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

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

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

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

5. Geographical distribution of chronic HBV

6. 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.

7. 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%.

8. mass

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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)

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

16. 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

17. 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

18. 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

19. 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.

20. 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

21. 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})

22. 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.

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

24. 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

25. 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

26. 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

27. 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.

28. 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.

29. 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

30. 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%

31. 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.

32. 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

33. 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

34. 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%

35. 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

36. 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.

37. 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.

38. 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

39. 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).

40. Targeting viral assembly/encapsidation
Bay , 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.

41. 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

42. 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.

43. Take home massage

44. 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.

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

46. 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

47. 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

48. 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.

49. Thank you

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