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HCV:
dalla terapia
efficace allo
screening di
massa?
Gloria Taliani
Sapienza Università di
Roma
1
Treated/cured patients represent only a
small proportion of diagnosed ones…
Eligibility
Reliability
Tolerability
Efficacy
North CS, et al. Gen Hosp Psych 2013;35:122–8.
Advances in hepatitis C therapy with respect to
tolerability and efficacy
Dore GJ and Feld JJ. Clinical Infectious Diseases® 2015;60(12):1829–36
3
New DAAs in GT 1 cirrhotic patients: high
rates of SVR with short duration regimens
SVR
(Compensated)
SVR
(Decompensated)
SOF
+ PEG-IFN + RBV
12–24
81%1
43% (3/7)*2
SOF
+ RBV
24–48
36–78%3–5
68% (CTP B)
12–24
86–100%7,8
7/7 17 (CTP B) 79%20
94-100%18
60-86 19
SOF +
SOF
SMV
+ DCV
± RBV
PTV/
OMV + DSV ± RBV
RTV
SOF
1.
Duration
(weeks)
LDV
±RBV
12- 24
12–24
89–100%9
No data
12–24
86–100%10–14
60–90%15,16
Lawitz E, et al. N Engl J Med 2013;368:1878–87; 2. Forns X, et al. Hepatology 2015;61:
1485-94; 3. Gilead Sciences Europe Ltd. SOVALDI▼ (sofosbuvir), SmPC, March 2015;
4. Sulkowski MS, et al. JAMA 2014;312:353–61; 5. Molina JM, et al. Lancet. 2015;385:1098–106; 6. Afdhal N, et al. EASL 2014;
Oral #68; 7. Lawitz E, et al. Lancet 2014;384:1756–65; 8. Janssen Products LP. OLYSIO▼(simeprevir), US PI, November 2014; 9.
•
AbbVie Ltd. VIEKIRAX▼ (ombitasvir/paritaprevir/ritonavir), SmPC, January 2015;
▼
10. Afdhal N, et al. N Engl J Med 2014;370:1889–98; 11. Gilead Sciences Europe Ltd. HARVONI (ledipasvir/sofosbuvir), SmPC,
November 2014; 12. Afdhal N, et al. N Engl J Med 2014;370:1483–93; 13. Reddy KR, et al. Hepatology 2015. doi:
10.1002/hep.27826; 14. Bourlière M, et al. Lancet Infect Dis 2015;15:397–404;
15. Flamm S, et al. AASLD 2014; Oral #239; 16. Reddy KR, et al. AASLD 2014; Oral #8
17. Reddy KR EASL 2015 Abst 0007. 18. Pol S et al EASL 2015 Abst LB03 19. Foster G et al EASL 2015 Abst 0002
20. Agel B et al AASLD 2014 Abst 19.
*Post-transplant patients (n=22);
†On-treatment response 95% at Week 24;
ǂSee late breaker presentation (S. Pol; Abstract L03) at
this meeting. DCV: daclatasvir; DSV: dasabuvir; GT:
genotype; LDV: ledipasvir; OMV: ombitasvir; PEG-IFN:
pegylated interferon; PI: prescribing information; PTV:
paritaprevir; RBV: ribavirin; RTV: ritonavir; SmPC:
Summary of Product Characteristics;
4
SMV: simeprevir; SOF: sofosbuvir
Interferon-Free Direct Acting Antiviral Regimens
for Chronic Hepatitis C Virus Genotype 1
Dore GJ and Feld JJ. Clinical Infectious Diseases® 2015;60(12):1829–36
5
12-week versus 6-week DAA Therapy
naive pts (no cirrhosis).
• HCV is a curable disease
• No animal reservoir
% SVR
Kohli A et al. Lancet 2015; 384: 1107-13
In F3/F4 SVR 76%
Kattakuzhy S et al. CID 2015 in press.
• DAAs may provide nearly 100% efficacy (SVR)
• In non-cirrhotic patients, treatment duration
may become as short as 6-8 weeks
• In cirrhotic patients maximum duration 12-24
weeks
DISEASE CONTROL : reduction by ongoing interventions in
morbidity and mortality
ELIMINATION :
No transmission/zero incidence,
reduced prevalence to an «acceptable»
level in a given region
Continued interventions needed
ERADICATION :
Total absence of human cases.
Interventions can be stopped
Dowdle WR, WHO Bull 2006
Disease Control
Hepatitis C
Elimination
Hepatitis C
Eradication
Significant/progressive
disease
High prevalence
cohorts
All HCV infected
Disease Control
Hepatitis C
Elimination
Hepatitis C
Eradication
Significant/progressive
disease
High prevalence
cohorts
All HCV infected
Disease Control
Hepatitis C
Elimination
Hepatitis C
Eradication
Significant/progressive
disease
High prevalence
cohorts
All HCV infected
Three biological criteria are deemed
important for disease eradication:
Human beings the sole pathogen reservoir
Existence of accurate diagnostic tests
Availability of an effective, practical
intervention at reasonable cost
HEPATITIS C VIRUS THERAPEUTIC DEVELOPMENT:
IN PURSUIT OF “PERFECTOVIR”
REQUIREMENTS
• Extremely high treatment efficacy (>95%)
• Pangenotypic activity (i.e. similar dosing and duration)
• Maintenance of high efficacy in all patients cathegories
including decompensated and peritrasplant settings
• Minimal toxicity and broad documented safety
including renal failure, children, and pregnant women
• High genetic barrier with minimal HCV resistance
• Easy of dosing, preferably 1 table one daily
• Limited DDI
• Short duration
• Affordability
12
Dore GJ and Feld JJ. Clinical Infectious Diseases® 2015;60(12):1829–36
PERSPECTIVES
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UNDER-DIAGNOSIS and UNDER-TREATMENT : THE REAL BARRIERS
Aghemo A et al. Journal of Viral Hepatitis 2015; 22: 1-3
HIGH-INCOME COUNTRIES
DR : 30-60%
INTERMEDIATE-INCOME COUNTRIES DR : 20-40%
LOW-INCOME COUNTRIES
DR : < 20%
TR 2-6%
TR 1-3%
TR <1%
Low prevalence
Intermediate prevalence
High prevalence
Limited impact on global HCV disease burden of
enhanced HCV treatment efficacy (SVR >90%),
under current treatment rates
Population impact calculated
by multiplying efficacy figures
(left) by % of individuals who
have started HCV treatment.
Thomas DL. Lancet. 2010 ; 376: 1441–1442.
Limited impact on global HCV disease burden of
enhanced HCV treatment efficacy (SVR >90%),
under current treatment rates
Population impact calculated
by multiplying efficacy figures
(left) by % of individuals who
have started HCV treatment.
Thomas DL. Lancet. 2010 ; 376: 1441–1442.
The flow of the HCV disease
progression model
16
Razavi H et al. Journal of Viral Hepatitis, 2014, 21, (Suppl. 1), 34–59
The present and future disease burden of HCV
infection with today’s treatment paradigm
The most dramatic example of the impact of
treatment rate was observed in France.
Using today’s treatment paradigm, the total
number of HCV infections is projected to decline
slowly or remain flat in all countries.
A high level of treatment with Peg-INF/RBV
starting in 2000 led to a marked decrease in the
number of infections.
(Razavi H et al. Journal of Viral Hepatitis, 2014, 21, 34–59)
STEPS AND REQUIREMENTS
IN HCV ERADICATION/ELIMINATION/CONTROL
BY ANTIVIRAL THERAPY
• Highly effective/easy to use/universally available therapy:
PERFECTOVIR
• High diagnosis rates, effective link between diagnosis and treatment
• Infra-structures, knowledge and capacity for high volume treatments
• Treater’s and patient’s education and adherence
• Treatment as prevention (reduced transmission)
• Public awareness , strong advocacy and efficacious lobbying
• Drug price reform
18
Dore GJ and Feld JJ. Clinical Infectious Diseases® 2015;60(12):1829–36
The estimated prevalence of chronic hepatitis C virus cases
in the United States from 2001 to 2050 under different
simulation scenarios.
Natural History: no screening, no treatment
Pre-DAA: risk-based screening and PR treatment
Base case: risk-based and birth-cohort screening and
Treatment (any kind)
Ideal: universal screening, treatment (any kind)
2026
Kabiri M et al. Ann Intern Med. 2014 August 5; 161(3): 170–180.
2036
1/1500
(< 0.066%)
FRANCE
Wedemeyer H et al. Journal of Viral Hepatitis, 2014, 21, (Suppl. 1), 60–89
Scenario
Base
New DAA
Treatment. Rate
5.2%
10.3%
SVR
60%
90%
Elegibility
60%
2013
90%
2016
FRANCE
SPAIN
Scenario
Base
New DAA
Treatment Rate
2.1%
4.5%
SVR
50%
90%
Elegibility
50%
2013
90%
2018
Wedemeyer H et al. Journal of Viral Hepatitis, 2014, 21, (Suppl. 1), 60–89
Scenario
Base
New DAA
Treatment. Rate
5.2%
10.3%
SVR
60%
90%
Elegibility
60%
2013
90%
2016
MAIN CONCLUSIONS
ANNUAL TREATMENT RATE OF 10%
TREATMENT IN >F2
TREATMENT IN F0-F1
HCV PREVALENCE
> 90% BY 2030
LARGEST IMPACT ON DISEASE CONTROL
TO REDUCE TRANSMISSION IN IDU
TO ACHIEVE HCV ELIMINATION
Wedemeyer H et al. Journal of Viral Hepatitis, 2014, 21, (Suppl. 1), 60–89
Mass screening is expensive
Before adopting wide-scale screening, we must have
a plan in place to care for infected individuals
• The World Health Assembly passed two resolutions
(63.18, May 2010 and A67/13 maggio 2013) that called for
the World Health Organization to develop a
comprehensive approach to control of chronic hepatitis.
• ITALIAN PLAN “PNEV” launched on 6 November, 2015
EPIDEMIOLOGY
PREVENTION
SENSITIZATION, INFORMATION, FORMATION
CURE and TREATMENT ACCESS
SOCIAL IMPACT
http://www.quotidianosanita.it/allegati/allegato9642946.pdf
PNEV: modello attuativo
3 elementi cardine:
1.Identificazione delle aree prioritarie di
intervento, definizione di azioni appropriate,
tempi di realizzazione e responsabilità
2.Piena adesione e collaborazione con la
Conferenza Stato-Regioni
3.Azione centralizzata di coordinamento e
monitoraggio di applicazione/efficacia del PNEV,
sotto la guida del Ministero della Salute.
STIMA DEI PAZIENTI CON EPATITE C DIAGNOSTICATI ED ELEGGIBILI A UN TRATTAMENTO
ANTIVIRALE CON I FARMACI INNOVATIVI (AL 1/1/2016)
*E’ ipotizzabile che una percentuale possa essere già inclusa nei pazienti con altra
esenzione, carcerati, TD
Sono esclusi dal conteggio
•Pazienti in tossicodipendenza attiva (non vi è indicazione terapeutica al momento)
•Extracomunitari senza permesso di soggiorno (soggetti ad elevatissima mobilità)
•Pazienti non ancora diagnosticati
Ipotesi spesa farmaceutica cura pazienti HCV 2016 - 2023
1) Non sono conteggiate le nuove infezioni diagnosticate e ed i decessi (effetto compensativo)
2) Al netto delle risorse già stanziate per il 2016 di 500 Milioni
* Costo farmaci ipotizzati in base alle informazioni disponibili, al netto dei pay back, rimborsi e note di credito.
Nel caso il costo dei farmaci fosse inferiore, la stima si ridurrebbe in proporzione
Studio e analisi: Associazione EpaC onlus Centre for Economic Evaluation and HTA (EEHTA),
Università di Roma “Tor Vergata”
Minimum Costs for Producing Hepatitis C DirectActing Antivirals for Use in Large-Scale Treatment
Access Programs in Developing Countries
The estimated
costs in this
analysis can only
be justified if the
eventual
procurement of
large (>1 Million)
orders is
guaranteed
Hill A et al. Clinical Infectious Diseases 2014;58(7):928–36
Conclusions
• Mass screening is expensive
• Before adopting wide-scale screening, we
must have a plan in place to care for
infected individuals.
• This plan should include an effort to
improve education about HCV across
health professions and to provide
universal access to emerging treatments.