This document provides an overview of evolving strategies for switching antiretroviral therapy (ART) regimens in HIV-infected patients who are virologically suppressed. It summarizes the results of two clinical trials investigating switches to elvitegravir/cobicistat/tenofovir/emtricitabine (EVG/COBI/TDF/FTC) from NNRTIs and to rilpivirine/tenofovir/emtricitabine (RPV/TDF/FTC) from boosted protease inhibitor regimens. Both studies found the switch strategies to be noninferior to remaining on the original regimen in maintaining viral suppression. The document also
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Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients.2014
1. Evolving Switch Strategies for
Virologically Suppressed
HIV-Infected Patients
This activity is supported by an independent educational
grant from Gilead Sciences.
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Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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.
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Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
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Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
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Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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.
10. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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”
11. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
12. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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)
Pozniak A, et al. CROI 2014. Abstract 553LB.
*Pts with previous VF ineligible.
13. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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(%)
93
88
Δ +5.3%
(95% CI: -0.5 to +12)
EVG/COBI/TDF/FTC
(n = 290)
Stable NNRTIs
(n = 143)
0
20
40
60
80
100
1
3
< 1
1
6
11
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.
271 126 16 16
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Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
*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.
SubjectReportingSymptoms(%)
HIV Symptom Index
Vivid Dreams Insomnia Anxiety Dizziness
100
136
224
75
212
65
101
56
87
119
224
84
209
48
100
41
87
103
222
71
208
40
100
34
87
90
225
49
211
37
99
32
87
BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48
†
†*
*
Baseline
EVG/COBI/TDF/FTC
NNRTI + TDF/FTC
Wk 48
EVG/COBI/TDF/FTC
NNRTI + TDF/FTC
Pozniak A, et al. Lancet Infect Dis. 2014;14:590-599.
STRATEGY-NNRTI: Outcomes in Patients
Switching from EFV-based Therapy
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)‡
70
60
50
40
30
20
10
0
61
35
64 64
53
40
48 47 46
34
40 39 40 37 37
23
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Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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)
Mollan K, et al. Ann Intern Med. 2014;161:1-10.
*Composite of suicide, suicide attempt, and suicidal ideation.
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
(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
Increased Suicidality With EFV-Free Increased Suicidality With EFV
0.02 1.00 50.00
16. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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)
Palella F, et al. AIDS. 2014;28:335-344.
*PIs: ATV/RTV, 37%; LPV/RTV, 33%; DRV/RTV, 20%; FPV/RTV, 8%; SQV/RTV, 2%.
Continue RPV/TDF/FTC
(n = 317)
17. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
(immediate switch, Day 1 - Wk 24)
(delayed, Day 1 - Wk 24)
(delayed switch, Wk 24 - Wk 48)
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
(immediate switch,
Day 1 - Wk 48)
Palella F, et al. AIDS. 2014;28:335-344.
Subjects(%)
0
20
40
60
80
100
Virologic
Suppression
Virologic
Failure
No Data
FDA Snapshot at Wk 24
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
0
20
40
60
80
100
Virologic
Suppression
Virologic
Failure
No Data
FDA Snapshot at Wk 48
89.3
2.5
8.2
RPV/TDF/FTC
19. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
Palella F, et al. AIDS. 2014;28:335-344.
MeanChangesFrom
Baseline(mmol/L)
0
-0.2
-0.4
-0.6
-0.8
-1.0
TC LDL TG HDL
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
-0.03
-0.41
-0.65
-0.62
-36
-0.41
-0.60
-0.90
-0.72
-0.1
-0.03
-0.05 -0.05
0
0.03
MeanChange
0
-0.1
-0.2
-0.3
-0.4
-0.5
0.1
-0.27
-0.43
-0.35
0.08
TC:HDL ratio
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Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
Pozniak A, et al. Lancet Infect Dis. 2014;14:590-599.
MedianChangeFrom
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
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
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Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
Sabin C, et al. CROI 2014. Abstract 747LB. Reproduced with permission.
35
30
25
20
15
10
5
0
Low CVD risk
Moderate CVD risk
High CVD risk
CVD risk unknown
Total cohort
2000200120022003200420052006200720082009201020112012
Patients on ABC by CVD Risk
Patients(%)
5
4
3
2
1
0.7
Overall Pre-3/08 Post-3/08
Adjusted Relative Rate of MI
in Pts Currently Receiving ABC
1.98
(1.72-2.29)
1.97
(1.68-2.33)
1.97
(1.43-2.72)
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Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
ACTG 5202: Change in Lipid Fractions
n = 326 290 326 300 303 270 310 281 322 288 324 299 325 289 324 300
Total
Cholesterol
LDL HDL Triglycerides
Daar E, et al. CROI 2010. Abstract 59LB.
ATV/RTV + ABC/3TC
EFV + ABC/3TC
ATV/RTV + TDF/FTC
EFV + TDF/FTC
45
40
35
30
25
20
15
10
5
0
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Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
Kirk O, et al. AIDS. 2010;24:1667-1678.
Cumulative Exposure to
ARVs and Risk of CKD
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
25. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
ARV Discontinuation According to Current
eGFR in D:A:D
Ryom L ,et al. J Infect Dis. 2013;207:1359-1369.
4
2
1
0.5
Discontinuation
IRR(95%CI)
> 90
80.1-90
70.1-80
60.1-70
< 60
Tenofovir
Current eGFR, mL/min
Univariate
Multivariate
4
2
1
0.5
> 90
80.1-90
70.1-80
60.1-70
< 60
Atazanavir/RTV
Current eGFR, mL/min
4
2
1
0.5
Discontinuation
IRR(95%CI)
> 90
80.1-90
70.1-80
60.1-70
< 60
Lopinavir/RTV
Current eGFR, mL/min
4
2
1
0.5
> 90
80.1-90
70.1-80
60.1-70
< 60
Abacavir
Current eGFR, mL/min
26. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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.
27. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
Switching to Boosted PI Monotherapy
Regimen Switch to Clinical Trial
Lopinavir/ritonavir BID
+ 2 NRTIs
Lopinavir/ritonavir BID
monotherapy
OK pilot[1]
OK04[2-3]
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]
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.
Monotherapy with a boosted PI is not recommended in the DHHS guidelines[11]
28. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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)
LPV/RTV 400/100 mg BID +
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
Cahn P, et al. EACS 2013. Abstract LBPS7/6. Reproduced with permission.
*ZDV/3TC: 54%; TDF/FTC: 37%; ABC/3TC: 9%
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Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
Patients(%)
88.3 83.7
Δ 4.6
(95% CI: -2.2 to 11.8;
P = .171)
Dual ART (n = 214)
Triple ART (n = 202)
189 169
0
20
40
60
80
100
4.7 5.9 0.9 4.9
n = 210 12
Virologic
Success*
Virologic
Non-
response
D/C Due
to AE or
Death
D/C for
Other
Reasons
6.1 5.4
10 13 11
Cahn P, et al. EACS 2013. Abstract LBPS7/6.
*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm.
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Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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%
Boyd MA, et al. Lancet. 2013;381:2091-2099.
LPV/RTV 400/100 mg BID +
2-3 NRTIs QD or BID
(n = 271)
LPV/RTV 400/100 mg BID +
2-3 NRTIs QD or BID
(n = 271)HIV-infected pts
with virologic failure on
first-line regimen of
2 NRTIs + NNRTI
(N = 541)
Wk 48
LPV/RTV 400/100 mg BID +
Raltegravir 400 mg BID
(n = 270)
LPV/RTV 400/100 mg BID +
Raltegravir 400 mg BID
(n = 270)
Stratified by baseline HIV-1 RNA
(≤ or > 100,000 copies/mL)
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Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
SECOND-LINE: Noninferiority of
LPV/RTV + RAL vs LPV/RTV + NRTIs
0
20
40
80
100
Wk
LPV/RTV + RAL
LPV/RTV + 2-3 NRTIs
60
0 12 24 36 48
HIV-1RNA<200c/mL(%)
82.6
80.8
P = .59
Humphries A, et al. CROI 2013. Abstract 180LB. Graphic used with permission.
32. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
Paton N, et al. IAS 2013. Abstract WELBB02.
*Including clinical, CD4+ cell count (HIV-1 RNA confirmed), or virologic criteria.
†
Selected by physician according to local standard of care.
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)
LPV/RTV + 2-3 NRTIs†
(n = 426)
LPV/RTV + RAL
(n = 433)
LPV/RTV + RAL
(n = 418)
Wk 144Wk 12
LPV/RTV Monotherapy
(n = 418)
33. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
EARNEST: Clinical Outcomes at Wk 96
*“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.
100
80
60
40
20
0
Good Disease
Control*
HIV-1 RNA
< 400 copies/mL
HIV-1 RNA
< 50 copies/mL
60
64
56
86 86
61
74 73
44
PI/NRTI
PI/RAL
PI mono
Patients(%)
34. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
LPV/RTV 400/100 mg BID +
RAL 400 mg BID
(n = 101)
LPV/RTV 400/100 mg BID +
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
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
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.
35. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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.
36. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
Raffi F, et al. Lancet. 2014. [Epub ahead of print].
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
(n = 401)
Wk 96
DRV/RTV 800/100 mg QD + TDF/FTC 300/200 mg QD
(n = 404)
37. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
NEAT: RAL + DRV/RTV Noninferior to
TDF/FTC + DRV/RTV at 96 Wks
Raffi F, et al. Lancet. 2014. [Epub ahead of print].
Overall N = 805
BL HIV-1 RNA
< 100,000 c/mL
≥ 100,000 c/mL
n = 530
n = 275
BL CD4+ cell count
< 200/mm3
≥ 200/mm3
n = 123
n = 682
Primary Endpoint at Wk 96:
Adjusted Difference Estimate (95% CI)
RAL - TDF/FTC
-10 0 10 20 30
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)
38. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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 30 mg QD + RPV 25 mg QD
*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)
744 60 mg QD + RPV 25 mg QD
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.
744 10 mg QD + 2 NRTIs
(n = 60)
744 30 mg QD + 2 NRTIs
(n = 60)
744 60 mg QD + 2 NRTIs
(n = 61)
Wk 48
primary analysis
Stratified by HIV-1 RNA
(≤ vs > 100,000 c/mL) and NRTI Wk 24
Induction Phase* Maintenance Phase
40. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
Continue TDF/FTC + ATV/RTV
(n = 97)
Switch to ABC/3TC + ATV
(n = 199)
ASSURE: Simplification to ABC/3TC + ATV
From TDF/FTC + ATV/RTV
Wohl DA, et al. PLoS One. 2014;9:e96187.
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
Wk 48Wk 24
41. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
ASSURE: Treatment Outcomes Through
48 Wks
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%)
Wohl DA, et al. PLoS One. 2014;9:e96187.
1.0
0.8
0.6
0.4
0.2
0
ProportionofSubjectsWith
HIV-1RNA<50c/mL
BL 2 4 12 24 36 48
Study Wk
ABC/3TC + ATV
TDF/FTC + ATV/RTV
42. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
ASSURE: Urine β2-Microglobulin:
Creatinine Ratio
Significant decline in urine β2-microglobulin creatinine ratio (P < .001) in the ABC/3TC +
ATV arm, but no significant change (P = .871) in the TDF/FTC + ATV/RTV arm
– Significant difference (P < .001) between groups
Wohl DA, et al. PLoS One. 2014;9:e96187.
ABC/3TC
+ ATV
(n = 139)
TDF/FTC +
ATV/RTV
(n = 77)
Urine β2-Microglobulin/Creatinine Ratio at Wk 24
400
300
200
100
0
Geometricmean(μg/g)
P < .001
P = .871
Baseline
Wk 24
44. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
Simeprevir and Darunavir/Ritonavir:
Day 7 PK Alone and in Combination
Simeprevir Darunavir Ritonavir
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.
6000
5000
4000
3000
2000
1000
0
0 4 8 12 16 20 24
Hrs
PlasmaConcentration
ofSIM(ng/mL),Day7
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
PlasmaConcentration
ofDRV(ng/mL),Day7
DRV/RTV 800/100 mg QD
for 7 days (n = 23)
DRV/RTV 800/100 mg QD +
SIM 50 mg QD for 7 days (n = 25)
10000
8000
6000
4000
2000
0
0 4 8 12 16 20 24
Hrs
PlasmaConcentration
ofRTV(ng/mL),Day7
DRV/RTV 800/100 mg QD
for 7 days (n = 23)
DRV/RTV 800/100 mg QD +
SIM 50 mg QD for 7 days (n = 25)
45. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
Simeprevir and Rilpivirine:
Day 7 PK Alone and in Combination
Simeprevir
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
Ouwerkerk-Mahadevan S, et al. IDWeek 2012. Abstract 36620.
Rilpivirine
4000
3000
2000
0
0 4 8 12 16 20 24
urs
PlasmaConcentration
ofSIM(ng/mL),Day7
SIM 150 mg QD for 11 days (n = 21)
1000
SIM 150 mg QD + RPV 25 mg QD for 11 days (n = 21)
RPV 25 mg QD for 11 days (n = 23)
250
200
150
100
0
0 4 8 12 16 20 24
Hrs
PlasmaConcentration
ofRPV(ng/mL),Day7
50
46. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
Simeprevir and Raltegravir:
Day 7 PK Alone and in Combination
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
Ouwerkerk-Mahadevan S, et al. IDWeek 2012. Abstract 36620.
RaltegravirSimeprevir
3500
3000
2500
2000
1500
0
0 4 8 12 16 20 24
Hours
Plasmaconcentration
ofSIM(ng/mL),Day7
Simeprevir (150 mg qd) for 7 days ( n = 24)
1000
500
Simeprevir (150mg qd) + RAL (400 mg bid) for 7 days ( n = 23)
RAL (400 mg bid) for 7 days ( n = 24)
3000
2500
2000
1500
0
0 2 4 6 8 10 12
Hours
Plasmaconcentration
ofRAL(ng/mL),Day7
1000
500
48. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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)
Martinez E, et al. AIDS. 2010;24:1697-1707.
*LPV/RTV: 44%; ATV/RTV: 35%; other: 21%.
49. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
SPIRAL: Switch to RAL Noninferior to
Maintaining Boosted PI Regimens
0
20
40
60
80
100
Switch to
RAL
Continue
PI/RTV
86.689.2
Free of Treatment Failure at Wk 48
(ITT, Switch = Failure)
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
50. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
HIV-infected patients with
viral suppression on
LPV/RTV-based ART
for ≥ 3 mos
(N = 702)
(SWITCHMRK 1: 348
SWITCHMRK 2: 354)
SWITCHMRK: Switch to RAL from
LPV/RTV in Pts With Viral Suppression
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.
51. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
Eron JJ, et al. Lancet. 2010;375:396-407.
Outcome
SWITCHMRK1 SWITCHMRK 2
RAL
(n = 174)
LPV/RTV
(n = 174)
RAL
(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
HIV-1 RNA < 50 copies/mL at Wk 24, % 86.1 86.7 89.3 94.5
Treatment difference, % (95% CI) -0.6 (-12.2 to 10.9) -5.3 (-16.9 to 5.7)
52. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
SWITCHMRK: Main Findings
Inferior efficacy of RAL appeared driven by higher failure rate among
patients with previous virologic failure
Eron JJ, et al. Lancet. 2010;375:396-407.
Outcome
SWITCHMRK1 SWITCHMRK 2
RAL
(n = 174)
LPV/RTV
(n = 174)
RAL
(n = 176)
LPV/RTV (n
= 178)
Patients without previous virologic failure
HIV-1 RNA < 50 copies/mL at Wk 24, % 85.1 85.8 92.5 93.5
Treatment difference, % (95% CI) -0.7 (-9.9 to 8.6) -1.0 (-8.5 to 6.3)
Patients with previous virologic failure
HIV-1 RNA < 50 copies/mL at Wk 24, % 72.3 89.7 79.7 93.8
Treatment difference, % (95% CI) -17.3 (-33.0 to -2.5) -14.2 (-26.5 to -2.6)
53. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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)
Arribas J, et al. CROI 2014. Abstract 551LB.
*Pts with previous VF ineligible.
54. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
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
Lipids in switch pts
– ↓ TGs vs all bPIs
– ↓ TC, TG, HDL-C vs LPV/RTV
– ↑ HDL-C vs DRV/RTV
Patients(%)
94
87
Δ +6.7%
(95% CI: 0.4-13.7)
EVG/COBI/TDF/FTC
(n = 290)
Stable boosted PIs
(n = 139)
0
20
40
60
80
100
< 1
2
1
2
6
12
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.
272 121 16 16
56. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
ACTG 5257: Open-Label ATV/RTV vs RAL
vs DRV/RTV in First-line ART
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.
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
57. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
Landovitz R, et al. CROI 2014. Abstract 85. Reproduced with permission.
1.0
ProportionWithHIV-1RNA≤50c/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)
RAL
DRV/RTV
ATV/RTV
Study Wk
0 24 48 64 80 96 120 144
88%
94%
63%
73%
80%
RAL
DRV/RTV
ATV/RTV
58. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
P = .004
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
– Significantly greater loss
in the combined PI arms
than in the RAL arm
ATV/RTV
RAL
DRV/RTV
Combined PI arms
-5
-4
0
-3
-2
-1
-3.9
-1.7
-3.4
-2.9
-3.7
-2.4
-1.8
-4.0
-3.8
-3.6
-1.6
P = .36
Total Hip Total Spine Total Body
P = .005
P = .42
P < .001
P = .001
P = .72
Brown T, et al. CROI 2014. Abstract 779LB. Reproduced with permission.
59. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
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
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
Femoral neck
1.4 (0.8-2.0)
1.5 (0.3-2.7)
.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.
60. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
SPIRAL-LIP: Body Composition Substudy
of Switch From RTV-Boosted PI to RAL
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.
Randomized, open-label, multicenter study
Baseline
CT scan
DXA scan
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
61. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
bPI baseline
bPI 48 wks
RAL baseline
RAL 48 wks
0.170
0.058
0.890
0.080
0.078
0.016 0.336
0.004
0.112
62. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
Wohl DA, et al. PLoS One. 2014;9:e96187.
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)
GeometricMean(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
63. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
64. clinicaloptions.com/hiv
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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
65. 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
Editor's Notes
I’m David Wohl, and I’ll be leading you through an interesting and I think informative discussion about switching in patients who are doing well on their HIV therapy.
You are invited to use these slides for personal study or in your own noncommercial presentations.
I’m at the University of North Carolina, and my disclosures are listed on this slide.
I was joined in this activity by several distinguished experts in HIV care: Oluwatoyin Adeyemi from Rush University Medical Center; Jose Arribas from Madrid, Spain;
Joseph Eron, my colleague at UNC; and Anton Pozniak, who works out of Chelsea-Westminster in London. As you’ll see, these faculty contributed not only to the content of the slide deck but also engaged in a very spirited and I think informative discussion regarding cases in which switching is a consideration, and as we’ll go through, each was able to provide their own opinions about whether or not we should switch and what we would switch to in different clinical scenarios.
The disclosures for my colleagues are listed here.
Alright, so let’s start with our discussion, and I’ll provide a little bit of background information.
ART, antiretroviral therapy.
So why switch ART in virologically suppressed patients at all? These patients are doing well; their virus is under control; many of them have been on their therapy for quite a while.
So why switch? Well, convenience. There may be tolerability issues. People may be on a medication for a long time and dealing with adverse effects and coping with them, and now that there’s alternatives, they may no longer have to do so. Drug interactions; as people age, they get new medications added to their list and there’s more potential for interactions between something they’re going to be administered now and their HIV therapy. So we may have to alter the HIV therapy when some of these other concomitant medications are needed.
Certainly in pregnancy there may be drugs that are more desirable than others based upon the guidelines. And we may want to reduce costs; it may be that if you can switch them, let’s say, to a single-tablet regimen, there is a smaller outlay of cost because of a single bottle vs multiple bottles if you have co-pays per prescription. So these are all considerations that I think lead us to think about it.
DHHS, US Department of Health and Human Services.
The Department of Health and Human Services have also discussed this and dealt with this and considered reasons that are justifiable for switching, and they’re listed on the slide.
Any time you change therapy in someone who’s doing basically well on their therapy immunologically and virologically, there could be potential downsides. Exposure to new agents always carries the risk of new toxicities. It’s impossible to predict how any one individual will react to a medication even when it has a relatively clean toxicity profile. If there’s any previous resistance, whether known or unknown, that can be an issue. We don’t always fully appreciate the viral resistance that our patients harbor because there may not have been a genotype done when this person started therapy, and transmitted drug resistance can be present and not detected.
It’s interesting. When we switch to a fixed-dose formulation, we add convenience, but there is this inconvenient problem when there is a side effect and we have to adjust one of the components in a fixed-dose combination. Using a fixed-dose combination formulation doesn’t allow for that manipulation. So there could be a downside, whereas if the person’s on a multitablet formulation, you can play with one of the medications and not have to mess with the others.
Any time we switch someone, you cannot underestimate the potential for either the patient or the pharmacy to make a mistake. And this unfortunately does happen where you’ve simplified things; you thought, the wrong drug’s administered or the instructions are wrong or the patient takes it in a different way than was intended due to some misunderstanding. That potential occurs when you’re switching from something that’s been tried and true.
It can also be more expensive to switch. Some of the fixed-dose combinations might be more expensive than the drug regimen that the person was on, so that has to be looked into. Co-pay may be higher for the 1 drug vs maybe, you know, 2 or 3 other medicines that the person was taking.
And there is this philosophy that some of my patients push back on, which is, “If it ain’t broke, don’t fix it.” “I’ve been doing well on my therapy, it’s been going on for a long time.” “I don’t see a need to switch; I’ve gotten into a routine.” I hear that in my patients who are on lopinavir/ritonavir. “I take my 2 pills twice a day; I take my tenofovir/FTC in the morning. I’m fine with it, I’ve no problems; why should I switch?”
If we do switch, I think there’s some basic principles that have to be maintained and have to be recognized. One is you want to keep the virus suppressed. That’s the key thing—it’s the “do no harm.” You don’t want to put this person in more peril. So you want to make sure that you’re choosing a regimen that you feel confident will maintain suppression of the virus. And we have some studies that can help us look at that. But there’s other areas where there’s not as much data, but one would believe based upon other types of data and other experiences that this should maintain viral suppression, that the virus should be susceptible to these medications.
So to do this, we need to know more about the history of the patient’s HIV therapy, know what they’ve taken, how long they took it, what were the circumstances of them getting off of a medication. I switched from, you know, one therapy to another not because of virologic failure but because I had side effects. That’s different than I failed because my virus rebounded. It would indicate with a viral rebound that resistance might have developed, whereas in the first case that would be very, very unlikely.
And we also want to understand more about adherence. There are some patients that take their medicines religiously and some, as we all know, who don’t. And there are regimens that are more forgiving of adherence than others, and so that would be an important consideration. Patient acceptance of any new potential adverse events: So there may be a new medication that you want to switch to, but it has a side effect that would be basically unacceptable to this person; that’s another thing to consider.
And then definitely drug-drug interactions. You’re switching from one regimen to another; you’ve got to think about what plays well with others within the mix of the patient’s current medications. And as we’ve kept mentioning and increasingly important is affordability. Whenever possible we want to use evidence, of course, to guide our decisions. And where there’s no evidence, as I’ve mentioned, we sometimes have to extrapolate.
COBI, cobicistat; CrCl, creatinine clearance; EVG, elvitegravir; FTC, emtricitabine; QD, once daily; RTV, ritonavir; TDF, tenofovir; VF, virologic failure.
For more information about this study, go online to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202014/Overview/Capsules/553LB.aspx
In the next slide we see a schema of that STRATEGY-NNRTI study. And as I mentioned, these were people who were doing really well on their drug, they had less than 50 copies of viral load. They had not been on very many regimens, so not a lot of treatment exposure; no known resistance to 3TC, FTC, or tenofovir. And they had to have adequate renal function. So it’s a large study, over 400 people. They were randomized to switch to the fixed-dose combination, including elvitegravir and cobicistat, or remain on their dual-nucleoside tenofovir/FTC and NNRTI.
AE, adverse event; COBI, cobicistat; EFV, efavirenz; ETR, etravirine; EVG, elvitegravir; FDA, US Food and Drug Administration; FTC, emtricitabine; NVP, nevirapine; RPV, rilpivirine; TDF, tenofovir; VF, virologic failure.
For more information about this study, go online to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202014/Overview/Capsules/553LB.aspx
The results are really encouraging. Whether they stayed on their therapy or switched, close to 90% maintained virologic suppression, and there was no significant difference here; noninferiority was reached. When we look at virologic nonresponse, again, very, very low numbers, so we can really say that these data indicate that switching was acceptable from an efficacy standpoint. It’s really interesting. Again, the regimen that most people switched from was an efavirenz-based regimen, so that’s very applicable to this case.
And when you look at the subgroup analyses of the patient-reported outcomes when you look at from baseline to week 48, all the orange are the people who had switched to the elvitegravir/cobicistat formulation. So vivid dreams were experienced at baseline in 61% of the people who ended up switching, and then at week 48—that’s after they had switched after a year—only 35% did. Similarly with insomnia or anxiety or dizziness. You can see that there’s a decrease in the orange from baseline report prior to switch to after the switch, a diminution in any of these adverse events. In the grey you see that there’s no change at all, and these are the people who stayed on their previous NNRTI/tenofovir/FTC combination. So, again, in this particular case, these data would indicate that switching him may very well improve some of the sleep outcomes that we’re interested in.
The next slide shows some of the data, and you can see the different studies that were listed and confidence intervals and the point estimates. And there was this increased suicidality with efavirenz, and the hazard was increased. So it’s about a twofold increase in the risk compared to regimens that didn’t have efavirenz. So in this particular case, again, given his depression, maybe a switch from efavirenz might be a good idea.
ATV, atazanavir; DRV, darunavir; FDA, US Food and Drug Administration; FPV, fosamprenavir; FTC, emtricitabine; LPV, lopinavir; RPV, rilpivirine; RTV, ritonavir; SQV, saquinavir; TDF, tenofovir; VL, viral load.
The SPIRIT study showed that you can switch to rilpivirine/tenofovir/FTC from boosted PI regimens in suppressed patients. And I have to say that the kind of lipid profiles you see in people on boosted PIs and you see on efavirenz-based regimens are not that different. So here’s a good indication of what we might see if we switch. In that study, of course, people were suppressed; they were on a boosted PI plus nucleosides. Then they switched to either rilpivirine/tenofovir/FTC or stayed on their regimen at least for 24 weeks and then were switched to the rilpivirine/tenofovir/FTC because we felt like people would likely be motivated to switch.
FDA, US Food and Drug Administration; FTC, emtricitabine; RPV, rilpivirine; TDF, tenofovir; PI, protease inhibitor; bPI, boosted protease inhibitor; NRTIs, nucleoside reverse transcriptase inhibitrs.
And efficacy data are there; it looks great. We know that at weeks 24 and 48, people maintained suppressed. This is a successful switch study.
NRTIs, nucleoside reverse transcriptase inhibitors; RPV, rilpivirine; TDF, tenofovir; FTC, emtricitabine; PI, protease inhibitor; RTV, ritonavir.
And it did not matter what the person’s viral load was previous to starting HIV therapy. So historic viral loads were collected as part of the data collection of the study, and we know that people starting HIV therapy with rilpivirine who have a viral load over 100,000 tend to not have as great success virologically as patients who have under 100,000. Similarly, there’s been data that show that lower CD4 cell count folks, people under 200, don’t respond as well virologically to rilpivirine/tenofovir/FTC as those with higher CD4 cell counts.
But this is a different story. These are people who have viral loads that are high or low prior to starting their regimen, then get undetectable, and then are switching to rilpivirine. And this study shows pretty convincingly that once you get suppressed, it doesn’t matter what your pretherapy viral load was; rilpivirine works just as well in the historically high viral load people and the historically low viral load people.
HDL, high-density lipoprotein; LDL, low-density lipoprotein; NRTI, nucleoside reverse transcriptase inhibitor; RPV/TDF/FTC, rilpivirine/tenofovir disoproxil fumarate/emtricitabine; RTV, ritonavir; TC, total cholesterol; TG, triglycerides.
But getting to the lipids, you can see that switching from the PI—and I would argue from efavirenz—to this particular regimen could be expected to lead to benefit. So just look at this; just switching, all except the orange bars represent people who got rilpivirine, either immediately or after some time. Orange represents people who stayed on their boosted PIs. And orange stays about the same; all the other bars are deflections. So you see total cholesterol, LDL, and triglyceride goes down. HDL went down a little slight bit but not that much, and the ratio is shown on the right-hand slide. So we can expect that this person may very well have some improvement in his lipid profile based upon these data and others.
HDL-c, high density lipoprotein cholesterol; LDL-c, low density lipoprotein cholesterol; Total-c, total cholesterol; TG, triglycerides.
There’s also data from the STRATEGY-NNRTI trial. So those were patients who were switched. From the NNRTI that we talked about before, mostly efavirenz to the cobicistat-based regimen. Again, here’s a booster. You don’t see much of an effect here, again, because the cobicistat has an effect that’s very similar to ritonavir. So, again, I think that the data that we have from the SPIRIT study indicates that switching him would probably improve his lipids.
ABC, abacavir; ART, antiretroviral therapy; CVD, cardiovascular disease; MI, myocardial infarction.
For more information about this study, go online to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202014/Overview/Capsules/747LB.aspx
Back in 2008, the D:A:D: study group showed us that abacavir in their large cohort of folks in Europe who are on HIV therapy that abacavir was associated with an increased risk in myocardial infarction. After that there were changes in the use of abacavir—and you can see that on the graph on the bottom of the slide—so around 2008, you can see the blue line: people at high risk for cardiovascular disease were not getting treated with abacavir as much as they were pre-2008.
But, interestingly, overall use—so white line in the middle—stayed about the same, and there might have even been some recent uptick in patients who were at lower cardiovascular risk of getting abacavir. And then there’s the folks who we don’t know about, and they’re also pretty stable. So the D:A:D: group updated their data, and the premise was if we continue to see a signal, an effect between abacavir and myocardial infarction even after 2008 when we let the world know that abacavir was a problem, and it was still seen today, that would indicate this is really a robust finding, that if we’re avoiding abacavir in high-risk people and we’re still seeing the signal, that would probably mean that our original results are even more likely to be correct because the channeling bias that we may have missed early on would be somewhat reduced.
I think that’s an important point. And they did find that there really was no difference in this association; that the risk continued, that people on abacavir continued to have a risk for myocardial infarction and CVD in general. But I think the one point to make here is that is probably not unexpected in that the people who stopped using abacavir were people at high risk for cardiovascular disease, but those were not the highest-risk people for abacavir-induced heart disease.
By that I mean when you go back to 2008, the people at the highest risk for cardiovascular disease related to abacavir exposure in their analysis were people who had lower risk of cardiovascular disease. The people at higher risk, well it’s harder to find an associated use of abacavir because they’re going to have cardiovascular disease due to their smoking, due to their hypertension, due to their diabetes. So the use of that drug in that population has dropped, but that wasn’t the population at greatest risk for an abacavir-associated outcome. So I think it adds some data, but we still don’t really know for sure whether or not abacavir increases the risk of myocardial infarction.
LDL, low-density lipoprotein; HDL, high-density lipoprotein; ATV, atazanavir; RTV, ritonavir; ABC, abacavir; 3TC, lamivudine; EFV, efavirenz; TDF, tenofovir; FTC, emtricitabine.
Dr. Pozniak’s point regarding the differences between abacavir and tenofovir vis-à-vis lipids in the ACTG study is well taken, and this is one of the best studies—very well powered—that shows us regardless of what you are on in addition, whether it be efavirenz or a boosted atazanavir, if you’re on abacavir, your risk of having a higher lipid fraction is higher than if you’re on tenofovir. And you can see the green are all the atazanavir folks, the blue are all the efavirenz folks, and the darker the shade, those are the folks that are on abacavir, and the lighter the shade of either of those colors are the people on tenofovir.
CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ARV, antiretroviral drug.
So what are the data regarding kidney disease and atazanavir? There was a EuroSIDA study—this is a large meta cohort in people in Europe—looking at chronic kidney disease in patients. And they found that looking at different exposures to antiretroviral therapy, certainly tenofovir, as you would expect, was associated with chronic kidney injury. It’s not very common, but it is an effect, and we know that and we’re familiar with it.
But interestingly as well, indinavir—maybe as no surprise, given what we know about the nephrotoxicity of that drug vis-à-vis kidney stones—but also atazanavir was associated very strongly with the increased risk of chronic kidney disease and not the other PIs that were being used at the time, including lopinavir/ritonavir.
So this was the first, I think, indication that atazanavir may be a problem. And we don’t have a mechanism at that time, but perhaps over time we’d find one, and that has been the case.
ARV, antiretroviral; RTV, ritonavir; eGFR, estimated glomerular filtration rate.
There’s also other studies that show that there is increased discontinuation due to elevated creatinine or decreased GFR in the D:A:D: study, and this has been associated, again, with atazanavir/ritonavir and not other PIs that were used at the same time. And there’s less data about darunavir in this cohort at the time that this analysis was done.
PYs, patient years; ATV, atazanavir; RTV, ritonavir; EFV, efavirenz; LPV, lopinavir; DRV, darunavir.
Nephrolithiasis may be part of what’s going on here. And you can have a kidney stone that’s clinical and painful, but you could also have subclinical nephrolithiasis—so instead of a stone, maybe gravel or pebbles—and this can cause some chronic kidney injury too. And this is a putative mechanism by which maybe atazanavir does it. But we do know that people on atazanavir—not to the extent of indinavir—can get kidney stones, and when they’re analyzed by spectroscopy, we do know that it is atazanavir. And data from Dr. Pozniak’s group has quantified how often this occurs. There’s also been recent data that show that stones can also develop in the gallbladder, and that’s another emerging problem with atazanavir exposure.
PI, protease inhibitor; BID, twice daily; NRTIs, nucleoside reverse transcriptase inhibitors; NNRTI, nonnucleoside reverse transcriptase inhibitor; QD, once daily.
So there’s been a bunch of different boosted PI monotherapy studies, and they’re listed here, and there’s been variable results. And I think that the bottom line is that we’re not sure that this is going to be effective in all of our patients. You get some good responses, but in general not as good as when you take 2 nucleosides along with the boosted PI. So at this point, the DHHS guidelines do not recommend monotherapy with a boosted PI.
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; BID, twice daily; FDA, US Food and Drug Administration; FDC, fixed-dose combination; FTC, emtricitabine; HBsAg, surface antigen of hepatitis B virus; ITT-e, intent to treat–exposed; LPV, lopinavir; PI, protease inhibitor; RTV, ritonavir; TDF, tenofovir; ZDV, zidovudine.
For additional information about GARDEL, go online and review the capsule summary:
http://www.clinicaloptions.com/HIV/Conference%20Coverage/Fall%202013%20HIV/Clinical%20Impact/Capsules/LBPS7_6.aspx
Dr. Arribas mentioned the GARDEL study, and this is an important study to go over. So this was patients who were treatment-naive who had a greater than a thousand copies of virus at baseline and no resistance to PIs or NRTIs. They were all hepatitis B surface antigen negative. And they were randomized to lopinavir/ritonavir BID plus lamivudine/3TC BID vs lopinavir/ritonavir plus 3TC or FTC and investigator-selected NRTIs in the 2 fixed-dose combinations.
AE, adverse event; ART, antiretroviral therapy; D/C, discontinued therapy; FDA, US Food and Drug Administration; VF, virologic failure.
For additional information about GARDEL, go online and review the capsule summary:
http://www.clinicaloptions.com/HIV/Conference%20Coverage/Fall%202013%20HIV/Clinical%20Impact/Capsules/LBPS7_6.aspx
What you see at week 48 is no difference between those who were on dual ART vs those who were on triple ART. So we see really nice responses; CD4 cell count responses with dual ART was similar to what we saw with the triple drug with the nucleosides. So dual therapy with just taking the lopinavir/ritonavir plus the 3TC looked to be effective. Grade 2 and 3 adverse events were more common in those who are on more drugs, as was hyperlipidemia. I think this is a boost in the arm for a more minimalist approach and that we may not have to rely upon NRTIs.
LPV, lopinavir; RTV, ritonavir; NRTIs, nucleoside reverse transcriptase inhibitors; NNRTI, nonnucloeside reverse transcriptase inhibitor; RAL, raltegravir; VF, virologic failure; BID, twice daily; QD, once daily
The SECOND-LINE study looked at lopinavir/ritonavir plus 2 nukes vs lopinavir/ritonavir plus an integrase inhibitor, which is, again, an interesting formulation to think about. Could we use that instead of nucleosides? These were HIV-infected patients who, unlike in the GARDEL study, had virologic failure in their first regimen of 2 nukes plus an NNRTI. One-to-one randomization over 270 people in each arm randomized to the 2 strategies.
LPV, lopinavir; mITT, modified intent to treat; RAL, raltegravir; RTV, ritonavir; NRTIs, nucleoside reverse transcriptase inhibitors.
For more detailed information about this study go to:
http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/180LB.aspx.
And the graph shows it nicely. In blue we see the lopinavir/ritonavir plus raltegravir, really nice response. Early response is expected with an integrase; that persisted out to week 48, and at that time, the lopinavir/ritonavir plus 2 nukes, the more standard approach, was very similar, and there was no difference between the 2.
ART, antiretroviral therapy; LPV, lopinavir; RAL, raltegravir; RTV, ritonavir; WHO, World Health Organization; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTIs, nucleoside reverse transcriptase inhibitors.
For detailed information on this study, go to:
http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB02.aspx
The EARNEST study is similar in its design. So these were people also who had received first-line therapy with an NNRTI-based regimen and had treatment failure randomized to lopinavir/ritonavir plus 2 to 3 nucleosides or this combination of lopinavir/ritonavir plus the integrase raltegravir, or that and then a switch to monotherapy—so an induction with the raltegravir/lopinavir/ritonavir and then switching to just the lopinavir/ritonavir.
RAL, raltegravir; WHO, World Health Organization; PI, protease inhibitor.
For detailed information on this study, go to:
http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB02.aspx
Outcomes, depending upon how you define them. Let’s look at the less than 50 copies on the right side. Boosted PI plus NRTI therapy looked good, 74%. PI therapy plus raltegravir, 73%. So that worked. The PI monotherapy arms induction and then monotherapy did not. And, again, cautious note regarding PI monotherapy again struck.
TLOVR, time to loss of virologic response; LPV, lopinavir; RTV, ritonavir; RAL, raltegravir; TDF, tenofovir; FTC, emtricitabine; Tx, treatment; ITT, intention-to-treat; NRTI, nucleoside reverse transcriptase inhibitor; BID, twice daily; QD, once daily.
PROGRESS was HIV-infected treatment-naive patients and again looked at lopinavir/ritonavir plus raltegravir as a strategy compared to more standard 2 nukes plus the boosted PI.
BL, baseline; LPV, lopinavir; RTV, ritonavir; RAL, raltegravir; TDF, tenofovir; FTC, emtricitabine; AE, adverse event; HDL, high-density lipoprotein; ITT, intention-to-treat; TLOVR, time to loss of virologic response.
Data looked really good, again indicating that this combination can work effectively in getting people suppressed, and I think that that’s important.
ART, antiretroviral therapy; BID, twice daily; DRV, darunavir; FTC, emtricitabine; RAL, raltegravir; QD, once daily; RTV, ritonavir; TDF, tenofovir.
If you look at the NEAT study—here’s the design as I pointed out—
BL, baseline; DRV, darunavir; FTC, emtricitabine; PDVF, protocol-defined virologic failure; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir.
then look at the data. While overall there was noninferiority, when you start to look at subgroup analyses, those who had the higher viral load or lower CD4 cell counts had much higher rates of virologic failure. And that’s a good indication that there was weakness with darunavir/ritonavir plus raltegravir.
Dr. Eron’s previous point about maybe the boosted PIs are not all created equal is a good one. There was an ACTG study, a single-arm study that looked at darunavir/ritonavir plus raltegravir, that also had results that were less than inspiring. So I think we have to be careful about extrapolating necessarily from the lopinavir/ritonavir minimalist studies to newer drugs.
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; QD, once daily; RPV, rilpivirine; TDF, tenofovir.
For more information about this study, go online to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202014/Overview/Capsules/91LB.aspx
So a really nice schematic of what could be considered a somewhat confusing study, but if you just think of it as 2 nucleosides and efavirenz vs 744 plus rilpivirine in the maintenance phase, everyone started out with 744 plus 2 nukes in the experimental arms. But they’re looking at different doses, so if you collapse the blue, the orange, and the green into one category of induction with the 2 nukes and the integrase, and then integrase plus rilpivirine, it makes it a little bit more simple.
BL, baseline; EFV, efavirenz; PDVF, protocol-defined virologic failure.
For more information about this study, go online to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202014/Overview/Capsules/91LB.aspx
And the slide next shows just the graphic responses. And you can see they all cluster towards the end of the slide, and you’re getting great responses, over 90%.
ABC, abacavir; 3TC, emtricitabine; ATV, atazanavir; TDF, tenofovir; FTC, lamivudine; RTV, ritonavir; TLOVR; time to loss of virologic response.
The ASSURE study was pretty basic; it was patients who were experienced, and they were on tenofovir/FTC/atazanavir/ritonavir regimen at baseline and then switched to either abacavir/3TC/atazanavir vs staying on their regimen.
TDF, tenofovir; FTC, emtricitabine; ATV, atazanavir; RTV, ritonavir; ABC, abacavir; 3TC, lamivudine.
Virologically, suppression rates were very similar at week 48.
ABC, abacavir; 3TC, lamivudine; ATV, atazanavir; TDF, tenofovir; FTC, emtricitabine; RTV, ritonavir.
The markers in the urine for renal function showed that there was some improvements in patients who were switched vs patients who stayed on their therapy, and there were some bone markers, too, that also looked good.
QD, once daily; DRV/RTV, darunavir/ritonavir; SIM; simeprevir; SD, standard deviation; QD, once daily; PK, pharmacokinetics.
So there’s data looking at different drugs and simeprevir, and the bottom line is that simeprevir exposure is pretty high when given with darunavir/ritonavir in this particular study and should be avoided. The darunavir level also is affected and increases by about 20%. Ritonavir exposure increases about 30%, so that’s an unfavorable interaction profile.
QD, once daily; RPV, rilpivirine; SIM; simeprevir; SD, standard deviation; QD, once daily; PK, pharmacokinetics.
In comparison, rilpivirine has no effect, and there’s no bidirectional interaction between simeprevir and rilpivirine, and those can be given together without trouble.
qd, once daily; RAL, raltegravir; SIM; simeprevir; SD, standard deviation; PK, pharmacokinetics
Raltegravir, similarly, there’s no interaction at all.
RTV, ritonavir; PIs, protease inhibitors; RAL, raltegravir; LPV, lopinavir; ATV, atazanavir; BID, twice daily; BL, baseline.
So what is this SPIRAL study that Dr. Arribas is talking about? It’s a switch from ritonavir-boosted PIs to raltegravir in suppressed patients; 273 people, suppressed, switched to raltegravir 400 mg BID from their boosted PI or continued their boosted PI regimen.
RAL, raltegravir; PI, protease inhibitors; ITT, intention to treat; RTV, ritonavir; VF, virologic failure; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.
Nice results here, showing almost identical rates of viral suppression of success. Lipids improved with the switch from the boosted PI to raltegravir. There was another substudy that looked at inflammatory markers that also improved.
RAL, raltegravir; LPV, lopinavir; RTV, ritonavir; BL, baseline; BID, twice daily; NRTIs, nucleoside reverse transcriptase inhibitors.
The SWITCHMRK study was very different, though, in its results. This was again switching from a boosted PI—in this case, lopinavir/ritonavir in patients with viral suppression—and switching that to raltegravir.
RAL, raltegavir; LPV, lopinavir; RTV, ritonavir.
And raltegravir did not meet the efficacy noninferiority criteria vs continuing on lopinavir/ritonavir 24 weeks, and the study was actually terminated early.
If you look at the patients who had been taking lopinavir/ritonavir as their first regimen, there was comparable efficacy, so it does seem that the accumulated resistance that developed in some of the patients handicapped the switch to the integrase inhibitor and the tenofovir/FTC.
RAL, raltegravir; LPV, lopinavir; RTV, ritonavir.
So a cautionary tale that we have to look very carefully at what exposures our patients have had before, because if you have a regimen with a lower barrier to resistance such as perhaps a tenofovir/FTC/raltegravir combination, and you have a 184V and maybe other mutations that can impact that regimen, it may not be as successful.
COBI, cobicistat; CrCl, creatinine clearance; EVG, elvitegravir; FTC, emtricitabine; QD, once daily; RTV, ritonavir; TDF, tenofovir; VF, virologic failure.
For more information about this study, go online to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202014/Overview/Capsules/551LB.aspx
The STRATEGY-PI study is analogous to what we saw with the STRATEGY-NNRTI study. Here, though, instead of switching from NNRTIs—as the title suggests—we’re switching from boosted PIs.
AE, adverse events; ATV, atazanavir; bPI, boosted PI; COBI, cobicistat; DRV, darunavir; EVG, elvitegravir; FDA, US Food and Drug Administration; FPV, fosamprenavir; FTC, emtricitabine; HDL-C, high density lipoprotein cholesterol; LPV, lopinavir; SQV, saquinavir; TC, total cholesterol; TDF, tenofovir; TG, triglycerides; VF, virologic failure.
For more information about this study, go online to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202014/Overview/Capsules/551LB.aspx
Results look very similar though. Patients did very well, and they were able to maintain suppression even after the switch.
ATV, atazanavir; BID, twice daily; CV, cardiovascular; DRV, darunavir; FTC, emtricitabine; RAL, raltegravir; RTV, ritonavir; QD, once daily; TDF, tenofovir; TF, tolerability failure; VF, virologic failure.
For more information about this study, go online to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202014/Overview/Capsules/85.aspx
So the ACTG study 5257, recently completed, open-label study, atazanavir/ritonavir vs raltegravir vs darunavir/ritonavir in first-line therapies—3 very, very popular non-NNRTI-containing regimens—large study, 1,800 patients.
ART, antiretroviral therapy; ATV, atazanavir; DRV, darunavir; ITT, intent to treat; NC , noncompleter; RAL, raltegravir; RTV, ritonavir.
For more information about this study, go online to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202014/Overview/Capsules/85.aspx
Looking at the virologic efficacy of this study before we get into the bone data, it’s interesting, when you look at the intent-to-treat analysis where switches were permitted, where no matter what you started on as long as you are undetectable at week 96 regardless of whether or not you switched, we saw that there was no difference. So the strategy of starting with any 1 of these 3 regimens was equally efficacious.
However, if you did consider a switch a failure, that if you were assigned to one regimen and you ended up switching to an alternative regimen, no matter what it was, we do see differences. And that’s pretty important. So raltegravir-based regimen was superior to both boosted PIs at week 96, which is key, and a lot of this was driven by tolerability. The greater tolerability of the raltegravir plus tenofovir/FTC arm above the boosted PIs really drove this, and it was especially true of the raltegravir vs the atazanavir/ritonavir arm. The atazanavir/ritonavir arm definitely had more toxicity issues, largely hyperbilirubinemia and other GI problems, than the darunavir/ritonavir and certainly the raltegravir.
ATV, atazanavir; BMD, bone mineral density; DRV, darunavir; RAL, raltegravir; RTV, ritonavir.
For more information about this study, go online to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202014/Overview/Capsules/779LB.aspx
But looking at the bone loss data, you can see here that the atazanavir/ritonavir arm in blue and the darunavir/ritonavir arm in green had deeper deflections in bone density generally overall compared to the raltegravir in orange. So we do see decreases overall—that’s what we’d expect. In any treatment-naive study, we see decreases. Remember, everyone got tenofovir as well, so there is an effect of that. But there does seem to be an added-on effect of being on a boosted PI, and we see that especially with the atazanavir/ritonavir.
TDF, tenofovir; RAL, raltegravir; PI, protease inhibitor; RTV, ritonavir; FTC, emtricitabine; BMD, bone mineral density; AE, adverse events.
The TROP study that Dr. Arribas mentioned was a smaller study, and it looked at improvements in bone density when tenofovir was switched to raltegravir. Not too surprising, when people stopped tenofovir, markers of bone turnover and also bone density improved.
RTV, ritonavir; PI, protease inhibitor; RAL, raltegravir; BID, twice daily; BL, baseline; BMD, bone mineral density.
The SPIRAL study was mentioned before, and there was a substudy looking at body composition that also is able to help us understand more about bone density. The results show significant improvements in femur BMD and T-score in those who switched to raltegravir.
BMD, bone mineral density; RAL, raltegravir; PI, protease inhibitor; RTV, ritonavir; bPI, boosted protease inhibitor.
There were no significant changes in BMD or T-score in those who continued on their boosted PI.
BL, baseline; ABC, abacavir; 3TC, lamivudine; ATV, atazanavir; TDF, tenofovir; FTC, emtricitabine; RTV, ritonavir.
And in the ASSURE study looking at a ritonavir-sparing atazanavir/abacavir/3TC regimen, switching to that from tenofovir/FTC/atazanavir/ritonavir led to improvements in every single bone marker that was looked at. DEXA scans were not done in that study.
NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.
So summarizing, I think what we learned from talking together and looking at these very challenging cases, there are some principles. So for most patients, 1 of the single-pill combinations is likely to be appropriate when the switch is pretty basic. So people who are doing well, who don’t really have many comorbidities, and combining medicines into a single tablet, that’s low-hanging fruit. But you have to individualize this, and we do have to think about the history, the concomitant medications, the adherence. These are important things to consider. And we have to weigh the tradeoffs and the characteristics of staying on what you’re on vs switching.
In some cases, an alternative regimen may be preferred for a particular patient, depending on these tradeoffs. Newer strategies such as dolutegravir, NRTI-sparing, or PI monotherapies may be appropriate, but again, these are areas where there’s either not a lot of data or the data indicate that there could be some liability with this. But for an individual patient, it may make sense, especially if we’re dealing with a toxicity.
You know, again, there’s a pipeline of drugs. There’s newer drugs that do come out even within HIV where we have a lot of different medications but still a need for better medications, so there may be drugs that are going to come out later on that may offer additional options, such as single-tablet regimens of more of the drugs that we’ve been talking about, but they will lack long-term safety and efficacy data, especially with switches. So more switch data would be nice, and that will hopefully follow the advent of these newer therapies.
ART, antiretroviral therapy; ARV, antiretroviral.
So, again, maintain viral suppression. Don’t do harm. You need to know about the ART history; about resistance, either what’s documented or likely; adherence; side effects; drug interactions; and then the whole issue of affordability. And use these to guide your decision making.