Riattivazione di HBV nei coinfetti HBV/ HCV trattati con DAA per HCV. Cagliari, 7 Dicembre 2018

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1 Riattivazione di HBV nei coinfetti HBV/ HCV trattati con DAA per HCV Cagliari, 7 Dicembre 2018

2 Disclosures? Nessun finanziamento personale Finanziamenti all istituto: assegno di ricerca per giovane specialista, Abbvie fellowship epatite C 2018, Gilead

3 HBV/HCV: epidemiology the dual hepatitis C virus (HCV)/hepatitis B virus(hbv) infection share modes of transmission is not uncommon in HCV or HBV endemic areas and among subjects at risk of parenteral transmission (1-9)

4 3.3% 1.6% 2.0% 3.5% 6.2% 0.7% 6.1% WHO: GLOBAL HEPATITIS REPORT, 2017

5 HCV infection worldwide The Polaris Observatory HCV Collaborators. Lancet Gastroenterol Hepatol 2017;2:161-76

6 Prevalence of HBsAg in HCVAb+ Author, Reference Country N of Patients HBsAg+ individuals Tyson 1 (USA) % Bini 2 (USA) % Siddiqui 3 (USA) 743 3% Italy 4 : Piter 7454 pz HCV+ HBsAg determined in 6211/ % HBsAg+ 69/ % 49/69 (71%) on anti HBV drugs 1. Tyson GL, et al.. Hepatology 2013; 58: Bini EJ, et al Hepatology 2010; 51: Siddiqui. Am J Gastroenterol 2001; 96: Kondili L Personal communication

7 Prevalence of anti HCV in HBsAg+ Author, Country N of subjects % anti HCV + Fong (USA) % Chen (China) ,4% Li (China) % Liaw (Taiwan) % Chan (Taiwan) % Dai (Taiwan) % Sato (Japan) 82 23% Okhawa (Japan) % Semnani (iran) % Gaeta (Italy) % Antonucci (Italy) % Di Marco (Italy) % Fattovich (Italy) % Crespo (Spain) %

8 HCV/HBV epidemiology General estimate from past studies: Approximately 2 10% of anti-hcv-positive patients are found to be HBsAg positive May be an underestimated due to the phenomenon of silent (occult) HBV infection Testing for HBsAg alone may substantially underestimate the true prevalence of HBV/HCV coinfection

9 HBV/HCV: disease In patients dually infected with hepatitis C and B, the disease manifestations are usually more severe than those with either virus infection. (1-9)

10 Median Time to Cirrhosis and Cofactors in Hepatitis C HIV coinfection 9 years Alcohol > 50 g / day 13.5 years HBV coinfection 15 years Stetosis/Type 2 Diabetes/MS 19 years NO cofactors 27 years YEARS FROM ESTIMATED DATE OF INFECTION 30 Alberti, 2002

11 HBV-HCV natural history: Long term evolution Higher prevalence of liver cirrhosis and hepatic decompensation (Fong 1991, Fattovich1991, Crespo1994 Zarsky 1998, Mohamed Ahel 1997, Sagnelli 2004 ) Increased risk of progression of liver fibrosis, establishment of cirrhosis and independent predictor of HCC development (Huang 1997, Kalamani 1991, Weltman 1995)

12 Clinical Outcomes of Hepatitis B Virus Coinfection in a United States Cohort of Hepatitis C Virus-Infected Patients Cirrhosis Death HCC Kruse RL et al. HEPATOLOGY 2014;60:

13 Impact of HBV/HCV Coinfection on Development of HCC Synergism between HBV and HCV in carcinogenesis and developing HCC Incidence of HCC (per 100 person years) 6.4 in co-infected patients 2.0 in HBV monoinfected 3.7 in HCV monoinfected Cumulative risk of developing HCC at 10 years 45% in co-infected patients 16% in HBV monoinfected 28% in HCV monoinfected

14 HBV HCV coinfection: treatments In patients with HBV/HCV coinfection, anti-hcv treatment may induce a reactivation of HBV replication and, conversely, anti-hbv treatment a reactivation of HCV replication. (1-9) treatment Rectivation EOT Reactivatio n Fup Potthof, 2008/2009 PegIfn Riba 4/13(31%) 11/13(45%) Liu, 2009 PegIfn Riba 47/76 (61.8%) idem Yu, 2009 PegIfn Riba 11/46 (23.9) idem

15 2014/15 HBV HCV coinfection No data on the efficacy and safety of new Directly Acting Antiviral regimens with/without Peg-IFN and ribavirin treatment in HBV/ HCV chronic coinfection have been published. (1-9) HBV reactivation was not reported as an adverse event in the clinical trials submitted for the DAA approvals because patients with HBV co-infection were excluded from the trials Current HCV treatment guidelines offer generic guidance on treatment and monitoring of patients coinfected with HBV

16 eventi clinici: 3 pazienti HBsAg+ Soggetti arruolati: 3 Caratteristiche cliniche: 2 con cirrosi stadio CPT B7 1 con cirrosi iniziale F4 Metavir+linfoma NH genotipi: 3, 1b, 2 rispettivamente Criterio prevalente di arruolamento: 1 di AIFA

17 3 pazienti HBsAg positivi 2015/16 Paziente 1 Paziente 2 Paziente 3 Stadio CPT B7 B7 A5 + linfo MELD Durata terapia con ETV 2y 1,5y 1y Genotipo 3 1b 2 HCV RNA HBV DNA NR NR 38 UI** Terapia HCV SOF RIB 24w* SOF DAK 24w SOF RIB 24w HCVRNA 4w NR NR NR HCVRNA EOT NR NR NR HBV DNA EOT NR NR NR HCV RNA 12 W F UP relapse NR NR HBV DNA 12 W F UP NR NR NR HBV DNA 24 W F UP NR NR 38 UI *Trattamento all epoca considerato ottimale, ** diventa NR dalla IV settimana

18 Altri 3 pazienti HBsAg positivi Paziente 4 Paziente 5 Paziente 6 METAVIR F3/11kPa F3/10.3kPa F4/16kPa Genotipo 3 1b 2 HCV RNA HBV DNA SI SI SI Terapia HCV SOF DAK RIBA 12 w* 3D 12w SOF LED 24w TERAPIA HBV ETV 10 gg prima ETV 10 gg prima ETV 10 gg prima HCVRNA 4w ND ND ND HCVRNA EOT ND ND ND HBV DNA EOT ND ND SI HCV RNA 12 W F UP ND ND ND HBV DNA 12 W F UP ND ND 60UI/mL HBV DNA 24 W F UP ND ND ND Terapia HBV Ongoing Ongoing Ongoing *Experienced PegIfn/riba

19 considerazioni La concomitante terapia soppressiva di HBV: compatibile e priva di effetti collaterali ha controllato la replicazione di HBV dopo la soppressione di HCV La paziente 3 ha presentato a W24 di follow up riattivazione di HBV ma anche della malattia ematologica

20 Evento clinico: una paziente HBsAg negativa 65 anni Stadio CPT A6 naive MELD 10 Genotipo 1b HCV RNA HBsAg ASSENTE Terapia HCV SOF SIM RIB 12w W4 HCVRNA NR ALT 0.5 EOT W12 HCVRNA NR ALT 0.4 ALT W4 X 9 VN FUP ALT W8 0.8 FUP

21 Percorso diagnostico EBV, CMV, HAV IgM ASSENTI ANA, AMA, SMA ASSENTI AFP, GGT, FA NELLA NORMA HCV RNA NON RILEVABILE A W f up RIPETE MARCATORI HBV: HBsAg assente, HBcAb e HBeAb Presenti HBV DNA RILEVABILE: 35UI (determinazione effettuata a w20 di follow up)

22 diagnosi Riattivazione di HBV (OBI) dopo la soppressione di HCV

23 FDA Drug Safety Communication: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C Safety Announcement [ ] The U.S. Food and Drug Administration (FDA) is warning about the risk of hepatitis B virus (HBV) becoming an active infection again in any patient who has a current or previous infection with HBV and is treated with certain direct-acting antiviral (DAA) medicines for hepatitis C virus. In a few cases, HBV reactivation in patients treated with DAA medicines resulted in serious liver problems or death.

24 Treatment of HBV/HCV Coinfection u FDA Drug Safety Communication u FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C 24 cases of HBV reactivation reported to FDA in HCV/HBV co-infected patients treated with DAAs during from November 22, 2013 to July 18, 2016 Two patients died and one required a liver transplan Baseline worse liver disease would be a greatest risk from Hep flare This number includes only cases submitted to FDA, so surely additional cases

25 The data on the efficacy of DAA regimens in HBV/HCV chronic coinfection are very few, suggesting a possible reactivation of HBV infection after the HCV control. CGH 2017

26 Patients with combined HBV and HCV infection may show a large spectrum of virologic profiles Virologic response are widely divergent / dynamic over time possibility that HBV and HCV can alternate their dominance during different periods of infection

27 Most HBV/HCV coinfected patients appear to have active HCV and inactive HBV replication HCV infection can directly suppress HBV replication mediated by HCV core protein Produces a phenomenon of occult or serologically silent HBV Undetectable hepatitis B virus surface antigen [HBsAg] Usually Hep B core (+), SAb (-) isolated core (+) Detectable HBV DNA in serum

28 Fewer patients have high HBV viremia levels and low/ undetectable HCV RNA In some HBV/HCV co-infected patients, each virus exerts its own pathogenetic role

29 Esercitazione anni, maschio italiano IFN experienced FIBROSI 8.5 Kpa AST x1.5vn, ALTx2vn HCV genotipo G1b GGT x2vn HCV RNA UI/mL HBsAg/HBeAb +/+ Scoperto nello screening pre terapia con DAA HBV DNA Assente HDV Ab - Le domande: 1. iniziare trattamento con DAA per HCV e monitoraggio di HBV 2. iniziare trattamento per HCV e HBV 3. se inizia trattamento anche per HBV lo sospende o lo continua dopo la eradicazione di HCV

30 Flow chart 1 HBV-HCV Coinfection Therapeutic approaches HBsAg/HCV RNA positive patients F0-F2 3-6 mo FU with repeated HBV DNA HCV RNA Inactive HBV infection Active HBV infection Advanced fibrosis Occult B Infection Treat as HCV mono-infection * Treat HBV then add anti-hcv therapy^ * monitor HBsAg or HBV DNA during and after treatment ^ Continue NUC therapy at the end of anti-hcv treatment independently of HCV response

31 Flow chart 2

32 HBV/HCV COINFECTION both predominant viruses HCV predominance HBV predominance HBVDNA+ HCVRNA+ treat both HBV DNA+ HCV RNA- HBsAg+ HBVDNA<10 E3IU/mL HCVRNA+ Treat HCV infection monitoring HBV DNA HBsAg HBcAb+ HBVDNA<10 E3 HCVRNA+ treat HBV infection monitoring HCV RNA every six months during HCV treatment and up to one year after the end of therapy Treat HCV infection monitoring HBsAg seroconversion up to one year after the end of therapy Flow chart 3

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34 Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection Persons with HBV/HCV coinfection There are no global prevalence data on HBV/HCV coinfection, but various studies have reported that 3 18% of people who are HBsAg positive are also HCV infected (138). HBV/HCV coinfection is more likely among PWID and persons living in areas where both viruses are endemic (138). Coinfection with HBV and HCV increases the risk for HCC, although the reasons for this are not well understood (139, 140). In 2016, the FDA issued a warning about the risk of HBV reactivation during DAA treatment (defined as >1000 IU/mL increase in HBV DNA or detection of HBsAg in a person who was previously negative) based on 29 case reports (95). Even though HBV reactivation appears rare, individuals may be considered for HBV testing before initiating HCV treatment (131,141). Persons with HBV/ HCV coinfection may be assessed for eligibility for HBV treatment and, if needed, started on HBV treatment before starting HCV treatment (131, 141). Persons with advanced disease may be considered for monitoring at regular intervals for HBV reactivation during HCV treatment. The risk of reactivation among persons who are anti-hbc positive but HBsAg negative is very low ( ).

35 Caratterizzazione del Paziente pre-terapia: i Dogmi I pazienti HBsAg+ con indicazione alla terapia antivirale per HBV devono essere trattati seguendo le raccomandazioni AISF. I pazienti HBsAg+ senza indicazione alla terapia antivirale per HBV dovrebbero essere sottoposti al monitoraggio dei valori di transaminasi e di HBV-DNA in concomitanza agli altri controlli biochimici previsti durante e dopo la terapia antivirale per HCV, o in base alle esigenze cliniche, al fine di identificare una possibile riattivazione di HBV. In questi pazienti è possibile iniziare una profilassi antivirale per prevenire il rischio di riattivazione, tale profilassi va mantenuta per almeno 12 settimane dopo la sospensione dei DAA. Nei pazienti HBsAg-, HBsAb+/-, HBcAb+, la ricerca di HBsAg e HBVDNA dovrebbe essere considerata in caso di documentato incremento dei valori delle transaminasi, in assenza di una definita etiologia, soprattutto nei pazienti immunocompromessi e/o trapiantati di organo solido o di midollo.

36 What Anna says. From AASLD 2018

37 Risk of HBV reactivation with HCV therapy IFN based: 1.45% ( %) Meta analysis of 15 studies (n=757) DAA based Meta-analysis of 13 studies: HBsAg+: 24% (19-30%) n=242. Hepatitis flares: 9% (83% less likely if HBV DNA -) isolated anti HBc+: 1.4% (0,8-2,4%), n=1379. Hepatitis flares: 0% Most individual studies are small studies. Above rates are likely over estimated

38 Risk of HBV reactivation with HCV therapy Evaluation of hepatitis B reactivation Among 62,920 Veterans treated with oral hepatitis C antivirals (PS Belperio, TS Shahoumian, LA Mole, L I Backus) A large scale retrospective study only 9 out patients treated with DAA s had HBV reactivation 8 were HBsAg + 1 was anti HBc+ 3/9 who reactivated had ALT >2x ULN 17 others had small increases in HBV DNA

39 Risk of HBV reactivation with HCV therapy Low incidence of hepatitis B virus reactivation and subsequent hepatitis in patients with chronic hepatitis C receiving DAA therapy (A Tamori, S Abiru, H enomoto, K Kioka, M Korenga, J Tani, M Enomoto,M Sugiyama, T Masaki, N Kawada, H Yatsuhashi, S Nishiguchi, M Mizokami) Partially prospective study, HBV DNA monitored serially during and after DAA therapy 1 out 765 (0.13%) isolated anti HBc patients treated with DAAs had HBV reactivation In isolated anti HBc patients with anti HBs, there were no significant changes in anti HBs titers between baseline and post DAA therapy 25 patients were HBsAg+, patients with HBV DNA<2000IU/mL did not developed hepatitis, but few cases

40 Key take away DAA treated HCV: treat up to 12 weeks post if HBsAg+ and HBV DNA >2000(or lower). Monitor only if isolated HBcAb+ up to 12 weeks, treat if HBsAg or HBV DNA become positive

41 Anna said so!

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