Hepatitis-2015 Orlando, USA July 20 - 22 2015 Ehab Abd-El-Atty

HBV: Challenges to cure in the future Prof, Ehab Abd-El-Atty Professor of Internal Medicine & Gastroenterology & Hepatology & Endoscopy Faculty of Medicine, Menoufia University

Agenda Epidemiology HBV Natural history of HBV Screening of HBV Phases of chronic HBV Prophylaxis of HBV Treatment of HBV Monitoring during therapy

Epidemiology 2 billions worldwide had past HBV infection at a time 350 millions Chronic HBV 40.000 new cases each year 750,000 annual deaths are attributed to HBV complications HBV is the second known carcinogen after smoking

Geographical distribution of chronic HBV

HBV genotypes Ten HBV genotypes (A-J). Genotypes A and D results in higher rates of chronicity than genotypes B and C. Genotypes C and D have lower rates of spontaneous HBeAg seroconversion as compared with genotype A and B. Genotype C and D are associated with cirrhosis and HCC. Genotype A and B shows better responses to IFN-based therapy than genotypes C and D.

Natural history of HBV Acute HBV 5-10% chronic HBV. 20% cirrhosis within 5 years (not treated) 20% decompensated cirrhosis within 5 years & HCC (not treated). 5 years survival will be 20%.

mass

Risk factors for progression to cirrhosis Viral factors Host Factors External Factors High HBV DNA levels HBV precore mutant HBV genotypes C & D Older age Male gender Advanced fibrosis Persistent ALT elevation Recurrent hepatitis flares HDV, HCV, HIV coinfections Obesity & steatosis Alcohol

Risk factors for HCC development Viral factors Host Factors External Factors High viral load (≥ 104 copies/mL) HBV genotypes B &C HBV mutations (preS, precore, core promoter region) Older age Male gender Advanced fibrosis Persistent ALT elevation Recurrent hepatitis flares HDV, HCV, HIV coinfections Obesity & steatosis Cirrhosis Low albumin & high bilirubin Alcohol Aflatoxin Family history of HCC

Who should be screened for HBV Hyperendemic areas (Asia, Africa, European Mediterranean) Sexual contacts with HBV persons Individuals infected with HCV or HIV Renal dialysis Pregnant women Chronic elevation of ALT or AST Family history of HCC or HBV Before Anti TNFᾳ therapy

Serological Markers of HBV Infection HBsAg Acute/Chronic infection Anti-HBc IgM Recent infection HBeAg High infectivity Anti-HBe Low infectivity Anti-HBs Immunity Anti-HBc IgG + HBsAg Chronic infection Anti-HBc IgG + anti-HBs Resolved infection

Acute HBV HBeAg +ve HBsAg +ve Anti-HBc IgM +ve HBV DNA PCR +ve Spontaneously resolution 90-95% adult 80% children 50% infants 10% neonates Treat only acute fulminant hepatitis

Chronic HBV Phases Egypt (90% genotype D) Immune tolerant HBe Ag +ve Immune active HBe Ag –ve Immune active (Immune escape) Carrier Occult Egypt (90% genotype D) (90% HBeAg -ve) (72% PCR +ve)

Immune Tolerant Phase First 10-30 years of perinatally acquired HBV infection Asymptomatic High HBV DNA levels but normal ALT HBe Ag +ve

HBe Ag +ve Immune Active Phase Either after long years from perinatal transmission or shortly after person to person transmission Relatively lower HBV DNA levels (>2000 IU/ml) with elevated ALT HBe Ag +ve Annual rate of spontaneous HBe Ag loss is 10% It ends by seroconversion of HBe Ag

HBe Ag -ve Immune Active Phase (Immune escape) It is the late immune active phase HBe Ag -ve (precore mutation) High serum HBV DNA Elevated ALT

Carrier State HBe Ag -ve, anti-HBe +ve Serum HBV DNA < 2000 IU/ml Persistently normal ALT for at least one year HBs Ag <1000 IU/ml 1% annual rate of spontaneous loss of HBs Ag Risk stratification for reactivation

Occult Chronic Hepatitis B HBs Ag -ve HBs Ab -ve HBe Ag -ve PCR <200 IU/ml Normal ALT HBc IgG Ab +ve Serum hs-HBsAg could assist differentiation of occult HBV patients from individuals with only past HBV exposure.

Prophylaxis Vaccine available 1982 worldwide 1992 in Egypt Neonates of HBV +ve mother should receive HBV immunoglobulin (HBIG) and vaccine in the first 12 hours post natal. Screening for HCC every 6 month by US ± AFP Each HBsAg-positive should be screened for anti-HDV

Treatment AASLD 2014 (40% require treatment) Goals of treatment Long-term suppression of HBV replication Decrease hepatic necroinflammation and fibrosis to prevent progression to cirrhosis, liver failure and HCC. In future (clearance of HBs Ag & cccDNA {covalently closed circular DNA})

Candidates not treated Candidates treated HBe Ag +ve or -ve immune active phases i.e. with PCR < 2000 and elevated ALT or with moderate to severe liver inflammation ± fibrosis. Cirrhotic patients with +ve PCR. Carrier and occult HBV with +ve PCR under immune suppression. Acute fulminated HBV Decompensated cirrhosis Candidates not treated Immunotolerant phase. Carrier phase. Occult phase.

Treatment options Peg IFN (2005) Nucleoside Lamivudine (LAM) (1999) Entecavir (2005) Telbuvidine (2006) Nucleotide Adefovir (2003) Tenofovir (2008)

HBe Ag Seroconversion at 24 w Peg IFN HBe Ag +ve only HBe Ag Seroconversion at 24 w Yes No Continue 48 w Stop & shift to oral Monitor during IFN therapy CBC & liver profile /4 w HBV DNA level / 12 w HBs Ag 6-12 month after HBe Ag seroconversion & undetectable HBV DNA

HBe Ag –ve has poor response to IFN. Response to Peg-IFN Low viraemia & high ALT Genotype A 47% Genotype B 44% Genotype C 28% Genotype D 25% HBe Ag –ve has poor response to IFN. Poor response in Egyptian patients with predominant genotype D & HBe Ag –ve

HBe Ag -ve Resistance to treatment is 15%, therefore all Naïve patients are candidates for the most potent drugs with high barrier of resistance e.g. Entecavir 0.5 mg or Tenofovir 300 mg as a first line therapy. Good response to therapy was found in patients with detectable HBV DNA and active inflammation

Tenofovir is preferred in: Patients who received Lamivudine previously. Young women who plan to start a family. Tenofovir is avoided in: Decompensated & advanced cirrhosis (renal impairment) Entecavir is preferred in: Older patients. Patients with medical conditions that increase risk of renal failure.

Patients already on treatment Patients on regular Lamivudine or combined Lamivudine & Adefovir (undetectable HBV DNA) continue treatment and HBV PCR every 3 to 6 months. Newly developed resistance to Lamivudine Shift to Tenofovir.

Response to oral therapy Entecavir HBV PCR –ve in 70% after 1 year, 75% 2 year, 95% 5 year HBe Ag seroconversion 30% after 2 year, 50% after 5 year. HBs Ag loss 1-2% every year Tenofovir therapy HBV PCR –ve in 93% after 3 year, 99% 6 year. HBe Ag seroconversion 34% after 3 year, 50% after 6 year. HBs Ag loss 9 % after 3 year, 11% after 6 year

EASL 2015 Late breaking news Combined Entecavir plus Tenofovir can be used in HBeAg-positive with high HBV DNA level Peg IFN add-on to Entecavir results in more sustained response HBe Ag loss from 25% to 64% ALT normalization from 25% to 79%

Duration of therapy AASLD 2014 & EASL 2015 & APASL 2015 Ideal end point is sustained HBs Ag loss and seroconversion into anti HBs Ab +ve. Peg IFN 48 week In HBe Ag +ve patients, NA therapy can be stopped 12 month after anti-HBe seroconversion life long treatment in HBe Ag -ve patients, HBe Ag +ve patients who did not achieve seroconversion and cirrhotics.

Pitfalls of current therapy Chronic suppression without cure No HBsAg loss in most of patients. Do not target defective immune response and persistence of cccDNA in the infected hepatocytes. Emergence of drug resistance Lamivudine resistance occurs at one level only (YMDD) Entecavir & Tenofovir resistance occurs at 3 levels

Future strategies to eradicate HBV AASLD 2014 & EASL 2015 & APASL 2015 Targeting the host Immune therapy Targeting the virus Inhibitors of cccDNA formation Inhibitors of HBV entry into the hepatocyte

Immune therapy (AASLD 2014) HBV-specific T cell impairment leads to failure of HBV clearance, Mechanism (improve impaired immunity against HBV and can eradicate cccDNA) Thymosin-α1 (APASL) Oral 1.6 mg twice weekly Augments host Th1 immune response HBV DNA–ve & HBeAg seroconversion & normal ALT in 40%

Oxymatrine (APASL) Suppress HBV replication (enhance degradation of HBV mRNA) Normalization of serum ALT 83% HBeAg seroconversion 40% of patients IFN-λ Potent anti-HBV activity in vitro and in transgenic mice

GS-9620 (oral agonist of TLR-7) Prolonged suppression of HBV DNA in serum and liver (HBV Ag +ve hepatocytes) Prolonged suppression of serum HBsAg, HBeAg and. It increases production of IFN-α and various cytokines and chemokines.

Inhibitors of cccDNA formation (AASLD) cccDNA plays a central role in HBV infection persistence and its rebound after stop of therapy. In order to clear HBV, a durable, curative antiviral therapy that directly reduces the level of cccDNA without killing infected hepatocytes is needed. They induced rapid and multi-log regression of viral DNA, HBsAg and HBeAg with long duration of effect.

Inhibitors of cccDNA formation Inactivation/elimination/degradation of cccDNA. Zinc-finger nucleases (ZFNs) directly targets HBV cccDNA within cells (block transcription of cccDNA). CCC-0975 and CCC-0346, which were confirmed as inhibitors of cccDNA production, ARC-520

Inhibitors of HBV entry into the hepatocyte prevented viral spreading in between hepatocytes, but also reduced levels of HBV DNA, HBsAg and cccDNA. Myrcludex-B is a synthetic lipopeptide derived from the HBV envelope protein which inactivates the HBV pre-S1 receptor (receptor antagonists) and blocks HBV infection. REP 9AC’, a nucleic acid-based polymer which clears serum HBsAg by blocking HBV subviral particle formation and release (achieved seroconversion).

Targeting viral assembly/encapsidation Bay 41-4109, inhibits viral replication through inhibition or decrease stability of normal capsids formation and reduces half-life of the core protein. It is active against HBV mutants resistant to NAs.

Targeting HBs Ag secretion: Antimicrobial nitazoxanide It reduces extracellular HBsAg, HBeAg, as well as intracellular HBcAg in a dose-dependent manner. It was a selective inhibitor of intracellular HBV replication and extracellular virus production, and synergistic activity in combination with Lamivudine or Adefovir

Targeting envelopment: Glucosidase inhibitors Inhibition viral morphogenesis and infectivity. They disrupt the development of HBV envelope, thereby inhibit its ability to bind target cells and establish infection. Targeting viral mRNA RNAi was able to inhibit all the steps of HBV replication that occur in cell culture and in mice.

Take home massage

HBV is the second known carcinogen after smoking Egypt (90% genotype D) (90% HBeAg -ve) Vaccination against HBV in infancy is the most effective approach to prevent HBV-related HCC Neonates of HBV +ve mother should receive HBV immunoglobulin and vaccine in the first 12 hours post natal.

Goals of treatment Suppression of HBV replication Decrease hepatic necroinflammation and fibrosis Prevent progression to cirrhosis, liver failure and HCC

Patients with minimal disease should not be treated. Patients at risk of developing complications (cirrhosis & HCC) should receive antiviral therapy It is better to use the most potent drugs with high barrier of resistance e.g. Entecavir or Tenofovir as a first line therapy. All HBV patients must be screened for HCC every 6 month by US ± AFP

Ideal end point of treatment is sustained HBs Ag loss and seroconversion into anti HBs Ab +ve. In HBe Ag +ve patients, satisfactory end point is seroconversion to HBe Ag -ve. life long treatment in HBe Ag -ve patients, HBe Ag +ve patients who did not achieve seroconversion and cirrhotics. Egyptian patients with predominant Genotype D had poor response Peg IFN

In Future Combined Immune therapy and antiviral therapy enhance immunity and achieve sustained control of infection, improve impaired immunity against HBV and can eradicate cccDNA.

Thank you

Hepatitis– 2016 Website: hepatitis.omicsgroup.com Meet the eminent gathering once again at Hepatitis-2016 Dubai, UAE October 17 - 19, 2016 Hepatitis– 2016 Website: hepatitis.omicsgroup.com