Viral Hepatitis Graham R Foster Professor of Hepatology Queen Marys School of Medicine Barts Health

Standardized Death Rates UK <65 yr (1970 = 100%) UK Standardised death rates (<65 years) Standardized Death Rates UK <65 yr (1970 = 100%) LIVER AND DIGESTIVE HEALTH - UCLPartners

Hepatitis Increased ALT (GGT can be ignored) Drugs Bugs (Autoimmune)

Hepatitis Increased ALT (GGT can be ignored) Drugs – ALCOHOL and FAT Bugs (Autoimmune)

Hepatitis Increased ALT (GGT can be ignored) Drugs – ALCOHOL and FAT Bugs – VIRAL HEPATITIS (Autoimmune)

Hepatitis Increased ALT (GGT can be ignored) Drugs – ALCOHOL and FAT Bugs – VIRAL HEPATITIS (Autoimmune) These are NOT mutually exclusive

Viral Hepatitis Hanging around together Alcohol and viruses hang around together Viruses and fat make a great team A drinker with high ALT remains at risk of viral hepatitis

Hepatitis Increased ALT (GGT can be ignored) Drugs – ALCOHOL and FAT Bugs –VIRAL HEPATITIS - rare in the UK (Autoimmune)

We live on planet earth >= 8% - High HBsAg Prevalence 2-7% - Intermediate <2% - Low 36

We live on planet earth >= 8% - High HBsAg Prevalence 2-7% - Intermediate <2% - Low 36

Planet Earth If it moves VACCINATE IT Combined HBV and HAV vaccine is best

We live on planet earth >= 8% - High HBsAg Prevalence 2-7% - Intermediate <2% - Low 36

Planet Earth Acute hepatitis is not uncommon Consider HAV, HBV, HEV

Planet Earth Acute hepatitis is not uncommon Consider HAV, HBV, HEV

Planet Earth Acute hepatitis is not uncommon Consider HAV, HBV, HEV Think FUNCTION – INR is all that counts If the INR is high – call us (Liver SpR or Liver Consultant or My Mobile)

Chronic Viral Hepatitis Chronic HBV Chronic HCV

HBV in East London HBV is a disease of immigrants

HBV in East London

Hepatitis B: Natural History Hepatitis B causes a slowly progressive disease that leads to cirrhosis and liver cancer At least 30% of people with HBV will die from it

HBV in East London Modelling the disease in people from India

Hepatitis B: Natural History

HBeAg– Virological Response: HBV DNA <400 copies/mL at Year 4 ‡ Study 102 - HBeAg-Negative Patients 100 90 80 70 60 50 40 30 20 10 87% 84% • TDF-TDF • ADV-TDF Percentage % ITT: LTE-TDF Analysis 0 4 8 12 16 20 24 28 32 36 40 44 48 56 64 72 80 88 96 108 120 132 144 156 168 180 192 100 90 80 70 60 50 40 30 20 10 Weeks on Study 100% 99% Percentage % On-Treatment Analysis 0 4 8 12 16 20 24 28 32 36 40 44 48 56 64 72 80 88 96 108 120 132 144 156 168 180 192 Marcellin P, et al. AASLD 2010; Poster #476. Weeks on Study

HBV Therapy We use:- Pegylated Inerferon OR Oral antiviral agents Monitoring

HBV If we find it – we can control it

HBV in Immigrants If we find it – we can control it If we don’t find it – patients will die

HCV Very common in immigrants Very common in people who have used drugs

HCV 45 year old man with diabetes Graphic designer in West London ALT 160

HCV 45 year old man with diabetes Graphic designer in West London ALT 160 Diabetic clinic asked GP to perform liver screen – no action Persistently high ALT

HCV 45 year old man with diabetes Graphic designer in West London ALT 160 Diabetic clinic asked GP to perform liver screen – no action Persistently high ALT Age 54 tested for HCV - +ve, in hepatology clinic described past drug use US shows HCC – palliative therapy given

Viral Hepatitis in East London Screening for hepatitis in the Mosque Bangladesh HCV – 4/726 (0.6%) HBV – 11/726 (1.5%)

Pakistan

Age Distribution & Ethnicity of Patients with HCV Admitted over 1 year at RLH 5 10 15 20 25 30 <20 20-29 30-39 40-49 50-59 60-69 70-79 White British - Yes Pakistani - Yes Bangladeshi - Yes Count of HCV Age Ethnicity HCV

People from Pakistan, living in UK Female Male People from Bangladesh, living in UK Female Male

HCV in Immigrants HCV is common in immigrants The number of immigrants with advanced fibrosis is about to explode

HCV in Immigrants HCV is common in immigrants The number of immigrants with advanced fibrosis is about to explode BUT – we have good treatments

Sofosbuvir with PEG-IFN + RBV (NICE approved for August) NEUTRINO Phase III trial Sofosbuvir plus PEG-IFN + RBV* for 12 weeks Treatment naïve, GT1 (89%), 4, 5 or 6 (N=327) 17% had compensated cirrhosis Primary endpoint: SVR12 Abbreviations: PEG-IFN + RBV = pegylated interferon and ribavirin GT = genotype SVR12 = sustained virological response after 12 weeks of stopping therapy EOT = end of treatment RBV administered according to body weight (1000mg/day in patients <75kg; 1200mg/day in patients≥75kg) *Dose administered according to body weight †Last observed measurement Lawitz et al. N Eng J Med 2013;368:1878–87

Results: SVR12 in GT 3 by Treatment History and Cirrhosis Status SOF + RBV 16 weeks SOF + RBV 24 weeks SOF + PEG/RBV 12 weeks SVR12 (%) DCV+SOF x 12 weeks for comparison: TN NC 97% (73/75), TN C 58% (11/19) 58 70 65 72 68 71 12 21 18 22 21 23 41 54 44 54 49 52 17 36 26 34 30 35 94/112 83/100 10/11 No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis Treatment Naïve Treatment Experienced Error bars represent 95% confidence intervals.

HCV – It gets even better Highly effective all oral therapies are now available (NICE approval pending)

Sofosbuvir/ledipasvir ± RBV for 8 weeks vs 12 weeks in treatment-naive non-cirrhotic G1 HCV-infected patients LDV/SOF n=216 LDV/SOF n=215 LDV/SOF + RBV n=216 Wk 0 Wk 8 Wk 12 Wk 24 Wk 20 SVR12 Stratified by HCV subtype (1a or 1b) G1 treatment-naive patients without cirrhosis LDV/SOF 8 weeks 12 weeks LDV/SOF + RBV 201/216 202/215 206/216 SVR12 (%) SVR12 G1 treatment naive Abstract not available Kowdley K.V, et al. NEJM 2014;370:1879

Baseline Characteristics Patients treated in the UK with cirrhosis   Total N = 467 G1 N = 235 G3 N = 189 Others N = 43 Decompensated cirrhosis (Past or present) 441 (94.4%) 223 (94.9%) 179 (94.7%) 39 (90.7%) CP-B 309 (66.2%) 161 (68.5%) 121 (64.0%) 27 (62.8%) CP-C 46 (9.9%) 19 (8.1%) 24 (12.7%) 3 (7.0%) MELD mean (range) 11.9 (6-36) 11.3 (6-24) 12.6 (6-22) Active ascites 178 (38.1%) 97 (41.3%) 67 (35.4%) 14 (32.6%) Previous variceal bleed 127 (27.2%) 61 (26.0%) 55 (29.1%) 11 (25.6%) Active encephalopathy 80 (17.1%) 41 (17.4%) 34 (18.0%) 5 (11.6%)

SVR12 by Genotype and Regime 164 21 45 5 SVR12 defined as HCV RNA at 12 weeks post-treatment < 30 IU/ml

Functional Outcome Change in MELD: Baseline – Follow up week 4 Comparative MELD scores available for 220 patients

HCV – Towards a global cure We now have drugs that allow us to eliminate HCV from the UK NHS E are working on a policy with regional networks, centrally funded drugs and a prioritisation program

HCV – Towards a global cure We now have drugs that allow us to eliminate HCV from the UK NHS E are working on a policy with regional networks, centrally funded drugs and a prioritisation program All we now is to find the patients!

HEP-Free (Foster/Griffiths) NIHR funded grant (£2 million) 90 GP practices – (Newham, SE London, Bradford, Oxford) All immigrants will be tested for viral hepatitis and offered therapy

HepFREE If HepFREE is a success screening immigrants for viral hepatitis will become a national priority We are looking for volunteers (You will be re-imbursed, supported and will play a role in chaning UK health care)

Viral Hepatitis Common –VERY common in East London (Think DRUGS – ETHNICITY) Major cause of preventable deaths/cancer Curable Test – Refer - Treat