1. HEPATITIS B VIRUS ; WHAT`S NEW
HEPATITIS B VIRUS ; WHAT`S NEW ? EASL treatment guidelines 2017 AASLD treatment guidelines 2018
Dr. Ahmed Zeid Prof. Internal Medicine- Hepatology Unit
Alexandria Faculty of Medicine

3. Agenda Basic data. Who to treat ? How to treat ?
When to stop treatment ?

4. HBV cannot be completely eradicated due to persistence of covalently closed circular DNA (cccDNA) in nucleus of infected hepatocytes

5. 4 Phases of Chronic HBV Infection
Current Understanding of HBV Infection
HBeAg
Anti-HBe
ALT activity
HBV DNA
Phase
Immune Tolerant
Immune Clearance
Inactive Carrier State
Reactivation
Liver
Minimal inflammation and fibrosis
Chronic active inflammation (HBeAg+ve CHB)
Mild hepatitis and minimal fibrosis
Active inflammation
(HBeAg-ve CHB)
Understanding the natural history or the 4 phases of chronic hep B infection is important because it helps us determine when we should treat the patient. So, if someone is E antigen positive in the very beginning of infection—they are E antigen positive; they have the wild type—they may start out, if they’re young, as immune tolerant. They are tolerant to the virus, meaning their virus will be very high but their liver enzymes will be normal and they, on liver biopsies, would have very minimal inflammation and no significant damage to the liver. Those patients are currently not recommended for therapy.
Some time in their life, they may go on to have immune clearance, where their immune system is no longer tolerant to the virus. It tries to clear the infection by creating immune activity in the liver, trying to clear those infected liver cells of the virus, and that immune reaction may cause damage to the liver. So, during that immune-clearance phase, you may see on a biopsy active inflammation, and if they are not able to clear the virus efficiently, then those patients go on to have significant injury or damage to the liver, histologically.
If they are able, however, to immune clear their virus, they go into an inactive carrier state where they have minimal activity, their liver enzymes are normal, their virus is undetectable, and those patients should have minimal activity on their biopsy as well, and you wouldn’t treat those patients who are inactive. Unfortunately, sometimes they develop that pre-core or basal core promoter mutation. The virus comes back and becomes reactivated. So, even though they were E antigen negative and cleared or seroconverted during the immune-clearance phase, they may reactivate and develop active virus again, even though they are E antigen negative, E antibody positive. So, again, the 2 phases where you would treat would be somebody who has got immune activity, and they have a lot of active inflammation, elevated liver tests and active virus in the blood, or reactivation, where they have, again, elevated liver tests, high virus in the blood, and they may have active inflammation on biopsy. E antigen negative or positive would be dependent on which phase of the natural history they’re in.
Optimum treatment times
Yim HJ, et al. Hepatology. 2006;43:S173-S181.

6. EASL 2017 Phase 5: ‘‘occult HBV infection”
HBsAg-negative ± HBsAb positive.
HBcAb positive.
± Serum HBV DNA.
HBV DNA (cccDNA) can be detected in liver.

7. WHO TO TREAT ??

8. ALT
HBV DNA
≥ 2000 IU
Severity of
liver disease
liver fibrosis ≥ F2

9. Inclusion criteria for treatment
HBsAg(+ve) for more than 6 months.
HBV DNA ≥ 2000 IU/ML.
ALT elevation above upper limit of normal on 2 successive occasions within months.
( or normal ALT with liver fibrosis ≥ F2 )
(Evidence level I, grade of recommendation 1)

10. Patients with immune tolerant phase (HBeAg-positive chronic HBV infection) may be treated if they are > 30 years regardless of severity of liver disease.
Patients with HBeAg-positive or HBeAg-negative chronic HBV infection and family history of HCC or cirrhosis and extrahepatic manifestations can be treated even if typical treatment indications are not fulfilled.
(Evidence level III, grade of recommendation 2).

11. HOW TO TREAT ??

12. FDA-Approved HBV Therapies
Schering-Plough PPT Template
FDA-Approved HBV Therapies
6/7/ :19 PM
Peginterferon alfa-2a
TAF
Entecavir
Lamivudine
Tenofovir
1990
1998
2002
2005
2006
2008
Interferon alfa-2b
Adefovir
Telbivudine
So, FDA-approved therapies go back to 1990 when we first had standard interferon alfa-2b. In 1998, we had lamivudine, which was the first oral drug approved for hepatitis B, and at the time, it was really remarkable. We used it and it worked, but we found that lamivudine resistance became a problem shortly thereafter, but at least we had an oral drug that was easy to take for hepatitis B. It wasn’t until 2002 that we had adefovir, and that improved things because the resistance rates were a little bit lower. But in 2005, we really started to see a lot of developments in hepatitis B with pegylated interferon approval alfa-2a, entecavir in 2005, telbivudine in 2006, and then tenofovir in So, we’ve had 5 oral therapies and 2 injectable therapies that are FDA approved for hepatitis B. 12

13. Interferon
Advantages of interferon
A finite course of therapy for naïve patients.
No viral resistance.
High rate of HBeAg loss with in 1 year.
High rate of HBsAg loss with short duration
The response rate is 20-30%

14. Interferon Pre-treatment predictors of response
In HBeAg positive CHB, predictors of anti-HBe seroconversion ) low viral load.
2) high serum ALT levels (above 2–5 times ULN).
3) HBV genotypes A and B.
4) high activity scores on liver biopsy (at least A2).
In HBeAg negative CHB,
There are no strong pre-treatment predictors of virological
response.

15. First line therapy for all naïve patients is:
Entecavir 0.5 mg once daily Or
Tenofovir 300mg once daily

16. In HBV patients with liver cirrhosis:
All cirrhotic patients should receive oral therapy if HBV DNA is detectable irrespective of viral load.
Compensated Cirrhosis:
Entecavir 0.5 mg or Tenofovir 300mg once daily.
Decompensated Cirrhosis:
Entecavir 1 mg once daily.
Note: The dose of antiviral needs to be adjusted in patients with low creatinine clearance (< 50ml/min).

17. Treatment of HBV in special populations

18. Acute HBV infection
Spontaneous recovery in more than 95% of cases and seroconversion to anti HBs without antiviral therapy. Supportive management and close monitoring for early detection of fulminant hepatitis.
Acute severe hepatitis and Fulminant hepatitis :
Entecavir 0.5 mg for at least 6 months after seroconversion to anti HBs or for at least 12 months after seroconversion to anti HBe without HBs Ag loss.

19. HCV co-infected patients

20. HBV and pregnancy
In pregnant women already on NA therapy, TDF should be continued while ETV or other NA switched to TDF
In all pregnant women with high HBV DNA levels (200,000 IU/ml), antiviral prophylaxis with TDF should start at week 24–28 of gestation and continue for up to 12 weeks after delivery  

21. New born
Newborns for chronic HBV mothers should receive HBIG and the first dose of HBV vaccine at birth (6-12 hours after delivery).
Breast feeding is not contraindicated in HBsAg-positive untreated women or on TDF treatment

22. Healthcare workers

23. Immune-suppressed patients

24. When to stop Treatment ?
The ideal endpoint is HBsAg loss with or without seroconversion to anti-HBs; however, this is rarely feasible.

25. When not to stop treatment ?
All cirrhotic patients (compensated and decompensated) should receive oral therapy if HBV DNA is detectable and should not stop treatment.

26. In HBeAg positive CHB patients,
NA (nucleoside/nucleotide analogue) therapy can be stopped 12 ms after Hbe seroconversion or idealy continued till HBsAg loss particularly in patients with advanced fibrosis.
(Evidence level II-2, grade of recommendation 2)
HBeAg(–) CHB disease is becoming more prevalent that HBeAg(+) CHB disease.

27. In HBeAg negative CHB patients
Discontinuation of NA in selected non-cirrhotic
HBeAg-negative patients who have achieved long-term
(3 years) virological suppression may be considered if
close monitoring can be guaranteed
(Evidence level II-2, grade of recommendation 2)
HBeAg(–) CHB disease is becoming more prevalent that HBeAg(+) CHB disease.

29. The first study, a collaboration between two expert centers in Greece and Taiwan. The study included 130 HBeAg- negative patients without cirrhosis.
The second study, by Jeng et al, reviewed the incidence and predictors of HBsAg seroclearance after NA cessation in 691 Taiwanese patients with HBeAg-negative chronic hepatitis B with (45%) and without (55%) cirrhosis who discontinued oral therapy according to the APASL.
During the off-therapy follow-up of approximately 3 years, the cumulative virologic and clinical relapse rates were assessed

31. Authors recommendations:
CHB without cirrhosis.
Persistently normal ALT and negative HBV DNA over 3 y
Close monitoring is guaranteed.
End-of-treatment HBsAg levels <100 IU/mL.

32. CONCLUSIONS
HBV infection is characterized by persistence owing to the presence of cccDNA.
Not all HBV infected patients are candidates for treatment.
Identification of the patient HBV status ( acute, chronic, carrier, past infection,….) is essential before the decision making to start therapy.

33. CONCLUSIONS
A finite NA treatment approach has an increasing evidence and leads to high HBsAg loss rates in selected HBeAg-negative patients without cirrhosis who are willing to comply with close follow-up.

34. THANK YOU