Introduzione

Dipartimento Malattie InfettiveASST Fatebenefratelli Sacco Hospital

Il Dipartimento di Malattie Infettive (DMI) è costituito da 2 Unità Complesse (UOC Malattie Infettive 1 * e UOC Malattie Infettive 3 clinicizzata), per un

totale di 68 posti letto accreditati (77 utilizzabili) per la degenza ordinaria, 1 Unita Semplice dipartimentale: hospice di malattie infettive con 10 posti

letto, 3 posti letto di DH e 15 postazioni per erogazione di attività ambulatoriali complesse -MAC-.

Alla UOC 1 sono assegnate l’ UOS di Allergologia e Immunologia clinica, l’UOS di Epatologia e l’UOS di Malattie Sessualmente Trasmesse.

Alla UOC III è assegnata l’ UOS di Emergenze Infettivologiche.Più di 6500 pazienti con infezione da HIV (una delle più grosse coorti di

pazienti sieropositivi d’Europa), di cui 5546 trattati nel 2016, e più di 3500 pazienti affetti da epatiti croniche di origine virale (centro accreditato da

Regione Lombardia per la prescrizione dei farmaci ad alto costo per il trattamento dell’epatite cronica C), sono seguiti costantemente presso parte

dei 18 ambulatori specialistici giornalieri afferenti al dipartimento (vedi sotto). Il DMI dell’ Ospedale Sacco è uno dei due centri di riferimento a livello

nazionale (l’altro è lo Spallanzani di Roma) per le emergenze infettivologiche (i.e patogeni infettivi di classe A che richiedono alto isolamento,

bioterrorismo), ed è stato centro di riferimento per le patologie infettive e di importazione durante Expo 2015. La ricerca e la formazione (corso di laurea

medicina e chirurgia e specializzazione e corso di laurea scienze infermieristiche) sono punti forti e qualificanti del DMI, come certificato

dall’elevato numero di pubblicazioni scientifiche internazionali prodotte (circa 50- 60 pubblicazioni indicizzate ogni anno, dipartimento con maggior impact

factor del polo universitario di competenza ).

Mission

The main mission is to provide the most technologically advanced, compassionate medical

care for our patients. We are committed to a “patients first” orientation and maintaining our well recognized excellence in patient care and

medical education.

• *1650-1700 Dimissioni/anno con oltre 9 Mi/anno ricavi

• *oltre 110000 prestazioni ambulatoriali anno con oltre 2,3 Mil/anno ricavi

• *Quasi 80 Mil file F spesi nel 2017

ResearchIn addition, we want to capture the synergies of existing and emerging opportunities

in the areas of clinical research and outcomes research to take advantage of the breadth of our clinical volume. Our research is focused mainly on HIV/AIDS (more

than 30 Phase II,III and IV trials are ongoing to date ) but our specific areas of interest range from tuberculosis through to gram positive sepsis, hospital acquired

infection, osteoarticular infections, endocarditis, travel acquired infections, etc. Some of the research programmes involve formal and informal collaboration with

colleagues at international level as well as collaboration in other university disciplines and other teaching hospitals

Who are you?

Hepatitis C virus (HCV) is a memberof the hepacivirus genus within theflaviviridae family of virus, and ithas a single positive stranded RNAmolecule (~9500 nucleotides) as itsgenome.

Although the high-resolution structure of the HCVvirion still needs to be fully elucidated, it is thought tobe around 45-100 nm in diameter and formed by anucleus of genomic RNA included in an icosahedralcapsid made of multiple copies of core protein. It islastly surrounded by a bilayer lipid membrane onwhich the viral-derived envelope glycoproteins E1and E2 are anchored (Gastaminza, J Virol 2010;Wakita Nat Med 2005).

HCV could have been coevolving with human populations during their migration out of

Africa within the past 100,000 to 150,000 years, but the current HCV genotypes

appeared much more recently.

A study suggested that types 6 and 4 could have originated 700 years and 350 years

ago, respectively, whereas subtypes 1a and 1b could have arisen less than 100

years ago.

Pybus et al Science 2001

The origin of the primate Flaviviridae could be as

ancient as the differentiation of primate species

some 35 million years ago

Viral biology

Budding

Endocytosis and uncoating

Translation and proteolyticcleavage

Replication

Assembly

Release

Recognition and entry

HCV(in hepatocytes)3

Core protein

RNARNA

Viral mRNAs RNA

pregenome Polymerase

- DNA

+/-DNA

ER/Golgi

HBV(in hepatocytes)2

Entry

Uncoating and trafficking

cccDNAformation

Endosome

Secretion

HBsAg

1. De Clercq E. Nat Rev Drug Discov 2002;1(1):13-25. 2. Zoulim F, et al. Antiviral Res 2012;96(2):256-9. 3. Schaefer E, Chung R. Gastroenterology 2012;142(6):1340-50. Covalently closed-circular HBV DNA, cccDNA

Viral proteins and RNA assemble at cell membrane

Proteolytic processing by viral protease

Translation

Transcription

Integration

Reverse transcription

Uncoating

DNA

Virus–cell fusion

Virus adsorption

Envelope

Receptor and co-receptor proteins

Capsid coreReverse transcriptase

RNA

HIV(in CD4)1

Moradpour D et al., Nature 2007

HCV replication occurs only in cytoplasm and viral

genome is not archived into the genome of

infected cells

… This makes HCV curable!!!!

Definition of cure differs depending on the virus

1. Katlama C, et al. Lancet 2013; Mar 29 [Epub ahead of print]. 2. Block TM, et al. Antiviral Res 2013;98(1):27–34. 3. Pearlman BL, et al. Clin Infect Dis 2011;52:889–900.

Host control of viral replication without

continued treatment

Immune function

restored and stabilised

HIV-induced inflammation is

reduced

Risk of transmission to others is reduced

(if low viral load)

Functional cure1

Replication competent

virus is eliminated

Possibly achieved in a few patients who have

undergone myeloablation

Ablative conditioning, immunosuppressive treatment, and post-

transplant graft-versus host disease might cause reductions in the size of

the reservoir

Sterilising cure1

HIV HBV

Is essentially HCV infection cure

SVR24 defined as the absence of detectable

HCV RNA in the serum, six months after completion of

therapy

Very low incidence of late relapse

(< 1%)

Sustained virologic response3

HCV

Sterilising cure2

Complete elimination of the

virus

Not possible with current treatment

regimens

Patient's life expectancy the same

as that of an individual who has resolved his HBV infection without

therapy

Outcome cannot be measured over the

short term

Functional cure2

Stable off-drug suppression of HBV

viraemia and antigenaemia and normalisation of

ALTs

Hepatitis C: 25 years since discovery

Pathogeneic mechanisms associated with the development of atherosclerosis in chronic HCV infection

Chronic HCV Infection Also Causes Extrahepatic Manifestations

Endocrine

Thyroid disease

Diabetes mellitus

Hematologic

Mixed cryoglobulinemia

Lymphoproliferative disorders

Thrombocytopenia

Renal

Membranoproliferative

glomerulonephritis

Ocular

Corneal ulcers

Sjögren syndrome

Vascular

Systemic vasculitis

Dermatologic

Lichen planus

Porphyria cutanea tarda

Musculoskeletal

Arthralgia

Myalgia

Peripheral neuropathy

Inflammatory polyarthritis

Co-morbidities in HCV patients are relevant – bringing potential for competing risks

Vutien P, et al. AASLD 2014; Poster #1481.

Depression

Atherosclerosis Lymphoma

Substance

misuse

Diabetes

Renal disease

Cognitive

impairmentPsychosis

Respiratory

disease

Dyslipidaemia

Cardiovascular

disease

Cancer HIV

co-infection

92% HCV patients

had co-morbidities

40% had 5 or more

co-morbidities

*Includes persons from CHeCS and SEER ages 25 and older. Includes 565 incident cancers in 543 patients; 22 second cancers were histologically distinct from first. Includes all SEER 13 registries except Alaska Natives. §Tobacco-related cancer. ||Alcohol-related cancer.

Journal of Hepatology 2015

• La gestione corrente dell’infezione cronica da HCV:

dati real-world

Real-wold data

•Perchè sono utili e quali ne sono i limiti

Observational vs randomized studies: Differences

• Randomized: • Treated/untreated groups more likely to be

comparable;• Treatment regimen and outcome assessment more

certain;• Risk factor, adherence info often better.

• Observational:• Subjects often more representative;• Usage conditions usually more typical;• Larger size/ longer duration possibilities permit

observation of rare / delayed outcomes.

Why perform observational studies?

• Understand experiences of actual users under conditions of actual use – nearly always different from clinical trials.

• Provide timely information by assessing accumulated experience.

• Assess very large populations.

Differences Between Clinical Trial Populations and Utilization Population

•Adapted from Cziraky M, Pollock M. Real-world evidence studies. Applied Clinical Trials;Oct 2015. •Available at: http://www.appliedclinicaltrialsonline.com/real-world-evidence-studies

Real-world populationMay differ in:

Age and demographicsComorbidities

Concomitant medicationsLifestyle

Disease severityCompliance

Population studiedPhases 1–3

High Rates of SVR in HCV GT1 Mono-Infected Patients in Clinical Trials

•* Not including patients with GT1a and baseline NS5A polymorphisms; testing is recommended for patients with GT1a infection; † Based on limited data.

•Zepatier US Prescribing Information (accessed May 2016);Viekirax & Exviera, Harvoni, Olysio, and Daklinza

•Summary of Product Characteristics (all accessed May 2016).

SVR90–100%

SVR87–100%

SVR90–100%

SVR98–100%

SVR94*–100%

OBV/PTV/r +

DSV ± RBV

EBR/GZR ± RBV

DCV + SOF

± RBV†

SMV + SOF

± RBV

LDV/SOF± RBV

High SVR12 rates in

GT1-infected patients in

clinical trials

•* Not including patients with GT1a and baseline NS5A polymorphisms; testing is recommended for patients with GT1a infection; † Based on limited data.

•Zepatier US Prescribing Information (accessed May 2016);Viekirax & Exviera, Harvoni, Olysio, and Daklinza

•Summary of Product Characteristics (all accessed May 2016).

SVR90–100%

SVR87–100%

SVR90–100%

SVR98–100%

SVR94*–100%

OBV/PTV/r +

DSV ± RBV

EBR/GZR ± RBV

DCV + SOF

± RBV†

SMV + SOF

± RBV

LDV/SOF± RBV

Are we replicating this in the real world?

?

Real-world

• Confronto tra diversi regimi di trattamento in real life• Dati real life e studi clinici

• Coinfezione HIV-HCV in real life• Il cirrotico scompensato

• Real-Italia• Real-Lombardia• Real-Sacco

Real-world

• Confronto tra diversi regimi di trattamento in real life• Dati real life e studi clinici

• Coinfezione HIV-HCV in real life• Il cirrotico scompensato

• Real-Italia• Real-Lombardia• Real-Sacco

• HCV-TARGET is a consortium of academic (n=39) and community (n=13) medical centers in the U.S., Germany, Israel and Canada conducting a longitudinal, observational study

• HCV treatment is administered according to local standard of care, and regimen selection is made by the patient’s health care provider

• Data from sequentially enrolled patients undergoing HCV therapy is captured from medical records within a common database utilizing novel, centralized data abstraction

• Demographic, clinical, adverse event, and virologic data is collected through treatment and follow-up

Methods

Terrault N et al AASLD 2015

Safety and Effectiveness of DAA Regimens in Kidney and/or Liver Transplant Recipients with HCV

Reddy, EASL 2016, Poster Sat-189 29

HCV-TARGET

Kidney

Transplant

N=31

Liver

Transplant

N=229

Kidney/Liver

Transplant

N=23

Total

N=283

Male, n (%) 19 (61.3) 173 (75.5) 18 (78.3) 210 (74.2)

Age 65+, n (%) 5 (16.1) 68 (29.7) 12 (52.2) 85 (30.0)

White, n (%) 14 (45.2) 178 (77.7) 13 (56.5) 205 (72.4)

Black, n (%) 10 (32.3) 18 (7.9) 4 (17.4) 32 (11.3)

GT, %

1a / 1b 51.6 / 32.3 58.1 / 26.6 56.5 / 34.8 57.2 / 27.9

TE, n (%) 10 (32.3) 136 (59.4) 13 (56.5) 159 (56.2)

Cirrhosis, n (%) 10 (32.3) 107 (46.7) 11 (47.8) 128 (45.2)

Treatment regimen, n

LDV/SOF±RBV

OBV/PTV/RTV/DSV±RBV

DCV+SOF±RBV

27

4

0

222

4

3

21

2

0

270 (95)

10 (4)

3 (1)

Safety and Effectiveness of DAA Regimens in Kidney and Liver Transplant Recipients with HCV

Reddy, EASL 2016, Poster Sat-189 30

HCV-TARGET

SVR12 (PP)

Kidney Transplant Liver TransplantKidney/

Liver Transplant

Patients

LDV/SOF

±RBV

N=265

AE, n (%) 189 (71.4)

SAE, n (%) 25 (9.4)

Kidney tx rejection 1 (0.4)

D/C due to AE 2 (0.8)

SV

R12 R

ate

(%

)

2425

88

1617

2020

205216

9499

111117

9096

109114

1921

810

1111

1314

55

Treatment in the real world with LDV/SOF+RBV in post-solid organ

transplantation patients with cirrhosis is effective

All Cirrhotic Non-Cirrhotic

LDV/SOF

LDV/SOF

+RBV

All Cirrhotic Non-Cirrhotic

LDV/SOF

LDV/SOF

+RBV

All Cirrhotic Non-Cirrhotic

LDV/SOF

LDV/SOF

+RBV

22