Dolutegravir in Clinical Context - GSKpro...Patient has a risk profile for cardiovascular disease (a serious non-AIDS-related event in the START study) ... reproduction of this is

JAN VAN LUNZEN; MD, PHD, DTM&HProfessor of Medicine

Senior Global Medical Director,

ViiV Healthcare, London, UK

Dolutegravir in Clinical Context

DISCLOSURES

JvL is a full time employee of ViiV Healthcare

2003–2015: CORE AGENTS DRIVE

ADVANCEMENTS IN HIV THERAPY

Key ARV achievements

Efficacy of first-line treatments continue to improve

Newer PIs introduced with improved efficacy

and tolerability

Booster-free options

Core agents with a higher barrier to resistance

GSK copyright material, reproduction of this is prohibited without the consent of the company Adapted from references 1-4

MOST THIRD AGENTS ARE UNABLE TO MEET ALL THE

CHALLENGES OF HIV THERAPY

Long-term

tolerability of ARVs

• RAL requires twice-daily dosing

• There are currently few co-formulated fixed-dose combinations, offering one pill, once-daily simple dosing

Convenience

• Many HIV ARVs (and in particular ARVs boosted with ritonavir or cobicistat) interact with the cytochrome P450 enzymes and are associated with drug interactionsDrug interactions

• EFV, RPV, RAL and EVG appear to be associated with a lower barrier to resistance compared with boosted PIsDrug resistance

• EFV has CNS AEs and is associated with skin rash and hyperlipidaemia

• Boosted PIs are associated with metabolic disorders (dyslipidaemia and insulin resistance)

Tolerability of ARVs

AE, adverse event; ARV, antiretroviral; CNS, central nervous system; DHHS, United States Department of Health and Human Services;

EFV, efavirenz; EVG, elvitegravir; PI, protease inhibitor; RAL, raltegravir; RPV, rilpivirine

Adapted from reference 4GSK copyright material, reproduction of this is prohibited without the consent of the company

HAS DTG THE POTENTIAL TO ADDRESS

CURRENT CHALLENGES IN HIV MANAGEMENT?

Tolerability

Drug resistance

Current challenges

How could DTG meet these

challenges?

Convenience

Equivalent or statistically

superior efficacy

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

DTG: STRUCTURE AND

PHARMACOLOGICAL PROPERTIES

O

O

N

N

O

O

NH

O

F

FH

CH3

Na+

Pharmacological properties

DTG can be administered orally, once daily with no PK booster

DTG demonstrated predictable and consistent PK with low PK variability

DTG has a low potential for DDIs

DTG can be administered with or without food

DDIs, drug-drug interactions


CASE 1

Hb 12,0, WBC 3,400/µl, PLT 89.000

AST/ALT 1,5 ULN

Creatinine 1,2mg/dl

CD4 count 380/µl (23%)

VL: 280.000 c/ml

HLA-B*5701: neg.

No genotypic resistance

48 yrs. old, MSM, no medication, mild hypertension, BMI 28,9, smoker


QUESTION

Yes

No

Need more information

Don`t know

Would you start cART?


WHEN TO START

IAS-USA

ART is recommended for treatment of HIV infection and prevention of transmission of

HIV regardless of CD4 cell count (AIa-BIII)

DHHS

ART recommended for all regardless of pre-treatment CD4. Strength of

recommendation A1 (strong recommendation based on RCT) for all

WHOStart ART in all regardless of WHO clinical stage or CD4. Prioritise severe/advance

clinical disease (WHO stage 3 or 4) and adults with CD4 ≤350

EACS

ART should always be recommended irrespective of the CD4 count. Strong

recommendation if CDC B or C (including TB) or CD4 <350

GSK copyright material, reproduction of this is prohibited without the consent of the company Adapted from references 4, 9-11


THE START STUDY DEMONSTRATED THAT

IMMEDIATE ART WAS SUPERIOR TO DEFERRED ART IN

PATIENTS WITH CD4 COUNT >500 CELLS/MM3

1.8% of participants in the

immediate and 4.1% in the

deferred group experienced the

primary outcome (serious AIDS

and non-AIDS events or death)

57% reduction in risk

Evident for both serious AIDS

and non-AIDS events

Greater for serious AIDS

events

For TB and cancer

Consistent regardless of:

Age, gender, race, region

of the world

CD4+ count, HIV viral load

at entry

Risk factors for serious

non-AIDS diseases

START study: Key results

Adapted from reference 12

GSK copyright material, reproduction of this is prohibited without the consent of the company Adapted from reference 12

THE RESULTS OF THE START STUDY INFLUENCED

RECOMMENDATIONS IN HIV TREATMENT GUIDELINES

START study: Key results and

implications

Combination ART should be

recommended for all HIV-

positive persons, regardless

of CD4+ count

The START study results

align the benefits of ART for

the HIV-positive individual

with those in reducing the risk

of viral transmission from HIV-

positive to non-HIV-infected

individuals

Most events occurred at high

CD4+ counts (also in the

immediate arm despite ART),

including AIDS events

HIV-induced

immunodeficiency

– Occurs early in HIV

infection

– CD4+ counts do not fully

capture this

Safety outcomes were similar

in the two groups


THE START STUDY SHOWED HIGHER

ABSOLUTE RISK REDUCTION AND LOWER NNT IN

PARTICIPANTS WITH HIV RNA ≥50,000 COPIES/ML

Patients with HIV RNA ≥50,000 copies/mL might benefit from immediate access to ART

NNT, number needed to treat

Immediate ART Deferred ART

Time (months)

HIV RNA <3000 copies/mL

Cu

mu

lati

ve p

rop

ort

ion

wit

h a

n e

ven

t (%

)

NNT = 992 NNT = 122 NNT = 67

HIV RNA 3000–49,999 copies/mL HIV RNA ≥50,000 copies/mL


A BENEFICIAL EFFECT OF IMMEDIATE ART

WAS EVIDENT FOR AIDS-RELATED AND

NON-AIDS-RELATED EVENTS IN START

Patient has a risk profile for cardiovascular disease (a serious non-AIDS-related event in the START study)

These results show that he may benefit from immediate ART

Serious AIDS-related event Serious non-AIDS-related eventP

atie

nts

(%)

Time (months)

10

8

6

4

2

00 6 12 18 24 30 36 42 48 54 60

Immediate initiation

Deferred initiation

10

8

6

4

2

00 6 12 18 24 30 36 42 48 54 60

Immediate initiation

Deferred initiation

QUESTION

2NRTI + NNRTI

2NRTI + PI/r

2NRTI + INI

3 NRTI

INI + PI/r

other

Which cART would you recommend?


HOW DO THE WHO RECOMMENDATIONS COMPARE WITH

OTHER INTERNATIONAL GUIDELINES?

Recommended

Alternative

Please see the guidelines for full recommendations and any conditions of recommended/alternative regimens; *Only in WHO guidelines

3TC, lamivudine; ABC, abacavir; /c, cobicistat boosted; CrCl, creatinine clearance; EVG, elvitegravir; FTC, emtricitabine;

NNRTI, non-nucleoside reverse transcriptase inhibitor; RPV, rilpivirine; TAF, tenofovir alafenamide;

Adapted from references 4, 9-11

DHHS EACS IAS WHO


FOLLOW UP

CD4 increased by 20%

VL 400 c/ml

Clinically well

Mild sleeping disturbances

Tends to forget medication at the weekend

Patients started with TDF/FTC/EFV, doing well after 3 months, reports

adherence issues after 6 mths.


QUESTION

Yes

No

Too early to say

Do resistance testing only after VL control

Would you be concerned? Perform a resistance test?


QUESTION

TAMs

M184V

K103N

All

None

Which resistance mutations are most likely to occur at this time?


QUESTION

Which regimen would you use if 184V and 103N mutations have developped?

2NRTI + NNRTI

2NRTI + PI/r

2NRTI + INI

2 NRTI + CCR5Ag

3 NRTI

INI + PI/r

other


QUESTION

EFV < PI/r

EFV < RTG

EFV < DTG

PI/r = RTG

RTG > PI/r

DTG = PI/r

DTG = RTG

DTG > RTG

How do you estimate the barrier to resistance of given drugs?


NO INI OR NRTI RESISTANCE THROUGH 48 WEEKS WITH DTGSPRING-2 SINGLE FLAMINGO

n (%)DTG 50 mg QD

(n=411)RAL 400 mg BID

(n=411)

DTG 50 mg +ABC/3TC QD

(n=414)

EFV/TDF/FTCQD

(n=419)

DTG 50 mg(n=234)

DRV/r 800/100 mg QD(n=234)

Subjects with PDVF 20 (5) 28 (7) 18 (4) 17 (4) 2 (<1) 2 (<1)

NRTI-resistant mutations 0 4/19 (21)* 0 1(K65K/R) 0 0

INI-resistant mutations 0 1/18 (6)† 0¶ 0 0a 0

NNRTI-resistant mutations – – 0 4‡ – –

BL, baseline; c/mL, copies/mL; INI, integrase inhibitor

PDVF, protocol defined virologic failure

*One participant had mutation M184M/I; one had mutation A62A/V; and one had mutation M184M/V.† One participant had integrase mutations T97T/A, E138E/D, V151V/I, and N155H and NRTI mutations A62A/V, K65K/R, K70K/E, and M184V

¶E157Q/P polymorphism detected with no significant change in IN phenotypic susceptibility‡n=1 with K101E, n=1 with K103K/N, n=1 with G190G/A and n=1 with K103N+G190G/A

aOne subject in the DTG treatment group had phenotypic resistance to nelfinavir. This subject had secondary PI resistance mutations L10V, I13V,K20R, E35D, M36I, I62I/V, L63T and L89M at

baseline and at PDVF


DTG REMAINED BOUND TO HIV INTEGRASE 8 TIMES

LONGER THAN RAL AND 26 TIMES LONGER THAN EVG

DTG dissociation from IN-DNA complexes was slower compared with RAL and EVG

The combination of multiple RAL signature substitutions or the accumulation of RAL secondary substitutions were

needed to impact on DTG dissociation

DTG

RAL

EVG

IN substitutions

100

10

1

0.1

Dis

soci

ativ

e t ½

(h)


DTG HAS A PREDICTABLE AND CONSISTENT PK PROFILE

At 24 hours post-DTG administration, plasma concentrations were 19 to 25 fold above IC90

GSK copyright material, reproduction of this is prohibited without the consent of the company Adapted from references 21, 22

OVERVIEW OF DTG STUDIES

Exploring the breadth of data to support DTG

DTG TRIALS IN TREATMENT-NAÏVE ADULT

SUBJECTS WITH HIV

NRTI, nucleoside reverse transcriptase inhibitor

QD, once daily; BID, twice daily; FDC, fixed-dose combination

Phase IIb dose-ranging, randomised, partially blinded study of:

•DTG 10 mg, 25 mg, 50 mg versus EFV 600 mg + 2 NRTIsSPRING-1 N=205

Phase III non-inferiority, randomised, double-blind, double-dummy, multicentre

study of:

•DTG (50 mg QD) plus RAL placebo (BID) + 2 NRTIs

•RAL (400 mg BID) plus DTG placebo (QD) + 2 NRTIs

SPRING-2 N=822

Phase III non-inferiority, randomised, double-blind, double-dummy, multicentre

study of:

•DTG (50 mg QD) with ABC/3TC FDC plus EFV/TDF/FTC placebo

•EFV/TDF/FTC (QD) plus DTG and ABC/3TC FDC placebos

SINGLE N=833

Phase IIIb non-inferiority, randomised, active-controlled, multicentre, open-label

study of:

•DTG (50 mg QD) + 2 NRTIs

•DRV/r (800/100 mg QD) + 2 NRTIs

FLAMINGO N=484

Adapted from references 14, 15, 19, 23GSK copyright material, reproduction of this is prohibited without the consent of the company

IN TREATMENT-NAÏVE PATIENTS, DTG WAS

SUPERIOR TO EFV AT 144 WEEKS

DTG + ABC/3TC remained statistically superior to EFV/TDF/FTC through to Weeks 96 and 144

Week

0

10

20

30

40

50

60

70

80

90

100P

rop

ort

ion

wit

h H

IV-1

RN

A <

50 c

/mL

BL 4 8 12 16 24 32 40 14448 60 72 84 96 108 120 132

71%

63%

DTG 50 mg + ABC/3TC FDC QD (n=414)

EFV/TDF/FTC QD (n=419)

Week 144 adjusted difference in response (95% CI):

+8.3% (+2.0% to +14.6%); p=0.010

88%

81%

80%

72%

Adapted from references 24-26GSK copyright material, reproduction of this is prohibited without the consent of the company

EFFICACY SNAPSHOT BY SUBGROUPS

AT WEEK 144

Response rates were consistently higher for the DTG + ABC/3TC arm than the EFV/TDF/FTC arm, including among people with a high baseline VL, low baseline

CD4 count, women and non-whites

73%69%

73%

60%

69%72% 72% 71%

64%61%

64%

56%

48%

66%

71%

47%

0%

20%

40%

60%

80%

Vir

olo

gic

su

cces

s* a

t w

eek

144

(%)

Gender Race

250/347

235/356

204/284

202/285

92/130

62/133

46/67

30/63

HIV-1 RNA

(c/mL)

CD4 cell count

(cells/mm3)

204/

280

185/

288

92/

134

80/

131

262/

357

230/

357

34/

57

35/

62

EFV/TDF/FTC QD (n=419)

DTG 50 mg + ABC/3TC QD (n=414)

*HIV-1 RNA <50 c/mL

Adapted from references 24, 25GSK copyright material, reproduction of this is prohibited without the consent of the company

TreatmentNumber of responders/

total assessed, n (%)

Difference in

proportion (95% CI) (DTG - RAL)

Adjusted difference in

proportion (95% CI) (DTG - RAL)

DTG 50 mg QD 332/411 (81) 4.4% (–1.2%, 10.0%) 4.5% (–1.1%, 10.0%)

RAL 400 mg BID 314/411 (76)

Error bars indicate 95% CI


NON-INFERIOR TO RAL AT 96 WEEKS

DTG and RAL were associated with similar increases in CD4+ cell count from baseline over time.

GSK copyright material, reproduction of this is prohibited without the consent of the company Adapted from references 14, 27, 28


SUPERIOR TO DRV/R AT 96 WEEKS

Pro

port

ion

with

HIV

-1 R

NA

<50

c/m

L (%

)DTG†: 80%

DRV/r†: 68%

BL 4 8 12 16 3624 48 96Week

Test for superiority: p=0.002

0% 25%–12%

4.7 12.4 20.2

95% CI for difference

Favours

DRV/r

Favours

DTG

Differences largely driven by lower virologic failure rate and fewer withdrawals due to AEs in the DTG arm

†plus 2 NRTIs

DTG 50 mg QD† (n=242)

DRV/r 800/100 mg QD† (n=242)

100

90

80

70

60

50

40

30

20

10

0


1 2

RU/DGR/0003/16

PATIENT CASE STUDY 2

28 year old lady

previously healthy, no regular co-medication

Newly diagnosed with HIV-1 infection at

gynaecologist during intervention for missed

abortion

No prior OI, no clinical complaints

Partner also tested positive for HIV-1


LAB TESTS

WBC normal, LFT + creatinine normal, normal lipids, coagulation tests

normal

CD4 count 490/µl, VL: 160.000 c/mL

Hepatitis B immune, HCV Ab positive, HCV DNA: >1.000.000 c/mL

Normal CXR and ultrasound, no signs of fibrosis


WOULD YOU START CART?

Yes

No

Don`t know


WHAT CART WOULD YOU CHOOSE?

2NA + NNRTI

2NA + PI/r

2NA + INI

Any other?


CASE 2 CONT`D

Patient received AZT/3TC + EFV

Initially mild CNS symptoms (dizziness, bad dreams), got better after 6

weeks

After 3 months: CD4 560/µL, VL: 600 c/mL

Other lab unchanged

Partner is also treated with same combination

Patient reports to use condoms but tends to forget sometimes, inquires

about alternative contraceptive measures


WHAT DO YOU RECOMMEND?

Oral contraceptives +

condoms, same cART

Oral contraceptives +

condoms, change cART

Condoms + female

diaphragm, same cART

Long acting contraceptives +

condoms, same cART

Long acting contraceptives +

condoms, change cART

other


CASE 2 CONT`D

Doctor recommended oral contraceptive + condom, same cART

Patient returns after 6 months feeling nauseated, vomiting in the mornings

LFT 2 times ULN, bilirubin 1,5mg/dl, other routine lab normal, VL<50 c/mL,

CD4 680/µL

Reports good adherence (95% drug intake)

Weight gain 2,5kg


WHAT HAS HAPPENED?

• Flare of hepatitis C

• GI toxicity of cART

• IRIS

• Drug induced liver injury (DILI)

• Pregnancy

• Other


DIAGNOSIS?

Liver failure, chronichepatitis C

Liver failure, DILI

Acute kidney failure

AZT toxicity

Pregnancy, HELLP syndrome

Other


CASE 2 CONT`D

Hb 8,6mg/dL, LDH 560U/L, bilirubin 3,4 mg/dL

LFT increase to 3 times ULN

HCV VL: 5.000.000 c/mL

Slight thrombopenia

Creatinine 1,8mg/dL, proteinuria ++

RR 180/120mmHG

Pregnancy test positive


WHY DID IT HAPPEN?

Toxic drug reaction

Drug-drug interaction

Co-infection with

hepatitis C

None of the above


CHOICE OF CONTRACEPTIVE AND HRT METHOD

SHOULD CONSIDER DDIs

*Only as contraceptive

EC, emergency contraceptive; IM, intramuscular

Levonogrestrel (EC)

Ulipristal

Ethinyl oestradiol

Mifepristone*

Oestradiol

ATV/booster DRV/booster EFV RPV DTG E/C/F/TAF E/C/F/TDF RAL

Desogestrel

Drospirenone

Dydrogesterone

Etonogestrel

Gestodene

Levonorgestrel

Medroxyprogesterone (IM)

Medroxyprogesterone (oral)

Norelgestromin

Noresthisterone (norethindrone)

Norgestimate

Norgestrel

Pro

gestins

Oestr

ogens

Oth

er

No clinically significant interaction expected Potential interaction – may require close monitoring oralteration of drug dose or timing of administration


THERE ARE SIGNIFICANT REGIONAL DIFFERENCES IN THE

PROPORTIONS* OF ADULTS LIVING WITH HIV WHO ARE WOMEN


*Proportions calculated from the unrounded 2013 HIV estimates published in: UNAIDS. Gap report 2014, pp A30–A35

50%

39%22%

59%

30%

The proportion of HIV-infected women compared with men is highest in Africa, the Caribbean, Asia and Eastern Europe

22%36%

38%

Adapted from references 32, 33

18

30 31

19

2326

24

12

8

1215 16

7

1613

1516

30 31

1820

2825

10 11 1114

17

7

1517

15

0

5

10

15

20

25

30

35

40

WOMEN ARE UNDER-REPRESENTED IN TREATMENT-NAÏVE,

REGISTRATIONAL ART CLINICAL TRIALS


EVG

DRV/r

RAL

EFV

DTG

RPV LPV/r

ATV/r

ATV

Third agent

Pro

po

rtio

n o

f w

om

en

re

cru

ite

d (

%)

ART clinical trials since 2005 have recruited on average ~20% women

Time (by start date)2005 2013

*Or ATV/r (24%); †DRV/r + RAL (12%) or DRV/r + TDF/FTC (11%); ‡LPV/r + 3TC (16%) or LPV/r + ABC/3TC (17%); §EVG/c/FTC/TDF vs EVG/c/FTC/TAF

ART, antiretroviral therapy; LPV, lopinavir

Adapted from references 14, 17, 19, 40-53

ARIA WAS A TREATMENT-NAÏVE STUDY

CONDUCTED ONLY IN WOMEN


• Key eligibility criteria: Women, ART-naïve, HLA-B*5701 negative, HIV-1 RNA >500 copies/mL, hepatitis B negative

• Stratification: By HIV-1 RNA (≤100,000 or >100,000 copies/mL), CD4+ count (≤350 or >350 cells/mm3)

• Women who became pregnant were withdrawn and, if possible, offered entry into an ABC/3TC + DTG pregnancy study

• Primary endpoint: Proportion with HIV-1 RNA <50 copies/mL at week 48 by FDA snapshot algorithm (–12% non-inferiority margin)

Week 48 primary analysis Randomisation

Open-label, randomised, non-inferiority, Phase IIIb study

ABC/3TC + DTG FDC*Open label,

randomised

1:1ATV/r +TDF/FTC FDC

ABC/3TC + DTG FDC*

Continuation phase

*ABC/3TC/DTG was administered as a single pill


ARIA FOUND DTG TO BE SUPERIOR TO ATV/r IN

HIV-POSITIVE, TREATMENT-NAÏVE WOMEN


82%

6%

12%

71%

14% 15%

86%

6% 8%

76%

11% 13%

0

20

40

60

80

100

Virologicalsuccess

Virologicalnon-response

No virologicaldata

HIV

-1 R

NA

<5

0 c

op

ies

/mL

(%

)ABC/3TC + DTG (ITT-E, n=248)

ATV/r + TDF/FTC (ITT-E, n=247)

ABC/3TC + DTG (PP, n=230)

ATV/r + TDF/FTC (PP, n=225)

Treatment differences (95% CI)Virological outcomes at week 48

ITT-E, intention to treat exposed; PP, per protocol

NO WOMEN RECEIVING THE DTG-BASED REGIMEN

DEVELOPED INI OR ABC/3TC RESISTANCE


Resistance analysisABC/3TC + DTG

(n=6)

ATV/r +TDF/FTC

(n=4)

INI 0 0

NRTI 0* 1

M184V 0 1

PI 0 0

*Two subjects receiving ABC/3TC + DTG had either K219K/Q (TAM) or E138E/G at CVW with no reduced susceptibility to ABC/3TC + DTG. K219K/Q is not

selected for by ABC or 3TC, nor does it affect their fold change

CVW, confirmed virological withdrawal

SUMMARY OF PSYCHIATRIC AES


Event

DTG/ABC/3TC

FDC

N=248

n (%)

ATV/r+

TDF/FTC

FDC

N=247

n (%)

Any event 35 (14) 35 (14)

Insomnia 10 (4) 9 (4)

Anxiety 5 (2) 7(3)

Depression 5 (2) 7 (3)

Suicidal ideation 4 (2) 3 (1)

Depressed mood 3 (1) 4 (2)

Abnormal dreams 2 (<1) 0

Panic attack 2 (<1) 2 (<1)

Agitation 1 (<1) 0

Bipolar disorder 1 (<1) 0

Elevated mood 1 (<1) 0

Mood altered 1 (<1) 2 (<1)

Mood swings 1 (<1) 0

Nightmare 1 (<1) 2 (<1)

Sleep disorder 1 (<1) 2 (<1)

Event

DTG/ABC/3TC

FDC

N=248

n (%)

ATV/r+

TDF/FTC

FDC

N=247

n (%)

Acute psychosis 0 1 (<1)

Affect lability 0 1 (<1)

Anxiety disorder 0 1 (<1)

Confusional state 0 1 (<1)

Hallucination,

visual0 1 (<1)

Intentional self-

injury0 1 (<1)

Irritability 0 1 (<1)

Mania 0 1 (<1)

Panic disorder 0 1 (<1)

Stress 0 1 (<1)

ARIA PROVIDES IMPORTANT INFORMATION TO HELP GUIDE

TREATMENT DECISIONS IN WOMEN


Effic

acy

• In treatment-naïve women, ABC/3TC + DTG (administered as a single pill)

was superior to ATV/r + TDF/FTC at 48 weeks of treatment

− Adjusted difference 10.5%, 95% CI 3.1–17.8%, P=0.005

− Difference driven by lower rate of virological non-response (snapshot)

and fewer discontinuations due to AEs in the DTG armTole

rabili

ty

Tole

rabili

ty

• ABC/3TC + DTG had a favourable safety profile to that of ATV/r + TDF/FTC

− Similar to overall safety profile for DTG from previous studies

Resis

tance

• There were no treatment-emergent primary INI or ABC/3TC resistance mutations

in the ABC/3TC + DTG group

CI, confidence interval

Raltegravir* Elvitegravir(as EVG/COBI/FTC/TDF)

Dolutegravir

Efavirenz Non-inferior Non-inferior Superior

Atazanavir/ritonavirEquivalent (VF)

Superior (TF)Non-inferior Superior

Darunavir/ritonavirEquivalent (VF)

Equivalent (TF)No data Superior

* Based on secondary composite endpoint, RAL was superior to ATV/r and DRV/r at 96 weeks

No direct cross-study comparisons can be made given different study designs and populations

EFFICACY OUTCOMES OF INIS VERSUS OTHER THIRD

AGENTS IN TRIALS OF TREATMENT-NAIVE PATIENTS

GSK copyright material, reproduction of this is prohibited without the consent of the company Adapted from references 15, 19, 48, 49, 55, 56

CASE 3

28 year old lady, history of IVDU

Initial HIV diagnosis 2008 during TB episode

CD4 nadir 120/µL, peak VL: 150.000 c/mL, no genotype available

Married to HIV negative partner, 2 healthy children

Since 2008 on TDF/3TC/EFV plus methadone substitution

In 2015:

Normal routine lab, doing well

HBV neg., HCV-Ab pos., GT 2, HCV-VL: 1 Mio c/mL

LFT: two times ULN

HLA-B*5701 negative

HIV-1 RNA: <50 c/mL, CD4+ cell count: 430cell/µL


CASE 3

Presents to you for first time seeking for a second opinion

Feels generally quite well, slightly abnormal dreams, sleeps not more than

5 hours per night

Is happy with medication, appreciates QD/STR regimen

Works in a factory (occasional night shifts), is worried about disclosure of

HIV status


WHAT WOULD YOU RECOMMEND?

a) stay on current therapy

b) switch to TDF/FTC/RPV

c) switch to 2NA/PI/r since no GT available

d) switch to TDF/FTC/EVG/c

e) switch to TDF/XTC/RAL

f) switch to ABC/3TC/DTG

g) other


WHAT I USE AND WHY

SELECTING THE BEST ART REGIMEN

Drug Factors

Efficacy

Safety and tolerability

Convenience: Dosing schedule, Time restrictions, Food requirement

Drug resistance

Drug-drug-interactions

Patient Factors

Age

Occupation

Co morbidities, co-medication

Immune deficiency, viral load


STRIIVING EVALUATED THE SAFETY AND EFFICACY OF

SWITCHING TO ABC/3TC + DTG IN STABLE SUPPRESSED PATIENTS


Primary endpoint at 24 weeks

Viral load <50 copies/mL (snapshot)

Inclusion criteria

• Virologically suppressed

(confirmed HIV-1 RNA

<50 copies/mL)

• HLA-B*5701 negative

Open label,

randomised

1:1

ABC/3TC + DTG*

0 Week 24Screening Week 48

Countries: USA, Canada, Puerto Rico

Current ART† ABC/3TC + DTG*

Assessments

• CD4 cell count changes

• Clinical and laboratory

safety

• Lipids, renal, bone, and

cardiovascular changes

• Development of resistance

• Treatment satisfaction

90% power based on 10% non-inferiority margin (estimated response rate = 85%)

*ABC/3TC/DTG was administered as a single pill;

†Stable suppressive current ART with 2 NRTIs plus a PI, an NNRTI, or an INI. ≥40% PIs, at least 25% INIs


STRIIVING DEMONSTRATED THAT SWITCHING TO

ABC/3TC + DTG MAINTAINS HIV SUPPRESSION AT 48 WEEKS


85%

1%

14%

88%

1%

10%

83%

<1%

17%

92%

<1%

7%

0

20

40

60

80

100

Virologicalsuccess

Virologicalnon-response

No virologicaldata

HIV

-1 R

NA

<50 c

op

ies/m

L (

%)

ABC/3TC + DTG, day 1 to week 24 (n=275)*

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

ABC/3TC + DTG, day 1 to week 48 (n=275)

cART, day 1 to week 24 (n=278)*

*Intention-to-treat exposed analysis

cART, combination antiretroviral therapy

NO SUBJECTS MET PROTOCOL-DEFINED

VIROLOGICAL FAILURE (PDVF) IN EITHER ARM


*Subjects with HIV-1 RNA ≥400 copies/mL at two consecutive assessments any time after randomisation were withdrawn and were considered to have PDVF

FEW SUBJECTS DISCONTINUED TREATMENT BECAUSE OF

ADVERSE EVENTS IN STRIIVING


*None were considered drug-related events

TREATMENT SATISFACTION IMPROVED SIGNIFICANTLY MORE

FOR PATIENTS SWITCHING TO ABC/3TC + DTG


Treatment satisfaction total score

0

1

2

3

4

ABC/3TC + DTG (n=269) Current ART (n=276)

Ad

juste

d m

ean

ch

an

ge

in s

co

re a

t w

eek 2

4

Adjusted mean difference at week 24:

2.4 (95% CI 1.3–3.5); P<0.001

STRIIVING SUPPORTS A SWITCH FROM STABLE,

SUPPRESSIVE ART TO ABC/3TC + DTG


Effi

cacy

• The virological response rate was maintained through 48 weeks in the early-switch group

• In the late-switch group, virological suppression was observed in 92% of patients on ABC/3TC + DTG

(24 weeks post-switch)

• There were no PDVFs in the study

Tole

rabi

lity

Tole

rabi

lity

• There were no further discontinuations due to AEs in the early-switch arm after week 24

• Rates of discontinuations in the late-switch arm were low (2%)

Sum

mar

y

• Data through 48 weeks support switching to ABC/3TC + DTG once daily for HIV-1 subjects on stable

suppressive cART

Early switch: DTG + ABC/3TC: n=275

Late switch: DTG + ABC/3TC: n=244

CASE 3 CONTD

Pat. switched to ABC/3TC/DTG

No dose adjustment needed for methadone

Very happy with new medication, QoL markedly improved

Sleeping disturbances disappeared

HIV VL stable <20 c/mL, CD4 count stable

Ready to start HCV therapy


DRUG-DRUG INTERACTIONS WITH HEPATITIS C DRUGS

ATV/booster DRV/booster LPV/booster RPV EFV DTG RAL

Boceprevir u u u

Daclatasvir u u u u u

Ombitasvir / paritaprevir/r +

dasabuvir u u

Sofosbuvir u u u u u u u

Simeprevir u u u

Ribavirin u u u u u u

Peginterferon alfa u u u u u u u

No clinically significant interaction expectedPotential interaction – may require close monitoring oralteration of drug dose or timing of administration Do not coadminister


SUMMARY

Different reasons to consider switching (adherence, failure, convenience, tolerability,

interactions, simplification etc.)

Patient and disease factors important

Switching effective in most scenarios due to excellent tolerablity, low potential for DDI, high

barrier to resistance, favorable PK

Improvements treatment satisfaction after switch versus CAR

Consider contraindications for ABC (e.g. HBV co-infection, HLA status, resistance, very high CV

risk)

Switch to Triumeq®

Adapted from reference 11, 57-60GSK copyright material, reproduction of this is prohibited without the consent of the company

CASE 4

58-year-old man with newly diagnosed asymptomatic HIV infection

He has Hepatitis B coinfection.

He is a diabetic and hypertensive, well controlled on the following medications, for the past 10

years:

Metformin

Sulfonylurea

ACE inhibitor

Nonsmoker, occasional alcohol use

His father had MI at 62 years of age


CASE 4 CONTD

Baseline laboratories are as follows:

Calculated creatinine clearance: 80 mL/min

Urinalysis: 2+ proteinuria

CD4+ cell count: 90 cells/mm3

HIV-1 RNA: 183,300 copies/mL

HBsAg positive


WHAT ART REGIMEN WOULD YOU SELECT FOR THIS PATIENT?

a) LPV/r + TDF/3TC

b) LPV/r + ABC/3TC

c) EFV/TDF/3TC

d) DTG + ABC/3TC

e) DTG + TDF/3TC

f) RAL + 3TC + DRV/r

g) RAL + TDF/3TC

h) Something else

58-yr-old man, tx naive

CD4+ cell count: 90 cells/mm3

HIV-1 RNA: 183,300 copies/mL

HBsAg positive

HTN and DM; CrCl: 80 mL/min

Taking metformin,sulfonylurea, ACE inhibitor

Father had MI at 62years


WHAT I USE AND WHY

AEs, n (%)DTG 50 mg QD

(n=411)

RAL 400 mg BID

(n=411)

WEEK 48

Any event 339 (82) 340 (83)

Nausea 59 (14) 53 (13)

Headache 51 (12) 48 (12)

Nasopharyngitis 46 (11) 48 (12)

Diarrhoea 47 (11) 47 (11)

WEEK 96

Any event 349 (85) 349 (85)

Nausea 60 (15) 56 (14)Nasopharyngitis 55 (13) 58 (14)Diarrhoea 57 (14) 55 (13)Headache 56 (14) 55 (13)

DTG OFFERED SIMILAR TOLERABILITY TO RAL

Discontinuations due to AEs were 2% for DTG vs 2% for RAL at Week 96

GSK copyright material, reproduction of this is prohibited without the consent of the company Adapted from references 14, 27, 61, 62

DTG WAS WELL TOLERATED WITH

FEW DISCONTINUATIONS

DTG

50 mg QD

(n=242)

DRV/r

800 mg/100 mg QD

(n=242)

Individuals with events leading to

discontinuation, n (%)

4 (2) 10 (4)

System organ class (>1 event in either arm)

Gastrointestinal disorders 2 (<1) 2 (<1)

Nervous system disorders 2 (<1) 2 (<1)

General disorders and administration site

conditions

0 2 (<1)

Abnormal transaminase 0 2 (<1)

Skin and subcutaneous tissue disorders 0 2 (<1)

Discontinuations due to AEs at 48 weeks were 2% for DTG and 4% for DRV/r


DTG HAD A LIPID-NEUTRAL PROFILE

0,21

0,05

0,13

0,08

0,26

0,06

0,16

0,07

0

0,05

0,1

0,15

0,2

0,25

0,3

Total cholesterol HDL cholesterol LDL cholesterol Triglycerides

RAL 400 mg BID + 2 NRTIs

DTG 50 mg QD + 2 NRTIs

Mean

ch

an

ge f

rom

baselin

e (

mm

ol/L

)

Median changes at Week 48 in mmol/L: Total cholesterol, DTG, +0.18 mmol/L, RAL +0.23 mmol/L;

Triglycerides, DTG +0.10 mmol/L, RAL +0.10mmol/L

IQR, interquartile range

No evidence of clinically significant impact on lipid profile (i.e. total cholesterol, HDL

cholesterol, LDL cholesterol or triglycerides) at 96 weeks

(n=291)(n=278) (n=292)(n=278)(n=289)(n=274)(n=291)(n=278)


DTG HAS FEW SIGNIFICANT INTERACTIONS WITH

COMMONLY USED MEDICATIONSCommonly used medications Dose adjustment required

Oral contraceptives No

Proton pump inhibitors No

H2 antagonists (including cimetidine, famotidine, nizatidine, ranitidine) No

Rifabutin No

Methadone No

Hepatitis B transcriptase inhibitor (adefovir) No*

Hepatitis C protease inhibitors (telaprevir, boceprevir) No

Antidepressants No*

Statins No*

Rifampicin Dose DTG 50 mg BID

Avoid in INI-class resistance

Magnesium/aluminium-containing antacids

Calcium and iron supplements

Multivitamins

Dose DTG 2 hours before or 6 hours after these

medicines

EFV, NVP, and TPV/r Dose DTG 50 mg BID

Avoid in INI-class resistance

ETV Must only be used in combination with ATV/r, DRV/r or

LPV/r

• DTG and dofetilide

co-administration

contraindicated due to potential

life-threatening toxicity caused

by high dofetilide concentration

• DTG is not primarily

metabolised via the CYP450

pathway†

• List is not complete, and for

further information the

TIVICAY® prescribing

information should be

consulted

* Based on results from other drug interaction trials, DTG is not expected to affect the pharmacokinetics of these drugs† DTG is metabolised by the UGT1A1 pathway

Adapted from references 31, 64-66GSK copyright material, reproduction of this is prohibited without the consent of the company

TOLERABILITY DATA: SUMMARY

ART-naïve patients (n=822)

DTG offers similar tolerability to RAL (DTG: n=411; RAL: n=411)

• 2% vs 2% discontinued due to AEs at 48 weeks• 2% vs 2% discontinued due to AEs at 96 weeks


DTG + ABC/3TC was better tolerated vs EFV/TDF/3TC with fewer discontinuations (DTG+ABC/3TC: n=414; EFV/TDF/3TC: n=419)

• 13% vs 27% experienced drug-related AEs (Grades 2 to 4)• 2% vs 10% discontinued due to AEs at 48 weeks

Treatment-experienced, INI-naïve (n=715)DTG offers similar tolerability to RAL (DTG: n=354; RAL: n=361)

• 1% vs 3% discontinued due to AEs


DTG was well tolerated with lower rates of diarrhoea vs darunavir/r (DTG: n=242; DRV/r: n=242)

• 2% vs 4% discontinued due to AEs at 48 weeks

GSK copyright material, reproduction of this is prohibited without the consent of the company Adapted from references 14, 15, 19, 27, 67, 68

DTG IS WELL TOLERATED WITH FEW DISCONTINUATIONS

DTG is well tolerated with few discontinuations

Tolerability

Challenge Characteristics of DTGDTG delivers rapid and sustained efficacy

Equivalent or statistically

superior efficacy

DTG has a high barrier to resistanceDrug resistance

Adapted from references 14, 15, 19, 27, 67, 68GSK copyright material, reproduction of this is prohibited without the consent of the company

CASE 5

Initial CD4 count 430/µL, VL: 230.000c/mL

Rapid response initially, VL<50c/ml since 18 mths

Last visit VL: 200 c/mL, CD4 stable

Doing well, tolerates ART without problems

43 yrs. old MSM, stable on TDF/3TC/RTG since 2 years


POSSIBLE EXPLANATIONS?

Non-adherence

PK interactions

Resistance

Viral blip

None of the above


WHAT WOULD YOU DO?

Order resistance testing

Perform therapeutic drug monitiring

Switch patient immediately to other ART regimen

Leave patient on current regimen, control in 3 months

Send patient for adherence counseling


CASE 5

Leave on current therapy after adherence counseling

Switch to TDF/FTC/EVG/c

Switch to DTG + TDF/FTC or ABC/3TC

Switch to PI/r

Something else

Patient admits to have missed morning doses of RTG. What would you do?


DTG TRIALS IN TREATMENT-EXPERIENCED ADULT

SUBJECTS WITH HIV

BID, twice daily; BR, background regimen

QD, once daily; OBR, optimised background regimen

Phase III, open-label, single-arm, multicentre study of:

• DTG (50 mg BID) + OBR (not incl. RAL)

VIKING-3 INI-resistant

N=183

Phase III, randomised, double-blind, active-controlled, parallel group,

non-inferiority, multicentre study of:

• DTG (50 mg QD) + BR

• RAL (400 mg BID) + BR

SAILINGINI-naïve

N=719

Phase IIb open-label, single-arm multicentre study

(Cohort I) of:

• DTG 50 mg QD + OBR (not incl. RAL)

VIKING

(Cohort I)INI-resistant

N=27

Phase IIb open-label, single arm multicentre study (Cohort II) of:

• DTG (50 mg BID) + OBR (not incl. RAL)

• Subjects required to have ≥1 fully active ARV for

Day 11 optimisation (not required for Cohort I)

VIKING

(Cohort II)INI-resistant

N=24

Phase III, open-label, placebo-controlled, multicentre study of:

• DTG 50 mg BID vs placebo (both plus current failing regimen)

• At Day 8, all subjects received DTG (50 mg BID) + OBR (containing

≥1 fully active ARV)

VIKING-4 INI-resistant

N=30


Mean (SD) CD4+ change from baseline to Week 48 was similar between arms: DTG: +162 (151) cells/mm3; RAL: +153 (144) cells/mm3

*Analysis based on all subjects randomised who received ≥1 dose of study drug, excluding four subjects at one site with violations of good clinical practice

SD, standard deviation†Adjusted difference based on stratified analysis adjusting for BL 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)

RAL 64%

Pro

po

rtio

n a

chie

vin

g

HIV

-1 R

NA

<50

c/m

L(%

)

Week

DTG 71%

Baseline 4 8 12 16 24 32 40 480

10

40

50

70

80

30

100

20

60

90

DTG 50 mg QD (n=354)RAL 400 mg BID (n=361)

IN TREATMENT-EXPERIENCED, INI-NAÏVE PATIENTS, DTG

HAD STATISTICALLY SUPERIOR EFFICACY VS RAL

Week 48 adjusted difference† in response (95% CI):

+7.4 in favour of DTG (0.7%, 14.2%); P = 0.03

DTG mg QD was statistically superior to RAL 400 mg BID based on a pre-specified snapshot analysis* (HIV-1 RNA <50 copies / mL) at Week 48 (P = 0.03)


DTG HAD FEWER RESISTANCE MUTATIONS

THAN RAL THROUGH 48 WEEKS

DTG

50 mg QD + OBR

(n=354)

RAL

400 mg BID + OBR

(n=361)

Protocol-defined virologic failure, n

(%)

21 (6) 45 (12)

INI mutations*, n (%) 4(1)† 16 (4) ‡

* Adjusted difference: -3.7% (95% CI:-6.1%,-1.2%); P=0.003. As the upper end of the 95% CI for the adjusted treatment difference was greater than 0, this finding demonstrated a

statistically significant difference in favour of DTG.

† Treatment-emergent INI mutations detected: R263K, R263R/K, V151V/I; one patient developed a T97A and E138T/A mutation, however this patient was subsequently found to have a

Q148 mutation at baseline.

‡One patient in each group had INI resistance at baseline

Substitutions seen at positions R263 and V151 did not confer high levels of resistance to DTG (2<fold change in IC50), or cross resistance to RAL.

The proportion of subjects with evidence of INI resistance was significantly lower in the DTG arm than in the RAL arm


ART-naive patients (n=822)

No INI or NRTI resistance through 48 or 96 weeks with DTG


No INI or NRTI resistance through 48 weeks with DTG

Treatment-experienced, INI-naïve (n=715)

Fewer resistance mutations with DTG than raltegravir (1% vs 5%) through 48 weeks


No emergent INI, NRTI or PI mutations through 48 or 96 weeks with DTG

DTG HAS A HIGH BARRIER TO RESISTANCE:

SUMMARY

GSK copyright material, reproduction of this is prohibited without the consent of the company Adapted from references 14, 15, 19, 27, 29, 68, 69

Raltegravir Elvitegravir(as EVG/COBI/FTC/TDF)

Dolutegravir

Once daily dosing*

Take with or without food*

Does not require PK boosting

High barrier to resistance

Few drug-drug interactions

Registrational trials with both TDF/FTC and ABC/3TC

backbones

Comparison of Currently Available INSTI in

HIV-Positive Patients Without Integrase Resistance

*For patients infected with HIV-1 with resistance to the integrase class (documented or clinically suspected), the recommended dose of dolutegravir is 50 mg twice daily and should

be preferably taken with food to enhance exposure.

Adapted from references 4, 14-19, 64, 73-75GSK copyright material, reproduction of this is prohibited without the consent of the company

CONVENIENCE BEYOND ONCE-DAILY DOSING

No boosting required

No time-of-day restrictions

Few DDIs with commonly used

medications

Small tablet sizeAttributes

of DTG

Can be taken with or

without food

GSK copyright material, reproduction of this is prohibited without the consent of the company Adapted from references 4, 14-19, 64, 75

DTG – THE REASON TO RETHINK HIV THERAPY

DTG is well tolerated with few discontinuations

Tolerability

Challenge Characteristics of DTG

DTG delivers rapid and sustained efficacyEquivalent or

improved efficacy

DTG has a high barrier to resistanceDrug

resistance

Convenience beyond once-daily dosingConvenience

Adapted from references 14, 15, 19, 27, 67, 68GSK copyright material, reproduction of this is prohibited without the consent of the company

THANK YOU

Informações Médicas GSK Canal de comunicação exclusivo para os Profissionais de Saúde

Faça a sua solicitação através de

[email protected]

Bulas completas dos produtos GSK

Artigos científicos na íntegra

Respostas a questionamentos científicos sobre os produtos GSK

Levantamentos bibliográficos relacionados às áreas terapêuticas de atuação da GSK

Construindo Confiança, Promovendo Transparência

INFORMAÇÕES DE SEGURANÇA

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.

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

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Material destinado exclusivamente para profissionais de saúde habilitados a prescrever

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