The topic of my presentation is "Advancement in treatment of viral hepatitis" which aim to discuss the different types of viruses causing hepatitis, pathogenesis, their prevention, novel vaccines and current as well as newer modalities of treatment of viral hepatitis.

1. PHYSIOLOGY SEMINAR
ADVANCEMENT IN TREATMENT
OF VIRAL HEPATITIS
BY PRABAL DAS
GUIDE: DR. NAVEEN P

2. • Understand the different types of viruses causing
hepatitis
• Understand the basics related to structure and
mechanism of pathogenesis of hepatitis A, B, C, D
and E viruses
• Understand the prevention of viral hepatitis
• Understand current and newer modalities of
treatment of viral hepatitis
OBJECTIVES OF
THIS SEMINAR

3. Courtesy: nobelprize.org
HARVEY J ALTER MICHAEL HOUGHTON CHARLES M. RICE
"FOR THE DISCOVERY OF HEPATITIS C VIRUS"

4. Courtesy: WHO; World Hepatitis Alliance

5. Courtesy: Harrison's Principle of Internal
Medicine 20th ed; shutterstock
HEPATITIS A:
• Positive sense, single stranded RNA virus
• Non-enveloped
• 27 nm icosahedral nucleocapsid core
• Belong to hepatovirus genus of picornavirus family

6. Courtesy: UpToDate ;ASM journals

7. Courtesy: XHP publishing;
PATHOGENESIS:
• Virus entry into the
cell
• Uncoatong of genome
• Viral replication
• Translation
• Egress

8. Courtesy: Hepatology-A clinical textbook 10th ed;
Robbins and Cotran SAE
• Host immune response leads to inflammaption and damage to
hepatocytes
• the necroinflammatory changes and mononuclear cell infiltrates are prominent
in periportal areas,
• but lobular focal necrosis, ballooning hepatocytes, and apoptosis are regular
features as well.
• In some cases, centrilobular cholestasis may be severe, particularly in adults.

9. Treatment and Prevention:
• Treatment is largely supportive
• consists of discontinuation of potentially hepatotoxic medications
• Most patients do not require hospitalization
• Cyclosporine and Silibinin inhibits HAV replication
• Use of post-exposure HAV vaccination or prophylaxis in patients
with household contact with HAV
Courtesy: memebase.com; UpToDate

10. Courtesy: Jawetz microbiology 27th ed; PMC8147224;
Hepatology- a clinical textbook 10th ed
HEPATITIS B:

11. Courtesy: Jawetz microbiology 27th ed

12. PATHOGENESIS:
Courtesy: Jawetz microbiology 27th
ed; PMC8147224

13. Courtesy:Robbins and Cotran, SAE

14. Courtesy: Harrison's Principle of
Internal Medicine 20th ed ; cdc.gov

15. Courtesy:Verywell Health
TREATMENT:
COMMONLY USED
INTERFERON ALPHA DERIVATIVES NUCLEOSIDE/NUCLEOTIDE ANALOGS
Interferon α (IFN-α) :
• first approved in 1991
• Was replaced by pegylated counterpart, PEG-IFN-α, in 2005
• Two forms of PEG-IFN-α used today

16. Courtesy:PMC8147224; indiamart
NUCLEOSIDE/NUCLEOTIDE ANALOGS:
• Inhibits HBV reverse transcripts activity
• active form of most of these drugs is the triphosphate that results
from their phosphorylation by hepatocyte kinases
• During reverse transcription, they act as immediate or delayed
transcriptional terminators and prevent the synthesis of both (−)
and (+) HBV DNA strands
• Many NAs have been approved against the HBV, of which the
current recommended ones are entecavir and the two tenofovir
prodrugs, disoproxil and alafenamide

17. Courtesy: Current Diagnosis and
Treatment gastroenterology
Hepatology and endoscopy 3th ed

18. Courtesy: mohfw.gov.in

19. NOVEL STRATEGIES:
1. Inhibiting HBV entry:
• Myrcludex B (also known as Bulevirtide)- synthetic myristoylated
lipopeptide consisting of 47 amino acids of the pre-S1 region.
2. Directly targeting cccDNA:
• IFN-α administration induces APOBEC3 expression, resulting in the
elimination of cccDNA in infected hepatocytes.
3. Immune therapies
(a)Targeting innate immunity:
• Phase I clinical trials for TLR7 agonists RO7020531, RG7795 (ANA773),
and RG7854 (Roche©) are currently underway. TLR7 agonist JNJ-
64794964 (Janssen©) demonstrated an excellent safety and
tolerability profile in healthy adults during a double-blinded,
randomized phase I trial. Phase II clinical trial results for TLR7 agonist
GS-9620 (also known as vesatolimod) revealed that it is safe and well-
tolerated in chronic hepatitis B patients receiving NAs.
• RIG-I agonist SB-9200 (also known as Inarigrivir) showed promising
results in a woodchuck model of HBV infection
• Phase II clinical trials demonstrated the increased benefit of
combining classic antiviral treatment with immune therapy.
Courtesy: Hepatology- a clinical
textbook 10th ed

20. (b) Targeting adaptive immunity:
• The PD-1 (programmed death-1) receptor is expressed on HBV-specific T cells, and compounds that block the interactions with its
physiological ligand, PD-L1, can increase the number and response of HBV-specific T cells, resulting in increased cytotoxic T cell activity
against HBV-infected cells.
• Anti-PD-1:PD-L1 monoclonal antibody Nivolumab has already been evaluated in phase I and II clinical trials in over 100 patients with
advanced HCC and no hepatotoxicity incidents were observed
4. RNA interference:
• An early RNAi drug against HBV, tested in human clinical trials, is ARC-520. The injection consists of two cholesterol-conjugated siRNAs,
along with N-acetylgalactosamine (NAG) to achieve hepatocyte-specific delivery
• Other examples are RG7834 and AB-729
5. RNase H inhibitors:
• Ribonucleases H are endonuclease enzymes that catalyze cleavage of RNA sequences in DNA:RNA hybrids.
• Inhibiting HBV RNaseH activity results in the accumulation of long DNA:RNA hybrids and halts the reverse transcription. Consequently,
newly synthesized virions are non-infectious since they contain a defective genome
• E.g., β-thujaplicinol, N-hydroxyisoquinolinediones (HIDs), N-hydroxynapthyrydinones (HNOs), N-hydroxypyridinediones (HPDs), and N-
hydroxypyrimidinediones

21. Courtesy: Frontiers; WJH
HEPATITIS C:
• positive-stranded RNA virus belonging to the Flaviviridae family
• nucleocapsid containing the viral RNA surrounded by an endoplasmic
reticulum (ER)-derived envelope in which viral E1 and E2 glycoproteins are
embedded as heterodimers
• highly infectious HCV particles circulate in patient serum in association
with very-low-density lipoproteins (VLDL) or low-density lipoproteins
(LDL), to form LVPs

22. Courtesy: Nature Reviews, Gastroenterology and Hepatology;
Frontiers
PATHOGENESIS:

23. • There is no vaccine, and hyperimmune globulins are not available.
• Pooled immune serum globulins are not useful for postexposure prophylaxis.
• There is no effective regimen for prophylaxis following needlestick injury; only monitoring is recommended.
PREVENTION:
Courtesy:PMC8795940

24. Courtesy: Robbins and Cotran, SAE;
nobelprize.org

25. Courtesy: Levinson's Review of
Microbiology and Immunology 17th ed
TREATMENT:
Acute hepatitis C: ( <6 months)
• peginterferon alfa
• ledipasvir and sofosbuvir
Chronic Hepatitis C: (>6 months)

26. Courtesy: ReasearchGate; Hepatology-
a clinical textbook 10th ed
HEPATITIS D:
• Viroid-like
• Negative sense, small,circular ssRNA
• Genome is surrounded by delta agent core
• Core is surrounded by HBsAg envelope, thus requires HBV to complete it's life cycle
• HDV encodes only one HDAg with two isoforms
• Makes use of host cellular machinery to accomplish essential processes for it's life cycle
• Requires an actively replicating Hepatitis B "helper" virus; only occurs in HBV+ patients
• HDV exacerbated the symptoms of HBV, responsible for causing 40% of fulmitant hepatitis infection

27. Courtesy: ResearchGate
PATHOGENESIS:

28. Courtesy:PMC6718034; AASLD
TREATMENT:

29. HEPATITIS E:
• small, icosahedral, nonenveloped single-stranded RNA virus
• Belongs to genus Hepevirus in the family Hepeviridae
• approximately 27 to 34 nm in diameter
• Disease resembles HAV - acute, self-limited, typically less severe
• Transmitted through foeco-oral route
• significant concern for pregnant women who become infected
and also in immunocompromised host

30. PREVENTION:
• Proper sanitation is an important measure
• Proper disposal of human waste
• Improved personal hygiene procedure
• Most importantly access to clean drinking water
Vaccines:
• At present no commercially available vaccines (only licensed in China)
VACCINES ON TRIAL
Recombinant vaccine Subunit vaccine
• A 55kDa recombinant HEV-derived ORF2 has
been used to vaccinate rhesus monkey
• Although primates could still be infected the
vaccine protected them from symptoms of
disease
• Direct intramuscular injection of purified
plasmid DNA containing the full-length
ORF2 has induced a prolong humoral
immune response (>12 months)

31. TREATMENT:
• In immunocompentent host, HEV virus usually does not need antiviral therapy and most cases are
spontaneously cleared.
• Ribavirin therapy shortens overall course of the disease.
IN PREGNANT WOMEN:
• Rivarin should not be used as it is a suspected teratogen.
• Immune serum globulins considerably reduce mortality in 3rd trimester of pregnancy

32. Courtesy: EASL
TREATMENT FOR IMMUNOCOMPROMISED HOST:
For patients still not clearing infection

33. Courtesy: UpToDate

34. Courtesy: Harrison 's Principles of Internal
Medicine 20th ed