Nuevas estrategias de tratamiento

para HIV:
Terapia doble
XV Simposio Científico Fundación Huésped 2018
5 de Septiembre
Maria Inés Figueroa
Médica Infectóloga/Fundación Huésped
 Global cascade of care 2017
• 36.9 million Globally,
36.9 million people
living with HIV in 2017

• 21.7 million21.7 million

people were receiving
antiretroviral treatment
by end 2017

• 59% of people living

with HIV were receiving
antiretroviral treatment
in 2017
 TARV: De 1996 a 2018

• Basado en 2 INTR mas INI o IP/r o INNTR, según las diferentes guías
El TARV de alta
eficacia sigue siendo
desde hace 20 años
el paradigma de
tratamiento.

• Co formulaciones
• Nuevas estrategias –biterapia-simplificación
• Drogas ARV inyectables, de larga duración
Tratamiento de • Drogas nuevas
por vida • Vacunas
 Reducción de drogas arv
¿Qué esperamos de la biterapia?
Menor toxicidad corto y largo
plazo ¿Potencia reducida?
Reducción del número de
¿Menor permisividad para
tabletas
dosis omitidas?
Mejor adherencia y calidad
¿Penetración reducida en
de vida
santuarios?
Menos interacciones de
¿Requerimiento de
drogas
monitoreo virológico mas
 Menores costos frecuente?
Preservación de drogas/clases
para futuras opciones
Escenarios para la terapia dual

• Inicio de tratamiento
• Mantenimiento-Simplificación
• Fallo temprano
 Terapia doble en primera línea
¿Qué se ha probado?
Inhibidores de proteasa
IP/r +INTR IP/r +INNTR IP/r +MVC
LOREDA(LPV/r+3TC) BMS-121 (ATV/r+EFV) MIDAS (MVC+DRV/r)
GARDEL(LPV/r+3TC) ACTG5142(LPV/r+EFV) MODERN (MVC+DRV/r)
ANDES (DRV/r+3TC) MEDICLAS (LPV/r+NVP) VEMAN (MVC+LPV/r)
CTN177 (LPV/r+NVP) A4001078 (MVC+ATV/r)

Inhibidores integrasa
RAL+ IP/r DTG + INTR
PROGRESS (LPV/r+RAL) PADDLE (DTG+3TC)
CCTG 589 (LPV/r+RAL) ACTG5353(DTG+3TC)
NEAT-01 (DRV/r+RAL) GEMINII (DTG+3TC)
RADAR (DRV/r+RAL)
ACTGA5262 (DRV/r+RAL)
SPARTAN (ATV+RAL)
Amit Achra , Mwasakifwa,Amin, Boyd LANCETHIV 201 6
 Estudio GARDEL: LOP/r + 3TC
No inferior a Triple ART pacientes naïve a 48 sem
Estudio fase III, randomizado, internacional, controlado, abierto, que incluyó pacientes adultos de
Argentina, Chile, México, Perú, España y EEUU.
Sem 48
Estratificado en el SCR por CV objetivo
HIV-1 (≤ o >100.000 copias/mL) primario

Pacientes naïve, 18 DT: LPV/r 400/100mg BID +

años, CV HIV-1 3TC 150 mg BID (n=217)
>1.000 copias/mL
Sin resistencia a
INTR o IP definida TT: LPV/r 400/100 mg BID
+3TC y 3º INTR seleccio
por panel IAS-USA al
por el investi
SCR*, HB(s)Ag (n=209)
negativo (N = 426)

• EA G2-3 más frecuentes en la rama de triple terapia (88 vs 65 eventos)

• Hiperlipidemia más frecuente en TAR dual (23 vs 16 pts.)
• Limitada resistencia (2 con mutación M184V en rama LPV/3TC)

Cahn P, et al. Lancet Infect Dis. 2014;14:572-580

 Estudio ANDES: DRV/r + 3TC
Estudio fase 4, randomizado, multicéntrico, abierto, objetivo primario de Sem 48

Estratificado en el SCR por CV

HIV-1 (≤ o >100.000 copias/mL)

145 pacientes naïve en 5

sitios de Argentina, 18 DT: DRV/r 800/100mg QD
años, 30 años, CV BSL 4.5 + 3TC 300 mg QD
log copias/mL, 24% >5 log,
n=75
CD4 de 383/mm3, s/R
definida por el panel IAS-
USA para INTR o IP al TT: DRV/r 800/100mg QD +
SCR, HB(s)Ag negativo 3TC/TDF 300/300mg QD
n=70

A 24 sem, CV <400 en el 95%DT y 97% TT (diferencia -

2.5%, 95% CI -7.0 a 2.9)
Fallo virológico:1(W24)en TT .
Ganancia de CD4: 206 con DT y 204 con TT.

ClinicalTrials.gov. NCT02770508 En la segunda etapa, 190 nuevos pacientes serán enrolados en

P.Cahn IAS 2017 Week 24 resuts ,MoAB0106LB 2018 (330 aleatorizados).
Figueroa M, et al. 25th CROI; Boston, MA; March 4-7, 2018. Abst. 489
 Terapia doble en primera línea
IP +MVC
IP +INNTR HIV-1 RNA <50
Study Treatment Arm Copies/mL
• ATV/r+EFV (BMS121) ATV/r + MVC 48 wk: 74.6% (ITT)
• LPV/r+EFV (ACTG 5142) A4001078
(n = 60) 96 wk: 67.8% (ITT)

ATV/r + TDF/FTC 48 wk: 83.6% (ITT)

• LPV/r+NVP (MEDICLAS, CTN- (n = 61) 96 wk: 82.0% (ITT)
177) 24 wk: 87.5%
MIDAS DRV/r + MVC (N =24)
48 wk: 83.3%
DRV/r + TDF/FTC
48 wk: 86.8%
demostraron adecuada supresión MODERN
(n = 406)
DRV/r +MVC
virológica pero mayor toxicidad (n = 406)
48 wk: 77.3%
que la rama triple LPV/r + MVC (n =26) 48 wk: 100%(PP)
Ward D et al. BMS-121 study. 46th ICAAC, San Francisco, abstract H-1057, 2006. VEMAN LPV/r + TDF/FTC
Van Vonderen MG, et al. MEDICLAS study group.PLoS One. 2009 May 21; 4(5):e5647 48 wk: 96%(PP)
Harris M, et al .CTN 177 Study Team. JAIDS 2009 Mar 1; 50(3):335-7 (n = 24)
Haubrich RH et al. AIDS Clinical Trials Group (ACTG) A5142 Study Team. AIDS. 2009 Jun 1; 23(9):1109-18

Baril JG, et al. PLoSOne.2016;11:e0148231

 SPARTAN:
ATV300 mg BID + RALen NAÏVE vs ATV/r 300 + TDF/FTC

100 NC =F 100 NC=M

80 81%
80
74.6%
70.4%
60 63.3% 60

40 40

20 20
ATV + RAL(n=63) ATV/RTV
+ TDF/FTC (n=30)
0 0
J0 4 8 12 16 20 24 J0 4 8 12 16 20 24
Weeks Weeks
HIV-1 RNA <50 c/mL (%),CVR

El perfil general no óptimo para el desarrollo clínico adicional : alta tasa de

resistencia a RAL (4/6 FV) y mayor % de hiperbilirrubinemia G4 con dosis BID de
ATV comparado con ATV/RTV (21% vs0%)

KozalMJ, et al. HIV Clin Trial 2012;13:119–30

 NEAT-001: DRV/r+RAL vs. DRV/r+TDF/FTC en
pacientes NAÏVE
• Estudio estratégico Fase III, randomizado, abierto, multicéntrico, de grupos paralelos, no inferior
• 78 centros, 15 países (Austria, Bélgica, Dinamarca, Francia, Alemania, Gran Bretaña, Grecia, Hungría, Irlanda, Italia,
Holanda, Polonia, Portugal, España,Suecia) 96 semanas
HIV-1 ART-naïve, ≥ 18años
HIV-1 RNA > 1000c/ml DRV+r 800+100 mg QD + RAL 400 mg BID Randomización 1:1
Estratificado por país y
CD4 ≤ 500/mm3 N 401
participación en subestudio
HBs Ag negativo virológico/inmunológico
N 805 DRV+r 800+100 mg QD + TDF/FTC FDC QD Objetivo primario virológico
n404 y clínico (6 componentes)

Análisis general (n=805): RAL + DRV/r noinferior

a TDF/FTC + DRV/r *

Otros estudios pequeños

(RADAR, ACTG 5262)mostraron
baja eficacia
DTG + 3TC en naive
Estudios pilotos
 GEMINI-1 and -2 Phase III Study Design
Identically designed, randomized, double-blind, parallel-group,
multicenter, noninferiority studies
Screening Double-blind Open-label Continuation
(28 d) 1:1 phase phase phase

DTG + 3TC (N=716) DTG + 3TC

• ART-naive adults
• VL 1000-500,000 c/mL
DTG + TDF/FTC (N=717)

Day Week Week Week Week

1 24 48 96 144

Eligibility criteria Primary endpoint Countries

• ≤10 days of prior ART Argentina Australia Belgium
at Week 48: Canada France Germany
• No evidence of pre-existing viral resistance
based on presence of any major resistance-
participants with Italy Republic of Korea Mexico
Netherlands Peru Poland
associated mutation HIV-1 RNA <50 c/mL
Portugal Romania RussianFederation
• No HBV infection or need for HCV therapy (ITT-E snapshot)a South Africa Spain Switzerland
Taiwan United Kingdom United States

Baseline stratification factors: plasma HIV-1 RNA (≤100,000 c/mL vs >100,000 c/mL) CD4+ cell count (≤200 cells/mm3 vs >200cells/mm3).

a−10% noninferiority margin for individual studies.

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

 Pooled Snapshot Outcomes at Week 48: ITT-E
and Per Protocol Populations
Wk 48 HIV-1 RNA < 50 Dual ART Triple ART
Virologic outc o e copies/mL, % (n/N)
m
ITT-E DTG + 3TC (N=716) DTG + TDF/FTC (N=717) ITT-E* 91 (655/716) 93 (669/717)
PPb DTG + 3TC (N=694) DTG + TDF/FTC (N=693) BL HIV-1 RNA
100 91 93 93 94  ≤ 100,000 copies/mL 91 (526/576) 94 (531/564)
 > 100,000 copies/mL 92 (129/140) 90 (138/153)
HIV-1 RNA <50 c/mL, %

80
BL CD4+ cell count
 > 200 cells/mm3 93 (605/653) 93 (618/662)
60  ≤ 200 cells/mm3 79 (50/63)† 93 (51/55)

40
• Virologic efficacy consistent across subgroups stratified by
20 baseline HIV-1 and CD4 cell count
3 2 2 1
6 5 5 4 • Overall safety comparable between arms
0 • Significant differences in renal and bone biomarkers observedin
Virologic Virologic No virologic favor of DT arm
success nonresponse data
• No emergent INSTI or NRTI resistance in 10 patients
DTG + 3TC is non-inferior to DTG + TDF/FTC with respect to with VF
proportion <50 c/mL at Week 48 (snapshot, ITT-E population) in – DTG + 3TC, n = 6
both studies – DTG + FTC/TDF, n = 4

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

 Guias :Terapia dual en primera línea
(alternativa)
EACS1 Alternativa
RAL400 mg, 1 tableta bid
+ DRV/c 800/150 mg, 1 tableta qd o
+ DRV800 mg, 1 tableta qd + RTV100 mg, 1 tableta qd

Sólo si el CD4 > 200 céls/µL y CV HIV < 100.000 copias/mL

DHHS2

IAS3 Cuando TDF/TAF o ABC no pueden usarse

DRV/r + RAL o 3TC (BIa)
1 EACS 2017
*GEMINI results not yet available at time of guideline release. 2 DHHS Guidelines. May 2018
3 Michael S. Saag et al JAMA 2018
 MANTENIMIENTO EN PACIENTES CON SUPRESION VIROLOGICA

¿Qué se ha probado?
Inhibidores de proteasa
IP +3TC IP +INNTR
ATLAS-M (ATV/r+3TC) A5116 (LPV/r+EFV)
SALT (ATV/r+3TC) NEKA(LPV/r+NVP)
OLE (LPV/r+3TC)
ANRS12286/MOBIDIP trial
(LPV/r+3TC, DRV/r+3TC

Inhibidores de integrasa
RAL+ IP INIs +INNTR RAL+ MVC
BATAR (RAL+ATV/r) Requilet et al. (RAL+NVP) ROCnRALANRS157 (RAL+MVC)
HARNESS (RAL+ATV/r) Calin et al. (RAL+ETV) NoNucNoBoos (RAL+MVC)
Ruane study (RAL+ATV) SWORD I-II (DTG+RPV)
KITE (RAL+LPV/r) LAMIDOL (DTG+3TC)
SPARE (RAL+DRV/r) ASPIRE (DTG+3TC)
Calza 2013 (RAL+DRV/r) LATTE-2 (CAB+RPV)

Amit Achra , Mwasakifwa,Amin, Boyd LANCETHIV 2016

IP/r + 3TC en simplificacion
 Estudio OLE: LPV/r 3TC en simplificación
• Estudio multicéntrico de 48S, prospectivo, randomizado, abierto, de no inferioridad
• Ptes. HIV+ con CV < 50 copias/ml por ≥ 6 meses en TT con LPV/r + 3TC/FTC + NRTI y sin
resistencia a LPV/r o 3TC/FTC
LPV/r BID + 3TC/FTC QD (DT)
Randomización
1:1 LPV/r BID + 3TC/FTC QD + NRTI (TT)
(n: 250)
48 semanas
97,3% 97,3%
89,8% 90,1%
87,3% 87,6%
Objetivo primario:
Proporción de pacientes sin FV a las 48 semanas.
Criterio de fallo: virológico (definido como 2 CV
consecutivas >= 50 copies/ml), muerte, progresión a
enf. Marcadoras de sida, pérdida de seguimiento o
cambio de TAR.

Diferencia (95% CI) 0,05% (-5,3% a + 5,1%)

Diferencia (95% CI) -0,25% (- 8,2 a + 7,6%)
Diferencia (95% CI) 0,3% (- 8,5 a + 8,3%)
 DUAL-GESIDA Switch study: DRV/RTV + 3TC
Dual ART Noninferior to Triple ART at Wk 48
• Stable regimen: DRV/r + TDF/FTC or ABC/3TC ≥ 2 months
• VL < 50 c/mL > 6 months
• HBs Ag (-)

Switch to Dual Therapy Continue Triple Therapy

(n = 126) (n = 123)

100 93 • No resistance detected for 2 pts with resistance

89 DualART data in dual arm
TripleART
80 • AErates similar betweenarms

60 • D/c for AEs: 0.8% dual vs 1.6% triple ART(P =.55)

Pts (%)

Wk 48 difference: -3.8%
(95% CI: -11.0% to 3.4%)
40

20
8 6
3 2
0
Virologic Virologic No Virologic Data at Wk
Success Nonresponse 48

Pulido F, et al. HIV Glasgow 2016. AbstractO331.

Clin Infect Dis.2017;65:2112-2118
 Terapia doble con IP/r + 3TC en simplificación

• Meta-analysis of individual patient data from4 studies

(N = 1051)[a]
• Assess noninferiority of boosted PI plus lamivudine vs triple therapy using
past and current FDA-established endpoints
(ie, a virologic failure noninferiority limit of 4%)
ATLAS- SALT[c] OLE[d] DUAL[e]
M[b] (n = (n =286) (n = 250) (n =249)
266)
Dual
ATV/r + LMV ATV/r + LMV LPV/r + LMV DRV/r + LMV
Therapy
Triple
ATV/r + 2 N(t)RTIs ATV/r + 2 N(t)RTIs LPV/r + 2 N(t)RTIs DRV/r + 2 N(t)RTIs
Therap
y

a. Pérez-Molina JA, et al. EACS2017. Abstract PS1/1; b. Di Giambenedetto S,et al. JAntimicrob Chemother. 2017;72:1163-1171; c. Perez-Molina JA, et al.
Lancet Infect Dis. 2015;15:775-784; d. Arribas JR,et al. Lancet Infect Dis. 2015;15:785-792; e. Pulido F,et al. Clin Infect Dis. 2017. [Epub ahead ofprint]
Terapia doble con DTG-3TC en simplificación

Fully powered phase III TANGO enrolling

 Impact of M184V on Virologic Efficacy of Switch to 3TC-Based
Dual ART
• Retrospective observational study comparing efficacy of 3TC-based dual ARTfor patients with
or without M184V history in Antiretroviral Resistance Cohort Analysis database (N= 436)
• Inclusion criteria:
HIV RNA≤ 50copies/mL,
switching to dual therapy 1%
(3TC + either PI/RTV or INSTI), 10%
≥ 1 prior genotyping
29% LPV/RTV + 3TC
• M184V determined in historic
ATV/RTV + 3TC
genotypic resistance tests and 24% DRV/RTV + 3TC
last genotyping
DTG + 3TC
• Primary endpoint: time to RAL + 3TC
virologic failure in M184V-positive
vs M184V-negative patients 36%

Gagliardini R, et al. CROI 2018. Abstract 498. Slide credit: clinicaloptions.com

 M184V and Switch to 3TC-Based Dual ART: More Blips But
No Greater Risk of Virologic Failure

Estimated Probability of Remaining VF- • No difference in 3-yr probability of

Free on Dual Therapy*† remaining free from virologicfailure
1.0 without vs with M184V (P =.323)
• Significantly higher 3-yr probability of
Proportion Free From VF

0.8
remaining free from viral blip‡ without vs
0.6 M184V+ overall
with M184V (log-rank
M184V- overall P= .016)
0.4 M184V+ with time of viral suppression ≤ 6.6 yrs • M184V: 79.8% (95% CI: 67.8% to 91.8%)
M184V- with time of viral suppression ≤ 6.6 yrs
M184V+ with time of viral suppression ≤ 3 yrs • No M184V: 90.1% (95% CI: 84.0% to
0.2 M184V- with time of viral suppression ≤ 3 yrs 96.2%)
0
0 0.5 1.0 1.5 2.0 2.5 3.0
Yrs From Dual ART Initiation
*VF: 2 HIV-1 RNA findings > 50 c/mL or 1 finding ≥ 200 c/mL. †No VF in 21 pts on DTG + 3TC over median f/u of 10 mos.
‡Viral blip: single HIV-1 RNA finding 51-199 c/mL, notconfirmed.

Gagliardini R, et al. CROI 2018. Abstract 498. Slide credit: clinicaloptions.com

 Terapia doble con DTG+RPV en simplificación
Estudios SWORD I y SWORDII
Screening Early switchphase Late switch phase Continuation phase
1:1
VL<50 c/mL DTG+ RPV(N=513)
on INI, NNRTI,
CAR(N=511)
DTG+RPV DTG+RPV
or PI + 2 NRTIs

Day 1 Week 52 Week 148

Inclusion criteria Primaryendpoint Countries
• On stable CAR>6 months before screening
• 1st or 2nd ARTwith no change in prior regimen
at 48 weeks: Argentina Australia Belgium Canada
subjects with France Germany Italy Netherlands
due to VF
Russia Spain Taiwan United
• Confirmed HIV-1 RNA <50 c/mL during the 12 VL <50 c/mL
Kingdom
months before screening
(ITT-E snapshot)a United States
• HBV negative

a-8% non-inferiority margin for pooled data. -

10% non-inferiority margin for individual

studies

One subject on DTG + RPV meeting virologic

withdrawal criteria had identified an NNRTI
resistance–associated mutation (K101K/E)
No INI resistance–associated mutations were
identified

Source: Llibre et al. CROI2017; Seattle, WA. Abstract2421.

 What’s New?
DTG/RPV FDA Approved for MaintenanceTherapy

 Once-daily single-tablet regimen of DTG and RPV

 First 2-drug STR FDA approved for use as a complete regimen in the US(Juluca®)

Key US Label Information

 For pts who have been virologically suppressed for ≥ 6 mos

Indication
 Pts must have no history of treatment failure and no resistance to DTG orRPV

Administration
 Must be taken with a meal
requirements

 Separate dose of DTG/RPV and antacid/polyvalent cation–containing medications

Key DDIs
 Avoid PPIs (eg, omeprazole, pantoprazole), dexamethasone

 None required for pts with mild/moderate renal impairment; in pts with CrCl
Dose adjustments
< 30 mL/min, increase monitoring forAEs

DTG/RPV [package insert]. November 2017.

Slide credit: clinicaloptions.com
 Terapia doble con +RPV en simplificación
LATTE-2: 96-Wk Results for Cabotegravir IM + Rilpivirine IM as Long-Acting
MaintenanceART
 Multicenter, open-label phase IIb study comparing continuation of oral CAB +
ABC/3TC vs switching to IM CAB + RPV Q4W or Q8W (after induction with oral
CAB + ABC/3TC)[1]
 Few drug-related AEs.
Virologic Outcomes  At 96 wks, ~ 30% pts receiving IM injection
94 87 84 experienced ISR )mild/moderate /
Q8W IM CAB + RPV (n = 115)
 AEs leading to withdrawal: Pooled Q4W/Q8W IM
Q4W IM CAB + RPV (n = 115) arms, 4%. PO arm, 2%
Oral CAB + ABC/3TC (n = 56)
 ~ 88% of pts receiving IM CAB very satisfied to
continue present treatment vs 43% receiving PO
CAB

Fully powered phase III

4 13 14
0 2 2 ATLAS, FLAIR (every
Virologic No Virologic month)[2,3] and ATLAS-2M
Nonresponse Data
(every 2 months)[4] enrolling
1. Margolis DA, et al. Lancet 2017;390:1499-1510. 2. ClinicalTrials.gov. NCT02951052.
Slide credit: clinicaloptions.com
3. Clinical Trials.gov. NCT02938520. 4. Clinical Trials.gov. NCT03299049.
 Guias :Terapia dual mantenimiento
EACS1 DTG + RPV
3TC + (DRV/r o DRV/c) o
3TC + (ATV/r o ATV/c)
La biterapia con 3TC+ IP/r sólo se deben dar a personas: a) sin resistencia a IP,b)
con supresión del CV-VIH <50 copias al menos 6 meses, c)ausencia coinfeccion VHB

DHHS2 DTG +RPV can be a reasonable option when the use of NRTIs is notdesirable and
when resistance to either DTGor RPVis not expected(AI).

A ritonavir-boosted PI plus 3TC may be a reasonable option when the use of TDF,
TAF,or ABCis contraindicated or not desirable(BI).

IAS3 DTG +RPV (evidence rating AIa),

boosted PI with 3TC (evidence rating AIIa),or
dolutegravir with 3TC(evidence rating AIIa) can be used in patients with noprior
virologic failure or transmitted drugresistance.
(Longer-term follow-up is needed to confirm the durability of these strategies)
1 EACS2017
2 DHHS Guidelines. May 2018
3 Michael S. Saag et al JAMA 2018
 Terapia doble con LPV/r+RAL en primer fallo

 Diferentes objetivos primarios: CLINICOS, VIROLOGICOS , TIEMPOALFALLO

 LPVmas RAL:Pueden ser opción efectiva en este escenario.

Boyd MA, et al. Lancet 2013;381:2091–99

Adapted from La Rosa et al. Lancet HIV. 2016 June ; 3(6): e247–e258.
Muchas Gracias por su atención