Terapia delle Epatiti Virali Croniche: la prospettiva della Farmacoeconomia

Raffaele Bruno, MD

Department of Infectious Diseases Hepatology Outpatients Unit San Matteo Hospital - University of Pavia Fondazione IRCCS Policlinico San Matteo Pavia, Italy

Il contesto socioeconomico

Le risorse sanitarie sono limitate Le risorse dedicate ad un intervento non possono essere dedicate ad un altro La domanda di salute imporrebbe un ’ espansione della spesa sanitaria pressoché illimitata È necessario decidere quali interventi finanziare, con quale priorità Quali informazioni supportano le decisioni?

Debito pubblico paesi UE

La Spesa Snitaria: le cifre

HCV - Scenario Attuale

HCV TECHNICAL REPORT Hepatitis B and C in the EU neighbourhood: prevalence, burden of disease and screening policies September 2010

Titanic consideration

•

April 1912: 2223 passengers – lifeboat capacity of 1178 – 32% survivors Courtesy of prof. P.Toniutto

www.thermstitanic.wikia.com

Percentage of Titanic survivors by class

100 80 % 60 40 20 0

Women and children Men 1st Class 2nd Class 3rd Class Total

http://www.icyousee.org/titanic.html

Medical and ethical consideration

1) Is there a risk of being inequitable in having first-class patients and patients of second- and third-class?

2) Are there patients who can wait for access to new therapies without having a clinical worsening?

Medical ethics

•

EQUITY: the need to distribute equitably the therapeutic resources available

•

INDIVIDUAL JUSTICE: the duty to promote the best interests of the individual patient

•

UTILITY: the duty to strive to obtain the best results for the correct population using the therapeutic resources

Calman KC and Downie RS. Oxford Textbook of Public Health. Chapter 4.4

Medical ethics

•

EQUITY: the need to distribute equitably the therapeutic resources available

•

INDIVIDUAL JUSTICE: the duty to promote the best interests of the individual patient

–

Medical urgency

•

UTILITY: the duty to strive to obtain the best results for the correct population using the therapeutic resources

Calman KC and Downie RS. Oxford Textbook of Public Health. Chapter 4.4

Principle

“

Everything that is effective should be given free

” Archie Cochrane 1971

La valutazione delle tecnologie sanitarie

La valutazione economica in sanità non si limita al solo esame dei costi

Background and Aims:

We aimed to assess the socio-economic burden of CHDs in Italy

Direct Costs

(medical and non medical)

Loss of productivity

(days of work/study/daily activities)

Health Related Quality of Life

(HRQoL)

Materials and Methods Type of study Patients and setting Point of view Time horizon Data

Naturalistic, multicentre, longitudinal Cost of Illness study, adopting the societal point of view Any CHD adult patient (>18 years) consecutively accessing a Gastroenterology Unit (Ospedali Riuniti, Bergamo and Ospedale Policlinico Federico II, Napoli) Society (patients, their family caregivers, National Health Service) 6 months before the enrollment in the study • • • • Clinical, Health Related Quality of Life (EQ-5D), Resource consumption (direct costs) • Medical: (related to hepatic disease) conventional drug and unconventional treatment (e.g., homeopathy, herbal medicines, vitamins, etc), hospitalization for reasons attributable to hepatic condition, outpatient medical visits and diagnostic examinations • Non Medical : formal (paid) assistance, travelling and/or accommodation Loss of productivity (indirect costs)

Materials and Methods



“Assisted” Questionnaire:

Patient own-compilation with Physician Supervision 

Retrospective Data collection for the previous 6 months on:

treatments, therapies, procedures, Hospital accesses (Admissions, DH), outpatient clinic pathology,  Costs derived from Regional Tariffary 

EQ5D:

Evaluation of Quality of Life

Results are expressed as



€/Patient/Month (Direct Costs)



Days/Patient/Month ( Loss of Productivity)



EQ5D:

% of Patients with Problems + Visual Analogue Scale

(VAS) score

the “COME” Study Results

1,088 patients enrolled 62.0% male, age range 19-90 (median=59,5)

Chronic Hepatitis

652 (60,0%)

Cirrhosis

222 (20,4%)

HCC

85 (7,8%)

OLT

129(11.9%)

HCV 53,1%

HBV 33,9% Other 46,9% Other 13,0%

HCV 52,3%

HBV 19,0% Other 28,7%

HCV 64,6%

HBV 14,6% Other 20,8%

HCV 26,4%

HBV 20,9% Other 52,8%

HCV: 50,6% HBV: 27,9%

Co-inf: 1,3%

Others: 21,5%

the “COME” Study Results Direct costs according to main condition € 400,00 € 300,00 €/patient/month € 200,00 € 100,00 € 0,00 HBV hepatitis (N=221) outpatient visits/examinations Conventional: antiviral therapy € 16,91 € 239,16 HCV hepatitis (N=346) € 17,48 € 156,32 OTHER hepatitis (includes HBV-HCV co infection) (N=85) € 14,89 € 24,81 Cirrhosis (N=222) € 25,46 € 47,95 HCC (N=85) € 23,61 € 62,82 OLT (N=129) € 8,23 € 150,57

the “COME” Study Results Direct costs according to main condition € 125,00 € 100,00 €/patient/month € 75,00 € 50,00 € 25,00 € 0,00 HBV hepatitis (N=221) travelling/accomodation Formal caregiving (assistance) Unconventional therapy € 12,85 € 1,96 € 8,40 HCV hepatitis (N=346) € 12,65 € 3,22 € 10,89 OTHER hepatitis (includes HBV-HCV co infection) (N=85) € 13,47 € 2,66 € 11,27 Cirrhosis (N=222) € 38,45 € 9,19 € 22,61 HCC (N=85) € 41,21 € 9,28 € 17,30 OLT (N=129) € 79,53 € 17,77 € 16,77

the “COME” Study Results Direct costs according to main condition € 125,00 € 100,00 €/patient/month € 75,00 € 50,00 € 25,00 € 0,00 HBV hepatitis (N=221) travelling/accomodation Formal caregiving (assistance) Unconventional therapy € 12,85 € 1,96 € 8,40 HCV hepatitis (N=346) € 12,65 € 3,22 € 10,89 OTHER hepatitis (includes HBV-HCV co infection) (N=85) € 13,47 € 2,66 € 11,27 Cirrhosis (N=222) € 38,45 € 9,19 € 22,61 HCC (N=85) € 41,21 € 9,28 € 17,30 OLT (N=129) € 79,53 € 17,77 € 16,77

the “COME” Study Results Direct costs according to main condition €/patient/month € 2 400,00 € 2 200,00 € 2 000,00 € 1 800,00 € 1 600,00 € 1 400,00 € 1 200,00 € 1 000,00 € 800,00 € 600,00 € 400,00 € 200,00 € 0,00 Hospitalizations Conventional, excluding antiviral therapy HBV hepatitis (N=221) € 40,08 € 1,64 HCV hepatitis (N=346) € 34,90 € 3,63 OTHER hepatitis (includes HBV HCV co infection) (N=85) € 132,49 € 11,73 Cirrhosis (N=222) € 260,48 € 99,14 HCC (N=85) € 999,84 € 75,10 OLT (N=129) € 1 483,93 € 917,90

the “COME” Study Results Direct costs according to main condition €/patient/month € 2 400,00 € 2 200,00 € 2 000,00 € 1 800,00 € 1 600,00 € 1 400,00 € 1 200,00 € 1 000,00 € 800,00 € 600,00 € 400,00 € 200,00 € 0,00 Hospitalizations Conventional, excluding antiviral therapy HBV hepatitis (N=221) € 40,08 € 1,64 HCV hepatitis (N=346) € 34,90 € 3,63 OTHER hepatitis (includes HBV HCV co infection) (N=85) € 132,49 € 11,73 Cirrhosis (N=222) € 260,48 € 99,14 HCC (N=85) € 999,84 € 75,10 OLT (N=129) € 1 483,93 € 917,90

the “COME” Study Results Direct costs according to main condition €/patient/month € 2 400,00 € 2 200,00 € 2 000,00 € 1 800,00 € 1 600,00 € 1 400,00 € 1 200,00 € 1 000,00 € 800,00 € 600,00 € 400,00 € 200,00 € 0,00 Hospitalizations Conventional, excluding antiviral therapy HBV hepatitis (N=221) € 40,08 € 1,64 HCV hepatitis (N=346) € 34,90 € 3,63 OTHER hepatitis (includes HBV HCV co infection) (N=85) € 132,49 € 11,73 Cirrhosis (N=222) € 260,48 € 99,14 HCC (N=85) € 999,84 € 75,10 OLT (N=129) € 1 483,93 € 917,90

the “COME” Study Results Direct costs according to main condition €/patient/month € 2 400,00 € 2 200,00 € 2 000,00 € 1 800,00 € 1 600,00 € 1 400,00 € 1 200,00 € 1 000,00 € 800,00 € 600,00 € 400,00 € 200,00 € 0,00 Hospitalizations Conventional, excluding antiviral therapy HBV hepatitis (N=221) € 40,08 € 1,64 HCV hepatitis (N=346) € 34,90 € 3,63 OTHER hepatitis (includes HBV HCV co infection) (N=85) € 132,49 € 11,73 Cirrhosis (N=222) € 260,48 € 99,14 HCC (N=85) € 999,84 € 75,10 OLT (N=129) € 1 483,93 € 917,90

the “COME” Study Results Direct costs according to main condition €/patient/month € 2 600,00 € 2 400,00 € 2 200,00 € 2 000,00 € 1 800,00 € 1 600,00 € 1 400,00 € 1 200,00 € 1 000,00 € 800,00 € 600,00 € 400,00 € 200,00 € 0,00 travelling/accomodation Formal caregiving (assistance) outpatient visits/examinations Hospitalizations Unconventional therapy Conventional, excluding antiviral therapy Conventional: antiviral therapy HBV hepatitis (N=221) € 12,85 € 1,96 € 16,91 € 40,08 € 8,40 € 1,64 € 239,16 HCV hepatitis (N=346) € 12,65 € 3,22 € 17,48 € 34,90 € 10,89 € 3,63 € 156,32 OTHER hepatitis (includes HBV HCV co infection) (N=85) € 13,47 € 2,66 € 14,89 € 132,49 € 11,27 € 11,73 € 24,81 Cirrhosis (N=222) € 38,45 € 9,19 € 25,46 € 260,48 € 22,61 € 99,14 € 47,95 HCC (N=85) € 41,21 € 9,28 € 23,61 € 999,84 € 17,30 € 75,10 € 62,82 OLT (N=129) € 79,53 € 17,77 € 8,23 € 1 483,93 € 16,77 € 917,90 € 150,57

the

“

COME

”

Study Results HCV : Total costs 2500 2000 1500 1000 500 0

Conventional drug treatment Unconventional treatment Hospitalizations Outpatient medical visits and examinations Formal caregiving Traveling/accomodation Hepatitis OTHER 184,06 9,31 65,5 16,29 2,14 13 Hepatitis HCV 160 10,9 34,4 17,38 3,17 12,6 Cirrhosis HCV 111,7 24,03 228,54 26,87 7,21 35,05 HCC HCV 83,63 18,71 952,12 26,21 11,24 39,86 Liver Transplantation HCV 781,26 18,28 1302,73 8,42 17,32 106,13 HCV Sample (Other Hepatitis not included) 181,25 14,84 242,64 19,64 5,67 25,71

Results Direct costs among patients on antiviral therapy €/patient/month € 1 400,00 € 1 200,00 € 1 000,00 € 800,00 € 600,00 € 400,00 € 200,00 € 0,00 Travelling/Accomodation Formal caregiving (assistance) outpatient visits/examinations Hospitalizations Unconventional therapy Conventional, excluding antiviral therapy Conventional: antiviral therapy HBV hepatitis (N=101) € 10,86 € 2,83 € 17,16 € 36,73 € 10,23 € 2,03 € 471,86 HCV hepatitis (N=42) € 16,00 € 8,00 € 20,84 € 58,20 € 25,04 € 3,46 € 1 269,15 other hepatitis (N=3) € 16,67 € 0,00 € 20,52 € 62,50 € 19,28 € 5,39 € 703,00 Cirrhosis (N=27) € 21,61 € 0,00 € 25,85 € 160,39 € 6,03 € 21,21 € 391,45

Results Direct costs among patients not on antiviral therapy € 500,00 €/ patient/month € 400,00 € 300,00 € 200,00 € 100,00 € 0,00 Travelling/Accomodation Formal caregiving (assistance) outpatient visits/examinations Hospitalizations Unconventional therapy Conventional, excluding antiviral therapy Conventional: antiviral therapy HBV hepatitis (N=118) € 14,56 € 1,21 € 16,70 € 42,94 € 6,82 € 1,23 € 0,00 HCV hepatitis (N=299) € 12,17 € 2,55 € 17,01 € 31,63 € 8,90 € 3,66 € 0,00 other hepatitis (N=82) € 13,35 € 2,76 € 14,68 € 135,05 € 10,98 € 11,96 € 0,00 Cirrhosis (N=194) € 40,80 € 10,47 € 25,41 € 274,41 € 24,91 € 109,98 € 0,00

Results Estimated direct costs (€/patient-month) according to etiology and disease condition

3 500 3 000 2 500 2 000 1 500 1 000 500

160 389 200

0 HCV HBV OTHER HEPATITIS

364 690 575

HCV HBV OTHER CIRRHOSIS

1 174 2 576 1 542 2 368 3 043 2 410

HCV HBV OTHER HCC HCV HBV OTHER OLT

Results Direct costs: Responder vs Non Responder to AV treatment € / month Responder (N=48) Non Responder (N=39) 150,0 100,0 Direct Costs (HCV) HEPATITIS 98,5 109,8 64,6 63,5 50,0 0,0 7,1 5,9 4,0 13,1 13,1 15,3 0,0 3,4 9,7 8,6

Conventional drug treatment Unconventional treatment Hospitalizations Outpatient medical visits and examinations Formal caregiving Travelling accommodation Total

Direct Costs (HCV) 1000 OTHER=OLT+HCC+CIRRHOSIS 800 600 400 200 0 100 136,5

Conventional drug treatment

13,2 18,7

Unconventional treatment

124,1 510,1 Responder (N=6) Non Responder (N=21) € 3.703,2 vs 9.669,6 / yr 16,8 21,3 23,8 13,6 30,7 105,6

Hospitalizations Outpatient medical visits and examinations Formal caregiving Travelling accommodation

308,6 805,8

Total

Results

Indirect Costs according with Patient condition

Loss of productivity* Days/patient/month 3,5 3 2,5 2 1,5 1 0,5 0 Informal caregiver's loss of productivity (days) Patients'loss of productivity (days) HBV hepatitis (N=221) 0,12 0,27 HCV hepatitis (N=346) 0,18 0,43 Other hepatitis (N=85) 0,14 Cirrhosis (N=222) 0,64 0,23 1,09 HCC (N=85) 0,77 0,98 OLT (N=129) 1,21 1,78

* It is reported as mean days lost from work/doing everyday activities per patient-month.

Loss of productivity includes both paid work and unpaid activities, e.g., from students and housewives

Results

Indirect Costs according with Patient condition

Loss of productivity* Days/patient/month 3,5 3 2,5 2 1,5 1 0,5 0 Informal caregiver's loss of productivity (days) Patients'loss of productivity (days) HBV hepatitis (N=221) 0,12 0,27 HCV hepatitis (N=346) 0,18 Other hepatitis (N=85) 0,14 Cirrhosis (N=222) 0,64 0,43 0,23 1,09 HCC (N=85) 0,77 0,98 OLT (N=129) 1,21 1,78

* It is reported as mean days lost from work/doing everyday activities per patient-month.

Loss of productivity includes both paid work and unpaid activities, e.g., from students and housewives

Results Estimated indirect cost (days/patient-month) according to disease condition

4 3,5 3 2,5 2 1,5 1 0,5

1,1 1,1 0,7

0 HCV HBV OTHER HEPATITIS

2,1 1,3 2,4

HCV HBV OTHER CIRRHOSIS

2,3 1,5 2,8 3,2 2,2 3,7

HCV HBV OTHER HCC HCV HBV OLT OTHER

Conclusions

This study provides with an exhaustive picture of the burden of CHDs in Italy, considering the point of view of:

The Third party payer

(NHS, for direct medical costs)

Patients

(HRQoL, productivity loss and some direct costs)

Families (loss of productivity)

Conclusions

The more advanced the Liver disease, the higher are the Global Costs, increasing from a mean of

300,00 €

/month/pt for CH, up to

550,00 €

/month/pt in Chirrosis patients

1.300,00 €

/month/ pt in HCC patients

1.450,00 €

/month/pt in OLT patients

Conclusions

CHD generates High Costs to the Healthcare System The use of effective treatments in the Early Stages of Liver Diseases appears necessary when aiming at:  Reducing worsening of Patient ’ Health  Reducing both Direct and Indirect Costs

• • • • •

Comorbid Conditions Associated with Decision-Making Regarding HCV Treatment in a Large US HMO Retrospective study using Kaiser Permanente database to compare characteristics of those treated vs. those not treated for HCV using IFN-based therapy and to identify significant predictors of not receiving treatment Factors Associated with NOT Receiving Treatment Factors associated with receiving treatment included age 45–65, male gender, cirrhosis, HIV, NAFLD, depression, prior liver transplant 15% (7,945/51,984) of the total number of patients identified with HCV were treated 17% (5,533/32,283) of the study population were treated 42% of the total study population were likely IFN-ineligible or intolerant 50% of the study population had a significant comorbid illness

–

15% were treated, 85% were not treated

Independent variables Anemia Autoimmune disorder Renal dysfunction Cardiovascular disease Psychosis/Bipolar Severe lung disease Substance abuse MELD (≥12) Odds Ratio 0.329

0.775

0.659

0.602

0.678

0.555

0.542

0.385

P-value <0.0001

0.0035

0.0195

<0.0001

0.0051

<0.0001

<0.0001

<0.0001

Nyberg LM, EASL, 2014, O67

The best cost-effective hepatitis C therapy for G1

Naive Relapsers Partial responders Null responders

Telaprevir

No CC +++ ++ >1 log drop HCV RNA in lead-in

Boceprevir

No RVR ++ + >1 log drop HCV RNA in lead-in

Dual

RVR - CC • • • •

Triple therapy is highly cost-effective compared to no therapy inprior relapsers and partial responders.

Either BOC or TLV should be used in prior interferon-experienced patients when the prior failure modality is unknown.

TLV is more cost-effective than BOC in relapsers and partial responders.

Prior null responders with <1 log drop in HCV-RNA in lead-in should stop therapy.

Camma et al. Hepatology 2012; 56: 850-60.

Camma et al. J Hepatol 2013

Estimation of the values of ICER for Sofosbuvir Based Triple Therapy versus DualTherapy under different modeling assumptions of cost per patient with SBTT

The ICER threshold at 60 000 euros is reached at a cost of 16 000 euros per package.

Messori A. et. al. European Journal of Gastroenterology & Hepatology 2014 Jul;26(7):813-4

In untreated Gt 1 chronic hepatitis C patients, at a willingness-to pay threshold of Eu 25,000 per life year gained, sofosbuvir:

•

was cost effective compared with boceprevir in all strategies with the exception of cirrhosis and IL28B CC patients

•

was cost effective compared with telaprevir in IL28B non-CC and Gt 1a patients, but not cost-effective in IL28B CC and in cirrhosis

Frequenza dei casi in cui i prezzi dei farmaci in Italia sono più bassi rispetto ad altri Paesi

I prezzi in Italia risultano generalmente più bassi del 18,9% in media per il mercato in farmacia e dell’8% in media per quello ospedaliero, con un 14,6% in meno come dato complessivo di mercato

CERGAS - Bocconi

IFN free DAA will expand the pool of treatable patients

Mild Severe HCV chronic disease spectrum Currently treated Decomp We must strive to obtain appropriate and effective treatment for all patients Courtesy of Prof.A.Craxì

HCV - Scenario Futuro

Cambio Culturale

Contenimento

SPESA

Accesso Cure

Assistenza Sanitaria INVESTIMENTO In SALUTE

Valore Aggiunto Sociale

Hepatitis B

Evolution of Approved HBV Therapy Over Time

1990 Interferon alfa-2b Lamivudine Peginterferon alfa-2a Entecavir 1998 2002 2005 2006 Adefovir Telbivudine Tenofovir 2008

Therapeutic strategies for HBeAg-negative CHB

PegIFN Short-term treatment Follow-up (yrs) Sustained immune control HBsAg Loss NUCs Long-term treatment Maintained HBV DNA undetectable 5-10 Years HBsAg seroconv.

Optimal first-line therapy in CHB

HBeAg-ve CHB 48 weks of PegIFN in patients having good predictors If not*, long-term therapy with ETV or TDF

*

contraindicated, side effects, not patient’s preference or ineffective EASL CPG: management of CHB virus infection. J Hepatol 2012

On treatment kinetics of HBsAg serum levels in HBeAg negative CHB to predict SVR Week 12 ↓ HBsAg ≥ 0.5 Log IU/mL Week 24 ↓ HBsAg ≥ 1 Log IU/mL 9 pts SVR PPV 8 89% 12 pts 11 92% Week 12 ↓ HBsAg < 0.5 Log IU/mL Week 24 ↓ HBsAg < 1 Log IU/mL 39 pts no SVR NPV 35 90% 36 pts 35 97% Moucari et al. Hepatology 2009

Risultati di costo-efficacia PegIFN in prima linea vs NUC Strategie a confronto PegINF+TDF in CHB vs TDF in CHB PegINF+TDF in Cirrosi vs TDF in Cirrosi PegINF+ETV in CHB vs ETV in CHB PegINF+ETV in Cirrosi vs ETV in Cirrosi ICER DOMINANTE 1.152

DOMINANTE DOMINANTE I risultati dimostrano un incremento di efficacia (QALYs) a favore delle strategie con PegIFN in prima linea rispetto all

’

impiego dei NUC in prima linea.

Tutte le strategie con PegINF in prima linea, ad esclusione di PegINF+TDF in cirrosi mostrano un incremento in efficacia (QALYs) corrispondente ad una riduzione di costi (II quadrante), e possono perciò essere considerate strategie dominanti PegIFN+TDF in Cirrosi consente un incremento di un QALY ad un costo di €1.152.

Cost-effectiveness plane

70

ΔCost (per 1,000)

50 30 -2 -1,5 -1 10 -0,5 -10 0 0,5 1 1,5 2

ΔQALY

-30 -50 PEG-INF + TDF in CHB vs TDF in CHB PEG-INF + ETV in CHB vs ETV in CHB -70 PEG-INF + TDF in CC vs TDF in CC PEG-INF + ETV in CC vs ETV in CC

Iannazzo S et al. AVT 2013

Total costs at 10 years for drugs and other health costs calculated for a cohort of 100 patients Within the Italian health care system, in patients with CHB, tenofovir is a Cost-effective strategy compared with other available therapies. Public health care authorities would benefit from mathematical models designed to estimate the future burden of CHB infection together with the impact of treatment and drug resistance

Economics is ...

“

... study of how societies use scarce resources to produce valuable commodities and distribute them among different people

”

Paul A Samuelson, Nobel Laureate 1970