Otimização do uso de Inibidores da Integrase na Prática Clínica

Otimização do uso de Inibidores

da Integrase na Prática Clínica

Carlos Brites

Professor Titular de Infectologia

Faculdade de Medicina

Declaração de Conflito de Interesse

Informo que presto ou prestei no passado serviços

remunerados de pesquisador, palestrante e consultor para

as seguintes empresas:

• Pesquisa Clínica: como médico investigador, participei de

estudos patrocinados pelos laboratórios farmacêuticos

Abbott, MSD, BMS, Jansen e GSK.

• Pesquisa Clínica: como médico investigador, participei de

estudos patrocinados pelos Institutos Nacionais de Saúde

(NIH-EUA), ANRS (França) e Ministério da Saúde (Brasil).

• Já recebi honorários por palestras e/ou assessoria científica

das empresas: GSK, Roche, MSD, BMS, Abbot, Janssen,

GILEAD.

0

Apesar da Extraordinária Eficácia, a Terapia

Atual do HIV Ainda Pode Ser Melhorada

•

As taxas de supressão virológica tem

pouco espaço para melhoria em

pacientes aderentes

•

Entretanto, ainda existe espaço para

melhorar a ATRV:

– Segurança a curto e longo prazo – Tolerabilidade

– Comodidade posológica – Custo

– Atividade contra virus multirresistentes – Cura ainda não disponível

1.0 0.8 0.6 0.4 0.2 0

ACTG A5257: Todos os Esquemas incluíam FTC/TDF Para pacientes VT[1] 24 48 64 80 96 120 144 RAL DRV/RTV ATV/RTV P roporç ã o de P a c ie nt e s Co m CV HIV -1 ≤ 5 0 copias /mL

1. Lennox JL, et al. Ann Intern Med. 2014;161:461-471.

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

Current Recommended Regimens for First-line ART DHHS[1] _IAS-USA[2] BIC/FTC/TAF BIC/FTC/TAF DTG/ABC/3TC DTG/ABC/3TC DTG + FTC/(TAF or TDF) DTG + FTC/TAF EVG/COBI/FTC/(TAF or TDF) RAL + FTC/(TAF or TDF)

Esquemas Recomendados Para TARV Inicial e

Estratégias Emergentes em Investigação

1. DHHS Guidelines. May 2018. 2. Saag MS, et al. JAMA. 2018;320:379-396.

Investigational Regimens in Late-Stage Development for First-line ART

DTG + 3TC DRV/RTV + 3TC

Doravirine/3TC/TDF

Risco de Falha Virológica na Vida real em Pcts

Iniciando 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, n

aHR* 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

Escolhendo os Inibidores da Integrase

Agente

Vantagens

Desvantagens

Bictegravir

▪

DFC 1X ao dia

▪

Disponível com TAF

▪

Poucas interações com

drogas ou alimentos

▪

Potencial alta barreira à

resistência

▪

Menor quantidade de dadosta

▪

Disponibilizado apenas como

DFC com with TAF/FTC

Dolutegravir

▪

DFC 1X ao dia apenas sem

TDF

▪

Alta barreira à resistência

▪

Poucas interações com

drogas ou alimentos

▪

Ativo contra algumas cepas

virais resistentes ao RAL e

EVG

▪

DFC apenas com ABC/3TC

▪

Eleva níveis de metformina

Elvitegravir

▪

DFC 1X ao dia

▪

Disponível com TAF e TDF

▪

Requer reforço de COBI

▪

Interações de drogas com

COBI

Raltegravir

▪

Maior experiência

▪

Poucas interações com

drogas ou alimentos

▪

Multiplas pílulas

▪

Sem DFC

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.

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 markedly

superior to other regimens after controlling for age, sex, adherence and

baseline 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

STRIIVING: Switch De Terapia Supressiva

Para 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 48

Wk 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

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 virologic

failure

• 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.

5 2 100 80 60 40 20 0 Virologic Success Virologic Nonresponse No Virologic Data H IV -1 R N A < 50 c /m L (%) DTG/3TC/ABC (n = 274) Baseline ART (n = 277) : DTG/3TC/ABC (n = 220) Baseline ART (n = 215) 85 88 93 93 14 10 6 1 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 _NonresponseVirologic _Virologic No Data ITT P o pu la tio n (%) 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 DTG PI/RTV 10 5 0 -5 -10 -15 -20 -25 DTG PI/RTV 0.7 -8.7 -11.3 0.5 4.2 2.0 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 < .001 P < .001 P < .001 P < .001 P < .001 P = .286 Mean Chan ge From BL to Wk 4 8 ( %)

SWORD 1 & 2: Switch de TARV Supressiva para Terapia

Dupla 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 Análise

Agrupada 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 Switch

Late

Switch

Wk 48

Wk

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

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

A mudança média nos valores basais de CD4+ foi semelhante entre os braços:

DTG: +162.4 células/mm

_{(n=294); RAL: +153.2 células/mm}

_(n=283).

71%

64%

Semana

Pr

o

p

o

rç

ão

(

%)

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

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

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

DAWNING: Resposta Virológica após 48 Sem

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

DTG + 2 NRTIs

LPV/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 <

50 c/mL

(%)

100

80

60

40

20

0

n/N =

ITT-E

PP

DTG

LPV/RTV

-12 -8 -4 0

4

8 12 16 2

0

2

4

ITT

-E

PP

7.

3

20

.3

5.

8

18

.7

12

.3

Ajustes de Dose Para Terapia Inicial em

Pcts 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 q24h} 600/100 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/TD

F/FTC[1]

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

DTG[2] _{50 mg q24h No adj No adj No adj No adj}

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

_RAL

ABC

DTG

ATV/RTV or ATV/COBI

DRV/RTV or DRV/COBI

EVG/COBI

EFV

RPV

Interações Droga–Droga Com TARV e

Terapia do Diabetes e da Dislipidemia

Antiretroviral Contraindicado Tatear Dose Sem Ajuste de Dose

RPV[1] _Atorvastatin Pitavastatin EVG/COBI/FTC/ TDF[1] Lovastatin Simvastatin Atorvastatin Rosuvastatin DTG[1,2] _Metformin ATV/RTV[1] _Lovastatin Simvastatin Atorvastatin Rosuvastatin Pitavastatin DRV/RTV[1] _Lovastatin Simvastatin Atorvastatin Pravastatin Rosuvastatin Pitavastatin EFV[1] _Atorvastatin Simvastatin Pravastatin Rosuvastatin Pitavastatin RAL[1] ATV/COBI or DRV/COBI Lovastatin Simvastatin

Interações Droga–Droga Adicionais Com TARV

EACS Guidelines. V7.1. November 2014.

ATV/R TV

DRV/

RTV EFV RPV DTG

EVG/

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

ATV + RTV













DRV + RTV













EFV













RPV













BIC

NR

NR

NR







DTG or RAL













EVG + COBI













3TC/ABC













TAF













TDF













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

Do not

Interações de Drogas Selecionadas

para os INI

Agente

Interações Potenciais

Raltegravir

▪

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

▪

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

▪

_{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

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

RNA

<

50 c

/mL

(%

)

Virologic

Success

Virologic

Nonresponse

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

6

14

₁₂

15

3.1% 10.5%

2.6%

17.8%

9.7%

_16.8%

ITT-E

(primary)

PP

Rápida Supressão Virológica em

Gestantes com Apresentação Tardia

ITT, off-ART=failure (SNAPSHOT)

W2 W4 W6 At delivery LPV/r

1/15 (6%)

2/11

(15%)

2/10

(20%)

4/12

(25%)

7/17

(41%)

9/12

(75%)

10/10

(100%)

13/17

(76%)

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

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

Pr

op

ortion With

HIV

-1

R

NA <

50 c

op

ie

s/

mL

Days From

Screening

P = .0001

DTG + 2

NRTIs

EFV + 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

▪

At latest analysis on July 15, 2018

‒ 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 EFV HIV Negativ e Pregnancy

Ne

u

ral

T

u

b

e

De

fec

ts*

(%,

9

5

%

CI

)

*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/mm

_{e coinfecção com}

TBC sensível a rifampicina

(N = 113)

EFV 600 mg QD + 2 NRTIs

(n = 44)

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

entual

<

50

c

ópi

as

/ml

(IC

95%)

Semanas

Estudo REFLATE:

Resposta virológica

▪ 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

Wk:

24

48

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

HIV

-1 RN

A

< 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/

20

▪ 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

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

90 ₈₉ Patients with BL HIV-1 RNA ≤ 100,000 c/mL

8 2 90

3

7

6

108/

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

0

Virologic

Nonsuccess

Virologic

Success

n/N =

Pa

tients (%

)

▪ 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

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

1900ral1900ral1900ral1900ral1900ral1900ral

Desfechos (Snapshot) após 48 Semanas

para GEMINI-1 e -2

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

a_{Based 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/mm}3_).

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 2 6 93 2 5 1900ral 1900ral 1900ral 0 20 40 60 80 100 Virologic success Virologic nonresponse No virologic data H IV -1 R N A <5 0 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)

Segurança e Eficácia do DTG e EFV600 na TARV inicial

(summary 2018 WHO Sys Review & NMA)

major outcomes

DTG vs EFV

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

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 nos

guidelines

GUIDELINES NRTI 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 girls

Women 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

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 3

_{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/switch _{5.2 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

Background drug resistance

Low Low Low Low Low Moderate

Prequalified generic

Yes Yes No Yes Yes Yes

Cost Moderate 220 Moderate 205 High 667 Moderate 518 Low 45 Low 20

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