + PI/RTV for 6+
mos with osteopenia/
osteoporosis
– TDF/FTC + PI/RTV
switched to RAL + PI/RTV
Mean % Change in BMD From Baseline (95% CI)
Wk 24 P Wk 48 P
Spine 1.5 (0.5-2.5) .0038 3.0 (1.9-4.0) < .0001
Left hip
Total hip
1.4 (0.8-2.0)
Femoral neck
1.5 (0.3-2.7)
 BMD significantly improved over 48 wks
 Markers of bone turnover (N-teleopeptide, osteocalcin, and bone alkaline
phosphatase) all improved
 Virologic suppression maintained
 No grade 3 or higher AE, serious AE, or fracture
.0001
.0131
2.5 (1.6-3.3)
2.1 (0.9-3.2)
< .0001
.0011
Right hip
 Total hip
Femoral
neck
0.6 (-0.3 to 1.5)
0.4 (-0.9 to 1.7)
.1902
.5402
2.7 (1.9-3.5)
2.3 (1.2-3.5)
< .0001
.0001
Bloch M, et al. CROI 2012. Abstract 878. Bloch M, et al. HIV Med. 2014;15:373-80.

SPIRAL-LIP: Body Composition Substudy
of Switch From RTV-Boosted PI to RAL
 Randomized, open-label, multicenter study
Baseline
CT scan
DXA scan
Switch RTV-Boosted PI to RAL 400 mg BID
+ maintain other BL antiretroviral agents
(n = 139)
Continue RTV-Boosted PI Regimen*
(n = 134)
Patients on stable
RTV-boosted PI
therapy, HIV-1 RNA <
50 copies/mL for
≥ 6 mos
(N = 273)
Curran AE, et al. CROI 2011. Abstract 845.
Wk 48
CT scan
DXA scan
CT scan: single cut at L4 to measure total, subcutaneous and visceral fat
DXA scan to assess body fat content and total body, lumbar and femoral BMD and T-scores

SPIRAL-LIP Substudy: Bone Mineral
Density Changes
 Significant improvements in
total femur BMD and T-score
in RAL arm
 No significant changes in
BMD or T-scores with
continued PI/RTV
 Significant difference
between arms in femoral
neck BMD and T-score,
favoring RAL
 No differences seen in
lumbar spine
Curran AE, et al. CROI 2011. Abstract 845.
0
-0.2
-0.4
-0.6
-0.8
-1
-1.2
-1.4
T-Score
L1-L4
T-Score
Femoral
Neck
T-Score
Total
Femoral
0.004
bPI baseline
bPI 48 wks
RAL baseline
RAL 48 wks
0.170
0.058
0.890
0.080
0.078
0.112
0.016 0.336

ASSURE: Bone Biomarkers
 Bone biomarkers all declined significantly (P < .001) from BL in the ABC/3TC + ATV
arm, with no significant change in the TDF/FTC + ATV/RTV arm
 Difference between groups was also significant (P < .001)
Parathyroid
Hormone
C-Telopeptide Osteocalcin Bone Alkaline
Phosphatase
ABC/3TC +
ATV
(n = 183)
TDF/FTC +
ATV/RTV
(n = 89)
ABC/3TC +
ATV
(n = 181)
TDF/FTC +
ATV/RTV
(n = 88)
ABC/3TC +
ATV
(n = 181)
TDF/FTC +
ATV/RTV
(n = 88)
ABC/3TC +
ATV
(n = 182)
TDF/FTC +
ATV/RTV
(n = 89)
Geometric Mean (pg/mL)
50
40
30
20
10
0
P < .001 P = .943
Baseline Wk 24
500
400
300
200
100
0
P < .001 P = .350
30
25
15
10
5
0
P < .001 P = .117
18
15
12
9
3
0
P < .001 P = .747
20
6

Summary
 Switch regimens
– For most patients, one of the single-pill combination regimens is likely to
be appropriate
– Individualized management requires weighing trade-offs among
characteristics of individual drugs
– In some cases, an alternative regimen may be preferred for a particular
patient depending on the trade-offs for that regimen vs preferred options
 Newer strategies such as dolutegravir, NRTI-sparing, or PI
monotherapy regimens may be appropriate for carefully selected
patients
 Drugs in development may offer additional options, including
additional single-tablet regimens, but lack long-term safety and
efficacy data

Summary: Principles of ART Switch
 Maintain viral suppression (do no harm or don’t mess up)
 Need to know beforehand
– Previous ART history
– Previous demonstrated or possible/probable ARV resistance based on
history
– Likelihood of patient adherence to new regimen and its requirements
– Patient acceptance of any new potential adverse effects
– Other medications for potential DDIs
– Affordability
 Use available evidence to guide switch decisions

Go Online for More Educational
Content on Switch Strategies in
HIV! Interactive Virtual Presentation featuring streaming narration of these
slides and case studies illustrating HIV switch strategies by expert faculty
David A. Wohl, MD and panel discussion by Oluwatoyin Adeyemi, MD,
Jose R. Arribas, MD, Joseph J. Eron, Jr., MD, and Anton L. Pozniak, MD
ClinicalThought™ with expert faculty
commentary on switch strategies in HIV
clinicaloptions.com/HIVSwitchStrategies

Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients.2014

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