ABC of Viral Hepatitis. Mark Thursz

Transcription

1 ABC of Viral Hepatitis Mark Thursz

2 Disclosures Research funding Affimmune Gilead GSK Novartis Vital Therapies Advisory Boards / Speaker Fees Affimmune Norgine Novartis Gilead

3 HAV

4 HAV Naked RNA virus Picornavirus Low ph resistant Inactivated by high temperature, formalin and chlorine Faeco-Oral transmission

5 Diagnosis

6 HAV Clinical Incubation period 28 days Jaundice < 6 years <10% 6 14 years 40 50% > % Complications Acute liver failure <1% Cholestatic 10 20% Relapsing 3 10%

7 Cholestatic Hepatitis A

8 Hepatitis A Outbreak in Europe

9 % IGG ANTI-HAV POSITIVE Seropositivity for HAV in African Regions AGE GROUP North Africa/Middle East Central sub-saharan Africa East sub-saharan Africa South sub-saharan Africa West sub-saharan Africa Jacobsen & Weirsma. Vaccine 2010

10 HBV

11 HBV Epidemiology 32 nm virus 250 Million chronically infected 1 Million deaths per year

12 Modes of Transmission HBV Vertical Horizontal 90% Chronicity 20% Chronicity Sexual transmission - < 5% chronicity

13 Genome structure of HBV

14 Life Cycle of HBV in the Hepatocyte Viral polymerase converts pregenomic RNA to partially ds DNA Infectious HBV virion Cytoplasm Subviral particles ER Partially dsdna Minus strand DNA Encapsulated pregenomic mrna HBcAg HBsAg HBeAg cccdna mrna Nucleus Hepatocyte Precore/core Adapted from Lai CL, et al. J Med Virol. 2000;61:

15 Before and After Vaccination - Gambia Peto BMC Infect Dis 2014

16 Rate of Hepatitis B Virus (HBV) Infection among Infants. Prevention of Mother to Child Transmission Birth Dose Vaccine Tenofovir for PMTCT Pan CQ et al. N Engl J Med 2016;374:

17 Natural History of Chronic HBV Immune Tolerance HBeAg+ HBeAg-/anti-HBe+ (precore/core promoter variants) < > < > HBV DNA Immune Clearance 2 x x IU/mL 200,000-2 x 10 9 IU/mL Low Replicative Phase < 2000 IU/mL Reactivation Phase > 2000 IU/mL ALT Normal/mild CH Moderate/severe CH Cirrhosis Normal/mild CH Inactive cirrhosis Moderate/severe CH Cirrhosis HBeAg+ chronic hepatitis Inactive-carrier state HBeAgchronic hepatitis

18 Progression of Disease in HBV Asymptomatic 1.0 4% % % % % Lin et al JGH %

19 The TREAT-B score Treatment Eligibility in Africa for the HBV HBsAg screening (<US$ 1-2 using rapid diagnostic test) HBsAg positive Evaluation of treatment eligibility High-income countries (good access to PCR) Conventional criteria Low-income countries (limited access to PCR) New simplified score TREAT-B ALT Liver fibrosis HBV DNA PCR ALT <20 IU/L IU/L IU/L IU/L + 3 HBeAg Negative + 0 Positive + 1 Eligible Score of 2 Antiviral therapy Shimakawa Y, J Hepatol 2018 Antiviral therapy at generic cost (<US$ 50/year)

20 EASL CPG: Indications for treatment Primarily based on the combination of 3 criteria HBV DNA, serum ALT and severity of liver disease Recommendations Should be treated Grade of evidence Grade of recommendation Patients with HBeAg-positive or -negative chronic hepatitis B* I 1 Patients with cirrhosis, any detectable HBV DNA, regardless of ALT level Patients with HBV DNA >20,000 IU/mL and ALT >2x ULN, regardless of severity of histological lesions May be treated Patients with HBeAg-positive chronic HBV infection >30 years old, regardless of severity of liver histological lesions I 1 II-2 1 III 2 Can be treated Patients with HBeAg-positive or -negative chronic HBV infection and family history of HCC or cirrhosis and extrahepatic III 2 manifestations *Defined by HBV DNA >2,000 IU/mL, ALT >ULN and/or at least moderate liver necroinflammation or fibrosis; Defined by persistently normal ALT and high HBV DNA levels; Even if typical treatment indications are not fulfilled EASL CPG HBV. J Hepatol 2017;67:370 98

21 Treatment Pros Finite therapy Increased HBsAg loss Cons Side effects Small proportion of responders Pros Control of viraemia No side effects Cons Indefinite treatment

22 Patients With Undetectable HBV DNA (%) Nucleoside Analogue Treatment ~ LAM ADV ETV LdT TDF Adapted from Lok AS, et al. Hepatology 2007;45: Marcellin P, et al. AASLD Abstract LB2.

23 Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use to treat CHB Efficacy at Year 5 Response HBeAg- Patients (Study 102) HBeAg+ Patients (Study 103) HBV DNA < 400 copies/ml Intent-to-Treat *, % (n/n) 83 (291/350) 65 (160/248) HBV DNA < 400 copies/ml On treatment, % (n/n) 99 (292/295) 97 (170/175) * ITT: missing = failure/addition of FTC = failure On treatment: missing = excluded/addition of FTC = included 84% of 585 patients entering the open-label phase remained on study at Year 5; 76% of enrolled patients remained on study HBeAg loss/seroconversion rates of 49% and 40%, respectively, through 5 years 10% of HBeAg+ patients had confirmed HBsAg loss (8% with seroconversion) No resistance to TDF was detected through 5 years Marcellin P, et al. Lancet 2013; 381:

24 Δ Ishak Fibrosis Score over 5 Years Change in Ishak Scores at Year 5 for Patients with Cirrhosis at Baseline In subjects with cirrhosis at baseline (Ishak fibrosis score 5-6), 74% (71/96) experienced reversal of cirrhosis at Week 240; 70/96 showed a reduction in Ishak fibrosis score of at least 2 points % of patients had reversal of cirrhosis n= n=15 n=41 n=14 n=1 n=24 Marcellin P, et al. Lancet 2013; 381:

25 Nucs Reduce Risk of HCC Hosaka. Hepatol 2013

26 HBsAg loss in patients with HBeAg(-) CHB who remained in virological remission under ADV for 4-5 years HBsAg loss, % Total SRs EOT Yr 1 Yr 2 Yr 3 Yr >4 Hadziyannis SJ et al. Gastro 2012

27 HCV

28 The HCV virus HCV is an blood-borne RNA virus that infects the liver cells 6 types of HCV (=genotypes, GT7 discovered recently) with multiple subtypes (a, b, c) with varying rates of progression & different response to treatment Some people clear the infection naturally. Those who do not clear the infection can either remain free of symptoms or develop cirrhosis or liver cancer.

29 Hepatitis C Epidemiology 70 million persons are infected with hepatitis C virus (HCV) 1,2 Prevalence of HCV Infection Lavanchy D Clin Microbiol Infect 2011; 17: Averhoff FM, et al. Clin Infect Dis. 2012;55(S1):S10-S Global Burden of Hepatitis C Working Group. Journal of Clinical Pharmacology. 2004;44:20-29

30 Progression of Disease in HCV 7.7% 6.3% 3.7% 4.6% % Alazawi. APT %

31 Diagnosis Acute Infection Chronic Infection

32 Routes of Transmission in LMIC

33 HCV Prevalence in Africa IVDU Riou J Viral Hep 2015 Mohammed Z. JVH 2018

34 SVR12 (%) Integrated Analysis of 8W vs 12W of GLE/PIB in Phase II/III Trials of GT1 6 Non-Cirrhotic Patients week G/P 12 week G/P BT 7 REL 1 BT 3 REL n N Overall GT1 GT2 GT3 GT4 GT5 GT BT, breakthrough; mitt, modified intent-to-treat, (excludes non-virologic failures); TE, treatment-experienced (includes patients with prior SOF use); TN, treatment-naive TN/TE* (mitt) * Includes patients with prior SOF use (8-week G/P [n = 7] and 12-week G/P [n = 9]); All GT3 patients were treatment-naïve. Puoti M, et al. J Hepatol 2017; 66(Suppl):S721 (poster presentation SAT-233).

35 SVR12, % POLARIS-2: SOF/VEL/VOX in HCV GT1 6 DAA-Naive Patients relapses 4 LTFU 16 relapses 14 relapses 2 relapses 2 relapses 1 LTFU 2 relapses 3 LTFU 1 relapse relapses 1 AEDC 4 LTFU 2 relapses 2 LTFU 1 relapse 1 LTFU 1 relapse 1 LTFU 1 AEDC 2 LTFU 1 relapse Overall G1 G1a G1b G2 G3 G4 G5 G6 Unknown SOF/VEL/VOX 8 wks, n=501 SOF/VEL 12 wks, n= Jacobson IR, et al. Hepatology. 2016;64(suppl):1126A. Abstract LB-12.

36 SVR is associated with a reduction in liver-related mortality and HCC Liver-related mortality or liver transplantation (%) Hepatocellular carcinoma (%) Liver-related mortality or liver transplantation P<0.001 N=530 Without SVR With SVR Time (y) P<0.001 N=530 Hepatocellular carcinoma Without SVR With SVR van der Meer AJ, et al. JAMA 2012;308: Time (y)

37 Delta Virus 20 million people worldwide HBV Superinfection Heterogeneous distribution < 30% respond to interferon

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39 HDV Lifecycle

40 Lonafarnib - Prenylation Inhibitor

41 Hepatitis E Neurology Vaccination Chronic HEV in immunosuppressed patients

42 HEV Vaccine Zhu Lancet 2010

43 Neurological Manifestations of HEV Bell s palsy Guillain Barré syndrome Encephalitis Meningoencephalitis Mononeuritis multiplex Myelitis Myositis Neuralgic amyotrophy Peripheral neuropathy Vestibular neuritis

44 Management of HEV in Immunosuppressed Patients

45 Summary Numerous tools to control viral hepatitis exist Tools need to be deployed more effectively