LA TERAPIA PER HBV ed HCV Differenze di Genere? Alfredo Alberti. Dipartimento di Medicina Molecolare UOC Medicina Generale VIMM Università di Padova

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1 LA TERAPIA PER HBV ed HCV Differenze di Genere? Alfredo Alberti Dipartimento di Medicina Molecolare UOC Medicina Generale VIMM Università di Padova

2 HBV ed HCV Due virus Diversi ma con molte Cose in Comune

3 HBV and HCV HBV Host cell Host cell HCV HCV RNA Host DNA cccdna H Host DNA H Integrated DNA Nucleus Nucleus DOUBLE STRAND DNA RETROVIRUS ABLE TO INTEGRATE LATENCY IMMUNOMEDIATED DAMAGE NO METABOLIC EFFECTS SINGLE STRAND RNA CYTOPLASMIC NO INTEGRATION / NO LATENCY DIRECT and IMMUNOMEDIATED DAMAGE METABOLIC VIRUS

4 Transmission HBV and HCV similarities Immune mediated Pathogenesis Escape Mutants Clinical Expression of Liver Disease and of End Stage Complications THERAPY ARMAMENTARIUM : Interferon alfa Direct antivirals

5 THERAPEUTIC STRATEGIES similar drugs but different endpoints HBV Virus suppression or Immune-control without virus Eradication HCV Virus Eradication with a Common Basic Pathway : Role of Host Immune response

6 THERAPY OPTIONS TODAY and IN PERSPECTIVE HBV a) IFN antiviral and immunemodulation HBeAg seroconversion HBV immune control b) ORAL NUCs direct antivirals Pharmacological Suppression HCV a) Dual PEG-IFN + RIBAVIRIN b) Triple PEG-IFN + RIBAVIRIN + DAA c) IFN-FREE DAAs Virus suppression eradication antiviral + immune control

7 GENDER and OUTCOME OF HBV and HCV THERAPY Pre-Menopause Females have a better response to IFN-based therapies vs Post-Menopause Females and Males Role of Female Hormones in Innate and Adaptive Immunity

8 Oestrogen and immunomodulation: new mechanisms that impact on peripheral and central immunity Suchita Nadkarni, Simon McArthur Current Opinion in Pharmacology Volume 13, Issue

9 VARIABLES AFFECTING RESPONSE TO ANTIVIRAL THERAPY WITH HBV and HCV a multifactorial network Age Stage of Liver Disease Comorbidities IR Obesity MetS Coinfections HIV HBV+HCV Virus Genotype HBV A>B>C>D HCV 2>3>4>1 Adherence Host Genetics (IL28B)

10 How do IL28B polymorphisms influence HCV recovery? Adapted from Thomas et al., Gastroenterology 2010

11 IL28B AND CLEARANCE OF HCV INFECTION Author SNP associated with outcome of infection Thomas DL et al. Nature 2009 Rauch A et al. Gastroenterology 2010 Montes-Cano MA et al Hepatology 2010 Tillmann H et al Gastroenterology 2010 rs (CC) associated with natural resolution of infection rs (GG) associated with progression to chronic infection rs (CC) associated with natural resolution of infection rs (CC) associated with natural resolution of infection Rauch A et al Gastroenterology 2010 Thomas DL et al. Nature 2009 Tillmann H et al Gastroenterology 2010

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13 % % % % 60 IL28B HCV-SANI 53,6 60 IL28B M HCV-SANI 54, ,9 44, ,9 44, ,9 16,5 10, ,1 14,9 10,9 CC CT TT 0 CC CT TT Genotipi IL28B Maschi Genotipo IL28B Popolazione HCV Popolazione sana IL28B maschi-femmine ,0 52, IL28B F HCV-SANI 52,8 44,9 44, ,1 28,3 14,9 18, ,3 18,9 10, CC CT TT 0 Genotipo IL28B CC CT TT Genotipo di IL28B Femmine Popolazione sana

14 % % % % IL28B HCV-1 IL28B HCV ,1 54, ,4 25,4 14,5 19, , ,9 39, CC CT TT ,3 11,3 Maschi Femmine Genotipo IL28 0 Maschi CC CT TT Genotipo IL28 Femmine IL28B HCV-3 IL28B HCV ,6 43,6 37,5 39,6 22,9 12,8 CC CT TT Genotipo IL28B Maschi ,0 57,7 22,2 19,2 23,8 23,1 CC CT TT Genotipo IL28B Maschi Femmine

15 THERAPY OF HBV gender related differences IFN and PEG-IFN Based Therapy FEMALES OR x SVR (95%CI) p HBeAg positive 1.56 ( ) 0.03 HBV-C 2.78 ( ) 0.02 HBV-D 7.69 ( ) 0.02 HBV-A and HBV-B not significant Buster et al Gastroenterology 2009 HBeAg Negative 1.93 ( ) 0.02 HBV-D 1.77 ( ) 0.02 HBV-A not significant Bonino et al Gut 2007, Alberti (Unpublished)

16 THERAPY OF HBV Response to oral NUCs FEMALES MALES HBV-DNA suppression at week % 77-88% HBV-DNA suppression week % 77-93% HBV-DNA reactivation at withdrawal 4/11 7/10 37% 70%

17 17 SVR Pre-menopause Females 67.5% Post-menopause Females 46.0% Males 51.1% p : < p : n.s.

18 Univariate and Multivariate Logistic Regression Analysis of Risk Factors for SVR Failure in 442 Female Patients with Chronic Hepatitis C Villa E et al., Gastro 2011

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20 THERAPY OF HCV gender-oriented analysis of outcome SVR (%) Males Females HCV-1 36% 46% HCV-2 78% 84% HCV-3 60% 87% Di Marco et al JVH 2013

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22 FEMALE PATIENTS

23 MALE PATIENTS

24 THERAPY OF HCV genetic/gender stratified analysis of outcome HCV-1 MALES FEMALES p IL28B(CC/CT) 50% 52% n.s. HCV-2 SVR (%) IN (TT) 20% 38% 0.01 IL28B (CC/CT) 85% 85% n.s. (TT) 68% 70% n.s. HCV-3 IL28B (CC/CT) 75% 81% n.s. TT 42% 60% 0.05

25 Treatment of insulin resistance with metformin in naïve genotype 1 chronic hepatitis C patients receiving peginterferon alfa 2a plus ribavirin

26 IFN-FREE THERAPY FOR HCV FALDAPREVIR (PI) plus DELEOBUVIR (NNUC) IN HCV-1 INFECTED PATIENTS Variables associated with SVR by multivariate analysis : HCV-1b IL28B CC normal GGT FEMALE SEX* (due to higher rates of relapse after therapy in males) Zeuzem et al NEJM 2013

27 CONCLUSIONS Gender is one of the many variables affecting the response to antiviral therapy in Hepatitis B and in Hepatitis C, females doing better This gender effect can be diluted out with easy to treat virus or absence of other cofactors The effect might be related to better immune response but the role of adherence and tolerability needs to be better explored.

28 LIVER DISEASE PROGRESSION WITH HCV Normal liver or Minimal hepatitis Chronic inflammation and fibrosis Cirrhosis and Portal Hypertension HCV Liver Cancer Bleeding Decompensation Transplant Death