Epatopatia croniche a eziologia virale:HCV-HBV ma non solo

Barbara Menzaghi

Criterio 1: Pazienti con cirrosi in classe di Child A o B e/o con HCC con risposta completa a terapie resettive chirurgiche o loco-regionali non candidabili a trapianto epatico nei quali la malattia epatica sia determinante per la prognosi.Criterio 2: Epatite ricorrente HCV-RNA positiva del fegato trapiantato in paziente stabile clinicamente e con livelli ottimali di immunosoppressione.Criterio 3: Epatite cronica con gravi manifestazioni extra-epatiche HCV-correlate (sindrome crioglobulinemica con danno d'organo, sindromi linfoproliferative a cellule B, insufficienza renale).Criterio 4: Epatite cronica con fibrosi METAVIR F3 (o corrispondente Ishak).Criterio 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 attesa in lista di almeno 2 mesi.Criterio 6: Epatite cronica dopo trapianto di organo solido (non fegato) o di midollo in paziente stabile clinicamente e con livelli ottimali di immunosoppressione.Criterio 7: Epatite cronica con fibrosi METAVIR F2 (o corrispondente Ishak) e/o comorbilità a rischio di progressione del danno epatico [coinfezione HBV, coinfezione HIV, malattie croniche di fegato non virali, diabete mellito in trattamento farmacologico, obesità (body mass index ≥30 kg/m2), emoglobinopatie e coagulopatie congenite].Criterio 8: Epatite cronica con fibrosi METAVIR F0-F1 (o corrispondente Ishak) e/o comorbilità a rischio di progressione del danno epatico [coinfezione HBV, coinfezione HIV, malattie croniche di fegato non virali, diabete mellito in trattamento farmacologico, obesità (body mass index ≥30 kg/m2), emoglobinopatie e coagulopatie congenite].Criterio 9: Operatori sanitari infetti.Criterio 10: Epatite cronica o cirrosi epatica in paziente con insufficienza renale cronica in trattamento emodialitico.Criterio 11: Epatite cronica nel paziente in lista d'attesa per trapianto di organo solido (non fegato) o di midollo.

AGENZIA ITALIANA DEL FARMACO DETERMINA 24 marzo 2017 Ridefinizione dei criteri di trattamento per la terapia dell'Epatite C cronica.

(Determina n. 500/2017). (17A02374) (GU n.75 del 30-3-2017)

Hepatitis C

• Not only a liver disease

• What HCV “cure” means…..

• Treatment options

HCV and Liver Disease

Liver

Chronic HCV Infection Also Causes Extrahepatic Manifestations

Endocrine

Thyroid disease

Diabetes mellitus

Hematologic

Mixed cryoglobulinemia

Lymphoproliferative disorders

Thrombocytopenia

Renal

Membranoproliferative

glomerulonephritis

Ocular

Corneal ulcers

Sjögren syndrome

Vascular

Systemic vasculitis

Dermatologic

Lichen planus

Porphyria cutanea tarda

Musculoskeletal

Arthralgia

Myalgia

Peripheral neuropathy

Inflammatory polyarthritis

130─160 Million Chronic HCV Carriers Are at Risk of Developing Cirrhosis and/or HCC1,2

Within 20 years

1. World Health Organization. Media Centre: Hepatitis C. April 2014. http://www.who.int/mediacentre/factsheets/fs164/en/. Accessed May 20,

2014.

2. World Health Organization. Guidelines for the screening, care and treatment of persons with hepatitis C infection. April 2014. 2002.

http://www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/. Accessed May 20, 2014.

Acute

infection

Spontaneous

clearance

(15%-45%)

Chronic

infection

(55%-85%)

Mild fibrosis

Moderate to

severe

fibrosis

Cirrhosis

(15%-30%)

Decompensated cirrhosis

Hepatocellular carcinoma

(2%-4% per year in cirrhosis)

HCV Host

Therapy

0

1

2

3

4

5

6

7

8

Lee et Al. J Infect Dis 2012; 206: 469-477

Is HCV more than a liver disease?Increased mortality “beyond” the liver

The REVEAL cohort study

All causes Extrahepatic Circulatory Nephritic Oesophageal Prostate Thyroiddiseases diseases Nephrotic cancer cancer cancer

Ad

juste

dH

aza

rdR

atio

fo

r D

ea

th

2.201.90-2.55

(p=0.0001)1.47

1.47-1.77(p=0.0002)

1.531.53-2.33

(p=0.0026)

2.981.43-6.22

(p=0.0032)

5.861.98-17.35(p=0.0014)

5.831.64-20.77(p=0.0065)

7.0710.73-68.35

(p=0.09)

Hazard ratio reference value:

1 for HCV negative in each disease cathegory

What about HCV infection and

Cardiovascular Diseases?

2014 April 7; 20(13): 3410-3417

Studies on the association

between HCV and atherosclerosis

2014 April 7; 20(13): 3410-3417

Studies on the association

between HCV and cardiac

diseases

2014 April 7; 20(13): 3410-3417

Studies on the association

between HCV and stroke

Pathogeneic mechanisms associated with the development of atherosclerosis

in chronic HCV infection

2014:8(s3) 1-5

Several factors might mediate the link between HCV infection and

atherogenesis: disrupted iron homeostasis,

increased oxidative stress,

induction of hepatic steatosis leading to aggravated insulin sensitivity and

other related metabolic abnormalities,

activation of immunological and/or inflammatory processes and

associated cytokine imbalance,

in situ viral replications.

There may be receptors for HCV entry in cerebrovascularendothelial cells, and HCV RNA has been observed in brain tissue from infected individuals1 and HCV RNA was presentwithin carotid plaques2. 1. Fletcher NF, et al. Gastroenterology. 2012;142(634–43) 2. Boddi M, et al.. J Clin Virol. 2010;47:72–5.

P <.0001

Risk of coronary artery disease (CAD) in HCV–infected and HCV-uninfected subjects

82,083 HCV-infected and 89,582 HCV-uninfected subjects in Veteran Affairs Cohort

Butt AA et sl., Clin Infect Dis. 2009 Jul 15;49(2):225-32

N° 82,083

N° 89,582

Hepatitis viruses - Liver - Kidney

Possible contraindication

for kidney transplantation

Etiologic factors for

Liver disease

HCVHBV

Chronic Hepatitis

Cirrhosis

Role in the pathogenesis

of kidney disease

Participants with undetectable or low HCV-RNA had similar odds of

progressive CKD as HCV seronegative, while participants with HCV-RNA

800,000 IU/ml had increased odds (OR 3.07; 95% CI 1.60–5.90).

Mocroft A et al., PLoSOne 2012; 7(7):e40245

Implications of HCV Infection for Behavioral Symptoms and Activities of Daily Living

Posada C et al., J Clin Exp Neuropsychol. 2010 July ; 32(6): 637–644

FatigueDepression

AnxietyBipolar

disordersSchizophrenia

Cognitive impairment

Higher incidenceof risk behaviorsamong HCV infectedpopulation

Advanced liverdisease maycontribute to some symptoms

Alcohol abuse

However, the majority of these symptoms:• does not appear to be related to the severity of liver disease, but

with the presence of HCV infection; • are more severe in HCV as compared to HBV or PBC patients• improves with the clearance of the infection

HCV and Neuro-psychiatric symptoms

Monaco S et al, WJG 2015; Negro F et al Gastroenterology 2015

HCV and Neuro-psychiatric symptoms

• Fatigue, sleep disturbance, depression and reducedquality of life are commonly associated with

neurocognitive alterations in patients with non-cirrhotic chronic HCV infection, regardless of the stage of liver fibrosis and the infecting genotype.

• These manifestations typically occur in the absence ofstructural brain damage or signal abnormalities on

conventional brain magnetic resonance imaging(MRI), although metabolic and microstructuralchanges can be detected by in vivo protonmagnetic resonance spectroscopy, perfusion-

weighted and diffusion tensor MRI, and neurophysiological tests of cognitive processing.

Monaco S et al, WJG 2015

Quantification and localization of brain metabolite concentrations in HCV patients exhibiting neuropsycological and neurocognitive dysfunction show at

proton magnetic resonance spectroscopy abnormalities at cortical and subcortical telencephalic areas

These findings suggest the presence of brain dysfunction that may be due toneuroinflammation, cerebral immune activation

HCV could directly penetrate into CNS with microglia activation or peripheralinflammation (citokines) could influence CNS by crossing the blood brain

barrier Monaco S et al, WJG 2015; Negro F et al Gastroenterology 2015

A strong effect of HCV infection on insulin pathway-

related gene and protein expression was found in vitro.

These results could lead to the identification of new

therapeutic targets in HCV infection and its co-

morbidities.

October 2012 | Volume 7 | Issue 10

Diabetes mellitus is an independent prognostic

factor for major liver-related outcomes in patients

with cirrhosis and chronic hepatitis C

Elkrief L, 2014

HCV and LPDs:

factors influencing the risk of progression

MCS (III/II)/MGUS

Lymphoma

CGs/RF…

1. Genetically determined modulation of

-immune response to HCV antigens

-autoreactivity triggered by HCV

2. Viral factors

3. Environmental factors

The replication of HCV in the extrahepatic organs

and, especially, lymphoid cells, might affect the

pathogenesis of extrahepatic diseases with HCV

infection. HCV persistent infection can cause

malignant lymphoma.

Most patients with HCV-associated lymphomapresent with mild liver disease: a call to revise

antiviral treatment prioritization

89 patients with HCV-NHL.Genotype 1 (62%), Diffuse large B cell lymphomas (62%)Detectable HCV RNA (90%) at NHL diagnosis.

Advanced liver disease (Metavir stage ≥ 3) in only 18% of the patients at the time of HCV-NHL diagnosis. In 53 patients chronic HCV infectiondocumented before lymphoma diagnosis

AVT not recommend in 44%,

Torres HA et al. Liver Int. 2015; 35: 1661–1664

Not Treated

44%

HCV HCV

Unknown Diagnosed

40% 60%

Because of the lackof advanced liverdisease at HCV diagnosis: 38%

Natural history of HIV infection

Pantaleo G et al., NEJM, 1993; High KP, et al., JAIDS, 2012

A RR 1.75p <0.0001*

0

2

4

6

8

10

12

HIV+ HIV-

Even

ts P

er 1

00

0 P

Ys

B

0

20

40

60

80

100

18-34 35-44 45-54 55-64 65-74

Age Group (Years)

Triant V et al. J Clin Endocrinol Metab 2007; 92: 2506-2512

* Adjusted for age, gender, race, hypertension, diabetes and dyslipidaemia. Proportion of patients with hypertension, diabetes and dyslipidaemia significantly higher in HIV-positive vs HIV-negative cohort

n = 1,044,589

n = 3,851

# of MI 189 26,142Ev

ents

Per

10

00

PYs

Incidence of myocardial infarction (MI): BWH/MGH Boston

HIV is an independent risk factor for renal impairment

HIV is an independent risk factor for renal impairment1,2

HIV-related factors, such as:HIV viral loadLow CD4+ cell countDirect effects of some antiretroviral therapy are also risk factors3,4

1. Gupta et al. Guidelines for the Management of Chronic Kidney Disease in HIV-Infected Patients: Recommendations of the HIV Medicine Association of the Infectious. Diseases Society of

America.CID 2005;40:1,559–85. Review Paper

2. Overton. Factors associated with renal dysfunction within an urban HIV-infected cohort in the era of highly active antiretroviral therapy.

HIV Med. 2009 Jul;10(6):343-50. Epub 2009 Mar 11. Cohort Study. N = 845 HIV + Patients

3. Winston. HIV and CKD epidemiology. Adv Chronic Kidney Dis. 2010 Jan;17(1):19-25. Review Paper

4. Sorli et al. Chronic Kidney Disease Prevalence and Risk Factors Among Human Immunodeficiency Virus–Infected Patients J Acquir Immune Defic Syndr 48 (4) August 1, 2008. Cross-

Sectional Study. N = 854

Prevalence of osteoporosis is higher in HIV+ patients than the general population

The prevalence of osteoporosis in HIV+ patients is > 3.5 times greater

than in uninfected controls

Odds ratio = odds of osteoporosis (T-score ≤ -2.5) in HIV-infected patients vs HIV-uninfected controls.

Brown TT, et al. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS. 2006;20(17):2165-74. A meta-analytic review of cross sectional

studies. N = 1,554 (including 884 HIV+ patients)

59 year old man less

“robust” than father

Gross G. AIDS Patients Face Downside of

Living Longer. NY Times. Jan 6, 2008

France D. Another Kind of AIDS Crisis.

New York. Nov 1, 2009

HIV associated with multiple

morbidities of aging

There is even a concern in the popular press that HIV “accelerates” aging

Hepatitis C

• Not only a liver disease

• What HCV “cure” means…..

• Treatment options

All treatment-naïve and treatment-experienced

patients with compensated or decompensated

chronic liver disease due to HCV should be

considered for therapy (recommendation A1)

EASL: Indications for treatment:

who should be treated?

METAVIR

F3–F4

Prioritise

treatment

A1 A2

METAVIR

F2

Treatment is

justified

METAVIR

F0–F1

Individualise

treatment

B1

Decompensated

cirrhosis

Urgently treated

IFN-free therapy

A1

1) Pazienti con cirrosi in classe di Child A o B e/o con epatocarcinoma con

risposta completa a terapie resettive chirurgiche o loco-regionali non

candidabili a trapianto epatico nei quali la malattia epatica sia determinante

per la prognosi

2) Recidiva di epatite dopo trapianto di fegato con fibrosi METAVIR1 ≥2 (o

corrispondente Ishack) o fibrosante colestatica

3) Epatite cronica con gravi manifestazioni extra-epatiche HCV-correlate

(sindrome crioglobulinemica con danno d'organo, sindromi linfoproliferative

a cellule B)

4) Epatite cronica con fibrosi METAVIR ≥3 (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 attesa in lista di almeno 2 mesi

6) Epatite cronica dopo trapianto di organo solido (non fegato) o di midollo

con fibrosi METAVIR ≥2 (o corrispondente Ishack).

7) Pazienti con epatite cronica con fibrosi METAVIR F0-F2 (o corrispondente

Ishak)

Categorie di pazienti affetti da epatite C cronica ammesse alla rimborsabilità in Italia

Factors Associated With Increased Risk Of Secondary Outcomes In Patients With HCV

McCombs, JAMA Intern Med 2014;174:204–212

Characteristic Cirrhosis HCCLiver related

Hospitalization

(n=123,988) (n=128,481)

Male gender 1.35 (1.21–1.50) 3.41 (2.39–4.88) 1.09 (1.01-1.17)

Age 1.02 (1.02–1.02) 1.07 (1.07–1.07) 0.99 (0.99-0.99)

Race White

Black

Other

1 (reference)

0.54 (0.52–0.56)

0.73 (0.70–0.76)

1 (reference)

0.73 (0.68–0.78)

0.80 (0.74–0.87)

1 (reference)

0.74 (0.72-0.76)

0.58 (0.56-0.60)

HCV genotype

1

2

3

Other

1 (reference)

0.64 (0.61–0.68)

1.24 (1.18–1.31)

0.87 (0.75–1.00)

1 (reference)

0.52 (0.46–0.58)

1.63 (1.47–1.79)

0.77 (0.57–1.04)

1 (reference)

0.80 (0.76-0.83)

1.10 (1.05-1.15)

0.89 (0.79-0.99)

Diabetes 1.38 (1.32–1.44) 1.31 (1.21–1.42) 1.19 (1.15-1.24)

Undetectable

HCV-RNA0.62 (0.54–0.73) 0.62 (0.42–0.81) 0.71 (0.63-0.80)

Cum

ulat

ive r

ates

of inc

idenc

eof

lym

phom

a(%

)

0

1

3

0 5 10 15

Years

Persistent Infection (n=2161)SVR (n=1048)

HCV Elimination Reduces The Incidence of Malignant Lymphoma

Follow-up duration (years)

2

4

0.36%

1.49%

0%0%

2.56%

0%

Log-rank test p=0.0159

Kawamura Y, et al. Am J Med 2007;120:1034-1041

Cumulative incidence of ischemic stroke, ESRD and acute coronary event in three study cohorts of

diabetic patientsModified log rank test with death adjusted as a competing risk event.

Hsu YC et al. HEPATOLOGY 2014;59:1293-1302

Antiviral therapy for concomitant HCV

infection is associatedwith improved renal and cardiovascular outcomes

in patients with DM

ESRDISCHEMIC

STROKE

ACUTE CORONARY

EVENT

Hepatitis C

• Not only a liver disease

• What HCV “cure” means…..

• Treatment options

What do we need….

• The most cost-effective treatment

–Short

–Effective

–Safe

CRITIERI DI PROGRAMMAZIONE DEL TRATTAMENTO PAZIENTI HCV IN REGIONE

LOMBARDIA

La presente nota ribadisce che secondo i criteri pubblicati recentemente da AIFA tutti i pazienti affetti da epatite cronica C (HCV-RNA rilevabile) devono essere trattati quale che sia il grado DI

fibrosi epatica

Nella programmazione del trattamento i clinici sono invitati ad avvalersi di quanto sotto suggerito

1

URGENZA CLINICA

(inizio rapido del trattamento nel soddisfacimento criteri AIFA 1,2,3,5,6) :

• criterio 1: pazienti con cirrosi in classe di Child A o B e/o con HCC con risposta completa a

terapie resettive chirurgiche o loco-regionali non candidabili a trapianto epatico nei quali

la malattia epatica sia determinante per la prognosi;

• criterio 2: epatite ricorrente HCV-RNA positiva del fegato trapiantato in paziente stabile

clinicamente e con livelli ottimali di immunosoppressione;

• criterio 3: epatite cronica con gravi manifestazioni extra-epatiche HCV-correlate

(sindrome crioglobulinemica con danno d'organo, sindromi linfoproliferative a cellule B,

insufficienza renale);

• criterio 5: in lista per trapianto di fegato con cirrosi MELD <25 e/o con HCC all'interno dei criteri

di Milano con la possibilita' di una attesa in lista di almeno due mesi;

• criterio 11: epatite cronica nel paziente in lista d'attesa per trapianto di organo solido (non

fegato) o di midollo,

• Condizioni di urgenza clinica non incluse nei criteri sopraesposti, identificate dal singolo clinico,

secondo scienza e coscienza

Nella programmazione del trattamento i clinici sono invitati ad avvalersi di quanto sotto suggerito

2

ACCESSO CONVENZIONALE ALLA TERAPIA

SI FA RIFERIMENTO AI SOTTELENCATI CRITERI AIFA

• CRITERIO 4, Epatite cronica con fibrosi metavir F3 (o corrispondente Ishak)

• CRITERIO 7, Epatite cronica con fibrosi METAVIR F2 (o corrispondente Ishak) e/o comorbilita' a

rischio di progressione del danno epatico [coinfezione HBV, coinfezione HIV, malattie croniche di

fegato non virali, diabete mellito in trattamento farmacologico, obesita' (body mass index ≥30

kg/m2), emoglobinopatie e coagulopatie congenite]

• CRITERIO 8. Epatite cronica con fibrosi METAVIR F0-F1 (o corrispondente Ishak) e/o comorbilita' a

rischio di progressione del danno epatico [coinfezione HBV, coinfezione HIV, malattie croniche di

fegato non virali, diabete mellito in trattamento farmacologico, obesita' (body mass index ≥30

kg/m2), emoglobinopatie e coagulopatie congenite]

• CRITERIO 9. Operatori sanitari infetti

• CRITERIO 10. Epatite cronica o cirrosi epatica* in paziente con insufficienza renale cronica in

trattamento emodialitico

*il pz cirrotico rientra nei criteri d’urgenza