Fàrmacs d’acció - jornadesvih.org
Transcript of Fàrmacs d’acció - jornadesvih.org
Fàrmacs d’acció
prolongada: La fi
del tractament
diari?
Dr. Daniel Podzamczer
Unitat de VIH i ITS
Servei de Malalties Infeccioses
Hospital Universitari de Bellvitge
L’Hospitalet. 08907 Barcelona
2
TDF/FTC/EFV
TDF/FTC/RPV
TAF/FTC/RPV
ABC/3TC/DTG
EVG/cobi/FTC/TAF
EVG/cobi/FTC/TDF
BIC/FTC/TAF
DRV/cobi/FTC/TAF
DTG/RPV
DTG/3TC
DOR/3TC/TDF
Cahn P, et al. Lancet HIV. 2017;4:e486-e494. Sax PE, et al. Lancet. 2015;385:2606-15. Eron JJ, et al. AIDS.2018;32:1431-1442. Gallant J, et al. Lancet. 2017;390:2063-2072. Sax PE, et al. Lancet. 2017;390:2073-2082.
• Supresión virológica ≈ 90% • Muy baja proporción de de efectos adversos que lleven a la retirada del TAR • Baja proporción de FV y selección de de Resistencia en caso de FV
TAR EVG/c/FTC/TAF RAL+FTC/TDFQD DRV/c/FTC/TAF DTG/3TC/ABC DTG+FTC/TAF BIC/FTC/TAF
Studio GS-104/111 ONCEMRK AMBER GS-1489 GS-1490 GS-1489/90
Eficacia 48s CV < 50c/mL ITT
92% 89% 91% 93% 93% 92%/89%
Retirada por EA 1% 1% 2% 1% 0,3% 0/2%
Fracaso virológico
4% 5,5% 4,4% 2,5% 1% 2,7%
Resistencia 7/866 5/531 1/362 0/315 0/325 0/634
Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
aCalculated from a repeated measures model adjusting for study, treatment, visit (repeated factor), baseline plasma HIV -1 RNA, baseline CD4+ cell count, treatment and visit interaction, and baseline CD4+ cell count and visit interaction.
0
70
85 89
90 93
91 93
72
87 89
88
93
90 91
0
10
20
30
40
50
60
70
80
90
100
-4 0 4 8 12 16 20 24 28 32 36 40 44 48
HIV
-1 R
NA
<5
0 c
/mL
, %
Study visit
CD4+ cell count (cells/mm3)
Adjusted mean change
from baseline at Week
48a
DTG + 3TC 224
DTG +
TDF/FTC 218
DTG + 3TC (n=716)
DTG + TDF/FTC (n=717)
Las PVVIH estarán en TAR durante décadas
EXPECTATIVA DE VIDA1
POBLACIÓN
GENERAL PVVIH
75 años
82 años
PVVIH: Personas que viven con VIH
1. Nakagawa F, Lodwick RK, Smith CJ, et al. Projected life expectancy of people with HIV according to timing of diagnosis. AIDS 2012;26:335-43.
39,1años
DURACIÓN MEDIA EN TRATAMIENTO EN 2012
1 año
39,1 años1
Triple terapia con
potenciador (QD)
Triple terapia sin potenciador
(QD)
2DRa
(QD)
1.460 1.095 730
57.086 42.815 28.543
a. 2DR: REGIMEN DE 2 FÁRMACOS BASADO EN DTG (2-DRUG RÉGIMEN)
NÚMERO DE DOSIS DE FÁRMACO
Nakagawa F, Lodwick RK, Smith CJ, et al. Projected life expectancy of people with HIV according to timing of diagnosis. AIDS 2012;26:335-43.
Infección por el VIH en el 2019 Grandes avances en los tratamientos para el VIH, aumento de la supervivencia a largo plazo y mejora de la calidad de vida de las PVVIH
Pero…
55% de pacientes en el mundo sin tratamiento y el 77% de pacientes en África presentan una mala adherencia
-Regímenes de pastillas y efectos secundarios -Dificultades del sistema de salud -Barreras psicológicas y sociales -Consumo de drogas y otras sustancias, salud mental -Discriminación y estigma social -Cansancio/desgaste (tomando pastillas durante décadas!!!!)
Fármacos de larga duración
Anticonceptivos reversibles
EPOC
Hipertensión
Esquizofrenia
Diabetes
…………
SE-ES-HIV-PPT-190002 9
Modos de administración de ARV de larga duración Larga duración por vía oral
Fármacos con vida media de eliminación muy larga Inyectables con formulaciones de liberación lenta
Subcutaneo (s.c.) Intramuscular (i.m.) Intravenoso (i.v.)
Implantes Biodegradable Recargables
Parches dérmicos con formulaciones de liberación lenta
Flexner CW, CROI 2017 Barnhart M, Global Health: Science and Practice 2017
SE-ES-HIV-PPT-190002 10
Características de los tratamientos de larga duración que mejoran el impacto del TAR
Reducción del número de dosis
No presentan requerimientos alimentarios y la resorción intestinal asociada a las interacciones fármaco-fármaco
Mayor privacidad de la salud porque no es necesario guardar medicación en casa
Mejora de la adherencia al tratamiento:
La dosificación diaria tiene un impacto substancial y negativo en la adherencia a largo plazo
La adherencia disminuye con el tiempo
Los beneficios individuales del TAR se reducen en aquellos pacientes con cumplimiento inadecuado del tratamiento
El impacto del “tratamiento como prevención” disminuye cuando los pacientes VIH+ no toman el TAR según lo prescrito
Posibilidad de observar directamente la terapia
Havlir D, Gandhi M, Curr Opin HIV AIDS. 2015 July Flexner CW, CROI 2017
• Favorece/mantiene la adherencia a largo plazo • Reduce el estigma/problema psicológicos
• Cabotegravir (CAB) es un inhibidor de la integrasa del VIH-1 en investigación; análogo estructural de DTG – Oral: comprimidos de 30 mg (t½, ~40 horas) – LA: nanosuspensión de 200 mg/mL (t½, ~20-40 días)
• Rilpivirina (RPV) es un INNTI del HIV-1 – Oral: comprimidos de 25 mg (t½, ~50 horas) – LA: nanosuspensión de 300 mg/mL (t½, ~30-90 días)
• Las características de CAB + RPV permiten el enfoque LA:
– Diferentes MdA, perfiles de resistencias, vías metabólicas
– Ausencia de interacción farmacológica entre CAB y RPV 1
– Los ensayos clínicos iniciales de LA Initial LA trials support q4-8 week synchronous dosing schedule
– Oral formulations to facilitate treatment initiation, oral-bridging and discontinuation strategies
Cabotegravir + Rilpivirina
CAB, cabotegravir; CI, confidence interval; LA, long-acting; NNRTI, non-nucleoside reverse transcriptase inhibitor; RPV, rilpivirine; t½, half-life. Margolis et al. Lancet Infect Dis. 55.; Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.
SE-ES-HIV-PPT-190002
Cabotegravir + Rilpivirine as Long-Acting Maintenance Therapy: LATTE-2 Week 48 Results
David A. Margolis,1 Daniel Podzamczer,2 Hans-Jürgen Stellbrink,3 Thomas Lutz,4 Jonathan B. Angel,5 Gary Richmond,6 Bonaventura Clotet,7 Felix Gutierrez,8 Louis Sloan,9 Sandy K. Griffith,1 Marty St Clair,1 David Dorey,10 Susan Ford,11 Joseph Mrus,12 Herta Crauwels,12 Kimberly Y. Smith,1 Peter E. Williams,12 William R. Spreen1
1ViiV Healthcare, Research Triangle Park, NC, USA; 2Ciudad Sanitaria y Universitaria de Bellvitge, Barcelona, Spain; 3ICH Study Center, Hamburg, Germany; 4Infektio Research, Frankfurt, Germany; 5The Ottawa Hospital, Ottawa, Canada;
6Fort Lauderdale, FL, USA; 7Hospital Germans Trias i Pujol, Badalona, Spain; 8Hospital Santa Cruz y San Pablo, Barcelona,
Spain; 9North Texas Infectious Disease Consultants, Dallas, TX, USA; 10GlaxoSmithKline, Mississauga, Ontario, Canada; 11PAREXEL International, Research Triangle Park, NC, USA; 12Janssen Research and Development, Beerse, Belgium
Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.
SE-ES-HIV-PPT-190002
LATTE-2: CAB LA and RPV LA for Maintenance of Virologic Suppression after Oral Induction
Study Design
– A Phase 2b, randomized, multi-center, parallel group, open-label, study to evaluate the antiviral activity, tolerability, and safety of two intramuscular dosing regimens of CAB LA plus RPV LA
Primary Objective
– Percentage of participants with HIV-1 RNA <50 copies/mL at maintenance Week 32, protocol defined virologic failure at Week 96
Eron et al. IAS 2017; Paris, France. Slides MOAX0205LB.Margolis, D., et al. Lancet 2017; 390(10101): 1499-1510.
*Subjects who withdrew after at least 1 IM dose entered the long-term follow-up period; †Subjects can elect to enter LA Extension Phase beyond Week 96;
Induction Period
Week 32 Primary analysis Dosing regimen
selection
Day 1 Randomization
2:2:1
Week 48 Analysis
Dosing regimen confirmation
CAB 400 mg IM + RPV 600 mg IM
Q4W (n=115)
CAB 600 mg IM + RPV 900 mg IM
Q8W (n=115)
Week 96†
CAB and RPV loading dose at Day 1
CAB and RPV loading doses at Day 1 and CAB at Week 4
CAB 30 mg + ABC/3TC PO
for 20 weeks
CAB 30 mg + ABC/3TC PO QD (n=56)
Maintenance period*
Add RPV PO QD
4 weeks
13
SE-ES-HIV-PPT-190002
Comparable Response Across Arms ITT-ME (Snapshot) Week 96 VL <50c/mL
Eron et al. IAS 2017; Paris, France. Slides MOAX0205LB.
Virologic outcomes Treatment differences (95% CI)
94
4 2
87
0
13
84
2
14
0
20
40
60
80
100
Virologicsuccess
Virologicnon-response
No virologicdata
HIV
-1 R
NA
<5
0 c
/mL,
%
CAB + RPV LA Q8W (n=115)CAB + RPV LA Q4W (n=115)CAB + NRTIs PO (n=56)
14 Eron et al. IAS 2017; Paris, France. Slides MOAX0205LB
3.0%
-12 -9 -6 -3 0 3 6 9 12 15
−8.4% 14.4%
Q4W IM
10.0%
− 0.6% 20.5%
Oral IM
Q8W IM
SE-ES-HIV-PPT-190002
Snapshot Outcomes:
HIV-1 RNA <50 c/mL at Week 48 (ITT-ME)
Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.
Week 48 outcome
Q8W IM
(n=115)
Q4W IM
(n=115)
Oral CAB
(n=56)
Virologic success 106 (92%) 105 (91%) 50 (89%)
Virologic non-response 8 (7%) 1 (<1%) 1 (2%)
Data in window not <50 c/mLa 6 (5%) 1 (<1%) 0
Discontinued for lack of efficacy 1 (<1%) 0 1 (2%)
Discontinued for other reason while not <50 c/mL 1 (<1%) 0 0
No virologic data in window 1 (<1%) 9 (8%) 5 (9%)
Discontinued due to adverse event or deathb 0 6 (5%) 2 (4%)
Discontinued for other reasonsc 1 (<1%) 3 (3%) 3 (5%)
aWeek 48 HIV-1 RNA Q8W: 50 c/mL, 57 c/mL, 97 c/mL, 110 c/mL, 135 c/mL, 463/205 c/mL; Q4W: 59 c/mL; Q8W: 5 of 6 remain in the study, 4 of 6 have HIV-1 RNA <50 c/mL at all subsequent visits through W80. bQ4W: hepatitis C, rash, depression, psychosis, epilepsy, and Churg-Strauss vasculitis; oral CAB: hepatitis C, DILI. cQ8W: ISR; Q4W: pregnancy, prohibited medication, relocation; oral CAB: lost to follow-up, relocation, withdrew consent (wanted injections rather than oral tablets).
SE-ES-HIV-PPT-190002
99% of ISR events were mild (84%) or moderate (15%), and 89% resolved within 7 days Most common ISR events: pain (66%), nodules (8%), swelling (6%), and pruritus (6%)
2 of 230 subjects (<1%) had an ISR that led to discontinuation (Q8W) through Week 96
Day 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96
1 Study visit, week Subjects at visit
Q8W IM 115 115 114 — 113 — 112 — 112 — 111 — 111 — 110 — 110 — 109 — 109 — 110 — 109
Q4W IM 115 115 115 114 112 111 109 109 107 107 105 105 104 104 104 104 102 103 103 102 99 100 101 101 101
Injection Site reactions for CAB LA or RPV LA Over 96 Weeks
Eron et al. IAS 2017; Paris, France. Slides MOAX0205LB. 16
85
38 46 46
57
38 50
37 43 45
29 36
28 31
88
42 40 35 31 28 35 31 29 29 32 30 30 29 32 34 31 33 33 30 28 27 27 31 28
0
20
40
60
80
100
Pat
ien
ts w
ith
AEs
, %
Q8W IM
SE-ES-HIV-PPT-190002
HIV Treatment Satisfaction Questionnaire Week 96
• At Week 96, patients in the Q8W and Q4W IM arms reported a statistically significant difference in satisfaction with their HIV treatment compared with patients in the oral ART arm
Murray M et al., AIDS 2018 Poster THPEB042 17
54
56
58
60
62
64
Day 1 Week 8 Week 32 Week 48 Week 96
HIV
TSQ
s to
tal s
core
, mea
n HIVTSQs Mean Values Through Week 96
Q8W IM Q4W IM Oral CAB 30 mg
p<0.05
p<0.05
p<0.05 p<0.05
p<0.05 p<0.05
Kerrigan D, et al. PlosOne 2018.
“Comodidad” “Libertad” “No pienso en pastillas”
“Menos estigmatizado” “Olvido el VIH”
“Molestias leves debido a las inyecciones” “Los beneficios compensan las molestias”
SE-ES-HIV-PPT-190002
FLAIR: CBV LA + RPV LA for Maintenance Following Switch From INI based ART in HIV-1 Infected Therapy Naive Participants
Study Design
– A Phase 3, randomized, multicenter, parallel-group, open-label non-inferiority study evaluating the efficacy, safety, and tolerability of LA IM CAB + RPV
Primary Objective
– Proportion of participants with a virologic failure endpoint as per FDA Snapshot algorithm at Week 48 (Missing, Switch or Discontinuation = Failure; Intent-to-Treat Exposed [ITT-E] Population
19 Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947
SE-ES-HIV-PPT-190002 SE-ES-HIV-PPT-190002
FLAIR Virologic Snapshot Outcomes at Week 48 for ITT-E: Noninferiority Achieved for Primary and Secondary Endpoints
Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.
3TC, lamivudine; ABC, abacavir; CAB, cabotegravir; CI, confidence interval; DTG, dolutegravir; ITT-E, intention-to-treat exposed; LA, long-
acting; NI, noninferiority; RPV, rilpivirine. *Adjusted for sex and baseline HIV-1 RNA (< vs ≥100,000 c/mL).
SE-ES-HIV-PPT-190002 SE-ES-HIV-PPT-190002
FLAIR Virologic Snapshot Outcomes at Week 48 for ITT-E: Noninferiority Achieved for Primary and Secondary Endpoints
Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.
3TC, lamivudine; ABC, abacavir; CAB, cabotegravir; CI, confidence interval; DTG, dolutegravir; ITT-E, intention-to-treat exposed; LA, long-
acting; NI, noninferiority; RPV, rilpivirine. *Adjusted for sex and baseline HIV-1 RNA (< vs ≥100,000 c/mL).
SE-ES-HIV-PPT-190002 SE-ES-HIV-PPT-190002
FLAIR Snapshot Outcomes at Week 48 for ITT-E
Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.
n (%)
CAB LA + RPV LA N=283
DTG/ABC/3TC N=283
HIV-1 RNA <50 copies/mL 265 (93.6) 264 (93.3)
HIV-1 RNA ≥50 copies/mL 6 (2.1) 7 (2.5)
Data in window not below threshold 2 (0.7) 2 (0.7)
Discontinued for lack of efficacy 4 (1.4) 3 (1.1)
Discontinued for other reason while not below threshold
0 2 (0.7)*
No virologic data 12 (4.2) 12 (4.2)
Discontinued due to AE† 8 (2.8) 2 (0.7)
Discontinued for other reasons‡ 4 (1.4) 10 (3.5)
1).
: †LA arm: hepatitis A (1), acute hepatitis B (1), acute hepatitis C (1), transaminases increase (1), hepatitis A/secondary syphilis (1), injection site pain (1), injection site pain/discomfort/diarrhea/vomiting (1), adenocarcinoma of colon (1). DTG/ABC/3TC arm: renal failure (1), suicide attempt (1).
: †LA arm: hepatitis A (1), acute hepatitis B (1), acute hepatitis C (1), transaminases increase (1), hepatitis A/secondary syphilis (1), injection site pain (1),
injection site pain/discomfort/diarrhea/vomiting (1), adenocarcinoma of colon (1). DTG/ABC/3TC arm: renal failure (1), suicide attempt (1).
SE-ES-HIV-PPT-190002 SE-ES-HIV-PPT-190002
FLAIR Confirmed Virologic Failures: CAB LA + RPV LA Arm • Plasma CAB and RPV concentrations at the time of failure were below the population means but within the range
for the large majority of individuals who maintained virologic suppression
• One additional participant had oral CAB/RPV dosing interrupted due to a false-positive pregnancy test and upon re-initiation of oral therapy had suspected VF that was confirmed
• Three participants in the DTG/ABC/3TC arm had CVF at Weeks 8, 12, and 16, respectively; no drug resistance mutations were selected
Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.
Sex, Country, HIV-1 Subtype,
Virologic Load (Baseline)
Baseline RAMs (HIV-1 RNA) SVF
Timepoint Viral Load at SVF/CVF
(c/mL)
SVF Timepoint RAMs (HIV-1 RNA) Drug Sensitivity at SVF†
(Fold Change) NNRTI INSTI* NNRTI INSTI*
F, Russia, A1, 54K
None L74I Week 20 373 / 456 E138E/A/K/T L74I, Q148R RPV (7.1) CAB (5.2) DTG (1.0)
M, Russia, A1, 23K
None L74I Week 28 287 / 299 K101E L74I, G140R RPV (2.6) CAB (6.7) DTG (2.2)
F, Russia, A1, 20K
None L74I Week 48 488 / 440 E138K L74I, Q148R RPV (1.0) CAB (9.4) DTG (1.1)
SE-ES-HIV-PPT-190002 SE-ES-HIV-PPT-190002
FLAIR Injection Site Reactions • The majority (99%, 2189/2203) of ISRs were
grade 1–2 and most (88%) resolved within ≤7 days
Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.
Event
CAB LA + RPV LA
N=283*
Participants receiving injections, n 278
Injections given, n 7704
ISR events, n (%) 2203 (28.6)
Pain 1879 (85.3)
Nodule 86 (3.9)
Induration 82 (3.7)
Swelling 38 (1.7)
Warmth 38 (1.7)
Grade 3 ISR pain 12 (<1)†
Median duration of ISRs, days 3
Participants with ISR leading to withdrawal, n (%) 2 (<1)‡
0
20
40
60
80
100
4B 8 12 16 20 24 28 32 36 40 44 48
Par
tici
pan
ts w
ith
ISR
s (%
)
Study Week
ISR Incidence by Week
SE-ES-HIV-PPT-190002 SE-ES-HIV-PPT-190002
FLAIR: High Participant Satisfaction (HIVTSQc) and Preference for Injectable Therapy • Change in satisfaction with current treatment vs induction phase treatment was significantly higher for LA vs
DTG/ABC/3TC
– HIVTSQs exhibited a ceiling effect, with very high baseline satisfaction scores in both groups (data not shown)†
Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.
33 -33
SE-ES-HIV-PPT-190002 SE-ES-HIV-PPT-190002
ATLAS Study Design: Randomized, Multicenter, International, Open-Label, Noninferiority Study in Adults with Virologic Suppression (Ongoing)
Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.
SE-ES-HIV-PPT-190002 SE-ES-HIV-PPT-190002
Sex, Country, HIV-1
Subtype
Previous CAR
SVF Timepoint
Viral Load at SVF/CVF
(c/mL)
SVF Timepoint RAMs (HIV-1 RNA)
Drug Sensitivity at SVF†
(Fold Change)
Baseline RAMs
(PBMC/HIV-1 DNA; Day 1)
RT INSTI* RT INSTI*
F, Russia, A/A1
3TC, AZT, LPV/r Week 8 79,166 / 25,745 E138A L74I RPV (2.4) CAB (0.8) DTG (0.9)
E138E/A L74I
F, France, AG
3TC, AZT, NVP to 3TC, ABC, NVP
Week 12 695 / 258 V108I E138K
None RPV (3.7) CAB (1.2) DTG (1.0)
V108V/I E138K
None
M, Russia, A/A1
FTC, RAL, TDF to ABC, EFV, 3TC
Week 20 544 / 1841 E138E/K N155H
L74I
RPV (6.5) CAB (2.7) DTG (1.2)
None L74I
ATLAS Confirmed Virologic Failure: CAB LA + RPV LA Arm
Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.
• Plasma CAB and RPV concentrations at the time of failure were below the population means but within the range for the large majority of individuals who maintained virologic suppression
SE-ES-HIV-PPT-190002 SE-ES-HIV-PPT-190002
Estudio ATLAS-2M (207966)
Press Release, 2Aug2019
ViiV Healthcare reports positive phase III study results of investigational, long-acting, injectable HIV-
treatment regimen administered every two months
ATLAS-2M study met its primary endpoint, showing similar efficacy of cabotegravir and rilpivirine administered every eight weeks compared to four-week administration. I
Tratamiento LA para la infección por VIH
Beneficios • Mejora de la satisfacción y la calidad de vida del paciente Aspectos psicológicos “Libertad” Estigma Confort • Favorece la adherencia
Preocupaciones • Si la adherencia es baja? • Si se producen efectos adversos? • Donde se administra? Hospital? Personal cualificado?
Grobler J, et al. CROI 2016. #98
Additional Long-Acting ART Options in Development • Monoclonal antibodies
• PRO140 • UB-421 • Many broadly neutralizing
antibodies with “extendification” – VRC01; VRC01-LS; 3BNC117; 10-1074
• Subcutaneous implants (e.g., tenofovir AF)
• Gastric “starfish” drug reservoir
Kirtane AR, et al. Nat Commun. 2018; 9: 2.
Resumen y Conclusiones
-El TAR de larga duración puede resultar en una mejoría en aspectos importantes del manejo del VIH, como comodidad, satisfacción del paciente y reducción del estigma -Aún debemos conocer las ventajas y limitaciones cuando se traslade la experiencia de los ensayos clínicos a la vida real -Aspectos prácticos: selección de pacientes (aderentes? Mal adherentes?) problemas durante el tratamiento (no-ad., EAs) donde administrarlo (hospitales? Centros de asistencia primaria? Centros comunitarios?) -El futuro: nuevos compuestos con actividad más prolongada y nuevas vías de administración
Resumen y Conclusiones II
El fin del tratamiento diario? NO a corto mediano plazo y probablemente ni a largo plazo. Habrá pts que prefieran inyectables y otros pastillas o una modalidad mixta según sus circunstancias Pero los inyectables de LD permitirán adaptar las opciones de TAR según las preferencias de los pacientes. Todo para mejorar la adherencia y la calidad de vida en pts en tto crónico, en espera de la curación del VIH
SE-ES-HIV-PPT-190002
http://www.vihhub.cat
@VIHHUB
web
Gràcies!!