INTEGRASE

INHIBITORS CLINICAL

CONSIDERATIONSBabafemi Taiwo, MBBS

Gene Stollerman Professor of Medicine

Chief, Division of Infectious Diseases

Northwestern University

Chicago

US

Disclosure

• Dr. Taiwo has served as a paid consultant to ViiV

Healthcare, GlaxoSmithKline, Gilead, and Merck

Rocky Road → New Horizon

First line ART regimens target

HIV enzymes:

Reverse Transcriptase (3)

Integrase (4)

Protease (6)

Source:

AIDS Info

Integrase Inhibitors

• Raltegravir (3 pills daily for full regimen)

• Elvitegravir/cobicistat (has booster)

• Dolutegravir (dual combinations, three-drug STR, or

other combinations)

• Bictegravir (oral co-formulation with FTC/TAF)

• Cabotegravir (IM long-acting, oral)

SHOULD EVERY PERSON

WITH HIV BE ON AN

INTEGRASE INHIBITOR?Naïve, suppressed and failing patients

7

Registrational Treatment-Naive Clinical Trials: Cross-Study Comparison*

HIV RNA <50 c/mL at Week 48

66686868686969707071

73767676777878

808282838484

868788

90

0 10 20 30 40 50 60 70 80 90 100

NRTI backbone

FTC/TDF

3TC/ABC qd

3TC+ABC bid

3TC/ZDV

3TC+TDF

% of Patients with HIV-1 RNA <50 copies/mL at Week 48

*This slide depicts data from multiple studies published from 2004-2012. Not all regimens have been compared head-to-head in a clinical trial

STARTMRK RAL (n=281)8

CASTLE ATV+RTV (n=440)6

ABT 730 LPV/r qd (n=333)5

CASTLE LPV/r (n=443)6

GS 934 EFV (n=243)4

MERIT ES EFV (n=303)3

KLEAN LPV/r (n=444)14

ECHO/THRIVE EFV (n=546)10

ABT 730 LPV/r bid (n=331)5

GS-102 QUAD (n=348)11

GS-103 QUAD (n=353)12

GS-103 ATV+RTV (n=355)12

GS-102 Atripla (n=352)11

MERIT ES MVC (n=311)3

ARTEMIS DRV+RTV (n=343)7

ECHO/THRIVE RPV (n=550)10

GS-903 EFV (n=299)9

STARTMRK EFV (n=282)8

GS 934 EFV (n=244)4

ARTEMIS LPV/r (n=346)7

KLEAN FPV/r (n=434)14

CNA 30024 EFV (n=324)13

CNA 30024 EFV (n=325)13

SOLO FPV/r (n=322)2

SOLO NFV (n=327)2

CNA 30021 EFV (n=386)1

CNA 30021 EFV (n=384)1

Era of Integrase Inhibitors

90%87%

82% 82%83%81%

71%69%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

FLAMINGO WAVES ARIA DAWNING

Viro

log

ica

lly s

up

resse

d p

atie

nts

(%

)

DTG DRV/r

(n=243

)

(n=245

)

DTG ATZ/r

(n=248

)

(n=247

)

DTG LPV/r

(n=257

)

(n=215

)

2 31 4

1. Clotet B, et al. Lancet 2014;383:2222−31; 2. Squires K, et al. Lancet HIV 2016;3:e410−20; 3. Orrell C, et al. Lancet 2017;S2352-3018:30095-4; 4 . Llibre JM, et

al. 24th CROI. Seattle, 2017. Abstract 44LB.

• Clinical trials favoring INSTI over boosted PI

EVG/c ATZ/r

(n=289

)

(n=286

)

SINGLE STUDY:

DTG superior to

EFV

bPI: drug

interactions

and

comorbidities

RESISTANCE

ADVANTAGE

BIC/FTC/TAF vs DTG-Containing Regimens

• No resistance for any regimen components detected for either group

1. Gallant J, et al. Lancet. 2017;[Epub ahead of print]. 2. Sax PE, et al. Lancet. 2017;[Epub ahead of

print].

GS-1489: Wk 48 Virologic

Efficacy[1]

GS-1490: Wk 48 Virologic

Efficacy[2]

Pts

(%

)

Pts

(%

)

100

80

60

40

20

0HIV-1 RNA

< 50 c/mL

HIV-1 RNA

≥ 50 c/mL

No Virologic

Data

BIC/FTC/TAF (n = 314)

DTG/ABC/3TC (n = 315)

92 93

1 3 7 4

100

80

60

40

20

0HIV-1 RNA

< 50 c/mL

HIV-1 RNA

≥ 50 c/mL

No Virologic

Data

BIC/FTC/TAF

DTG + FTC/TAF

8993

4 16

0

99> 99

1 <

1

60

PP1°

Treatment difference: -

0.6%

(95% CI: -4.8% to 3.6%) Treatment difference (1°):

-3.5%

(95% CI: -7.9% to 1.0%)

Transmitted resistance by drug class in US (CDC data)

Are Baseline Resistance Genotypes Still

Needed?• Modeling analysis of clinical benefit and cost-

effectiveness of baseline genotype vs no genotype if

starting a DTG plus dual NRTI regimen

• Results

• Baseline genotype provides minimal projected impact on survival (<

1 day)

• Not cost-effective – $420,000/quality-adjusted life year gained

• Only beneficial under extreme parameters – e.g., < 50% viral

suppression in the setting of transmitted NRTI resistance

• Limitation: Modeling analysis; does not take into account

starting with or switching to two-drug regimens

Hyle E, et al. Clinical Infectious Diseases

2019.

International first line guidelines

EACS

(2018)1

DHHS

(2018)2,3

IAS–USA

(2018)4

WHO

(2018)6

NRTI

backbone

TAF/FTC

TDF/FTC

ABC/3TC*

TAF/FTC

TDF/FTC

ABC/3TC*

TAF/FTC

ABC/3TC*

2 NRTIs†

NNRTI RPV* – – -

INSTI BIC

DTG

RAL

BIC

RAL

DTG

DTG

BIC

DTG‡

PI DRV/c or /r – – –

BIC, bictegravir; c, cobicistat; DRV, darunavir; DTG, dolutegravir;; EVG, elvitegravir; FTC, emtricitabine;; r, ritonavir; RAL, raltegravir; RPV, rilpivirine; TAF, tenofovir

alafenamide fumarate; TDF, tenofovir disoproxil fumarate. *Use recommended only if baseline viral load <100,000 copies/mL.†Optimised backbone should be used.‡ Women and adolescent girls of childbearing potential with consistent and reliable contraception and who are fully informed of the benefits and risks can use DTG

1. EACS. Available from: http://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html. 2. DHHS. Available from: https://aidsinfo.nih.gov/guidelines/html/1/adult-

and-adolescent-arv/0. 3. DHSS. Available from: https://aidsinfo.nih.gov/news/2044/adult-arv-panel-classifies-bic-taf-ftc-as-recommended-initial-regimen-for-hiv. 4. Saag MS et al.

JAMA 2018;320:379-396. 5.. All URLs accessed July 2018.

Recommended and preferred regimens-

SHOULD EVERY PERSON

WITH HIV BE ON AN

INTEGRASE INHIBITOR?NAIVES- A LOT OF PATIENTS CONSIDERING THE

GUIDELINES AND THE NEW DTG/3TC APPROACH

Switching to a New 3-drug Regimen

Works

VL < 50

BTG

TAF

FTC

DTG

ABC

3TC

DTG

TAF

FTC

DRV/c

TAF

FTC

Pros Cons

There is an integrase

inhibitor combination

to address almost any

concern

Pre-existing NRTI ResistanceStudy 380-4030

*20 participants stratified to categories 1 or 2 based on investigator-suspected NRTI resistance (19 participants category 2, and 1 participant category 1); †Includes K65R/E/N, or ≥3 TAMs that include M41L or L210W, or T69 insertions; ‡Includes only M184V/I mutations confirmed by genotype.

Catego

ry

NRTI Mutation,

n (%)

Stratificatio

n at

randomizati

on*

n=565

Final

analysis

n=565

B/F/TAF

n=284

DTG +

F/TAF

n=281

1K65R/E/N or ≥3

TAMs† 15 (3) 30 (5) 16 (6) 14 (5)

2 Any other pattern 63 (11) 108 (19) 55 (19) 53 (19)

3No NRTI

mutation487 (86) 427 (76) 213 (75) 214 (76)

M184V/I‡ ± other

mutations

(from category 1 or 2)

29 (5) 81 (14) 47 (17) 34 (12)

M184V/I‡ only 12 (2) 21 (4) 15 (5) 6 (2)

♦ For more details on the resistance mutations in study 380-4030, see poster MOPEB241

15

<1

93

61

91

8

0

20

40

60

80

100

HIV-1 RNA

<50 c/mL

HIV-1 RNA

≥50 c/mL

No Virologic

Data

 1 

284

 3 

281

265

284

256

281

 22 

281

 18 

284

Virologic Outcome at Week 48Study 380-4030

• Switching to B/F/TAF was noninferior to remaining on DTG + F/TAF

• No participant with pre-existing NRTI resistance had HIV-1 RNA ≥50 c/mL in either group

CI, confidence interval. 16

Treatment Difference in % Participants With HIV-1 RNA

≥50 c/mL (95.001% CI)

-… 1.0

-0.7

-4 -2 0 2 4

Favors

B/F/TAF

Favors

DTG + F/TAFDTG+ F/TAF

(n=281)

B/F/TAF (n=284)

Virologic Outcome by FDA

Snapshot

Pa

rtic

ipa

nts

, %

Barrier to Resistance - ARVs

• Incidence of resistance at week 96 in pivotal

clinical trials in treatment-naive patientsLibre JM, AIDS Rev 2015:17;56

DTG and BTG

have remarkable

barriers

DAWNING: DTG Superior to LPV/r (+ ≥1

active NRTI) After First-line NNRTI Failure

• Design: Randomized,

open label

• Participants: N=624. At

least 1 active NRTI in new

regimen

• Primary endpoint: HIV-1 <50 c/mL at Week

48

18

Aboud et al. Lancet Infect Dis 2019

RESULTS

DTG

(n =

312)

LPV/R

(n =

312)

Difference, %

(95% CI)

VL <50 84% 70% 13.8 (7.3-20.3)

Gr 2-4

AEs4% 14% NR

RESISTANCE2/11 DTG

(1 RTI)3/30 NRTI NR

DOLUTEGRAVIR AFTER INTEGRASE INHIBITOR

FAILURE

• Cabotegravir (CAB) is an HIV-1 integrase strand transfer inhibitor

– Oral 30 mg tablet: t½ ≈ 40 hours

– Long-acting IM injection, 200 mg/mL: t½ ≈ 40 days

• Rilpivirine (RPV) is an NNRTI

• Oral 25 mg tablet: t½ ≈ 50 hours

– Long-acting IM injection, 300 mg/mL: t½ ≈ 90 days

• LATTE-2: CAB LA + RPV LA given every 4 or 8 weeks maintained HIV-

1 RNA <50 c/mL for >3 years1

• Two pivotal phase 3 studies (ATLAS and FLAIR) have reached their

primary endpoints at 48 weeks. ATLAS 2M also reached week 48

Long Acting Cabotegravir

Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.

CAB, cabotegravir; IM, intramuscular; LA, long-acting; RPV, rilpivirine; t½, half-life.

1. Margolis D, et al. HIV Glasgow 2018; UK. Poster 118; 2. Swindells S, et al. CROI 2019; Seattle, WA, Abstract 1475.

Conference on Retroviruses and Opportunistic Infections;

SHOULD EVERYONE BE ON

AN INTEGRASE INHIBITOR?TREATMENT EXPERIENCED PATIENTS- A LOT OF

PATIENTS CAN, PARTICULARLY DTG OR BTG; AND

NOW WITH DTG/3TC AND DTG/RPV

Integrase inhibitors: a host of benefits

• Avoid Boosting

• Excellent resistance barrier with DTG and BTG

• Limited drug interactions

• No food restrictions

• New concepts (DTG/RPV, DTG/3TC, CAB LA + LA RPV)

• Special populations

• Pregnancy (RAL)

• TB (DTG) . NOT BTG

Co-morbidities in Older PLWHIV

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

No. Conditions N N N N N N N N N N

4,172 6,325 8,365 9,121 9,733 10,861 11,166 12,277 9,074 3,705

1 1,162 1,705 2,512 2,833 3,137 3,517 3,687 4,004 2,892 1,195

2 287 452 727 923 1,108 1,375 1,601 1,756 1,363 562

3 73 126 179 234 296 405 499 592 530 214

4 2 8 16 30 39 69 96 111 120 52

5 0 1 1 1 1 1 8 10 8 3

6 0 0 0 0 0 0 0 0 1 0

28 2730 31 32 32 33 33 32 32

7 7

910

11 1314 14 15 15

2 2

23

34

4 5 6 6

0

10

20

30

40

50

60

Per

cen

t o

f In

div

idu

als

in H

IV C

are

wit

h A

ge-

Ass

oci

ated

Co

nd

itio

ns

6 conditions

5 conditions

4 conditions

3 conditions

2 conditions

1 condition

NA-ACCORD (n-22,969), crude annual prevalence of

age-associated diseases among ART-experienced

persons living with HIV and receiving clinical care by

calendar year

Clin Infect Dis. 2017 Nov 15. doi: 10.1093/cid/cix998.

[Epub ahead of print]

Multimorbidity

increased by nearly

three-fold from 2000-

2009 .

• Hypertension and

hypercholesterole

mia most

common

Weight Gain and INSTIs: Data From

CROI 2019

Positive Association

• NA-ACCORD, initial

therapy

(N = 24,001)[1]

• ACTG A5001, A5322

switch cohort (N =

691)[2]

• Women’s Interagency

HIV Study, switch

cohort (N = 1118)[3]

No Association

• TRIO retrospective

switch cohort (N =

3468)[4]

• HPTN 077 cohort of

HIV-uninfected people

receiving cabotegravir

(N = 199)[5]

1. Bourgi. CROI 2019. Abstr 670. 2. Lake. CROI 2019. Abstr 669. 3. Kerchberger. CROI 2019 Abstr 672.4. McComsey. CROI 2019. Abstr 671. 5. Landovitz. CROI 2019. Abstr 34.

ADVANCE STUDY (DTG IN FIRST LINE in RLS)

FIGURE 1. ADVANCE study design.

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. 25

The ADVANCE study: a groundbreaking trial to evaluate a candidate universal antiretroviral regimen

Venter, Willem D.F.; Clayden, Polly; Serenata, Celicia; for the OPTIMIZE Consortium

Current Opinion in HIV and AIDS12(4):351-354, July 2017.

doi: 10.1097/COH.0000000000000389

Does DTG have CNS

adverse effects?

ADVANCE Study: Changes in Weight

Dolutegravir-Based Regimen at Week 96

Dolutegravir

+F/TAF

(n=351)

Dolutegrav

ir

+ F/TDF

(n=351)

Efavirenz/F/

TDF

(n=351)

Mean weight change (kg)

Overall

Men

Women

+8*†

+5*

+10*‡

+5*

+4*

+5*

+2

+1

+3

≥10% change in body weight (%) 25*† 13* 11

Treatment-emergent obesity (BMI ≥30

kg/m2; %)

19*† 8* 4

*P<0.001 versus efavirenz/F/TDF; †P<0.01 versus dolutegravir + F/TAF, and ‡P<0.001 versus dolutegravir + F/TDF.

Hill A, et al. J Int AIDS Soc. 2019;22(suppl 5):92. Abstract MOAX0102LB.Venter WF, et al. N Engl J Med. 2019;July 24, 2019. [Epub ahead of print].

?BICTEGRAVIR/FTC/TAF

CONCLUSION

• ART is in the integrase inhibitor era

• DTG and BTG provide options across the ART continuum

• Newer approaches include dual ART (DTG/3TC,

DTG/RPV) and CAB LA regimens

• New association with weight gain needs further

investigation to quantify risk, isolate risk factors, and

understand consequences

Conclusion