vhc: papel de las resistencias virales en 2018...muy efectivos con menor posibilidad de resistencias...

VHC: papel de las resistencias

virales en 2018

Javier Salmerón

Changing Terminology: RAV (resistance associated variant) Versus RAS (resistance associated substitution)

Resistance Associated Substitution = RAS

Resistant Variant

Pawlotsky Gastroenterology 2016

Fitness viral (capacidad replicativa) • Los virus salvajes (wild type/no mutados) tienen más capacidad replicativa

• Es posible que existan RAS a muy baja replicación que emergen con la presión de los AAD (Sarrazin Gastroenterology 2010)

• Las mutaciones en general condicionan una pérdida de la capacidad replicativa

García F, Cap 8. Guías de Tratamiento AAEH/Seimc 2016

Mutación: capacidad replicativa (fitness)

Pérdida de la CR SI NO

El virus con mutaciones NO SOBREVIVE (desaparece)

El virus con mutaciones SOBREVIVE (NO desaparece)

Kurt Trends in Microbiology 2016

Para evitar resistencias se necesitan fármacos: 1. Dirigidos frente a diferentes regiones del VHC 2. Muy potentes con alta barrera genética 3. Muy efectivos con menor posibilidad de resistencias

Fármacos de última generación: 1+2+3

Moderador

Notas de la presentación

Figure3.Substrate EnvelopeofHCV NS3/4A Protease and the Fit of Protease Inhibitor (PI) MK-5172 in the Envelope. (A) The substrate envelope (teal volume) displayed at the active site of HCV protease (light purple ribbon). The catalytic side chains are in yellow sticks. (B) The ﬁt of PI MK-5172 (magenta sticks) in the substrate envelope. The protease is displayed as a gray surface, with catalytic residues (yellow) and residues at the S2 subsite (purple, green, and red) that mutate to confer resistance colored on the surface. The large P2 extension moiety of MK-5172 protrudes beyond the envelope but avoids contacts with the S2 residues and instead packs against the catalytic residues.

Antivirales de acción directa

3’UTR 5’UTR Core E1 E2 NS2 NS4B NS3 NS5A NS5B p7

Paritaprevir Grazoprevir Voxilaprevir* Glecaprevir*

Ombitasvir Ledipasvir Elbasvir Daclatasvir Velpatasvir* Pibrentasvir*

Sofosbuvir* Dasabuvir

NS5B NUC Inhibitors

NS3 Protease Inhibitors

NS5A Replication

Complex Inhibitors

Ribavirin NS5B

Non-NUC Inhibitors

Polymerase Protease

* Fármacos pangenotípicos

Moderador


En 2017, el tratamiento de la hepatitis C crónica se basa en la combinación de 1 a 3 DAA de 4 clases, con o sin Ribavirina ,en la tabla estan reflejadas los diferentes farmacos. Inhibidores de las proteasas, inhibidores de NS5A , y los inhibidores de la polimerasa nucleotidos y no nucleotidos. El sofosbuvir ha sido el centro del tratamiento, asociado con otros compuestos.

¿Es necesario estudiar RAVs basales? • Eficacia AAD en vida real, casi 100% • Sin necesidad de hacer resistencias

basales

Efficacy of NS5A Inhibitors Against Hepatitis C Virus Genotypes 1–7 and Escape Variants

Judith M. Gottwein Gastroenterology 2018

Moderador


BACKGROUND & AIMS: Inhibitors of the hepatitis C virus (HCV) NS5A protein are a key component of effective treatment regimens, but the genetic heterogeneity of HCV has limited the efficacy of these agents and mutations lead to resistance. We directly compared the efficacy of all clinically relevant NS5A inhibitors against HCV genotype 1–7 prototype isolates and resistant escape variants, and investigated the effects of pre- existing resistance-associated substitutions (RAS) on HCV escape from treatment. METHODS: We measured the efficacy of different concentrations of daclatasvir, ledipasvir, ombitasvir, elbasvir, ruzasvir, velpatasvir, and pibrentasvir in cultured cells infected with HCV recombinants expressing genotype 1–7 NS5A proteins with or without RAS. We engineered HCV variants that included RAS identified in escape experiments, using recombinants with or without T/Y93H and daclatasvir, or that contained RAS previously reported from patients. RESULTS: NS5A inhibitors had varying levels of efficacy against original and resistant viruses. Only velpatasvir and pibrentasvir had uniform high activity against all HCV genotypes tested. RAS hotspots in NS5A were found at amino acids 28, 30, 31, and 93. Engineered escape variants had high levels of fitness. Pibrentasvir had the highest level of efficacy against variants; viruses with RAS at amino acids 28, 30, or 31 had no apparent resistance to pibrentasvir, and HCV with RAS at amino acid 93 had a low level of resistance to this drug. However, specific combinations of RAS and deletion of amino acid 32 led to significant resistance to pibrentasvir. For the remaining NS5A inhibitors tested, RAS at amino acids 28 and 93 led to high levels of resistance. Among these inhibitors, velpatasvir was more effective against variants with RAS at amino acid 30 and some variants with RAS at amino acid 31 than the other agents. Variants with the pre- existing RAS T/Y93H acquired additional NS5A changes dur- ing escape experiments, resulting in HCV variants with specific combinations of RAS, showing high fitness and high resistance. CONCLUSIONS: We performed a comprehensive comparison of the efficacy of the 7 clinically relevant inhibitors of HCV NS5A and identified variants associated with resistance to each agent. These findings could improve treatment of patients with HCV infection.

Antivirales de acción directa

3’UTR 5’UTR Core E1 E2 NS2 NS4B NS3 NS5A NS5B p7

Voxilaprevir* Glecaprevir*

Velpatasvir* Pibrentasvir*

Sofosbuvir*

NS5B NUC Inhibitors

NS3 Protease Inhibitors

NS5A Replication

Complex Inhibitors

Ribavirin NS5B

Non-NUC Inhibitors

Polymerase Protease

* Fármacos pangenotípicos

Moderador


En 2017, el tratamiento de la hepatitis C crónica se basa en la combinación de 1 a 3 DAA de 4 clases, con o sin Ribavirina ,en la tabla estan reflejadas los diferentes farmacos. Inhibidores de las proteasas, inhibidores de NS5A , y los inhibidores de la polimerasa nucleotidos y no nucleotidos. El sofosbuvir ha sido el centro del tratamiento, asociado con otros compuestos.

Phase 3b, Multi-Center, Randomized, Open-Label, Pragmatic Study of Glecaprevir/Pibrentasvir (G/P) +/- Ribavirin for GT1 Subjects with Chronic Hepatitis C Previously Treated with an NS5A Inhibitor + Sofosbuvir Therapy

Anna S. Lok,1 Ira Willner,2 K. Rajender Reddy,3 Mohamed A. Hassan,4 Federico Hinestrosa,5 Mitchell L. Shiffman,6 Mark S. Sulkowski,7 Ira M. Jacobson,8 Robert S. Brown Jr,9 Giuseppe

Morelli,10 Joy Peter,10 Michael W. Fried,11 Monika Vainorius,11 Larry Michael,11 Gary P. Wang,10 Bonnie Yiran Hu,12 Jens Kort,12 David R. Nelson,10

1University of Michigan, Ann Arbor, Michigan; 2Medical University of South Carolina, Charleston, South Carolina; 3University of

Pennsylvania, Philadelphia, Pennsylvania; 4University of Minnesota, Minneapolis, Minnesota; 5Orlando Immunology Center, Orlando, Florida; 6Liver Institute of Virginia, Richmond, Virginia; 7Johns Hopkins University, Baltimore, Maryland; 8New York University, New

York, New York; 9Cornell University, New York, New York; 10University of Florida, Gainesville, Florida; 11University of North Carolina, Chapel Hill, North Carolina; 12AbbVie Inc., North Chicago, Illinois.

Presented at The European Association for the Study of the Liver: International Liver Congress Paris, France 14 April 2018

9

Moderador


On behalf of my HCV TARGET co-investigators, I would like to thank EASL scientific committee for the opportunity to present the preliminary data of our study .. Phase 3b …

Objective

10

• To compare the efficacy and safety of 12- or 16-weeks of open-label G/P ± RBV regimen in GT1-infected patients who had virologic failure following NS5Ai + SOF ± RBV treatment

Network Study

Moderador


The objective of this study was ..

11

Study Design

RBV, ribavirin

Treatment Period Post-Treatment Period

Arm A SVR12

G/P

Arm B SVR12

G/P

Non-Cirrhotics (2:1 arm A:B)

* Weight-based RBV

Arm D SVR12

G/P

0 24 12 16 28

Arm C SVR12

G/P + RBV* Cirrhotics

(1:1 arm C:D)

Design: Phase 3b, open-label, randomized, pragmatic, multi-center study in US sites

Network Study

Moderador


This is a phase 3b, open label… With stratified randomization for cirrhosis status AND HCV genotype 1 subtype (1b or non-1b). Non-cirrhotic patients are randomized 2:1 to receive G/P for 12 weeks (arm A) or 16 weeks (arm B) while Cirrhotic patients are randomized 1:1 to receive G/P+RBV x 12 weeks (arm C) or G/P x 16 weeks (arm D) This study was designed and initiated prior to FDA approval of G/P

SVR

4 (%

)

22 23

High SVR4 rates achieved in the retreatment of NS5Ai+SOF failures

12

0

20

40

60

80

100

Arm A G/Px12wks

Arm B G/Px16wks

n N

28 29

96 96

65 68

2 Relapse 1 BT 3 BT

86

18 21

Arm C G/P+RBV x12wks

100

21 21

Arm D G/Px16wks

Network Study

22 patients not yet reached SVR4 time point No patient lost to follow-up BT=breakthrough

SVR12 Concordance with SVR4: N, % 55, 98% 18, 100% 16, 100% 12, 100%

1 Relapse

Arm C Enrollment stopped- 2/19/18

Efficacy: SVR4 among patients reaching time point

Los no respondedores a Sofos+NS5A, presentan alta efectividad de G/P 12 semanas en no cirróticos y de

16 semanas en cirróticos

Moderador


Because of the inferior response in arm C, enrollment into this arm was stopped in Feb and all subsequent cirrhotic patients were enrolled into the 16 week treatment ARM D

Glecaprevir/Pibrentasvir in Patients With Chronic Hepatitis C Virus Infection and Prior Treatment Experience: An Integrated Phase II/III Analysis Fred Poordad EASL 2018 April 11-15 Paris France.

La RVS a los tratados con inhibidores NS5A (94%) y NS3 (92%) es <95%

G/P + SOFOS + RBV-16s

12 S 16 S

Mensaje: si un paciente G3 no responde a G/P tiene un 100 % de posibilidades de responder a G/P + Sofo + RBV

Ficha técnica: Maviret

• Composición: combinación a dosis fija, cada comprimido de SOF/VEL/VOX contiene 400mg de sofosbuvir (SOF), 100mg de velpatasvir (VEL), y 100 mg de voxilaprevir (VOX).

• SOF: inhibidor pangenotípico de la polimerasa de ARN dependiente del ARN NS5B del VHC. • VEL: inhibidor de 2ª generación de la NS5A, con perfil de resistencias mejorado. • VOX: inhibidor de la proteasa NS3/4A con actividad pangenotípica y alta barrera de resistencias.

• Indicación: tratamiento de la hepatitis C crónica (HCC) GT1-6 en adultos.

• Posología: un comprimido de SOF/VEL/VOX una vez al día acompañado de alimentos, independientemente del genotipo.

Indicación SOF/VEL/VOX - Vosevi (EMA)

*AAD: Antivirales de Acción Directa; Ficha técnica de Vosevi® (sofosbuvir/ velpatasvir/Voxilaprevir). (Disponible en: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004350/WC500235373.pdf)

Población de pacientes Duración del tratamiento

Pacientes no tratados previamente con AAD y sin cirrosis 8 semanas

Pacientes no tratados previamente con AAD y con cirrosis compensada

12 semanas Se puede considerar la duración de 8 semanas en pacientes infectados por el genotipo 3

Pacientes tratados previamente con AAD* sin cirrosis o pacientes con cirrosis compensada 12 semanas

POLARIS-3 POLARIS-1 POLARIS-2 POLARIS-4

Programa POLARIS: Fase 3 con Vosevi

N = 941 ± cirrhosis

N = 415 N = 219 N = 333

GT 1 2 3 4 5 6 GT 1 2 3 4 5 6

Cirrhosis

Placebo (n=152)

SOF/VEL/VOX 12 weeks (n=263)


SOF/VEL 12 weeks (n=151)





Non-NS5A-experienced ± cirrhosis

DAA-Experienced DAA-Naïve

NS5A-experienced ± cirrhosis

GT 1 2 3 4 5 6 GT 1 2 3 4 5 6

‡

Bourliere M, et al. N Engl J Med 2017;376:2134-46; Jacobson I, et al. Gastroenterology 2017, doi: 10.1053/j.gastro.2017.03.047. 18

• Todos los ensayos clínicos de fase 3 con Vosevi fueron controlados (SOF/VEL o placebo) • Todos los ensayos clínicos de fase 3 están publicados y disponibles desde hace meses en

revistas de alto impacto (NEJM, Gastroenterology)

POLARIS-1 y -4: Características demográficas

Roberts, EASL 2017, SAT-280

Pacientes pretratados: Análisis integrado POLARIS-1 y -4

Patients, n (%)

DAA-Experienced Patients SOF/VEL/VOX 12 weeks

N=445 GT 1 / 2 / 3 / 4 / 5 / 6, % 51 / 8 / 30 / 9 / <1 / 1 Cirrhosis, n (%) 205 (46) Platelet count <100 x 103/µL, n (%) 61 (14) FibroScan ≥12.5 kPa*, n (%) 139 (31) Prior NS5A inhibitor experience, n (%) 262 (59) Prior PEG/RBV experience, n (%) n/a Baseline HCV RNA ≥800,000 IU/mL, n (%) 326 (73) USA, n (%) 236 (53)

Integrated efficacy analysis of SOF/VEL/VOX in DAA-experienced patients treated for 12 weeks

El Programa POLARIS ha supuesto la participación de una gran diversidad de pacientes, incluidos aquellos con factores históricamente vinculados al fallo en el tratamiento

*Patients without FibroScan scores are included in denominator.

‡

Prior NS5A Treatment (%) POLARIS-1: SOF/VEL/VOX for 12 Weeks in NS5A Inhibitor-Experienced HCV GT 1–6 ‡

*Other included SOF/VEL experienced, EBR/GZR experienced, and other investigational combinations and/or medications from discontinued programs. 3 patients received both LDV and DCV; DCV, daclatasvir; LDV, ledipasivir; OMB, ombitasvir. Bourliere M, AASLD 2016, Oral 194

51

27

11 13

0

10

20

30

40

50

60

Pat

ient

s, %

LDV DCV OMB Other*

133 263

70 263

30 263

33 263

Prior DAA HCV Treatment

POLARIS-4: SOF/VEL/VOX or SOF/VEL for 12 Weeks in Non-NS5A Inhibitor DAA-Experienced HCV GT 1–4 ‡

NS5B NS5B + NS3 Other

Pat

ient

s, %

69

4

11 14

2 0

10

20

30

40

50

60

70

SOF Other SOF+SMV Other Other

231 12 37 47 5

Other NS5B included mericitabine (n=7); other NS5B+NS3 included deleobuvir+faldaprevir (n=14), mercitabine+danoprevir (n=8), and SOF+telaprevir (n=6); one patient without prior DAA exposure is excluded; SMV, simeprevir; SOF, sofosbuvir. Bourliere M, et al. N Engl J Med 2017;376:2134-46;; Zeuzem S, AASLD 2016, Oral 109.

Efficacy of SOF/VEL/VOX for 12 Weeks in DAA-Experienced Patients

Breakthrough 1* 1 1 0 0 0 0 0 0 0

Relapse 7 2 2 0 0 4 1 0 0 0

Other 6 3 2 1 0 2 1 0 0 0

*Patient had drug levels consistent with nonadherence. Roberts, EASL 2017, SAT-280

97 97 97 99 100 96 95 100 100 100

0

20

40

60

80

100

SV

R12

, %

GT 4

1 1

431 445

150 155

36 36

126 132

39 41

222 228

Total GT 1 Total

GT 1a GT 1b GT 2 GT 3 GT 5 GT 6 Other

1 1

6 6

68 69

The SVR12 rate was 97% (431/445) in DAA-experienced patients treated with SOF/VEL/VOX for 12 weeks; Rates were similar regardless of genotype

‡ Pacientes pretratados: Análisis integrado POLARIS-1 y -4

Efficacy of SOF/VEL/VOX for 12 Weeks in DAA-Experienced Patients (Cirrhosis vs. Non-cirrhosis)


Cirrhotic TE patients achieved high SVR12 with SOF/VEL/VOX and were

similar to non-cirrhotic patients



Análisis Integrado de Eficacia de POLARIS-1 y -4

% (n/N) TOTAL GT 1a GT 1b GT 2 GT 3 GT 4

Cirrosis Si 95

(195/205) 94

(47/50) 100

(27/27) 100

(13/13) 94

(82/87) 92

(24/26)

No 98 (236/240)

98 103/105

98 (41/42)

100 (23/23)

98 (44/45)

100 (15/15)

Plaquetas <100 x 103/μL 100

(61/61) 100

(16/16) 100 (7/7)

100 (3/3)

100 (28/28)

100 (7/7)

≥100 x 103/μL 96 (370/384)

96 (134/139)

98 (61/62)

100 (33/33)

94 (98/104)

94 (32/34)

Fibroscan <12.5 kPa 98

(178/182) 98

(78/80) 97

(33/34) 100

(16/16) 97

(32/33) 100

(11/11)

≥12.5 kPa 95 (132/139)

92 (33/36)

100 (20/20)

100 (9/9)

96 (53/55)

88 (15/17)

Con experiencia de tto NS5A

Sin experiencia 98 (179/183)

98 (53/54)

96 (23/24)

100 (31/31)

96 (53/55)

100 (19/19)

Con experiencia 96 (252/262)

96 (97/101)

100 (45/45)

100 (5/5)

95 (73/77)

91 (20/22)

Region USA 97

(230/236) 97

(94/97) 97

(35/36) 100

(23/23) 96

(55/57) 100

(17/17)

No-USA 96 (201/209)

97 (56/58)

100 (33/33)

100 (13/13)

95 (71/75)

92 (22/24)

Alta eficacia de SOF/VEL/VOX en pacientes experimentados a AAD Independiente de factores predictores negativos de respuesta

Resistance Analysis of SOF/VEL/VOX for 12 Weeks in DAA-Experienced Patients

Sarrazin, EASL 2017, THU-248

SOF/VEL/VOX 12 semanas en pacientes pretratados no se ve impactado por la presencia de RAS basales

POLARIS-1: DAA-experienced patients who had previously

received NS5A inhibitor

POLARIS-4: DAA-experienced patients who had not received

NS5A inhibitor

4% NS3 9/248

17% No RASs

43/248

50% NS5A 124/248

29% NS3+NS5A

72/248

97% SVR12

199/205

98% SVR12

42/43

100% SVR12

83/83

51% No RASs

86/169 24% NS5A 40/169

2% NS3+NS5A

4/169

99% SVR12

85/86

23% NS3 39/169


Indicaciones de tratamiento en pacientes con fallo al tratamiento

• IFN peg/IFN peg + RBV • Sofos • Sofos + RBV

Sin CH (tratamiento estándar) • SOF/VEL 12s • G/P 8s (G3, 16s) Con CH compensada • SOF/VEL 12s (no G3) • G/P 12s (G3, 16s)

• Inhibidores a la proteasa • Inhibidores a NS5A

Sin CH • G/P 12s (G1-NS5a) • SOF/VEL/VOX 12s Con CH compensada • G/P 16s (G1-NS5a) • SOF/VEL/VOX 12s

NO- G/P SÍ- G/P

• G/P-SOF-RBV 16s (G3)* (no aprobado en FT)

• SOF/VEL/VOX 12s (no datos)

EASL Recommendations on Treatment of Hepatitis C 2018

Diagnóstico y monitorización del tratamiento después de los fármacos pangenotípicos

ANTI-VHC/ARN-VHC Agc VHC FIB-4/APRI No Resistencias

Negativo No VHC

• Positivo • Fibrosis

leve Tratamiento

Monitorización de RV 12s postratamiento ARN-VHC o AgcVHC

Nuevos fármacos pangenotípicos

Negativo >97%: Curación Infección

Positivo <3%. No curación Estudio de resistencias (Micro)

• SOF/VEL/VOX 12s

Fibrosis intensa Estudio: Eco, Fibroscan..

Moderador


HCV, hepatitis C virus.

vhc: papel de las resistencias virales en 2018...muy efectivos con menor posibilidad de resistencias...

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