Otimização do uso de Inibidores da Integrase na Prática Clínica

Carlos BritesFaculdade de Medicina

UFBA

Que ARVs precisamos?

•Potente

•Alta barreira à resistência

•Boa biodisponibilidade por via oral e parenteral

•Seguro a curto e longo prazo

•Boa comodidade posológica

•Não interage com alimentos

•Sem interações farmacológicas significativas

•Baixo custo

Para tratar que pacientes?

• Em início de terapia

• Com necessidade de troca

• Pacientes mais velhos

• Que apresentem necessidades especiais (gestantes, tuberculose)

“switch”

falha à terapia

comorbidades

Polifarmácia (DDI!!)

Risco de Falha Virológica na Vida real em PctsIniciando TARV Baseada ou Não em DTG

• Comparação das taxas de falha virológica entre pcts infectados pelo HIV que iniciaram TARV de Agosto 2013 a Março 2017 em 8 sites da CNICS (N = 5177)

Nance R, et al. IDWeek 2017. Abstract 1688.

† Falha Virológica : HIV-1 RNA > 400 c/mL ≥ 6 meses após inicio da TARV.

*Cox models ajustados para idade, CD4, dias desde última CV, CNICS site, sexo, HBV, HCV, fator de

risco para HIV, e raça.

Pcts Eventos, naHR* para Falha Virológica† de DTG vs

Comparador (95% CI)

Todos pcts

▪ Outro INSTI

▪ DTG

245

143 0.82 (0.65-1.03)

▪ DRV

▪ DTG

98

143 0.41 (0.30-0.55)

Pts VT

▪ Outro INSTI

▪ DTG

93

28 0.93 (0.58-1.48)

▪ DRV

▪ DTG

23

28 0.32 (0.14-0.75)

3

Comparative effectiveness of first-

line antiretroviral therapy regimens:

results from a large real-world

cohort in Brazil after the

implementation of Dolutegravir

Meireles MV, Pascom ARP, Perini F, Rick F, Benzaken A.

Ministry of Health of Brazil, Department of STI, AIDS and Viral Hepatitis

Baseline characteristics Multivariable analysis

% VS (%) aOR 95% CI

Regimen 3TC+TDF+DTG 7.2 85.2 1.42 (1.32-1.52)

3TC+TDF+EFV 74.0 78.0 1

3TC+AZT+LPV/r 4.9 67.2 0.59 (0.55-0.63)

3TC+TDF+ATV/r 4.6 71.3 0.67 (0.63-0.72)

3TC+AZT+EFV 3.5 72.9 0.94 (0.87-1.02)

3TC+TDF+LPV/r 2.0 63.7 0.54 (0.49-0.60)

Others 3.7 67.9 0.67 (0.62-0.73)

Results

The observed effectiveness of 3TC+TDF+DTG in our cohort was markedlysuperior to other regimens after controlling for age, sex, adherence andbaseline CD4 and VL

• 42% superior to 3TC+TDF+EFV

• 51% - 162% superior to other regimens

Our results support the decision made by the MoH to switch its recommendations for preferred first-line ART from EFV to DTG

Estudos de switch

STRIIVING: Switch De Terapia SupressivaPara Combinação de DTG/ABC/3TC• Randomized, open-label phase IIIB study

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

• 12% to 13% of pts withdrew after randomization; ~ one half of withdrawals were for protocol deviations

HIV-1 RNA < 50 copies/mL

on stable ART ≥ 6 mos;

no previous virologic failure;

HLA-B*5701 negative

(N = 551)

DTG/3TC/ABC(n = 274)

Wk 48Wk 24

Trottier B, et al. ICAAC 2015.

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

Baseline ART*(n = 277)

DTG/3TC/ABC

PI NNRTI INSTI FTC/TDF

BL ART use, % 42 31 26 77

STRIIVING: Desfechos Após 24 Semanas

• Switch to DTG/3TC/ABC noninferior to continued BL ART

• Treatment difference (95% CI):

• ITT-exposed (E): -3.4 (-9.1 to 2.3)

• Per protocol (PP): -0.3 (-4.9 to 4.4)

• No cases of protocol-defined virologicfailure

• 3 pts in DTG/3TC/ABC arm (1%) and 4 pts in BL ART arm (1%) had HIV-1 RNA > 50 but < 100 copies/mL through Wk 24

• 11 pts discontinued for AEs in DTG/3TC/ABC arm vs 0 in baseline ART arm

• However, significantly greater increase in treatment satisfaction score from baseline to Wk 24 in DTG/3TC/ABC arm vs baseline ART arm (P < .001)

Trottier B, et al. Trottier Antivir Ther 2017.

52

100

80

60

40

20

0Virologic

Success

Virologic

Nonresponse

No Virologic Data

HIV

-1 R

NA

< 5

0 c

/mL (

%)

DTG/3TC/ABC (n = 274)

Baseline ART (n = 277)

:

DTG/3TC/ABC (n = 220)

Baseline ART (n = 215)

85 8893 93

1410

61 1 < 1

ITT-E:

PP

NEAT 022: Switch De IP-r para DTG em Pcts com Supressão virológia e RCV elevado

▪ PI-based regimens associated with increased risk of dyslipidemia[1]

▪ NEAT 022: international, randomized, open-label phase IV study[2,3]

– Primary endpoints at Wk 48: proportion with HIV RNA < 50 c/mL (ITT), change in total plasma cholesterol

1. Ofotokun I, et al. Clin Infect Dis. 2015;60:1842-1851.

2. Gatell JM et al. IAS 2017. Abstract TUAB0102. 3. ClinicalTrials.gov. NCT02098837.

Pts with stable HIV-1 RNA

< 50 c/mL on PI/RTV + 2 NRTIs,

high CV risk,*

no resistance mutations, no VF

(N = 415)

Immediate switch to DTG + 2 NRTIs†

(n = 205)

Continue

PI/RTV + 2 NRTIs

(n = 210)

Deferred switch to

DTG + 2 NRTIs†

Wk 48 Wk 96

*> 50 yrs of age and/or Framingham risk score > 10% at 10 yrs. †NRTIs to remain the same

throughout study.

NEAT 022: Switch De IP-r para DTG em Pcts com Supressão virológia e RCV elevado

• Switching to DTG noninferior to continuing boosted PI through Wk 48

• Switching to DTG associated with improved lipid profile vs continuing boosted PI through Wk 48

Gatell JM et al. IAS 2017. Abstract TUAB0102.

▪ No emergent resistance in pts with VF

▪ No significant differences in grade 3/4 AEs, serious AEs, AE-related d/c

Virologic Success

Virologic Nonresponse

No Virologic

Data

ITT

Po

pu

lati

on

(%

)

Treatment difference: -2.1% (95% CI: -6.6% to 2.4%)

4.9 4.4

100

80

60

40

20

0

93.1 95.2

2.0 0.5

DTGPI/RTV 10

5

0

-5

-10

-15

-20

-25

DTGPI/RTV

0.7

-8.7-11.3

0.5

4.22.0

1.12.5

0.4

-18.4

-7.7 -7.0

TC Non-HDL-C TG

LDL-C

HDL-C TC/HD

L

Ratio

P < .001P < .001

P < .001

P < .001 P < .001

P = .286

Mea

n C

han

ge

Fro

m B

L to

Wk

48

(%

)

SWORD 1 & 2: Switch de TARV Supressiva para TerapiaDupla com DTG + RPV

• Randomized, open-label, multicenter phase III trials

• HIV-1 RNA < 50 c/mL at Wk 48 (primary endpoint; ITT-E snapshot)

– 95% in both arms; Wk 48 treatment difference showed noninferiority of switch: -0.2% (95% CI: -3.0% to 2.5%)

• Significantly greater improvement in bone turnover markers from baseline to Wk 48 in switch arm

Switch to DTG + RPV

(n = 513)

Continue Baseline ART

(n = 511)

Pts with HIV-1 RNA < 50 c/mL

for ≥ 12 mos while receiving first

or second ART regimen with 2

NRTIs + INSTI, NNRTI, or PI; no

previous VF; HBV negative(N = 1024)

Wk 52

Switch to DTG + RPV

Continue DTG + RPV

Walmsley S, et al. IDWeek 2017. Abstract 1382. Llibre JM, et al. CROI 2017. Abstract 44LB.

SWORD 1 & 2: Eficácia e Segurança em AnáliseAgrupada de Subgrupos

Walmsley S, et al. IDWeek 2017. Abstract 1382.

HIV-1 RNA < 50

c/mL at Wk 48, %

(n/N)

DTG + RPV

(n = 513)

Continue

BL ART

(n = 511)

Age

▪ < 50 yrs 96 (350/366) 94 (348/369)

▪ ≥ 50 yrs 93 (136/147) 96 (137/142)

Sex

▪ Male 95 (375/393) 96 (387/403)

▪ Female 93 (111/120) 91 (98/108)

Race

▪ White 94 (395/421) 95 (378/398)

▪ African heritage 97 (36/37) 94 (44/47)

▪ Asian 100 (38/38) 98 (49/50)

▪ Other 100 (17/17) 88 (14/16)

P Value for Change From BL in Mean Serum Concentration

Early SwitchLate

Switch

Wk 48Wk 100

Wk 100

Osteocalcin < .001 < .001 < .001

Bone-specific alkaline phosphatase

< .001 < .001 < .001

Procollagen 1 N-terminal propeptide

< .001 - .05

Type 1 collagen-C telopeptide

< .001 < .001 .05

Aboud M, et al. AIDS 2018. Abstract THPEB047.

Uso de INI na falha à terapia

CAHN, P. et al. Lancet, 382: 700-08, 2013.

Dolutegravir versus raltegravir em adultos com HIV experimentados com antirretrovirais, mas virgens de

INI: 48 semanas.

Pedro Cahn, Anton L Pozniak, Horacio Mingrone, Andrey Shuldyakov, Carlos Brites, Jaime F Andrade-Villanueva, Gary Richmond, Carlos Beltran Buendia, Jan Fourie, Moti Ramgopal, Debbie Hagins, Franco Felizarta, Jose Madruga, Tania Reuter, Tamara Newman, Catherine B Small, John Lombaard, Beatriz Grinsztejn, David Dorey, Mark Underwood, Sandy Griffi th, Sherene Min, on behalf of the extended SAILING Study Team

A mudança média nos valores basais de CD4+ foi semelhante entre os braços: DTG: +162.4 células/mm3 (n=294); RAL: +153.2 células/mm3 (n=283).

71%

64%

DTG 50 mg QD

RAL 400 mg BID

100908070605040302010

0

BL 4 8 12 16 24 32 40 48

Semana

Pro

po

rção

(%

)

Dolutegravir foi estatisticamente superior ao raltegravir na semana 48.

*Diferença do tratamento ajustada (95% IC): 7.4% (0.7%, 14.2%); P=0.03

*Diferença ajustada com base na análise estratificada para valores basais de RNA HIV-1 (≤ 50.000 c/mL vs>50.000 c/mL), o uso DRV/r sem mutações primárias de IP e valores basais do score fenotípico, PSS (2 vs <2).

CV < 50 c/mL

1 x ao dia

2 x ao dia

CAHN, P. et al. Lancet, 382: 700-08, 2013.

Dolutegravir em pacientes vivendo com HIV experimentados em TARV e com resistência ao

raltegravir e/ou ao elvitegravir: VIKING-3

Antonella Castagna,1 Franco Maggiolo,2 Giovanni Penco,3 David Wright,4 Anthony Mills,5 Robert Grossberg,6 Jean-Michel Molina,7 Julie Chas,8 Jacques Durant,9 Santiago Moreno,10 Manuela Doroana,11 Mounir Ait-Khaled,12 Jenny Huang,13 Sherene Min,14 Ivy Song,14 Cindy Vavro,14

Garrett Nichols,14 and Jane M. Yeo,12 for the VIKING-3 Study Group

CASTAGNA, A. et al. J Infect Dis, 2014. Epub.

CV < 50 c/mL (Snapshot)

• População da semana 24 (N = 183) inclui o número total de recrutados.

• População da semana 48 (N = 114) inclui aqueles indivíduos que atingiram a semana 48 no momento do corte de dados.

Resultados DTG 50 mg 2x dia

Semana 24

ITT-E

(N=183)

Semana 48

ITT-E

(N=114)

Sucesso virológico 126 (69%) 64 (56%)

Sem resposta

virológica

50 (27%) 44 (39%)

Sem CV no momento

da análise

7 (4%) 6 (5%)

Descontinuado

devido à EAs ou

óbito

5 (3%) 5 (4%)

Descontinuado por

outras razões

2 (1%) 1 (<1%)

69% da população suprimida (<50 c/mL) na semana 24

56% dos primeiros 114 indivíduos suprimidos (<50 c/mL) até a semana 48

*Intention-to-treat Exposed

CASTAGNA, A. et al. J Infect Dis, 2014. Epub.

DAWNING: Resposta Virológica após 48 Sem

Aboud M, et al. AIDS 2018. Abstract THPEB040.

DTG + 2 NRTIsLPV/RTV + 2 NRTIs

Virologic Outcomes Treatment Difference, % (95% CI)

*P < .001 for superiority.

13.8*

219/

312

84

70

261/312

219/312

246/

283

204/

274

87

74

HIV

-1 R

NA

< 5

0 c

/mL

(%)

100

80

60

40

20

0

n/N =

ITT-E PP

DTGLPV/RTV

-12 -8 -4 0 4 8 12 16 20

24

ITT-E

PP

7.3

20.3

5.8

18.7

12.3

Comorbidades

Ajustes de Dose Para Terapia Inicial emPcts Com Função Renal Comprometida

ARV eGFR (mL/min)

≥ 50 30-49 10-29 < 10 Hemodialysis

ABC[1] 300 mg q12h No adj No adj

FTC[1] 200 mg q24h 200 mg q48h 200 mg q72h 200 mg q96h 200 mg q96h

3TC[1] 300 mg q24h 150 mg q24h 100 mg q24h 50-25 mg q24h 50-25 mg q24h after dialysis

TDF[1] 300 mg q24h 300 mg q48h Not recommended

Not recommended

300 mg q7d after dialysis

DRV/RTV[1] 800/100 mg q24h600/100 mg q12h

No adj No adj No adj No adj

RAL[1] 400 mg q12h No adj No adj No adj No adj/dose after dialysis

EVG/COBI/TDF/FTC[1]

Do not use if < 70 D/C if < 50

DTG[2] 50 mg q24h No adj No adj No adj No adj

1. EACS Guidelines. November 2014. 2. Dolutegravir [package insert].

Considerações Na Terapia ARV Para Pcts Com Complicações ósseas

• DHHS considerations: – Consider avoiding TDF: associated with greater

decrease in BMD along with renal tubulopathy, urine phosphate wasting, and osteomalacia

– Consider ABC/3TC

• Significantly greater BMD loss with PI-based regimens vs RAL-based regimens

• DTG + ABC/3TC associated with less bone turnover than EFV/TDF/FTC

TARV e Efeitos Sobre Lípides

TDF ABCRAL

DTG

ATV/RTV or ATV/COBI

DRV/RTV or DRV/COBI

EVG/COBI

EFVRPV

Interações Droga–Droga Com TARV e Terapia do Diabetes e da Dislipidemia

Antiretroviral Contraindicado Tatear Dose Sem Ajuste de Dose

RPV[1] AtorvastatinPitavastatin

EVG/COBI/FTC/TDF[1]

LovastatinSimvastatin

AtorvastatinRosuvastatin

DTG[1,2] Metformin

ATV/RTV[1] LovastatinSimvastatin

AtorvastatinRosuvastatin

Pitavastatin

DRV/RTV[1] LovastatinSimvastatin

AtorvastatinPravastatin

Rosuvastatin

Pitavastatin

EFV[1] AtorvastatinSimvastatinPravastatin

Rosuvastatin

Pitavastatin

RAL[1]

ATV/COBI or DRV/COBI

LovastatinSimvastatin

1. DHHS Guidelines. April 2015. 2. Dolutegravir [package insert].

Interações Droga–Droga Adicionais Com TARV

EACS Guidelines. V7.1. November 2014.

ATV/RTV

DRV/RTV

EFV RPV DTGEVG/COBI

RAL ABC FTC 3TC TDF

Antacids

PPIs

Alfuzosin

Budesonide

Fluticasone

Slidenafil

St John’s wort

Escitalopram

Aspirin

Ibuprofen

Codeine

Methadone

Morphine

Oxycodone

Tramadol

Diazepam

Midazolam

Pimozide

Phenytoin

Rifampicin

No clinically significant interaction expected

These drugs should not be coadministered

Potential interaction that may require a dosage adjustment

Potential interaction predicted to be of weak intensity

Guia das AASLD/IDSA Sobre DDI

em HIV/HCV

AASLD/IDSA HCV Guidance. September 2017. BIC/FTC/TAF

[package insert].

DCV + SOF EBR/GZR GLE/PIB LDV/SOF SOF/VEL SOF/VEL/VOX

ATV + RTV

DRV + RTV

EFV

RPV

BIC NR NR NR

DTG or RAL

EVG + COBI

3TC/ABC

TAF

TDF

No clinically significant interaction expected

Potential interaction may require adjustment to dosage, timing of administration, or monitoring

Do not coadminister

Interações de Drogas Selecionadaspara os INI

Agente Interações Potenciais

Raltegravir[1]

▪ Metabolizado pelo UGT1A

▪ ATV eleva concentrações de RAL; ajuste de dose desnecessário

▪ Evite antiácidos contendo aluminio- e/ou magnesio

▪ Rifampicina reduz níveis de RAL; dose dobrada?

Elvitegravir/

cobicistat[2]

▪ Metabolizado pelos CYP3A, CYP2D6

▪ COBI eleva níveis de drogas metabolizadas pelo CYP3A

▪ Administrar separado de antiácidos contendo aluminio- e/ou magnesio

▪ Não deve ser utilizado com rifamicinas

Dolutegravir[3]▪ Metabolizado pelo UGT1A, com contribuição do CYP3A

▪ Evite uso com ETR a menos que seja coadministrado com IP reforçado;

Evitar uso com NVP

▪ Administrar separado de antiácidos contendo aluminio e/ou magnesio

▪ DTG pode elevar concentrações de metformina; ajuste na dose de

metformina pode ser necessário; monitorar clinicamente quando iniciar

ou interromper DTG

1. Raltegravir [package insert]. 2. EVG/COBI/TDF/FTC [package insert]. 3. Dolutegravir [package insert].

Populações especiais:mulheres, gestantes, tb

ARIA: DTG/ABC/3TC Superior a ATV/RTV +

TDF/FTC Em Mulheres VT após 48 Sem

Orrell C, et al. AIDS 2016. Abstract THAB0205LB.

ARIA: Phase III Trial of DTG/ABC/3TC vs ATV/RTV +

TDF/FTC in ART-Naive Women (N = 495)

0

20

40

60

80

100

HIV

-1 R

NA

< 5

0 c

/mL (

%)

VirologicSuccess

VirologicNonresponse

No Virologic

Data

Virologic Outcomes Treatment Difference (95% CI)

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

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

82

71

614 12

15

-12-10 -8 -6 -4 -2 0 2 4 6 8 10 12 1416 18 20

3.1% 10.5%

2.6%

17.8%

9.7% 16.8%

ITT-E(primary)

PP

Favors

ATV/RTV + TDF/FTC

Favors

DTG/ABC/3TC

Rápida Supressão Virológica em

Gestantes com Apresentação TardiaITT, off-ART=failure (SNAPSHOT)

W2 W4 W6At

delivery

LPV/r 1/15 (6%)2/11

(15%)

2/10

(20%)

4/12

(25%)

RAL7/17

(41%)

9/12

(75%)

10/10

(100%)

13/17

(76%)

RR

(95% CI)

6.6

(0.9-47.8)

4.9

(1.3-

18.2)

5.0

(1.4-17.3)

3.1

(1.3-7.4)

Mean time to delivery was similar for RAL(43 days) and LPV/r (42.4 days) arms

Probability of PVL<50 cps/mL at delivery in late presenters pregnant women treated either with Raltegravir or Lopinavir/r

plus NRTIs

Brites et al, HIV Clin Trials, 2018

DolPHIN-1: Virologic Response

▪ Median time to virologic suppression approximately halved with DTG vs EFV

Orrell C, et al. AIDS 2018. Abstract THAB0307LB.

HIV-1 RNA < 50 copies/mL, n (%)

DTG + 2

NRTIs(n = 29)

EFV+ 2

NRTIs(n = 31)

P Valu

e

2 wks postpartum

20 (69.0)

12 (38.7)

.02

Pro

po

rtio

n W

ith

HIV

-1

RN

A <

50

co

pie

s/m

L

Days From Screening

P = .0001

DTG + 2 NRTIsEFV + 2 NRTIs

0.50

0.25

0.00

1.00

0.75

0 20 40 60 80 100

Tsepamo: Defeitos do Tubo Neural e Exposição ao DTG

▪ Unplanned analysis of ongoing birth outcomes surveillance study among Botswanan women ± HIV infection[1,2]

▪ At latest analysis on July 15, 2018[2]

‒ NTD prevalence with DTG exposure at conception: 4/596(0.67%; 95% CI: 0.26% to 1.7%)

‒ NTD prevalence with DTG started during pregnancy: 1/3104(0.03%; 95% CI: 0.01% to 0.18%)

▪ Next formal analysis to occur after March 31, 2019, which will include 72% of national births

1. Zash R, et al. N Engl J Med. 2018;[Epub ahead of print]. 2. Zash R, et al. AIDS 2018. Session TUSY15.

DTG Any Non-DTG ART

EFVHIV

Negative

Pregnancy

Ne

ura

l Tu

be

Def

ect

s*

(%, 9

5%

CI)

DTG

Conception

*In 89,064 births as of May 1, 2018.

0.94

0.12 0.05 0.00 0.09

2.5

1.5

0.5

2

1

0

INSPIRING: DTG BID + 2 NRTIs em pacientes sem TARV prévia em tratamento para TBC em uso de rifampicina

• Análise de interim; estudo aberto, randomizado, não comparativo de fase IIIb

– Desfecho principal: HIV-1 RNA < 50 c/ml na semana 48 (FDA snapshot, ITT-E)

– Pacientes da África do Sul, Brasil, Peru, México Rússia, Argentina e Tailândia

Dooley KE, et al. CROI 2018. Abstract 33.

RNA ≥ 1000 c/ml; CD4+ ≥

50/mm3 e coinfecção com

TBC sensível a rifampicina

(N = 113)EFV 600 mg QD + 2 NRTIs

(n = 44)

Semana

48

DTG 50 mg BID + 2

NRTIs

(n = 69)

*tratamento poderia começar até 8 semanas antes da randomização e não após a triagem (14 a 28

antes da randomização). †DTG em dose reduzida após 2 semanas ao término do tratamento da TBC.

Semana

24†

DTG 50 mg QD + 2

NRTIs

(n = 69)

RHZE (2

meses)*

HR (4

meses)Tratamento TBC

Randomização

INSPIRING Study: eficácia e segurança após 24 semanas

Dooley KE et al. CROI 2018 #33.

81 (72, 90)

89 (79, 98)

Análise pelo FDA snapshot modificado (ITT-E)

Perc

entu

al <

50

cópia

s/m

l (I

C 9

5%

)

Semanas

Estudo REFLATE:

Resposta virológica

Grinstejn et al, Lancet, 2014

Simplificação da Terapia inicial

▪ Single-arm phase IV study of DTG + 3TC (N = 20)

– Baseline: 20% HIV-1 RNA ≥ 100,000 c/mL

– No major tolerability/safety issues

PADDLE: DTG + 3TC em Pcts VT

10

0

80

60

40

20

0

100

90

Wk: 4824

Cahn P, et al. J Int AIDS Soc. 2017;20:21678.

HIV

-1 R

NA

< 5

0 c

/mL

(%

)

▪ n = 1 with PDVF at Wk 35 (BL HIV-1 RNA > 100,000 c/mL; resuppressed HIV-1 RNA without ART change at final visit after Wk 48)

▪ n = 1 patient died by suicide (HIV-1 RNA undetectable at last visit)

20/

20

18/

20n/N =

▪ Single-arm phase II study of DTG + 3TC (N = 120)

– Baseline: 43% HIV-1 RNA > 100,000 c/mL

n = 2 patients with grade 3 AEs related to treatment, none leading to d/c

All patients

Patients with BL HIV-1 RNA > 100,000 c/mL

90 Patients with BL HIV-1 RNA ≤ 100,000 c/mL89

82

90

3 74 6108/

120

33/

37

75/

83

A5353: DTG + 3TC em Pcts VT

Taiwo BO, et al. Clin Infect Dis. 2017;[Epub ahead of print].

10

0

80

60

40

20

0Virologic

Nonsuccess

Virologic

Success

n/N =

Pati

en

ts (

%)

No Data

▪ n = 3 with PDVF (n = 1 had BL HIV-1 RNA > 100,000 c/mL, n = 2 had BL HIV-1 RNA ≤ 100,000 c/mL);n = 1 with emergent M184V and R263R/K mixture

▪ n = 2 with Wk 24 HIV-1 RNA between 50 and 200 c/mL (both had BL HIV-1 RNA > 100,00 c/mL)

22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands

1900ral1900ral1900ral1900ral1900ral1900ral

Desfechos (Snapshot) após 48 Semanaspara GEMINI-1 e -2

Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.

aBased on Cochran-Mantel-Haenszel stratified analysis adjusting for the following baseline stratification factors: plasma HIV-1

RNA (≤100,000 c/mL vs >100,000 c/mL) and CD4+ cell count (≤200 cells/mm3 vs >200 cells/mm3).

Virologic outcome Adjusted treatment difference (95% CI)a

Percentage-point difference

DTG + 3TC is non-inferior to DTG +

TDF/FTC with respect to proportion

<50 c/mL at Week 48 (snapshot, ITT-E

population) in both studies

DTG + TDF/FTC

-6.7 1.5

-4.3 2.9

GEMINI-1

GEMINI-2 -0.7

-2.6

DTG + TDF/FTC DTG + 3TC

90

4 6

93

26

93

25

1900ral

1900ral 1900ral

0

20

40

60

80

100

Virologicsuccess

Virologicnonresponse

No virologicdata

HIV

-1 R

NA

<50

c/m

L, %

GEMINI-1 DTG + 3TC (N=356) DTG + TDF/FTC (N=358)

GEMINI-2 DTG + 3TC (N=360) DTG + TDF/FTC (N=359)

Em Resumo...

Segurança e Eficácia do DTG e EFV600 na TARV inicial(summary 2018 WHO Sys Review & NMA)

major outcomes DTG vs EFV600 QUALITY OF EVIDENCE

Viral suppression (96 weeks) DTG better moderate

Treatment discontinuation DTG better high

CD4 recovery (96 weeks) DTG better moderate

Mortality comparable low

AIDS progression comparable low

SAE comparable low

WHO, 2018

Reference: Steve Kanters, For WHO ARV GDG, 16-18 May 2018

ART history Clinical scenarios DHHS BHIVA WHO

ART naive or on using a non-DTG

containing regimen

Early pregnancy

Late pregnancy

Childbearing age potential, not using contraception

Childbearing age potential, using effective/consistent contraception

On DTG containing

regimen

Early pregnancy

Late pregnancy

Childbearing age potential , not using contraception

Childbearing age potential, using contraception

Do not initiate DTG/ switch to other effective options

Initiate /continue to DTG or switch to other effective options

initiate/ switch to DTG

* The definition of early pregnancy period varies in different guidelines. DHHS: < 8 weeks from LMP; BHIVA : 1st trimester; WHO: < up to 8 weeks from conception.

Abordagem para uso do DTG de acordo com os diferentes cenários nosguidelines

GUIDELINESNRTI BACKBONE NNRTI INSTI PI

TAF/XTC TDF/XTC ABC/3TC AZT/3TC EFV NVP RIL DTG* EVG RAL ATV DRV LPV

EACS (2017)

DHHS (2018)

WHO (2018)

preferred alternative not recommended/use in special situations

Comparação das opções preferenciais e alternativas para terapia inicial de adultos/adolescents com HIV

DHHS, EACS and WHO ART guidelines

* In childbearing age women and adolescent girls, DTG should be used with consistent and reliable contraception.

Population Preferred Alternatives Special situations

Adult men and adolescent boys

TLDa

TLE600

TLE400

AZT+3TC+ EFV600b

TDF+3TC (or FTC)+PI/rc

Pregnant (from eight weeks after conception) and breastfeeding women and adolescent girlsWomen and adolescent girls with effective contraception or not of childbearing potential

Women and adolescent girls of childbearing potential who want to become pregnant and have no effective contraception TLE600

TLE400

TDF+3TC (or FTC)+PI/rc

AZT+3TC+ EFV600b

TDF+3TC (or FTC)+ RAL

Recomendações da OMS 2018 para TARV inicial

a) In PLHIV with TB using rifampicin, the dose of DTG needs to be increased to 50 mg twice daily.

b) NVP may be used in special circumstances where alternative options are not available.

c) If national prevalence of EFV pretreatment drug resistance exceeds 10% or if no other alternatives are available.

TLD = TDF + 3TC + DTG

TLE = TDF + 3TC (or FTC) + EFV

Recomendações da OMS 2018 para TARV : ESQUEMAS ARV PARA SEGUNDA LINHA

Riscos e Benefícios

• Available clinical evidence as well as assessment of the risk and benefits support the use of DTG as a preferred 3rd agent in all lines of antiretroviral treatment and post-exposure prophylaxis in adults and adolescents, including women and adolescents girls using consistent and reliable contraception.

• Concerns around the safety of DTG use during periconception period were acknowledged resulting in specific qualifications on the use of DTG in women and adolescents girls of childbearing potential

LPV/r ATV/r RAL DRV/r DTG EFV

Completion 65.8 63.3 75.1 93.3 89.6 12.2

Stop/switch5.2 17.0 2.7 0.9 1.4 87.8

Single dosing Yes Yes Yes No Yes Yes

Heat stable Yes Yes Yes No Yes Yes

Accessibility High Moderate Low Moderate Moderate High

Provider acceptability

High High High High High Low

Backgrounddrug

resistance

Low Low Low Low Low Moderate

Prequalified generic

Yes Yes No Yes Yes Yes

Cost Moderate220

Moderate205

High667

Moderate518

Low45

Low20

Para tratar que pacientes?

• Em início de terapia

• Com necessidade de troca

• Pacientes mais velhos

• Que apresentem necessidades especiais (gestantes, tuberculose)

“switch”

falha à terapia

comorbidades

Polifarmácia (DDI!!)

Convite!