Upload
hivlifeinfo
View
116
Download
1
Tags:
Embed Size (px)
Citation preview
Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
This activity is supported by an independent educational grant from Gilead Sciences.
clinicaloptions.com/hivEvolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
About These Slides
Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent
These slides may not be published or posted online without permission from Clinical Care Options (email [email protected])
DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
clinicaloptions.com/hivEvolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
Program Director
David A. Wohl, MDAssociate Professor of Medicine School of MedicineSite Leader, AIDS Clinical Trials Unit-Chapel HillUniversity of North Carolina at Chapel HillChapel Hill, North CarolinaCo-Director for HIV ServicesNorth Carolina Department of CorrectionRaleigh, 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.
clinicaloptions.com/hivEvolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
Other Faculty Who Contributed to This ProgramOluwatoyin Adeyemi, MDAssociate Professor of MedicineDepartment of Internal Medicine/Infectious DiseasesRush University Medical CenterAttending Physician, Infectious Diseases Co-Director, Hepatitis ClinicRuth Rothstein CORE Center and Stroger HospitalCook County Health and Hospital System Chicago, Illinois
José R. Arribas, MDResearch Director (HIV and Infectious Diseases) Hospital La Paz. IdiPAZ.Madrid, Spain
clinicaloptions.com/hivEvolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
Other Faculty Who Contributed to This ProgramJoseph J. Eron, Jr., MDProfessor of Medicine and EpidemiologyUniversity of North Carolina School of MedicineDirector, AIDS Clinical Trials UnitUniversity of North CarolinaChapel Hill, North Carolina
Anton L. Pozniak, MD, FRCPConsultant PhysicianDirector of HIV ServicesDepartment of HIV and Genitourinary MedicineChelsea and Westminster Hospital NHS TrustLondon, United Kingdom
clinicaloptions.com/hivEvolving 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.
Background on Switching Strategies
clinicaloptions.com/hivEvolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
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.
clinicaloptions.com/hivEvolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
DHHS ART Treatment Guidelines 2014
DHHS. Adult antiretroviral guidelines, May 2014.
clinicaloptions.com/hivEvolving 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”
clinicaloptions.com/hivEvolving 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
clinicaloptions.com/hivEvolving 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.
clinicaloptions.com/hivEvolving 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
Pat
ien
ts (
%)
9388
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
13
< 11
611
Virologic Success*
Virologic Nonresponse
No Data
n =
*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithmDiscontinued for AE, death, or missing data.
Pozniak A, et al. CROI 2014. Abstract 553LB. Reproduced with permission.
271 126 16 16
clinicaloptions.com/hivEvolving 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.
Su
bje
ct R
epo
rtin
g S
ymp
tom
s (%
)
HIV Symptom IndexVivid Dreams Insomnia Anxiety Dizziness
100
136224
75212
65101
5687
119224
84209
48100
4187
103222
71208
40100
3487
90225
49211
3799
3287
BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48
††*
*
BaselineEVG/COBI/TDF/FTCNNRTI + TDF/FTC
Wk 48EVG/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
4048 47 46
3440 39 40 37 37
23
clinicaloptions.com/hivEvolving 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
StudyA5095A5142A5175A5202
RegionUSMultinational
47/5817
6/739 8/1001
13/1763 20/2315
39/43468/1471
(8.08)
(8.12) (7.99) (7.38) (8.64)
(8.97) (5.44)
15/4099
1/364 2/510 2/889
10/2336
13/33542/745
(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
clinicaloptions.com/hivEvolving 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 48Wk 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)
clinicaloptions.com/hivEvolving 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.
Su
bje
cts
(%
)
0
20
40
60
80
100
Virologic Suppression
Virologic Failure
No Data
FDA Snapshot at Wk 2493.7
89.9 92.1RPV/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
2.58.2
RPV/TDF/FTC
clinicaloptions.com/hivEvolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
SPIRIT: Pretreatment HIV-1 RNA and Outcomes
Palella F, et al. IAC 2012. Abstract TUAB0104.
Pretreatment HIV-1 RNA, copies/mL
95% CI for Difference
FavorsPI/RTV + 2 NRTIs
FavorsPI/RTV + 2 NRTIs
≥ 100K≥ 100K
FavorsRPV/TDF/FTCFavorsRPV/TDF/FTC
-12-12 00 +12+12
-4.8-4.8 3.23.2 11.311.3
-1.4-1.4 5.85.8 12.912.9
0
20
40
60
80
100
< 100K ≥ 100K
RPV/TDF/FTC PI/RTV + 2 NRTIs
95.089.2
95.5 92.3
152/160 83/93 128/134 48/52
< 100K< 100K
HIV
-1 R
NA
< 5
0 c/
mL
at
Wk
24,
(%
)
clinicaloptions.com/hivEvolving 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.
Mea
n C
han
ges
Fro
m
Bas
elin
e (m
mo
l/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 -0.050
0.03
Mea
n C
han
ge 0
-0.1-0.2-0.3-0.4-0.5
0.1
-0.27
-0.43
-0.35
0.08TC:HDL ratio
clinicaloptions.com/hivEvolving 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.
Med
ian
Ch
ang
e F
rom
B
asel
ine
(mm
ol/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
clinicaloptions.com/hivEvolving 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.
353025201510
50
Low CVD riskModerate CVD riskHigh CVD riskCVD risk unknownTotal cohort
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
Patients on ABC by CVD Risk
Pat
ien
ts (
%)
5432
10.7
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)
clinicaloptions.com/hivEvolving 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
TotalCholesterol
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
Is There a Role forNRTI-Sparing Regimens?
clinicaloptions.com/hivEvolving 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
clinicaloptions.com/hivEvolving 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
Dis
co
nti
nu
atio
n
IRR
(95
% C
I)
> 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
Dis
co
nti
nu
atio
n
IRR
(95
% C
I)
> 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
clinicaloptions.com/hivEvolving 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):
Y 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.
clinicaloptions.com/hivEvolving 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]
clinicaloptions.com/hivEvolving 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 48primary analysis
Stratified by HIV-1 RNA (≤ vs > 100,000 copies/mL)
Wk 24interim analysis
Cahn P, et al. EACS 2013. Abstract LBPS7/6. Reproduced with permission.
*ZDV/3TC: 54%; TDF/FTC: 37%; ABC/3TC: 9%
clinicaloptions.com/hivEvolving 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
Pat
ien
ts (
%)
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 1690
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.
clinicaloptions.com/hivEvolving 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 ptswith virologic failure on
first-line regimen of 2 NRTIs + NNRTI
(N = 541)
HIV-infected ptswith 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)
clinicaloptions.com/hivEvolving 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 + RALLPV/RTV + 2-3 NRTIs
60
0 12 24 36 48
HIV
-1 R
NA
< 2
00 c
/mL
(%
) 82.6
80.8
P = .59
Humphries A, et al. CROI 2013. Abstract 180LB. Graphic used with permission.
clinicaloptions.com/hivEvolving 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)
clinicaloptions.com/hivEvolving 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
0Good Disease
Control*HIV-1 RNA
< 400 copies/mLHIV-1 RNA
< 50 copies/mL
60 6456
86 86
61
74 73
44
PI/NRTIPI/RALPI mono
Pat
ien
ts (
%)
clinicaloptions.com/hivEvolving 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 96Week 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.
clinicaloptions.com/hivEvolving 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 48LPV/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.
clinicaloptions.com/hivEvolving 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)
clinicaloptions.com/hivEvolving 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)
clinicaloptions.com/hivEvolving 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 48primary analysis
Stratified by HIV-1 RNA (≤ vs > 100,000 c/mL) and NRTI Wk 24
Induction Phase* Maintenance Phase
clinicaloptions.com/hivEvolving Switch Strategies for Virologically Suppressed HIV-Infected Patients
LATTE: Virologic Success During Induction and Maintenance Phases
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
HIV
-1 R
NA
< 5
0 c/
mL
by
Sn
apsh
ot
Alg
ori
thm
(%
)
100
80
60
40
20
0BL 2 4 8 12 16 24
Wks
92%94%96%
91%
GSK1265744 10 mg (n = 60)GSK1265744 30 mg (n = 60)GSK1265744 60 mg (n = 61)EFV 600 mg (n = 62)
Induction Phase Maintenance Phase
26 28 32 36 40 48
clinicaloptions.com/hivEvolving 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)
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
clinicaloptions.com/hivEvolving 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
0Pro
po
rtio
n o
f S
ub
ject
s W
ith
H
IV-1
RN
A <
50
c/m
L
BL 2 4 12 24 36 48
Study Wk
ABC/3TC + ATV
TDF/FTC + ATV/RTV
clinicaloptions.com/hivEvolving 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
Geo
met
ric
mea
n (
μg
/g)
P < .001P = .871
BaselineWk 24
HCV Coinfection
clinicaloptions.com/hivEvolving 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
00 4 8 12 16 20 24
Hrs
Pla
sma
Co
nce
ntr
atio
n
of
SIM
(n
g/m
L),
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
00 4 8 12 16 20 24
Hrs
Pla
sma
Co
nce
ntr
atio
n
of
DR
V (
ng
/mL
), D
ay 7
DRV/RTV 800/100 mg QDfor 7 days (n = 23) DRV/RTV 800/100 mg QD +SIM 50 mg QD for 7 days (n = 25)
10000
8000
6000
4000
2000
00 4 8 12 16 20 24
Hrs
Pla
sma
Co
nce
ntr
atio
n
of
RT
V (
ng
/mL
), D
ay 7
DRV/RTV 800/100 mg QDfor 7 days (n = 23) DRV/RTV 800/100 mg QD +SIM 50 mg QD for 7 days (n = 25)
clinicaloptions.com/hivEvolving 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
00 4 8 12 16 20 24
urs
Pla
sma
Co
nce
ntr
atio
n
of
SIM
(n
g/m
L),
Da
y 7
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
00 4 8 12 16 20 24
Hrs
Pla
sma
Co
nce
ntr
atio
n
of
RP
V (
ng
/mL
), D
ay 7
50
clinicaloptions.com/hivEvolving 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
35003000250020001500
00 4 8 12 16 20 24
Hours
Pla
sma
co
nce
ntr
ati
on
o
f S
IM (
ng
/mL
), D
ay
7
Simeprevir (150 mg qd) for 7 days ( n = 24)
1000500
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
00 2 4 6 8 10 12
Hours
Pla
sma
co
nce
ntr
ati
on
o
f R
AL
(n
g/m
L),
Day
7
1000
500
Considering Switching Due to Drug-Drug Interactions
clinicaloptions.com/hivEvolving 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 48Stratified 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%.
clinicaloptions.com/hivEvolving 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 VFRAL
(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
clinicaloptions.com/hivEvolving 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: 348SWITCHMRK 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 = 174SWITCHMRK 2: n = 176)
Continue Lopinavir/Ritonavir 200 mg/50 mg BID+ other BL antiretroviral agents*
(SWITCHMRK 1: n = 174SWITCHMRK 2: n = 178)
Stratified by duration of LPV/RTV use (≤ 1 yr vs > 1 yr), age, race, sex,
region, hepatitis B and CWk 12 lipid
analysisWk 24 efficacy
analysis
*All patients continued background regimen including ≥ 2 NRTIs.
Eron JJ, et al. Lancet. 2010;375:396-407.
clinicaloptions.com/hivEvolving 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)
clinicaloptions.com/hivEvolving 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)
clinicaloptions.com/hivEvolving 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.
clinicaloptions.com/hivEvolving 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
Pat
ien
ts (
%)
9487
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
< 12
12
612
Virologic Success*
Virologic Nonresponse
No Data
n =
*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithmDiscontinued for AE, death, or missing data.
Arribas J, et al. CROI 2014. Abstract 551LB.
272 121 16 16
Considerations for HBV Coinfection
clinicaloptions.com/hivEvolving 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
clinicaloptions.com/hivEvolving 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
Pro
po
rtio
n W
ith
HIV
-1 R
NA
≤ 5
0 c
/mL
0.8
0.6
0.4
0.2
0
ITT, Regardless of ART Change
0 24 48 64 80 96 120 144
1.0
0.8
0.6
0.4
0.2
0
ITT, NC = Failure (Snapshot)
RALDRV/RTVATV/RTV
Study Wk
0 24 48 64 80 96 120 144
88%
94%
63%73%80%
RALDRV/RTVATV/RTV
clinicaloptions.com/hivEvolving 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 RALDRV/RTVCombined 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 < .001P = .001
P = .72
Brown T, et al. CROI 2014. Abstract 779LB. Reproduced with permission.
clinicaloptions.com/hivEvolving 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 hipTotal hipFemoral neck
1.4 (0.8-2.0)1.5 (0.3-2.7)
.0001
.01312.5 (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
.54022.7 (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.
clinicaloptions.com/hivEvolving 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
BaselineCT scan
DXA scan
Wk 48CT 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
clinicaloptions.com/hivEvolving 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-ScoreL1-L4
T-ScoreFemoral
Neck
T-ScoreTotal
Femoral
bPI baselinebPI 48 wksRAL baselineRAL 48 wks
0.170
0.058
0.890
0.080
0.078
0.016 0.336
0.004
0.112
clinicaloptions.com/hivEvolving 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)
Geo
met
ric
Mea
n (
pg
/mL
)
50
40
30
20
10
0
P < .001 P = .943
Baseline Wk 24
500
400
300
200
100
0
P < .001 P = .35030
25
15
10
5
0
P < .001 P = .11718
15
12
9
3
0
P < .001 P = .747
20
6
clinicaloptions.com/hivEvolving 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
clinicaloptions.com/hivEvolving 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
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 facultycommentary on switch strategies in HIV
clinicaloptions.com/HIVSwitchStrategies