CRIOGLOBULINEMIA MISTA E LINFOMI NELLrsquoERA DEI DAAsDI II GENERAZIONE

Anna Linda Zignego

Eur J Gastroenterol Hepatol 2017

MC in the setting of HCV-related pathologies a typically female disease

Direct medical costs of extrahepatic manifestations of HCV in USA

Younossi et al

Evaluation of the annual costs (inpatientoutpatient and pharmacy) associated withextrahepatic manifestations of HCV

Total direct medical costs of extrahepaticmanifestations of HCV in 2014 US dollars were

estimated to be $1506 million (range $922 millionndash$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of disease to obtain a more

accurate assessment of the total burden of HCVinfection

Direct medical costs of extrahepatic manifestations of HCV in EUROPE

ISG-EHCV

Ferri C Ramos-Casals M Zignego AL et al Autoimmun Rev 2016

Eur J Gastroenterol Hepatol 2017

MC in the setting of HCV-related pathologies a typically female disease

Direct medical costs of extrahepatic manifestations of HCV in USA

Younossi et al

Evaluation of the annual costs (inpatientoutpatient and pharmacy) associated withextrahepatic manifestations of HCV

Total direct medical costs of extrahepaticmanifestations of HCV in 2014 US dollars were

estimated to be $1506 million (range $922 millionndash$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of disease to obtain a more

accurate assessment of the total burden of HCVinfection

Direct medical costs of extrahepatic manifestations of HCV in EUROPE

ISG-EHCV

Ferri C Ramos-Casals M Zignego AL et al Autoimmun Rev 2016

MC in the setting of HCV-related pathologies a typically female disease

Direct medical costs of extrahepatic manifestations of HCV in USA

Younossi et al

Evaluation of the annual costs (inpatientoutpatient and pharmacy) associated withextrahepatic manifestations of HCV

Total direct medical costs of extrahepaticmanifestations of HCV in 2014 US dollars were

estimated to be $1506 million (range $922 millionndash$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of disease to obtain a more

accurate assessment of the total burden of HCVinfection

Direct medical costs of extrahepatic manifestations of HCV in EUROPE

ISG-EHCV

Ferri C Ramos-Casals M Zignego AL et al Autoimmun Rev 2016

Direct medical costs of extrahepatic manifestations of HCV in USA

Younossi et al

Evaluation of the annual costs (inpatientoutpatient and pharmacy) associated withextrahepatic manifestations of HCV

Total direct medical costs of extrahepaticmanifestations of HCV in 2014 US dollars were

estimated to be $1506 million (range $922 millionndash$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of disease to obtain a more

accurate assessment of the total burden of HCVinfection

Direct medical costs of extrahepatic manifestations of HCV in EUROPE

ISG-EHCV

Ferri C Ramos-Casals M Zignego AL et al Autoimmun Rev 2016

Direct medical costs of extrahepatic manifestations of HCV in EUROPE

ISG-EHCV

Ferri C Ramos-Casals M Zignego AL et al Autoimmun Rev 2016

ISG-EHCV

Ferri C Ramos-Casals M Zignego AL et al Autoimmun Rev 2016

1465

496717

Total Piter cohort no 8005 subjects the presence of MC was never tested in 80 ofcases in spite of its clinical and therapeutical importance Among the centres thatconsidered MC=-64 evaluated cryoglobulinemia only following a clinical suspicion-58 evaluated routinely cryoglobulinemia at admission with Complement RF levels-42 only in case of RF positivity-Cryo testing was not adequate in 39 of centres

252

These results for the first time showed the real-life variability of the MC diagnosticapproach suggesting that MC prevalence in HCV+ is generally underestimated

Kondili et al Liver Intern2017

CLASSIFICATION OF HCV EHDS ACCORDING TO THE STRENGTH OF SPECIFIC DATA SUPPORTING THE CURATIVE EFFECT OF AVT

Mixed Cryoglobulinemia Effectiveness of both IFN-based and IFN-free AVT

Marginal Zone NHL Effectiveness of both IFN- and DAA-based

AVT

Other low-grade B-cell NHL

HRQOL Available data also in DAA-based AVT

High-grade NHL= DLBCL Insufficient but positive data

CKD Sufficient specific data only for MC-CKD

Neuropsychiatric disorders Problematic IFN-based AVT Insufficient

data with DAAs

Curaneous= PCT and LP (OLP) Problematic IFNRBV-based AVT

Insufficient data with DAAs

Endocrinologic Thyroid and DM 2 Insufficient specific data with DAAs

Arthritis Insufficient specific data with DAAs

Zignego et al 2017

Landau DA et al Arthritis Rheum 2008 Montalbano M et al J Clin Gastroenterol 2007 Cacoub P et al Arthritis Rheum 2002

Mazzaro C et alJ Rheumatol 2003 Zignego AL et al Hepatology 2016 Gragnani L et al Hepatology 2015 Pietrogrande M

et al Autoimmun Rev 2011

Antiviral Treatment (AVT) of MC in the IFN Era

AVT of MC followed the evolution of hepatitis C AVT with frequent adjustments

essentially due to the possible side-effects of IFN andor RBV therapy (ie IFN

neurotoxicity and myelo-inhibitory action and RBV hemolytic effects)

Virological and clinical results progressively improved in spite of frequent side-effects

IFN-based AVT was recommended as the first-line option in mild to moderate MC

Clinical remission was generally correlated with virological response

Long follow-up showed that the majority (57) of SVR pts cleared all MC stigmata

Antiviral Treatment (AVT) of MC IFN-free regimensLimited data so-far concordant are available regarding IFN-free AVT in MC patients

Available data suggest that IFN-free AVT is safe generally well tolerated and effective in MC patients high rate of

clinical response (87) and low rates of serious adverse events was reported

Zignego AL Ramos-Casals M Ferri C et al AutoimmunReviews 2017

Antiviral Treatment (AVT) of MC IFN-free regimens

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical R in 100 (64 CR and 36 PR)

Progression of the small lymphocytic lymphoma

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic MC treated with

DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical R in 1117 (CR in 711) Lower clinical R inseverelife-threatening ndashespecial renal and neurological- vasculitis

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in 100 and

clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse of vasculitis

A case of rapid amelioration of HCV-associated cryoglobulinemic MPGN treated by

IFN-free DAAs for HCV in the absence of immunosuppressant

Fumiaki et al 2017

Zignego et al 2017

TIME POINTS

baseline EOT and week 12 and 24 of post-treatment f-up (SVR12 and SVR24 respectively)

HRQoL EVALUATION THROUGH PROs

the Short Form (36) Health Survey (SF-36)

the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) from which we computed the Trial

Outcome Index (TOI)

Evaluation of The Impact on HRQol of IFN-free AVT In HCV CM

1 Physical Component Summary Score (PCS)

MC (54)

HCV (43) CV (85)

deg

A B C

degdegdeg

2 Mental Component Summary Score (MCS)

MCHCV CVD E F

degdegdegdegdeg

HCV

=plt001 vs baseline scores

degdeg=plt001 and degdegdeg=plt0001 vs EOT scores

Gragnani et al AASLD 2017

HCV Eradicationwith DAAs

To be preceded or combined with non-etiological pathogenetic therapy in severecatastrophic MCS

MCS Therapy in the IFN and DAAs Era from the complex to the simplified flow-chart

Dammacco F Sansonno D NEJM 2013

Zignego AL Pawlotsky JM Cacoub P Antiviral Ther in press Cacoub P et al Am J Med 2015

Mechanisms of HCV-related lymphomagenesis

DLBC HCV- induced

direct transformation

MCindolent NHL

accumulation of B RF

following BCR activation

and BC apoptosisinhibition

Zignego AL Ramos-Casals M Ferri C et al Autoimmun Rev 2017

Wang et al Hepatology 2016 Canioni et al Plos one 2016

Observational study on in situ expression of the oncogenic HCV NS3 protein on 116 HCV patients with B-NHL (DLBCL 36 and MZL 34)

NS3 immunostaining positive in 1214 DLBCL vs only 414 MZL (p = 0006) moreover 24 NS3+ MZL

were enriched in large cells

This study supports a new mechanism of transformation with a direct oncogenic role of

HCV proteins in the occurrence of high-grade B lymphomas

IN SITU HEPATITIS C NS3 PROTEIN DETECTION IS ASSOCIATED WITH HIGH GRADE

FEATURES IN HCV-ASSOCIATED B-CELL NON-HODGKIN LYMPHOMAS Danielle

Canioni et al 2016

In addition to the role of chronic antigenic stimulation in HCV related

lymphomagenesis this study supports a second mechanism of transformation due to a

direct oncogenic role of HCV infection of B-cells promoting the occurrence of high-grade Bcell lymphomas

Cohort study of 704 consecutive HIV-negative HCV-positive patients with indolent NHL from 1993 to

2009 in 39 centers of the FIL

Arcaini et al 2016

DLBC HCV- induced

direct transformation

No place of AVT as

1st line

Need of immediate delivery of

chemotherapy or concomitant (NHL

+ HCV targets)

THERAPY OF HCV+ DLBCL

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDY Michot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell Lymphoma Evan C Ewers et al 2016

absolute neutrophil count and Hgb ALT and HCV viral load

Both complete response and SVR of HCV-associated DLBCL after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-based regimen

CLASSIFICATION OF HCV EHDS ACCORDING TO THE STRENGTH OF SPECIFIC DATA SUPPORTING THE CURATIVE EFFECT OF AVT

Mixed Cryoglobulinemia Effectiveness of both IFN-based and IFN-free AVT

Marginal Zone NHL Effectiveness of both IFN- and DAA-based

AVT

Other low-grade B-cell NHL

HRQOL Available data also in DAA-based AVT

High-grade NHL= DLBCL Insufficient but positive data

CKD Sufficient specific data only for MC-CKD

Neuropsychiatric disorders Problematic IFN-based AVT Insufficient

data with DAAs

Curaneous= PCT and LP (OLP) Problematic IFNRBV-based AVT

Insufficient data with DAAs

Endocrinologic Thyroid and DM 2 Insufficient specific data with DAAs

Arthritis Insufficient specific data with DAAs

Zignego et al 2017

Landau DA et al Arthritis Rheum 2008 Montalbano M et al J Clin Gastroenterol 2007 Cacoub P et al Arthritis Rheum 2002

Mazzaro C et alJ Rheumatol 2003 Zignego AL et al Hepatology 2016 Gragnani L et al Hepatology 2015 Pietrogrande M

et al Autoimmun Rev 2011

Antiviral Treatment (AVT) of MC in the IFN Era

AVT of MC followed the evolution of hepatitis C AVT with frequent adjustments

essentially due to the possible side-effects of IFN andor RBV therapy (ie IFN

neurotoxicity and myelo-inhibitory action and RBV hemolytic effects)

Virological and clinical results progressively improved in spite of frequent side-effects

IFN-based AVT was recommended as the first-line option in mild to moderate MC

Clinical remission was generally correlated with virological response

Long follow-up showed that the majority (57) of SVR pts cleared all MC stigmata

Antiviral Treatment (AVT) of MC IFN-free regimensLimited data so-far concordant are available regarding IFN-free AVT in MC patients

Available data suggest that IFN-free AVT is safe generally well tolerated and effective in MC patients high rate of

clinical response (87) and low rates of serious adverse events was reported

Zignego AL Ramos-Casals M Ferri C et al AutoimmunReviews 2017

Antiviral Treatment (AVT) of MC IFN-free regimens

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical R in 100 (64 CR and 36 PR)

Progression of the small lymphocytic lymphoma

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic MC treated with

DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical R in 1117 (CR in 711) Lower clinical R inseverelife-threatening ndashespecial renal and neurological- vasculitis

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in 100 and

clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse of vasculitis

A case of rapid amelioration of HCV-associated cryoglobulinemic MPGN treated by

IFN-free DAAs for HCV in the absence of immunosuppressant

Fumiaki et al 2017

Zignego et al 2017

TIME POINTS

baseline EOT and week 12 and 24 of post-treatment f-up (SVR12 and SVR24 respectively)

HRQoL EVALUATION THROUGH PROs

the Short Form (36) Health Survey (SF-36)

the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) from which we computed the Trial

Outcome Index (TOI)

Evaluation of The Impact on HRQol of IFN-free AVT In HCV CM

1 Physical Component Summary Score (PCS)

MC (54)

HCV (43) CV (85)

deg

A B C

degdegdeg

2 Mental Component Summary Score (MCS)

MCHCV CVD E F

degdegdegdegdeg

HCV

=plt001 vs baseline scores

degdeg=plt001 and degdegdeg=plt0001 vs EOT scores

Gragnani et al AASLD 2017

HCV Eradicationwith DAAs

To be preceded or combined with non-etiological pathogenetic therapy in severecatastrophic MCS

MCS Therapy in the IFN and DAAs Era from the complex to the simplified flow-chart

Dammacco F Sansonno D NEJM 2013

Zignego AL Pawlotsky JM Cacoub P Antiviral Ther in press Cacoub P et al Am J Med 2015

Mechanisms of HCV-related lymphomagenesis

DLBC HCV- induced

direct transformation

MCindolent NHL

accumulation of B RF

following BCR activation

and BC apoptosisinhibition

Zignego AL Ramos-Casals M Ferri C et al Autoimmun Rev 2017

Wang et al Hepatology 2016 Canioni et al Plos one 2016

Observational study on in situ expression of the oncogenic HCV NS3 protein on 116 HCV patients with B-NHL (DLBCL 36 and MZL 34)

NS3 immunostaining positive in 1214 DLBCL vs only 414 MZL (p = 0006) moreover 24 NS3+ MZL

were enriched in large cells

This study supports a new mechanism of transformation with a direct oncogenic role of

HCV proteins in the occurrence of high-grade B lymphomas

IN SITU HEPATITIS C NS3 PROTEIN DETECTION IS ASSOCIATED WITH HIGH GRADE

FEATURES IN HCV-ASSOCIATED B-CELL NON-HODGKIN LYMPHOMAS Danielle

Canioni et al 2016

In addition to the role of chronic antigenic stimulation in HCV related

lymphomagenesis this study supports a second mechanism of transformation due to a

direct oncogenic role of HCV infection of B-cells promoting the occurrence of high-grade Bcell lymphomas

Cohort study of 704 consecutive HIV-negative HCV-positive patients with indolent NHL from 1993 to

2009 in 39 centers of the FIL

Arcaini et al 2016

DLBC HCV- induced

direct transformation

No place of AVT as

1st line

Need of immediate delivery of

chemotherapy or concomitant (NHL

+ HCV targets)

THERAPY OF HCV+ DLBCL

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDY Michot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell Lymphoma Evan C Ewers et al 2016

absolute neutrophil count and Hgb ALT and HCV viral load

Both complete response and SVR of HCV-associated DLBCL after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-based regimen

Landau DA et al Arthritis Rheum 2008 Montalbano M et al J Clin Gastroenterol 2007 Cacoub P et al Arthritis Rheum 2002

Mazzaro C et alJ Rheumatol 2003 Zignego AL et al Hepatology 2016 Gragnani L et al Hepatology 2015 Pietrogrande M

et al Autoimmun Rev 2011

Antiviral Treatment (AVT) of MC in the IFN Era

AVT of MC followed the evolution of hepatitis C AVT with frequent adjustments

essentially due to the possible side-effects of IFN andor RBV therapy (ie IFN

neurotoxicity and myelo-inhibitory action and RBV hemolytic effects)

Virological and clinical results progressively improved in spite of frequent side-effects

IFN-based AVT was recommended as the first-line option in mild to moderate MC

Clinical remission was generally correlated with virological response

Long follow-up showed that the majority (57) of SVR pts cleared all MC stigmata

Antiviral Treatment (AVT) of MC IFN-free regimensLimited data so-far concordant are available regarding IFN-free AVT in MC patients

Available data suggest that IFN-free AVT is safe generally well tolerated and effective in MC patients high rate of

clinical response (87) and low rates of serious adverse events was reported

Zignego AL Ramos-Casals M Ferri C et al AutoimmunReviews 2017

Antiviral Treatment (AVT) of MC IFN-free regimens

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical R in 100 (64 CR and 36 PR)

Progression of the small lymphocytic lymphoma

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic MC treated with

DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical R in 1117 (CR in 711) Lower clinical R inseverelife-threatening ndashespecial renal and neurological- vasculitis

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in 100 and

clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse of vasculitis

A case of rapid amelioration of HCV-associated cryoglobulinemic MPGN treated by

IFN-free DAAs for HCV in the absence of immunosuppressant

Fumiaki et al 2017

Zignego et al 2017

TIME POINTS

baseline EOT and week 12 and 24 of post-treatment f-up (SVR12 and SVR24 respectively)

HRQoL EVALUATION THROUGH PROs

the Short Form (36) Health Survey (SF-36)

the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) from which we computed the Trial

Outcome Index (TOI)

Evaluation of The Impact on HRQol of IFN-free AVT In HCV CM

1 Physical Component Summary Score (PCS)

MC (54)

HCV (43) CV (85)

deg

A B C

degdegdeg

2 Mental Component Summary Score (MCS)

MCHCV CVD E F

degdegdegdegdeg

HCV

=plt001 vs baseline scores

degdeg=plt001 and degdegdeg=plt0001 vs EOT scores

Gragnani et al AASLD 2017

HCV Eradicationwith DAAs

To be preceded or combined with non-etiological pathogenetic therapy in severecatastrophic MCS

MCS Therapy in the IFN and DAAs Era from the complex to the simplified flow-chart

Dammacco F Sansonno D NEJM 2013

Zignego AL Pawlotsky JM Cacoub P Antiviral Ther in press Cacoub P et al Am J Med 2015

Mechanisms of HCV-related lymphomagenesis

DLBC HCV- induced

direct transformation

MCindolent NHL

accumulation of B RF

following BCR activation

and BC apoptosisinhibition

Zignego AL Ramos-Casals M Ferri C et al Autoimmun Rev 2017

Wang et al Hepatology 2016 Canioni et al Plos one 2016

Observational study on in situ expression of the oncogenic HCV NS3 protein on 116 HCV patients with B-NHL (DLBCL 36 and MZL 34)

NS3 immunostaining positive in 1214 DLBCL vs only 414 MZL (p = 0006) moreover 24 NS3+ MZL

were enriched in large cells

This study supports a new mechanism of transformation with a direct oncogenic role of

HCV proteins in the occurrence of high-grade B lymphomas

IN SITU HEPATITIS C NS3 PROTEIN DETECTION IS ASSOCIATED WITH HIGH GRADE

FEATURES IN HCV-ASSOCIATED B-CELL NON-HODGKIN LYMPHOMAS Danielle

Canioni et al 2016

In addition to the role of chronic antigenic stimulation in HCV related

lymphomagenesis this study supports a second mechanism of transformation due to a

direct oncogenic role of HCV infection of B-cells promoting the occurrence of high-grade Bcell lymphomas

Cohort study of 704 consecutive HIV-negative HCV-positive patients with indolent NHL from 1993 to

2009 in 39 centers of the FIL

Arcaini et al 2016

DLBC HCV- induced

direct transformation

No place of AVT as

1st line

Need of immediate delivery of

chemotherapy or concomitant (NHL

+ HCV targets)

THERAPY OF HCV+ DLBCL

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDY Michot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell Lymphoma Evan C Ewers et al 2016

absolute neutrophil count and Hgb ALT and HCV viral load

Both complete response and SVR of HCV-associated DLBCL after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-based regimen

Antiviral Treatment (AVT) of MC IFN-free regimensLimited data so-far concordant are available regarding IFN-free AVT in MC patients

Available data suggest that IFN-free AVT is safe generally well tolerated and effective in MC patients high rate of

clinical response (87) and low rates of serious adverse events was reported

Zignego AL Ramos-Casals M Ferri C et al AutoimmunReviews 2017

Antiviral Treatment (AVT) of MC IFN-free regimens

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical R in 100 (64 CR and 36 PR)

Progression of the small lymphocytic lymphoma

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic MC treated with

DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical R in 1117 (CR in 711) Lower clinical R inseverelife-threatening ndashespecial renal and neurological- vasculitis

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in 100 and

clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse of vasculitis

A case of rapid amelioration of HCV-associated cryoglobulinemic MPGN treated by

IFN-free DAAs for HCV in the absence of immunosuppressant

Fumiaki et al 2017

Zignego et al 2017

TIME POINTS

baseline EOT and week 12 and 24 of post-treatment f-up (SVR12 and SVR24 respectively)

HRQoL EVALUATION THROUGH PROs

the Short Form (36) Health Survey (SF-36)

the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) from which we computed the Trial

Outcome Index (TOI)

Evaluation of The Impact on HRQol of IFN-free AVT In HCV CM

1 Physical Component Summary Score (PCS)

MC (54)

HCV (43) CV (85)

deg

A B C

degdegdeg

2 Mental Component Summary Score (MCS)

MCHCV CVD E F

degdegdegdegdeg

HCV

=plt001 vs baseline scores

degdeg=plt001 and degdegdeg=plt0001 vs EOT scores

Gragnani et al AASLD 2017

HCV Eradicationwith DAAs

To be preceded or combined with non-etiological pathogenetic therapy in severecatastrophic MCS

MCS Therapy in the IFN and DAAs Era from the complex to the simplified flow-chart

Dammacco F Sansonno D NEJM 2013

Zignego AL Pawlotsky JM Cacoub P Antiviral Ther in press Cacoub P et al Am J Med 2015

Mechanisms of HCV-related lymphomagenesis

DLBC HCV- induced

direct transformation

MCindolent NHL

accumulation of B RF

following BCR activation

and BC apoptosisinhibition

Zignego AL Ramos-Casals M Ferri C et al Autoimmun Rev 2017

Wang et al Hepatology 2016 Canioni et al Plos one 2016

Observational study on in situ expression of the oncogenic HCV NS3 protein on 116 HCV patients with B-NHL (DLBCL 36 and MZL 34)

NS3 immunostaining positive in 1214 DLBCL vs only 414 MZL (p = 0006) moreover 24 NS3+ MZL

were enriched in large cells

This study supports a new mechanism of transformation with a direct oncogenic role of

HCV proteins in the occurrence of high-grade B lymphomas

IN SITU HEPATITIS C NS3 PROTEIN DETECTION IS ASSOCIATED WITH HIGH GRADE

FEATURES IN HCV-ASSOCIATED B-CELL NON-HODGKIN LYMPHOMAS Danielle

Canioni et al 2016

In addition to the role of chronic antigenic stimulation in HCV related

lymphomagenesis this study supports a second mechanism of transformation due to a

direct oncogenic role of HCV infection of B-cells promoting the occurrence of high-grade Bcell lymphomas

Cohort study of 704 consecutive HIV-negative HCV-positive patients with indolent NHL from 1993 to

2009 in 39 centers of the FIL

Arcaini et al 2016

DLBC HCV- induced

direct transformation

No place of AVT as

1st line

Need of immediate delivery of

chemotherapy or concomitant (NHL

+ HCV targets)

THERAPY OF HCV+ DLBCL

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDY Michot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell Lymphoma Evan C Ewers et al 2016

absolute neutrophil count and Hgb ALT and HCV viral load

Both complete response and SVR of HCV-associated DLBCL after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-based regimen

Antiviral Treatment (AVT) of MC IFN-free regimens

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical R in 100 (64 CR and 36 PR)

Progression of the small lymphocytic lymphoma

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic MC treated with

DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical R in 1117 (CR in 711) Lower clinical R inseverelife-threatening ndashespecial renal and neurological- vasculitis

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in 100 and

clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse of vasculitis

A case of rapid amelioration of HCV-associated cryoglobulinemic MPGN treated by

IFN-free DAAs for HCV in the absence of immunosuppressant

Fumiaki et al 2017

Zignego et al 2017

TIME POINTS

baseline EOT and week 12 and 24 of post-treatment f-up (SVR12 and SVR24 respectively)

HRQoL EVALUATION THROUGH PROs

the Short Form (36) Health Survey (SF-36)

the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) from which we computed the Trial

Outcome Index (TOI)

Evaluation of The Impact on HRQol of IFN-free AVT In HCV CM

1 Physical Component Summary Score (PCS)

MC (54)

HCV (43) CV (85)

deg

A B C

degdegdeg

2 Mental Component Summary Score (MCS)

MCHCV CVD E F

degdegdegdegdeg

HCV

=plt001 vs baseline scores

degdeg=plt001 and degdegdeg=plt0001 vs EOT scores

Gragnani et al AASLD 2017

HCV Eradicationwith DAAs

To be preceded or combined with non-etiological pathogenetic therapy in severecatastrophic MCS

MCS Therapy in the IFN and DAAs Era from the complex to the simplified flow-chart

Dammacco F Sansonno D NEJM 2013

Zignego AL Pawlotsky JM Cacoub P Antiviral Ther in press Cacoub P et al Am J Med 2015

Mechanisms of HCV-related lymphomagenesis

DLBC HCV- induced

direct transformation

MCindolent NHL

accumulation of B RF

following BCR activation

and BC apoptosisinhibition

Zignego AL Ramos-Casals M Ferri C et al Autoimmun Rev 2017

Wang et al Hepatology 2016 Canioni et al Plos one 2016

Observational study on in situ expression of the oncogenic HCV NS3 protein on 116 HCV patients with B-NHL (DLBCL 36 and MZL 34)

NS3 immunostaining positive in 1214 DLBCL vs only 414 MZL (p = 0006) moreover 24 NS3+ MZL

were enriched in large cells

This study supports a new mechanism of transformation with a direct oncogenic role of

HCV proteins in the occurrence of high-grade B lymphomas

IN SITU HEPATITIS C NS3 PROTEIN DETECTION IS ASSOCIATED WITH HIGH GRADE

FEATURES IN HCV-ASSOCIATED B-CELL NON-HODGKIN LYMPHOMAS Danielle

Canioni et al 2016

In addition to the role of chronic antigenic stimulation in HCV related

lymphomagenesis this study supports a second mechanism of transformation due to a

direct oncogenic role of HCV infection of B-cells promoting the occurrence of high-grade Bcell lymphomas

Cohort study of 704 consecutive HIV-negative HCV-positive patients with indolent NHL from 1993 to

2009 in 39 centers of the FIL

Arcaini et al 2016

DLBC HCV- induced

direct transformation

No place of AVT as

1st line

Need of immediate delivery of

chemotherapy or concomitant (NHL

+ HCV targets)

THERAPY OF HCV+ DLBCL

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDY Michot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell Lymphoma Evan C Ewers et al 2016

absolute neutrophil count and Hgb ALT and HCV viral load

Both complete response and SVR of HCV-associated DLBCL after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-based regimen

Zignego et al 2017

TIME POINTS

baseline EOT and week 12 and 24 of post-treatment f-up (SVR12 and SVR24 respectively)

HRQoL EVALUATION THROUGH PROs

the Short Form (36) Health Survey (SF-36)

the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) from which we computed the Trial

Outcome Index (TOI)

Evaluation of The Impact on HRQol of IFN-free AVT In HCV CM

1 Physical Component Summary Score (PCS)

MC (54)

HCV (43) CV (85)

deg

A B C

degdegdeg

2 Mental Component Summary Score (MCS)

MCHCV CVD E F

degdegdegdegdeg

HCV

=plt001 vs baseline scores

degdeg=plt001 and degdegdeg=plt0001 vs EOT scores

Gragnani et al AASLD 2017

HCV Eradicationwith DAAs

To be preceded or combined with non-etiological pathogenetic therapy in severecatastrophic MCS

MCS Therapy in the IFN and DAAs Era from the complex to the simplified flow-chart

Dammacco F Sansonno D NEJM 2013

Zignego AL Pawlotsky JM Cacoub P Antiviral Ther in press Cacoub P et al Am J Med 2015

Mechanisms of HCV-related lymphomagenesis

DLBC HCV- induced

direct transformation

MCindolent NHL

accumulation of B RF

following BCR activation

and BC apoptosisinhibition

Zignego AL Ramos-Casals M Ferri C et al Autoimmun Rev 2017

Wang et al Hepatology 2016 Canioni et al Plos one 2016

Observational study on in situ expression of the oncogenic HCV NS3 protein on 116 HCV patients with B-NHL (DLBCL 36 and MZL 34)

NS3 immunostaining positive in 1214 DLBCL vs only 414 MZL (p = 0006) moreover 24 NS3+ MZL

were enriched in large cells

This study supports a new mechanism of transformation with a direct oncogenic role of

HCV proteins in the occurrence of high-grade B lymphomas

IN SITU HEPATITIS C NS3 PROTEIN DETECTION IS ASSOCIATED WITH HIGH GRADE

FEATURES IN HCV-ASSOCIATED B-CELL NON-HODGKIN LYMPHOMAS Danielle

Canioni et al 2016

In addition to the role of chronic antigenic stimulation in HCV related

lymphomagenesis this study supports a second mechanism of transformation due to a

direct oncogenic role of HCV infection of B-cells promoting the occurrence of high-grade Bcell lymphomas

Cohort study of 704 consecutive HIV-negative HCV-positive patients with indolent NHL from 1993 to

2009 in 39 centers of the FIL

Arcaini et al 2016

DLBC HCV- induced

direct transformation

No place of AVT as

1st line

Need of immediate delivery of

chemotherapy or concomitant (NHL

+ HCV targets)

THERAPY OF HCV+ DLBCL

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDY Michot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell Lymphoma Evan C Ewers et al 2016

absolute neutrophil count and Hgb ALT and HCV viral load

Both complete response and SVR of HCV-associated DLBCL after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-based regimen

TIME POINTS

baseline EOT and week 12 and 24 of post-treatment f-up (SVR12 and SVR24 respectively)

HRQoL EVALUATION THROUGH PROs

the Short Form (36) Health Survey (SF-36)

the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) from which we computed the Trial

Outcome Index (TOI)

Evaluation of The Impact on HRQol of IFN-free AVT In HCV CM

1 Physical Component Summary Score (PCS)

MC (54)

HCV (43) CV (85)

deg

A B C

degdegdeg

2 Mental Component Summary Score (MCS)

MCHCV CVD E F

degdegdegdegdeg

HCV

=plt001 vs baseline scores

degdeg=plt001 and degdegdeg=plt0001 vs EOT scores

Gragnani et al AASLD 2017

HCV Eradicationwith DAAs

To be preceded or combined with non-etiological pathogenetic therapy in severecatastrophic MCS

MCS Therapy in the IFN and DAAs Era from the complex to the simplified flow-chart

Dammacco F Sansonno D NEJM 2013

Zignego AL Pawlotsky JM Cacoub P Antiviral Ther in press Cacoub P et al Am J Med 2015

Mechanisms of HCV-related lymphomagenesis

DLBC HCV- induced

direct transformation

MCindolent NHL

accumulation of B RF

following BCR activation

and BC apoptosisinhibition

Zignego AL Ramos-Casals M Ferri C et al Autoimmun Rev 2017

Wang et al Hepatology 2016 Canioni et al Plos one 2016

Observational study on in situ expression of the oncogenic HCV NS3 protein on 116 HCV patients with B-NHL (DLBCL 36 and MZL 34)

NS3 immunostaining positive in 1214 DLBCL vs only 414 MZL (p = 0006) moreover 24 NS3+ MZL

were enriched in large cells

This study supports a new mechanism of transformation with a direct oncogenic role of

HCV proteins in the occurrence of high-grade B lymphomas

IN SITU HEPATITIS C NS3 PROTEIN DETECTION IS ASSOCIATED WITH HIGH GRADE

FEATURES IN HCV-ASSOCIATED B-CELL NON-HODGKIN LYMPHOMAS Danielle

Canioni et al 2016

In addition to the role of chronic antigenic stimulation in HCV related

lymphomagenesis this study supports a second mechanism of transformation due to a

direct oncogenic role of HCV infection of B-cells promoting the occurrence of high-grade Bcell lymphomas

Cohort study of 704 consecutive HIV-negative HCV-positive patients with indolent NHL from 1993 to

2009 in 39 centers of the FIL

Arcaini et al 2016

DLBC HCV- induced

direct transformation

No place of AVT as

1st line

Need of immediate delivery of

chemotherapy or concomitant (NHL

+ HCV targets)

THERAPY OF HCV+ DLBCL

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDY Michot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell Lymphoma Evan C Ewers et al 2016

absolute neutrophil count and Hgb ALT and HCV viral load

Both complete response and SVR of HCV-associated DLBCL after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-based regimen

HCV Eradicationwith DAAs

To be preceded or combined with non-etiological pathogenetic therapy in severecatastrophic MCS

MCS Therapy in the IFN and DAAs Era from the complex to the simplified flow-chart

Dammacco F Sansonno D NEJM 2013

Zignego AL Pawlotsky JM Cacoub P Antiviral Ther in press Cacoub P et al Am J Med 2015

Mechanisms of HCV-related lymphomagenesis

DLBC HCV- induced

direct transformation

MCindolent NHL

accumulation of B RF

following BCR activation

and BC apoptosisinhibition

Zignego AL Ramos-Casals M Ferri C et al Autoimmun Rev 2017

Wang et al Hepatology 2016 Canioni et al Plos one 2016

Observational study on in situ expression of the oncogenic HCV NS3 protein on 116 HCV patients with B-NHL (DLBCL 36 and MZL 34)

NS3 immunostaining positive in 1214 DLBCL vs only 414 MZL (p = 0006) moreover 24 NS3+ MZL

were enriched in large cells

This study supports a new mechanism of transformation with a direct oncogenic role of

HCV proteins in the occurrence of high-grade B lymphomas

IN SITU HEPATITIS C NS3 PROTEIN DETECTION IS ASSOCIATED WITH HIGH GRADE

FEATURES IN HCV-ASSOCIATED B-CELL NON-HODGKIN LYMPHOMAS Danielle

Canioni et al 2016

In addition to the role of chronic antigenic stimulation in HCV related

lymphomagenesis this study supports a second mechanism of transformation due to a

direct oncogenic role of HCV infection of B-cells promoting the occurrence of high-grade Bcell lymphomas

Cohort study of 704 consecutive HIV-negative HCV-positive patients with indolent NHL from 1993 to

2009 in 39 centers of the FIL

Arcaini et al 2016

DLBC HCV- induced

direct transformation

No place of AVT as

1st line

Need of immediate delivery of

chemotherapy or concomitant (NHL

+ HCV targets)

THERAPY OF HCV+ DLBCL

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDY Michot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell Lymphoma Evan C Ewers et al 2016

absolute neutrophil count and Hgb ALT and HCV viral load

Both complete response and SVR of HCV-associated DLBCL after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-based regimen

Mechanisms of HCV-related lymphomagenesis

DLBC HCV- induced

direct transformation

MCindolent NHL

accumulation of B RF

following BCR activation

and BC apoptosisinhibition

Zignego AL Ramos-Casals M Ferri C et al Autoimmun Rev 2017

Wang et al Hepatology 2016 Canioni et al Plos one 2016

Observational study on in situ expression of the oncogenic HCV NS3 protein on 116 HCV patients with B-NHL (DLBCL 36 and MZL 34)

NS3 immunostaining positive in 1214 DLBCL vs only 414 MZL (p = 0006) moreover 24 NS3+ MZL

were enriched in large cells

This study supports a new mechanism of transformation with a direct oncogenic role of

HCV proteins in the occurrence of high-grade B lymphomas

IN SITU HEPATITIS C NS3 PROTEIN DETECTION IS ASSOCIATED WITH HIGH GRADE

FEATURES IN HCV-ASSOCIATED B-CELL NON-HODGKIN LYMPHOMAS Danielle

Canioni et al 2016

In addition to the role of chronic antigenic stimulation in HCV related

lymphomagenesis this study supports a second mechanism of transformation due to a

direct oncogenic role of HCV infection of B-cells promoting the occurrence of high-grade Bcell lymphomas

Cohort study of 704 consecutive HIV-negative HCV-positive patients with indolent NHL from 1993 to

2009 in 39 centers of the FIL

Arcaini et al 2016

DLBC HCV- induced

direct transformation

No place of AVT as

1st line

Need of immediate delivery of

chemotherapy or concomitant (NHL

+ HCV targets)

THERAPY OF HCV+ DLBCL

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDY Michot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell Lymphoma Evan C Ewers et al 2016

absolute neutrophil count and Hgb ALT and HCV viral load

Both complete response and SVR of HCV-associated DLBCL after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-based regimen

Observational study on in situ expression of the oncogenic HCV NS3 protein on 116 HCV patients with B-NHL (DLBCL 36 and MZL 34)

NS3 immunostaining positive in 1214 DLBCL vs only 414 MZL (p = 0006) moreover 24 NS3+ MZL

were enriched in large cells

This study supports a new mechanism of transformation with a direct oncogenic role of

HCV proteins in the occurrence of high-grade B lymphomas

IN SITU HEPATITIS C NS3 PROTEIN DETECTION IS ASSOCIATED WITH HIGH GRADE

FEATURES IN HCV-ASSOCIATED B-CELL NON-HODGKIN LYMPHOMAS Danielle

Canioni et al 2016

In addition to the role of chronic antigenic stimulation in HCV related

lymphomagenesis this study supports a second mechanism of transformation due to a

direct oncogenic role of HCV infection of B-cells promoting the occurrence of high-grade Bcell lymphomas

Cohort study of 704 consecutive HIV-negative HCV-positive patients with indolent NHL from 1993 to

2009 in 39 centers of the FIL

Arcaini et al 2016

DLBC HCV- induced

direct transformation

No place of AVT as

1st line

Need of immediate delivery of

chemotherapy or concomitant (NHL

+ HCV targets)

THERAPY OF HCV+ DLBCL

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDY Michot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell Lymphoma Evan C Ewers et al 2016

absolute neutrophil count and Hgb ALT and HCV viral load

Both complete response and SVR of HCV-associated DLBCL after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-based regimen

Cohort study of 704 consecutive HIV-negative HCV-positive patients with indolent NHL from 1993 to

2009 in 39 centers of the FIL

Arcaini et al 2016

DLBC HCV- induced

direct transformation

No place of AVT as

1st line

Need of immediate delivery of

chemotherapy or concomitant (NHL

+ HCV targets)

THERAPY OF HCV+ DLBCL

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDY Michot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell Lymphoma Evan C Ewers et al 2016

absolute neutrophil count and Hgb ALT and HCV viral load

Both complete response and SVR of HCV-associated DLBCL after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-based regimen

Arcaini et al 2016

DLBC HCV- induced

direct transformation

No place of AVT as

1st line

Need of immediate delivery of

chemotherapy or concomitant (NHL

+ HCV targets)

THERAPY OF HCV+ DLBCL

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDY Michot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell Lymphoma Evan C Ewers et al 2016

absolute neutrophil count and Hgb ALT and HCV viral load

Both complete response and SVR of HCV-associated DLBCL after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-based regimen

DLBC HCV- induced

direct transformation

No place of AVT as

1st line

Need of immediate delivery of

chemotherapy or concomitant (NHL

+ HCV targets)

THERAPY OF HCV+ DLBCL

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDY Michot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell Lymphoma Evan C Ewers et al 2016

absolute neutrophil count and Hgb ALT and HCV viral load

Both complete response and SVR of HCV-associated DLBCL after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-based regimen

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDY Michot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell Lymphoma Evan C Ewers et al 2016

absolute neutrophil count and Hgb ALT and HCV viral load

Both complete response and SVR of HCV-associated DLBCL after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-based regimen

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell Lymphoma Evan C Ewers et al 2016

absolute neutrophil count and Hgb ALT and HCV viral load

Both complete response and SVR of HCV-associated DLBCL after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-based regimen

DAA-treatment in concomitance with chemotherapy showed to be safe and effective in influencing the remission of aggressive lymphomas in HCV patients

Persico M et al 2017

DFS in DAA treated and historical not-treated ptsAntiviral response rates in DAA treated patients

ANTIVIRAL THERAPY IN HCV+ B CELL NHL

IFN-based AVT induced hematological response along with SVR in patients with HCV-related indolent NHLs (especially

MZL)

Recent data with IFN-free regimens in HCV-associated LPDs suggest their anti-lymphoma activity too

AVT should be considered the first-line approach in HCV low grade lymphomas if there is no urgency of a conventional

treatment (ie systemic symptoms bulky disease or symptomatic splenomegaly) (ESMO NCCN EASL guidelines)

In aggressive lymphomas antiviral therapy after induction treatment is to be considered the standard at the moment but

in the next years (months) the association of immunochemotherapy and antiviral therapy will be considered the standard

Zignego AL Ramos-Casals M Ferri C et al Autoimmun Rev 2017

The Masve group

BASIC RESEARCH

Laura Gragnani

Patrizio Caini

Serena Lorini

Antonella Simone

CLINICAL RESEARCH

Monica Monti

Luisa Petraccia

Sinan Sadalla

Guia Cerretelli

Cristina Stasi

Adela Xheka

Universitagrave degli Studi di FirenzeDipartimento di Medicina Sperimentale e Clinica

Centro Manifestazioni Sistemiche da Virus EpatiticildquoMASVErdquo

Anna Linda Zignego

MASVE

UNDERGRADUATE STUDENTS Andrea Genovese Adrian Piscopo

ANTIVIRAL THERAPY IN HCV+ B CELL NHL

IFN-based AVT induced hematological response along with SVR in patients with HCV-related indolent

NHLs (especially MZL)

Recent data with IFN-free regimens in HCV-associated LPDs suggest their anti-lymphoma activity too

AVT should be considered the first-line approach in HCV low grade lymphomas if there is no urgency

of a conventional treatment (ie systemic symptoms bulky disease or symptomatic splenomegaly)

(ESMO NCCN EASL guidelines)

Main drugs for HCV-related MCS according to the target

HCV= DAAsB-cell Expansion= (a) B cell-depleting Mabs

-First-generation Rituximab (anti-CD20)-Second-generation Ofatumumab (anti-CD20) Veltuzumab (humanized

anti-CD20)-Third-generation Obinutuzumab (GA101) Oceratuzumab (humanized

anti-CD20)

(b) Alkylating agents

-Cyclophosfamide

Inflammation= Antiinflammatory agents

- Corticosteroids

Altered regulatory T-cell activity=

- IL-2

The impact on HRQoL of IFN-free AVT was prospectively evaluated in a cohort of HCV CV patients with limited

influencing variables linked to therapeutic schedulesviral GT

44 HCV GT2 CV patients mostly F0-F2 (29) and naiumlve (30) treated with SOFRBV for 1224wks

TIME POINTS

baseline EOT and week 12 and 24 of post-treatment f-up (SVR12 and SVR24 respectively)

HRQoL EVALUATION THROUGH PROs

the Short Form (36) Health Survey (SF-36)

the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) from which we computed the Trial

Outcome Index (TOI)

Observational study on in situ expression of the oncogenic HCV NS3 protein on 116 HCV

patients with B-NHL (DLBCL 36 and MZL 34)

NS3 immunostaining positive in 1214 DLBCL vs only 414 MZL (p = 0006) moreover 24 NS3+

MZL were enriched in large cells

This study supports a new mechanism of transformation with a direct oncogenic role of

HCV proteins in the occurrence of high-grade B lymphomas

IN SITU HEPATITIS C NS3 PROTEIN DETECTION IS ASSOCIATED WITH HIGH GRADEFEATURES IN HCV-ASSOCIATED B-CELL NON-HODGKIN LYMPHOMAS Danielle

Canioni et al 2016

In addition to the role of chronic antigenic stimulation in HCV related

lymphomagenesis this study supports a second mechanism of transformation due toa direct oncogenic role of HCV infection of B-cells promoting the occurrence of high-grade Bcell lymphomas

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDYMichot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

(A) absolute neutrophil count and Hgb

(B) ALT and HCV viral load

This patient had HCV-associated DLBCL achieving both complete response and SVR after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-basedregimen

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell LymphomaEvan C Ewers et al 2016

ANTIVIRAL THERAPY IN HCV+ B CELL NHL

IFN-based AVT induced hematological response along with SVR in patients with HCV-related indolent NHLs (especially

MZL)

Recent data with IFN-free regimens in HCV-associated LPDs suggest their anti-lymphoma activity too

AVT should be considered the first-line approach in HCV low grade lymphomas if there is no urgency of a conventional

treatment (ie systemic symptoms bulky disease or symptomatic splenomegaly) (ESMO NCCN EASL guidelines)

In aggressive lymphomas antiviral therapy after induction treatment is to be considered the standard at the moment but

in the next years (months) the association of immunochemotherapy and antiviral therapy will be considered the standard

Zignego AL Ramos-Casals M Ferri C et al Autoimmun Rev 2017

The Masve group

BASIC RESEARCH

Laura Gragnani

Patrizio Caini

Serena Lorini

Antonella Simone

CLINICAL RESEARCH

Monica Monti

Luisa Petraccia

Sinan Sadalla

Guia Cerretelli

Cristina Stasi

Adela Xheka

Universitagrave degli Studi di FirenzeDipartimento di Medicina Sperimentale e Clinica

Centro Manifestazioni Sistemiche da Virus EpatiticildquoMASVErdquo

Anna Linda Zignego

MASVE

UNDERGRADUATE STUDENTS Andrea Genovese Adrian Piscopo

ANTIVIRAL THERAPY IN HCV+ B CELL NHL

IFN-based AVT induced hematological response along with SVR in patients with HCV-related indolent

NHLs (especially MZL)

Recent data with IFN-free regimens in HCV-associated LPDs suggest their anti-lymphoma activity too

AVT should be considered the first-line approach in HCV low grade lymphomas if there is no urgency

of a conventional treatment (ie systemic symptoms bulky disease or symptomatic splenomegaly)

(ESMO NCCN EASL guidelines)

Main drugs for HCV-related MCS according to the target

HCV= DAAsB-cell Expansion= (a) B cell-depleting Mabs

-First-generation Rituximab (anti-CD20)-Second-generation Ofatumumab (anti-CD20) Veltuzumab (humanized

anti-CD20)-Third-generation Obinutuzumab (GA101) Oceratuzumab (humanized

anti-CD20)

(b) Alkylating agents

-Cyclophosfamide

Inflammation= Antiinflammatory agents

- Corticosteroids

Altered regulatory T-cell activity=

- IL-2

The impact on HRQoL of IFN-free AVT was prospectively evaluated in a cohort of HCV CV patients with limited

influencing variables linked to therapeutic schedulesviral GT

44 HCV GT2 CV patients mostly F0-F2 (29) and naiumlve (30) treated with SOFRBV for 1224wks

TIME POINTS

baseline EOT and week 12 and 24 of post-treatment f-up (SVR12 and SVR24 respectively)

HRQoL EVALUATION THROUGH PROs

the Short Form (36) Health Survey (SF-36)

the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) from which we computed the Trial

Outcome Index (TOI)

Observational study on in situ expression of the oncogenic HCV NS3 protein on 116 HCV

patients with B-NHL (DLBCL 36 and MZL 34)

NS3 immunostaining positive in 1214 DLBCL vs only 414 MZL (p = 0006) moreover 24 NS3+

MZL were enriched in large cells

This study supports a new mechanism of transformation with a direct oncogenic role of

HCV proteins in the occurrence of high-grade B lymphomas

IN SITU HEPATITIS C NS3 PROTEIN DETECTION IS ASSOCIATED WITH HIGH GRADEFEATURES IN HCV-ASSOCIATED B-CELL NON-HODGKIN LYMPHOMAS Danielle

Canioni et al 2016

In addition to the role of chronic antigenic stimulation in HCV related

lymphomagenesis this study supports a second mechanism of transformation due toa direct oncogenic role of HCV infection of B-cells promoting the occurrence of high-grade Bcell lymphomas

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDYMichot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

(A) absolute neutrophil count and Hgb

(B) ALT and HCV viral load

This patient had HCV-associated DLBCL achieving both complete response and SVR after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-basedregimen

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell LymphomaEvan C Ewers et al 2016

The Masve group

BASIC RESEARCH

Laura Gragnani

Patrizio Caini

Serena Lorini

Antonella Simone

CLINICAL RESEARCH

Monica Monti

Luisa Petraccia

Sinan Sadalla

Guia Cerretelli

Cristina Stasi

Adela Xheka

Universitagrave degli Studi di FirenzeDipartimento di Medicina Sperimentale e Clinica

Centro Manifestazioni Sistemiche da Virus EpatiticildquoMASVErdquo

Anna Linda Zignego

MASVE

UNDERGRADUATE STUDENTS Andrea Genovese Adrian Piscopo

ANTIVIRAL THERAPY IN HCV+ B CELL NHL

IFN-based AVT induced hematological response along with SVR in patients with HCV-related indolent

NHLs (especially MZL)

Recent data with IFN-free regimens in HCV-associated LPDs suggest their anti-lymphoma activity too

AVT should be considered the first-line approach in HCV low grade lymphomas if there is no urgency

of a conventional treatment (ie systemic symptoms bulky disease or symptomatic splenomegaly)

(ESMO NCCN EASL guidelines)

Main drugs for HCV-related MCS according to the target

HCV= DAAsB-cell Expansion= (a) B cell-depleting Mabs

-First-generation Rituximab (anti-CD20)-Second-generation Ofatumumab (anti-CD20) Veltuzumab (humanized

anti-CD20)-Third-generation Obinutuzumab (GA101) Oceratuzumab (humanized

anti-CD20)

(b) Alkylating agents

-Cyclophosfamide

Inflammation= Antiinflammatory agents

- Corticosteroids

Altered regulatory T-cell activity=

- IL-2

The impact on HRQoL of IFN-free AVT was prospectively evaluated in a cohort of HCV CV patients with limited

influencing variables linked to therapeutic schedulesviral GT

44 HCV GT2 CV patients mostly F0-F2 (29) and naiumlve (30) treated with SOFRBV for 1224wks

TIME POINTS

baseline EOT and week 12 and 24 of post-treatment f-up (SVR12 and SVR24 respectively)

HRQoL EVALUATION THROUGH PROs

the Short Form (36) Health Survey (SF-36)

the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) from which we computed the Trial

Outcome Index (TOI)

Observational study on in situ expression of the oncogenic HCV NS3 protein on 116 HCV

patients with B-NHL (DLBCL 36 and MZL 34)

NS3 immunostaining positive in 1214 DLBCL vs only 414 MZL (p = 0006) moreover 24 NS3+

MZL were enriched in large cells

This study supports a new mechanism of transformation with a direct oncogenic role of

HCV proteins in the occurrence of high-grade B lymphomas

IN SITU HEPATITIS C NS3 PROTEIN DETECTION IS ASSOCIATED WITH HIGH GRADEFEATURES IN HCV-ASSOCIATED B-CELL NON-HODGKIN LYMPHOMAS Danielle

Canioni et al 2016

In addition to the role of chronic antigenic stimulation in HCV related

lymphomagenesis this study supports a second mechanism of transformation due toa direct oncogenic role of HCV infection of B-cells promoting the occurrence of high-grade Bcell lymphomas

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDYMichot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

(A) absolute neutrophil count and Hgb

(B) ALT and HCV viral load

This patient had HCV-associated DLBCL achieving both complete response and SVR after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-basedregimen

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell LymphomaEvan C Ewers et al 2016

ANTIVIRAL THERAPY IN HCV+ B CELL NHL

IFN-based AVT induced hematological response along with SVR in patients with HCV-related indolent

NHLs (especially MZL)

Recent data with IFN-free regimens in HCV-associated LPDs suggest their anti-lymphoma activity too

AVT should be considered the first-line approach in HCV low grade lymphomas if there is no urgency

of a conventional treatment (ie systemic symptoms bulky disease or symptomatic splenomegaly)

(ESMO NCCN EASL guidelines)

Main drugs for HCV-related MCS according to the target

HCV= DAAsB-cell Expansion= (a) B cell-depleting Mabs

-First-generation Rituximab (anti-CD20)-Second-generation Ofatumumab (anti-CD20) Veltuzumab (humanized

anti-CD20)-Third-generation Obinutuzumab (GA101) Oceratuzumab (humanized

anti-CD20)

(b) Alkylating agents

-Cyclophosfamide

Inflammation= Antiinflammatory agents

- Corticosteroids

Altered regulatory T-cell activity=

- IL-2

The impact on HRQoL of IFN-free AVT was prospectively evaluated in a cohort of HCV CV patients with limited

influencing variables linked to therapeutic schedulesviral GT

44 HCV GT2 CV patients mostly F0-F2 (29) and naiumlve (30) treated with SOFRBV for 1224wks

TIME POINTS

baseline EOT and week 12 and 24 of post-treatment f-up (SVR12 and SVR24 respectively)

HRQoL EVALUATION THROUGH PROs

the Short Form (36) Health Survey (SF-36)

the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) from which we computed the Trial

Outcome Index (TOI)

Observational study on in situ expression of the oncogenic HCV NS3 protein on 116 HCV

patients with B-NHL (DLBCL 36 and MZL 34)

NS3 immunostaining positive in 1214 DLBCL vs only 414 MZL (p = 0006) moreover 24 NS3+

MZL were enriched in large cells

This study supports a new mechanism of transformation with a direct oncogenic role of

HCV proteins in the occurrence of high-grade B lymphomas

IN SITU HEPATITIS C NS3 PROTEIN DETECTION IS ASSOCIATED WITH HIGH GRADEFEATURES IN HCV-ASSOCIATED B-CELL NON-HODGKIN LYMPHOMAS Danielle

Canioni et al 2016

In addition to the role of chronic antigenic stimulation in HCV related

lymphomagenesis this study supports a second mechanism of transformation due toa direct oncogenic role of HCV infection of B-cells promoting the occurrence of high-grade Bcell lymphomas

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDYMichot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

(A) absolute neutrophil count and Hgb

(B) ALT and HCV viral load

This patient had HCV-associated DLBCL achieving both complete response and SVR after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-basedregimen

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell LymphomaEvan C Ewers et al 2016

Main drugs for HCV-related MCS according to the target

HCV= DAAsB-cell Expansion= (a) B cell-depleting Mabs

-First-generation Rituximab (anti-CD20)-Second-generation Ofatumumab (anti-CD20) Veltuzumab (humanized

anti-CD20)-Third-generation Obinutuzumab (GA101) Oceratuzumab (humanized

anti-CD20)

(b) Alkylating agents

-Cyclophosfamide

Inflammation= Antiinflammatory agents

- Corticosteroids

Altered regulatory T-cell activity=

- IL-2

The impact on HRQoL of IFN-free AVT was prospectively evaluated in a cohort of HCV CV patients with limited

influencing variables linked to therapeutic schedulesviral GT

44 HCV GT2 CV patients mostly F0-F2 (29) and naiumlve (30) treated with SOFRBV for 1224wks

TIME POINTS

baseline EOT and week 12 and 24 of post-treatment f-up (SVR12 and SVR24 respectively)

HRQoL EVALUATION THROUGH PROs

the Short Form (36) Health Survey (SF-36)

the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) from which we computed the Trial

Outcome Index (TOI)

Observational study on in situ expression of the oncogenic HCV NS3 protein on 116 HCV

patients with B-NHL (DLBCL 36 and MZL 34)

NS3 immunostaining positive in 1214 DLBCL vs only 414 MZL (p = 0006) moreover 24 NS3+

MZL were enriched in large cells

This study supports a new mechanism of transformation with a direct oncogenic role of

HCV proteins in the occurrence of high-grade B lymphomas

IN SITU HEPATITIS C NS3 PROTEIN DETECTION IS ASSOCIATED WITH HIGH GRADEFEATURES IN HCV-ASSOCIATED B-CELL NON-HODGKIN LYMPHOMAS Danielle

Canioni et al 2016

In addition to the role of chronic antigenic stimulation in HCV related

lymphomagenesis this study supports a second mechanism of transformation due toa direct oncogenic role of HCV infection of B-cells promoting the occurrence of high-grade Bcell lymphomas

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDYMichot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

(A) absolute neutrophil count and Hgb

(B) ALT and HCV viral load

This patient had HCV-associated DLBCL achieving both complete response and SVR after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-basedregimen

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell LymphomaEvan C Ewers et al 2016

The impact on HRQoL of IFN-free AVT was prospectively evaluated in a cohort of HCV CV patients with limited

influencing variables linked to therapeutic schedulesviral GT

44 HCV GT2 CV patients mostly F0-F2 (29) and naiumlve (30) treated with SOFRBV for 1224wks

TIME POINTS

baseline EOT and week 12 and 24 of post-treatment f-up (SVR12 and SVR24 respectively)

HRQoL EVALUATION THROUGH PROs

the Short Form (36) Health Survey (SF-36)

the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) from which we computed the Trial

Outcome Index (TOI)

Observational study on in situ expression of the oncogenic HCV NS3 protein on 116 HCV

patients with B-NHL (DLBCL 36 and MZL 34)

NS3 immunostaining positive in 1214 DLBCL vs only 414 MZL (p = 0006) moreover 24 NS3+

MZL were enriched in large cells

This study supports a new mechanism of transformation with a direct oncogenic role of

HCV proteins in the occurrence of high-grade B lymphomas

IN SITU HEPATITIS C NS3 PROTEIN DETECTION IS ASSOCIATED WITH HIGH GRADEFEATURES IN HCV-ASSOCIATED B-CELL NON-HODGKIN LYMPHOMAS Danielle

Canioni et al 2016

In addition to the role of chronic antigenic stimulation in HCV related

lymphomagenesis this study supports a second mechanism of transformation due toa direct oncogenic role of HCV infection of B-cells promoting the occurrence of high-grade Bcell lymphomas

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDYMichot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

(A) absolute neutrophil count and Hgb

(B) ALT and HCV viral load

This patient had HCV-associated DLBCL achieving both complete response and SVR after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-basedregimen

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell LymphomaEvan C Ewers et al 2016

Observational study on in situ expression of the oncogenic HCV NS3 protein on 116 HCV

patients with B-NHL (DLBCL 36 and MZL 34)

NS3 immunostaining positive in 1214 DLBCL vs only 414 MZL (p = 0006) moreover 24 NS3+

MZL were enriched in large cells

This study supports a new mechanism of transformation with a direct oncogenic role of

HCV proteins in the occurrence of high-grade B lymphomas

IN SITU HEPATITIS C NS3 PROTEIN DETECTION IS ASSOCIATED WITH HIGH GRADEFEATURES IN HCV-ASSOCIATED B-CELL NON-HODGKIN LYMPHOMAS Danielle

Canioni et al 2016

In addition to the role of chronic antigenic stimulation in HCV related

lymphomagenesis this study supports a second mechanism of transformation due toa direct oncogenic role of HCV infection of B-cells promoting the occurrence of high-grade Bcell lymphomas

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDYMichot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

(A) absolute neutrophil count and Hgb

(B) ALT and HCV viral load

This patient had HCV-associated DLBCL achieving both complete response and SVR after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-basedregimen

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell LymphomaEvan C Ewers et al 2016

ANTIVIRAL THERAPY IS ASSOCIATED WITH A BETTERSURVIVAL IN PATIENTS WITH HCV AND B-CELL NON-HODGKIN LYMPHOMAS ANRS HC-13 LYMPHO-CSTUDYMichot JM et al

Outcomes of HCV-associated B-NHL according to HCV AVT in prospective patients only (n 5 64)

(A) absolute neutrophil count and Hgb

(B) ALT and HCV viral load

This patient had HCV-associated DLBCL achieving both complete response and SVR after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-basedregimen

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell LymphomaEvan C Ewers et al 2016

(A) absolute neutrophil count and Hgb

(B) ALT and HCV viral load

This patient had HCV-associated DLBCL achieving both complete response and SVR after concurrent chemoimmunotherapy and antiviral therapy using a sofosbuvir-basedregimen

Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell LymphomaEvan C Ewers et al 2016

HCV-EHDs are responsible for increasing morbidity and mortality with important

consequences in terms of social costs

The analysis of mortality rates in large cohorts confirmed the association of HCV with

several EHDs including cardiovascular neurologic metabolic or renal diseases and tumors

Viral eradication significantly reduced the rate of extra-hepatic deaths

Cacoub P et al DLD 2014 Lee MH et al J Infect Dis 2012 Backus LI et al Clin Gastroenterol Hepatol 2011 El-Kamary S et al

Clin Infect Dis 2011 Hsu YC et al Hepatology 2014 Kawamura Y et al Am J Med 2007 Adinolfi LE et al WJG 2014

Extrahepatic Manifestations of HCV

Con il contributo di

Lee M-H et al J Infect Dis 2012206469-477

Follow-Up

(Years)

20

18

16

14

12

10

2

00 2 4 6 8 10 12 14 16 18 20

8

6

4

Follow-Up

(Years)

12

10

8

6

4

2

00 2 4 6 8 10 12 14 16 18 20

All Causes(n=2394)

Liver Cancer(n=115)

Extrahepatic Diseases(n=2199)

Cum

ula

tive M

ort

ali

ty (

)

Anti-HCV+ HCV RNA detectable Anti-HCV+ HCV RNA undetectable Anti-HCVndash

Follow-Up

(Years)

35

30

25

20

15

10

5

00 2 4 6 8 10 12 14 16 18 20

301

128124

104

16

03

198

122

110

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

CGs reversibly precipitate when the temperature is lower than 37degC and

comprise IgMs with RF activity [mono- or oligo-clonal in type II MC or

polyclonal in type III MC] and polyclonal IgGs

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC since HCV infects about 170 million individuals worldwide the

number of patients at risk for developing MC is substantial

Type II

CGs

Type III

CGs

Zignego AL et al Autoimmun Rev 2017 Ferri C et al Autoimmunity rev 2016 Zignego AL et al DLD 2007 Cacoub P et al DLD

2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev Immunol 2012 Zignego

AL et al Expert Rev Clin Immunol 2015

MC clinical aspects MC Syndrome

MCS is characterized by the clinical triad -purpura weakness and

arthralgias- low complement C4 and various organsystem

involvement including cutaneous articular renal neurological

cardiac or digestive

It ranges from mild disease to severe even life-threatening

conditions

More serious lesions are generally characterized by neurologic and

renal involvement

Prognosis is highly dependent on renal involvement or on the extent

of vasculitis lesions

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

From P Cacoub 2015

HCV infection is closely related to LPDs mostly MC

40 to 60 of HCV patients show circulating CGs among this latter population 5-30

develop a symptomatic CV

AVT has been considered the first-line option in HCV-CV patients in fact in the majority

of cases viral eradication leads to CV clinical remission

Data about IFN-free regimens for the treatment of CV patients are still limited

HCV and MC

HCV and MC

Zignego 2015Ferri 2016Pozzato 2016 Sise 2016Saadoun 2015Gragnani 2016Gragnani 2016

Bonacci 2016Hegazy 2016Kondili 2016Emery 2017

Younossi et al

The annual costs (inpatient outpatient andpharmacy) associated with extrahepatic

manifestations of HCV were evaluated

Total direct medical costs of extrahepatic

manifestations of HCV in 2014 US dollars wereestimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related

burden of disease to obtain a more accurateassessment of the total burden of HCV infection

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

Extrahepatic Manifestations of HCV

Extrahepatic Manifestations of HCV

HCV may cause extrahepatic disorders (HCV-EHDs) classified according to the number and

strength of supporting scientific data

HCV-EHDs are responsible for increasing morbidity and mortality with important

consequences in terms of social costs

The analysis of mortality rates in large cohorts confirmed the association of HCV with

several EHDs including cardiovascular neurologic metabolic or renal diseases and tumors

Viral eradication significantly reduced the rate of extra-hepatic deaths

Cacoub P et al DLD 2014 Lee MH et al J Infect Dis 2012 Backus LI et al Clin Gastroenterol Hepatol 2011 El-Kamary S et al

Clin Infect Dis 2011 Hsu YC et al Hepatology 2014 Kawamura Y et al Am J Med 2007 Adinolfi LE et al WJG 2014

Con il contributo di

Lee M-H et al J Infect Dis 2012206469-477

Follow-Up

(Years)

20

18

16

14

12

10

2

00 2 4 6 8 10 12 14 16 18 20

8

6

4

Follow-Up

(Years)

12

10

8

6

4

2

00 2 4 6 8 10 12 14 16 18 20

All Causes(n=2394)

Liver Cancer(n=115)

Extrahepatic Diseases(n=2199)

Cum

ula

tive M

ort

ali

ty (

)

Anti-HCV+ HCV RNA detectable Anti-HCV+ HCV RNA undetectable Anti-HCVndash

Follow-Up

(Years)

35

30

25

20

15

10

5

00 2 4 6 8 10 12 14 16 18 20

301

128124

104

16

03

198

122

110

Extrahepatic Manifestations of HCV

The annual costs (inpatient outpatient andpharmacy) associated with extrahepatic

manifestations of HCV were evaluated

Total direct medical costs of extrahepatic

manifestations of HCV in 2014 US dollars wereestimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related

burden of disease to obtain a more accurateassessment of the total burden of HCV infection

Younossi et al

Younossi et al

Costs up to $71000 per patient per year (ESRD) Among the most frequent EHM depression (245 in HCV vs 172 in non-HCV) had estimated annual cost of

$4307 million DM (15 vs 10 in non- HCV) had an annual cost of $4434 million in the USA= given the importance of DM and

its association with CVDs and mortality the clinical and economic impacts of HCV-related DM are substantial

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

The OBJECTIVE of the study was to estimate the annual direct medicalcosts associated with HCV related EHM in the EU5 (France Germany

Italy United Kingdom Spain)

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

The most studied and frequent HCV-EHDs are B-LPDs andor autoimmune disorders

Their prototype is Mixed Cryoglobulinemia (MC) from researches on MC derived most of the

available information

MC as a precious model for all the HCV-EHDs and to evaluate the effects of viral eradication

Anti-HCV Treatment Evolution

IFN

6 mos

PegIFN RBV 12

mos

IFN

12 mos

IFNRBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN

RBV

DAA

IFNRBV

6 mos

6

16

34

4239

55

70+

0

20

40

60

80

100

DAAs

826

weeks

gt90

2015

Few side effects absence major

contraindications

Younossi et al

The annual costs (inpatient outpatient and pharmacy) associatedwith extrahepatic manifestations of HCV were evaluated

Total direct medical costs of extrahepatic manifestations of HCV in 2014US dollars were estimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of diseaseto obtain a more accurate assessment of the total burden of HCV

infection

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

CGs reversibly precipitate when the temperature is lower than 37degC and

comprise IgMs with RF activity [mono- or oligo-clonal in type II MC or

polyclonal in type III MC] and polyclonal IgGs

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC since HCV infects about 170 million individuals worldwide the

number of patients at risk for developing MC is substantial

Type II

CGs

Type III

CGs

Zignego AL et al Autoimmun Rev 2017 Ferri C et al Autoimmunity rev 2016 Zignego AL et al DLD 2007 Cacoub P et al DLD

2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev Immunol 2012 Zignego

AL et al Expert Rev Clin Immunol 2015

MC clinical aspects MC Syndrome

MCS is characterized by the clinical triad -purpura weakness and

arthralgias- low complement C4 and various organsystem

involvement including cutaneous articular renal neurological

cardiac or digestive

It ranges from mild disease to severe even life-threatening

conditions

More serious lesions are generally characterized by neurologic and

renal involvement

Prognosis is highly dependent on renal involvement or on the extent

of vasculitis lesions

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

From P Cacoub 2015

HCV infection is closely related to LPDs mostly MC

40 to 60 of HCV patients show circulating CGs among this latter population 5-30

develop a symptomatic CV

AVT has been considered the first-line option in HCV-CV patients in fact in the majority

of cases viral eradication leads to CV clinical remission

Data about IFN-free regimens for the treatment of CV patients are still limited

HCV and MC

HCV and MC

Zignego 2015Ferri 2016Pozzato 2016 Sise 2016Saadoun 2015Gragnani 2016Gragnani 2016

Bonacci 2016Hegazy 2016Kondili 2016Emery 2017

Younossi et al

The annual costs (inpatient outpatient andpharmacy) associated with extrahepatic

manifestations of HCV were evaluated

Total direct medical costs of extrahepatic

manifestations of HCV in 2014 US dollars wereestimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related

burden of disease to obtain a more accurateassessment of the total burden of HCV infection

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

Extrahepatic Manifestations of HCV

Extrahepatic Manifestations of HCV

HCV may cause extrahepatic disorders (HCV-EHDs) classified according to the number and

strength of supporting scientific data

HCV-EHDs are responsible for increasing morbidity and mortality with important

consequences in terms of social costs

The analysis of mortality rates in large cohorts confirmed the association of HCV with

several EHDs including cardiovascular neurologic metabolic or renal diseases and tumors

Viral eradication significantly reduced the rate of extra-hepatic deaths

Cacoub P et al DLD 2014 Lee MH et al J Infect Dis 2012 Backus LI et al Clin Gastroenterol Hepatol 2011 El-Kamary S et al

Clin Infect Dis 2011 Hsu YC et al Hepatology 2014 Kawamura Y et al Am J Med 2007 Adinolfi LE et al WJG 2014

Con il contributo di

Lee M-H et al J Infect Dis 2012206469-477

Follow-Up

(Years)

20

18

16

14

12

10

2

00 2 4 6 8 10 12 14 16 18 20

8

6

4

Follow-Up

(Years)

12

10

8

6

4

2

00 2 4 6 8 10 12 14 16 18 20

All Causes(n=2394)

Liver Cancer(n=115)

Extrahepatic Diseases(n=2199)

Cum

ula

tive M

ort

ali

ty (

)

Anti-HCV+ HCV RNA detectable Anti-HCV+ HCV RNA undetectable Anti-HCVndash

Follow-Up

(Years)

35

30

25

20

15

10

5

00 2 4 6 8 10 12 14 16 18 20

301

128124

104

16

03

198

122

110

Extrahepatic Manifestations of HCV

The annual costs (inpatient outpatient andpharmacy) associated with extrahepatic

manifestations of HCV were evaluated

Total direct medical costs of extrahepatic

manifestations of HCV in 2014 US dollars wereestimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related

burden of disease to obtain a more accurateassessment of the total burden of HCV infection

Younossi et al

Younossi et al

Costs up to $71000 per patient per year (ESRD) Among the most frequent EHM depression (245 in HCV vs 172 in non-HCV) had estimated annual cost of

$4307 million DM (15 vs 10 in non- HCV) had an annual cost of $4434 million in the USA= given the importance of DM and

its association with CVDs and mortality the clinical and economic impacts of HCV-related DM are substantial

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

The OBJECTIVE of the study was to estimate the annual direct medicalcosts associated with HCV related EHM in the EU5 (France Germany

Italy United Kingdom Spain)

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

The most studied and frequent HCV-EHDs are B-LPDs andor autoimmune disorders

Their prototype is Mixed Cryoglobulinemia (MC) from researches on MC derived most of the

available information

MC as a precious model for all the HCV-EHDs and to evaluate the effects of viral eradication

Anti-HCV Treatment Evolution

IFN

6 mos

PegIFN RBV 12

mos

IFN

12 mos

IFNRBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN

RBV

DAA

IFNRBV

6 mos

6

16

34

4239

55

70+

0

20

40

60

80

100

DAAs

826

weeks

gt90

2015

Few side effects absence major

contraindications

Younossi et al

The annual costs (inpatient outpatient and pharmacy) associatedwith extrahepatic manifestations of HCV were evaluated

Total direct medical costs of extrahepatic manifestations of HCV in 2014US dollars were estimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of diseaseto obtain a more accurate assessment of the total burden of HCV

infection

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

Zignego AL et al Autoimmun Rev 2017 Ferri C et al Autoimmunity rev 2016 Zignego AL et al DLD 2007 Cacoub P et al DLD

2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev Immunol 2012 Zignego

AL et al Expert Rev Clin Immunol 2015

MC clinical aspects MC Syndrome

MCS is characterized by the clinical triad -purpura weakness and

arthralgias- low complement C4 and various organsystem

involvement including cutaneous articular renal neurological

cardiac or digestive

It ranges from mild disease to severe even life-threatening

conditions

More serious lesions are generally characterized by neurologic and

renal involvement

Prognosis is highly dependent on renal involvement or on the extent

of vasculitis lesions

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

From P Cacoub 2015

HCV infection is closely related to LPDs mostly MC

40 to 60 of HCV patients show circulating CGs among this latter population 5-30

develop a symptomatic CV

AVT has been considered the first-line option in HCV-CV patients in fact in the majority

of cases viral eradication leads to CV clinical remission

Data about IFN-free regimens for the treatment of CV patients are still limited

HCV and MC

HCV and MC

Zignego 2015Ferri 2016Pozzato 2016 Sise 2016Saadoun 2015Gragnani 2016Gragnani 2016

Bonacci 2016Hegazy 2016Kondili 2016Emery 2017

Younossi et al

The annual costs (inpatient outpatient andpharmacy) associated with extrahepatic

manifestations of HCV were evaluated

Total direct medical costs of extrahepatic

manifestations of HCV in 2014 US dollars wereestimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related

burden of disease to obtain a more accurateassessment of the total burden of HCV infection

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

Extrahepatic Manifestations of HCV

Extrahepatic Manifestations of HCV

HCV may cause extrahepatic disorders (HCV-EHDs) classified according to the number and

strength of supporting scientific data

HCV-EHDs are responsible for increasing morbidity and mortality with important

consequences in terms of social costs

The analysis of mortality rates in large cohorts confirmed the association of HCV with

several EHDs including cardiovascular neurologic metabolic or renal diseases and tumors

Viral eradication significantly reduced the rate of extra-hepatic deaths

Cacoub P et al DLD 2014 Lee MH et al J Infect Dis 2012 Backus LI et al Clin Gastroenterol Hepatol 2011 El-Kamary S et al

Clin Infect Dis 2011 Hsu YC et al Hepatology 2014 Kawamura Y et al Am J Med 2007 Adinolfi LE et al WJG 2014

Con il contributo di

Lee M-H et al J Infect Dis 2012206469-477

Follow-Up

(Years)

20

18

16

14

12

10

2

00 2 4 6 8 10 12 14 16 18 20

8

6

4

Follow-Up

(Years)

12

10

8

6

4

2

00 2 4 6 8 10 12 14 16 18 20

All Causes(n=2394)

Liver Cancer(n=115)

Extrahepatic Diseases(n=2199)

Cum

ula

tive M

ort

ali

ty (

)

Anti-HCV+ HCV RNA detectable Anti-HCV+ HCV RNA undetectable Anti-HCVndash

Follow-Up

(Years)

35

30

25

20

15

10

5

00 2 4 6 8 10 12 14 16 18 20

301

128124

104

16

03

198

122

110

Extrahepatic Manifestations of HCV

The annual costs (inpatient outpatient andpharmacy) associated with extrahepatic

manifestations of HCV were evaluated

Total direct medical costs of extrahepatic

manifestations of HCV in 2014 US dollars wereestimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related

burden of disease to obtain a more accurateassessment of the total burden of HCV infection

Younossi et al

Younossi et al

Costs up to $71000 per patient per year (ESRD) Among the most frequent EHM depression (245 in HCV vs 172 in non-HCV) had estimated annual cost of

$4307 million DM (15 vs 10 in non- HCV) had an annual cost of $4434 million in the USA= given the importance of DM and

its association with CVDs and mortality the clinical and economic impacts of HCV-related DM are substantial

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

The OBJECTIVE of the study was to estimate the annual direct medicalcosts associated with HCV related EHM in the EU5 (France Germany

Italy United Kingdom Spain)

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

The most studied and frequent HCV-EHDs are B-LPDs andor autoimmune disorders

Their prototype is Mixed Cryoglobulinemia (MC) from researches on MC derived most of the

available information

MC as a precious model for all the HCV-EHDs and to evaluate the effects of viral eradication

Anti-HCV Treatment Evolution

IFN

6 mos

PegIFN RBV 12

mos

IFN

12 mos

IFNRBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN

RBV

DAA

IFNRBV

6 mos

6

16

34

4239

55

70+

0

20

40

60

80

100

DAAs

826

weeks

gt90

2015

Few side effects absence major

contraindications

Younossi et al

The annual costs (inpatient outpatient and pharmacy) associatedwith extrahepatic manifestations of HCV were evaluated

Total direct medical costs of extrahepatic manifestations of HCV in 2014US dollars were estimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of diseaseto obtain a more accurate assessment of the total burden of HCV

infection

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

From P Cacoub 2015

HCV infection is closely related to LPDs mostly MC

40 to 60 of HCV patients show circulating CGs among this latter population 5-30

develop a symptomatic CV

AVT has been considered the first-line option in HCV-CV patients in fact in the majority

of cases viral eradication leads to CV clinical remission

Data about IFN-free regimens for the treatment of CV patients are still limited

HCV and MC

HCV and MC

Zignego 2015Ferri 2016Pozzato 2016 Sise 2016Saadoun 2015Gragnani 2016Gragnani 2016

Bonacci 2016Hegazy 2016Kondili 2016Emery 2017

Younossi et al

The annual costs (inpatient outpatient andpharmacy) associated with extrahepatic

manifestations of HCV were evaluated

Total direct medical costs of extrahepatic

manifestations of HCV in 2014 US dollars wereestimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related

burden of disease to obtain a more accurateassessment of the total burden of HCV infection

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

Extrahepatic Manifestations of HCV

Extrahepatic Manifestations of HCV

HCV may cause extrahepatic disorders (HCV-EHDs) classified according to the number and

strength of supporting scientific data

HCV-EHDs are responsible for increasing morbidity and mortality with important

consequences in terms of social costs

The analysis of mortality rates in large cohorts confirmed the association of HCV with

several EHDs including cardiovascular neurologic metabolic or renal diseases and tumors

Viral eradication significantly reduced the rate of extra-hepatic deaths

Cacoub P et al DLD 2014 Lee MH et al J Infect Dis 2012 Backus LI et al Clin Gastroenterol Hepatol 2011 El-Kamary S et al

Clin Infect Dis 2011 Hsu YC et al Hepatology 2014 Kawamura Y et al Am J Med 2007 Adinolfi LE et al WJG 2014

Con il contributo di

Lee M-H et al J Infect Dis 2012206469-477

Follow-Up

(Years)

20

18

16

14

12

10

2

00 2 4 6 8 10 12 14 16 18 20

8

6

4

Follow-Up

(Years)

12

10

8

6

4

2

00 2 4 6 8 10 12 14 16 18 20

All Causes(n=2394)

Liver Cancer(n=115)

Extrahepatic Diseases(n=2199)

Cum

ula

tive M

ort

ali

ty (

)

Anti-HCV+ HCV RNA detectable Anti-HCV+ HCV RNA undetectable Anti-HCVndash

Follow-Up

(Years)

35

30

25

20

15

10

5

00 2 4 6 8 10 12 14 16 18 20

301

128124

104

16

03

198

122

110

Extrahepatic Manifestations of HCV

The annual costs (inpatient outpatient andpharmacy) associated with extrahepatic

manifestations of HCV were evaluated

Total direct medical costs of extrahepatic

manifestations of HCV in 2014 US dollars wereestimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related

burden of disease to obtain a more accurateassessment of the total burden of HCV infection

Younossi et al

Younossi et al

Costs up to $71000 per patient per year (ESRD) Among the most frequent EHM depression (245 in HCV vs 172 in non-HCV) had estimated annual cost of

$4307 million DM (15 vs 10 in non- HCV) had an annual cost of $4434 million in the USA= given the importance of DM and

its association with CVDs and mortality the clinical and economic impacts of HCV-related DM are substantial

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

The OBJECTIVE of the study was to estimate the annual direct medicalcosts associated with HCV related EHM in the EU5 (France Germany

Italy United Kingdom Spain)

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

The most studied and frequent HCV-EHDs are B-LPDs andor autoimmune disorders

Their prototype is Mixed Cryoglobulinemia (MC) from researches on MC derived most of the

available information

MC as a precious model for all the HCV-EHDs and to evaluate the effects of viral eradication

Anti-HCV Treatment Evolution

IFN

6 mos

PegIFN RBV 12

mos

IFN

12 mos

IFNRBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN

RBV

DAA

IFNRBV

6 mos

6

16

34

4239

55

70+

0

20

40

60

80

100

DAAs

826

weeks

gt90

2015

Few side effects absence major

contraindications

Younossi et al

The annual costs (inpatient outpatient and pharmacy) associatedwith extrahepatic manifestations of HCV were evaluated

Total direct medical costs of extrahepatic manifestations of HCV in 2014US dollars were estimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of diseaseto obtain a more accurate assessment of the total burden of HCV

infection

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

HCV infection is closely related to LPDs mostly MC

40 to 60 of HCV patients show circulating CGs among this latter population 5-30

develop a symptomatic CV

AVT has been considered the first-line option in HCV-CV patients in fact in the majority

of cases viral eradication leads to CV clinical remission

Data about IFN-free regimens for the treatment of CV patients are still limited

HCV and MC

HCV and MC

Zignego 2015Ferri 2016Pozzato 2016 Sise 2016Saadoun 2015Gragnani 2016Gragnani 2016

Bonacci 2016Hegazy 2016Kondili 2016Emery 2017

Younossi et al

The annual costs (inpatient outpatient andpharmacy) associated with extrahepatic

manifestations of HCV were evaluated

Total direct medical costs of extrahepatic

manifestations of HCV in 2014 US dollars wereestimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related

burden of disease to obtain a more accurateassessment of the total burden of HCV infection

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

Extrahepatic Manifestations of HCV

Extrahepatic Manifestations of HCV

HCV may cause extrahepatic disorders (HCV-EHDs) classified according to the number and

strength of supporting scientific data

HCV-EHDs are responsible for increasing morbidity and mortality with important

consequences in terms of social costs

The analysis of mortality rates in large cohorts confirmed the association of HCV with

several EHDs including cardiovascular neurologic metabolic or renal diseases and tumors

Viral eradication significantly reduced the rate of extra-hepatic deaths

Cacoub P et al DLD 2014 Lee MH et al J Infect Dis 2012 Backus LI et al Clin Gastroenterol Hepatol 2011 El-Kamary S et al

Clin Infect Dis 2011 Hsu YC et al Hepatology 2014 Kawamura Y et al Am J Med 2007 Adinolfi LE et al WJG 2014

Con il contributo di

Lee M-H et al J Infect Dis 2012206469-477

Follow-Up

(Years)

20

18

16

14

12

10

2

00 2 4 6 8 10 12 14 16 18 20

8

6

4

Follow-Up

(Years)

12

10

8

6

4

2

00 2 4 6 8 10 12 14 16 18 20

All Causes(n=2394)

Liver Cancer(n=115)

Extrahepatic Diseases(n=2199)

Cum

ula

tive M

ort

ali

ty (

)

Anti-HCV+ HCV RNA detectable Anti-HCV+ HCV RNA undetectable Anti-HCVndash

Follow-Up

(Years)

35

30

25

20

15

10

5

00 2 4 6 8 10 12 14 16 18 20

301

128124

104

16

03

198

122

110

Extrahepatic Manifestations of HCV

The annual costs (inpatient outpatient andpharmacy) associated with extrahepatic

manifestations of HCV were evaluated

Total direct medical costs of extrahepatic

manifestations of HCV in 2014 US dollars wereestimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related

burden of disease to obtain a more accurateassessment of the total burden of HCV infection

Younossi et al

Younossi et al

Costs up to $71000 per patient per year (ESRD) Among the most frequent EHM depression (245 in HCV vs 172 in non-HCV) had estimated annual cost of

$4307 million DM (15 vs 10 in non- HCV) had an annual cost of $4434 million in the USA= given the importance of DM and

its association with CVDs and mortality the clinical and economic impacts of HCV-related DM are substantial

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

The OBJECTIVE of the study was to estimate the annual direct medicalcosts associated with HCV related EHM in the EU5 (France Germany

Italy United Kingdom Spain)

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

The most studied and frequent HCV-EHDs are B-LPDs andor autoimmune disorders

Their prototype is Mixed Cryoglobulinemia (MC) from researches on MC derived most of the

available information

MC as a precious model for all the HCV-EHDs and to evaluate the effects of viral eradication

Anti-HCV Treatment Evolution

IFN

6 mos

PegIFN RBV 12

mos

IFN

12 mos

IFNRBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN

RBV

DAA

IFNRBV

6 mos

6

16

34

4239

55

70+

0

20

40

60

80

100

DAAs

826

weeks

gt90

2015

Few side effects absence major

contraindications

Younossi et al

The annual costs (inpatient outpatient and pharmacy) associatedwith extrahepatic manifestations of HCV were evaluated

Total direct medical costs of extrahepatic manifestations of HCV in 2014US dollars were estimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of diseaseto obtain a more accurate assessment of the total burden of HCV

infection

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

Younossi et al

The annual costs (inpatient outpatient andpharmacy) associated with extrahepatic

manifestations of HCV were evaluated

Total direct medical costs of extrahepatic

manifestations of HCV in 2014 US dollars wereestimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related

burden of disease to obtain a more accurateassessment of the total burden of HCV infection

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

Extrahepatic Manifestations of HCV

Extrahepatic Manifestations of HCV

HCV may cause extrahepatic disorders (HCV-EHDs) classified according to the number and

strength of supporting scientific data

HCV-EHDs are responsible for increasing morbidity and mortality with important

consequences in terms of social costs

The analysis of mortality rates in large cohorts confirmed the association of HCV with

several EHDs including cardiovascular neurologic metabolic or renal diseases and tumors

Viral eradication significantly reduced the rate of extra-hepatic deaths

Cacoub P et al DLD 2014 Lee MH et al J Infect Dis 2012 Backus LI et al Clin Gastroenterol Hepatol 2011 El-Kamary S et al

Clin Infect Dis 2011 Hsu YC et al Hepatology 2014 Kawamura Y et al Am J Med 2007 Adinolfi LE et al WJG 2014

Con il contributo di

Lee M-H et al J Infect Dis 2012206469-477

Follow-Up

(Years)

20

18

16

14

12

10

2

00 2 4 6 8 10 12 14 16 18 20

8

6

4

Follow-Up

(Years)

12

10

8

6

4

2

00 2 4 6 8 10 12 14 16 18 20

All Causes(n=2394)

Liver Cancer(n=115)

Extrahepatic Diseases(n=2199)

Cum

ula

tive M

ort

ali

ty (

)

Anti-HCV+ HCV RNA detectable Anti-HCV+ HCV RNA undetectable Anti-HCVndash

Follow-Up

(Years)

35

30

25

20

15

10

5

00 2 4 6 8 10 12 14 16 18 20

301

128124

104

16

03

198

122

110

Extrahepatic Manifestations of HCV

The annual costs (inpatient outpatient andpharmacy) associated with extrahepatic

manifestations of HCV were evaluated

Total direct medical costs of extrahepatic

manifestations of HCV in 2014 US dollars wereestimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related

burden of disease to obtain a more accurateassessment of the total burden of HCV infection

Younossi et al

Younossi et al

Costs up to $71000 per patient per year (ESRD) Among the most frequent EHM depression (245 in HCV vs 172 in non-HCV) had estimated annual cost of

$4307 million DM (15 vs 10 in non- HCV) had an annual cost of $4434 million in the USA= given the importance of DM and

its association with CVDs and mortality the clinical and economic impacts of HCV-related DM are substantial

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

The OBJECTIVE of the study was to estimate the annual direct medicalcosts associated with HCV related EHM in the EU5 (France Germany

Italy United Kingdom Spain)

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

The most studied and frequent HCV-EHDs are B-LPDs andor autoimmune disorders

Their prototype is Mixed Cryoglobulinemia (MC) from researches on MC derived most of the

available information

MC as a precious model for all the HCV-EHDs and to evaluate the effects of viral eradication

Anti-HCV Treatment Evolution

IFN

6 mos

PegIFN RBV 12

mos

IFN

12 mos

IFNRBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN

RBV

DAA

IFNRBV

6 mos

6

16

34

4239

55

70+

0

20

40

60

80

100

DAAs

826

weeks

gt90

2015

Few side effects absence major

contraindications

Younossi et al

The annual costs (inpatient outpatient and pharmacy) associatedwith extrahepatic manifestations of HCV were evaluated

Total direct medical costs of extrahepatic manifestations of HCV in 2014US dollars were estimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of diseaseto obtain a more accurate assessment of the total burden of HCV

infection

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

Extrahepatic Manifestations of HCV

Extrahepatic Manifestations of HCV

HCV may cause extrahepatic disorders (HCV-EHDs) classified according to the number and

strength of supporting scientific data

HCV-EHDs are responsible for increasing morbidity and mortality with important

consequences in terms of social costs

The analysis of mortality rates in large cohorts confirmed the association of HCV with

several EHDs including cardiovascular neurologic metabolic or renal diseases and tumors

Viral eradication significantly reduced the rate of extra-hepatic deaths

Cacoub P et al DLD 2014 Lee MH et al J Infect Dis 2012 Backus LI et al Clin Gastroenterol Hepatol 2011 El-Kamary S et al

Clin Infect Dis 2011 Hsu YC et al Hepatology 2014 Kawamura Y et al Am J Med 2007 Adinolfi LE et al WJG 2014

Con il contributo di

Lee M-H et al J Infect Dis 2012206469-477

Follow-Up

(Years)

20

18

16

14

12

10

2

00 2 4 6 8 10 12 14 16 18 20

8

6

4

Follow-Up

(Years)

12

10

8

6

4

2

00 2 4 6 8 10 12 14 16 18 20

All Causes(n=2394)

Liver Cancer(n=115)

Extrahepatic Diseases(n=2199)

Cum

ula

tive M

ort

ali

ty (

)

Anti-HCV+ HCV RNA detectable Anti-HCV+ HCV RNA undetectable Anti-HCVndash

Follow-Up

(Years)

35

30

25

20

15

10

5

00 2 4 6 8 10 12 14 16 18 20

301

128124

104

16

03

198

122

110

Extrahepatic Manifestations of HCV

The annual costs (inpatient outpatient andpharmacy) associated with extrahepatic

manifestations of HCV were evaluated

Total direct medical costs of extrahepatic

manifestations of HCV in 2014 US dollars wereestimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related

burden of disease to obtain a more accurateassessment of the total burden of HCV infection

Younossi et al

Younossi et al

Costs up to $71000 per patient per year (ESRD) Among the most frequent EHM depression (245 in HCV vs 172 in non-HCV) had estimated annual cost of

$4307 million DM (15 vs 10 in non- HCV) had an annual cost of $4434 million in the USA= given the importance of DM and

its association with CVDs and mortality the clinical and economic impacts of HCV-related DM are substantial

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

The OBJECTIVE of the study was to estimate the annual direct medicalcosts associated with HCV related EHM in the EU5 (France Germany

Italy United Kingdom Spain)

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

The most studied and frequent HCV-EHDs are B-LPDs andor autoimmune disorders

Their prototype is Mixed Cryoglobulinemia (MC) from researches on MC derived most of the

available information

MC as a precious model for all the HCV-EHDs and to evaluate the effects of viral eradication

Anti-HCV Treatment Evolution

IFN

6 mos

PegIFN RBV 12

mos

IFN

12 mos

IFNRBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN

RBV

DAA

IFNRBV

6 mos

6

16

34

4239

55

70+

0

20

40

60

80

100

DAAs

826

weeks

gt90

2015

Few side effects absence major

contraindications

Younossi et al

The annual costs (inpatient outpatient and pharmacy) associatedwith extrahepatic manifestations of HCV were evaluated

Total direct medical costs of extrahepatic manifestations of HCV in 2014US dollars were estimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of diseaseto obtain a more accurate assessment of the total burden of HCV

infection

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

Extrahepatic Manifestations of HCV

Extrahepatic Manifestations of HCV

HCV may cause extrahepatic disorders (HCV-EHDs) classified according to the number and

strength of supporting scientific data

HCV-EHDs are responsible for increasing morbidity and mortality with important

consequences in terms of social costs

The analysis of mortality rates in large cohorts confirmed the association of HCV with

several EHDs including cardiovascular neurologic metabolic or renal diseases and tumors

Viral eradication significantly reduced the rate of extra-hepatic deaths

Cacoub P et al DLD 2014 Lee MH et al J Infect Dis 2012 Backus LI et al Clin Gastroenterol Hepatol 2011 El-Kamary S et al

Clin Infect Dis 2011 Hsu YC et al Hepatology 2014 Kawamura Y et al Am J Med 2007 Adinolfi LE et al WJG 2014

Con il contributo di

Lee M-H et al J Infect Dis 2012206469-477

Follow-Up

(Years)

20

18

16

14

12

10

2

00 2 4 6 8 10 12 14 16 18 20

8

6

4

Follow-Up

(Years)

12

10

8

6

4

2

00 2 4 6 8 10 12 14 16 18 20

All Causes(n=2394)

Liver Cancer(n=115)

Extrahepatic Diseases(n=2199)

Cum

ula

tive M

ort

ali

ty (

)

Anti-HCV+ HCV RNA detectable Anti-HCV+ HCV RNA undetectable Anti-HCVndash

Follow-Up

(Years)

35

30

25

20

15

10

5

00 2 4 6 8 10 12 14 16 18 20

301

128124

104

16

03

198

122

110

Extrahepatic Manifestations of HCV

The annual costs (inpatient outpatient andpharmacy) associated with extrahepatic

manifestations of HCV were evaluated

Total direct medical costs of extrahepatic

manifestations of HCV in 2014 US dollars wereestimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related

burden of disease to obtain a more accurateassessment of the total burden of HCV infection

Younossi et al

Younossi et al

Costs up to $71000 per patient per year (ESRD) Among the most frequent EHM depression (245 in HCV vs 172 in non-HCV) had estimated annual cost of

$4307 million DM (15 vs 10 in non- HCV) had an annual cost of $4434 million in the USA= given the importance of DM and

its association with CVDs and mortality the clinical and economic impacts of HCV-related DM are substantial

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

The OBJECTIVE of the study was to estimate the annual direct medicalcosts associated with HCV related EHM in the EU5 (France Germany

Italy United Kingdom Spain)

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

The most studied and frequent HCV-EHDs are B-LPDs andor autoimmune disorders

Their prototype is Mixed Cryoglobulinemia (MC) from researches on MC derived most of the

available information

MC as a precious model for all the HCV-EHDs and to evaluate the effects of viral eradication

Anti-HCV Treatment Evolution

IFN

6 mos

PegIFN RBV 12

mos

IFN

12 mos

IFNRBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN

RBV

DAA

IFNRBV

6 mos

6

16

34

4239

55

70+

0

20

40

60

80

100

DAAs

826

weeks

gt90

2015

Few side effects absence major

contraindications

Younossi et al

The annual costs (inpatient outpatient and pharmacy) associatedwith extrahepatic manifestations of HCV were evaluated

Total direct medical costs of extrahepatic manifestations of HCV in 2014US dollars were estimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of diseaseto obtain a more accurate assessment of the total burden of HCV

infection

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

Extrahepatic Manifestations of HCV

HCV may cause extrahepatic disorders (HCV-EHDs) classified according to the number and

strength of supporting scientific data

HCV-EHDs are responsible for increasing morbidity and mortality with important

consequences in terms of social costs

The analysis of mortality rates in large cohorts confirmed the association of HCV with

several EHDs including cardiovascular neurologic metabolic or renal diseases and tumors

Viral eradication significantly reduced the rate of extra-hepatic deaths

Cacoub P et al DLD 2014 Lee MH et al J Infect Dis 2012 Backus LI et al Clin Gastroenterol Hepatol 2011 El-Kamary S et al

Clin Infect Dis 2011 Hsu YC et al Hepatology 2014 Kawamura Y et al Am J Med 2007 Adinolfi LE et al WJG 2014

Con il contributo di

Lee M-H et al J Infect Dis 2012206469-477

Follow-Up

(Years)

20

18

16

14

12

10

2

00 2 4 6 8 10 12 14 16 18 20

8

6

4

Follow-Up

(Years)

12

10

8

6

4

2

00 2 4 6 8 10 12 14 16 18 20

All Causes(n=2394)

Liver Cancer(n=115)

Extrahepatic Diseases(n=2199)

Cum

ula

tive M

ort

ali

ty (

)

Anti-HCV+ HCV RNA detectable Anti-HCV+ HCV RNA undetectable Anti-HCVndash

Follow-Up

(Years)

35

30

25

20

15

10

5

00 2 4 6 8 10 12 14 16 18 20

301

128124

104

16

03

198

122

110

Extrahepatic Manifestations of HCV

The annual costs (inpatient outpatient andpharmacy) associated with extrahepatic

manifestations of HCV were evaluated

Total direct medical costs of extrahepatic

manifestations of HCV in 2014 US dollars wereestimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related

burden of disease to obtain a more accurateassessment of the total burden of HCV infection

Younossi et al

Younossi et al

Costs up to $71000 per patient per year (ESRD) Among the most frequent EHM depression (245 in HCV vs 172 in non-HCV) had estimated annual cost of

$4307 million DM (15 vs 10 in non- HCV) had an annual cost of $4434 million in the USA= given the importance of DM and

its association with CVDs and mortality the clinical and economic impacts of HCV-related DM are substantial

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

The OBJECTIVE of the study was to estimate the annual direct medicalcosts associated with HCV related EHM in the EU5 (France Germany

Italy United Kingdom Spain)

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

The most studied and frequent HCV-EHDs are B-LPDs andor autoimmune disorders

Their prototype is Mixed Cryoglobulinemia (MC) from researches on MC derived most of the

available information

MC as a precious model for all the HCV-EHDs and to evaluate the effects of viral eradication

Anti-HCV Treatment Evolution

IFN

6 mos

PegIFN RBV 12

mos

IFN

12 mos

IFNRBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN

RBV

DAA

IFNRBV

6 mos

6

16

34

4239

55

70+

0

20

40

60

80

100

DAAs

826

weeks

gt90

2015

Few side effects absence major

contraindications

Younossi et al

The annual costs (inpatient outpatient and pharmacy) associatedwith extrahepatic manifestations of HCV were evaluated

Total direct medical costs of extrahepatic manifestations of HCV in 2014US dollars were estimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of diseaseto obtain a more accurate assessment of the total burden of HCV

infection

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

HCV-EHDs are responsible for increasing morbidity and mortality with important

consequences in terms of social costs

The analysis of mortality rates in large cohorts confirmed the association of HCV with

several EHDs including cardiovascular neurologic metabolic or renal diseases and tumors

Viral eradication significantly reduced the rate of extra-hepatic deaths

Cacoub P et al DLD 2014 Lee MH et al J Infect Dis 2012 Backus LI et al Clin Gastroenterol Hepatol 2011 El-Kamary S et al

Clin Infect Dis 2011 Hsu YC et al Hepatology 2014 Kawamura Y et al Am J Med 2007 Adinolfi LE et al WJG 2014

Con il contributo di

Lee M-H et al J Infect Dis 2012206469-477

Follow-Up

(Years)

20

18

16

14

12

10

2

00 2 4 6 8 10 12 14 16 18 20

8

6

4

Follow-Up

(Years)

12

10

8

6

4

2

00 2 4 6 8 10 12 14 16 18 20

All Causes(n=2394)

Liver Cancer(n=115)

Extrahepatic Diseases(n=2199)

Cum

ula

tive M

ort

ali

ty (

)

Anti-HCV+ HCV RNA detectable Anti-HCV+ HCV RNA undetectable Anti-HCVndash

Follow-Up

(Years)

35

30

25

20

15

10

5

00 2 4 6 8 10 12 14 16 18 20

301

128124

104

16

03

198

122

110

Extrahepatic Manifestations of HCV

The annual costs (inpatient outpatient andpharmacy) associated with extrahepatic

manifestations of HCV were evaluated

Total direct medical costs of extrahepatic

manifestations of HCV in 2014 US dollars wereestimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related

burden of disease to obtain a more accurateassessment of the total burden of HCV infection

Younossi et al

Younossi et al

Costs up to $71000 per patient per year (ESRD) Among the most frequent EHM depression (245 in HCV vs 172 in non-HCV) had estimated annual cost of

$4307 million DM (15 vs 10 in non- HCV) had an annual cost of $4434 million in the USA= given the importance of DM and

its association with CVDs and mortality the clinical and economic impacts of HCV-related DM are substantial

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

The OBJECTIVE of the study was to estimate the annual direct medicalcosts associated with HCV related EHM in the EU5 (France Germany

Italy United Kingdom Spain)

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

The most studied and frequent HCV-EHDs are B-LPDs andor autoimmune disorders

Their prototype is Mixed Cryoglobulinemia (MC) from researches on MC derived most of the

available information

MC as a precious model for all the HCV-EHDs and to evaluate the effects of viral eradication

Anti-HCV Treatment Evolution

IFN

6 mos

PegIFN RBV 12

mos

IFN

12 mos

IFNRBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN

RBV

DAA

IFNRBV

6 mos

6

16

34

4239

55

70+

0

20

40

60

80

100

DAAs

826

weeks

gt90

2015

Few side effects absence major

contraindications

Younossi et al

The annual costs (inpatient outpatient and pharmacy) associatedwith extrahepatic manifestations of HCV were evaluated

Total direct medical costs of extrahepatic manifestations of HCV in 2014US dollars were estimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of diseaseto obtain a more accurate assessment of the total burden of HCV

infection

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

The annual costs (inpatient outpatient andpharmacy) associated with extrahepatic

manifestations of HCV were evaluated

Total direct medical costs of extrahepatic

manifestations of HCV in 2014 US dollars wereestimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related

burden of disease to obtain a more accurateassessment of the total burden of HCV infection

Younossi et al

Younossi et al

Costs up to $71000 per patient per year (ESRD) Among the most frequent EHM depression (245 in HCV vs 172 in non-HCV) had estimated annual cost of

$4307 million DM (15 vs 10 in non- HCV) had an annual cost of $4434 million in the USA= given the importance of DM and

its association with CVDs and mortality the clinical and economic impacts of HCV-related DM are substantial

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

The OBJECTIVE of the study was to estimate the annual direct medicalcosts associated with HCV related EHM in the EU5 (France Germany

Italy United Kingdom Spain)

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

The most studied and frequent HCV-EHDs are B-LPDs andor autoimmune disorders

Their prototype is Mixed Cryoglobulinemia (MC) from researches on MC derived most of the

available information

MC as a precious model for all the HCV-EHDs and to evaluate the effects of viral eradication

Anti-HCV Treatment Evolution

IFN

6 mos

PegIFN RBV 12

mos

IFN

12 mos

IFNRBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN

RBV

DAA

IFNRBV

6 mos

6

16

34

4239

55

70+

0

20

40

60

80

100

DAAs

826

weeks

gt90

2015

Few side effects absence major

contraindications

Younossi et al

The annual costs (inpatient outpatient and pharmacy) associatedwith extrahepatic manifestations of HCV were evaluated

Total direct medical costs of extrahepatic manifestations of HCV in 2014US dollars were estimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of diseaseto obtain a more accurate assessment of the total burden of HCV

infection

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

Younossi et al

Costs up to $71000 per patient per year (ESRD) Among the most frequent EHM depression (245 in HCV vs 172 in non-HCV) had estimated annual cost of

$4307 million DM (15 vs 10 in non- HCV) had an annual cost of $4434 million in the USA= given the importance of DM and

its association with CVDs and mortality the clinical and economic impacts of HCV-related DM are substantial

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

The OBJECTIVE of the study was to estimate the annual direct medicalcosts associated with HCV related EHM in the EU5 (France Germany

Italy United Kingdom Spain)

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

The most studied and frequent HCV-EHDs are B-LPDs andor autoimmune disorders

Their prototype is Mixed Cryoglobulinemia (MC) from researches on MC derived most of the

available information

MC as a precious model for all the HCV-EHDs and to evaluate the effects of viral eradication

Anti-HCV Treatment Evolution

IFN

6 mos

PegIFN RBV 12

mos

IFN

12 mos

IFNRBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN

RBV

DAA

IFNRBV

6 mos

6

16

34

4239

55

70+

0

20

40

60

80

100

DAAs

826

weeks

gt90

2015

Few side effects absence major

contraindications

Younossi et al

The annual costs (inpatient outpatient and pharmacy) associatedwith extrahepatic manifestations of HCV were evaluated

Total direct medical costs of extrahepatic manifestations of HCV in 2014US dollars were estimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of diseaseto obtain a more accurate assessment of the total burden of HCV

infection

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

The OBJECTIVE of the study was to estimate the annual direct medical costsassociated with HCV related EHM in the EU5 (France Germany Italy United Kingdom

Spain)

The OBJECTIVE of the study was to estimate the annual direct medicalcosts associated with HCV related EHM in the EU5 (France Germany

Italy United Kingdom Spain)

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

The most studied and frequent HCV-EHDs are B-LPDs andor autoimmune disorders

Their prototype is Mixed Cryoglobulinemia (MC) from researches on MC derived most of the

available information

MC as a precious model for all the HCV-EHDs and to evaluate the effects of viral eradication

Anti-HCV Treatment Evolution

IFN

6 mos

PegIFN RBV 12

mos

IFN

12 mos

IFNRBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN

RBV

DAA

IFNRBV

6 mos

6

16

34

4239

55

70+

0

20

40

60

80

100

DAAs

826

weeks

gt90

2015

Few side effects absence major

contraindications

Younossi et al

The annual costs (inpatient outpatient and pharmacy) associatedwith extrahepatic manifestations of HCV were evaluated

Total direct medical costs of extrahepatic manifestations of HCV in 2014US dollars were estimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of diseaseto obtain a more accurate assessment of the total burden of HCV

infection

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

The OBJECTIVE of the study was to estimate the annual direct medicalcosts associated with HCV related EHM in the EU5 (France Germany

Italy United Kingdom Spain)

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

The most studied and frequent HCV-EHDs are B-LPDs andor autoimmune disorders

Their prototype is Mixed Cryoglobulinemia (MC) from researches on MC derived most of the

available information

MC as a precious model for all the HCV-EHDs and to evaluate the effects of viral eradication

Anti-HCV Treatment Evolution

IFN

6 mos

PegIFN RBV 12

mos

IFN

12 mos

IFNRBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN

RBV

DAA

IFNRBV

6 mos

6

16

34

4239

55

70+

0

20

40

60

80

100

DAAs

826

weeks

gt90

2015

Few side effects absence major

contraindications

Younossi et al

The annual costs (inpatient outpatient and pharmacy) associatedwith extrahepatic manifestations of HCV were evaluated

Total direct medical costs of extrahepatic manifestations of HCV in 2014US dollars were estimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of diseaseto obtain a more accurate assessment of the total burden of HCV

infection

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

1 HCV is the main etiopathological agent as concordantly demonstrated by epidemiological clinico-pathological virological and laboratory investigations2 the association between HCV and disease is demonstrated in a significant proportion of patients and supported by in depth clinico-pathogeneticstudies3 the association is suggested by cohort studies a possible causative role may be limited to a small number of patients andor possibly more relevant in specific geographical areas 4 a number of anecdotal observations suggested a possible role of HCV further investigations are required

The most studied and frequent HCV-EHDs are B-LPDs andor autoimmune disorders

Their prototype is Mixed Cryoglobulinemia (MC) from researches on MC derived most of the

available information

MC as a precious model for all the HCV-EHDs and to evaluate the effects of viral eradication

Anti-HCV Treatment Evolution

IFN

6 mos

PegIFN RBV 12

mos

IFN

12 mos

IFNRBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN

RBV

DAA

IFNRBV

6 mos

6

16

34

4239

55

70+

0

20

40

60

80

100

DAAs

826

weeks

gt90

2015

Few side effects absence major

contraindications

Younossi et al

The annual costs (inpatient outpatient and pharmacy) associatedwith extrahepatic manifestations of HCV were evaluated

Total direct medical costs of extrahepatic manifestations of HCV in 2014US dollars were estimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of diseaseto obtain a more accurate assessment of the total burden of HCV

infection

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

Anti-HCV Treatment Evolution

IFN

6 mos

PegIFN RBV 12

mos

IFN

12 mos

IFNRBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN

RBV

DAA

IFNRBV

6 mos

6

16

34

4239

55

70+

0

20

40

60

80

100

DAAs

826

weeks

gt90

2015

Few side effects absence major

contraindications

Younossi et al

The annual costs (inpatient outpatient and pharmacy) associatedwith extrahepatic manifestations of HCV were evaluated

Total direct medical costs of extrahepatic manifestations of HCV in 2014US dollars were estimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of diseaseto obtain a more accurate assessment of the total burden of HCV

infection

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

Younossi et al

The annual costs (inpatient outpatient and pharmacy) associatedwith extrahepatic manifestations of HCV were evaluated

Total direct medical costs of extrahepatic manifestations of HCV in 2014US dollars were estimated to be $1506 million (range $922 millionndash

$2208 million in sensitivity analysis)

These estimates should be added to the liver-related burden of diseaseto obtain a more accurate assessment of the total burden of HCV

infection

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

The OBJECTIVE of the study was to estimate the annual direct medical costs associated with HCV related EHM in the EU5 (France Germany Italy United Kingdom Spain)

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

22 MCS treated with DAAs including 2 HCC and 2 NHL 100 SVR12 Clinical CR in 64 and PR in remaining 36 The small lymphocytic lymphoma progressed despite viral clearance

Lauletta et al 2017

Emery CS et al 2017

Retrospective analysis 17 MCS (10 with severelife-threatening vasculitis) and 65 asymptomatic CGs+ pts treated with DAAs SVR 889 MCS and 908 asymptomatic pts In MCS clinical response in 1117 (complete in 717) In severelife-threatening vasculitis lower clinical response especially in renal and neurological symptoms

Saadoun D et al 2017

Open-label prospective multi-center study on sofosbuvir plus daclatasvir treatment of 41 HCV MCS SVR in100 and clinical CR in 902 Disappearance of CGs in 50 of pts No serious adverse event or relapse ofvasculitis

Antiviral Treatment (AVT) of MCIFN-free regimens

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal

MC is clinically benign but sometimes severe HCV EHD invalidating symptoms occur and

it may evolve into lymphoma

Cacoub P et al DLD 2014 Zignego AL et al DLD 2007 Zignego AL et al Intern Emerg Med 2012 Zignego AL et al Clin Dev

Immunol 2012 Zignego AL et al Expert Rev Clin Immunol 2015 Sene D et al J Rheumatol 2004

Mixed Cryoglobulinemia-MC

MC pathological substrate is an HCV-driven B-cell

proliferation with consequent production of cryo- and non-

cryoprecipitable CICs in turn responsible for vasculitic

manifestations

Most (70ndash90) MC patients are HCV+ and HCV-patients are CGs+ (40ndash60) while 5ndash30 of

CGs+ have symptomatic MC or cryoglobulinemic vasculitis since HCV infects about 170

million individuals worldwide the number of patients at risk for developing MC is

substantial

Type II CGs

monoclonal

RF+policlonal IgG

Type III CGs both

RF and IgG

polyclonal