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

[email protected]

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.


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


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


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).


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


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”


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).


FLAIR Snapshot Outcomes at Week 48 for ITT-E


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).


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


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)


FLAIR Injection Site Reactions • The majority (99%, 2189/2203) of ISRs were

grade 1–2 and most (88%) resolved within ≤7 days


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


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)†


33 -33


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.


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


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


http://www.vihhub.cat

@VIHHUB

[email protected]

web

Gràcies!!

http://www.vihhub.cat/



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