Hora de mudança do paradigma

Terapia dupla vs terapia tripla

Estevão Portela Nunes

estevao.nunes@ini.fiocruz.br

Instituto Nacional de Infectologia

(INI)

FIOCRUZ

Conflitos de Interesse

De acordo com a Resolução 1931/2009 do Conselho Federal de Medicina e com aRDC 96 / 2008 da ANVISA, declaro que:

• Pesquisa Clínica: como médico investigador, participo de estudos patrocinadospor: Abbvie

• Apresentações: como palestrante convidado, participo dos eventos de:GSK/ViiV,Janssen, Abbvie, Bristol-Meyers

• Consultoria: como membro de advisory boards, participo de reuniões com:Abbvie,GILEAD, GSK;ViiV

Não possuo ações de quaisquer destas companhias farmacêuticas.

Os meus pré-requisitos para participar destas atividades são a autonomia dopensamento científico, a independência de opiniões e a liberdade de expressão,aspectos que esta empresa respeita.

Racionalidade para TARV combinada

• Potência: TARV deve reduzir a carga viral para níveis indetectáveis

• Barreira genética: TARV deve evitar a seleção de cepas resistentes

Simplificação de tratamento

• Poupar classes

• Melhorar tolerabilidade

• Redução da toxicidade a longo prazo

• Redução de custos

Terapia Inicial: 2x3 drogas

• ACTG 343: Pacientes suprimidos virologicamentecom ATZ + 3TC + IDV:

– IDV mono: 23% CV > 50 cp/mL

– AZT + 3TC: 23% CV > 50 cp/mL

– Terapia tripla: 4% CV > 50 cp/mL

Havlir NEJM 1998

Estudo 720

Slope of VL decay was similar in both groups.

Estudo N ITRN IP sem Genotip na falha

Mutações primárias IP

720 100 d4T+3TC LPV/r 312 17 0

863 653 d4T+3TC LPV/r 108 51 0

940 44 d4T+3TC LPV/r 72 13 0

056 38 d4T+3TC LPV/r 72 5 0

418 190 TDF+3TC LPV/r 48 15 0

SOLO 649 ABC+3TC FPV/r 64 32 0

Staccato 258 d4T+ddI SQV/r 48 10 0

BMS089 200 d4T+3TC ATV/r 48 2 0

Falha de TARV Inicial com IP/r: Mutações de IP

Gulick RM HIV7,2004#P28; Kempf DJ,JID 2004,189:51; Cahn P. IAS 2001 #779;

Feinberg J XIV ICAAC 2002 #TuPeB4445; Molina JM XV IAC 2004 #WePeB5701;

MacManus S. AIDS 2004, 18:651; Ananworanich J III IAS 2005 #WePe 4.4c12; Malan N 13ºCROI 2006 #107LB

Terapia baseada em ITRN: riscos

• Análogos timidínicos- Alteraçoes metabólicas, neuropatia, lipodistrofia

• Tenofovir: Lesão renal, Osteoporose/ Osteopenia

• Abacavir: IAM, Reação de hipersensibilidade, Intolerância GI

Monoterapia com IP-r

Estudo MO3-613[1] MONARK[2] OK04[3] KALMO[4]

Resultados FV < 50 copias/mLna semana 96 (ITT, falha em qqmomento):

• Mono: 50%

• EFV + ZDV/3TC: 61 % (p=0.23)

CV < 400 na semana24 and <50 na 48:

• Mono: 65%

• LPV/r + ZDV/3TC: 75% (p=0.25)

Proporção de falhaterapêutica nasemana 48:

• Mono: 94%

FV sem diferençaestatisticamentesignificativa

CV < 80 at Wk 96:

• Mono: 86%

• HAART: 83%

Resistência Grupos deLPV/r (combinados):

• 3/15 (20%): mutações de IP

• 2/15 (13%): M184V

EFV :

• 1/5(20%) mutação de NNRTI

• 1/5 (20%)M184V

Monoterapia:

• 2/21 mutações para IP

• Nenhuma mutação para NRTI

LPV/RTV +

ZDV/3TC:

• 1 paciente comM184V

• Ausência de mutações para IP

• 2 pacientes com mutações primariaspara IP vs 1 on HAART

• 2 FV, 1 em cadabraço.

• Sem evidencia de resistência emqualquer dos casos

1. Cameron DW, et al. IAC 2006. Abstract THLB0201. 2. Delfraissy JF, et al. IAC 2006. Abstract THLB0202.

3. Arribas J et al. IAC 2006. Abstract THLB0203. 4. Nunez EP, et al. IAC 2006. Abstract THAB0102. 1. Cameron DW, et al. IAC 2006. Abstract THLB0201. 2. Delfraissy JF, et al. IAC 2006. Abstract THLB0202.

3. Arribas J et al. IAC 2006. Abstract THLB0203. 4. Nunez EP, et al. IAC 2006. Abstract THAB0102.

10

NEAT 001/ARNS 1Raltegravir + Darunavir/r em Pacientes Virgens

de Treatmento

Randomização1:1

Darunavir/r 800/100 mg qd + Emtricitabine/Tenofovir DF qd (n=404)

Darunavir/r 800/100 mg qd +Raltegravir 400 mg bid (n=401)

Estudo Fase 3

(96 semanas)

Pacientes virgens de tratamento

Estudo aberto

HIV RNA >1000 copias/mL

CD4 <500 cels/mm3

Sem mutações major IAS

sem HBV

78 centros em in 15 países europeus.Desfecho primário: tempo até falha virológica:

•Resposta virológica insuficiente até a semana 32 (ie, redução de HIV RNA <1 log10 copies/mL na semana 18 ou HIV RNA >400 copias/mL na semana 24)

•HIV RNA >50 copias/mL na semana 32, ou qualquer momento após semana 32•Morte•Evento AIDSt•Qualquer evento sério não-aids

Raffi F, et al. 21st CROI. Boston, 2014. Abstract 84LB.

11

NEAT 001/ARNS 143Raltegravir + Darunavir/r em pacientes virgens

de tratamento

● Braço Darunavir/r + raltegravir:

- Atingiu não-inferioridade na

semana 96: diferença ajustada

3.7% [-1.1%, 8.6%]; P=0.12)

- Inferior a darunavir/r + FTC/TDF

em pacientes com CD4 basal<200

cél./mm3

● Segurança similar nos 2 braços

● Resistência detectada com

genotipagem disponível na falha:

- Darunavir/r + raltegravir: 18%

(5/28)

• 4/5 com HIV RNAbasal>500K

cópias/mL

- Darunavir/r + FTC/TDF: 0% (0/16)

DRV/r

+ RAL

DRV/r + FTC/TDF

Falha virológica clínica (%)

Total

CD4 basal<200 cells/mm3

HIV RNA basal>100K

cópias/mL

17.4

39.0

36.0

13.7

21.3

27.0

Secundários

HIV RNA <50 cópias/mL (%)

Ganho CD4 (cel./mm3)

Alterações lipídicas (%)

Colesterol total

LDL-C

HDL-C

Triglicerídeos

Alterações na eGFR (mL/min)

89

267

+0.9

+0.5

+0.2

+0.3

+0.9

93

266

+0.5*

+0.4*

+0.1*

+0.2

-3.8*

Resultados principais

*P<0.05 versus RAL + DRV/r.Raffi F, et al. 21st CROI. Boston, 2014. Abstract 84LB.

Limite não inferioridade 9%

MODERN: MVC QD + DRV/RTV Not Noninferior to TDF/FTC + DRV/RTV

• HARNESS: suppressed pts switched from any ART to ATV/RTV + RAL had higher rates of virologic rebound vs those switched to ATV/RTV + TDF/FTC[2]

• Similar rates of HIV-1 RNA suppression at Wk 48 by screening assay type

1. Stellbrink HJ, et al. AIDS 2014 Graphic used with permission. Abstract MOAB0101. 2. van Lunzen J, et

al. AIDS 2014. Abstract LBPE19.

MVC + DRV/RTV (n = 396)

TDF/FTC + DRV/RTV (n = 401)

100

80

60

40

20

0

Wk

Pts

With

HIV

-1 R

NA

< 5

0 c

op

ies/m

L[1

]

BL 4 8 12 16 20 24 36 48

77.3%

86.8%

Adjusted treatment difference: -9.5% (95%% CI: -14.8% to -4.2%)

Assay

Type

MVC +

DRV/RTV

(n = 396)

TDF/FTC +

DRV/RTV

(n = 401)

Phenotypic 74.4 87.0

Genotypic 80.7 86.5

Δ (95% CI)6.9% (-1.3% to

15%)NR

• Randomized, open-label phase III noninferiority trial

• Primary endpoint:

HIV-1 RNA < 50 copies/mL

ART-naive patients with HIV-1 RNA > 1000 c/mL;

no NRTI/PI resistance; HBsAg negative(N = 426)

Lopinavir/Ritonavir 400/100 mg BID +Lamivudine 150 mg BID

(n = 217)

Lopinavir/Ritonavir 400/100 mg BID +Lamivudine or Emtricitabine +

Investigator-selected NRTIs in FDC*(n = 209)

Wk 48primary analysis

Stratified by HIV-1 RNA

(≤ vs > 100,000 copies/mL)

Wk 24interim analysis

GARDEL: Dual ART With LPV/RTV + 3TC vs Triple ART With LPV/RTV + 2 NRTIs

Cahn P, et al. EACS 2013. Abstract LBPS7/6. Reproduced with permission.

*ZDV/3TC: 54%; TDF/FTC: 37%; ABC/3TC: 9%

GARDEL: Dual ART Noninferior to Triple ART at Wk 48

• CD4+ cell count increase

– +227 with dual ART vs +217 with triple ART

• Grade 2-3 adverse events more frequent in triple-ART arm (88 vs 65 events)

• Hyperlipidemia more common in dual-ART arm (23 vs 16 pts)

• Lab abnormalities similar

• VF in 22 pts, of whom 2 had resistance (M184V)

– Both on dual ART

Pa

tie

nts

(%

)

88.3 83.7

Δ 4.6 (95% CI: -2.2 to 11.8;

P = .171)

Dual ART (n = 214)

Triple ART (n = 202)

189 1690

20

40

60

80

100

4.7 5.90.9 4.9

n = 210 12

Virologic

Success*

Virologic

Non-

response

D/C Due

to AE or

Death

D/C for

Other

Reasons

6.1 5.4

10 13 11

Cahn P, et al. EACS 2013. Abstract LBPS7/6.

*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm.

ANDES: DRV/RTV + 3TC vs DRV/RTV + 3TC/TDF em pcts VT- resultados da semana 48

• Estudo aberto, randomizado, Fase IV

– Desfecho primário: HIV-1 RNA < 50 c/mL na sem 48 (FDA snapshot)

Figueroa MI, et al. CROI 2018. Abstract 489.

DRV/RTV + 3TC*

(n = 75)

DRV/RTV + 3TC/TDF†

(n = 70)

Pcts VT com

HIV-1 RNA > 1000 copies/mL,

Sem resistência a ITRN ou IP,

e HBsAg negativo

(N = 145)

Sem 48:

Desfecho PrimarioSem 24:

Análise interina

Estratificado por HIV-1 RNA

(≤ or > 100,000 copies/mL)

*DRV/RTV 800/100 mg QD + 3TC 300 mg QD.†DRV/RTV 800/100 mg QD + 3TC/TDF 300/300 mg QD.

ANDES: Eficácia e segurança até sem 48

• Diferença entre os braços (HIV-1 RNA < 50 c/mL; ITT snapshot):

– Todos os pts: -1.0% (95% CI: -7.5% to 5.6%)

– Pts com HIV-1 RNA elevada: -1.4 (95% CI: -17.2 to 14.4)

• Sem diferença significativa em EA levandoa descontinuação, EA sério ou morte entre os braços

• Alterações do CT a partir do início do estudo maior na terapia dupla vs triple (19% vs 4%; P = .01); LDL-C e TG apresentaram também tendência a maiorelevação com terapia dupla

Figueroa MI, et al. CROI 2018. Abstract 489.

Pts

(%

)

HIV-1 RNA < 50 copies/mL at Wk 48 (ITT)

DRV/RTV + 3TC DRV/RTV3TC/TDF

n/N = 70/75 66/70

Revisão sistemáticaTeraapia Dupla com IP-r

Diferença +3% ( IC 95 -2% a + 6%)

p= 0,4

Liew et al Glasgow 2019 #0114

Diferença -2 (IC 95 -3 a 0) p=0,04

Preferência por dose única diária e pílulas combinadas

Como Iniciar? Primeira opção para a maioria das PVH nas principais diretrizes

Eficácia em indivíduosNaïve no programa de fase III de DTG

Estudo SPRING-2 (Sem. 96) SINGLE (Sem. 96) FLAMINGO (Sem. 48)

Terapia DTG +2 ITRN

RAL +2 ITRN

DTG +ABC/3TC

EFV/TDF/FTC DTG +2 ITRN

DRV/r +2 ITRN

<50 c/mL,a

n/N (%)332/411

(81%)314/411

(76%)331/414

(80%)302/419

(72%)217/242

(90%)200/242

(83%)

PDVF,b

n (%)22 (5%) 29 (7%) 25 (6%) 25 (6%) 15 (6%) 18 (7%)

aAlgoritmo Snapshot do FDA. bFalha virológica definida por protocolo.

• DTG demonstrou superioridade estatística em análises pré-especificadas do SINGLE e FLAMINGO

• Em indivíduos tratados com DTG:

• Nenhuma resistência surgiu durantes as 96 semanas do SPRING-2 e do SINGLE

• Nenhuma resistência surgiu durantes as 48 semanas do FLAMINGO

18. DEMAREST, J. DTG-Based Regimens Are Active in INI-Naive Patients With a History of NRTI Resistance. et al. In: IAC 2014; Melbourne, Australia. Abstract TUAB0104. Disponível em: <http://www.natap.org/2014/IAC/IAC_16.htm>. Acesso em: 30 jul 2014.

DTG + 3TC

Click to edit Master title style

• ACTG A5353: Estudo Fase II, Braço único de DTG + 3TC em pacientes virgens de

tratamento (N = 120)[2]

– Baseline: 31% HIV-1 RNA > 100,000 c/mL

Tratamento inicial ART com terapia dupla

1.

Taiwo BO, et al. IAS 2017. Abstract MOAB0107LB.

Virologic

Outcome at Wk

24, n (%)

Baseline HIV-1 RNA, c/mLTotal

(N = 120)> 100,000

(n = 37)

≤ 100,000

(n = 83)

Sucesso* 33 (89) 75 (90) 108 (90)

Falha 3 (8) 2 (2) 5 (4)

Sem dados 1 (3) 6 (7) 7 (6)

▪ n = 3 com FVDP n = 1 com mutaçõesemergentes associadas a resistênciaM184V and R263RK

*HIV-1 RNA < 50 copies/mL.

Click to edit Master title style

ACTG A5353: HIV-1 RNA Levels and DTG

Concentration in Pts Experiencing PDVF

Taiwo BO, et al. IAS 2017. Abstract MOAB0107LB. Reproduced with permission.

Pt 1

BL HIV-1 RNA > 100,000 copies/mL

Pt 2

BL HIV-1 RNA ≤ 100,000 copies/mL

Pt 3

BL HIV-1 RNA ≤ 100,000 copies/mL

HIV-1 RNA < limit of detection

No detectable DTG

HIV

-1 R

NA

(co

pie

s/m

L)

0

100

1000

10,000

100,000

1,000,000

Study Wk

0

1000

2000

3000

4000

50

0 24 8 12 16 20 24 32

None

0

100

1000

10,000

100,000

1,000,000

Study Wk

0

1000

2000

3000

4000

50

0 24 8 12 16 20 24 32

DT

G C

on

cen

tratio

n

(ng

/mL

)

0

100

1000

10,000

100,000

1,000,000

Study Wk

0

1000

2000

3000

4000

50

0 24 8 12 16 20 24 32

Off DTG

None M184VM184V

R263RK

Off DTG

V1061

HIV-1 RNA (copies/mL)

DTG concentration (ng/mL)

GEMINI-1 and -2: DTG + 3TC vs DTG + FTC/TDF in Treatment-Naive Patients

• Parallel, international, randomized, double-blind phase III noninferiority studies[1]

• Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 (FDA Snapshot) (noninferiority margin: -10%)[2]

– DTG + 3TC vs DTG + FTC/TDF: 91% vs 93% (difference: -1.7%; 95% CI: -4.4% to 1.1%)

– No treatment-emergent INSTI or NRTI mutations in patients with VF in either arm

ART-naive adults with HIV-1 RNA 1000-500,000 copies/mL, ≤ 10 days on previous ART,

no major resistance associated mutation, no HBV infection or HCV requiring therapy

(N = 1433)

DTG + 3TC PO QD (n = 716)

DTG + FTC/TDF PO QD(n = 717)

Wk 144Primary Analysis

Wk 48

Stratified by HIV-1 RNA (≤ vs > 100,000 copies/mL), CD4+ cell count (≤ vs > 200 cells/mm³)

Cahn et al Lancet 2018

Screening within 28 days of study start; studies double blinded until Wk 96, open label until Wk 144.

Continuation of DTG + 3TC permitted

GEMINI-1 and -2: Wk 48 Subgroup Analysis

Orkin. Glasgow 2018. Abstr P021. Reproduced with permission. Slide credit: clinicaloptions.com

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

DTG + 3TC (n = 716)

DTG + FTC/TDF (n = 717)

Age, yrs

▪ < 35 386/420 (92) 381/408 (93)

▪ 35 to < 50 211/231 (91) 216/229 (94)

▪ ≥ 50 58/65 (89) 72/80 (90)

Sex▪ Female 100/113 (88) 89/98 (91)

▪ Male 555/603 (92) 580/619 (94)

Race

▪ White 447/480 (93) 471/497 (95)

▪ Black 83/99 (84) 64/76 (84)

▪ Asian 67/71 (94) 68/72 (94)

HIV-1 RNA, copies/mL

▪ ≤ 100,000 526/576 (91) 531/564 (94)

▪ > 100,000 129/140 (92) 138/153 (90)

▪ > 250,000 45/51 (88) 41/46 (89)

▪ > 400,000 16/18 (89) 20/24 (83)

CD4+ count, cells/mm3

▪ ≤ 200 50/63 (79) 51/55 (93)

▪ > 200 605/653 (93) 618/662 (93)

2-Drug Regimen

3-Drug Regimen

% Treatment Difference (95% CI)

-30 -20 0 10 30

-0.1

-10 20

-0.7

-13.4

5.6

-0.9

1.9

-2.8

-0.4

-1.6

-1.7

-2.3

-0.8

-3.0

-1.5

Details of Nonresponse to DTG + 3TC Among 13 Patients With Baseline CD4+ Cell Count ≤

200 cells/mm3

Orkin. Glasgow 2018. Abstr P021. Reproduced with permission. Slide credit: clinicaloptions.com

Participant[1

]

Wk 48 Snapshot Outcome Clinical Reason for Study D/c Last Study VL, c/mL

1 VL ≥ 50 c/mL NA, continued in study ≥ 50 (Wk 60)

2 VL ≥ 50 c/mL NA ,continued in study < 50 (Wk 60)

3 VL ≥ 50 c/mL NA, continued in study < 50 (Wk 60)

4 VL ≥ 50 c/mL Protocol-defined virologic withdrawal 362 (d/c Day 205)

9 VL ≥ 50 c/mL NA, unplanned change in ART ≥ 50 (Wk 60)

10 VL ≥ 50 c/mLProtocol violation, randomized in

error102 (d/c Day 15)

12 VL ≥ 50 c/mL Lost to follow-up 64,366 (d/c Day 356)

5 No virologic data AE, pulmonary TB < 50

6 No virologic data AE, cerebral chagoma 507,564 (d/c ART before study d/c)

7 No virologic data Treatment for HCV infection < 50

8 No virologic data Withdrew consent < 50

11 No virologic dataProtocol violation, randomized in

error1,848,435 (Day 1 result)

13 No virologic data Lost to follow-up < 50

GEMINI-1 and -2: Virologic Response at Wk 96

▪ DTG + 3TC met criteria for noninferiority vs DTG + FTC/TDF inGEMINI-1, -2, and pooled analysis

Cahn. IAS 2019. Abstr WEAB0404LB. Reproduced with permission.

*Adjusted for BL HIV-1 RNA, BL CD4+ cell count, and study.

Endpoint, % (n)

DTG + 3TC(n = 716)

DTG + FTC/TDF(n = 717)

Difference,* % (95% CI)

Responders 86.0 (616) 89.5 (642) -3.4 (-6.7 to 0)

HIV

-1 R

NA

< 5

0 c

op

ies/

mL,

%

(9

5%

CI)

100

80

60

40

20

00 4 8 12 16 24 36 48 60 72 84 96

Wk

87.093.2 91.5 87.2 86.0

89.589.493.393.4

84.4

GEMINI-1 and -2: Virologic Response at Wk 96 by Baseline HIV-1 RNA and CD4+ Cell Count

FDA Snapshot Analysis TRDF Analysis*

> 100,000≤ 100,000BL HIV-1 RNA,

copies/mL

> 200 ≤ 200BL CD4+ Cell Count,

cells/mm3

> 200

≤ 200

BL CD4+ Cell Count, cells/mm3

BL HIV-1 RNA, copies/mL

499/576

510/564

117/140

132/153

573/653

594/662

43/63

48/55

560/576

545/564

132/140

146/153

633/653

638/662

59/63

53/55

.

n/N =

DTG + 3TC DTG + FTC/TDF

*Accounts for CVW, withdrawal for lack of efficacy or treatment-related AEs, and participants meeting protocol-defined stopping criteria.

Pati

ents

Wit

h H

IV-1

R

NA

< 5

0 c

op

ies/

mL

(%)

100

80

60

40

20

0

87 90 84 86 88 90

68

87

Pati

ents

Wit

ho

ut

TRD

F (%

)

n/N =

100

80

60

40

20

0

97 97 9794 9495 96 96

> 100,000≤ 100,000

GEMINI-1 and -2: Renal and Bone Safety at Wk 96

Cahn. IAS 2019. Abstr WEAB0404LB.

EndpointDTG + 3TC (n = 716)

DTG + FTC/TDF(n = 717)

P Value

Mean change from BL in plasma/serum markers*†

▪ GFR from cystatin C (CKD-EPI), mL/min/1.73 m2

▪ Creatinine, µmol/L▪ GFR from creatinine (CKD-EPI), mL/min/1.73 m2

10.712.3-14.6

8.8015.4-18.2

< .005< .001< .001

Change from BL in urine markers‡

▪ Protein/creatinine, g/mol▪ Retinol-binding protein/creatinine, µg/mmol▪ β2-microglobulin/creatinine, mg/mmol

-12.216.2-18.7

3.250.835.0

< .001< .001< .001

Mean change from BL in serum bone markers,*§ µg/L▪ Bone-specific alkaline phosphatase▪ Osteocalcin▪ Procollagen 1 N-terminal propeptide▪ Type 1 collagen C-telopeptide

0.290.2711.00.10

2.364.2123.70.24

< .001< .001< .001< .001

*Repeated measures model adjusted for study, treatment, visit, BL HIV-1 RNA, BL CD4+ cell count, age, sex, race, BL biomarker value, treatment and visit interaction, and BL biomarker value and visit interaction. †Also adjusted for diabetes and HTN. ‡Estimated from GMR for BL and Wk 48. §Also adjusted for BMI, smoking status, and current vitamin D use.

▪ Primary endpoint: virologic failure at Wk 48 (FDA Snapshot in ITT-E)

‒ Noninferiority margin: 4%

▪ Multicenter, randomized, open-label phase III noninferiority study

TANGO: Study Design

Van Wyk J. IAS 2019. Abstr WEAB0403LB. NCT03446573. Slide credit: clinicaloptions.com

Adults with confirmed HIV-1 RNA < 50 c/mL for > 6 mos on stable TAF-based ART,* no prior VF and

no NRTI or INSTI resistance mutation, no HBV infection or

HCV requiring therapy(N = 741)

Switch to DTG/3TC PO QD (n = 369)

Continue TAF-based ART(n = 372)

Wk 196Primary Analysis

Wk 48 Stratified by 3rd agent

Continuation of DTG /3TC permitted

Wk 144

*Pts eligible if initial regimen was TAF/FTC with PI, NNRTI, or INSTI, or TDF switched to TAF ≥ 3 mos prior to screening with no other regimen changes.

Switch toDTG/3TC PO QD

Early-Switch Phase Late-Switch Phase Continuation Phase

TANGO: Baseline Characteristics

Van Wyk J. IAS 2019. Abstr WEAB0403LB.

CharacteristicDTG/3TC (n = 369)

TAF-Based ART

(n = 372)

Median age, yrs (range)▪ ≥ 50 yrs of age, n (%)

40 (20-74)79 (21)

39 (18-73)92 (25)

Female, n (%) 25 (7) 33 (9)

Race, n (%)▪ Black/African heritage▪ Asian▪ White▪ Other

51 (14)13 (4)

296 (80)9 (2)

58 (16)13 (3)

289 (78)12 (3)

Hispanic/Latino, n (%) 70 (19) 66 (18)

CharacteristicDTG/3TC (n = 369)

TAF-Based ART

(n = 372)

Median CD4+ cell count, cells/mm3 (range)

682 (133-1904)

720 (119-1810)

CD4+ cell count, cells/mm3, n (%)▪ < 350▪ ≥ 350

35 (9)334 (91)

30 (8)342 (92)

BL 3rd agent, n (%)▪ INSTI

• EVG/COBI▪ NNRTI

• RPV▪ PI

• Boosted DRV

289 (78)243 (66)51 (14)43 (12)29 (8)25 (7)

296 (80)249 (67)48 (13)45 (12)28 (8)27 (7)

Median ART duration at Day 1, mos (range)

33.8 (7.1-201.2)

35.1(7.0-160.8)

TANGO: Virologic Outcomes by FDA Snapshot at Wk 48 (ITT-E)

▪ No CVW in DTG/3TC arm, CVW in 1 (< 1%) patient in TAF-ART arm; no resistance detected at failure

▪ All 7 patients (4 in DTG/3TC group and 3 in TAF-based ART group) with proviral M184V/I mutation at BL maintained HIV-1 RNA < 50 copies/mL at Wk 48

Van Wyk J. IAS 2019. Abstr WEAB0403LB. Slide credit: clinicaloptions.com

Difference (%)

TAF-Based ARTDTG/3TC

Difference (%)

TAF-Based ART DTG/3TC

-3.4

0.2

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

3.9

-1.2 0.7

-0.3

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

Pat

ien

ts (

%)

100

80

40

60

20

0Virologic

Nonresponse (≥ 50 c/mL)

Virologic Success

(< 50 c/mL)

No Virologic Data

0.3 0.5

93.2 93.0

6.5

6.5

Switch to DTG/3TC(n = 369)

Continue TAF-based ART(n = 372)

Virologic Outcomes Adjusted Treatment Difference (95% CI)*

Key Secondary Endpoint(HIV-1 RNA < 50

copies/mL)DTG/3TC noninferior to

continued TAF-based ART

Primary Endpoint(HIV-1 RNA ≥ 50

copies/mL)DTG/3TC noninferior to

continued TAF-based ART

4% NImargin

-8% NImargin

*Adjusted for BL third agent class.

TANGO: Safety at Wk 48

▪ Mean weight gain and frequency of weight gain comparable between arms

Van Wyk J. IAS 2019. Abstr WEAB0403LB.

AE, n (%)DTG + 3TC (n = 369)

TAF-Based ART

(n = 371)

Any AE▪ Nasopharyngitis▪ Upper RTI▪ Diarrhea▪ Headache▪ Syphilis▪ Back pain▪ Fatigue▪ Bronchitis

295 (80)43 (12)31 (8)30 (8)24 (7)24 (7)21 (6)20 (5)8 (2)

292 (79)41 (11)32 (9)26 (7)17 (5)13 (4)28 (8)3 (1)

20 (5)

AE, n (%)DTG + 3TC (n = 369)

TAF-Based ART

(n = 371)

Drug-related grade 2-5 AE 17 (6) 3 (< 1)

Drug-related grade 2-5 AE occurring in ≥ 0.5%*▪ Insomnia▪ Constipation▪ Flatulence▪ Headache

4 (1)2 (1)2 (1)2 (1)

01 (< 1)

00

AEs leading to withdrawal▪ Drug-related AEs

leading to withdrawal

13 (4)†

9 (2)2 (1)

1 (< 1)

Any serious AE‡ 21 (6) 16 (4)*All drug-related AEs were grade 2 severity. †Includes 1 fatal AE due to homicide. ‡None was drug related.

SWORD 1 & 2: Switch From Suppressive ART to DTG + RPV Dual Therapy

▪ Estudos abertos multicêntricos, randomizados, fase III

‒ Desfecho primário: HIV-1 RNA < 50 copies/mL na sem 48 (ITT-E snapshot)

▪ 70% to 73% dos pacientes recebiam TDF

Llibre JM, et al. CROI 2017. Abstract 44LB.

Troca para DTG + RPV

(n = 513)

Continue Baseline ART

(n = 511)

Pts com

HIV-1 RNA < 50 c/mL por

≥ 12 meses recebendo

esquema de 1a ou 2a linha

com 2 NRTIs + INSTI,

NNRTI, or PI; sem falha

virológica prévia; HBV

negativo

(N = 1024)

Wk 52 Wk 148

Troca para DTG + RPV

DTG + RPV

DTG + RPV

Click to edit Master title style

Switch para DTG + RPV não inferior quando

comparado à manutenção da Tarv até sem 48

• 1 pt com falha virológica

confirmada na semana 36 no

braço DTG + RPV com presença

de K101K/E

– Não aderência documentada na

FV VF

– Resupressão com manutençao

de DTG + RPV

– Sem resistênciapara INI

Llibre JM, et al. 2017.

Virologic

Nonresponse

Wk 48

HIV-1 RNA

< 50 c/mL

No Data

100

80

60

40

20

0

Pts

(%

)

95 95

< 1 1 5 4

Treatment difference: -

0.2%

(95% CI: -3.0% to 2.5%)

TARV basal (n = 513)DTG + RPV n = 511)

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DHHS, IAS-USA Guidelines:

Recommendations on 2DR for First-line ART

• Caveats to first-line DTG + 3TC use: HBV coinfection, GEMINI-1/2 excluded patients with HIV-1

RNA > 500,000 copies/mL, tuberculosis, pregnancy/woman with childbearing potential

• Data that could potentially support DTG + 3TC as a recommended initial regimen in DHHS

guidelines:

durability (96-wk GEMINI data), longer-term resistance data

DHHS*[1] IAS-USA†[2]

Consider when ABC, TAF, or TDF cannot be used or are not optimal:▪ DTG + 3TC▪ DRV/RTV + RAL BID, if HIV RNA < 100,000

copies/mL and CD4+ cell count > 200 cells/mm3

▪ DRV/RTV QD + 3TC

Initial 2DR only recommended when patient cannot take ABC, TAF, or TDF:▪ DRV/RTV + RAL, if HIV RNA < 100,000 copies/mL

and CD4+ cell count > 200 cells/mm3

▪ DRV/RTV + 3TC

*DHHS does not recommend DTG for pregnant individuals within 12 wks post conception, women of childbearing potential planning to become pregnant, or sexually active women of childbearing potential not using effective contraception. †IAS-USA recommends documenting negative pregnancy test in women of childbearing age before initiating DTG and counseling on potential risk of NTDs.

1. DHHS Guidelines. October 2018. 2. Saag. JAMA. 2018;320:379.

MOBIDIP: Study design • MULTICENTER:

• Central and Military Hospital - Yaoundé, Cameroon;

• CRCF and CTA H. Fann - Dakar, Senegal;

• Day Hospital CHU - Bobo-Dioulasso, Burkina Faso

ANRS 12169 2LADY* > 48 weeks ANRS 12286 MOBIDIP

FTC + TDF + LPV/r

ABC + DDI + LPV/r

FTC + TDF + DRV/r

LPV/r

LPV/r + 3TC

DRV/r + 3TC

DRV/r

Do = Randomisation W 96

N=152

N=147

N=155

N = 82

N = 82

N = 50

N = 50

N = 264 (Expected)

N = 454

Arm A

Arm B’

Arm B

Arm A’

AIDS 2015, 29:1473–1481

Resultados Semana 48

• At 48 weeks MOBIDIP trial showed superiority of dual therapy (IP/r+3TC) on monotherapy (IP/r)

• At 48 weeks DSMB advised for interruption of monotherapywhile patients on dual therapy continued follow up to 96 weeks

HR 0.11 (95% CI 0.04- 0.32); p<0.00010

20

40

60

80

100

Failure

-fre

e s

urv

ival (%

)

132 132 131 129 128bPI+3TC133 133 127 112 103bPI

Number at risk

0 12 24 36 48Follow-up (weeks)

bPI

bPI+3TC

Lancet HIV. 2017 May

26

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Conclusões

➢ Terapia dupla pode ser uma alternativa atraente para pacientes com limitações para uso de ITRN.

➢ DTG + 3TC-esquema sem booster, sem TDF/Abacavir, baixocusto.

➢ IPr + 3TC- necessidade de booster, menor risco de resistência em pacientes com adesão subótima ?

➢ Papel da 184V? Papel do CD4 e carga viral basal? Simplificação seria a melhor estratégia?