Tratamiento de la Infección crónica del VHC en la … · ensayos de registro.Por ejemplo Paciente cirroticos. Genotipo 4 , etc La frecuencia real de los afectos adversos y la seguridad

Tratamiento de la Infección

crónica del VHC en la vida real

Enrique Ortega González

Unidad de Enfermedades Infecciosas

Hospital General Universitario

Programas de Acceso Temprano

Regulado por el RD de disponibilidad de medicamentos en situaciones especiales

(REAL DECRETO 1015/2009, DE 19 DE JUNIO)

Regulados por el RD de EECCsEECCs(REAL DECRETO 223/2004, DE 6 DE FEBRERO)

Importancia de datos de clínica real

Datos del mundo real pueden ser diferentes de lo previsto

por los estudios de fase III.

Algunas poblaciones no estaban bien estudiadas en los

ensayos de registro.Por ejemplo Paciente cirroticos.

Genotipo 4 , etc

La frecuencia real de los afectos adversos y la seguridad , se

detectan mas tarde con el uso en la clínica.

Cohortes vida real Tratamientos

libres de interferón

Genotipo 1

Sofosbuvir +Simeprevir +- Ribavirina

HCV - Target

• Estudio longitudinal, observacional, de práctica clínica habitual

• Pacientes incluidos: adultos > 18 años en tratamiento para el VHC

Jensen DM et al; Safety and Efficacy of Sofosbuvir- Containing Regimens for Hepatitis C: Real-World Experience in a Diverse, Lo ngitudinal Observational Cohort

Boston Nov 2014

Sofosbuvir+Simeprevir +-RBV

Distribution of HCV Regimens

N=1994

Genotype 1

SOF/SMV/RBV14.9%

SOF/PEG/RBV 23.1%

SOF/RBV8.8%

Genotype 3

SOF/PEG/RBV8.5%

SOF/RBV91.5%

Genotype 2

SOF/PEG/RBV0.9%

SOF/RBV99.1%

SOF Containing Regimens

Demographics

SOF PEG RBV

SOF RBV SOF SMV SOF SMV RBV

Total*

n(%) N=384 N=667 N=784 N=228 N=2063

MALE 253(66.2) 422 (63.6) 478 (62.0) 147 (65.3) 1300 (63.7)

MEAN Age, y (range) 53.9 (23 - 79) 56.9 (21 - 82) 59.5 (20 - 83) 58.8 (29 - 80) 57.6 (20 - 83)

Age 65+ 31 (8.1) 131 (19.7) 190 (24.6) 40 (17.8) 392 (19.2)

CAUCASIAN 270 (70.3) 539 (80.8) 584 (74.5) 177 (77.6) 1570 (76.1)

BLACK 68 (17.8) 37 (5.6) 96 (12.5) 33 (14.7) 234 (11.5)

TREATMENT STATUS

NAIVE 211 (54.9) 371 (55.6) 318 (40.6) 82 (36.0) 982 (47.6)

EXPERIENCED 172 (44.8) 296 (44.4) 465 (59.3) 144 (63.2) 1077 (52.2)

PI FAILURE 47 (27.3) 25 (8.4) 76 (24.8) 45 (31.3) 193 (17.9)

CIRRHOSIS 120 (31.3) 302 (45.3) 440 (56.1) 137 (60.1) 999 (48.4)

Hx Decompensation 12 (11.4) 136 (49.5) 167 (44.8) 60 (50.8) 375 (43.1)

MELD >10 18 (17.1) 120 (43.6) 122 (32.7) 34 (28.8) 294 (33.8)

LIVER CANCER 25 (6.5) 66 (9.9) 88 (11.2) 32 (14.0) 211 (10.2)

LIVER TRANSPLANT 27 (7.0) 57 (8.5) 111 (14.2) 32 (14.0) 227 (11.0)

HIV 14 (3.6) 18 (2.7) 8 (1.0) 7 (3.1) 47 (2.3)

*Total, patients who started therapy SOF Containing Regimens

SOF + SMV ± RBVN=378

Latest Available HCV RNA BLOQ91% (335/369)

Latest Available HCV RNA Quantified9% (34/369)

Cohort of patients with treatment start on or before 4/15/14 ; BLOQ=Below Level of Quantitation;

HCV RNA Outcomes for SOF/SMV±RBV: Genotype 1

SVR4+ evaluable303/369

SVR4+ 89%269/303

Non-Response2%

(6/303)

SVR4+

No cirrhosis: 92% (113/123) Cirrhosis: 87% (156/180)Prior decomp: 75% (61/81)

SVR4+

G1a: 86% (154/180)G1b: 95% (88/93)

Lost to f/u0%

(0/303)


Prior PI Failures excluded from this analysis

SOF + SMV ± RBVN=72

Latest Available HCV RNA BLOQ86% (59/69)

Latest Available HCV RNA Quantified14% (10/69)

Cohort of patients with treatment start on or before 4/15/14 ; BLOQ=Below Level of Quantitation;

HCV RNA Outcomes for SOF/SMV±RBV: Genotype 1 PRIOR PI FAILURES

SVR4+ evaluable54/69

SVR4+ 81%44/54

Non-Response0%

(0/54)

SVR4+

No cirrhosis: 85% (17/20) Cirrhosis: 79% (27/34)

Lost to f/u0%

(0/303)


Adjusted* SVR4 for SOF/SMV±RBV

To compare SVR rates, logistic regression models with inverse probability weights (IPW) were constructed to adjust for potential selection bias.

*Adjusted for 5 characteristics including: cirrhosis status, genotype, treatment naïve/experienced, prior decompensation, and prior triple therapy failure


Adjusted SVR4 for SOF/SMV±RBV:Impact of Cirrhosis and Genotype


SVR4/SVR12 Concordance*

SVR12,n Summary %,n

Genotype Regimen SVR4 Yes No PPV NPV

1 SMV/SOF±RBV Yes 143 4 97.2 100

No 0 37

1 SOF/PEG/RBV Yes 51 3 94.4 100

NO 0 20

*Analyzed only in patients with an HCV RNA result at both FUWk4 and FUWk12

(N=259).

(Standard practice at many centers includes post-treatment efficacy testing only

at SVR12) SOF Containing Regimens

Minimally Adjusted Logistic Regression AnalysisPredictors of SVR4 for SOF/SMV±RBV


Adverse Events (>10%) By Regimen Impact of PEG and RBV

*Total, patients with EOT date SOF Containing Regimens

Preferred Term, n(%)

SOF PEG RBV(N=343)

SOF RBV(N=462)

SOF SMV(N=683)

SOF SMV RBV(N=196)

Total*(N=1684)

ANY AE 306 (89) 389 (84) 516 (76) 173 (88) 1384 (82)

Fatigue 144 (42) 177 (38) 168 (25) 74 (38) 563 (33)

Headache 55 (16) 74 (16) 108 (16) 46 (23) 283 (17)

Nausea 75 (22) 77 (17) 81 (12) 34 (17) 267 (16)

Anemia 95 (28) 98 (21) 7 (1) 58 (30) 258 (15)

Flu like Sx 93 (27) 58 (13) 72 (11) 24 (12) 247 (15)

Insomnia 54 (16) 66 (14) 58 (9) 35 (18) 213 (13)

Rash 62 (18) 50 (11) 57 (8) 28 (14) 197 (12)

Pruritus 34 (9) 39 (8) 56 (8) 28 (14) 157 (9)

Infections (ANY) 29 (9) 40 (9) 56 (8) 20 (10) 145 (9)

Dyspnea 54 (16) 43 (9) 28 (4) 12 (6) 137 (8)

Irritability 55 (16) 32 (7) 19 (3) 15 (8) 121 (7)

Depression 33 (10) 27 (6) 16 (2) 13 (7) 89 (5)

Neutropenia 28 (8) 0 (0) 3 (0) 0 (0) 31 (2)

Of patients who started treatment did the patient experience SAE (Serious

Adverse Event)?

SOF PEG RBVN=384

SOF RBVN=667

SOF SMVN=784

SOF SMV RBVN=228

AllN=2063

YES 11 (2.9%) 53 (7.9%) 36 (4.6%) 17 (7.5%) 117 (5.7%)

NO 373 (97.1%) 614 (92.1%) 748 (95.4%) 211 (92.5%) 1946 (94.3%)

Cause of Death (n=12)SOF PEG RBV: Sepsis

SOF RBV: Multi organ failure, Cardiac arrest (2)

SOF SMV: Ischemic stroke, Hepatic failure (2), Renal & Hepatic failure, Aspiration pneumonia, Vascular shock

SOF SMV RBV: Cause unknown, Suicide (accomplished)

SAEs To Date By Treatment Regimen


9 of the 12 deaths were in cirrhotic patients

Safety and Efficacy of SOF-Containing Regimens in Patients with Reduced Renal Function

17Saxena, EASL, 2015, LP08

HCV-TARGET: Real-World Use of SOF Regimens in Patients With Reduced Renal Function

19 patients with eGFR ≤ 30 mL/min (5 on HD) treated with SOF regimens in US & EU

Treatment Regimen by Baseline eGFR (n=1893)

eGFR ≤ 30 eGFR 31–45 eGFR 46–60 eGFR > 60

SOF+PegIFN+RBV SOF+RBV SOF+SMV SOF+SMV+RBV

eGFR ≤ 30 eGFR 31–45 eGFR 46–60 eGFR > 60

1/1 4/4 8/10 2/2 1/3 8/10 20/25 9/9 13/14 38/45 62/68 12/13188/232

292/ 400

480/ 552

135/ 171

‡

n=19 n=63 n=168 n=1643

SOF-Based Treatment Under Real Life Conditions in Germany

1

8Buggisch, EASL, 2015, P0777

SOFGER Trial – Interim Analysis

Prospective, multi-center study of 790 TN/TE, NC/CC patients

Treatment Regimen by Genotype

GT 1a (n=275)

GT 1b (n=278)

GT 2 (n=60)

GT 3 (n=128)

GT 4 (n=48)

SOF+PegIFN+RBV SOF+RBVSOF+SMV SOF+DCVLDV/SOF

SOF+PegIFN+RBV12 weeks

SOF+RBVGT 2: 12 weeks

Non-GT 2: 24 weeks

SOF+SMV12 weeks

SOF+DCV12 weeks

132/156

65/84

100/115

136/161

‡

COHORTE TRIO

Disposición de los pacientes en la COHORTE TRIO

Dieterich et al; Evaluation of sofosbuvir and simeprevir-based regimens

in the TRIO network, AASLD Boston 2014

* SVRs for cell with n<=5 not shown

Características basales de los pacientes en

tratamiento con SIM/SOF ± RBV (G1)

ITT PP

276 252

SVR

12

(%

)



RVS12 de los pacientes en tratamiento con SIM/SOF± RBV (cirrosis vs no cirrosis) naïve y previamente tratados

55 77 48 69

SVR

12

(%

)

PACIENTES NAÏVE

70 74 65 70SV

R1

2 (

%)

PACIENTES PREVIAMENTE TRATADOS



RVS12 de los pacientes fracasados a IP`s previos

40 37

RETRATAMIENTO CON SOF/PR RETRATAMIENTO CON SIM/SOF

SVR

12

(%

)

33 31

SVR

12

(%

)




libres de interferon

Genotipo 1

Sofosbuvir+Ledipasvir/daclatasvir + - RBV

Treatment of decompensated HCV cirrhosis in patients with diverse genotypes:

12 weeks sofosbuvir and NS5A inhibitors with/without ribavirin is effective in HCV Genotypes 1 and 3

GR Foster, J. McLauchlan, W. Irving, M. Cheung, B. Hudson, S. Verma, K. Agarwal, HCVResearch UK EAP Group

1392ES15NP02941-02

Preparado en: abril 2015

English EAP Program

Criterios de inclusión:Cirrosis descompensada con ascitis / várices

sangrado / encefalopatía

Puntuación CTP ≥7

Ausencia probable de alteraciones hepáticas

irreversible en 12 meses

No tolerancia al pr

Circunstancias excepcionales de revisión del

panel

SFV +LED or DCV

Caracteristicas Basales G1

N235

(50.3%)

Mean Age, years(Range)

56.1

(29-76)

Male174

(74.0%)

Treatment experienced107

(45.5%)

Liver transplanted27

(11.5%)

White193

(82.1%)

BMI – mean, kg/m2 28.5

HIV positive 17 (4.2%)

Mean HCV RNA,log10 iu/ml

6

G1N = 235

Decompensated cirrhosis (Past or present)

223

(94.9%)

CP-B161

(68.5%)

CP-C19

(8.1%)

MELD mean (range)11.3

(6-24)

Active ascites97

(41.3%)

Previous variceal bleed61

(26.0%)

Active encephalopathy

41

(17.4%)

G1

Sof/LDV/RBV N (%)

164

(35.1)

Sof/DCV/RBV45

(9.6)

Without RBV26

(5.6)

Total235

(50.3)

Diapositiva 26

MC1 perhaps should delete IL28B status given so few done in total?Michelle Cheung; 06/04/2015

SVR12 by Genotype and Regime

SVR12 defined as HCV RNA at 12 weeks post-treatment < 30 IU/ml

N 252 28 172 15 164 21 45 5

• DACLATASVIR PLUS SOFOSBUVIR WITH OR WITHOUT RIBAVIRIN IN PATIENTS WITH HIV-HCV COINFECTION: INTERIM ANALYSIS OF A FRENCH MULTICENTER COMPASSIONATE USE PROGRAM (AI444-258)

• K. Lacombe1, ANRS CO13-HEPAVIH Cohort

German Real-World LDV/SOF for 8 Weeks

3

3

N=45

Median (range) age, years 51 (22–73)

Male gender, n (%) 24 (53.3)

Caucasian, n (%) 45 (100)

Genotype, n (%)

GT 1a

GT 1b

GT 4

22 (48.9)

21 (46.7)

2 (4.4)

Metavir stage, n (%)

F0

F1

F2

F3

17 (37.8)

15 (33.3)

11 (24.4)

2 (4.4)

Median (range) baseline HCV RNA, IU/mL*700,259

(5,495–4,677,351)

Treatment-naïve, n (%)† 44 (97.8)

At least one comorbidity, n (%) 39 (86.7)

Baseline Characteristics

*Roche COBAS® AmpliPrep/COBAS® TaqMan®, cut-off < 12 IU/mL† including 1 PegIFN+RBV RelapserBuggisch, EASL, 2015, LP32

Single center German study of 45 primarily naïve, non-cirrhotic patients with baseline

HCV RNA < 6 million IU/mL treated with LDV/SOF for 8 weeks

‡German Real-World LDV/SOF for 8 weeks in NC with HCV RNA < 6M, primarily TN GT 1

Effectiveness and Safety

34

SVR

4

*3 patients had no SVR4 data available at time of analysis

LDV/SOF for 8 weeks resulted in high rates of SVR4 and was well tolerated

N=42*

Virologic Response Safety Results

Total cohortn=45

Any AEs (Grades 3 & 4), n (%) 1 (2.2)

Headache, n (%) 1 (2.2)

AE related to LDV/SOF, n (%) 1 (2.2)

AE leading to D/C, n (%) 0

Deaths, n (%) 0

German Real-World LDV/SOF for 8 weeks in NC with HCV RNA < 6M, primarily TN GT 1

Buggisch, EASL, 2015, LP32

‡



Genotipo 3

Daclatasvir Plus Sofosbuvir With or Without Ribavirin for the Treatment of HCV in Patients

With Severe Liver Disease: Interim Results of a Multicenter Compassionate Use Program

Welzel TM,1 Herzer K,2 Ferenci P,3

The International Liver Congress™ 2015: The 50th Annual Meeting of the European Association for the Study of the Liver.

Vienna, Austria, April 22–26, 2015

Poster PO772

Week 24 Week 36Day 1

DCV + SOF ± RBV Follow-Up

SVR12

Additional Optional Follow-Up

Week 48 Week 72

SVR24

European Multicenter Compassionate Use Program (AI444-237)

Open-label DCV 60 mg plus SOF 400 mg once daily for 24 weeks

•Dose adjustment for DCV was allowed for patients on concomitant

antiretroviral therapy

Addition of RBV at the discretion of the physician


42

ParameterAll Patients

(N = 601)

Age, median (range) years 54 (27–83)

Male, n (%) 442 (75.1)

Liver transplant patients, n (%) 53 (8.8)

Patient at pre-liver or renal transplant stage, n (%) 50 (8.3)

Past treatment category, n/N (%)

Treatment naive 163 (27.3)

Relapse 229 (38.5)

Null response 81 (13.6)

Partial response 65 (10.9)

Other treatment failures 1 (0.2)

Previous failure not specified 57 (9.5)

Coinfection, n (%)

HIV-HCV 95 (15.8)

HBV-HCV 9 (1.5)

HCV RNA level, median (range) log UI/mL 5.751 (1.18–8.00)

Hezode C, et al. EASL 2015; Poster LP05.


43

ParameterAll Patients

(N = 601)

Child-Pugh category, n (%)

A (F3/F4) 420 (69.9)

B 55 (9.2)

C 19 (3.2)

Missing data 107 (17.8)

Fibrosis stage, n (%)

F4 447 (75.5)

F0-F3 145 (24.5)

Hepatocellular carcinoma (previous or present), n (%) 50 (8.4)

Treatment duration, n (%)

12 weeks 41 (6.8)

24 weeks 560 (93.2)

Treatment regimen, n (%)

DCV + SOF 481 (80.4)

DCV + SOF + RBV 117 (19.6)


44

SVR4 Rates With DCV + SOF ± RBV By Treatment Duration

■ Treatment discontinuations were related to adverse events (1 patient),

death (2 patients), or patient decision (1 patient)

Cirrhotic

patientsNon-cirrhotic

patients

12 Weeks

24 weeks


22/29 52/59 11/12 5/6

Treatment of decompensated HCV cirrhosis in patients with diverse genotypes:

12 weeks sofosbuvir and NS5A inhibitors with/without ribavirin is effective in HCV Genotypes 1 and 3

GR Foster, J. McLauchlan, W. Irving, M. Cheung, B. Hudson, S. Verma, K. Agarwal, HCVResearch UK EAP Group

1392ES15NP02941-02

Preparado en: abril 2015

English EAP Program

Criterios de inclusión:Cirrosis descompensada con ascitis / várices

sangrado / encefalopatía

Puntuación CTP ≥7

Ausencia probable de alteraciones hepáticas

irreversible en 12 meses

No tolerancia al pr

Circunstancias excepcionales de revisión del

panel

Caracteristicas Basales G3

N189

(40.5%)

Mean Age, years

(Range)54

(36-75)

Male131

(69.3%)

Treatment experienced88

(46.6%)

Liver transplanted15

(7.9%)

White128

(67.7%)

BMI – mean, kg/m2 28.3

HIV positive 6 (1.5%)

Mean HCV RNA,log10 iu/ml 5.9

Decompensated cirrhosis (Past or present)

CP-B

CP-C

MELD mean (range)

Active ascites

Previous variceal bleed

Active encephalopathy

G3N = 189

179

(94.7%)

121

(64.0%)

24

(12.7%)

12.6

(6-36)

67

(35.4%)

55

(29.1%)

34

(18.0%)

Diapositiva 46

MC2 perhaps should delete IL28B status given so few done in total?Michelle Cheung; 06/04/2015

SVR12 by Genotype and Regime

SVR12 defined as HCV RNA at 12 weeks post-treatment < 30 IU/ml

N 252 28 172 15 164 21 45 5





Genotipo 4



Conclusiones

• Los datos en vida real confirman los

resultados de los ensayos clínicos con los

fármacos de acción directa .

Documents

Tratamiento de la Infección crónica del VHC en la … · ensayos de registro.Por ejemplo Paciente cirroticos. Genotipo 4 , etc La frecuencia real de los afectos adversos y la seguridad