BUILDING A HIGH BARRIER TO RESISTANCE WITH DOVATO

BUILDING A HIGH BARRIER TO RESISTANCE WITH DOVATO

PM-IE-DLL-PPT-210002. March 2021

Dovato is indicated for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults and adolescents above 12years of age weighing at least 40kg, with no known or suspected resistance to the integrase inhibitor class, or lamivudine.

Prescribing Information and Adverse Event Reporting is provided at the end of this slide set

For Healthcare Professionals Only

2

/ What contributes towards the barrier to resistance of ARVs?

/ Why does DOVATO have a high barrier to resistance?

/ Virologic barrier

/ Pharmacological barrier

/ Target binding

/ Conclusions

CONTENTS

ARV, antiretroviral


WHAT CONTRIBUTES TOWARDS THE BARRIER TO RESISTANCE OF ARVS?

3


4

THE BARRIER TO RESISTANCE IS A FUNCTION OF THREE KEY PARAMETERS

Virologic Barrier

/ Potency1

/ Genetic barrier1

/ IQ2,3

/ PK2,3

/ Potential for DDIs4

/ Target binding time5,6

DDI, drug-drug interactionIQ, inhibitory quotient; PK, pharmacokinetics

1. Clutter DS, et al. Infect Genet Evol 2016;46:292–307; 2. University of Liverpool. Disposition of ARV – PIs and boosting, 2017. Available from: https://www.hiv-druginteractions.org/videos. Accessed October 2020; 3. Boffito M, et al. AIDS Res Hum Retroviruses 2020;36:13–8; 4. Lee KSS, et al. ACS Cent Sci 2019;5:1614–24

5. Dierynck I, et al. J Virol 2007;81:13845–51; 6. Hightower KE, et al. Antimicrob Agents Chemother 2011;55:4552–9


5

FIRST-GENERATION CORE AGENTS HAVE A LOW BARRIER TO RESISTANCE

AZT

FTC3TC

NVP RPV

1 2 3 4Genetic barrier to resistance

Approximate number of mutations needed to fail

3

2

1

Pote

ncy

Esti

mat

ed lo

g ch

ange

in V

L

Increasing barrier to resistanceATV/r

MVC

EVGRALEFV

ETRENF

ABCTDF

The low barrier to resistanceof first generation ARVsreflects potency and thelow number of mutationsrequired for development of resistance

/r, ritonavir booster; 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; AZT, zidovudine; EFV, efavirenz; ENF, enfuvirtide; ETR, etravirineEVG, elvitegravir; FTC, emtricitabine; MVC, maraviroc; NVP, nevirapine; RAL, raltegravir; RPV, rilpivirine; RT, reverse transcriptaseTDF, tenofovir disoproxil fumarate; VL, viral load Clutter DS, et al. Infect Genet Evol 2016;46:292–307


6

WITH FIRST-GENERATION CORE AGENTS, THREE LOW-GENETIC-BARRIER ARVS WERE NEEDED TO CREATE A HIGH-BARRIER REGIMEN1–6

1 mutation required for resistance

1 mutationrequired for resistance

1 mutationrequired for resistance

1 mutation required for resistance

Single ARV drug Three ARV drugs

X

1. Hirsch MS, et al. JAMA 1998;279:1984–91; 2. Ratner L, et al. Nature 1985;313:277–843. Lloyd SB, et al. AIDS Res Hum Retroviruses 2014;30:8–16; 4. Perelson AS, et al. Science 1996;271:1582–6

5. Feng Q, et al. BMJ 2019;366:l4179; 6. Tseng A, et al. Br J Clin Pharmacol 2015;79:182–94


7

SECOND-GENERATION CORE AGENTS HAVE A HIGHER BARRIER TO RESISTANCE

ATV/r

MVC

AZT

FTC3TC

EVGRALEFV

ETRENF

NVP RPV

1 2 3 4Genetic barrier to resistance

Approximate number of mutations needed to fail

3

2

1

Pote

ncy

Esti

mat

ed lo

g ch

ange

in V

L Increasing barrier to resistance

Second-generation core agents combine high potencywith a requirement for at least two mutations for resistance to develop

DTG

LPV/r

DRV/r

ABCTDF

DRV, darunavir; DTG, dolutegravir; LPV, lopinavir Clutter DS, et al. Infect Genet Evol 2016;46:292–307


8

TWO WELL-CHOSEN AGENTS CAN ACHIEVE A HIGH BARRIER TO RESISTANCE1–5

1mutation required for resistance




Drugs A + B + C Drugs A + D

X X

1. Clutter DS, et al. Infect Genet Evol 2016;46:292–307; 2. Tseng A, et al. Br J Clin Pharmacol 2015;79:182–943. Hirsch MS, et al. JAMA 1998;279:1984–91; 4. Perelson AS, et al. Science 1996;271:1582–6; 5.Feng Q, et al. BMJ 2019;366:l4179


WHY DOES DOVATO HAVE AHIGH BARRIER TO RESISTANCE?

9


10

DTG AS A CORE AGENT TO BUILD A 2DR

DTG

Breadth and depth of data for DTG-based 3DRs demonstrating superiority in 5 Phase III

trials vs 5 different ART comparators and non-inferiority in 2 Phase III trials, and more than 2 million patient years of DTG exposure

in real-world clinical practice16–22

Low-dose, easy to co-formulate, booster free and few clinically

significant DDIs5

Favourable PK/PD profile with a long binding time to WT INI-DNA

complex, high IQ and long “tail”1–3

Rapid and potent antiviral activity4

Established short and long-term tolerability6–22

High barrier to resistance proven in clinical trials up to 3 years and real-world settings6–18

2DR, 2-drug regimenART, antiretroviral therapyINI, integrase inhibitorPD, pharmacodynamic; WT, wild type

1. Hightower KE, et al. Antimicrob Agents Chemother 2011;55:4552–9; 2. van Lunzen J, et al. Lancet Infect Dis 2012;12:111–8; 3. Elliot E, et al. IWCPHIV 2015. Abstract 134. Min S, et al. AIDS 2011;25:1737–45; 5. Tivicay. Summary of Product Characteristics. August 2020; 6. Walmsley S, et al. J Acquir Immune Defic Syndr 2015;70:515–9; 7. Molina JM, et al. Lancet HIV 2015;2:e127–36; 8. Aboud M, et al. Lancet Infect Dis 2019;19:253–64; 9. Raffi F, et al. Lancet Infect Dis 2013;13:927–35; 10. Castagna A, et al. J Infect Dis 2014;210:354–62; 11. Gallant J, et

al. Lancet 2017;390:2063–72; 12. Sax PE, et al. Lancet 2017;390:2073–82; 13. Molina JM, et al., Lancet HIV 2018;5:e357–65; 14. Aboud M, et al. IAC 2018. Poster THPEB047; 15. Messiaen P, et al. PLoS One 2013;8:e52562; 16. Orrell C, et al. Lancet HIV 2017;4:e536–46; 17. Cahn P, et al. Lancet 2013;382:700–8; 18. Trottier B, et al. Antivir Ther 2017;22:295–305; 19. Raffi F, et al. Lancet

2013;381:735–43; 20. Walmsley S, et al. N Engl J Med 2013;369:1807–18; 21. Clotet B, et al. Lancet 2014;383:2222–31; 22. ViiV Healthcare data on file. Global dolutegravir patient years estimates. December 2019


11

3TC AS A COMPLEMENTARY PARTNER FOR DTGOver 20 years legacy

of efficacy and safety and listed in all major guidelines since 19981–5

Favourable safety profile and no significant DDIs6–11

Convenient dosingincluding co-formulation11

Potential economic benefits

Acts at a different viral lifecycle target, blocking RT11

Intracellular 3TC-TP PK tail matches the plasma PK ‘tail’ of DTG and booster free11–14

3TC

3TC-TP, 3TC-5’-triphosphate

1. FDA-approved HIV Medicines. Updated September 2020. Available from: https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/21/58/fda-approved-hiv-medicines. Accessed October 20202. DHHS Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. December 2019. Available from: https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/

AdultandAdolescentGL.pdf. Accessed October 2020; 3. Saag MS, et al. JAMA 2020;324:1651–69; 4. EACS Guidelines, Version 10.1, October 2020. Available from: https://www.eacsociety.org/files/ guidelines-10.1.finalsept2020.pdf. Accessed October 2020; 5. WHO Consolidated Guidelines on the Use of antiretroviral drugs for treating and preventing HIV infection. 2016. Available from:

http://www.who.int/hiv/pub/arv/arv-2016/en/. Accessed October 2020; 6. Eron JJ, et al. AIDS 1996;5:S11–9; 7. Bartlett JA, et al. Ann Intern Med 1996;125:161–72 8. Result summary for NUCB3001, ViiV Healthcare 2005; 9. Result summary for NUCB3002, ViiV Healthcare 2005; 10. Clotet B, et al. Lancet 2014;383:2222–31

11. Epivir. Summary of Product Characteristics. May 2020; 12. Moore KH, et al. AIDS 1999;13:2239–50; 13. Yuen GJ, et al. Antimicrob Agents Chemother 2004;48:176–82; 14. Min S, et al. AIDS 2011;25:1737–45


12

WHY DOES DOVATO HAVE A HIGH BARRIER TO RESISTANCE?

/ Potent antiviral activity1–3

/ DTG: high genetic barrier4

/ DTG: high IQ5

/ Well-matched PK6–10

/ Few significant DDIs11

/ DTG: long target-binding time >24 hours12–14

/ Blocks virus lifecycle at two different targets, like traditional 3DRs11

See slide notes for references

Virologic Barrier


HIGH VIROLOGIC BARRIER

13


-1.99

-1.29

-1.52 -1.52

-1.85

-1.5 -1.58 -1.5

-0.85

-1.61-1.5

-1.73 -1.67 -1.7

-2.16

-2.46

-1.99 -2.06

-1.6

-1.96

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

ART monotherapy: maximum change in HIV-1 RNA (log10 c/mL) over 7–14 days*

14

DTG and 3TC are not indicated as monotherapies*Mean/median value as available; †Day 21; ‡Day 28; §Single dose; ¶Median change on Day 15BIC, bictegravir; BID, twice daily; c/mL, copies/mL; EI, entry inhibitor; ISL, islatravirNNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; QD, once daily; TAF, tenofovir alafenamide

DTG IS ONE OF THE MOST POTENT ARVS AVAILABLEM

axim

um c

hang

e in

HIV

-1 R

NA

, lo

g 10 c/

mL*

900

mg

BID

25 m

g Q

D

200

mg

QD

lead

-in

200/

100

mg

or 4

00/1

00 m

g BI

D

600/

100

mg

BID

500

mg

QD

150

mg

BID

300

mg

BID

600

mg

BID

300

mg

QD

40 m

g Q

D

10 m

g si

ngle

-dos

e

200

mg

QD

600

mg

BID

50 m

g Q

D

50/1

00 m

g Q

D

50 m

g Q

D

300

mg

BID

100

mg

BID

NNRTIs PIs NRTIs INIs EIs

1. Gruzdev B, et al. AIDS 2003;17:2487–94; 2. Goebel F, et al. AIDS 2006;20:1721–6; 3. de Jong MD, et al. J Infect Dis 1997;175:966–704. Schürmann D, et al. AIDS 2016;30:57–63; 5. Murphy RL, et al. AIDS 2001;15:F1–9; 6. Arastéh K, et al. AIDS 2005;19:943–7

7. BMS Clinical Study Report AI424007. August 2002; 8. Rousseau FS, et al. J Infect Dis 2003;188:1652–8 9. Ruane PJ, et al. Pharmacotherapy 2004;24:307–12; 10. Staszewski S, et al. AIDS 1998;12:F197–202

11. Louie M, et al. AIDS 2003;17:1151–6; 12. Ruane PJ, et al. J Acquir Immune Defic Syndr 2013;63:449–55 13. Friedman E, et al. CROI 2016. Abstract 437LB; 14. Rousseau FS, et al. J Infect Dis 2003;188:1652–8

15. Markowitz M, et al. J Acquir Immune Defic Syndr 2006;43:509–15; 16. Min S, et al. AIDS 2011;25:1737–4517. DeJesus E, et al. J Acquir Immune Defic Syndr 2006;43:1–5; 18. Gallant JE, et al. J Acquir Immune Defic Syndr 2017;75:61–6

19. Fätkenheuer G, et al. Nat Med 2005;11:1170–2; 20. Kilby JM, et al. Nat Med 1998;4:1302–7

25 m

g Q

D


15The GEMINI-1 and -2 studies evaluated DTG 50 mg + 3TC 300 mgNI, non-inferior treatment difference

EFFICACY ACROSS DTG-BASED 2DR AND 3DR STUDIES AT WEEK 48 IN TREATMENT-NAÏVE POPULATIONS

DOVATO DTG +TDF/FTC

DTG + 2NRTIs

DRV/r + 2NRTIs

DTG + 2NRTIs

RAL + 2NRTIs

DTG +ABC/3TC

EFV/TDF/FTC

DTG/ABC/3TC

ATV/r + TDF/FTC

DTG +ABC/3TC

BIC/TAF/FTC

DTG + TAF/FTC

BIC/TAF/FTC

GEMINI 1 & 21 FLAMINGO2 SPRING-23 SINGLE4,5 ARIA6 GS-14897 GS-14908

0

10

20

30

40

50

60

70

80

90

100

Pati

ents

wit

h H

IV-1

RN

A <5

0 c/

mL,

%

p=0.025 NI p=0.003 NI NINI p=0.005

217/242

89

200/242

83

361/411

88

351/411

85

364/414

88

338/419

81

293/315

93

290/314

92

302/325

93

286/320

89

203/248

82

176/247

71

655/716

91

669/717

93

Study name:

Women only study

2DR study

3DR study

1. Cahn P, et al. Lancet 2019;393:143–55; 2. Clotet B, et al. Lancet 2014;383:2222–31; 3. Raffi F, et al. Lancet Infect Dis 2013;13:927–354. Walmsley S, et al. N Engl J Med 2013;369:1807–18; 5. Walmsley S, et al. ICAAC 2012. Abstract H-556b; 6. Orrell C, et al. Lancet HIV 2017;4:e536–46

7. Gallant J, et al. Lancet 2017;390:2063–72; 8. Sax PE, et al. Lancet 2017;390:2073–82


93 93

8588

83

92 95 95 94 95

16

EFFICACY ACROSS DTG-BASED 2DR AND 3DR STUDIES AT WEEK 48 IN SUPPRESSED-SWITCH POPULATIONS

TANGO1 STRIIVING2 SWORD 1 & 23 Study 18444

DOVATO TAF-based regimenDTG/ABC/3TC

Day 1 to Week 24

CAR Day 1 to Week 24

DTG/ABC/3TC Day 1 to Week 48

Switch to DTG/ABC/3TC Week 24 to 48

DTG + RPV CAR BIC/TAF/FTC DTG/ABC/3TC

486/513

485/511

346/372

224/244

227/275

344/369

264/282

267/281

NI at Week 24NI NI NI

Pati

ents

wit

h H

IV-1

RN

A <5

0 c/

mL,

%

0

10

20

30

40

50

60

70

80

90

100

2DR study

3DR study

CAR, current ART regimen

Study name:

233/275

245/278

1. van Wyk J, et al. Clin Infect Dis 2020;71:1920-9; 2. Trottier B, et al. Antiviral Therapy 2017;22:295–3053. Llibre JM, et al. Lancet 2018;391:839–49; 4. Molina J, et al. Lancet HIV 2018;5:e357–65


17The GEMINI-1 and -2 studies evaluated DTG 50 mg + 3TC 300 mg

MAGNITUDE AND SPEED OF VIRAL LOAD DECLINE IN GEMINI-1 & -2

DOVATO, n

DTG + TDF/FTC, n

716

717

708

706

704

699

686

699

688

688

681

688

674

681

664

675

140

153

138

152

139

153

135

151

138

145

135

149

132

141

132

139

All participantsParticipants with baseline HIV-1 RNA >100,000 c/mL

Mea

n ch

ange

fro

m b

asel

ine

in p

lasm

a H

IV-1

RN

A,

log 1

0c/

mL

-4

-3

-2

-1

0

-4 0 4 8 12 16 20 24 28 32 36 40 44 48Weeks

DOVATO

DTG + TDF/FTC

-4

-3

-2

-1

0

0 4 8 12 16 20 24 28 32 36 40 44 48Weeks

DOVATO

DTG + TDF/FTC

Eron J, et al. HIV DART and Emerging Viruses 2018. Oral Presentation 7


048

121620242832364044485256606468

18

A MINIMUM OF TWO INI-ASSOCIATED-RESISTANCE MUTATIONS ARE REQUIRED FOR PHENOTYPIC RESISTANCE TO DTG1

DTG

EC

50FC

DTG1

Singlemutations

Doublemutations

Triplemutations

Monogram clinical cut-offs for DTG, IC50 FC2

FC = 4

FC = 13

EC50, 50% effective concentration; FC, fold-change; IC50, half-maximal inhibitory concentration; 1. Tsiang M, et al. Antimicrob Agents Chemother 2016;60:7086–97 (and supplementary materials)

2. Ji H, et al. J Acquir Immune Defic Syndr 2018;78:e1–3


19

The GEMINI-1 and -2 studies evaluated DTG 50 mg + 3TC 300 mg*Patients met CVW criteria if a second and consecutive HIV-1 RNA value met any of the following definitions: decrease from baseline HIV-1 RNA of <1 log10 c/mL unless HIV-1 RNA <200 c/mL by Week 12, confirmed plasma HIV-1 RNA of ≥200 c/mL after confirmed consecutive HIV-1 RNA <200 c/mL2

†One non-CVW participant with reported non-adherence in the DTG + 3TC group developed M184V at Week 132 (HIV-1 RNA 61,927 c/mL) and R263R/K at Week 144 (HIV-1 RNA 135 c/mL), conferring a 1.8-fold change in susceptibility to DTG. The participant was withdrawn due to lack of efficacy after Week 144, switched to DTG + DRV/c, and regained virologic suppression1

/c, cobicistat boosted; CVW, confirmed virologic withdrawal

1. Cahn P, et al. HIV Glasgow 2020; Virtual. Poster P018

2. Cahn P, et al. Lancet 2019;393:143–55

GEMINI-1 & -2: FEW CVWS THROUGH 3 YEARS AMONG TREATMENT-NAÏVE PARTICIPANTS

1

One participant, who did not meet CVW criteria but with documented non-adherence, developed resistance associated mutations while taking DTG + 3TC separates†

n (%)DOVATO(N=716)

DTG + FTC/TDF(N=717)

Patients with CVW* 12 (2) 9 (1)

Among >700 treatment-naïve participants treated with DOVATO for 3 years, only one developed resistance, demonstrating the high barrier to resistance of DOVATO1

Baseline HIV-1 RNA Baseline CD4+ T-cell count Resistance mutations (week) DTG susceptibility Modified ART

93,515 c/mL 393 cells/mm3 M184V R263K(Week 132) (Week 144)

1.8-fold change DTG + DRV/c


20

The GEMINI-1 and -2 studies evaluated DTG 50 mg + 3TC 300 mgArrows represent the week in which CVW occurred. The color of the arrow corresponds to the color assigned to each participantBL, baseline; SVW, suspected virologic withdrawal

GEMINI-1 & -2: CVWS – VIRAL LOAD PROGRESSIONS

Viral load progressions consistent with non-adherence/treatment interruption and subsequent re-adherence to study drugs

DTG + FTC/TDF

BL 4 8 1216 24 36

SVWCVW

48 60 72 84 96 108Week

1,000,000

HIV

-1 R

NA

, c/

mL

100,000

10,000

1,000

100

0

DOVATO

1,000,000

HIV

-1 R

NA

, c/

mL

BL 4 8 1216 24 36 48 60 72 84 96 108Week

SVWCVW

100,000

10,000

1,000

100

0

Underwood M, et al. CROI 2020. Poster 3359


21The GEMINI-1 and -2 studies evaluated DTG 50 mg + 3TC 300 mgPLHIV, people living with HIV Ait-Khaled M, et al. ID Week 2020. Poster 1024

GEMINI-1 & -2: SIMILAR RATES OF VIROLOGIC SUPPRESSION WITH DOVATO VERSUS DTG + FTC/TDF ACROSS ADHERENCE SUBGROUPS AT WEEK 48

These results provide additional support for the robustness of DOVATO in treatment-naïve PLHIV

⁄ Proportion of participants with HIV-1 RNA <50 c/mL at Week 48 was lower in those with <90% adherence compared with those with ≥90% adherence, regardless of treatment regimen

93%

69%

96%

65%

0

20

40

60

80

100

Prop

orti

on o

f pa

rtic

ipan

ts,

%Proportion of participants with HIV-1 RNA <50 c/mL at Week 48

by adherence level (Snapshot)

631/679

647/677

24/35

22/34

DOVATO ≥90% adherence

DOVATO <90% adherence

DTG + FTC/TDF ≥90% adherence

DTG + FTC/TDF <90% adherence


92%

78%87%

74%

0

20

40

60

80

100

HIV-1 RNA<50 c/mL

On DOVATO

102/131

102/111

97/131

Irrespective of treatment

97/111Pr

opor

tion

of

part

icip

ants

, %

22*11 (8%) of 131 participants had no virologic data at Week 24FDA, US Food and Drug Administration; ITT-E, intention-to-treat exposed Rolle C, et al. HIV Glasgow 2020. Poster P020

STAT: 0 TREATMENT-EMERGENT RESISTANCE WITH DOVATO AMONG TREATMENT-NAÏVE PARTICIPANTS IN A TEST-AND-TREAT SETTING

Proportion of participants with HIV-1 RNA <50 c/mL at Week 24Observed (N=111) ITT-E (missing=failure) (N=131)

FDA Snapshot (N=131)*

0 cases of treatment-emergent HIV-1 resistance and 0 discontinuations due to lack of efficacy


23*CVW defined as one assessment with HIV-1 RNA ≥200 c/mL after Day 1 with an immediately prior HIV-1 RNA ≥50 c/mL2

TANGO: 0 CVWS AND 0 CASES OF RESISTANCE WITH DOVATO IN VIROLOGICALLY SUPPRESSED PATIENTS AT 2 YEARS

1

0 cases of treatment-emergent resistance with DOVATO among participants with CVW through 2 years in TANGO

N CVW, n (%)*Treatment-emergent

INI mutationsTreatment-emergent

NRTI mutations

DOVATO 369 0 0 0

TAF-based regimens 372 3 (<1) 0 0

1. van Wyk J, et al. HIV Glasgow 2020. Oral presentation O4412. van Wyk J, et al. Clin Infect Dis 2020;71:1920-9


24

REAL-WORLD EFFECTIVENESS STUDIES SUPPORT THE HIGH BARRIER TO RESISTANCE OF DOVATO SHOWN IN PHASE III RCTS1–10

real-worldeffectiveness

studies1–8*

DOVATO has demonstrated a high barrier to resistance in 874 patients across eight real-world switch studies

1. Maggiolo F, et al. HIV Glasgow 2018. Poster P104; 2. Hidalgo-Tenorio C, et al. Medicine 2019;98:1–7; 3. Borghetti A, et al. Clin Infect Dis 2020;cia313; 4. Diaco N, et al. EClinicalMedicine 2018;6:21–5; 5. Moreno Zamora A, et al. EACS 2017. Poster PE9/38; 6. Lanzafame M, et al. New Microbiol 2018;41:262–7; 7. Postel N, et al. HIV Glasgow 2020. Poster P044

8. Calza L, et al. J Antimicrob Chemother 2020;75:3327–33; 9. Cahn P, et al. J Acquir Immune Defic Syndr 2020;83:310–8 10. van Wyk J, et al. Clin Infect Dis 2020; 2020;71:1920-9

Reported real-world studies evaluated DTG 50 mg + 3TC 300 mg*From a literature search, up to October 2020, for studies including patients with no known or suspected resistance to INIs or 3TC at baseline, but with post-baseline resistance data†Full study population=177; however, 4 patients have been excluded here in accordance with the EU SmPCRCT, randomised controlled trial

Real-world study*

Maggiolo20181

(N=218)

Hidalgo-Tenorio2019†2

(N=173)

Borghetti20203

(N=145)

Diaco20184

(N=9)

Moreno20175

(N=8)

Lanzafame20196

(N=14)

Postel20207

(N=248)

Calza20208

(N=59)

Endpoint or time of follow-up

Mean: 2 years 48 weeks 144 weeks ≥48 weeks Median: 291 weeks

Mean:3.5 months

(1–8 months)6 months 12 months

Cases of treatment-emergentresistance

0 0 0 0 0 0 0 0


PREVALENCE OF TRANSMITTED M184V IN TREATMENT-NAÏVE PATIENTS IS LOW, GENERALLY REPORTED AS BEING ≤1%1

WHO HIV drug-resistance report 2017: Proportion of pre-treatment and acquired M184V by region1

Acquired M184VCameroon 12Cameroon 48+Guatemala 12Guatemala 48+Zambia 12Vietnam 36+

Pre-treatment M184VCameroonNamibiaUgandaZimbabweArgentinaColumbiaGuatemalaMexicoNicaraguaMyanmar

0102030405060708090

100

M18

4V p

reva

lenc

e, %

Pre-treatment M184Vdrug resistance

Acquired M184Vdrug resistance

In GEMINI-1 & -2, only 3/1,975 (0.15%) participants failed screening due to transmitted M184V/I resistance, while only 1/131 (0.76%) participants

in STAT underwent treatment modification due to baseline M184V2,3

25TDR, transmitted drug resistance; WHO, World Health Organisation1. HIV Drug Resistance Report 2017. Available from: http://apps.who.int/iris/bitstream/10665/255896/1/9789241512831-eng.pdf?ua=1.

Accessed October 2020; 2. Underwood M, et al. CROI 2020. Poster 3359; 3. Rolle C, et al. HIV Glasgow 2020. Poster P020


2.4%(n=44)

2.4%(n=43)

0.05%(n=1)

0.05%(n=1)

0

20

40

60

80

100

EVG RAL DTG BIC

Prop

orti

on o

f pa

tien

ts w

ith

clin

ical

ly r

elev

ant

tran

smit

ted

resi

stan

ce,

%

26

MeditRes: Newly diagnosed, ART-naïve PLHIV from France, Greece, Italy, Portugal and Spain from 2018 to 2019 (N=1,844)1

*Clinically relevant transmitted resistance was evaluated using Stanford v8.9-1 HIVDB Algorithm and defined as any resistance level for Stanford interpretation ≥3 (low-level resistance)RAM, resistance-associated mutation

1. de Salazar A, et al. HIV Glasgow 2020. Oral presentation O3222. Mbisa JL, et al. J Antimicrob Chemother 2020;dkaa309

PREVALENCE OF CLINICALLY RELEVANT TRANSMITTED* RESISTANCE TO SECOND-GENERATION INIS AMONG TREATMENT-NAÏVE PATIENTS IS VERY LOW

⁄ Similar findings were observed in a UK-based study, in which no major INI RAMs were detected as high-frequency variants (≥20%) among 655 ART-naïve PLHIV sampled between 2014 and 20162

Based on the low prevalence of clinically relevant transmitted resistance to second-generation INIs observed in the MeditRes analysis, it is very unlikely that a newly

diagnosed patient would present with baseline resistance to second-generation INIs1


27




/ DTG: high IQ5






Virologic barrier


HIGH PHARMACOLOGICAL BARRIER

28


DTG MAINTAINS DRUG LEVELS WELL ABOVE THE IN VITRO PROTEIN-ADJUSTED IC90

0 5 10 15 20 25Post-dose time, hours

Mea

n D

TG 5

0 m

gpl

asm

a co

ncen

trat

ion,

µg/

mL

0.1

1.0

10.0

Protein-adjusted IC90=0.064 µg/mL

DTG 50 mg QD

With 50 mg DTG QD, the IQ is 19 times greater than protein-adjusted IC90. DTG is indicated in combination with other ARV products1,2

IQ19x

291. van Lunzen J, et al. Lancet Infect Dis. 2012;12:111–8 (IQ)

2. Rockstroh J, et al. HIV Glasgow 2010 (Graph)


Intracellular 3TC-TP (following 3TC 300 mg QD)

DTG 50 mg QD

Dashed lines represent extrapolated data

DTG AND 3TC HAVE COMPLEMENTARY PK PROFILES

Steady-state DTG plasma or intracellular 3TC-TP concentration-time profiles1–410

1

0.1

0.01

Stea

dy-s

tate

DTG

pla

sma

conc

entr

atio

n (µ

g/m

L)

In vitro DTG PA-IC90 (0.064 µg/mL)

Steady-state intracellular3TC-TP (pm

ol/106

cells)10

1

0.1

0.01

12010896847260483624120Time after last dose, hours

Range of 3TC-TP observedat 150 mg BID (NUCB4001)

30PA, protein-adjusted1. Moore KH, et al. AIDS 1999;13:2239–50; 2. Yuen GJ, et al. Antimicrob Agents Chemother 2004;48:176–82

3. Min S, et al. AIDS 2011;25:1737–45; 4. Tivicay. Summary of Product Characteristics. August 2020


DOVATODTG/3TC

88%

31

*Includes 43 non-ARVs across cardiovascular drugs, CNS drugs, anti-infectives and miscellaneous (e.g. antacids, PPIs, H2 blockers, methadone and St John’s wort) included in EACS guidelines as commonly co-prescribed or of particular clinical relevance. Original data source: University of Liverpool HIV drug interaction data2

CNS, central nervous system; DOR, doravirine; EACS, European AIDS Clinical Society; PPI, proton pump inhibitors

1. European AIDS Clinical Society Guidelines. Version 10.1. October 2020. Available from: https://www.eacsociety.org/files/guidelines-10.1.finalsept2020.pdf. Accessed October 2020

2. University of Liverpool HIV Drug Interactions. Available from: https://www.hiv-druginteractions.org/checker. Accessed October 2020

DDIS BETWEEN SINGLE-PILL REGIMENS AND COMMONLY PRESCRIBED NON-ARVS1*

BIKTARVYBIC/FTC/TAF

72%

86%

TRIUMEQDTG/ABC/3TC

72%

DELSTRIGODOR/3TC/TDF

58%

ODEFSEYFTC/RPV/TAF

58%

EVIPLERAFTC/RPV/TDF

16%

SYMTUZADRV/c/FTC/TAF

No clinically significant interaction expected

Adapted from EACS guidelines 2020Interactions between regimens and non-ARVs

Potential interaction likely of weak intensity – additional monitoring/dosage adjustment unlikely

Potential clinically significant interaction – additional monitoring/dosage adjustment likely

These drugs should not be co-administered


32




/ DTG: high IQ5






Virologic Barrier


TARGET BINDING

33


DTG EXHIBITS AN IN VITRO HALF-LIFE OF DISSOCIATION FROM A WT INTEGRASE-DNA COMPLEX OF MORE THAN 24 HOURS

Compared with RAL and EVG, DTG and BIC have a longer residency time, dissociating more slowly (>24 hours) from a WT IN-DNA complex at 37°C in vitro1

1.0

0.8

0.6

0.4

0.2

0.0

Rela

tive

bin

ding

Time, hours

0 10 20 30 40 50 60

INI koff (s–1)Dissociation t1/2 (hours)

DTG1 2.7 × 10–6 71–792

BIC2 1.4 × 10–6* 135

EVG1 71 × 10–6 2.7–3.6

RAL1 22 × 10–6 8.8–14

34*Value calculated using BIC t1/2 value; see slide notes for calculation2

IN, integrase; Koff, first-order rate constant for dissociation of a protein-ligand complex; t1/2, terminal half-life1. Hightower KE, et al. Antimicrob Agents Chemother 2011;55:4552–9

2. White K, et al. CROI 2017. Poster 497


35

DOVATO is not indicated for patients with known or suspected resistance to the INI class or 3TC*Dissociative t1/2 values were calculated using the mean koff; †ND due to low signal with [3H]ELVND, not determined

DTG DISSOCIATES MORE SLOWLY THAN RAL OR EVGFROM MUTANT IN-DNA COMPLEXES IN VITRO

Compared with RAL and EVG, DTG dissociates more slowly from mutant IN-DNA complexes at 37°C in vitro

IN

Dissociative t1/2*, hours Fold change in EC50

DTG RAL EVG DTG RAL EVGWild type 71 8.8 2.7 1 1 1E92Q 17 3.3 0.4 1.6 3.5 19E138K 84 11 3.7 0.97 1.0 0.93G140S 20 4.4 1.1 0.86 1.1 2.7Y143C 60 2.0 2.1 0.95 3.2 1.5Y143H 44 2.5 1.6 0.89 1.8 1.5Y143R 42 1.1 1.7 1.4 16 1.8Q148H 5.2 0.2 0.2 0.97 13 7.3Q148K 11 0.3 ND† 1.1 83 >1,700Q148R 9.2 0.4 ND† 1.2 47 240N155H 9.6 0.6 0.4 0.99 8.4 25E92Q/N155H 3.9 0.3 ND† 2.5 >130 320E138K/Q148R 3.6 0.2 N† 4.0 110 460G140S/Q148H 3.3 0.2 ND† 2.6 >130 >890

Hightower KE, et al. Antimicrob Agents Chemother 2011;55:4552–9


DOVATO BLOCKS THE VIRAL LIFE CYCLE AT TWO DIFFERENT TARGETS LIKE 3DRS

36

Viral DNA

Integrase

Nucleus

Human genomic DNA

Reversetranscriptase

DTG

3TC

ViralRNA

1. Tivicay. Summary of Product Characteristics. August 20202. Epivir. Summary of Product Characteristics. May 2020

3. DOVATO. Summary of Product Characteristics. July 2020


37




/ DTG: high IQ5






Virologic Barrier


CONCLUSIONS

38


39




/ DTG: high IQ5






Virologic Barrier


40

BUILDING A HIGH BARRIER TO RESISTANCE WITH DOVATO:CONCLUSIONS

DOVATO (N=369) vs TAF-based regimens (N=372)

2 yearsin virologically

suppressed patients

DOVATO single-arm (N=131)test and treat at

24 weeksin newly diagnosed

patients

DTG + 3TC (N=716) vs DTG + TDF/FTC (N=717)

3 yearsin treatment-naïve

patients

8 studiesin 874 switch

patients

Real-world data

DOVATO has demonstrated a high barrier to resistance in broad patient populations across clinical trials and real-world studies

/ Due to the continued development of more potent and effective core agents, the barrier to resistance of ART has improved over time

/ DOVATO is a complete regimen with complementary virological and pharmacological properties and target binding


41

Abridged Prescribing Information Dovato (dolutegravir 50mg/lamivudine 300mg) tablets See Summary of Product Characteristics (SmPC) before prescribing.

Adverse events should be reported directly to the Health Products Regulatory Authority (HPRA) on their website: www.hpra.ie. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255.


Presentation: Film-coated tablet containing dolutegravir sodium equivalent to 50 mg dolutegravir and 300 mg lamivudine debossed with “SV-137” on one face.Indication: HIV-1 in adults & adolescents above 12 years of age weighing >40kg, with no known or suspected resistance to the integrase inhibitor class, or lamivudine. Dosing: One tablet once daily with or without food. Use an additional 50mg tablet of dolutegravir approximately 12 hours after the dose of Dovato when co-administered with efavirenz, nevirapine, tipranavir/ritonavir, etravirine (without boosted PI), carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St John’s Wort or rifampicin. Elderly: Limited data in 65+ yrs. Not recommended in patients with creatinine clearance < 50 mL/min. Caution in severe hepatic impairment. Contraindications: Hypersensitivity to any ingredient. Co-administration with substrates of OCT-2 with narrow therapeutic windows, such as fampridine. Special warnings/precautions: Risk of hypersensitivity reactions. Discontinue dolutegravir and other suspect agents immediately. Risks of osteonecrosis, immune reactivation syndrome. Monitor LFTs in Hepatitis B/C co-infection and ensure effective Hepatitis B therapy. Caution with metformin: monitor renal function and consider metformin dose adjustment. Use with etravirine requires boosted PI or increased dose of dolutegravir. Use with Mg/Al-containing antacids requires dosage separation. Use with calcium, multivitamins or iron also requires dosage separation if not taken at the same time with food. Use with cladribine or emtricitabine not recommended. When possible, avoid chronic co-administration of sorbitol or other osmotic acting alcohols (see SmPC section 4.5). If unavoidable, consider more frequent viral load monitoring. Fertility, pregnancy and lactation:Human fertility - no data; animal fertility - studies indicate no effects. Women of childbearing potential (WOCBP) should be counselled about the potential risk of neural tube defects including consideration of effective contraceptive measures. If a woman plans pregnancy, the benefits and the risks of continuing treatment should be discussed with the patient. The safety and efficacy of a duel regime has not been studied in pregnancy. If a pregnancy is confirmed in the first trimester while on Dovato, the benefits and risks of continuing Dovato versus switching to another antiretroviral regimen should be discussed with the patient taking the gestational age and the critical time period of neural tube defect development into account (see SmPC section 4.6). There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues. Do not breast-feed. Side effects: See SmPC for full details. Headache, GI disturbance, insomnia, abnormal dreams, depression, anxiety, dizziness, somnolence, rash, pruritus, alopecia, fatigue, arthralgia, myalgia, hypersensitivity, suicidal ideation or suicide attempt, hepatitis, blood dyscrasias, acute hepatic failure, pancreatitis, angioedema, rhabdomyolysis, lactic acidosis, peripheral neuropathy. Elevations of ALT, AST and CPK. MA Nr: EU/1/19/1370/001. MA holder: ViiV Healthcare BV, Van Asch van Wijckstraat 55H, 3811 LP Amersfoort, Netherlands. Legal Category: POM A. Date of preparation of API: January2021. Code: PI-6305. Further information available from GlaxoSmithKline, 12 Riverwalk, Citywest, Business Campus, Dublin 24. Tel: 01-4955000.

DOVATO is owned by or licenced to the ViiV Healthcare group of companies. ©2021 ViiV Healthcare group of companies or its licensor

42

Presentation: Film-coated tablets containing dolutegravir sodium equivalent to 10 mg, 25 mg or 50 mg dolutegravir. Indication: HIV in >6 years and >14kg as part of combination therapy. Dosing: Adults with no proven/suspected integrase resistance: 50mg once daily with or without food. Adults with proven/suspected integrase resistance: 50mg twice daily preferably with food. Adolescents aged 12 to 18 years, and weighing >20 kg with no proven/ suspected integrase resistance: 50mg once daily with or without food or if preferred, 25mg twice daily. Not recommended in presence of integrase resistance. Children 6 to <12 years with no proven/suspected integrase resistance: dose according to bodyweight: 14-<20kg: 40mg once daily or 20mg twice daily; >20kg: 50mg once daily or 25mg twice daily. Not recommended in presence of integrase resistance. Use Tivicay 5 mg dispersible tablets for patients aged 4 weeks and above and weighing >3 kg, or for patients in whom filmcoated tablets are not appropriate. Refer to SmPC for 5 mg dispersible tablets for dosing as dispersible tablets are not bioequivalent to film-coated tablets. When co-administered with efavirenz, nevirapine, tipranavir/ritonavir, etravirine (without boosted PI), carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St John’s Wort or rifampicin in the absence of integrase resistance, Tivicay 50mg should be administered twice daily in adults and in paediatric patients the weight-based once daily dose should be administered twice daily. In the presence of integrase class resistance, alternative combinations should be considered.Contraindications: Hypersensitivity to any ingredient. Co-administration with substrates of OCT-2 with narrow therapeutic windows, such as fampridine. Special warnings/precautions: Risk of hypersensitivity reactions. Discontinue dolutegravir and other suspect agents immediately if suspected. The two-drug regimen of dolutegravir and lamivudine is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase inhibitor class, or to lamivudine. Risks of osteonecrosis, immune reactivation syndrome. Monitor blood lipids and glucose according to established HIV treatment guidelines. Monitor LFTs in Hepatitis B/C co-infection and ensure effective Hepatitis B therapy. Caution with metformin: monitor renal function and consider metformin dose adjustment. Use with etravirine requires boosted PI or increased dose of dolutegravir. Use with Mg/Al-containing antacids, calcium, multivitamins or iron requires dosage separation. Fertility, pregnancy and lactation: Human fertility - no data; animal fertility - studies indicate no effects. Women of childbearing potential (WOCBP) should be counselled about the potential risk of neural tube defects including consideration of effective contraceptive measures. If a woman plans pregnancy, the benefits and the risks of continuing treatment should be discussed with the patient. If a pregnancy is confirmed in the first trimester while on dolutegravir, the benefits and risks of continuing dolutegravir versus switching to another antiretroviral regimen should be discussed with the patient taking the gestational age and the critical time period of neural tube defect development into account (see SmPC section 4.6). Do not breast-feed. Side effects: See SmPC for full details. Headache, GI disturbance, insomnia, abnormal dreams, depression, anxiety, dizziness, rash, pruritus, fatigue, elevations of ALT, AST and CPK, arthralgia, myalgia, hypersensitivity, suicidal ideation or suicide attempt, acute hepatic failure. MA Nr: EU/1/13/892/001-006). MA holder:ViiV Healthcare BV, Van Asch van Wijckstraat 55H, 3811 LP Amersfoort, Netherlands. Legal Category: POM A. Date of preparation of API: February 2021. Code: PI-7543. Further information available from GlaxoSmithKline, 12 Riverwalk, Citywest, Business Campus, Dublin 24. Tel: 01-4955000.

Adverse events should be reported directly to the Health Products Regulatory Authority (HPRA) on their website: www.hpra.ie. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255

TIVICAY is owned by or licenced to the ViiV Healthcare group of companies. ©2021 ViiV Healthcare group of companies or its licensor

Abridged Prescribing Information Tivicay (dolutegravir) 10mg, 25mg and 50mg tablets See Summary of Product Characteristics (SmPC) before prescribing.

43

Abridged Prescribing Information Juluca▼ (dolutegravir 50mg/rilpivirine 25mg) tablets See Summary of Product Characteristics (SmPC) before prescribing.


Presentation: Film-coated tablet containing dolutegravir sodium equivalent to 50 mg dolutegravir and rilpivirine hydrochloride equivalent to 25 mg rilpirivirine.Indication: HIV-1 in virologically suppressed adults (HIV-1 RNA <50 copies/mL) on stable ART for at least 6 months with no history of virological failure and no known resistance to any NNRTI or INI. Dosing: Adults (over 18 years): one tablet once daily with food. Elderly: Limited data in 65+ yrs. Caution in severe hepatic or renal impairment. Contraindications: Hypersensitivity to any ingredient. Co-administration with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampicin, rifapentine, proton pump inhibitors, systemic dexamethasone (excluding single dose), St John’s Wort or fampridine. Special warnings/precautions: Risk of hypersensitivity reactions. Discontinue Juluca immediately if suspected. Risks of prolongation of QTc interval, osteonecrosis, opportunistic infections, immune reactivation syndrome. Monitor LFTs in Hepatitis B/C co-infection and ensure effective Hepatitis B therapy. Small rise in serum creatinine in first 4 weeks of treatment, not considered clinically relevant. Do not co-administer with other antiretrovirals (except in case of co-administration of rifabutin, when an extra dose of rilpivirine 25mg should be used). Use with antacids or once-daily H2-receptor antagonists requires dosage separation. Calcium, iron or other multivitamins should be taken at the same time as Juluca with food, otherwise dosage separation recommended. Caution with metformin: monitor renal function and consider metformin dose adjustment to minimise risk of lactic acidosis. If macrolide antibiotics are required, consider azithromycin. Caution with antimalarials (artemether/lumefantrine) or anticoagulants (dabigatran). Fertility, pregnancy and lactation: Human fertility - no data; animal fertility - studies indicate no effects. Not recommended during pregnancy. Women of childbearing potential (WOCBP) should be counselled about the potential risk of neural tube defects including consideration of effective contraceptive measures. If a woman plans pregnancy, the benefits and the risks of continuing treatment should be discussed with the patient. Do not breast-feed. Side effects: See SmPC for full details. Increased total and LDL cholesterol, insomnia, headache, dizziness, nausea, diarrhoea, increased triglycerides, decreased appetite, abnormal dreams, depression, anxiety, sleep disorders, GI disorders, rash, pruritus, fatigue, decreased white blood cell count, haemoglobin and platelet count, arthralgia, myalgia, hypersensitivity, hepatitis, suicidal ideation or suicide attempt, acute hepatic failure. Changes in laboratory biochemistries: elevations of ALT, AST, pancreatic amylase, bilirubin and CPK. MA Nr: EU/1/18/1282/001. MA holder: ViiV Healthcare BV, Van Asch van Wijckstraat 55H, 3811 LP Amersfoort, Netherlands. Legal Category: POM A. Date of preparation of API: January 2021. Code: PI-5717. Further information available from GlaxoSmithKline, 12 Riverwalk, Citywest, Business Campus, Dublin 24. Tel: 01-4955000.


▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

JULUCA is owned by or licenced to the ViiV Healthcare group of companies. ©2021 ViiV Healthcare group of companies or its licensor

44

Abridged Prescribing Information Epivir - Lamivudine 300mg tabletsSee Summary of Product Characteristics (SmPC) before prescribing.


Presentation: Grey, diamond shaped, film-coated tablet containing 300 mg lamivudine engraved with “GX CJ7” on both faces.Indications: HIV in adults, adolescents and children weighing at least 25 kg as part of combination therapy. Dose: Adults: one 300mg tablet daily with or without food. See SmPC for dosage in children and adolescents. Additional formulations available: 150mg tablets and Oral Solution (10mg/mL) – see SmPCs. Elderly: No specific data. Renal impairment: Creatinine clearance <50ml/min: see SmPC for dosage adjustment. Hepatic impairment: no dose adjustment required. Contraindications: Hypersensitivity to any ingredient. Warnings/precautions: Patients should be monitored by physicians experienced in treatment of HIV. High risk of virological failure (when used in a triple nucleoside regimen), immune reactivation syndrome, osteonecrosis, increased weight, lipids, glucose. If used concomitantly to treat HIV and HBV see Zeffix SmPC. Monitor LFTs in Hepatitis B/C co-infection. Treatment should be stopped if signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur. Use with cladribine, emtricitabine or high doses of co-trimoxazole not recommended. When possible, avoid chronic co-administration of sorbitol or other osmotic acting alcohols (see SmPC section 4.5). If unavoidable, consider more frequent viral load monitoring. Pregnancy/lactation: Can be used during pregnancy if clinically needed. Avoid breast-feeding. Side effects: See SmPC for full details. Headache, GI disturbance, insomnia, cough, nasal symptoms, rash, alopecia, arthralgia, muscle disorders, fatigue, malaise, fever, blood dyscrasias, pancreatitis, hepatitis, angioedema, rhabdomyolysis, lactic acidosis, peripheral neuropathy. Transient increases in liver enzymes. MA Nr: EU/1/96/015/003, EU/1/96/015/00. MA holder: ViiV Healthcare BV, Van Hasch van Wijckstraat 55H, 3811 LP Amersfoort, Netherlands. Legal Category:POM A. Date of preparation: February 2021. Code: PI-5287. Further information available from GlaxoSmithKline, 12 Riverwalk, Citywest, Business Campus, Dublin 24. Tel: 01-4955000.


EPIVIR is owned by or licenced to the ViiV Healthcare group of companies. ©2021 ViiV Healthcare group of companies or its licensor

Documents

BUILDING A HIGH BARRIER TO RESISTANCE WITH DOVATO