HIV Treatment Update - UCLA Health

11/1/2016

1

Joel Gallant, MD, MPH

Southwest CARE CenterSanta Fe, NM

Johns Hopkins University School of Medicine

University of New Mexico School of Medicine

HIV Treatment UpdateWhen and What to Start

When and How to Switch

Disclosures

Consulting, Advisory Boards, and DSMBs

Bristol-Myers Squibb

Gilead Sciences

Janssen Therapeutics

Theratechnologies

ViiV Healthcare/GSK

Research Support

AbbVie

Bristol-Myers Squibb

Gilead Sciences

Janssen Therapeutics

Merck & Co.

Sangamo BioSciences

ViiV Healthcare/GSK

When to Start

11/1/2016

2

START: 57% Reduced Risk of Serious Events or Death With Immediate ART

1.8% vs 4.1% in deferred vs immediate arms experienced serious AIDS or non-AIDS related event or death: HR = 0.43 (95% CI: 0.30 to 0.62); P < .001

10

8

6

4

2

0

Cum

ulat

ive

Per

cent

With

Eve

nt

0 6 12 18 24 30 36 42 48 54 60

Month

Deferred ART

Immediate ART

Lundgren J, et al. N Engl J Med. 2015

When to Start?: GuidelinesSymptoms CD4

<200CD4

200-350CD4

350-500CD4 >500

US DHHS YES YES YES YES YES

IAS-USA YES YES YES YES YES

EACS YES YES YES YES YES

BHIVA (UK) YES YES YES YES YES

WHO YES YES YES YES YES

T.F.

• 28-year-old gay man presents with 3 days of fever, night sweats, lymphadenopathy, and sore throat. A rapid 4th

generation HIV test is positive

• Tested negative 6 months ago. Has been having condomless sex with multiple partners. He asked his primary care provider about PrEP and was told he would have to see “a specialist.”

• Otherwise in good health. Has well controlled depression on citalopram. He has been vaccinated against hepatitis B.

• Sees a nurse and case manager the day after diagnosis, and baseline lab tests are drawn. Has appointment with HIV provider in 10 days. Wants to start ART as soon as possible

11/1/2016

3

T.F.

When would you start ART?

1. After he keeps several clinic appointments (~3 months)

2. After baseline genotype results are available (~2-3 weeks)

3. At the HIV provider visit (10 days)

4. If creatinine is normal and HBsAg is negative (1-2 days)

5. Today

Same-Day ART vs Standard of Care in Haiti

HIV Dx

CD4, CXR, physician evaluation

ART readiness questionnaire

If no TB on CXR, and wants to start ART

Koenig S, et al. AIDS 2016; Durban, July 18-22, 2016; Abst. WEAE0202.

SOC• Days 7, 14, 21: physician &

social work visits• Day 21: ART initiation• Week 5: physician and social

work visit

Immediate ART• Days 1: counseling and ART

initiation• Days 3, 10, 17: physician &

social work visits• Day 24: physician visit

• 1255 patients evaluated

• 821 patients referred to study team

• 762 enrolled/randomized

Monthly visits

Standard Group (n=285)

Same-Day ART Group (n=279)

P-value

262 (92%) 279 (100%) p<0.001

Died 19 (7%) 8 (3%) p=0.035

Alive and in care 201 (71%) 224 (80%) p=0.007

In care, VL <50 120 (42%) 151 (54%) p=0.004

In care, VL <1000 143 (50%) 171 (61%) p=0.008

Koenig S, et al. AIDS 2016; Durban, South Africa; July 18-22, 2016; Abst. WEAE0202.

IMMEDIATE ART Study: 12 Month Outcomes

11/1/2016

4

561

Referral 1st Clinic Visit

1st PCPVisit

ART Prescribed

Viral load suppressed

RAPID Start of ART: UCSF experience

CD4-guided(2006-9)

Universal(2010-3)

RAPID

13237

Pilcher CD, et al. J Acquir Immune Defic Syndr 2016

Rapid Start:Potential regimens

Regimens to consider

DTG + FTC/TAF

EVG/c/FTC/TAF

DRV/c + FTC/TAF

Drugs to avoid

ABC (need HLA B*5701)

TDF (need eGFR)

RPV (need VL, CD4)

EFV, NVP (need genotype)

What to Start

11/1/2016

5

DHHS Guidelines, July 2016: What to Start

Recommended regimens

PI based DRV/r + (TDF/FTC or TAF/FTC)

INSTI based RAL + (TDF/FTC or TAF/FTC) EVG/c/TDF/FTC or EVG/c/TAF/FTC DTG + (TDF/FTC or TAF/FTC) DTG/ABC/3TC

Alternative regimens

NNRTI based EFV/TDF/FTC or EFV + TAF/FTC RPV/TDF/FTC or RPV/TAF/FTC (VL <100,000; CD4 >200)

PI based (ATV/c or ATV/r) + (TDF/FTC or TAF/FTC) (DRV/c or DRV/r) + ABC/3TC DRV/c + (TDF/FTC or TAF/FTC)

DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents, July 2016.

IAS–USA Guidelines, July 2016:What to Start

Günthard HF, et al. JAMA 2016;316:191-210.

Recommended Regimens

DTG/ABC/3TCDTG + FTC/TAFEVG/c/FTC/TAFRAL + FTC/TAF

Regimens When INSTIs are Not an Option

DRV/c or DRV/r + (FTC/TAF, FTC/TDF or ABC/3TC)EFV/FTC/TDFRPV/FTC/(TAF or TDF)

E/c/F/TAF studies 104 and 111:Efficacy Outcome (VL<50) at Week 48, 96, 144

Wohl D, et al. EACS 2015. Barcelona, Spain. Poster #LBBPD1/1.Wohl, D, et al, JAIDS 73(1), p 58-64 (2016)Ward D, HIV and Aging 2016 Poster #33.

Virologic Outcome Treatment Difference (95% CI)

9287

84

4 5 5 49 11

9085

80

4 4 4 611

16

0

20

40

60

80

100

Wk 48 Wk 96 Wk 144 Wk 48 Wk 96 Wk 144 Wk 48 Wk 96 Wk 144

Virologic Success

VirologicFailure

No VirologicData

E/C/F/TAF (n=866)

E/C/F/TDF (n=867)

HIV

-1 R

NA

<50

co

pie

s/m

L,

%

E/C/F/TAFE/C/F/TDF

-1.8 4.8

1.5

-0.7 4.7

2

-12% 12%

Week 48

Week 96

0.6

4.2

7.8

-12 0

Week 144

11/1/2016

6

GARDEL: LPV/r + 3TC noninferior to LPV/r + 2 NRTIs at Wk 48

CD4 increase similar

Grade 2-3 AEs more frequent in triple-ART arm (88 vs 65 events)

VF in 22 pts, of whom 2 had resistance (M184V)

– Both on dual ART Pat

ient

s (%

)

88.3 83.7

∆ 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 4.9n = 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. Lancet Infect Dis 2014;14:572-80

*VL< 50 c/mL by FDA Snapshot algorithm.

PADDLE: All Pts Virologically Suppressed by Wk 8 of DTG + 3TC

Included 4 pts with VL > 100,000 at BL

Figueroa MI, et al. EACS 2015. Abstract 1066.

Pt #

HIV‐1 RNA (copies/mL)

Screen BL Day 2 Day 4 Day 7 Day 10 Wk 2 Wk 3 Wk 4 Wk 6 Wk 8 Wk 12 Wk 24

1 5584 10,909 3701 383 101 71 < 50 < 50 < 50 < 50 < 50 < 50 < 50

2 8887 10,233 5671 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

3 67,335 151,569 37,604 1565 1178 266 97 53 < 50 < 50 < 50 < 50 < 50

4 99,291 148,370 11,797 3303 432 179 178 55 < 50 < 50 < 50 < 50 < 50

5 34,362 20,544 4680 1292 570 168 107 < 50 < 50 < 50 < 50 < 50 < 50

6 16,024 14,499 3754 1634 162 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

7 37,604 18,597 2948 819 61 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

8 25,071 24,368 6264 1377 Not done 268 105 < 50 < 50 < 50 < 50 < 50 < 50

9 14,707 10,832 Not done 516 202 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

10 10,679 7978 5671 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

11 50,089 273,676 160,974 68,129 3880 2247 784 290 288 147 < 50 < 50 < 50

12 13,508 64,103 3496 3296 135 351 351 84 67 < 50 < 50 < 50 < 50

13 28,093 33,829 37,350 26,343 539 268 61 < 50 < 50 < 50 < 50 < 50 < 50

14 15,348 15,151 3994 791 198 98 < 50 61 64 < 50 < 50 < 50 < 50

15 23,185 23,500 15,830 4217 192 69 < 50 < 50 < 50 Not done < 50 < 50 < 50

16 11,377 3910 370 97 143 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

17 39,100 25,828 11,879 1970 460 147 52 < 50 < 50 < 50 < 50 < 50 < 50

18 60,771 73,069 31,170 2174 692 358 156 < 50 < 50 < 50 < 50 < 50 < 50

19 82,803 106,320 35,517 2902 897 352 168 76 < 50 < 50 < 50 < 50 < 50

20 5190 7368 3433 147 56 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

Initial Therapy:My choices for specific clinical scenarios

Scenario Regimens

Wants single-tablet regimen (STR) DTG/ABC/3TC EVG/c/FTC/TAF

STR doesn’t matter DTG + FTC/TAF

HBV Coinfection FTC/TAF-based regimen

Starting without resistance test results DRV/c or DTG-based regimen

Desire for pregnancy (FTC/TDF or ABC/3TC) + RAL (FTC/TDF or ABC/3TC) + DRV/r

Questionable adherence DTG/ABC/3TC DRV/c + FTC/TAF

Tuberculosis EFV/FTC/TDF

Drug interactions (including HCV) DTG or RAL-based regimen

11/1/2016

7

Switching Therapy in Virologically Suppressed Patients

D.F.

48-year-old man with HIV since 2008. His nadir CD4 count was 362 and peak VL was 89,000.

Has been on EFV/TDF/FTC since diagnosis, with undetectable VL and a CD4 >500

2 years ago he declined switch to a newer regimen because he had no side effects other than vivid dreams, which he usually enjoyed, and he wanted a single-tablet regimen

eGFR consistently >60

Other medications: losartan 50 mg/d and atorvastatin 10 mg/d

HLA B*5701-negative

D.F.

What do you recommend now?1. Make no changes

2. Suggest switch to EFV + FTC/TAF

3. Suggest switch to DTG/ABC/3TC

4. Suggest switch to EVG/c/FTC/TAF

5. Suggest switch to DTG + FTC/TAF

6. Order bone density scan before deciding

11/1/2016

8

Switching therapy in suppressed patients: When and why?

• To manage side effects

• To manage or prevent drug toxicity

• To simplify regimen (number of doses or pills)

• To address food restrictions

• To address drug interactions

• To plan for pregnancy

Reasons to consider switching therapy in patients on older regimens

Nevirapine: Maybe– Reduce pill burden– Not toxicity (most toxicity

occurs with initiation)

Efavirenz: Maybe– CNS side effects– No TAF-based

coformulation

Older PIs: Maybe– Reduce pill burden– Decrease metabolic effects– Decrease GI side effects

Older NRTIs: Yes– d4T, ddI: SWITCH! (toxicity)– AZT: consider switch (toxicity,

side effects, simplification)

TDF: Why not?– Advantages of TAF over TDF

with no known disadvantages if no price difference

Switch studies in suppressed ptsTrial From To Outcome

GS-123 TDF/FTC + RAL EVG/COBI/FTC/TDF ✔

GS-264 TDF/FTC/EFV RPV/FTC/TDF ✔

Strategy-NNRTI TDF/FTC + NNRTI EVG/COBI/FTC/TDF ✔

Strategy-PI TDF/FTC + PI/r EVG/COBI/FTC/TDF ✔

SPIRIT 2 NRTI + PI/r RPV/FTC/TDF ✔

SPIRAL 2 NRTI + PI/r (exp’d pts) 2 NRTI + RAL ✔

SALT ATV/r + 2 NRTI ATV/r + 3TC ✔

OLE LPV/r + 2 NRTIs LPV/r + 3TC ✔

GS-109 TDF-based ART EVG/COBI/FTC/TAF ✔

STRIIVING Suppressive ART DTG/ABC/3TC ✔

ATLAS-M ATV/r + 2 NRTIs ATV/r + 3TC ✔

GS-119 “Salvage regimen” EVG/COBI/FTC/TAF + DRV ✔

LATTE CAB or EFV + 2 NRTIs CAB + RPV (PO) ✔

GS-1089 TDF/FTC + 3rd agent TAF/FTC + 3rd agent ✔

LATTE-1 CAB + ABC/3TC CAB + RPV (IM) ✔

GS-1160 EFV/FTC/TAF RPV/FTC/TAF ✔

GS-1216 RPV/FTC/TDF RPV/FTC/TAF ✔

Adapted from David Wohl

11/1/2016

9

STRIIVING: Switch to DTG/ABC/3TCEarly Switch Arm Week 24 and 48

85

1

14

88

1

10

83

<1

17

92

<17

0

20

40

60

80

100

Virologicsuccess

Virologicnon-response

No virologicdata

HIV

-1 R

NA

<50

co

pie

s/m

L, %

DTG/ABC/3TC, Day 1–Week 24 (n=275)a

Switch to DTG/ABC/3TC , Week 24–Week 48 (n=244)b

DTG/ABC/3TC, Day 1–Week 48 (n=275)

cART, Day 1–Week 24 (n=278)a

aITT-E analysis.

Lake J, et al. AIDS 2016; Durban, South Africa. Abstract THAB0203.

LYMPHOCYTE

TFV

TFV

RENAL TUBULAR

CELL

RENAL TUBULAR

CELL

91% lower plasma TFV

HIV

PLASMAGI

TRACT

TDF(tenofovirdisoproxilfumarate)

300 mg

TAF(tenofovir

alafenamide)

25 mg

TAF vs. TDF: Mechanism of Action

1. Lee W et al. Antimicr Agents Chemo 2005;49:1898-906; 2. Birkus G, et al. Antimicr Agents Chemo 2007;51:543-50;3. Babusis D, et al. Mol Pharm 2013;10:459-66; 4. Ruane P, et al. JAIDS 2013;63:449-5; 5. Sax P, et al. JAIDS 2014;67:52-8; 6. Sax P, et al. Lancet 2015;385:2606-15.

Summary of TAF Switch Studies (suppressed patients)

Trials:

GS 109: TDF-containing regimens to EVG/c/FTC/TAF

GS 112: Switch to EVG/c/FTC/TAF in patients with impaired renal function

GS 119: Switch to EVG/c/FTC/TAF + DRV in ART-experienced patients

GS 1089: FTC/TDF to FTC/TAF

GS 1160: EFV/FTC/TDF to RPV/FTC/TAF

GS 1216: RPV/FTC/TDF to RPV/FTC/TAF

Results:

Non-inferiority, with superiority in GS 109 for switch to EVG/c/FTC/TAF from EFV/FTC/TDF or ATV/r + FTC/TDF

Increase in bone density

Stability of eGFR (increase in GS 1089) with no tubular toxicity and decrease in overall and tubular proteinuria

11/1/2016

10

GS-109: Switching to E/C/F/TAF from TDF-based regimens

Mills A, et al. Lancet Infect Dis 2016;16:43-52

100

80

60

40

20

0

Wk

48

VL

< 5

0, %

All Prior Regimens

Prior EFV/TDF/FTC

Prior Boosted

ATV + TDF/FTC

Prior EVG/COBI/FTC/TDF

EVG/COBI/FTC/TAF TDF-Based RegimenPrimary Endpoint

P < .001 P = .02 P = .02P = NS

9793 96

9097

9298 97

932/959

444/477

241/251

112/125

390/402

183/199

301/306

149/153n/N =

-2.5 5.1

1.3

-5.3

-0.5

4.4

-10 0 10

GS 1089: Switch from F/TDF to F/TAFWeeks 48 and 96 Efficacy

FTC/TAF noninferior to FTC/TDF at Weeks 48 and 96

Raffi F, et al. HIV Glasgow, October 2016, Glasgow, UK, Presentation O125

FTC/TDF FTC/TAF

Pa

tien

ts, %

94

05

93

26

89

29

89

1

10

0

20

40

60

80

100

Treatment Difference (95% CI)Virologic Outcome

48 48 4896 96 96Week

Wk 48

Wk 96

Success(< 50 copies/mL)

Failure No Virologic Data

FTC/TAF (n=333) FTC/TDF (n=330)

-4.2 3.7

-0.3

-8 0 8

GS 1216: RPV/FTC/TDF to RPV/FTC/TAFVirologic Suppression at Week 48 (FDA snapshot)

Efficacy comparable across age, sex, geographic region

No emergent resistance mutations detected in either group

94

<16

94

06

0

20

40

60

80

100

Success Failure No Data

RPV/FTC/TAF n=316RPV/FTC/TDF n=313

Treatment Difference, % (95% CI)Virologic Outcome

Pat

ient

s, %

296 294n= 2 0 18 19

Orkin C, et al. HIV Glasgow 2016, Glasgow, UK

11/1/2016

11

-5.9 1.8

-2.0

-8 0 8

GS-1160: EFV/FTC/TDF to RPV/FTC/TAFVirologic Suppression at Week 48 (FDA snapshot)

Efficacy comparable across age, sex, geographic region No emergent resistance mutations detected in RPV/FTC/TAF group 1 pt in EFV/FTC/TDF group developed mutations (M184V, V106I/L, Y188L)

90

19

92

17

0

20

40

60

80

100

Success Failure No Data

RPV/FTC/TAF n=438EFV/FTC/TDF n=437

394 402n= 5 4 39 31

Pat

ient

s, %

Virologic Outcome Treatment Difference, % (95% CI)


GS 119: E/C/F/TAF + DRV for treatment-experienced patients

Objectives Primary

– Efficacy of E/C/F/TAF + DRV vs. BR at Week 24: FDA snapshot (<50) Secondary

– Safety and tolerability in both treatment arms over 24 and 48 weeks– Efficacy at Week 48: VL <50– Efficacy at Week 48: VL <20

Primary Efficacy Endpoint

Week 0

E/C/F/TAF + DRV 800 mg QD

Baseline Regimen (BR)

14448

n=89

n=46

Randomized (2:1), open-label (N=135)24

Eligibility: ≥4 mos <50 on ART containing DRV 2 prior failures ≥ 2-class resistance by

historical genotype (inc. ≤3 TAMs and K65R) Historical genotype with no INSTI-R or

currently on RAL No Q151M, T69ins, or DRV RAMS eGFR >50 mL/min

E/C/F/TAF +DRV 800 mg QD

Huhn G, et al. J Aquir Immune Defic Syndr 2016 [in press]

GS 119: Baseline Characteristics

%, unless otherwise indicated E/C/F/TAF + DRVn=89

Baseline Regimenn=46Characteristics

Median age, years 49 47

Male 82 61

Black (or African descent) 39 57

Median CD4 count, cells/μL 519 518

Median eGFRCG, mL/min 99 100

DM / HTN / CVD / Hyperlipidemia 8 / 34 / 7 / 46 11 / 37 / 4 / 28

Baseline Regimen

Median No. pills per day 5 5

≥6 pills per day 40 37

At least BID dosing 65 65

TDF / ABC / other NRTIs 61 / 11 / 12 54 / 11 / 13

RAL 56 50

Resistance

2-class / 3-class resistance 70 / 26 74 / 20

M184V/I 85 78

K65R 20 30

NNRTI-R / PI-R 89/ 38 87 / 28


11/1/2016

12

GS 119: Virologic Outcome (VL<50)Weeks 24 and 48

At Week 48, higher virologic success (VL <20) with E/c/F/TAF + DRV vs. BR (90% vs 72%, p=0.012)

No emergent resistance in E/c/F/TAF + DRV arm; 1 pt with viral rebound (Week 36) developed resistance (M184V+K65R) in BR arm

97

2 1

94

2 3

91

09

76

11 13

0

20

40

60

80

100

Success Failure No Data Success Failure No Data

Week 24

Proportional difference (95% CI)

5.3% (-3.4%, 17.4%)p=0.23

18.3% (3.5%, 33.0%)p=0.004

E/c/F/TAF + DRV (n=89)

Baseline Regimen (n=46)

Week 48


86

104

92

3 6

0

20

40

60

80

100

<29 IU/mL ≥29 IU/mL Missing

GS-1249: Switch to E/c/F/TAF in HIV/HBV co-infected patients

94

1 4

92

3 6

0

20

40

60

80

100

VirologicSuccess

Virologic Failure No Data

35

Pat

ient

s (%

)

FDA Snapshot HIV-1 RNA <50 c/mL

HBV DNA <29 IU/mL (Missing=Failure)

Outcomes of 3 patients on non-TDF based regimens• LPV/r+ ABC/3TC: HIV RNA <50 c/mL; HBV DNA declined from 143 to <20 IU/mL• RAL+ATV/r : HIV RNA remained <50 c/mL; HBV DNA declined from 259,000,000 to 51 IU/mL• ATV/r monotherapy: HIV RNA remained <50 c/mL; HBV DNA remained <20 IU/mL

Week 24

Week 48

Gallant J, et al. JAIDS 2016

TAF: Renal safety

11/1/2016

13

-26

3

-4

-30

3

27

43 47

-50

-25

0

25

50

GS 1089: Switch from F/TDF to F/TAF Change in Renal Biomarkers at Weeks 48 and 96

All differences between treatments statistically significant (p <0.001)

Med

ian

% C

hang

e

UrineAlbumin:Cr

Urine Protein:Cr

Urineβ2M:Cr

UrineRBP:Cr

10 4

-20

-10

0

10

20

Me

dian

Cha

nge,

mL/

min

eGFR

FTC/TAF FTC/TDF


4.5

p=0.002

Med

ian

(Q1,

Q3)

Cha

nge

eGF

R (

mL/

min

)*

Week Week

-0.6-4.1

p <0.001

GS 1216 and 1160:Change in eGFR at Week 48

0.7

Study 1216 Study 1160

RPV/FTC/TAFEFV/FTC/TDF

RPV/FTC/TAFRPV/FTC/TDF


TAF: Bone safety

3

11/1/2016

14

GS 1089: Switch from F/TDF to F/TAF: Bone density changes through Week 96

321 310 300

320 310 306

294

297

287

292

321 309 300

317 305 303

293

296

288

289

FTC/TAF

FTC/TDF

n

Mea

n %

Cha

nge

(95%

CI)

Spine

WeekWeek

2.2

-0.2

p <0.001

Hip

1.9

-0.3

p <0.001

1.7

-0.1

1.2

-0.1

FTC/TAF FTC/TDF p value FTC/TAF FTC/TDF p value

≥ 3% increase 40% 18% < 0.001 29% 11% < 0.001

≥ 3% decrease 8% 19% < 0.001 6% 15% < 0.001


-2

-1

0

1

2

BL Wk 24 Wk 48

GS 1216 and 1160Change in Spine BMD Through Week 48

Mea

n %

Cha

nge

(95%

CI)

1.61

0.08

1.65

-0.05

p <0.001 p <0.001

-2

-1

0

1

2

BL Wk 24 Wk 48

Study 1216 Study 1160

187 178 172

(n=) 176 174 168

394 373 351

400 382 369

(n=)

(n=)

(n=)

RPV/FTC/TAFEFV/FTC/TDF

RPV/FTC/TAFRPV/FTC/TDF

RPV/FTC/TAF RPV/FTC/TDF RPV/FTC/TAF EFV/FTC/TDF

≥3% increase 27% 11% p<0.001 29% 13% p<0.001

≥3% decrease 6% 13% p=0.044 7% 14% p=0.001


TDF to TAF switch

Advantages:

Greater renal safety

Improved bone density

Smaller pill size

Disadvantages:

Loss of TDF lipid effect

TAF will be more expensive than generic TDF

Günthard HF, et al. JAMA 2016;316:191-210.

IAS-USA recommendations: “If there is no increase in the price of TAF vs. that of TDF, switching from TDF to

TAF is reasonable even if patients are not experiencing TDF-related toxic effects.”

11/1/2016

15

Slide 43 of 39

D.F.

Outcome: D.F. decided to make a switch based on the greater safety of TAF. He considered switching to FTC/TAF + EFV but decided that the dreams weren’t always enjoyable, and ended up switch to EVG/c/FTC/TAF

LATTE-2: IM Cabotegravir + Rilpivirine For Long-Acting Maintenance ART

Phase IIb, multicenter, open-label study

– Primary endpoints: VL < 50 by FDA snapshot, PDVF, and safety at maintenance Wk 32

Margolis DA, et al. CROI 2016. Abstract 31LB.

CAB 400 mg IM + RPV 600 mg IM Q4W(n = 115)

CAB 600 mg IM + RPV 900 mg IM Q8W(n = 115)

*Pts with VL < 50 from Wk 16 to Wk 20 continued to maintenance phase.

ART-naive HIV+ pts with

CD4 > 200(N = 309)

CAB 30 mg PO + ABC/3TC PO QD(n = 56)

CAB 30 mg PO QD + ABC/3TC

Wk 32primary analysis; dose selection

Wk 20

Induction Phase* Maintenance Phase

Wk 1 Wk 96

LATTE-2: Week 48 Results: VL <50 Snapshot (ITT-ME)

Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.

Snapshot success

D1 W32

Q4W 99% 94%

Q8W 95% 95%

Oral 98% 91%Pro

po

rtio

n o

f p

atie

nts

wit

h

viro

log

ical

su

pp

ress

ion

, %

BL W-16 W-12 W-8 D1 W4 W8 W12 W16 W20 W24 W28 W32

Study visit

Induction period Maintenance period

W-4 W36 W40 W44 W48

Oral CAB induction (ME population) Oral CAB (n=56) Q4W IM (n=115) Q8W IM (n=115)

11/1/2016

16

LATTE-2 VL <50 at Week 48 ITT-ME (Snapshot)

Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.

Oral IM

Virologic outcomes Treatment differences (95% CI)

-6.6 12.4

Q8W IM

-7.6 11.6

Q4W IM

Both Q8W and Q4W comparable to Oral CAB at Week 48a

2 subjects with resistance in 8 wk arm: 1 with INSTI mutations, 1 with NNRTI mutations

Switch to DTG + RPV in Suppressed Pts With Multiple Previous Treatment Failures

Open-label cohort study based in clinical practice setting (N = 38)

– DTG 50 mg/day + RPV 25 mg/day for pts with long-term virologic suppression but virologic failure on > 1 previous ART regimens

VL suppressed to < 35 in 92% (35/38) at Wk 48

– No virologic failures; 3 pts d/c (GI toxicity, DDI, physician decision, n = 1)

DTG + RPV associated with improved liver function tests, improved lipid profile, and stable kidney function at Wk 48

Díaz A, et al. AIDS 2016. Abstract TUPDB0106.

Baseline Characteristic , % Switch to DTG + RPV (N = 38)

Regimen at time of switch NRTI + NNRTI + PI

NRTI + NNRTI + PI + INSTI

85

53

Reasons for switch to DTG + RPV Drug–drug interaction Toxicity Simplification

383325

Pre-existing resistance mutations NRTI: 65; NNRTI: 37; PI: 32; INSTI: NA

DTG Monotherapy

• 113 virologically suppressed patients in 4 observational studies at 4 centers switched to DTG monotherapy

• Virologic failure with emergence of integrase resistance occurred in 5 patients (4.4%)

• 4 had history of prior INSTI use, one with RAL failure. None had documented INSTI resistance

Oldenbuettel C, et al. Antiviral Ther 2016Rojas J, et al. J Antimicrob Chemother 2016 Jul;71:1975-81. Katlama C, et al. J Antimicrob Chemother 2016 Sep;71:2646-50. Gabavu, C, et al. J Antimicrob Chemother 2016;71:1046-50.

11/1/2016

17

Switch studies in suppressed ptsTrial From To Outcome

GS-123 TDF/FTC + RAL EVG/COBI/FTC/TDF ✔

GS-264 TDF/FTC/EFV RPV/FTC/TDF ✔

Strategy-NNRTI TDF/FTC + NNRTI EVG/COBI/FTC/TDF ✔

Strategy-PI TDF/FTC + PI/r EVG/COBI/FTC/TDF ✔

SPIRIT 2 NRTI + PI/r RPV/FTC/TDF ✔

SPIRAL 2 NRTI + PI/r (exp’d pts) 2 NRTI + RAL ✔

SALT ATV/r + 2 NRTI ATV/r + 3TC ✔

OLE LPV/r + 2 NRTIs LPV/r + 3TC ✔

GS-109 TDF-based ART EVG/COBI/FTC/TAF ✔

STRIIVING Suppressive ART DTG/ABC/3TC ✔

ATLAS-M ATV/r + 2 NRTIs ATV/r + 3TC ✔

GS-119 “Salvage regimen” EVG/COBI/FTC/TAF + DRV ✔

LATTE CAB or EFV + 2 NRTIs CAB + RPV (PO) ✔

GS-1089 TDF/FTC + 3rd agent TAF/FTC + 3rd agent ✔

LATTE-2 CAB + ABC/3TC CAB + RPV (IM) ✔

GS-1160 EFV/FTC/TAF RPV/FTC/TAF ✔

GS-1216 RPV/FTC/TDF RPV/FTC/TAF ✔

SWITHCMRK 2 NRTI + LPV/r (exp’d pts) 2 NRTI + RAL ✗

HARNESS 2 NRTI + 3rd Agent ATV/r + RAL ✗

Inferior efficacy of RAL appeared driven by more failure among pts with previous virologic failure

SWITCHMRK: Prior failure predicts failure

Eron JJ, et al. Lancet. 2010;375:396-407.

Outcome

SWITCHMRK1 SWITCHMRK 2

RAL(n = 174)

LPV/r (n = 174)

RAL(n = 176)

LPV/r (n = 178)

Patients without previous virologic failure

VL < 50 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

VL < 50 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)

Switching: Caveats

Know the treatment and resistance history

Avoid switching from high barrier to lower barrier agents when you don’t

11/1/2016

18

Switching and simplifying therapy

“Vertical Switches”: switch to drug with lower resistance barrier

Most drug discontinuations

Boosted PI → NNRTI

Boosted PI → INSTI

Boosted PI → any STR

DRV/r twice daily → once daily

“Horizontal Switches”: switch to drug with equal or higher resistance barrier

RTV → COBI (boosters)

Switches within INSTI class

EFV or NVP → RPV or ETR

LPV/r or ATV/r → DRV/r

ABC or AZT → TDF/TAF

TDF → TAF

Toma J, et al. ICAAC 2015, September 17-21, 2015, San Diego.

• Concordance with historical resistance (individual ARVs): 85%

• NNRTIs: 93%• PIs: 84%• NRTIs: 76%

• Identified major wild-type (nonmutant) variants at 97% • False omission rate 3%.

The rationale for 2-drug regimens

• (To avoid NRTI toxicity)

• Reduce cost (e.g. 3TC + X)

• Allow for long acting therapy (e.g. CAB + RPV)

11/1/2016

19

“Nuke-sparing” and “nuke-lite” regimens

Regimen Results

DRV/r + RAL (ACTG 52621) Poor performance at high VL

DRV/r + RAL (NEAT2) Less effective at high VL, low CD4

DRV/r + MVC (MODERN3) Less effective than standard ART

ATV/r + RAL (HARNESS4 – switch) Less effective than standard ART

LPV/r + RAL (PROGRESS5) Small study; few pts with high VL

LPV/r + EFV (ACTG 51426) Poorly tolerated but effective

LPV/r + 3TC (GARDEL7) As effective as standard ART

LPV/r + 3TC or FTC (OLE8 – switch) As effective as standard ART

ATV/r + 3TC (SALT9 – switch) As effective as standard ART

DTG + 3TC (PADDLE10) Promising but preliminary1. Taiwo B, et al. AIDS. 2011;25:2113-222. Raffi et al. CROI 2014, Abstract 84LB3. Stellbrink H-J, et al. IAD 2014. Abstract MOAB01014. Van Lunzen J et al. IAC 2014. Abstract A-641-0126-113075. Reynes J, et al. AIDS Res Hum Retroviruses. 2013;29:256-65

6. Daar ES et al. Ann Intern Med 2011 7. Cahn P, et al. Lancet Infect Dis 2014;14:572-808. Gatell J, et al. AIDS 2014. Abstract LBPE17. 9. Perez-Molina, JA, et al. IAC 2014. Abstract LBPE18.10 Figueroa MI, et al. EACS 2015. Abstract 1066.

The pipeline

Integrase Inhibitors• Raltegravir: Once daily formulation (two 600 mg tabs)• Bictegravir: Once-daily unboosted INSTI coformluated with FTC/TAF• Cabotegravir: Long-acting injectable for treatment or PrEP

NNRTIs• Doravirine: Active against resistant virus, better tolerated than EFV• Rilpivirine: Long-acting injectable version for treatment or PrEP

Entry Inhibitors• Ibalizumab: Monoclonal antibody that binds to CD4, given by IV infusion

every 2 weeks • Fostemsavir: Binds to gp120

Conclusions

ART should be started as soon as possible after diagnosis in patients who are ready

Immediate initiation (e.g. day of diagnosis) is now feasible with some regimens and shortens time to suppression

TAF- and integrase inhibitor-based regimens now dominate the list of recommended regimens

Switching therapy can be considered in suppressed patients to improve convenience, tolerability, or safety

Resistance and resistance barriers must be considered when switching therapy in experienced patients

HIV Treatment Update - UCLA Health

Documents

Transcript of HIV Treatment Update - UCLA Health