Optimizing Clinical Utility of

Integrase Inhibitors

Anton Pozniak MD FRCP

INSTIs-Characteristics

• Rapid viral load decline

• Low rates resistance/ Transmitted Resistance

• Less chance of side effects

• Less pills, some are formulated as an STR

• Few drug interactions with unboosted INSTIS

3 Drug therapy is Standard of Care in ART Naive

Regimen EACS IAS-USA DHHS

RPV/TDF/FTCRecommended

or use TAFAlternative Alternative

DRV/r or/ c + TDF/FTC

Recommendedor use TAF

Alternative Recommended or

use TAF

ATV/r + TDF/FTC Alternative Alternative Alternative

EVG/c +TDF/FTCRecommended

or use TAFRecommended*

Use TAFRecommended or

use TAF

RAL + TDF/FTCRecommended

or use TAFRecommended*

Use TAFRecommended or

use TAF

DTG + TDF/3TCRecommended

or use TAFRecommended*

Use TAFRecommended or

use TAF

DTG + ABC/3TC Recommended Recommended Recommended

DHHS ART Guidelines. July 2016. Günthard HF, et al. JAMA. 2016;316:191-210.

EACS ART Guidelines. October 2016.

WHO Guidelines Programs in Botswana and Brazil and more coming

Regimen WHO

EFV 600mg TDF/XTC Recommended-

EFV 400mg TDF/XTC Alternative

DRV/r or ATV/r + TDF/FTC -

EVG/c +TDF/FTC -

RAL + TDF/FTC -

DTG + TDF/3TC Alternative

DTG + ABC/3TC -

WHO 2016

Naïve Patients The Future is Integrase?

Summary of Primary endpoint Efficacy Data: ARV Naïve at 48 weeks VL< 50/ml 85-90%

• Raltegravir– non-inferior to atripla at 48 weeks, superior at 5 years (Startmrk)

– Equivalent to atazanavir/r and darunavir/r at 96 weeks (ARDENT- ACTG 5257)

• Elvitegravir– Non- inferior to atripla or to atazanavir/r at 48 weeks ( Gilead 102 and 103)

– Superior to atazanavir/r in women (WAVES)

• Dolutegravir– Non inferior to raltegravir at 48 weeks (Spring-2)

– Superior to atripla at 48 and 96 weeks (Single)

– Superior to darunavir/r at 48 and 96 weeks (Flamingo)

– Superior to atazanavir/r in women (ARIA)

Rockstroh, JAIDS, 2013; Landowitz, CROI 2014; Elion CROI 2013; De Jesus, CROI; 2013; Raffi, Lancet, 2013; Walmsley

NEJM, 2013, Clotet, Lancet, 2014 ; Squires IAS 2015

6

In ART Naïve

What about 4 Drug Therapy with an INSTI

Are the Outcomes Better especially in Late

presenters

Try and get VL down fast and CD4 higher quickly

REALITY

Design

Objective– Primary endpoint: 24-week mortality

2 NRTI + NNRTI + 12 weeks of RAL

2 NRTI + NNRTI

Adults, adolescents and children > 5 years

ARV-naïveCD4 < 100/mm3

Two other factorial randomisations: 12 weeks enhanced prophylaxis, 12 weeks supplementary food

REALITY Study: raltegravir-intensified quadruple therapy in first-line antiretroviral therapy

Randomisation1 : 1

Open label

N = 903

N = 902

W48

Kityo C. AIDS 2016, Durban, Abs. FRAB0102LB

REALITY Kityo C. AIDS 2016, Durban, Abs. FRAB0102LB

REALITY Study: raltegravir-intensified quadruple therapy in first-line antiretroviral therapy

Mortality HIV RNA < 50 copies/mL (95% CI)

902 825 801 786 775 766 657

903 830 801 789 776 760 669

10.2%

13.0%

10.9%12.4%

0

5

10

15

20

N at risk

0 8 16 24 32 40 48Weeks

0

20

40

60

80

100

0 4 12 24 48Weeks

14.5%

54.6%

76.0%79.5%

42.8%

74.1% 77.2%82.9%

%%

Mean change in CD4/mm3 at W48:

+ 163 vs + 148 (p = 0.04)

W24: HR =1.09

(95% CI: 0.82-1.46) ; p = 0.54

Additional RAL Standard ART

Warning in Late presenters?

INSTIs and IRISATHENA cohort study

2.7 times higher risk of IRIS for

Integrase inhibitors vs Non INSTI

Clumeck N, et al. 14th EACS; Brussels, Belgium;

October 16-19, 2013. Abst. LBPS7/2.

n(%)

EVG/c/FTC/TDF

(n=701)

W96

Population Analyzed 36 (5.1%)

Emergent Resistance 16 (1.9%)

Primary INSTI-R 14 (2.0%)

or NNRTI-R or PI-RE92QN155HQ148RT66I T97A

95320

Primary NRTI-R

M184V/IK65R

15 (2.1%)

155

Can we use this data to advantage?Elvitegravir:Raltegravir and Dolutegravir Emergent Resistance

Through Weeks 48-96

RAL

18 Any Resistance

(3%)

0 TDF

7 FTC

0 TDF+FTC

1 RAL

7 RAL+FTC

3 RAL+FTC+TDF

65/85 VF

Available DTG 50 mg

OD

DRV/r 800/100 mg OD

PDVF, n (%) 2 (<1) 2 (<1)

INI mutations, n

0 0

NRTI mutations, n

0 0

PI mutations, n

0* 0

Plus..Rate of Transmitted resistance to INSTIs low

so

Lets start with DTG regimen (as high genetic barrier) before we have resistance tests back

A consequence-Viral load reduction much earlier as not waiting for tests and renders patient undetectable and non-transmitterand Patients engaged in care immediately

‘Standard’ pathway

U&E

LFT

FBC

Hep A/B/C

Syphilis

glucose

lipids

CD4 VL

HLA-B5701

VRT

RITA

New pathway

U&E

LFT

FBC

Hep A/B/C

Syphilis

glucose

lipids

CD4 VL

HLA-B5701

VRT

RITA

48 h

San Francisco RAPID programmeAntiretroviral Regimens

• Truvada + Dolutegravir 26 (67%)

• STRIBILD 7 (18%)

• Truvada + Darunavir/r 4 (10%)

• Truvada+Raltegravir 1 ( 2%)

• Triumeq 1 ( 2%)

RAPID

Time to VL suppression by ART initiation strategy: SFGH 2006-2014

RAPID vs. universal ARTP<0.001

Universal ART

CD4-guided ART

Proportion<200 copies

And if transmitted resistance increases can we still use an INSTI in this way?

a Primary and other integrase strand transfer inhibitor resistance (INSTI-R) mutations are listed. Primary INSTI-R mutations are T66I/A/K,

E92Q/G, T97A, Y143C/H/R, S147G, Q148H/K/R, N155H, and other INSTI-R mutations are H51Y, L68I/V, V72A/N/T, L74M, Q95K/R,

F121C/Y, A128T, E138A/K, G140A/C/S, P145S, Q146I/K/L/P/R, V151L/A, S153A/F/Y, E157K/Q, G163K/R, E170A, and R263K in IN.b Susceptibility was determined as the fold-change in EC50 vs. NL4-3 wild-type vector by Monogram Biosciences, Inc. The biological or lower

clinical cut-offs for reduced susceptibility in this assay are 4.0 for DTG, 1.5 for RAL, and 2.5 for EVG. No cut-off has been determined for BIC.

≤ 2.5-fold

> 2.5 to ≤ 5-fold

> 5 to ≤ 10-fold

> 10-fold

Confidential GS-9883/F/TAF Virology Ad Board, Rome, May 27, 2016Data on file, Gilead Sciences

Switching Therapy in Virologically Suppressed Pts

Switching Therapy in Virologically Suppressed Pts: When and Why?

To manage adverse events

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

To reduce cost

Switch Studies with INSTISin Virologically Suppressed Pts

Trial From To Outcome vs Suppressive

ART

GS-123 TDF/FTC + RAL EVG/COBI/FTC/TDF Virologic suppression

maintained

Strategy-NNRTI TDF/FTC + NNRTI EVG/COBI/FTC/TDF Noninferior or superior

Strategy-PI TDF/FTC + PI/RTV EVG/COBI/FTC/TDF Noninferior or superior

SPIRAL 2 NRTI + PI/RTV (experienced

pts)

RAL + 2 NRTIs Noninferior or superior

GS-109 TDF-based ART EVG/COBI/FTC/TAF Noninferior or superior

STRIIVING Suppressive ART DTG/ABC/3TC Noninferior or superior

GS-119 DRV/RTV-containing “salvage”

regimen

EVG/COBI/FTC/TAF +

DRV

Noninferior or superior

LATTE CAB or EFV + 2 NRTIs CAB + RPV (PO) Noninferior or superior

LATTE-1 CAB + ABC/3TC CAB + RPV (IM) Noninferior or superior

SWORD-1 & 2 3-drug regimen DTG + RPV Noninferior or superior

A lesson: If you switch with Background resistanceMore Virological failures SWITCHMRK -1 and -2:

Switch from stable LPV/RTV to RAL-based HAART Virologic outcomes at Wk 24, NC = F

Median previous antiretroviral drugs, n (range)

RAL5.0 (4.0-16.0)

LOP/r5.0 (2.0-15.0)

RAL5.5 (3.0-13.0)

LOP/r6.0 (4.0-14.0)

Eron J, et al. CROI 2009. Abstract 70aLB. Adapted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA. Copyright © 2009 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.

RAL + ARVs, n 174 166 169 173 172 176 176 176 176 175

LPV/RTV + ARVs, n 174 171 171 171 174 178 178 177 177 178

Switching can cause problems!STRIIVING: Switch From Suppressive ART to Fixed-

Dose DTG/ABC/3TC

• Ongoing randomized, open-label phase IIIB study

– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 24

HIV-1 RNA < 50 copies/mL on

stable ART ≥ 6 mos;

no previous virologic failure;

HLA-B*5701 negative

(N = 551)

DTG/ABC/3TC(n = 274)

Wk 48Wk 24

Trottier B, et al. ICAAC 2015.

*Containing 2 NRTIs plus NNRTI, PI, or INSTI.

Baseline ART*(n = 277)

DTG/ABC/3TC(n = 277)

PI NNRTI INSTI TDF/FTC

BL ART use, % 42 31 26 77

STRIIVING: Virologic Outcomes at Wk 24

• Switch to DTG/ABC/3TC noninferior to maintaining baseline ART

Trottier B, et al. ICAAC 2015..

Primary Efficacy Analysis: ITT-Exposed and Per Protocol Populations

52

100

80

60

40

20

0Virologic

Success

Virologic

Nonresponse

No Virologic Data

HIV

-1 R

NA

< 5

0 c

/mL

(%

)

DTG/ABC/3TC (ITT-E, n = 274)

Baseline ART (ITT-E, n = 277)

DTG/ABC/3TC (PP, n = 220)

Baseline ART (PP, n = 215)

85 8893 93

1410

61 1 < 1

But Switching had a Price!STRIIVING: Adverse Events

• 10 pts discontinued for AEs in DTG/ABC/3TC arm vs0 in baseline ART arm

Trottier B, et al. ICAAC 2015..

AEs in 10 Pts Who Withdrew* Grade

Insomnia 2

Diarrhea, flatulence, rash

Abdominal pain, anxiety, nausea, body ache

1

2

Euphoric mood

Headache

1

2

Abdominal cramps, chills, diarrhea, dizziness,

headache2

Pruritus 2

Abdominal pain, diarrhea, flulike syndrome, profuse sweating,

change in body odor

Fatigue,† malaise, depression

1

2

Nasal congestion

Worsening fatigue

Nausea

1

2

3

Alopecia 1

Fatigue† 1

Homicide† N/A

*None serious AEs except homicide. †Not drug related.

Switching with history of resistance GS-119: Immediate vs Delayed Switch to

EVG/COBI/FTC/TAF + DRV for Tx-Experienced Pts

Multicenter, open-label phase III trial

– Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 24 (FDA Snapshot)

– Secondary endpoints: HIV-1 RNA < 50 c/mL at Wk 48, CD4+ cell count change, safety

Tx-experienced pts,

HIV-1 RNA < 50 c/mL for

≥ 4 mos on DRV/RTV-

containing ART, with

history of drug resistance*

and eGFR > 50 mL/min

(N = 135)

Switch to EVG/COBI/FTC/TAF

+ DRV 800 mg QD

(n = 89)

Wk

144

Wk 48

Baseline ART(n = 46)

EVG/COBI/FTC/TAF+ DRV 800 mg QD

(n = 46)

Wk 24Randomized 2:1

*Resistance to ≥ 2 ARV classes, including ≤ 3 thymidine analogue mutations and/or K65R, but not integrase inhibitors, unless currently suppressed on RAL, EVG, or DTG (50 mg QD only), and no DRV resistance.

Huhn GD, et al. J Acquir Immun Defic Syndr. 2017;74:193-200.

GS-119: Virologic Suppression After Switch to EVG/COBI/FTC/TAF + DRV (2 pills)

At Wk 48, virologic efficacy of switch to EVG/COBI/FTC/TAF + DRV was noninferior and statistically superior to continuing baseline regimen (P = .004)[1]

No emergent resistance in EVG/COBI/FTC/TAF + DRV arm; 1 pt in baseline ART arm with viral rebound (Wk 36) developed resistance (M184V + K65R)[1]

No impact of genotypic susceptibility score on the efficacy of the switch regimen[2]

EVG/COBI/FTC/TAF + DRV (n = 89)

Baseline ART (n = 46)

Wk 48

HIV-1 RNA< 50 c/mL

Virologic

Failure

No Data

94

76

211

313

Treatment difference: 18.3%

(95% CI: 3.5% to 33.0%; P =

.004)

1. Huhn GD, et al. J Acquir Immun Defic Syndr. 2017;74:193-200.2. Margot N, et al. HIV Glasgow 2016. Abstract O123.

Can INSTIS be used in Dual therapy?Why optimise dosing?

• Less cost

• Less drug to be manufactured and stored

• Less chance of side effects

• Less pills (though cant get less than STR!)

Also useful in Nuke limiting Strategies•Abacavir-HLA and CVS risk•Tenofovir Renal and Bone toxicity•Now we have TAF but no clinical TB or Pregnancy data

2 drugs without TDF or TAF Health Warning!

Not in Hepatitis B co-infected1-5% in Eastern european region

? Pregnancy?TB

Analysing the efficacy of2-drug versus 3-drug treatments

PI/r + raltegravir-no benefitDTG + 3TC- low VL experimentalDTG + RPV-non inferiorCTV + RPV-experimental for LA injectable

PI/r + maraviroc-no benefitPI/r + NRTI (mainly 3TC) -non inferior

Switch From Suppressive ART to DTG + RPV Noninferior to Continued Baseline ART at Wk 48

• AE rates generally similar between treatment arms through Wk 52

– Numerically higher rate of drug-related grade 1/2 AEs with switch: 17% vs 2%

– Numerically higher rate of withdrawal for AEs with switch: 4% vs < 1%

Llibre JM, et al. CROI 2017. Abstract 44LB.

Virologic Nonresponse

Wk 48

HIV-1 RNA< 50 c/mL

No Data

100

80

60

40

20

0

Pts

(%

)

95 95

< 1 15 4

Treatment difference: -0.2% (95% CI: -3.0% to 2.5%)

DTG + RPV (n =513)Baseline ART (n = 511)

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

HIV-1 RNA suppressed to < 35 copies/mL 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

38

33

25

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

Has PI/r plus integrase a role in Treatment experience ?

In treatment-experienced patients, RAL+LPV/r was non-inferior to 2NRTI+LPV/r

No efficacy advantage

No significant difference in number of Grade 3 or 4 adverse events

Costs of RAL+LPV/r significantly higher than 2NRTI+LPV/r in most countries

EARNEST and SECOND-LINE studies

Ernest 2nd Line treatment studyVL responses by randomized arm

32Week 96 outcomes: Paton, NEJM 2014; 371; 234-47; Week 144 outcomes: Hakim, Poster 552, CROI 2015

0

20

40

60

80

100

Perc

ent

wit

h V

L<4

00

co

pie

s/m

l

0 4 12 24 36 48 64 80 96 112 128 144

Weeks from switch to second-line

PI/NRTI

PI/RALPI mono

Global p<0.0001 PI/RAL vs PI/NRTI global p<0.0001 PI-mono vs PI/NRTI global p<0.0001

Open-label, single-arm phase IV exploratory trial

Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 (ITT-e, FDA snapshot analysis)

Simple Start Integrase plus 3TC

PADDLE: Dolutegravir + Lamivudine in Treatment-Naive Pts

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

Treatment-naive pts with HIV-1 RNA

5000-100,000 copies/mL; CD4+ cell count

≥ 200 cells/mm3;HBsAg negative

(N = 20)

Second Cohort

DTG 50 mg QD +Lamivudine 300 mg QD

(n = 10)

Dolutegravir 50 mg QD +Lamivudine 300 mg QD

(n = 10)

First Cohort

Second cohort to be enrolled following confirmation of

first cohort success at Wk 8

PADDLE Study: Efficacy-DTG and 3TC in Naïve patientsExperimental Study

# SCR BSL DAY 4 DAY 7 W.2 W.3 W.4 W.6 W.8 W.12 W.24 W.36 W.48

1 5.584 10.909 383 101 <50 <50 <50 <50 <50 <50 <50 <50 <50

2 8.887 10.233 318 <50 <50 <50 <50 <50 <50 <50 <50 <50 <50

3 67.335 151.569 1.565 1.178 97 53 <50 <50 <50 <50 <50 <50 <50

4 99.291 148.370 3.303 432 178 55 <50 <50 <50 <50 <50 <50 <50

5 34.362 20.544 1.292 570 107 <50 <50 <50 <50 <50 <50 <50 <50

6 16.024 14.499 1.634 162 <50 <50 <50 <50 <50 <50 <50 <50 <50

7 37.604 18.597 819 61 <50 <50 <50 <50 <50 <50 <50 <50 <50

8 25.071 24.368 1.377 Not done 105 <50 <50 <50 <50 <50 <50 <50 <50

9 14.707 10.832 516 202 <50 <50 <50 <50 <50 <50 <50 SAE

10 10.679 7.987 318 <50 <50 <50 <50 <50 <50 <50 <50 <50 <50

11 50.089 273.676 68.129 3.880 784 290 288 147 <50 <50 <50 <50 <50

12 13.508 64.103 3.296 135 351 84 67 <50 <50 <50 <50 <50 <50

13 28.093 33.829 26.343 539 61 <50 <50 <50 <50 <50 <50 <50 <50

14 15.348 15.151 791 198 <50 61 64 <50 <50 <50 <50 <50 <50

15 23.185 23.500 4.217 192 <50 <50 <50 Not done <50 <50 <50 <50 <50

16 11.377 3.910 97 143 <50 <50 <50 <50 <50 <50 <50 <50 <50

17 39.100 25.828 1.970 460 52 <50 <50 <50 <50 <50 <50 <50 <50

18 60.771 73.069 2.174 692 156 <50 <50 <50 <50 <50 <50 <50 <50

19 82.803 106.320 2.902 897 168 76 <50 <50 <50 <50 <50 PDVF

20 5.190 7.368 147 56 <50 <50 <50 <50 <50 <50 <50 <50 <50

Cahn P, et al. AIDS 2016; Durban, South Africa; July 18-22, 2016; Abst. FARB0104LB.

SAE = serious adverse event PDVF = protocol defined virologic failure

0

25

50

75

100

DTG+3TC

% <

50

Week 4

0

• 110 Subjects

• No Hx of failure, No Hep B

• 8 week Switch to 2NRTI+DTG

• Then to DTG/3TC-40 Weeks FU

• 97% (101/104) pts maintained therapeutic success through 40 wks of dual therapy (study Wk 48)[1]

– No INSTI resistance in 3 pts with virologic failure

– 7 pts with serious AEs, only 2 related to dual therapy

ANRS 167 LamiDol Study DTG/3TC Maintenance

Joly V, et al. 24th CROI; Seattle, WA; February 13-16, 2017. Abst. 458.

LATTE-2: Maintenance Therapy With Cabotegravir IM + RPV IM (ITT-ME Population)

HIV-1 RNA <50 c/mL at Week 48: ITT-ME (Snapshot)

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

aMet prespecified threshold for concluding IM regimen is comparable to oral regimen (Bayesian Posterior Probability >90% that true IM response rate is no worse than -10% compared to the oral regimen). Observed Bayesian Probabilities: Q8W vs Oral = 99.7%; Q4W vs Oral = 99.4%.

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

• NNRTI—K103N, E138G, and K238T (FC RPV=3.3; Etravirine=1.9); INI—Q148R (FC CAB=5.1; Dolutegravir=1.38)c

• No additional PDVFs beyond W48 on any arm (all subjects through W72)d

Protocol-Defined Virologic Failure (PDVF)

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

Maintenance periodaQ8W IM (n=115)

Q4W IM(n=115)

Oral CAB(n=56)

Subjects with PDVF 2 (1%)b 0 1 (2%)

INI-r mutations 1c 0 0

NRTI-r mutations 0 0 0

NNRTI-r mutations 1c 0 0

PDVF: <1.0 log10 c/mL decrease in plasma HIV-1 RNA by Week 4, OR confirmed HIV-1 RNA ≥200 c/mL after prior

suppression to <200 c/mL, OR >0.5 log10 c/mL increase from nadir HIV-1 RNA value ≥200 c/mL. aOne additional PDVF

without treatment-emergent resistance occurred during oral Induction Period due to oral medication non-adherence. bOne

PDVF at Week 4: no detectable RPV at Week 4 and Week 8, suggesting maladministration. cOne PDVF at Week 48 at HIV-

1 RNA 463 c/mL (confirmed at 205 c/mL). dContains data beyond W48.

MonotherapySimplest of all!

But perhaps the most risky?

Emergent INSTI Resistance After Switch to DTG Monotherapy

• International, multicenter retrospective study

– Evaluated virologically suppressed pts switched to DTG 50 mg QD monotherapy

– Pts with history of VF on INSTI and INSTI resistance excluded

• 11 of 122 pts switched to DTG monotherapy experienced VF

– 9 of 11 had genotypic INSTI resistance at VF

• INSTI resistance pathways varied

Blanco JL, et al. CROI 2017. Abstract 42.

INSTI Resistance

at VF

92Q/155H (n = 1)

97A/155H (n = 1)

155H/148R (n = 1)

118R (n = 2)

148K (n = 1)

148H (n = 2)

148R (n = 1)

Conclusions

1. No clinical advantage of 4 (with INSTI) drugs-even in low CD4

and high VL.

2. Need RT inhibitors plus high barrier to resistance in 2 drug Rx

3. Dual therapy Regimen in naïve or switch-some data evolving

4. Utility in Long acting injectables

5. Monotherapy is a niche area but only with boosted Pis not

InSTIs

6. Stay with the data use triple therapy and wait for trials to

report.