17/10/16 · terapie per l’epa*te C nei ... Life Expectancy in Patients With Chronic HCV Infection...

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Le terapie per l’epa*te C nei pazien* con emofilia: stato dell’arte Giuseppe Fo/ Unità Opera/va Complessa di Mala=e Infe=ve Azienda Ospedaliera “Bianchi – Melacrino – Morelli” Reggio Calabria

fo*giuseppe@*n.it

Stanaway et al. The Lancet, Vol 388, N. 10049, p1081–1088, 10 September 2016

EMOFILIA NEL NUOVO MILLENNIOnuove prospettive terapeutiche e sociali in emofilia

Reggio Calabria,1-2 Ottobre 2016

II CONGRESSO INTERREGIONALE

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Number of HCV Infected Individuals in the Countries With the Highest Burden of HCV

Thrift et al,Nat Rev Gastroenterol Hepatol in press

170 million people infected worldwide

Piano nazionale per la prevenzione delle epatiti virali da virus B e C (PNEV)

27 ottobre 2015

Epa/te C Nel nostro Paese, si s/ma che i pazien/ portatori cronici del virus HCV siano oltre un milione, di cui 330.000 con cirrosi. L’Italia ha il triste primato in Europa per numero di sogge= HCV posi/vi e mortalità per tumore primi/vo del fegato. 12 Oltre 20.000 persone muoiono ogni anno per mala=e croniche del fegato (due persone ogni ora) e, nel 65% dei casi, l’Epa/te C risulta causa unica o concausa dei danni epa/ci. Le regioni del Sud sono le più colpite: in Campania, Puglia e Calabria, per esempio, nella popolazione ultra se[antenne la prevalenza dell’HCV supera il 20%.12

12 Libro Bianco AISF 2011 – Proposta per un piano nazionale per il controllo delle malattie epatiche. Definizione ambiti e possibili interventi; 2011.




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• The goal of therapy is to cure HCV infec/on to prevent hepa/c cirrhosis, decompensa/on of cirrhosis, HCC, severe extrahepa/c manifesta/ons and death (A1).

• The endpoint of therapy is undetectable HCV RNA in blood by a sensi/ve assay (lower limit of detec/on ≤15 IU/ml) 12 weeks (SVR12) and/or 24 weeks (SVR24) ader the end of treatment (A1).

HCV - Therapy

SVR Susteined

Virological

Response

EASL Recommenda/ons on Treatment of Hepa//s C 2016

Life Expectancy in Patients With Chronic HCV Infection and Cirrhosis Compared With a General Population

van der Meer AJ et al. JAMA. 2014;312(18):1927-1928. doi:10.1001/jama.2014.12627




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Chronic HCV Infection May Lead to Chronic Liver Disease and Liver Cancer

Fibrosis1

Chronic HCV infection can lead to the development of fibrous scar tissue within the liver

Fibrosis Cirrhosis Hepatocellular Carcinoma (with cirrhosis)

Cirrhosis1,2

Over time, fibrosis can progress, causing severe scarring of the liver, restricted blood flow, impaired liver function, and eventually liver failure

HCC3

Cancer of the liver can develop after years of chronic HCV infection

Chronic liver disease includes fibrosis, cirrhosis, and hepatic decompensation; HCC=hepatocellular carcinoma.1. Highleyman L. Hepatitis C Support Project. http://www.hcvadvocate.org/hepatitis/factsheets_pdf/Fibrosis.pdf. Accessed August 18, 2011; 2. Bataller R et al. J Clin Invest. 2005;115:209-218; 3. Medline Plus. http://www.nlm.nih.gov/medlineplus/enxy.article/000280.htm. Accessed August 28, 2012; 4. Centers for Disease Control and Prevention. http://www.cdc.gov/hepatitis/HCV/HCVfaq.htm. Accessed May 8, 2012.

Decompensated cirrhosis: Ascites Bleeding gastroesophageal varices Hepatic encephalopathy Jaundice

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Endocrine Thyroid disease Diabetes mellitus

Hematologic Mixed cryoglobulinemia

Lymphoprolifera*ve disorders Thrombocytopenia

Renal Membranoprolifera*ve glomerulonephri*s

Ocular Corneal ulcers

Sjögren syndrome

Vascular Systemic vasculi*s

Dermatologic Lichen planus

Porphyria cutanea tarda

Musculoskeletal Arthralgia Myalgia

Peripheral neuropathy Inflammatory polyarthri*s




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HCV Cure Reduces All-Cause Mortality

•  Long-‐term follow-‐up study of 530 pts with chronic HCV infec/on and advanced fibrosis or cirrhosis –  HCV treatment 1990-‐2003 –  Follow-‐up median 8.4 yrs

(IQR: 6.4-‐11.4) •  Main outcome: all-‐cause mortality

–  Secondary outcomes: liver failure, HCC, liver-‐related mortality, transplanta/on

•  10-‐year cumula/ve incidence of all outcome measures decreased with SVR

van der Meer AJ, et al. JAMA. 2012;308:2584-2593.

Virus profile SVR

HCV-2 80-95% EASY-TO-TREAT

HCV-3 low viremia 75-80%

HCV-3 high viremia 60-70%

HCV-4 50-60%

HCV-1 low viremia 50%

HCV-1 high viremia 30-35% DIFFICULT-TO-TREAT

Peg-IFN/RBV – SVR responses




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SVR according to baseline Viral Load, fibrosis staging, IL28b genotype

IDEAL Study – SVR rates IL28b

CC CT TT

OVERALL 69% 33% 27%

HCV RNA < 600,000 / METAVIR F0-‐F2 86% 63% 52%

HCV RNA < 600,000 / METAVIR F3-‐F4 63% 25% 0%

HCV RNA > 600,000 / METAVIR F0-‐F2 70% 29% 23%

HCV RNA > 600,000 / METAVIR F3-‐F4 37% 21% 12%

Testing for IL28b performed in 1604/3070 pts (52%)

HCV Terapia – Principali problemi irrisolti

SV

R%




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N Engl J Med. 2011 Mar 31;364(13):1272-4.

# 28%

# 49%

# 31%

# 45%




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…previr

…asvir

…buvir

IFN-free combinations approved in Europe

RBV RBV

NS5A inhibitor NS5B inhibitor (Nucl. or non nucl.) Protease inhibitor

Ledipasvir or Daclatasvir Sofosbuvir Simeprevir Sofosbuvir

Paritaprevir/ ritonavir

Ombitasvir

Dasabuvir




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NS5A inhibitor

NS5B inhibitor (Nucl. or Non Nucl.)

Protease inhibitor

…. near future ….

Elbasvir NS5A inh

MK 3682 Polym.inh

Grazoprevir Protease inh

Daclatasvir NS5A inh

Asunaprevir Protease inh

Beclabuvir Polym.inh

Sofosbuvir Polym inh

GS 5816 Velpatasvir NS5A inh

ABT-‐530 NS5A inh

ABT-‐493 Protease inh

MK 8408 NS5A inh

GS-‐9857 Protease inh

EMA Approved IFN-free Regimens for HCV Treatment

Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir (± RBV)

Sofosbuvir + Simeprevir (± RBV)

Sofosbuvir + Daclatasvir (± RBV)

Ombitasvir/Paritaprevir/Ritonavir (± RBV)

Sofosbuvir + Velpatasvir (± RBV)

Grazoprevir + Elbasvir (± RBV)

Sofosbuvir + RBV

Sofosbuvir/Ledipasvir (± RBV)

GT

1

1, 4

All

4

1, 4

2, 3

1, 4, 5, 6

All coming soon

coming soon




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Large Real-world Data Confirm Clinical Trial Results 16,236 HCV-1 Patients

McCombs et al; McGinnis et al; Afdhal et al; Aghemo et al; Marinho et al; Crespo et al; Calleja et al; Mauss et al, ILC2016 Barcelona

No impact of HIV, HBV, diabetes and obesity on SVR

Following the EASL guidelines (93% vs 87%)

Hypo Alb < 35g/l nega/ve predictor of SVR

Nb=2363/4104/773 103/208/13 1378 872343/73/42 1504/1422 284/1836/390/528

hepcoalition.org

HCV Treatment Prices and Access Restrictions in Western Europe




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HCV patients

F0 F1 F2

S*ffness <10 kpa

F3 F4

S*ffness >10 kpa

HCV patients

F0 F1 F2

S*ffness <10 kpa

F3 F4

S*ffness >10 kpa




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EASL Recommendations on Treatment of Hepatitis C 2016

§  All treatment-‐naive and treatment-‐experienced pa/ents with compensated or decompensated chronic liver disease due to HCV must be considered for therapy (A1).

§  Treatment should be considered without delay in pa/ents with significant fibrosis or cirrhosis (METAVIR score F2, F3 or F4), …… (A1).

§  Treatment is not recommended in pa/ents with limited life expectancy due to non-‐liver-‐related comorbidi/es (B2).

Indications for treatment: who should be treated?

Registro Nazionale delle Coagulopa*e Congenite. Rapporto 2011 Francesca Abbonizio (a), Adele Giampaolo (a), Romano Arcieri (b, c), Hamisa Jane Hassan (a), e Associazione Italiana Centri Emofilia (AICE)

(a) Dipar8mento di Ematologia, Oncologia e Medicina Molecolare, Is8tuto Superiore di Sanità, Roma (b) Dipar8mento del Farmaco, Is8tuto Superiore di Sanità, Roma (c) Federazione delle Associazioni Emofilici, Milano

205 HIV coinfetti




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Haemophilia and Hepatitis C Infection

33%

Fransen van de Putte et al, Journal of Hepatology 2014 vol. 60 j 39–45




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Fransen van de Putte et al, Journal of Hepatology 2014 vol. 60 j 39–45

Data involving 824 haemophilic HCV-‐infected pa/ents treated with IFN plus ribavirin were collected from 18 ar/cles (14 prospec/ve cohort studies, 1 retrospec/ve study and 3 randomized controlled trials)




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Data involving 824 haemophilic HCV-‐infected pa/ents treated with IFN plus ribavirin were collected from 18 ar/cles (14 prospec/ve cohort studies, 1 retrospec/ve study and 3 randomized controlled trials)

These results were comparable to those observed in the general popula/on of HCV treated pa/ents. As observed in non-‐haemophilic pa/ents, genotype 1 (OR, 0.15; 95% CI, 0.09 – 0.25) and HIV-‐1 co-‐infec/on (OR, 0.25; 95% CI, 0.08 – 0.81) were strong predictors of worse response to IFN therapy. In conclusion, this meta-‐analysis documents that chronic hepa//s C in haemophiliacs has a behaviour similar to that in non-‐haemophilic pa/ents both in terms of response to ribavirin plus IFN therapy and in terms of nega/ve predictors of IFN therapy efficacy. The heterogeneity of treatment effect was explained by HCV genotype, HIV infec/on status and, to a lesser extent, to the type of IFN used.




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Walsh C et al. Presented at AASLD: The Liver Meeting®, November 13–17, 2015, San Francisco, CA

120 patients





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GT1 GT2 GT3





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Stedman CA et al. Hemophilia. 2016 Mar; 22 (2), 214-‐217




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Stedman CA et al. Hemophilia. 2016 Mar; 22 (2), 214-‐217

Virologic response All pa/ents experienced rapid viral suppression ader ini/a/ng treatment and all 14 (100%, 95% CI: 77– 100%) achieved both SVR4 and SVR12. No pa/ent in this cohort experienced virologic failure during treatment and no pa/ent had experienced virologic relapse by pos[reatment week 24.




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Study Design

Hezode C, et al. 51st EASL; Barcelona, Spain; April 13-17, 2016. Abst. SAT-128


Demographics




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SVR12: Primary Efficacy Analysis Immediate Treatment Group, Full Analysis Set

LTFU= Lost to follow up / Early discontinuation due to reasons other than virologic failure mFAS = Modified Full Analysis Set


Resistance Associated Variants in Patients with HCV G1A Infection

Prevalence of NS3 RAVs at Baseline Prevalence of NS5A RAVs at Baseline




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Characteristics of Patients with Virologic Failure: All Relapses

Relapse pa*ents generally had baseline viral load >2M IU/mL and NS5A RAVs at baseline


Adverse Events – Liver Enzymes – On-Treatment Hemoglobin Levels




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Conclusions


Treatment of special groups

Bleeding disorders The management of chronic hepa//s C in haemophilia is similar to the non-‐haemophilic popula/on and HCV DAAs are applicable to pa/ents with haemophilia. In a study with the fixed-‐dose combina/on of grazoprevir and elbasvir administered for 12 weeks without ribavirin, SVR12 was achieved in 91% (42/46) of pa/ents with von Willebrand disease or haemophilia A or B. [144]

Over 100 liver transplants have been carried out in haemophilic pa/ents worldwide. Factor VIII/IX concentrate is administered immediately before the surgery, either by bolus injec/on or con/nuous infusion, and for the immediate post-‐opera/ve period for 12–48 h, ader which no further concentrate is required. Coinfec/on with HIV/HCV is not a contraindica/on to liver transplanta/on in haemophilia. The indica/ons for liver transplanta/on in humans with haemophilia are the same as non-‐haemophilic individuals, but the procedure has the major advantage of producing a phenotypic cure of the haemophilia as a result of factor VIII produc/on by the transplanted liver.




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Bleeding disorders The management of chronic hepa//s C in haemophilia is similar to the non-‐haemophilic popula/on and HCV DAAs are applicable to pa/ents with haemophilia. In a study with the fixed-‐dose combina/on of grazoprevir and elbasvir administered for 12 weeks without ribavirin, SVR12 was achieved in 91% (42/46) of pa/ents with von Willebrand disease or haemophilia A or B. [144]

Over 100 liver transplants have been carried out in haemophilic pa/ents worldwide. Factor VIII/IX concentrate is administered immediately before the surgery, either by bolus injec/on or con/nuous infusion, and for the immediate post-‐opera/ve period for 12–48 h, ader which no further concentrate is required. Coinfec/on with HIV/HCV is not a contraindica/on to liver transplanta/on in haemophilia. The indica/ons for liver transplanta/on in humans with haemophilia are the same as non-‐haemophilic individuals, but the procedure has the major advantage of producing a phenotypic cure of the haemophilia as a result of factor VIII produc/on by the transplanted liver.




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Anticoagulant, Anti-platelet and Fibrinolytic




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Riunione Annuale Neo Gr.E.Ca.S Reggio Calabria Hotel Excelsior 16-‐17 Dicembre 2016




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The WHO Viral Hepatitis Elimination Goals

By 2030: 90% chronic HCV diagnosed 80% treated 65% mortality reduc/on Treatment-‐as-‐preven*on: People who inject drugs (PWID) HIV + men who have sex with men (MSM)




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Criterio Tipologia di paziente

1

Pazien/ con cirrosi in classe di Child A o B e/o con HCC con risposta completa a terapie rese=ve chirurgiche o locoregionali non candidabili a trapianto epa/co nei quali la mala=a epa/ca sia determinante per la prognosi

2 Recidiva di epa/te dopo trapianto di fegato con fibrosi METAVIR ≥ F2 (o corrispondente Ishack) o fibrosante colesta/ca

3 Epa/te cronica con gravi manifestazioni extra-‐epa/che HCV correlate (sindrome crioglobulinemica con danno d'organo, sindromi linfoprolifera/ve a cellule B)

4 Epa/te cronica con fibrosi METAVIR ≥ F3 (o corrispondente Ishack)

5 In lista per trapianto di fegato con cirrosi MELD <25 e/o con HCC all'interno dei criteri di Milano con la possibilità di una a[esa in lista di almeno 2 mesi

6 Epa/te cronica dopo trapianto di organo solido (non fegato) o di midollo con fibrosi METAVIR ≥2 (o corrispondente Ishack)

7 Epa/te cronica con fibrosi METAVIR F0-‐F2 (o corrispondente Ishack)

Negro F. Diges/ve and Liver Disease 46 (2014) S158–S164

Although before 1990 the risk of transmi=ng HCV via blood transfusions was significant (0.45% per unit transfused) [19], the introduc/on of screening assays reduced this risk to less than 1 per 1,000,000 units of blood [20], and the transmission of HCV via other blood products and even organ transplanta/on has been reduced to zero. Similarly, the prevalence of HCV in haemophiliacs has been tradi/onally very high [21] , but ader the introduc/on of recombinant clo=ng factors new cases of HCV in haemophiliacs have become excep/onal [22].




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Haemoglobinopathies The most frequent haemoglobinopathy associated with chronic hepa//s C is thalassemia major, which requires frequent blood transfusions and is prevalent in countries where blood supply screening may be, or has been, subop/mal. Chronic HCV infec/on is also frequent in individuals with sickle cell anaemia or thalassemia, with a more rapid course of liver disease because of the concurrent iron overload [143]. Treatment has oden been withheld in these pa/ents because both pegylated IFN-‐a and ribavirin can cause anaemia. Few trials with an/viral therapy have been published in this popula/on, but there is no reason to consider that HCV DAAs are specifically contraindicated. For instance, in the C-‐EDGE IBLD study, the fixed-‐dose combina/on of grazoprevir and elbasvir was administered for 12 weeks without ribavirin in pa/ents with haemoglobinopathies infected with genotypes 1a, 1b or 4. Approximately one pa/ent out of four had cirrhosis. Pa/ents with a haemoglobin level <7 g/dL were excluded. SVR12 was achieved in 95% (18/19) of pa/ents with sickle cell anaemia and in 98% (40/41) of pa/ents with b-‐thalassemia [144]. On treatment, haemoglobin levels were maintained. Thus, IFN-‐free, ideally ribavirin-‐free drug regimens should be used in these pa/ents because they have the great advantage of not aggrava/ng the anaemia. Sofosbuvir-‐based studies in this group are in progress.



Haemoglobinopathies The most frequent haemoglobinopathy associated with chronic hepa//s C is thalassemia major, which requires frequent blood transfusions and is prevalent in countries where blood supply screening may be, or has been, subop/mal. Chronic HCV infec/on is also frequent in individuals with sickle cell anaemia or thalassemia, with a more rapid course of liver disease because of the concurrent iron overload [143]. Treatment has oden been withheld in these pa/ents because both pegylated IFN-‐a and ribavirin can cause anaemia. Few trials with an/viral therapy have been published in this popula/on, but there is no reason to consider that HCV DAAs are specifically contraindicated. For instance, in the C-‐EDGE IBLD study, the fixed-‐dose combina/on of grazoprevir and elbasvir was administered for 12 weeks without ribavirin in pa/ents with haemoglobinopathies infected with genotypes 1a, 1b or 4. Approximately one pa/ent out of four had cirrhosis. Pa/ents with a haemoglobin level <7 g/dL were excluded. SVR12 was achieved in 95% (18/19) of pa/ents with sickle cell anaemia and in 98% (40/41) of pa/ents with b-‐thalassemia [144]. On treatment, haemoglobin levels were maintained. Thus, IFN-‐free, ideally ribavirin-‐free drug regimens should be used in these pa/ents because they have the great advantage of not aggrava/ng the anaemia. Sofosbuvir-‐based studies in this group are in progress.




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17/10/16 · terapie per l’epa*te C nei ... Life Expectancy in Patients With Chronic HCV Infection...

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