Il trattamento dei DAA nei consumatori di sostanze ...

Danilo TacconiMalattie Infettive – Asl Toscana Sud Est

Il trattamento dei DAA nei consumatori di sostanze: efficacia e sicurezza

Previsto un incremento degli stadi avanzati della malattia epatica e di HCC nella popolazione dei SERD

Difficoltà al trattamento nel passato

• Complessità gestione

• Scarsa adesione ai trattamenti

• Presenza di eventi avversi correlati alla terapia

• Rischio di reinfezione

Rivedere il paradigma

Responsabilità /barriere

• Serd

• Minore consapevolezza e importanza screening (T0 e successivi)

• Incremento carichi di lavoro per aumento popolazione con dipendenze

• Maggiore orientamento verso parte psichiatrica-sociale

• Percepita mancanza di valore nel trattamento di alcuni pazienti

Responsabilità /barriere

• Epatologi (Infettivologi, Gastroenterologi, Internisti)

• Fino a poco tempo fa considerati una popolazione scomoda per essere trattata

• Incremento carichi di lavoro per tutti gli altri pazienti HCV+ e le varie emergenze

• Percepita mancanza di valore nel trattamento di alcuni pazienti

• Preoccupazioni per l'adesione

Responsabilità/barriere

• Pazienti

• Comorbidità

• Altre priorità

• Difficoltà abitative e di trasporto

• Conoscenza limitata di HCV e sue conseguenze

• Diffidenza per esperienze negative in ambito sanitario

VIEKIRAX - EXVIERA

HARVONI

SOVALDI

MAVIRET

HEPCLUSA

ZEPATIER

VOSEVIOLYSIO

DAKLINZA

Manns, von Hahn, Nat Rev Drug Discov 2013

Direct Acting Antiviral Againts HCV

Great Tools Available

3’UTR5’UTR Core E1 E2 NS2 NS3 NS5A NS5BP7

Ribavirin

(RBV)

Polymerase

Daclatasvir (DCV)

Elbasvir (EBR)

Ledipasvir (LDV)

Ombitasvir (OBV)

Velpatasvir (VEL)

Pibrentasvir (PIB)

Sofosbuvir

(SOF)

Dasabuvir

(DSV)

NS5B

NUC

Inhibitors

(-buvir)

NS5A

Replication

Complex

Inhibitors

(-asvir)

NS5B

Non-NUC

Inhibitors

(-buvir)

Grazoprevir (GZR)

Paritaprevir/Ritonavir

(PTV/RTV)

Simeprevir (SMV)

Voxilaprevir (VOX)

Glecaprevir (GLE)

NS3

Protease

Inhibitors

(-previr)

Protease

Structural Domain

4A NS4B

Nonstructural Domain

NS5A

• Secondo gli ultimi dati dell’AIFA (Agenzia Italiana del Farmaco), aggiornati al 7 ottobre 2019, sono 193.815 i trattamenti finora avviati nei soli pazienti eleggibili, con almeno una scheda di dispensazione farmaco.

• Si tratta di numeri importanti, ma non ancora sufficienti: risultano infatti ancora da trattare fra 60.000 e i 120.000 pazienti.

• Si stima, inoltre, che siano ancora oltre 200.000 le persone con virus ignare della propria condizione.

I DAA avvicinano sempre più il momento in cui sarà possibile

eliminare HCV e le patologie correlate

Obiettivi raggiungibili con la risposta virologica sostenuta (SVR)

• Ridurre la necro-infiammazione

• Fermare la progressione della fibrosi

• Prevenire la cirrosi e le sue complicazioni

• Prevenire l’epatocarcinoma

• Ridurre le manifestazioni extra-epatiche

• Incrementare la sopravvivenza

Schinazi & Asselah. From HCV to HBV cure. Liver Int. 2017;37 S1:73-80

Il trattamento come modello di prevenzione

(Treatment as Prevention - TasP)

HCV Treatment Scale-up in High-Risk Populations Can

Prevent Onward Transmission

� Observed and modeled HCV chronic prevalence among PWID in Melbourne, Australia

Slide credit: clinicaloptions.comMartin. Hepatology. 2013;58:1598.

HC

V C

hro

nic

Pre

vale

nce

Am

on

g P

WID

(%

)

Yr

Data

No scale-up from baseline (3/1000 PWID annually)

Scale-up to 10/1000 PWID annually




100

80

60

40

20

02007 2012 2017 2022 20272002

Global Call for HCV Elimination

• WHO vision[1]: “Eliminate viral

hepatitis as a major global public

health threat by 2030”

• US HBV/HCV Elimination Strategy (National Academies of Sciences, Engineering, and Medicine)[2]

• “Elimination” = 90% reduction in incidence by 2030

• HCV elimination in US not feasible without engaging, treating PWID

• 30.5% of all HCV infections in North America are among people with recent IDU[3]

2030 Targets

90% Diagnosed

80% Treated

65% Reduced mortality

1. WHO. Global Health Sector Strategy on Viral Hepatitis, 2016-2021. 2. NASEM. A national strategy for the elimination of hepatitis B and C.

Washington, DC: The National Academies Press; 2017. 3. Grebely. Addiction. 2019;114:150.

The Challenge: HCV Care Cascade Among PWID

Grebely. Nat Rev Gastroenterol Hepatol. 2017;14:641. Iversen. Int J Drug Policy. 2017;47:77. Slide credit: clinicaloptions.com

100

90

80

70

60

50

40

30

20

10

0

Nu

mb

er

of

Pe

op

le (

Th

ou

san

ds)

Cured (SVR)PWID Screened

for HCV

Antibody

HCV

Antibody

Positive

Confirmatory

HCV RNA or

GT Test

HCV

Specialist

Assessment

Treated

Lo screening

• lo screening per HCV deve essere proposto a tutti i consumatori di sostanze;

• la proposta dello screening deve essere accompagnata da un counseling psicoeducazionale e motivazionale;

• la proposta dello screening deve essere associata alla distribuzione di materiale informativo sulla malattia, sui trattamenti e sulle modalita di contagio;

• lo screening se negativo deve essere riproposto periodicamente (almeno ogni 3 mesi);

• lo screening se rifiutato deve essere riproposto periodicamente abbinato ad un counseling motivazionale (almeno ogni mese);

• lo screening deve essere proposto ai consumatori attivi trattati con successo con DAA per la diagnosi precoce della reinfezione (almeno ogni 3-6 mesi).

Checklist for Choosing a Regimen:

A Few Things to Know

� Fibrosis assessment: Essential in ALL patients!

‒ Presence of cirrhosis increases urgency of therapy and may affect regimen, duration, use of ribavirin

‒ If cirrhosis:

‒ Any history or signs of decompensation

‒ Need for post-SVR follow up

� Genotype & subtype for GT 1

‒ Still necessary?

� Treatment history

‒ Regimen + duration

� Comorbidities

‒ CKD, coinfection (HIV/HBV)

‒ Drug-drug interactions

‒ Ongoing risk exposures: drug use, sex, alcohol

Slide credit: clinicaloptions.com

Can We Avoid Genotyping?

� It’s a delicate balancing act


Maximizing SVR in Individual Patient

� Genotyping may be helpful

� Helpful in cirrhosis, particularly GT3

Maximize SVR in the Population

� Simplicity is key

� Genotyping adds some: cost, delay, and

complexity

A Reasonable

CompromiseGenotype only for:

Cirrhosis

Treatment-experienced

(DAA/IFN)

Other Labs?

� Work-up for other liver diseases?

‒ Could do pretreatment or else wait for post-SVR if ALT still high

‒ Iron saturation

‒ Maybe nothing else

� HBV

‒ HBsAg is important

‒ Anti-HBc not very important (but very common!)

� HIV

‒ Important due to common risk factors and importance of diagnosis

Fibrosis Assessment: How To

� Transient elastography

‒ > 12.5 KPa = cirrhosis

� Serum tests

‒ FibroTest (0.75 = cirrhosis)

‒ APRI or FIB-4 – very attractive, can be done anywhere by any provider

‒ Very good negative predictive value – rule out cirrhosis

� What about ultrasound – needed in all patients?

‒ Insensitive for cirrhosis – only needed if cirrhotic to exclude HCC before treatment

� Biopsy rarely needed

AIFA: criterio 12

A partire dal 17/10/2019, nei Registri AIFA dei farmaci ad azione antivirale diretta di ultima generazione (DAAs) per il trattamento dell’epatite C cronica verrà introdotto un nuovo criterio di trattamento (cosiddetto “criterio 12”) che è stato così formulato: “Epatite cronica o cirrosi epatica in pazienti che non possono accedere alla biopsia epatica e/o al fibroscan per motivi socio-assistenziali”. Solo per questo criterio sarà possibile utilizzare dei punteggi clinico-laboratoristici quali l’APRI (AST to Platelet Ratio Index) o il Fib-4 (Fibrosis 4 Score) per la valutazione preliminare della compromissione epatica (cirrosi/non cirrosi).

The Long Journey to an HCV Diagnosis . . .

Anti-HCV antibody

(physician)Phlebotomy

(phlebotomist)

Receive diagnosis

(physician)

Central lab

Antibody test

1-2 wks

Phlebotomy

(phlebotomist)

Central lab

RNA test

1-2 wks

Receive diagnosis

(physician)

Visit #1 Visit #2 Visit #3 Visit #4 Visit #5

Grebely. Expert Rev Mol Diagn. 2017;17:1109. Slide credit: clinicaloptions.com

Moving Toward a Single-Visit Hepatitis C Diagnosis

Grebely. Expert Rev Mol Diagn. 2017;17:1109. Slide credit: clinicaloptions.com

Trattamento

• tutti i pazienti HCV RNA + possono essere eleggibili al trattamento;

• tutti i pazienti eleggibili al trattamento devono essere inviati allo specialista (infettivologo/epatologo);

• tutti i pazienti che vengono inviati allo specialista (infettivologo/epatologo) per il trattamento devono ricevere un programma strutturato di riduzione del danno;

• tutti i pazienti che presentano i criteri clinici per l’inizio del trattamento devono essere trattati con i DAA;

• tutti i pazienti devono ricevere un programma strutturato di riduzione del danno (con training di abilità);

• il monitoraggio del trattamento deve prevedere la valutazione dell’aderenza alla terapia e la valutazione del raggiungimento degli outcome infettivologici, tossicologici e comportamentali;

Recommended Treatment Regimens

� Genotype-specific

‒ Elbasvir/Grazoprevir: GT 1, 4

‒ Ledipasvir/Sofosbuvir: GT 1, 4, 5, 6

� Pangenotypic

‒ Sofosbuvir/Velpatasvir – GT 1-6

‒ Glecaprevir/Pibrentasvir – GT 1-6

‒ Sofosbuvir/Velpatasvir/Voxilaprevir – GT 1-6 (reserved for salvage therapy)

AASLD/IDSA. HCV Guidance. 2018.

Comparison of Pangenotypic HCV Regimens for

Treatment-Naive Patients Without Cirrhosis

Comparative Measure GLE/PIB SOF/VEL

Regimen constituents Protease inhibitor/NS5A inhibitor NS5B inhibitor/NS5A inhibitor

Dosing 3 pills QD 1 pill QD

Duration 8 wks 12 wks

Food requirement Yes No

Select DDI

considerations

Anticonvulsants, statins, St John’s

wort, warfarin

Anticonvulsants, proton pump

inhibitors, rifampin, St. John’s wort,

warfarin

Contraindications� Severe hepatic impairment (CP C)

� Concurrent ATV or rifampin use

� Do not use with RBV in patients

with RBV contraindication

Warnings/precautions � HBV reactivation risk

� HBV reactivation risk

� Bradycardia with amiodarone

coadministration

GLE/PIB [package insert]. SOF/VEL [package insert]. Slide credit: clinicaloptions.com

Treating This Patient’s HCV Infection:

SVR Rates High Among PWID, Even With Ongoing IDU

� 90.4% in C-EDGE CO-STAR (n = 136)

� 94% in SIMPLIFY (n = 102)

� 98% in pooled analysis from 6 phase III trials (mITT; n = 63)

Feld. NEJM. 2014;370:1594. Puoti. AASLD 2014. Abstr 1938. Grebely. EASL 2017. Abstr FRI-236. Grebely. CID. 2016;63:1405.

Grebely. CID. 2016;63:1479. Zeuzem. Ann Intern Med. 2015;163:1. Dore. Ann Intern Med. 2016;165:625. Foster. AASLD 2017. Abstr 1182.

0

60

80

40

20

10095-98

SV

R1

2 (

%)

91-96

No OST

(n > 7000)

OST

(n = 622)

SVR12 rates also > 90% among

patients with current/recent IDU


HCV DAA Therapy Is Effective Among PWID, Even in the

“Real-World”

� In meta-regression, clinical trials significantly associated with higher SVR rates vs observational studies

‒ aOR: 2.18 (95% CI: 1.27-3.75; P = .006)

� Difference due to loss to follow-up, not virologic failure

0

60

80

40

20

100 87.4

(82.0-92.8)

Po

ole

d S

VR

12

(%

)

90.7

(88.5-93.0)

Recent IDUOAT

Slide credit: clinicaloptions.comHajarizadeh. Lancet Gastroenterol Hepatol. 2018;3:754

Recent IDU

Bielen 2017

Boglione 2017

Boscaillou 2017

Conway 2017

Grebely 2018

Mazhnaya 2017

Milne 2017

Valencia 2017

Overall

83.3 (60.8-94.2)

93.9 (89.1-96.6)

80.4 (73.0-86.2)

96.7 (88.8-99.1)

94.2 (87.9-97.3)

64.0 (44.5-79.8)

87.4 (80.2-92.2)

74.4 (59.8-85.1)

87.4 (82.0-92.8)

Study SVR, % (95% CI)

SIMPLIFY: Adherence to 12 Wks of SOF/VEL Among

Persons With Recent (Within 6 Mos) IDU

� 97% (100/103) completed treatment; median treatment adherence: 94%

� 32% had < 90% adherence (nonadherent)

� SVR rate 94% in adherent and nonadherent group (P = .944)

Cunningham. Int J Drug Policy. 2018;62:14. Slide credit: clinicaloptions.com

Sample Daily Adherence for 4 Participants

Adherent Nonadherent

Tim

e o

f D

ay

6 AM12 PM

6 PM

6 AM12 PM

6 PM

Day Day

Drug-Drug Interactions

http://www.hep-druginteractions.org/

Don’t trust your memory – look up all drugs including OTC!


OST and HCV Therapy: Drug–Drug Interactions

https://www.hep-druginteractions.org Slide credit: clinicaloptions.com

EBR/GZR GLE/PIB LDV/SOF SOF/VEL SOF/VEL/VOX

Buprenorphine

Methadone

Naloxone

Naltrexone

Do not coadminister

Potential weak interaction

No interaction expected

DDIs Between DAAs and Hormonal Contraception

Slide credit: clinicaloptions.comhttps://www.hep-druginteractions.org

Contraceptive Drug EBR/GZR GLE/PIB LDV/SOF SOF/VEL SOF/VEL/VOX

Desogestrel

Dienogest

Drospirenone

Estradiol

Ethinylestradiol

Etonogestrel (implant)

Etonogestrel (vaginal ring)

Levonorgestrel (COC)

Levonorgestrel (implant)

Levonorgestrel (IUD)

Levonorgestrel (POP)

Medroxyprogesterone (depot injection)

Medroxyprogesterone (oral)

Norethisterone

Do not coadminister Potential weak interaction No interaction expected

HCV Reinfection Rates After SVR Among PWIDs

Slide credit: clinicaloptions.comHajarizadeh. EASL 2019. Abstr SAT-233.

• With OAT (methadone/ buprenorphine)

• Meta-analysis of 25 studies

3.81/100 PY

(95% CI: 2.51-5.80)

• With recent IDU

• Meta-analysis of 28 studies

5.86/100 PY

(95% CI: 3.96-8.66)

Acute HCV Infection: Treat or Wait?

� Risks of waiting

‒ Potential for forward transmission

‒ In this case, childbearing-aged woman, so also could be risking HCV+ pregnancy

� Barriers to treating acute HCV infection immediately

‒ Guidelines do not endorse immediate treatment

‒ HCV DAAs not approved for acute HCV treatment

Slide credit: clinicaloptions.comAASLD-IDSA. HCV guidance. 2018.

Recommended Treatment for Patients With Acute HCV Infection

If the clinician and patient decide that a delay in treatment initiation is acceptable, monitoring for

spontaneous clearance is recommended for a minimum of 6 mos. When the decision is made to

initiate treatment after 6 mos, treating as described for chronic hepatitis C is recommended

If a decision is made to initiate treatment during the acute infection period, monitoring HCV RNA for

at least 12 to 16 wks before starting treatment is recommended to allow time for spontaneous

clearance

Issues After Treatment

� Consequences of liver disease

‒ Only an issue with cirrhosis (fibrosis assessment pretreatment!)

‒ HCC risk

‒ Liver function – MELD purgatory

� Reinfection risk

‒ Ongoing exposures – HCV RNA testing every 6-12 mos

‒ No ongoing exposures – annual ALT, promote liver health (diet & alcohol), and nothing else!


HCV Elimination Requires More Than Good Drugs

SVR in individuals SVR in the population

Grebley. JID. 2013;207(S1):S19. Slide credit: clinicaloptions.com

Pa

tie

nts

Ach

iev

ing

SV

R (

%)

0

20

40

60

80

100

1998 2001 2012 2018P

op

ula

tio

n L

eve

l SV

R (

%)

0

20

40

60

80

100

1998 2001 2012 2018

IFN

IFN + RBV

PegIFN + RBV

PegIFN + RBV + PI

IFN-free

Potential benefits of treatment in PWIDSocietal and individual benefits

Bamvita JM, et al. Hepat Res Treat 2014;2014:631481;

DOT

Semplificazione esami pretrattamento

Incremento Centri prescrittori

(SERD)

Telemedicina

Monitoraggio durante il trattamento

Epatologo al SERD

Pacchetto DAY SERVICE

Screening universale HBV-HCV-HIV-MTS

Ritiro dei farmaci al SERD

Follow-up post-trattamento

Rischio reinfezione, stili di vita

Interventi per ridurre le barriere al trattamento

Testing Linkage to careTreatment uptake

Treatment adherence Viral suppression

Treatment uptake

Treatment adherence

HCV Elimination Requires More Than Good Drugs

Il trattamento dei DAA nei consumatori di sostanze ...

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