PROBLEMA DE SANATATE PUBLICA HEPATITA VIRALA C – PROBLEMA DE SANATATE PUBLICA IN ROMANIA Laura Iliescu Centrul de Medicina Interna IC Fundeni

VHB + VHC 1 milion decese / an 0.5 miliarde pacienti cu infectie cronica 2

Cauze de deces boli infectioase : VHB (locul7) si VHC (locul 10) DECESE/AN 1. Infectii ap respirator ~ 3.5 mil 2. HIV/SIDA ~ 3.0 mil 3. Boli diareice ~ 2.2 mil 4. Tuberculoza ~ 2.0 mil 5. Malarie ~ 1-3 mil 6. Boli eruptive ~ 888,000 This slide shows the 10 leading causes of infectious disease deaths worldwide. Hepatitis B is number 7 and hepatitis C is number 10. If hepatitis B and C are grouped together, viral hepatitis is nearly number 5 in terms of the risk of infectious disease death. This, of course, relates to cirrhosis and cancer deaths for both of these chronic viral hepatitis infections. 7. Hepatita B ~ 500,000 - 750,000 10. Hepatita C ~ 250,000 8. Pertussis ~ 355,000 9. Tetanos Neonatal ~ 300,000 WHO. Hepatitis B. 2002. Maynard JE, et al. In: Viral Hepatitis and Liver Disease. New York: Alan R. Liss, Inc. 1988. CDC. Epidemiology & prevention of vaccine-preventable diseases. The Pink Book. 8th ed. CDC. MMWR. 2001;50:RR-11. 3 3

Hepatita cronica VHC Impactul la nivel global al bolilor hepatice cronice datorate VHC este substantial Slide 2 Moxonidine (4-chloro-N-(imidazolidine-2-ylidene)-6-methoxy-2-methyl-5-pyrimidinamine) is a centrally acting antihypertensive drug. The blood pressure-lowering effect of moxonidine is due to a highly selective action in the rostral ventrolateral medulla, which leads to a reduction in overactivity of the sympathetic nervous system.

Epidemiologie Hepatita cronica VHC Infectia cronica VHC reprezinta o problema majora de sanatate pubilca, in intreaga lume existand 170 milioane persoane infectate Slide 2 Moxonidine (4-chloro-N-(imidazolidine-2-ylidene)-6-methoxy-2-methyl-5-pyrimidinamine) is a centrally acting antihypertensive drug. The blood pressure-lowering effect of moxonidine is due to a highly selective action in the rostral ventrolateral medulla, which leads to a reduction in overactivity of the sympathetic nervous system.

- VHC - 170 milioane subiecti (3%) din intreaga lume - 5 milioane in Europa de Vest - rata crescuta in Europa de Est - prima cauza de transolant hepatic - a doua cauza la nivel mondial si prima cauza in Europa de cancer hepatic 6

Estimari globale VHC Prevalenta Anti VHC: 7 7 7 Pozitivi, % Taiwan 0.13-16.9 Vietnam 4-9 China 2.1 Africa 1.6-13.8 Filipine 1.6 Tailanda 2.0 Japonia 0-5.1 Coreea Sud 1.4 India 0.0012-5.5 Rusia 1.3-5.3 USA 0.1 HBsAg, hepatitis B surface antigen.   This slide illustrates the prevalence of hepatitis B using global estimates by region and country. As seen on this slide, there are wide ranges of hepatitis B surface antigen (HBsAg) prevalence in different countries. However, some information on this slide may not fully reflect the current situation. For instance, in some communities in Vietnam and China, the prevalence is as high as 30%. Fortunately, in a number of countries that instituted vaccination, which will also be discussed later, there has been a declining prevalence of hepatitis B, especially in babies, infants, and young children. Prevalenta Anti VHC: Inalta (≥ 8%) Intermediara (2% to 8%) Scazuta (< 2%) Mast EE, et al. MMWR Recomm Rep. 2006;55:1-33. Custer B, et al. J Clin Gastroenterology. 2004;38(10 suppl):S158-S168. 7 7 7

VHC Epidemiologie Genotipurile VHC au semnificatie si importanta clinica in stabilirea raspunsului la tratament si a prognosticului Distributia geografica a genotipurilor VHC este variabila Slide 2 Moxonidine (4-chloro-N-(imidazolidine-2-ylidene)-6-methoxy-2-methyl-5-pyrimidinamine) is a centrally acting antihypertensive drug. The blood pressure-lowering effect of moxonidine is due to a highly selective action in the rostral ventrolateral medulla, which leads to a reduction in overactivity of the sympathetic nervous system.

Eastern Mediterranean GENOTIPURI VHC 1, 2, 3 1 1, 3 1,3 3 4 4,5 Asia: 6 Europe 8.9 million (1.03%) The Americas 13.1 million (1.7%) Africa 31.9 million (5.3%) Southeast Asia 32.3 million (2.15%) Western Pacific 62.2 million (3.9%) Eastern Mediterranean 21.3 million (4.6%) It is estimated by the World Health Organization that approximately 170 million individuals, or 3.1% of the world population, are infected with HCV—more than 4 times the number of people living with HIV. Relative Prevalence There is, however, considerable geographic variation in the prevalence of HCV infection. In the Americas, approximately 1.7% of the population is currently living with HCV. In a survey conducted from 1999-2002, the prevalence of HCV in the United States was estimated to be 1.6% (95% confidence interval: 1.3% to 1.9%), corresponding to 4.1 million individuals with anti-HCV antibodies nationwide, and 1.3% or 3.2 million persons had chronic hepatitis. Areas of higher prevalence include some countries of Africa, the eastern Mediterranean, southeast Asia, and the western Pacific. In some areas, the prevalence of infection exceeds 10% in the general population. For example, in Egypt, there are some areas in which one out of every 5 individuals has chronic hepatitis C. The virus spread in Egypt drastically as a result of unsafe injection practices during a campaign to eradicate schistosomiasis. That practice has since stopped and ongoing transmission of hepatitis C has reduced dramatically in that country. Genotip World Health Organization. Hepatitis C: global prevalence: update. 2003. Farci P, et al. Semin Liver Dis. 2000;20:103-126. Wasley A, et al. Semin Liver Dis. 2000;20:1-16. 9 9 9

Studiul ARSF : Prevalenta VHB, VHD, VHC, VHE 22 judete HBsAg, hepatitis B surface antigen.   This slide illustrates the prevalence of hepatitis B using global estimates by region and country. As seen on this slide, there are wide ranges of hepatitis B surface antigen (HBsAg) prevalence in different countries. However, some information on this slide may not fully reflect the current situation. For instance, in some communities in Vietnam and China, the prevalence is as high as 30%. Fortunately, in a number of countries that instituted vaccination, which will also be discussed later, there has been a declining prevalence of hepatitis B, especially in babies, infants, and young children. - 22/42 judete (126.867,6 km2) - 12.512.581 subiecti 10 10 10

Populatia studiata : 5678 - 4 categorii : - populatie care se adreseaza pt evaluare medicala sau cu ALT (>x1.5N) = 5367 - risc scazut = 93 subjecti - risc crescut = 174 subiecti - studenti = 44 subiecti HBsAg, hepatitis B surface antigen.   This slide illustrates the prevalence of hepatitis B using global estimates by region and country. As seen on this slide, there are wide ranges of hepatitis B surface antigen (HBsAg) prevalence in different countries. However, some information on this slide may not fully reflect the current situation. For instance, in some communities in Vietnam and China, the prevalence is as high as 30%. Fortunately, in a number of countries that instituted vaccination, which will also be discussed later, there has been a declining prevalence of hepatitis B, especially in babies, infants, and young children. 11 11 11

ARSF 5-7 % din populatia tarii infectata cu HVC   No. sub AgHBs PCRVHB Anti VHC PCR VHD VHE ALT >2N Populatia Generala 2.54 5.59% - 4.56% 37.69% Risc foarte scazut (studenti) 44 2.27% 0% 12.5% 6.82% Risc scazut (medici si asistente) 93 2.15% 1,2% 1.075% 13.98% 4.3% Risc crescut (hemodializa) 174 7.91% 39.26% 20.69% 15% 5-7 % din populatia tarii infectata cu HVC ~ 1 mil. persoane infectate (95,5% GENOTIP 1) 12

ARSF Nr. subiecti AgHBs PCR VHB Anti VHC PCR VHC Anti VHD Anti VHE ALT >2N Populatia Generala 2696 8,87% - 7,67% 37,69% Risc scazut 93 2,15% 1,2% 1,07% 13,98% 4,3% Risc crescut 174 7,91% 39,26% 20,69% 15% Studenti 44 2,27% 0% 12.5% 6,82% 13

VHC SURPRIZE VIRUSOLOGIC EPIDEMIOLOGIC CLINIC TERAPEUTIC

GLOBALIZAREA INFECTIEI CRONICE VHC CONSECINTE EPIDEMIOLOGICE 170 -200 milioane peroane infectate VHC 27% ciroza hepatica 25% carcinom hepatocelular JANSEN D., DDW 2009

Evoluţia naturală a infecţiei VHC primară Clearance viral Infecţie cronică Asimptomatică 75% Infecţie persistentă 80-95% Ciroză CHC Simptomatică 25% Clearance al infecţiei 5-20% Infecţie asimptomatică 20%

Progresia Hepatitei Cronice C Rata de progresie Rapidă Intermediară Lentă 5-10 ani 15-30 ani >30 ani Ciroză Decompensare 5-10% /an CHC 3-5%/an Decese 2-5%/an

HETEROGENITATEA SPECTRULUI ACTUAL AL INFECTIEI VHC POOL ASTEPTAT ANTI VHC Calculat dupa date prevalenta% Infectii noi (dupa incidenta /100000) 15-20% ARN-VHC – SURPRIZA F1: 7.5% F2/3: 89,5% 80-85% ARN -VHC + HUARE Mg. et al., Hepatology 2008; 48: 1737.

HETEROGENITATEA SPECTRULUI ACTUAL AL INFECTIEI VHC Încărcătură virală pozitivă 80-85 % DIN Anti VHCpozitivI DATE REALE SUA Diagnostic < 25% NON DIAGNOSTIC 75% TRATATI 11% NETRATATI 89% NON RESPONDER RECADERE 50-60% RESPONDER RVS 10-50% Lista de asteptare Post transplant Psihopatii Utilizatori droguri Afectare hepatica usoara Alte cauze :obezitate,DZ necontrolat,boli CV , anemie, leucopenie, trombocitopenie ASTEAPTA NOI TERAPII RETRATAMENT Donald Jansen, DDW 2009.

HETEROGENITATEA SPECTRULUI ACTUAL AL INFECTIEI VHC IN ROMANIA ANTI HCV (+) ~5% 710.600 NOI INFECTII 8.64/100.000 1308/AN INCARCATURA VIRALA (-) ~ 15-20%, ~142120-106590 MONITORIZARE 80-85% INCARCATURA VIRALA (+) ~ 568480-604010 DIAGNOSTIC ~ 30000 1.81%: TRATATI 20.000 63,33% IN TRATAMENT 6000 20% LISTA ASTEPTARE 3000 16.67% CONTRAIND. TRAT 1000 Al. Oproiu

Modalitati de transmitere VHC Modalitati de transmitere Slide 2 Moxonidine (4-chloro-N-(imidazolidine-2-ylidene)-6-methoxy-2-methyl-5-pyrimidinamine) is a centrally acting antihypertensive drug. The blood pressure-lowering effect of moxonidine is due to a highly selective action in the rostral ventrolateral medulla, which leads to a reduction in overactivity of the sympathetic nervous system.

Transmitere verticala (materno-fetala) 6-8% Transmitere VHC Transmitere orizontala Transfuzii<1995 droguri i.v. Interventii chirurgicale Stomatologie Tatuaje, piercing Acupunctura Parenteral (i.m./i.v.) Sexual (<10%) Transmitere verticala (materno-fetala) 6-8%

Noi modalitati de transmitere asigurarile de sanatate din fiecare tara VHC Epidemiology Noi modalitati de transmitere Caile de transmitere variaza si s-au modificat in functie de diferiti factori pt fiecare regiune geografica in parte : nivel socio-economic asigurarile de sanatate din fiecare tara Slide 2 Moxonidine (4-chloro-N-(imidazolidine-2-ylidene)-6-methoxy-2-methyl-5-pyrimidinamine) is a centrally acting antihypertensive drug. The blood pressure-lowering effect of moxonidine is due to a highly selective action in the rostral ventrolateral medulla, which leads to a reduction in overactivity of the sympathetic nervous system. Alter MJ. Prevention of spread of hepatitis C. Hepatology 2002; 36:S93–98. Dore GJ, Law M, MacDonald M, Kaldor JM. Epidemiology of hepatitis C virus infection in Australia. J Clin Virol 2003; 26: 171–84.

injectii cu materiale nesterile sau utilizate in comun VHC droguri injectabile injectii cu materiale nesterile sau utilizate in comun transfuzii ocupational perinatal transmitere sexuala necunoscut Slide 2 Moxonidine (4-chloro-N-(imidazolidine-2-ylidene)-6-methoxy-2-methyl-5-pyrimidinamine) is a centrally acting antihypertensive drug. The blood pressure-lowering effect of moxonidine is due to a highly selective action in the rostral ventrolateral medulla, which leads to a reduction in overactivity of the sympathetic nervous system.

Categorii de risc Ac VHC TGP crescute Boala hepatica neprecizata Contacti familiali-sexuali pacienti VHC Consumatori droguri Hemodializati Hemofilici Receptori transfuzii<1991 Interventii chirurgicale, endoscopice, stomatologice-multiple Personal medical (expunere la sange) Contacte sexuale multiple neprotejate, BTS Alte hepatite virale, HIV Sarcina ALTE

SIMPTOMATOLOGIE Hepatita cronica VHC este silentioasa dpdv clinic Simptomatologie nespecifica Majoritatea manifestarilor nu apar decat in momentul in care se dezvolta ciroza hepatica Pacientii suspectati a avea infectie cronica VHC vor fi testati pentru Ac-anti VHC RNA-VHC va fi determinat la: pacientii cu Ac anti-VHC pozitivi pacientii evaluati in vederea tratamentului antiviral, utilizand o metoda cantitativa pacienti imunodeprimati cu afectare hepatica neexplicata, cu Ac anti-VHC negativi

Theresa Wright and M. Manns 2006 SURPRIZE CLINICE 1. FAZA ACUTA ASIMPTOMATICA IN 80% CAZURI 2. MANIFESTARI EXTRAHEPATICE CRIOGLOBULINEMIE MIXTA +++ GN MEMBRANO – PROLIFERATIVA ++ ARTRALGII ++ TIROIDITA AUTOIMUNA ++ PORPHIRIA CUTANEA TARDA – LICHEN PLANUS ++ DIABET ZAHARAT +++ OBOSEALA ++ LIMFOM NONHODGKIN ± Theresa Wright and M. Manns 2006

LOCALIZARI EXTRAHEPATICE LIMFOCITE B LIMFOCITE T MONOCITE CELULE DENDRITICE MONONUCLEARE PERIFERICE CELULE EPITELIU INTESTINAL SNC CASTILLO J., PARDO M., BARTOLONE J., 2004 DEFORGE S. et al., 2004 FORTON DM et al., 2004

Infectia HCV: Manifestari Extrahepatice Hematologic . Crioglobulinemia Anemia aplastica Trombocitopenie • Non-Hodgkin limfom Ocular Ulcer corneean Uveite Sindrom Sjogren Vascular Vasculita necrotizanta PAN PIF Dermatologic Porfiria cutanea tarda Lichen plan Vasculita necrotizanta cutanata Neuromuscular Mialgii Neuropatie periferica Artrite sero-/artralgii Renal Glomerulonefrita membranoasa Neurologic FENOMENE AUTOIMUNE Sindrom CREST Granulom nespecific Autoanticorpi Endocrine Tiroidita autoimuna Diabet zaharat Salivar Sialoadenite Hadziyannis. J Eur Acad Dermatol Venereol. 1998. 29

TEST SCREENING: antiHCV ALT(TGP) NU! sensibilitate redusă (multe hepatite cronice HCV evoluează cu TGP normale, dar necesita tratament) specificitate minima (numeroase cauze de citoliza)

Screening Beneficii Costuri

Screening al populaţiei generale: probabil NU!... ..dar screening al persoanelor cu : risc expunere/expunere certă la HCV: DA! suferinţă hepatică de cauză incertă: DA!

Screening – Expunere HCV certă 1. Personal medical expus (ac contaminat cu sânge pacient): implicaţii medicale şi sociale – accident de muncă! RISC = 1,5-2% după înţepătură accidentală ac contaminat

2. Copiii mamelor HCV+ Screening – Expunere HCV certă RISC = 4% (15-20% dacă mama este si HIV+)

Screening – Categorii la risc pentru expunere HCV Toxicomanii – emergenţa unei categorii de risc şi în România RISC = 10-20% pentru fiecare an de toxicomanie

Screening – Categorii la risc pentru expunere HCV Persoane cu transfuzii înainte de 1993 Hemodializaţi Partener sexual HCV+/- comportament sexual dezordonat RISC = 1,5-6% dintre partenerii sexuali ai celor infectaţi HCV+

« Valul » de pacienti prilejuit de programul national de evaluare Screening – Afecţiune hepatică de cauză incertă Valori crescute ale ALT O singura data: de evaluat indicaţia în contextul stării prezente a pacientului Doua sau mai multe determinari: obligatoriu ! « Valul » de pacienti prilejuit de programul national de evaluare

Testare anonimă şi gratuită în unele state, împreună cu testarea HIV + Screening – la cerere Aprox. 10% dintre infecţiile HCV sunt astfel descoperite Testare anonimă şi gratuită în unele state, împreună cu testarea HIV + Consiliere dacă test pozitiv

EVALUARE PACIENTI ANTI-HCV POZITIVI

Dacă antiHCV+, care sunt următorii paşi? Confirmarea infecţiei NU DA Reluarea anamnezei Consiliere COMPLETARE BILANŢ

Prezenta antiHCV  infecţie HCV Confirmarea diagnosticului de infecţie HCV ATENŢIE! Prezenta antiHCV  infecţie HCV

Confirmarea diagnosticului de infecţie HCV antiHCV+ RNA-HCV (–) (2 în 6 luni) RNA-HCV (+) (60-90%) RIBA + RIBA - Infecţie HCV Infecţie HCV vindecată Test antiHCV fals pozitiv

Severitatea afectiunii: Bilanţul pacientului cu hepatită HCV: are indicaţie de terapie antivirala? Severitatea afectiunii: morfologic: rolul PBH pentru evaluarea fibrozei (teste noi: fibroscan, fibrotest, fibromax) - risc carcinom hepatic: alfafetoproteina, imagistica sindrom hipertensiune portală (varice esofagiene) - manifestari extrahepatice (citopenii…)

Patologie asociată ce poate schimba conduita: - coinfecţii HBV, HIV; Bilanţul pacientului cu hepatita HCV: are indicaţie de terapie antivirala? Patologie asociată ce poate schimba conduita: - coinfecţii HBV, HIV; - afecţiuni extrahepatice (mai ales neoplazice, cardiace, tiroidiene); tratamente cronice care pot interfera cu terapia antiHCV

Contraindicaţii terapie Afectare Hepatică severa: Afectări Extrahepatice: anemie, trombocitopenie severe Alte afecţiuni ce pot fi agravate: coronariene, tiroidiene severe, boli autoimune, neoplazii + REFUZUL PACIENTULUI – informare corectă

TERAPIA: condusă de specialist Interferon pegilat + ribavirină

Tratamentul Hepatitei Cronice C Criterii de includere in terapie ALT crescute/normale Ac anti HVC+ ARN-VHC DETECTABIL PBH- modificari evolutive (Metavir>A2F1) FibroScan / FibroMax Varsta – nu exista limita varsta; fara comorbiditati majore Manifestari extrahepatice (Vasculita crioglobulinemica, Glomerulonefrita cu virus C )

Nedecontate de CNAS: FIBROTEST- Inflamatia(A) si Fibroza(F) FIBROSCAN- Fibroza

In ultima perioda s-au obtinut progrese importante in tratamentul Gross AASLD NP-PA SCU-03-1319 8/7/2018 10:52 AM In ultima perioda s-au obtinut progrese importante in tratamentul hepatitei cronice VHC 49

Interferon/ ribavirin Tratmentul HC VHC PI + PegIFN/RBV (6-12 mos)[8-10] 100 70-75 80 PegIFN/ribavirin (6-12 mos)[6,7] Interferon/ ribavirin (6-12 mos)[3,4] 50-60 60 PegIFN monotherapy (6-12 mos)[5,6] SVR (%) Standard interferon (12-18 mos)[2,3] 38-43 40 Standard interferon (6 mos)[1] 25-30 15-20 20 8-12 1991 1995 1998 2001 2011 1. Carithers RL Jr., et al. Hepatology. 1997;26(3 suppl 1):83S-88S. 2. Zeuzem S, et al. N Engl J Med. 2000;343:1666-1672. 3. Poynard T, et al. Lancet. 1998;352:1426-1432. 4. McHutchison JG, et al. N Engl J Med. 1998;339:1485-1492. 5. Lindsay KL, et al. Hepatology. 2001;34:395-403. 6. Fried MW, et al. N Engl J Med. 2002;347:975-982. 7. Manns MP, et al. Lancet. 2001;358:958-965. 8. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 9. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 10. Sherman KE, et al. N Engl J Med. 2011;365:1014-1024. 50

NOI MEDICAMENTE ANTIVHC MOLECULE MICI TERAPIA ANTIVHC NOI MEDICAMENTE ANTIVHC MOLECULE MICI inhibitori proteaza (PI) inhibitori polimeraza (Pol I) Mai avem nevoie de IFN RBV? IFN protejeaza impotiva aparitiei rezistetei la PI RBV scade rate recaderilor

Concluzii 1. In ciuda progreselor obtinute in preventie si terapie, virusurile hepatitice reprezinta o problema majora de sanatate publica si trebuie sa fie o prioritate in fiecare tara 2. In ultimii 10 ani au aparut modificari importante in epidemiologia virusurilor hepatitice Slide 2 Moxonidine (4-chloro-N-(imidazolidine-2-ylidene)-6-methoxy-2-methyl-5-pyrimidinamine) is a centrally acting antihypertensive drug. The blood pressure-lowering effect of moxonidine is due to a highly selective action in the rostral ventrolateral medulla, which leads to a reduction in overactivity of the sympathetic nervous system.

Concluzii 3. Incidenta si prevalenta infectiei VHC raman ridicate in anumite regiuni datorita absentei unui vaccin si a unui tratament antiviral care sa determine eradicarea intr-un procent ridicat 4. Sunt necesare programe noi mai eficiente de preventie, de screening , de cresterea adresabilitatii si nu in ultimul rand de tratament Slide 2 Moxonidine (4-chloro-N-(imidazolidine-2-ylidene)-6-methoxy-2-methyl-5-pyrimidinamine) is a centrally acting antihypertensive drug. The blood pressure-lowering effect of moxonidine is due to a highly selective action in the rostral ventrolateral medulla, which leads to a reduction in overactivity of the sympathetic nervous system.

Concluzii 5. Pentru anumite situaţii/categorii de risc testarea antiHCV este obligatorie: toxicomani, expunere profesională, copii mame infectate, tratamente injectabile multiple 1980-95, partener HCV pozitiv 6. Un test anti HCV pozitiv nu inseamna infecţie actuală cu HCV: trebuie evaluat! 7. Consilierea pacienţilor cu HCV este un element important al îngrijirii lor corecte Slide 2 Moxonidine (4-chloro-N-(imidazolidine-2-ylidene)-6-methoxy-2-methyl-5-pyrimidinamine) is a centrally acting antihypertensive drug. The blood pressure-lowering effect of moxonidine is due to a highly selective action in the rostral ventrolateral medulla, which leads to a reduction in overactivity of the sympathetic nervous system.

10. Nu exista loc sigur unde sa ne ascundem de virusuri ! Concluzii 8. Tratamentul antiviral este regula îngrijirii acestor pacienţi, abţinerea de la tratament – excepţia. 9. Pacientul care nu a răspuns / nu a putut urma tratamentul trebuie monitorizat în continuare pentru riscul de evoluţie severă / în aşteptarea unor antivirale noi. 10. Nu exista loc sigur unde sa ne ascundem de virusuri ! Slide 2 Moxonidine (4-chloro-N-(imidazolidine-2-ylidene)-6-methoxy-2-methyl-5-pyrimidinamine) is a centrally acting antihypertensive drug. The blood pressure-lowering effect of moxonidine is due to a highly selective action in the rostral ventrolateral medulla, which leads to a reduction in overactivity of the sympathetic nervous system.