hiv alert: best practices in art following recent drug approvals.2016

HIV Alert: Best Practices in ART Following Recent Drug Approvals

This program is supported by independent educational grants from Gilead Sciences and ViiV Healthcare.

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Faculty

Eric S. Daar, MDChief, Division of HIV MedicineHarbor-UCLA Medical CenterProfessor of MedicineDavid Geffen School of Medicine at UCLALos Angeles, California

Joel E. Gallant, MD, MPHMedical Director of Specialty ServicesSouthwest CARE CenterSanta Fe, New MexicoAdjunct Professor of MedicineDivision of Infectious DiseasesJohns Hopkins University School of MedicineBaltimore, Maryland

Faculty Disclosure Information

Eric S. Daar, MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Teva, and ViiV and funds for research support from Bristol-Myers Squibb, Gilead Sciences, Merck, and ViiV.

Joel E. Gallant, MD, MPH, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV and funds for research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Sangamo, and ViiV.


Program Overview

Indications and Supporting Data for FTC/TAF How FTC/TAF Compares With Other NRTI

Backbones Expert Perspective

– When I’ll Use FTC/TAF… and When I Won’t



FTC/TAF Recently FDA Approved

Label information:

– Indicated in combination with other ARVs for the treatment of HIV infection

– Not recommended for pts with CrCl < 30 mL/min

– No dose adjustment necessary CrCl ≥ 30 mL/min; FTC/TDF requires dose adjustment CrCl 30-49 mL/min

– Not indicated for PrEP or for pts coinfected with HBV

– Dose: FTC 200 mg, TAF 25 mg

Joins other approved TAF-containing fixed-dose combinations

– EVG/COBI/FTC/TAF

– RPV/FTC/TAF

FTC/TAF [package insert]. April 2016. FTC/TDF [package insert]. April 2016.


Clinical Trials Supporting FTC/TAF Use

Study Pt Population Treatment

GS-104/111[1] Treatment naive(N = 1733)

Pts randomized to EVG/COBI/FTC/TAF* or

EVG/COBI/FTC/TDF

GS-109[2]Virologically suppressed on

TDF-based regimen(N = 1436)

Pts switched to EVG/COBI/FTC/TAF* or remained on TDF-based regimen

GS-1089[3]Virologically suppressed on

FTC/TDF + third ARV(N = 663)

Pts switched to FTC/TAF† + continued third ARV or remained on FTC/TDF +

third ARV

GS-112[4]

Virologically suppressed on varied regimens;

stable eGFRCG 30-69 mL/min(N = 242)

Pts switched to EVG/COBI/FTC/TAF*


1. Sax PE, et al. Lancet. 2015;385:2606-2615. 2. Mills A, et al. Lancet Infect Dis. 2016;16:43-52. 3. Gallant JE, et al. Lancet HIV. 2016;3:e158-e165. 4. Pozniak A, et al. J Acquir Immune Defic Syndr. 2016;71:530-537.

*EVG/COBI/FTC/TAF dosing: 150/150//200/10 mg.†FTC/TAF dosing: 200/10 mg with boosted PIs; 200/25 mg with unboosted third drug.


Wk 48 Efficacy: TAF-Based Treatment Noninferior to TDF-Based Treatment

1. Sax PE, et al. Lancet. 2015;385:2606-2615. 2. Mills A, et al. Lancet Infect Dis. 2016;16:43-52. 3. Gallant JE, et al. Lancet HIV. 2016;3:e158-e165.

100

80

60

40

20

0

Wk

48 H

IV-1

RN

A

< 50

c/m

L (%

)GS-104/111[1]

Tx Naive*

TAF-based regimenTDF-based regimen

92 9097 93 94 93


GS-109[2]

Switch†GS-1089[3]

Switch‡

2.0%(-0.7% to 4.7%)

Tx Difference(95% CI)

4.1%(1.6% to 6.7%)

P = .0002

1.3%(-2.5% to 5.1%)

*GS-104/111: EVG/COBI/FTC/TAF vs EVG/COBI/FTC/TDF. †GS-109: Switched to EVG/COBI/FTC/TAF or remained on TDF-based ART. ‡GS-1089: Switched to FTC/TAF + third ARV or remained on FTC/TDF + third ARV.

n/N =932/959

444/477

314/333

307/330

800/866

784/867


TAF Associated With Improvements in Renal Markers vs TDF In each of the GS-104/111,[1] GS-109,[2] and GS-

1089[3] studies, FTC/TAF-based treatment was associated with each of the following (vs TDF-based treatment) at treatment Wk 48:

– Higher eGFRCG

– Less proteinuria (urinary protein, albumin, RBP, and β2-microglobulin to Cr ratio)

No proximal renal tubulopathy or Fanconi syndrome associated with FTC/TAF-based treatment


1. Sax PE, et al. Lancet. 2015;385:2606-2615. 2. Mills A, et al. Lancet Infect Dis. 2016;16:43-52.3. Gallant JE, et al. Lancet HIV. 2016;3:e158-e165.


TAF Associated With Improved BMD vs TDF

GS-104/111[1]: smaller declines in spine and hip BMD associated with starting EVG/COBI/FTC/TAF vs EVG/COBI/FTC/TDF at Wk 48 (P < .0001)

GS-109[2] and GS-1089[3]: switching to FTC/TAF-based treatment improved spine and hip BMD vs remaining on FTC/TDF-based treatment at Wk 48



Spine4

2

0

Mea

n %

Cha

nge

in B

MD

(95%

CI)

1.5

-0.2

P < .001

BL Wk 24 Wk 48

Hip4

2

0

1.1

-0.2BL Wk 24 Wk 48

GS-1089: Mean % BMD Change From BLFTC/TAFFTC/TDF

P < .001


Lipid Increases Greater With TAF Than TDF

TAF lacks lipid-lowering effects of TDF but does not have negative impact on lipids

Similar lipid effects observed in GS-109[2] and GS-1089[3]


GS-104/111: Median Lipid Changes in Treatment-Naive Pts[1]


200

150

100

50

0

5

4

3

2

1

0

189

160

177

163115

101

109104

5144 44

48

114

95

108100

3.73.6

3.73.6

TC:HDL RatioP = .84

TriglyceridesP = .027

HDLP < .001

LDLP < .001

TCP < .001

EVG/COBI/FTC/TAF Wk 48 Baseline

EVG/COBI/FTC/TDF Wk 48 Baseline

Med

ian

Valu

es (m

g/dL

)

GS-1249: Switching Pts With HIV/HBV Coinfection to EVG/COBI/FTC/TAF International, multicenter, single-arm, open-label phase IIIb trial (N = 72)

– Pts with virologically suppressed HIV infection on any regimen, chronic HBV coinfection, and eGFR > 50 mL/min switched to EVG/COBI/FTC/TAF for 48 wks

By Wk 48, 2/70 (3%) pts lost HBsAg/gained HBsAb; 2/30 (7%) pts had lost HBeAg; 1/30 (3%) pts gained HBeAb

20

Gallant J, et al. IAS 2015. Abstract WELBPE13.

Pts

(%)

94 92

Wk 24Wk 48

100

80

60

40

20

0

HBV DNA < 29 IU/mL

86 92

HIV-1 RNA < 50 c/mL 100

80

60

40

0


GS-119: Switch to EVG/COBI/FTC/TAF + DRV in Treatment-Experienced Pts Multicenter, open-label, randomized trial in which virologically suppressed,

treatment-experienced pts on DRV-containing ART with history of drug resistance* switched to EVG/COBI/FTC/TAF + DRV (n = 89) or continued on baseline ART (n = 46)

– 39% of pts receiving ≥ 6 pills/day at BL; median pills/day at BL = 5

2

100

Huhn G, et al. IDWeek 2015. Abstract 726. Slide credit: clinicaloptions.com

*Resistance to ≥ 2 ARV classes, including ≤ 3 thymidine analogue mutations and K65R, but not integrase inhibitors, unless currently receiving raltegravir, and there is no DRV resistance.

HIV-1 RNA < 50 c/mL

94

80

60

40

20

0Virologic Failure No Data

76

113

13

EVG/COBI/FTC/TAF + DRVBaseline ART

Treatment difference: 18.3% (95% CI: 3.5% to 33.0%; P = .004)

Pts,

Wk

48 (%

)

Comparing NRTI Backbones


Considerations With NRTI Backbones and Associated RegimensNRTIs Considerations

ABC/3TC

DTG/ABC/3TC* only STR including unboosted INSTI Mixed data on CVD risk with ABC in high-risk pts Cannot be used in HLA-B*5701–positive pts Not recommended for pts with CrCl < 50 mL/min

FTC/TDF

STRs: EVG/COBI/FTC/TDF,* EFV/FTC/TDF, RPV/FTC/TDF Potential for renal toxicity and proximal tubulopathy EVG/COBI/FTC/TDF should not be initiated in pts with CrCl < 70 mL/min;

discontinue in pts with CrCl < 50 mL/min EFV/FTC/TDF or RPV/FTC/TDF: not for use in pts with CrCl < 50 mL/min FTC/TDF must be dose adjusted when CrCl 30-49 mL/min Potential for decreases in BMD Lipid-lowering effects

FTC/TAF

STRs: EVG/COBI/FTC/TAF* and RPV/FTC/TAF Comparable efficacy and improved renal and bone profiles vs FTC/TDF No dose adjustment necessary when CrCl ≥ 30 mL/min

*DHHS guideline–recommended initial regimen.

References in slidenotes.

Expert Perspective: Selecting Therapy in the New

Treatment Landscape


Key Questions and Considerations Surrounding Use of FTC/TAF Should TDF-based regimens be dropped from

consideration of “optimal” first-line regimens? When considering DTG, what are the pros and cons

of DTG/ABC/3TC vs DTG + FTC/TAF? Are there specific pts for whom the FTC/TAF

backbone should ALWAYS be used? Specific pts for whom it should NEVER be used?

Should all pts on TDF-based regimens be switched proactively to TAF-based regimens?


Should TDF-Based Regimens Still Be Considered as Initial Therapy?

DHHS-Recommended First-line Regimens, January 2016

INSTI based

DTG/ABC/3TC

RAL + FTC/TDF

DTG + FTC/TDF

EVG/COBI/FTC/TDF

EVG/COBI/FTC/TAF

Boosted PI based

DRV/RTV + FTC/TDF

DHHS ART Guidelines. January 2016.


Should TDF-Based Regimens Still Be Considered as Initial Therapy?

EFV/FTC/TDF remains effective, economical, convenient choice for many pts in resource-constrained settings

DHHS ART Guidelines. January 2016.

DHHS-Recommended First-line Regimens With TAF Replacements

INSTI based

DTG/ABC/3TC

RAL + FTC/TAF

DTG + FTC/TAF

EVG/COBI/FTC/TAF

Boosted PI based

DRV/RTV + FTC/TAF


If DTG Is Your Preferred INSTI, How Do You Choose DTG/ABC/3TC vs DTG + FTC/TAF?

ConsiderationPotential Choice

DTG/ABC/3TC DTG + FTC/TAFPt might benefit from STR vs MTR (adherence or preference)

Pt has high CVD risk

Pt is HLA-B*5701 positive

Pt has osteopenia or osteoporosis

Pt has renal impairment * *DTG/ABC/3TC not recommended for pts with CrCl < 50 mL/min as 3TC dose adjustment required.

DTG/ABC/3TC [package insert]. September 2015. FTC/TAF [package insert]. April 2016.


Opinion: For Which Pts Will I Always/ Never Use TAF-Based Therapy? Always/usually

– Pts with high CVD risk

Relative contraindications

– Pts with potential COBI drug interactions (EVG/COBI/FTC/ TAF)

– Pt receiving PPIs or H2 blockers (RPV/FTC/TAF)

– Pt with CD4+ cell count < 200 c/mm3 (RPV/FTC/TAF)

Never/unlikely

– Pt with CrCl < 30 mL/min

– Pt with severe hepatic impairment (EVG/COBI/FTC/ TAF)

– Pt with HIV-1 RNA > 100,000 copies/mL (RPV/FTC/TAF)

– Pt receiving rifamycin

– Pregnant pt

– As PrEP

References in slidenotes.


Should All Pts on TDF-Based Regimens Be Switched to TAF-Based Regimens? Considerations for switching to TAF-based regimen

– Efficacy maintained

– Renal and bone improvements

Considerations for maintaining therapy

– Does switch require adjustment from STR to MTR?

– Relevant for pts on EFV/FTC/TDF

– Long-term data with TDF-based regimens


Take-Home Points

Guideline-recommended regimens for first-line therapy likely to evolve to FTC/TAF + an INSTI or DRV/RTV or DTG/ABC/3TC

TAF-based treatment noninferior to TDF-based treatment in terms of efficacy in first-line and switch settings

– TAF-based treatment associated with improved BMD and renal function vs TDF-based treatment

TAF-based regimens should be considered:

– To replace TDF-based regimens as optimal agents in the first-line setting

– As switch options for pts on TDF-based regimens

Use of FTC/TAF-containing vs ABC/3TC-containing regimens should be considered for each individual pt

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