EPATITE CRONICA DA HCV: Impatto della clearance virale e rischio di carcinoma epatocellulare Rodolfo Sacco, M.D., PhD Direttore U.O.C. Gastroenterologia ed Endoscopia Digestiva A.O.U. Ospedali Riuniti" - Foggia
Hepatitis C is the silent global epidemic of the 21st Century Viraemic prevalence 0.0 <0.6% 0.6 <0.8% 0.8 <1.3% 1.3 <2.9% 2.9 <6.7% 2015 ~72 million people with viraemic HCV ~8.1 million people with HCV-related liver cirrhosis ~261,000 people with HCV-related HCC ~7000 HCV-related liver transplants ~370,000 HCV liver-related deaths Blach S, et al. Lancet Gastroenterol Hepatol 2017;2:161 76; The Polaris Observatory. Hepatitis C. Available at: http://polarisobservatory.org/polaris/hepc.htm (accessed April 2017)
Chronic HCV infection may lead to liver disease and liver cancer Cirrhosis is the strongest risk factor for HCC, with hepatitis C virus (HCV) being a major risk factor in the Western world as well as in Japan HCC is characterized by high rate of mortality and first cause of death in patients with compensated cirrhosis
Lifecycle of the Hepatitis C Virus Entry Differently from HIV and HBV: Assembly HCV replication occurs only in NS5B NS5A Replication NS3-NS4A complex RNA the genome of infected cells NS4B Translation Processing Golgi complex Fusion and Viral RNA uncoating cytoplasm replication Endoplasmic reticulum Viral genome is no archived into Nonstructural proteins play a key role in the replication and assembly of new virions This makes HCV curable!!!! Structural and nonstructural proteins contribute to different processes in the viral life cycle 1. Asselah and Marcellin. Liver Int. 2011;31(suppl 1):68; 2. Scheel and Rice. Nat Med. 2013;19:837.
Direct Acting Antivirals Against HCV Manns, von Hahn, Nat Rev Drug Discov 2013
Nearly Everyone With HCV Can Now Be Treated Successfully Very high SVR rates; therapies highly tolerable All-oral therapy for almost every pt Treatment generally just 12 wks 100 80 60 40 Standard Interferon 1991 Ribavirin 1998 34 Peginterferon 2001 42 39 55 Direct- Acting Antivirals 2011 70+ 2013 90+ All-Oral Therapy Current 98+ 20 0 6 16 IFN IFN 6Mos 12 Mos IFN/RBV 6 Mos IFN/RBV 12 Mos PegIFN 12 Mos PegIFN/ RBV 12 Mos PegIFN/ RBV + DAA DAA + RBV ± PegIFN All Oral DAA± RBV
Goals obtained by achieving Sustained Virological Response (SVR) cure Reduce necroinflammation Stop fibrosis progression Prevent cirrhosis & complications Prevent hepatocellular carcinoma Reduce extra-hepatic manifestations Increase survival No AE Eradicate the virus (HCV clearance) Adapted by Schinazi & Asselah. From HCV to HBV cure. Liver Int. 2017;37 S1:73-80.
Efficacy of sofosbuvir and velpatasvir for 12 weeks in TN/TE patients with and without compensated cirrhosis
Efficacy of glecaprevir and pibrentasvir for 12 or 16 weeks in patients with compensated cirrhosis
Elbasvir/Grazoprevir (Zepatier) Programma di studi clinici vasto e robusto 8 studi clinici principali, oltre 2.300 pazienti SVR in Real World *Real-World Experience of EBR/GZR in the VA Healthcare System RCP ZEPATIER Clark VC. Liver Int. 2013 Zeuzem S. Ann Intern Med. 2015 Forns X. J. Hepatol. 2015 Kwo P. DOI 10.1053/j.gastro.2016.09.045 Roth D. Lancet. http://dx.doi.org/10.1016/s0140-6736(15)00349-9 7 Rockstroh JK. Lancet. 2015;2:e319-e327 http:// Dore GJ. Ann Intern Med.August 2016 *Adapted from Utilization and Effectiveness of Elbasvir/Grazoprevir for the Treatment of Hepatitis C Virus Genotype 1b Infection: Updated Cohort From the US Veteran Affairs Healthcare System A. Puenpatom et al. Abstract 660, AASLD 2018
What is the impact of SVR on the occurrence/recurrence of HCC? OCCURRENCE: De novo appearance of HCC in a subject with no history or previous evidence of a liver tumor RECURRENCE: Reappearance of HCC in a subject with a previous HCC judged to be radically cured
HCC occurrence and recurrence in IFN-era
Stage 1 (no varices) Prospective study: - 444 pts with compensated cirrhosis - IFN-based treatment Stage 2 ( F1 varices) Annual HCC rate by SVR: - Stage 1: 0.7% vs 2.9% (P =.0017) - Stage 2: 0.9% vs 3.6% (P =.0018)
Meta-analysis: interferon improves outcomes following ablation or resection of hepatocellular carcinoma Benefit of IFN in reducing the risk of HCC; however, strategy was not included in HCC guidelines
HCC occurrence in DAA-era
EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma 2018 ü Once cirrhosis has been established, antiviral therapy is beneficial in preventing cirrhosis progression and decompensation. Furthermore, successful antiviral therapy reduces but does not eliminate, the risk of HCC development (evidence moderate). Antiviral therapies should follow EASL guidelines for the management of chronic hep- B and C infection. European Association for the Study of the Liver, J Hepatol 2018
EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma 2018 ü Patients with HCV-associated cirrhosis and HCC treated by curative intent maintain a high rate of HCC recurrence even after subsequent directly acting antiviral (DAA) therapy. It is presently unclear whether this presents the inherent risk of advanced cirrhosis to develop HCC or if DAA therapy increases recurrence rates. Thus, further research is encouraged. Currently, in these patients close surveillance is advised and the benefit of viral cure must be outweighed against a potentially higher recurrence risk (evidence low; recommendation high). European Association for the Study of the Liver, J Hepatol 2018
Risk of HCC occurrence after DAAs Retrospective Prospective Calvaruso, Cabibbo, et al Gastroenterology 2018 Consideration: occurrence rate after DAA-therapy may be mainly due to the fact that patients with more advanced stages of cirrhosis (also in unselected Child Pugh B class or with significant portal hypertension), who are at an intrinsically higher risk of cancer with respect to patients treated with IFN-based regimens in the past.
INCIDENCE AND PREDICTORS OF DE NOVO HCC FOLLOWING SVR WITH DAA: RESULTS FROM THE GILEAD SVR AND CIRRHOSIS REGISTRIES Ø Aim: To evaluate the incidence and predictors of de novo HCC following SVR in a well characterized cohort of over 6700 patients enrolled in Gilead registries. Ø Methods: Pooled analysis to assess the incidence and predictors of de novo HCC among patients enrolled in the Gilead SVR and Cirrhosis registries Patients with SVR who had received a sofosbuvir-based regimen could be enrolled < 60 weeks of completing a study or 2 years of achieving SVR following treatment in clinical practice Reddy K, et al. AASLD 2018. Abstract #635
INCIDENCE AND PREDICTORS OF DE NOVO HCC FOLLOWING SVR WITH DAA: RESULTS FROM THE GILEAD SVR AND CIRRHOSIS REGISTRIES 6757 patients who received interferon-free DAA regimens were included in this interim analysis 81 patients (1.2%) developed de novo HCC or suspected HCC from SVR12 Median observation time of 135 weeks (range 0.3 288) Median time to HCC onset from SVR12: 68 weeks (range 3-181) Exposure-adjusted incidence rates of HCC from SVR12 0.07 per 100 PY (8 cases) in patients without cirrhosis 1.13 per 100 PY (46 cases) in patients with compensated cirrhosis 4.35 per 100PY (27 cases) in patients with decompensated cirrhosis Factors associated with development of HCC (per multivariate analysis): Decompensated cirrhosis, Compensated cirrhosis, Pretreatment albumin 3.5g/dL, GT3 infection, Pretreatment platelets 150x10 3 /ul, Male gender, age 60 years Reddy K, et al. AASLD 2018. Abstract #635
INCIDENCE AND PREDICTORS OF DE NOVO HCC FOLLOWING SVR WITH DAA: RESULTS FROM THE GILEAD SVR AND CIRRHOSIS REGISTRIES In this analysis of a large cohort of patients successfully treated with DAAs and followed long term (median 135 weeks), the incidence rate of de novo HCC was low Patients with decompensated cirrhosis who were traditionally excluded from interferon therapy were at the highest riskof de novo HCC Cirrhosis, genotype 3 infection, older age, lower pretreatment albumin and platelet count were independently associated with the development of HCC Reddy K, et al. AASLD 2018. Abstract #635
NO DIFFERENCE BETWEEN DIRECT-ACTING ANTIVIRALS FOR HEPATITIS C IN HEPATOCELLULAR CARCINOMA RISK Aims: To compare different DAA regimens with respect to risk of de novo HCC following antiviral therapy Rationale: If some DAAs truly increased HCC risk, there would be differences between different DAA regimens in the risk of HCC after antiviral treatment If no differences between DAA regimens in the risk of HCC are found, it would strongly suggest that DAAs do not have direct carcinogenic effects, as it would be extremely unlikely that different DAAs, belonging to different classes, would have identical carcinogenic effects Mun E, et al. AASLD 2018. Abstract #654
NO DIFFERENCE BETWEEN DIRECT-ACTING ANTIVIRALS FOR HEPATITIS C IN HEPATOCELLULAR CARCINOMA RISK Methods: 33,137 patients were identified to have initiated HCV antiviral treatment between 12/06/2013 and 12/31/2015 with one of four DAAonly regimens (±ribavirin): Ledipasvir/ Sofosbuvir (n=19,282) Paritaprevir/ Ritonavir/Ombitasvir/Dasabuvir (ProD) (n=6,289) Sofosbuvir (n=4,356) Sofosbuvir+Simeprevir (n=3,210) Results: Mean follow-up: 1.52 years 741 new cases of HCC were diagnosed after antiviral treatment Incidence = 1.47 per 100 PY After adjustment for baseline characteristics associated with HCC, there were no significant differences in HCC risk between the four DAA regimens Mun E, et al. AASLD 2018. Abstract #654
HCC recurrence in DAA-era
Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing IFN-free therapy 1-year recurrence rate HCC recurrence rate of almost 28% (16 HCC/58 pts) after a median follow-up of only 5 7 months (range 0 4 24 6) after DAA therapy. 30% Bruix et al. Lancet 2015 - Multicenter, retrospective study - Short follow-up - Crude (not actuarial) rate Reig M. J Hepatol. 2016
Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing IFN-free therapy (?!?!?!?!?!) 1-year recurrence rate HCC recurrence rate of almost 28% (16 HCC/58 pts) after a median follow-up of only 5 7 months (range 0 4 24 6) after DAA therapy. 30% Bruix et al. Lancet 2015 - Multicenter, retrospective study - Short follow-up - Crude (not actuarial) rate Reig M. J Hepatol. 2016
Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing IFN-free therapy (?!?!?!?!?!) 1-year recurrence rate HCC recurrence rate of almost 28% (16 HCC/58 pts) after a median follow-up of only 5 7 months (range 0 4 24 6) after DAA therapy. 30% Bruix et al. Lancet 2015 - Multicenter, retrospective study - Short follow-up - Crude (not actuarial) rate Reig M. J Hepatol. 2016
Direct antiviral agents and risk for HCC early recurrence: Much ado about nothing
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DIRECT-ACTING ANTIVIRAL THERAPY SIGNIFICANTLY REDUCES EARLY HCC RECURRENCE: A MULTICENTER U.S. COHORT STUDY Aim: To compare HCC recurrence patterns among DAA-treated and untreated patients who achieved HCC complete response (CR) Methods: North-American multicenter retrospective cohort study of patients with HCV-related HCC who achieved CR after resection, ablation, transarterialchemo/radioembolization or radiation therapy from 1/2013 to 12/2016 Patients who received DAA prior to CR or achieved CR via transplant or systemic therapy were excluded Singal A, et al. AASLD 2018. Abstract #92
DIRECT-ACTING ANTIVIRAL THERAPY SIGNIFICANTLY REDUCES EARLY HCC RECURRENCE: A MULTICENTER U.S. COHORT STUDY Results: 866 HCV-HCC patients from 31 health systems were included 355 patients (41%) received DAA therapy 511 patients (59%) were untreated Median time from HCC treatment to CR: 1.6 months Median time from CR to DAA initiation: 4.9 months Singal A, et al. AASLD 2018. Abstract #92
DIRECT-ACTING ANTIVIRAL THERAPY SIGNIFICANTLY REDUCES EARLY HCC RECURRENCE: A MULTICENTER U.S. COHORT STUDY DAA therapy was associated with significantly reduced HCC recurrence risk (HR 0.41, 95% CI 0.32 0.52) Adjusting for study site, age, sex, Child-Pugh class, AFP level, initial tumor burden and HCC therapy leading to CR Results were similar when considering early recurrence only (HR 0.42 95% CI 0.30 0.60) More DAA treated than untreated patients received potentially curative therapy (transplant, resection or ablation) for HCC recurrence (34.2% vs 25.7%, p=0.06) Similar proportions achieved CR/PR to treatment of recurrence (49.6% vs 51.0%, p=0.80) Singal A, et al. AASLD 2018. Abstract #92
DIRECT-ACTING ANTIVIRAL THERAPY SIGNIFICANTLY REDUCES EARLY HCC RECURRENCE: A MULTICENTER U.S. COHORT STUDY In the largest cohort study to date, DAA therapy was associated with significantly reduced HCC recurrence, including early recurrence, after CR. HCC recurrence patterns, including tumor burden and treatment response, were similarin DAA treated and untreated patients. Singal A, et al. AASLD 2018. Abstract #92
WHO: Elimination of HCV as a Public Health Goal Defined as achievement of measurable global targets in relation to infection and burden of disease Intensity of interventions required will vary by setting Setting-specific model required to determine what is necessary to achieve the impact targets Elimination: reduction to zero of incidence in a defined geographical area as a result of deliberate efforts; continued intervention measures required WHO. Global health sector strategy on viral hepatitis 2016-2021. 2016.
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