the role of tivicay (dolutegravir) in the hiv treatment ......the hiv treatment armamentarium jean...

The Role of Tivicay (dolutegravir) in

the HIV Treatment Armamentarium

Jean van WykGlobal Medical Affairs Director, Dolutegravir

ViiV Healthcare

GSK copyright material, reproduction of this is prohibited without the consent of the company

Disclosures

Jean van Wyk is a full time employee of ViiV Healthcare

The Evolution of HIV Therapy

Adapted from references 1, 2

1995 – 2010: Core Agents Drive Advancements In HIV Therapy

Meta-analysis shows that from 1995 to 2010 the overall mean efficacy of initial therapy for

HIV-1 improved

Adapted from reference 3

Genetic Barrier

Long-term Safety

Convenience

Avoid resistance

Tolerability

Durable virological

suppression

PK Profile

Achieving the goal:

long-term

treatment

success

Efficacy

What do HCPs want from therapy?

Can I still conceive?

Will it affect my Mental state?

Will it

cause any

further

health

problems?

Will it Intrude into my life?

Will it affect my Physical appearance?

ANormal

Life

Will it

affect the

other

medication

I am taking?

How will it make me feel?

Achieving the goal:

Live Long and

Prosper

What do patients want from therapy?

Regimen* IAS-USA DHHS EACS

INI + NRTIs DTG/ABC/3TC

DTG + tenofovir/FTC TAF TDF or TAF TDF or TAF

EVG/c/tenofovir/FTC TAF TDF or TAF TDF or TAF

RAL + tenofovir/FTC TAF TDF or TAF TDF or TAF

RAL + ABC/3TC

NNRTI +

NRTIs

EFV/TDF/FTC TDF or TAF

EFV + ABC/3TC

RPV/tenofovir/FTC TDF or TAF TDF or TAF TDF or TAF

Boosted

PI + NRTIsBoosted ATV + tenofovir/FTC

/r or /c

TDF or TAF

/r or /c

TDF or TAF

Boosted ATV + ABC/3TC /r or /c

Boosted DRV + tenofovir/FTC TDF or TAF

TDF or TAF

/c as alternative

regimen

/r or /c

TDF or TAF

Boosted DRV + ABC/3TC /r or /c /r or /c

LPV/r + tenofovir/FTC TDF or TAF

Key preferred and alternative initial regimens for adults

*Regimens or components may have restrictions on use, such as HLA genotype, viral load, CD4 cell count or co-morbidities.

The recommended prodrug of tenofovir (TDF or TAF) and PK booster (ritonavir [/r] or cobicistat [/c]) are listed in the table

Preferred/recommended Alternative Not listed/other

WHO guidelines recommend different

regimens

Preferred:

• EFV + TDF + [3TC or FTC]

Alternative:

• DTG + TDF + [3TC or FTC]

• EFV400 + TDF + [3TC or FTC]

• NVP + TDF + [3TC or FTC]

• EFV + AZT + 3TC

• NVP + AZT + 3TC

Adapted from references 4-7

Case Study – Patient A

50 y/o MSM

Recently diagnosed with HIV-1 infection, ART-Naïve, HLA-B*5701 negative

Clinical findings:

- Complains of general tiredness/feeling ‘run down’

- CD4 120 cells/uL; VL 50,000 c/mL

Comorbidities:

- Type 2 diabetes, taking metformin 1g bd but admits generally poor adherence

- History of moderate depression, no therapy

Socially:

- Occasional use of recreational drugs (cocaine and MDMA)


What core agent would you prescribe as the first line ARV in this patient?

1) EFV

2) RAL

3) DTG

4) ATV/r

5) Other


What backbone combination would you prescribe as the first line ARV in this

patient?

1) TDF/3TC

2) TDF/FTC

3) ABC/3TC

4) Other

An Introduction To Dolutegravir

O

O

N

N

O

O

NH

O

F

FH

CH3

Na+


Integrase inhibitors: Mechanism of action

Integrase inhibitors prevent integration of viral DNA into the host chromosome

Integrase inhibitors bind specifically to the integrase/viral DNA complex and act to chelate the

divalent metal ions in the catalytic core domain, which are essential for strand transfer

Integrase

inhibitor


In vitro, DTG is broadly potent

Inhibition of recombinant HIV INI and HIV replication

Broad potency across HIV types in different cell types

*Integrase strand transfer enzyme assay; †Extrapolated to 100% human serum; ‡PMBC IC50 x HS foldshift

INIINI*

IC50 (nM)

IC50 in PBMCs

(nM)HS

foldshift†PA-IC50

(nM)PA-IC90

(nM)PA-IC90

(µg/mL)

DTG 2.7 0.51 75 38‡ 152 0.064

RAL 3.3 2 4.7 5.6 23 Not stated

EVG 6 2 22 20 78 Not stated

Assay n Mean IC50 (nM) (range)

HIV-1 isolates in PBMCs 25 0.36 (0.02–2.14)

HIV-1 isolates in MDMs 3 1.07 (0.37–1.98)

HIV-2 isolates in PBMCs 3 0.25 (0.09–0.61)


Change in HIV-1 RNA from baseline with DTG monotherapy

(ING111521)

0.5

–0.5

–2.0

2 3 4 7 8 9 10 11 14 21

(follow-up)Day

0

–1.0

–1.5

–2.5

1

(BL)

Me

an

ch

an

ge

fro

m B

L i

n H

IV-1

RN

A (

log

10

c/m

L)

Dosing period Follow-up period

2 mg

10 mg

50 mg

Placebo


DTG in vitro resistance profile versus RAL or EVG during

passage study

Integrase substitutions observed during passage of wild-type HIV-1 IIIB strain in the presence of DTG, RAL or EVG; list excludes polymorphisms

Mutations in bold indicate those seen in clinical trials

DTG (56 days)

FC IC50 = 1.2–4.1

RAL (84 days)

FC IC50 = 6 – >138

EVG (56 days)

FC IC50 = 2–497

S153F Q148K T66I

Q148R E92Q

E138K/Q148K P145S

DTG (84 days)

FC IC50 = 1.2–4.1

E138K/Q148R Q148K

G140S/Q148R Q148R

S153Y N17S/Q148K/G163R T66K

S153F G140C/Q148K/G163R E92V

E138K/Q148K/G163R P145S

DTG (112 days)

FC IC50 = 1.2–4.1

E92Q/E138K/Q148K/M154I Q146L

N155H/I204T Q148R

S153Y V151I/N155H T66I/V72A/A128T

S153F V151I/N155H T66I/E92Q

T66I/Q146L

All substitutions observed during DTG passage had low level impact on

DTG susceptibility (FC IC50 ≤4.1)


INDICATION

• DTG is indicated for the treatment of human immunodeficiency virus (HIV) infection in combination

with other antiretroviral agents in adults and children over 12 years of age

CONTRAINDICATIONS

• DTG is contraindicated in patients:

– with known hypersensitivity to dolutegravir

– receiving dofetilide or pilsicainide

WARNINGS/PRECAUTIONS

• This medicine should not be used by pregnant women without the advice of a doctor.

• Discontinue DTG and other suspect agents immediately if signs or symptoms of hypersensitivity

reactions develop

• Patients with underlying hep B or C may be at increased risk for worsening or development of

transaminase elevations with use of DTG

Dolutegravir


Metabolism and potential DDIs

DTG is primarily metabolized by UGT1A1 with some contribution from CYP3A.

Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro.

Drugs that induce those enzymes and transporters may decrease dolutegravir

plasma concentration and reduce the therapeutic effect of dolutegravir.

In vivo, DTG inhibits tubular secretion of creatinine by inhibiting OCT2 and

potentially MATE1, and may increase plasma concentrations of drugs eliminated

via these transporters (dofetilide and metformin)


PK BoostingAntiretrovirals

PIs

Indinavir

RitonavirSaquinavir

NNRTIs

Nevirapine

P450 OR

CYP

SUBSTRATE

OXIDISED SUBSTRATE

INDUCERS

Calcium channel

blockers

Immunosuppressant

s

Cyclosporine

Sirolimus

Tacrolimus

Other

Other

Antiepileptics

Carbamazepine

Phenytoin

Phenobarbital

Glucocorticoids

(especially

dexamethasone)

St. John's wort

Anti-TB

Rifabutin

Rifampicin

Other

Macrolides

NOT azithromycinAntifungals

Fluconazole

Itraconazole

Ketoconazole

VoriconazoleAntiarrhythmics

Amiodarone

Calcium channel

blockers

Diltiazem

Verapamil

Anti-HCV

Boceprevir

Telaprevir

Other

Macrolides

NOT azithromycin

Calcium channel

blockers

Antiarrhythmics

QuinidineImmunosuppressants

Cyclosporine

Sirolimus

Tacrolimus

Statins

Atorvastatin

Lovastatin

Simvastatin

NOT pravastatin

NOT rosuvastatin

INHIBITORS

Antiretrovirals

RitonavirIndinavir

Nelfinavir

Saquinavir

Efavirenz

Antiretrovirals

Efavirenz

Nevirapine

Ritonavir


Drug-Drug Interactions*

Commonly used medications Interactions

Oral contraceptives No dose adjustment necessary

H2-receptor antagonists (including ranitidine, cimetidine) No dose adjustment necessary

Rifabutin No dose adjustment necessary

Rifampicin The recommended dose of dolutegravir is 50 mg twice daily

LPV/r, DRV/r, ATV, ATV/r, Rilpivirine and Tenofovir No dose adjustment necessary

Metformin Co-administration of Tivicay increased the plasma concentration of metformin.

To maintain glycemic control, adjustment of the dose of metformin may be

considered when initiating or discontinuing the use of metformin in co-

administration with dolutegravir.

Calcium supplements, iron supplements Dolutegravir recommended to be administered 2 hours before or 6 hours after

taking these agents. When accompanied by food, can be co-administered.

Magnesium/aluminium-containing antacids Dolutegravir recommended to be administered 2 hours before or 6 hours after

taking these agents

Etravirine, efavirenz; nevirapine and tipranavir/r The recommended dose of DTG is 50 mg twice daily when co-administered

with these agents. It is not necessary to adjust the dose of dolutegravir when

co-administered with etravirine and LPV/r, DRV/R or ATV/r. In the presence of

integrase class resistance, combination with these agents should be avoided

Phenytoin, phenobarbital, Carbamazepine The recommended dose of dolutegravir is 50 mg twice daily. Alternative ARV

to be used where possible.

Oxicarbazepine No dose adjustment necessary

*Brazilian Ministry of Health:

- Carbamazepine: The recommended dose of dolutegravir is 50 mg twice daily. Avoid this combination for INI resistant patients.

- Phenytoin / Phenobarbital / Oxicarbazepine: contraindicated with dolutegravirAdapted from references 16, 18, 19

Dolutegravir-based regimens: booster-free with few significant

interactions with commonly used medications

Selected miscellaneous drugs – Drug-drug interactions between ARVs and non-ARVs†

Key to symbols#

Further information (in vivo, in vitro, or from label) at

www.hiv-druginteractions.org

a Ergot derivative interactions may vary with individual products and should be individually checked before prescribing.b According to the Intelence® Summary of Product Characteristics, no changes in methadone dosage were required based on clinical status during or after the period of etravirine co-administration.†This table is based on data provided by the University of Liverpool and summarises the drug-drug interactions between HIV therapy and some commonly prescribed co-medicines as well as the drug-drug interactions of particular clinical relevance. This table is not exhaustive; for additional drug-drug

interaction data and dosage adjustments, see www.hiv-druginteractions.org (University of Liverpool).§According to the TIVICAY SPC, the recommended dose of dolutegravir is 50 mg twice daily when co-administered with this drug. Alternative combinations should be used where

possible in INI-resistant patients.|| According to the TIVICAY local label, metformin concentrations may be increased by dolutegravir. Patients should be monitored during therapy and a dose adjustment of metformin may be required.#The symbols (green, amber, red) used to rank the clinical significance of the drug interaction are based on www.hiv-druginteractions.org.

BOOSTED FREE AGENTS BOOSTED

AGENTS

DTGII RAL EFV ETV RPV EVG/c DRV/r

antacids

PPIs

H2-blockers

beclometasone inhaler

buprenorphine

budesonide inhaler

ergot derivativea

ethinyl estradiol

Fluticasone inhaler

Methadone b

Salmeterol inhaler

Sildenafi (erectile

dysuntion)

St. John’s Wort§

varenicline

metformin

These drugs should not be co-administered

Potential interaction-may require close monitoring, alteration of drug dosage or timing of administration

No clinically significant expected

Adapted from references 16, 18, 20

Dolutegravir-based regimens: booster-free with few significant

interactions with commonly used medications

Selected recreational drugs – Drug-drug interactions between ARVs and non-ARVs†

Key to symbols#

Further information (in vivo, in vitro, or from label) at

www.hiv-druginteractions.org

BOOSTED FREE AGENTS BOOSTED AGENTS

DTGII RAL EFV ETV RPV EVG/c DRV/r

Stim

ula

nts

amyl nitrate

cocaine

ecstasy (MDMA)

mephedrone

methamphetamine

Depre

ssants

alcohol

alprazolam

codeine

diazepam

GHB (gamma hydroxybutyrate)

heroin (diamorphone)

hydrocodone

hydromorphone

ketamine

pethidine (meperideine)

methadone a

midazolam (oral)

morphine

oxycodone

temazepam

triazolam

Hallu

cin

ogens cannabis

lysergic acid dietheylamide (LSD)

phencyclidine (PCP, angle dust)

These drugs should not be co-administered

Potential interaction-may require close monitoring, alteration of drug dosage or timing of administration

No clinically significant expected

aAccording to the Intelence® Summary of Product Characteristics, no changes in methadone

dosage were required based on clinical status during or after the period of etravirine co-

administration.2

†This table is based on data provided by the University of Liverpool and summarises the drug-

drug interactions between HIV therapy and some commonly prescribed co-medicines as well

as the drug-drug interactions of particular clinical relevance. This table is not exhaustive; for

additional drug-drug interaction data and dosage adjustments, see www.hiv-

druginteractions.org (University of Liverpool).¶No formal DDI studies have been performed with dolutegravir and recreational drugs.#The symbols (green, amber, red) used to rank the clinical significance of the drug interaction

are based on www.hiv-druginteractions.org



Considering that the patient uses metformin and occasionally recreational drugs, does that

change your choice of first line core agent?

1) EFV

2) RAL

3) DTG

4) ATV/r

5) Other

Dolutegravir:

Clinical Trial Program

Overview of DTG Treatment-naïve Trials

*Overall results

vs

INIs SPRING-2

DTG + 2 NRTIs QD vs RAL + 2 NRTIs BID

(N=822)

COMPARABLE EFFICACY

vs RAL

at Weeks 48 and 96*

vs

EF

V/T

DF

/

FT

C

SINGLEDTG/ABC/3TC QD

vs EFV/TDF/FTC QD

(N=833)

SUPERIOR EFFICACY

vs EFV/TDF/FTC

at Weeks 48, 96 and 144*

FLAMINGODTG + 2 NRTIs QD

vs DRV/r + 2 NRTIs QD

(N=484)

vs

BO

OS

TE

DP

Is

ARIA

Women only

DTG/ABC/3TC QD

vs ATV/r + TDF/FTC QD

(N=495)

SUPERIOR EFFICACY

vs DRV/r

at Weeks 48 and 96*

SUPERIOR EFFICACY

vs ATV

at Week 48

The efficacy of DTG vs standard-of-care comparators at Week 48 was

consistent in subgroups defined by sex, race and age

DTG is generally

well tolerated


Overview of DTG Treatment in ARV-experienced and INI-naïve or

INI-resistant Trials

*Overall results

ARV-experienced, INI-naïve patients

vs

INIs DTG 50 mg QD

vs RAL 400 mg BID(N=719)

SUPERIOR EFFICACY

vs RAL

at Week 48*

ARV-experienced patients with INI-resistant virus

VIKING-3

DTG 50 mg BID + OBR vs baseline (OBR)

(N=183)

GOOD EFFICACYin highly treatment-experienced

population at 24 and 48 weeks

ARV-experienced patients, stable on ARV regimen (switch study)

vs

CO

NT

INU

ING

AR

T

STRIIVING

DTG/ABC/3TC QD

vs continuing ARV regimen

(N=551)

MAINTAINED EFFICACY

at 24 and 48 weeks

SAILING

DTG has demonstrated good efficacy in a range of treatment-experienced populations


Dolutegravir:

Efficacy

Virologic Response

(n=414)

(n=419)DTG (n=242)

DRV/r (n=242)

(n=411)

(n=411)

Adapted from references 21-26, 28, 33-36

Parameter Dolutegravir Comparator Study Comparator Favours DTG

Overall88% (361/411) 85% (351/411) SPRING-288% (364/414) 81% (338/419) SINGLE90% (217/242) 83% (200/242) FLAMINGO

Baseline viral load ≤100,000 c/mL 90% (267/297) 89% (264/295) SPRING-290% (252/280) 83% (238/288) SINGLE88% (160/181) 87% (157/181) FLAMINGO

Baseline viral load >100,000 c/mL 82% (94/114) 75% (87/116) SPRING-283% (111/134) 76% (100/131) SINGLE93% (57/61) 70% (43/61) FLAMINGO

CD4* T-cell count <200 cell/mm3

78% (43/55) 68% (34/50) SPRING-279% (45/57) 77% (48/62) SINGLE91% (21/23) 79% (19/24) FLAMINGO

CD4* T-cell count 200-350 cell/mm3


CD4* T-cell count ≥350 cell/mm3


Background NRTI: ABC/3TC86% (145/169) 87% (142/164) SPRING-290% (71/79) 85% (68/80) FLAMINGO

Background NRTI: TDF/FTC89% (216/242) 85% (209/247) SPRING-290% (146/163) 81% (132/162) FLAMINGO

Female84% (53/63) 82% (46/56) SPRING-285% (57/67) 75% (47/63) SINGLE84% (26/31) 73% (30/41) FLAMINGO

Age <36 years87% (162/186) 83% (181/219) SPRING-287% (175/202) 80% (171/215) SINGLE89% (117/131) 81% (108/134) FLAMINGO

Age ≥36 years88% (199/225) 89% (170/192) SPRING-289% (189/212) 82% (167/204) SINGLE90% (100/111) 85% (92/108) FLAMINGO

African American/African heritage84% (41/49) 85% (33/39) SPRING-282% (80/98) 75% (74/99) SINGLE85% (51/60) 77% (41/53) FLAMINGO

Dolutegravir-Based Regimens Effective Across Subgroups

Dolutegravir-based regimens showed consistent efficacy across key subgroups regardless of viral load, sex, age, race, CD4+ T-cell count and NRTI backbone at week 48

3TC = lamivudine; ABC = abacavir; FTC = emtricitabine; NRTI = nucleos(t)ide reverse transcriptase inhibitor; TDF = tenofovir disoproxil fumarate.

-10-15-20 -5 0 5 10 15 20 25 30 35 40


Snapshot Outcomes at Week 24

• CI, confidence interval; ITT-E, intent-to-treat exposed; PP, per protocol

CAR DTG/ABC/3TC

Virologic outcomes Treatment differences (95% CI)

-3,4

-12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12

-9.1 2.3

ITT-E Population85

1

14

88

1

10

93

<16

93

25

0

20

40

60

80

100

Virologicsuccess

Virologic non-response

No virologicdata

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

CAR (ITT-E, N=277)

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

CAR (PP, N=215)

Pro

port

ion

with

HIV

-1 R

NA

<50

c/m

Lat

Wee

k 24

(%

)

DTG/ABC/3TC

(N=274)

CAR

(N=277)

PDVF 0 0

HIV-1 RNA ≥50 c/mL in W24 window 3 (1%) 4 (1%)

HIV-1 RNA in subjects with ≥50 c/mL 58, 64, 71 c/mL 55, 55, 61, 85

c/mL


Mean CD4+ change from Baseline was similar between arms: DTG: +162.4 cells/mm3 (n=294); RAL: +153.2 cells/mm3 (n=283).

71%

64%

DTG 50 mg QD

RAL 400 mg BID

100

90

80

70

60

50

40

30

20

10

0

BL 4 8 12 16 24 32 40 48

Week

Pro

po

rtio

n (

%)

DTG 50 mg QD was statistically superior to RAL 400 mg BID at Week 48.

*Adjusted treatment difference (95% CI): 7.4% (0.7%, 14.2%); P=0.03

*Adjusted difference based on stratified analysis adjusting for Baseline HIV-1 RNA (≤50,000 c/mL vs >50,000 c/mL), DRV/r use without primary PI mutations and Baseline PSS (2 vs <2).

Proportion (95% CI) With HIV-1 RNA <50 c/mL

(Snapshot, mITT-E)

95% CI for difference

Favors

RAL

Favors

DTG

-20% 0 20%

7.40.7 14.2

-12%


(n=354)

(n=361)

CD4+ cell count changes

Change from baseline in CD4+ cell

count (cells/mm3), median (IQR)

DTG 50 mg QD

(N=411)

RAL 400 mg BID

(N=411)

Week 48 230 230

Week 96 276 264

Adapted from references 23-26, 35

(n=242)

(n=242)

Dolutegravir:

Safety

Dolutegravir-Based Regimens Were Generally Well Tolerated With

Few Discontinuations In Treatment-Naïve Patients

3TC = lamivudine; ABC = abacavir; AE = adverse events; BID = twice daily; DRV/r = darunavir/ritonavir; DTG = dolutegravir; QD = once daily; RAL = raltegravir.

4%

2%3%

14%

2%

6%

0%

5%

10%

15%

20%

Pro

po

rtio

n (

%)

of

pa

tie

nts

wit

h A

E

lea

din

g t

o d

isc

on

tin

ua

tio

n

EFV/TDF/FTCQD

(n=419)

DTG 50 mg QD

(n=411)

RAL 400 mg BID

(n=411)

DTG 50 mg(n=242)

DTG 50 mg +ABC/3TC

QD(n=414)

DRV/r 800/100 mg

QD(n=242)

SINGLE FLAMINGOSPRING-2


Body system (≥2% in either arm*), n (%)

DTG 50 mg +

ABC/3TC QD

(N=414)

EFV/TDF/FTC QD

(N=419)

Overall 16 (4) 58 (14)

Psychiatric disorders 4 (<1) 24 (6)

Nervous system disorders 1 (<1) 17 (4)

Skin and subcutaneous tissue disorders 2 (<1) 10 (2)

General disorders and administration site conditions

0 11 (3)

Gastrointestinal disorders 0 8 (2)

• At Week 144, withdrawals due to AEs were 4% vs 14% in the DTG + ABC/3TC and EFV/TDF/FTC arms, respectively

AEs leading to discontinuation over 144 weeks

*Individual may have had an AE in ≥1 body systemAdapted from references 22, 33

ARIA: Summary of AEs in the Randomised Phase

(Up to Week 48)

*Additional AEs identified post-hoc for two ATV + RTV + TDF/FTC subjects at one site are not included in this table. AEs were not considered to impact overall safety findings; †Death certificate noted death due to natural causes. Investigator deemed event unrelated to study drug

Patients, n (%)DTG/ABC/3TC

(n=248)

ATV/r + TDF/FTC

(n=247)Any AE 195 (79) 197 (80)*Grade 2 to 4 AE 115 (46) 137 (55)Drug-related AE (occurring in ≥5% of subjects in either arm)

83 (33) 121 (49)

Nausea 31 (13) 35 (14)Diarrhoea 12 (5) 18 (7)Dyspepsia 4 (2) 15 (6)Ocular icterus 0 18 (7)Headache 5 (2) 14 (6)Jaundice 0 13 (5)

Serious AE 12 (5) 20 (8)Fatal AE 1† 0Drug-related serious AE 0 3 (1)Discontinuations due to AEs 10 (4) 17 (7)


Adverse EventsDTG

50 mg QD(N=357)

RAL 400 mg BID

(N=362) Discontinuations due to safety events 9 (3%) 14 (4%)

Most commonly reported (≥10%) AEs in either arm

Diarrhea 71 (20%) 64 (18%)

Upper respiratory tract infection 38 (11%) 29 (8%)

Drug-related (≥2% in either arm) 73 (20%) 85 (23%)

Diarrhea 29 (8%) 21 (6%)

Nausea 13 (4%) 16 (4%)

Vomiting 8 (2%) 11 (3%)

Headache 7 (2%) 7 (2%)

Fatigue 4 (1%) 10 (3%)

Rash 5 (1%) 6 (2%)

Insomnia 0 6 (2%)

Abdominal pain upper 6 (2%) 0

Drug-related Grade 2-4 28 (8%) 32 (9%)

Drug-related Grade 4 1 (<1%) 1 (<1%)

Serious – any event 33 (9%) 42 (12%)

Serious drug-related – any event 2 (<1%)a 4 (1%)b

Fatal AEs 0 3 (<1%)c

a DTG: 1 hepatotoxicity, 1 myositis and acute renal failureb RAL: 1 oral mucosal blistering and rash pruritic, 1 pancreatitis, 1 hepatitis, 1 suicidal ideationc 1 adenocarcinoma, 1 acute hepatic and renal failure, 1 cervical carcinoma


Renal Safety over 48 weeks

Mean change from baseline in creatinine at Week 48:

DTG+ABC/3TC: +0.11mg/dL (+9.27µmol/L);

EFV/TDF/FTC: –0.01 mg/dL (-0.88µmol/L)

*10 µmol/L=0.11mg/dL

Urine albumin/creatinine (mg/mmol

CR)

DTG 50

mg+ABC/3TC QD EFV/TDF/FTC QD

Median change (IQR) from baseline to

Week 480.00 (-0.30, 0.30) +0.05 (-0.20, 0.30)

-10

-5

0

5

10

15

20

25

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

Mean Change from

Baseline in CR (μmol/L*)

Weeks


DTG Clinical Data: Selected CNS AE Profiles in

ART-naïve SubjectsSPRING-2

(96 weeks)

FLAMINGO

(96 weeks)

SINGLE*

(144 weeks)

ARIA

(48 weeks)

Cases, n (%)

DTG

(N=411)

RAL

(n=411)

DTG

(n=242)

DRV/r

(n=242)

DTG

(n=414)

EFV

(n=419)

DTG

(n=248)

ATV/r

(n=247)

Insomnia

Overall 25 (6) 20 (5) 20 (8) 16 (7) 71 (17) 52 (12) 10 (4) 8 (3)

Drug-related 6/25 (24) 3/20 (15) 4/20 (20) 5/16 (31) 43/71 (61) 28/52 (54) 5/10 (50) 1/8 (13)

Severe/grade 3/4 0 0 0 0 3/71 (4) 0 1/10 (10) 0

Led to withdrawal 0 0 0 0 1/71 (1) 4/52 (8) 1/10 (10) 0

Anxiety

Overall 17 (4) 23 (6) 13 (5) 9 (4) 28 (7) 30 (7) 5 (2) 8 (3)

Drug-related 1/17 (6) 2/23 (9) 1/13 (8) 0 4/28 (14) 11/30 (37) 0 1/8 (13)

Severe/grade 3/4 1/17 (6) 0 0 0 0 3/30 (10) 0 2/8 (25)

Led to withdrawal 0 0 0 0 0 4/30 (13) 0 0

Depression

Overall 29 (7) 21 (5) 16 (7) 12 (5) 35 (8) 44 (11) 9 (4) 11 (4)

Drug-related 1/29 (3) 2/21 (10) 0 0 13/35 (37) 19/44 (43) 1/9 (11) 1/11 (9)

Severe/grade 3/4 1/29 (3) 1/21 (5) 3/16 (19%) 1/12 (8) 5/35 (14) 8/44 (18) 0 1/11 (9)

Led to withdrawal 0 0 0 0 1/35 (3) 6/44 (14) 0 0

Suicidality

Overall 4 (<1) 6 (1) 4 (2) 1 (<1) 3 (<1) 7 (2) 3 (1) 4 (2)

Drug-related 0 0 1/4 (25) 0 0 4/7 (57) 1/3 (33) 0

Severe/grade 3/4 3/4 (75) 5/6 (83) 3/4 (75) 0 2/3 (67) 5/7 (71) 0 1/4 (25)

Led to withdrawal 0 2/6 (33) 1/4 (25) 0 0 1/7 (14) 0 0

All third agents were part of a three-drug regimen containing 2 NRTIs *Higher rates in SINGLE trial could potentially be attributed to proactive CNS questionnaire use and double-blind comparison with EFV

ART, antiretroviral therapyAdapted from reference 40

Dolutegravir

Resistance and Genetic Barrier

INI koff (s-1

)

Dissociation

t1/2 (h)

DTG 2.7 x 10–6 71

RAL 22 x 10–6 8.8

EVG 71 x 10–6 2.7

DTG

RAL

EVG

1.0

0.8

0.6

0.4

0.2

0.0

Re

lati

ve

bin

din

g

Time (h)

0 10 20 30 40 50 60

• DTG dissociated more slowly from a WT IN-DNA complex at 37°C compared with RAL and EVG

• DTG dissociation was eight times slower than RAL and 26 times slower than EVG

INI dissociation from WT integrase-DNA complex at 37°C


DTG maintains drug levels well above the in vitro PA-IC90*

With 50mg DTG the peak drug

level is 3.40 ug/mL – an

inhibitory quotient 19 times

greater that the PA-IC90, which

may contribute to the high barrier

to resistance

*PA-IC90 is the protein-adjusted 90& inhibitory concentration Adapted from reference 42

Emergent mutations in DTG Phase III clinical trials in treatment-naїve

subjects

PDVF defined as two consecutive plasma HIV-1 RNA values: **≥50 c/mL between Weeks 24 and 96; ††>200 c/mL on or after Week 24; †≥400 c/mL on or after Week 24. *One

subject had INI-resistance mutations and NRTI-resistance mutations; ¶E157Q/P polymorphism detected with no significant change in phenotypic susceptibility; ‡2 subject had either

K219K/Q (TAM) or E138E/G with no reduced susceptibility to DTG/ABC/3TC.

SPRING-2(to Week 96)**

SINGLE(to Week 144)**

FLAMINGO(to Week 96)††

ARIA(to Week 48)†

n (%)

DTG50 mg

QD(N=411)

RAL400 mg

BID(N=411)

DTG 50 mg + ABC/3TC

QD(N=414)

EFV/TDF/ FTCQD

(N=419)

DTG 50 mg

QD (N=242)

DRV/r 800/100 mg

QD (N=242)

DTG/ABC/ 3TC QD

(N=248)

ATV/r + TDF/FTC

QD (N=247)

Subjects with PDVF 22 (5) 29 (7) 39 (9) 33 (8) 2 (<1) 4 (2) 6 (2) 4 (2)

INI-resistant mutations 0 1 (6)* 0¶ 0 0 0 0 0

NRTI-resistant mutations

0 4 (21)* 0 1 (K65K/R) 0 0 0‡ 1 (M184V)

NNRTI-resistant mutations

– – 0

6 (K101E,K103N,

K103K/N G190G/A)

– – – –

PI-resistant mutations – – 0 0 0 0 0 0

Adapted from references 22, 24, 26, 28, 33

Supportive Analysis

–Treatment-emergent resistance to background regimen was also

statistically significant.**- DTG 1% vs RAL 3%, adjusted difference (95% CI) of -2.2% (-4.3%, -0.1%)

Proportion of Subjects With INI Treatment-Emergent Genotypic/Phenotypic Resistance

TreatmentFailure with INI-r (n)/mITT-E population (N)

Adjusted difference inproportion

(95% CI)(DTG-RAL)

DTG 50 mg QD 4/354 (1%)

RAL 400 mg BID 17/361 (5%) -3.7% (-6.1%, -1.2%)*

*DTG was superior vs RAL at Week 48 (P=0.003), pre-specified and adjusted for multiple testing.

Treatment-Emergent Resistance to INI and to Background

Regimen

**This analysis was pre-specified but was unadjusted for multiple testing.Adapted from references 29, 38

In Conclusion

• The estimated life expectancy of someone infected with with HIV at age 30 (71.5−75 years) is

approaching that of the general population (82 years)

• Therefore, it has been calculated that people with HIV will spend, on average, 39.1 years on

treatment

Diagnosis rate* Life expectancy (median age at death)† IQR of age at death

No HIV 82.0 (72.8, 89.3)

Very high 75.3 (63.5, 83.3)

High 75.0 (62.5, 83.3)

Medium 74.5 (61.5, 83.3)

Low 71.5 (51.8, 81.8)

*The rate of diagnosis was altered such that the CD4 cell counts at diagnosis were 140, 351, 432 and 509 cells/ul respectively for low, medium, high and very high diagnosis rates.†Age at death presented in years.

IQR, interquartile range.

People with HIV may spend decades on treatment


• Life expectancy of HIV patients in the UK at the age of 20 years increased between 1996−2008

from 30 years to over 45 years. A similar increase was seen in the US and Canada between

2000−2007.

• Mortality rates in HIV patients with high CD4 cell counts are similar to that observed in the general

population

• The HIV-infected population is getting older. In the UK, the proportion of patients aged 50 years or

more under HIV care doubled to 25% in the 10 years from 2003 to 2012

Year

12,1 12,8 13,4 14,215,4

16,818,5

20,622,5

24,6

0

5

10

15

20

25

30

200320042005 200620072008 2009201020112012P

erso

ns ≥

50 Y

ears

(%

)4

HIV patients under care in the UK

DDI, drug-drug interaction.

• Age-related comorbidities, associated

polypharmacy, drug interactions and

functional decline all complicate the

treatment of older HIV-infected patients

With an ageing HIV population there is a need to initiate treatment

with effective, well tolerated regimens with few significant DDIs


Dolutegravir has the potential to address the key challenges of

HIV treatment

• Once-daily dosing in INI-naïve subjects

• Can be administered with or without food

Still need for more

convenient

regimens

• Predictable/manageable DDIs

• Does not require use of a PK boosterDrug interactions

• No treatment emergent mutations leading to drug resistance observed in clinical trials in treatment-naїve subjects

• Active in the majority of subjects with RAL resistanceDrug resistance

• Good safety and tolerability profile to-date in treatment naïve and experienced patients

Safety and

Tolerability

• Superior efficacy versus three ARV classes in treatment naive and experienced patientsEfficacy

Adapted from references 16, 18, 21-30

Discussion

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Levantamentos bibliográficos relacionados às áreas terapêuticas de atuação da GSK

Construindo Confiança, Promovendo Transparência

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INFORMAÇÕES DE SEGURANÇA16

REAÇÕES ADVERSAS

As reações a seguir foram identificadas em estudos clínicos realizados com Tivicay: cefaleia, náusea, diarreia, insônia,

tontura, vômito, erupção cutânea, hipersensibilidade, síndrome de reconstituição imune, dor e desconforto abdominal,

hepatite.

PRECAUÇÕES E ADVERTÊNCIAS

Há relato de reações de hipersensibilidade aos inibidores da integrase, inclusive ao Tivicay, caracterizadas por erupção

cutânea, sintomas gerais inespecíficos e, às vezes, disfunção de órgãos, inclusive lesão hepática. Interrompa imediatamente

o uso de Tivicay e de outros agentes suspeitos caso surjam sinais ou sintomas de reações de hipersensibilidade. Deve‐se

monitorar o estado clínico, inclusive as aminotransferases hepáticas, e iniciar tratamento adequado. A demora em

interromper o tratamento com Tivicay ou outros medicamentos suspeitos depois do início da reação de hipersensibilidade

pode ser fatal.

CONTRAINDICAÇÃO:

É contraindicada a administração de Tivicay em combinação com a dofetilida ou pilsicainida.

É contraindicada a administração de Tivicay a pacientes com hipersensibilidade conhecida ao dolutegravir ou a algum dos

excipientes.

INTERAÇÕES MEDICAMENTOSAS

A etravirina sem reforço de inibidor de protease diminuiu a concentração plasmática de dolutegravir. A dose recomendada de

Tivicay é de 50 mg duas vezes ao dia quando há coadministração de etravirina sem reforço de inibidor de protease. Não se

deve usar Tivicay com etravirina sem a coadministração de darunavir/ritonavir ou lopinavir/ritonavir em pacientes resistentes

a INI.

MINIBULA DE TIVICAY (DOLUTEGRAVIR SÓDICO)Tivicay (dolutegravir sódico). Indicação: tratamento da infecção pelo HIV em combinação com outros agentes antirretrovirais em adultos e crianças acima de 12 anos, com peso mínimo de 40 kg.

Contraindicações: administração de Tivicay com a dofetilida, pilsicainida e em pacientes com hipersensibilidade conhecida ao dolutegravir ou a algum dos excipientes. Precauções e

advertências: Relato de reações de hipersensibilidade aos inibidores da integrase, inclusive ao Tivicay. Interrompa imediatamente o uso caso surjam sinais ou sintomas (erupção cutânea intensa ou

acompanhada de febre, mal-estar geral, fadiga, dor muscular ou articular, vesículas, lesões orais, conjuntivite, edema facial, hepatite, eosinofilia, angioedema). Deve-se monitorar o estado clínico,

inclusive as aminotransferases hepáticas, e iniciar tratamento adequado. A demora em interromper o tratamento depois do início da reação de hipersensibilidade pode ser fatal. Pacientes podem

apresentar uma reação inflamatória e infecções oportunistas residuais ou assintomáticas (retinite por citomegalovírus, micobacterianas generalizadas e/ou focais e a pneumonia por Pneumocystis

jiroveci (P. carinii)), que causa distúrbios clínicos graves ou agravamento dos sintomas. Distúrbios autoimunes podem ocorrer (doença de Graves, polimiosite e síndrome de Guillain-Barré) nos casos

de reconstituição imune. O tempo até o início é mais variável e podem ocorrer muitos meses do início do tratamento e, às vezes, têm apresentação atípica. A elevação de marcadores bioquímicos da

função hepática compatível com a síndrome de reconstituição imune foi observada em alguns pacientes coinfectados por hepatite B e/ou C no início do tratamento com Tivicay. Recomenda-se o

monitoramento bioquímico da função hepática. Cuidado especial em iniciar ou manter tratamento efetivo da hepatite B ao instituir a terapia com dolutegravir nos pacientes coinfectados por hepatite

B. Pacientes tratados com Tivicay ou qualquer outra terapia antirretroviral ainda podem ter infecções oportunistas e outras complicações da infecção por HIV. Não deve ser coadministrado com

antiácidos que contenham cátions polivalentes. Recomenda-se a administração duas horas antes ou seis horas depois desses medicamentos. Tivicay pode aumentar a concentração de metformina.

Os pacientes devem ser monitorados durante o tratamento e pode ser necessário ajustar a dose de metformina. Gravidez e Lactação: Não existem estudos satisfatórios e bem controlados sobre o

uso em gestantes. Estudos de toxicidade reprodutiva em animais mostraram que o dolutegravir atravessa a placenta. Só deve ser usado durante a gravidez se o benefício esperado justificar o risco

potencial para o feto. É recomendado que as mulheres com HIV não amamentem para evitar a transmissão do HIV. Em situações em que o uso de fórmulas infantis não é viável e o aleitamento

materno durante o tratamento antirretroviral for considerado, devem seguir os guias locais para amamentação e tratamento. De acordo com dados obtidos em animais, presume-se que o dolutegravir

seja secretado no leite humano, embora não haja confirmação disso. Reações adversas: Reações muito comuns (>1/10): cefaleia, náusea e diarreia. Reações comuns (>1/100 e <1/10): insônia,

tontura, sonhos anormais, depressão, vômito, flatulência, dor na porção alta do abdômem, dor e desconforto abdominal, erupção cutânea, prurido e fadiga. Reações incomuns (>1/1000 e <1/100):

Hipersensibilidade, síndrome de reconstituição imune, hepatite e ideias suicidas ou tentativas de suicídio (especialmente em pacientes com histórico de depressão ou alterações psiquiátricas pré-

existentes). Observou-se semelhança do perfil de segurança entre a população de pacientes virgens de tratamento, a daqueles previamente tratados com antirretrovirais (sem uso prévio de inibidor

de integrase) e a dos resistentes a inibidor da integrase. Os aumentos de creatinina foram comparáveis aos observados na terapia de base com ITRNs e semelhantes em pacientes previamente

tratados. O perfil de segurança em pacientes coinfectados por hepatite B e/ou C foi semelhante ao observado em pacientes sem coinfecção por esses, embora as taxas de anormalidades de AST e

ALT fossem maiores no subgrupo coinfectado. A elevação de marcadores bioquímicos da função hepática compatível com a síndrome de reconstituição imune foi observada em alguns indivíduos

coinfectados por hepatite B e/ou C no início do tratamento com Tivicay, sobretudo naqueles cuja terapia da hepatite B foi interrompida. Interações Medicamentosas: Pode aumentar a concentração

plasmática de fármacos cuja excreção dependa do OCT2. Efavirenz, etravirina, nevirapina, rifampicina, carbamazepina e tipranavir combinado ao ritonavir reduziram consideravelmente a

concentração plasmática de Tivicay, o que requer ajuste da dose para 50 mg duas vezes ao dia. Não é necessário ajustar a dose de Tivicay quando coadministrado com etravirina e

lopinavir/ritonavir, darunavir/ritonavir ou atazanavir/ritonavir. Fosamprenavir combinado ao ritonavir, reduziu a concentração plasmática de Tivicay, mas não exigiu ajuste da dose. Um estudo da

interação medicamentosa com atazanavir, que inibe a UGT1A1, não demonstrou aumento clinicamente importante da concentração plasmática de Tivicay. O efeito de tenofovir, lopinavir/ritonavir,

darunavir/ritonavir, rilpivirina, boceprevir, telaprevir, prednisona, rifabutina, daclastavir e omeprazol na farmacocinética do Tivicay foi nulo ou mínimo, portanto, não é necessário ajustar a dose.

Posologia: Adultos sem resistência a inibidores de integrase: dose recomendada de Tivicay é de 50 mg uma vez ao dia. Adultos com resistência a inibidores de integrase (documentada ou com

suspeita clínica): dose recomendada de Tivicay é de 50 mg duas vezes ao dia. Adolescentes: dose recomendada de Tivicay para os pacientes nunca tratados com inibidores da integrase (de 12 até

menos de 18 anos e com peso mínimo de 40 kg) é de 50 mg uma vez ao dia. Crianças: Não há dados suficientes sobre a segurança e a eficácia para recomendação de uma dose de Tivicay a

crianças com menos de 12 anos ou menos de 40 kg. Idosos: Não existem evidências de que os pacientes idosos necessitem de uma dose diferente. Superdosagem: A experiência limitada com

doses maiores isoladas (até 250 mg em indivíduos saudáveis) não mostrou sinais nem sintomas específicos, exceto aqueles citados como reações adversas. Outros procedimentos devem ser

instituídos de acordo com a indicação clínica ou segundo a recomendação do centro nacional de toxicologia, quando disponível. Não há tratamento específico para a superdosagem de Tivicay. A

terapia recomendada é de suporte com monitoramento apropriado, quando necessário. Em razão da alta ligação do às proteínas plasmáticas, é improvável que seja removido em quantidade

considerável por diálise. Dados pós-comercialização: Reações incomuns (>1/1000 e <1/100): artralgia e mialgia. Para dados completos sobre a segurança do medicamento, a bula na íntegra

deverá ser consultada e poderá ser solicitada à empresa através do Departamento de Informação Médica da GSK (SAC 08007012233 e/ou [email protected]). VENDA SOB PRESCRIÇÃO

MÉDICA. Reg MS:101070300. mBL_ Tivicay_com_rev_GDS08_IPI08_L0833

Material destinado exclusivamente para médicos e farmacêuticos.

A bula completa do medicamento e outras informações estão à disposição sob solicitação ao

departamento de Informações Médicas (DDG 0800 701 22 33 ou e-mail [email protected]). Para notificar

eventos adversos ocorridos durante o uso de medicamentos da GlaxoSmithKline/Stiefel, entre em contato

diretamente com o Departamento de Farmacovigilância da empresa pelo e-mail

[email protected] ou através do representante do grupo de empresas GSK.

As marcas registradas pertencem ou são licenciadas ao grupo ViiV Healthcare.

Material de autoria e propriedade GSK, a reprodução deste é proibida sem o consentimento da empresa.

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the role of tivicay (dolutegravir) in the hiv treatment ......the hiv treatment armamentarium jean...

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