evolving switch strategies for virologically suppressed hiv-infected patients.2014

Evolving Switch Strategies for Virologically Suppressed HIV-Infected Patients

This activity is supported by an independent educational grant from Gilead Sciences.

clinicaloptions.com/hivEvolving Switch Strategies for Virologically Suppressed HIV-Infected Patients

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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.


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


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


Faculty Disclosures

Oluwatoyin Adeyemi, MD, has disclosed that she has received consulting fees from Bristol-Myers Squibb and Gilead Sciences.

José R.Arribas, MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Tobira, and ViiV.

Joseph J. Eron, Jr., MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Merck, Tibotec/Janssen, and Tobira; has received funds for research support paid to the University of North Carolina from GlaxoSmithKline/ViiV; and has served on a data and safety monitoring board for Vertex.

Anton L. Pozniak, MD, FRCP, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Merck, Tobira, and ViiV; has received fees for non-CME/CE services received directly from a commercial interest or their agents (eg, speaker bureaus) from Gilead Sciences; and has received funds for research support from Bristol-Myers Squibb, Gilead Sciences, and ViiV.

Background on Switching Strategies


Why Switch ART in Virologically Suppressed Patients? Convenience

– Reduce pill count/dosing frequency

– Adjust food restrictions

Tolerability

– Eliminate/reduce adverse effects

Drug–drug interactions

– Avoid deleterious interactions with non-HIV medications

Pregnancy

– Reduce risk of teratogenicity

– Achieve adequate drug levels

Cost

– To patient (copays)

– To healthcare system (generics, competitive pricing, discounts)DHHS. Adult antiretroviral guidelines, May 2014.


DHHS ART Treatment Guidelines 2014

DHHS. Adult antiretroviral guidelines, May 2014.


Why Switch ART in Virologically Suppressed Patients? Potential drawbacks

– Exposure to new agents risks new toxicities

– If any previous resistance or history of resistance, switching even if undetectable can be an issue

– Inability to adjust dose of a component if necessary when switching to a fixed-dose formulation

– Potential for pharmacy/patient error

– Can be more expensive

– “If it ain’t broke, don’t fix it”


Principles of ART Switch

Maintain viral suppression (do no harm or don’t mess up)

Need to know beforehand

– Previous ART history

– Previously demonstrated or possible/probable ARV resistance based on history

– Drug-resistant virus remains archived in latently infected cells and does not disappear even if not detected by resistance tests

– Likelihood of patient adherence to new regimen and its requirements

– Patient acceptance of any new potential adverse effects

– Other mediations for potential DDIs

– Affordability

Use available evidence to guide switch decisions


STRATEGY-NNRTI: Switch to EVG/COBI/TDF/FTC in Suppressed Pts Randomized, open-label switch study in pts virologically suppressed on an

NNRTI + TDF/FTC regimen for ≥ 6 mos

Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48

HIV-1 RNA < 50 c/mL, 2 previous regimens, no resistance to FTC or TDF

and CrCl ≥ 70 mL/min(N = 434)

Switch to EVG/COBI/TDF/FTC QD(n = 291)

Remain on NNRTI + TDF/FTC(n = 143)

Pozniak A, et al. CROI 2014. Abstract 553LB.

*Pts with previous VF ineligible.


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


*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


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


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)


(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)


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


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,

(%

)


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


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


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


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)


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?


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


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


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


4

2

1

0.5

> 90

80.1-90

70.1-80

60.1-70< 60

Abacavir



Atazanavir Nephrolithiasis

Renal calculi in which the ATV content was 41% to 49% by weight[1]

Chelsea and Westminster Hospital comparison[2] of rate of development of renal stones in ATV/RTV recipients (n = 1206) vs combined group of EFV, LPV/RTV, or DRV/RTV recipients (n = 4449):

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.


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]


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%


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.


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)


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.


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)


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 (

%)


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.


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.


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)


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)


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)


(n = 60)


(n = 61)

Wk 48primary analysis

Stratified by HIV-1 RNA (≤ vs > 100,000 c/mL) and NRTI Wk 24

Induction Phase* Maintenance Phase


LATTE: Virologic Success During Induction and Maintenance Phases

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


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


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%)


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


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


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


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)


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


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


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


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


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%.


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


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.


SWITCHMRK: Main Findings

RAL did not meet efficacy noninferiority criteria vs continued LPV/RTV at Wk 24; study terminated

– However, comparable efficacy between arms among patients receiving LPV/RTV as first regimen at study entry


Outcome

SWITCHMRK1 SWITCHMRK 2

RAL(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




SWITCHMRK: Main Findings

Inferior efficacy of RAL appeared driven by higher failure rate among patients with previous virologic failure


Outcome

SWITCHMRK1 SWITCHMRK 2

RAL(n = 174)

LPV/RTV (n = 174)

RAL(n = 176)

LPV/RTV (n = 178)

Patients without previous virologic failure



Patients with previous virologic failure


Treatment difference, % (95% CI) -17.3 (-33.0 to -2.5) -14.2 (-26.5 to -2.6)


STRATEGY-PI: Switch to EVG/COBI/TDF/FTC in Suppressed Pts Randomized, open-label switch study in pts virologically suppressed

on a boosted PI–based regimen (both with TDF/FTC) for ≥ 6 mos

Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48

HIV-1 RNA < 50 c/mL, 2 previous regimens, no resistance to FTC or TDF

and CrCl ≥ 70 mL/min(N = 433)

Switch to EVG/COBI/TDF/FTC QD(n = 293)

Remain on Boosted PI + TDF/FTC(n = 140)

Arribas J, et al. CROI 2014. Abstract 551LB.

*Pts with previous VF ineligible.


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


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


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


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.


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.


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


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


ASSURE: Bone Biomarkers

Bone biomarkers all declined significantly (P < .001) from BL in the ABC/3TC + ATV arm, with no significant change in the TDF/FTC + ATV/RTV arm

Difference between groups was also significant (P < .001)

Parathyroid Hormone

C-Telopeptide Osteocalcin Bone Alkaline Phosphatase


ABC/3TC + ATV

(n = 183)


ABC/3TC + ATV

(n = 181)


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


Summary

Switch regimens

– For most patients, one of the single-pill combination regimens is likely to be appropriate

– Individualized management requires weighing trade-offs among characteristics of individual drugs

– In some cases, an alternative regimen may be preferred for a particular patient depending on the trade-offs for that regimen vs preferred options

Newer strategies such as dolutegravir, NRTI-sparing, or PI monotherapy regimens may be appropriate for carefully selected patients

Drugs in development may offer additional options, including additional single-tablet regimens, but lack long-term safety and efficacy data


Summary: Principles of ART Switch

Maintain viral suppression (do no harm or don’t mess up)

Need to know beforehand

– Previous ART history

– Previous demonstrated or possible/probable ARV resistance based on history

– Likelihood of patient adherence to new regimen and its requirements

– Patient acceptance of any new potential adverse effects

– Other medications for potential DDIs

– Affordability

Use available evidence to guide switch decisions

Go Online for More Educational Content on Switch Strategies in

HIV!Interactive Virtual Presentation featuring streaming narration of these slides and case studies illustrating HIV switch strategies by expert faculty David A. Wohl, MD and panel discussion by Oluwatoyin Adeyemi, MD, Jose R. Arribas, MD, Joseph J. Eron, Jr., MD, and Anton L. Pozniak, MD

ClinicalThought™ with expert facultycommentary on switch strategies in HIV

clinicaloptions.com/HIVSwitchStrategies

http://www.clinicaloptions.com/HIV/Treatment%20Updates/HIV%20Switch%20Strategies.aspx

evolving switch strategies for virologically suppressed hiv-infected patients.2014

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