The document summarizes recent advances in the management of viral hepatitis, focusing on hepatitis B and hepatitis C. It discusses new drug regimens and guidelines for treating different genotypes of hepatitis B and C. For hepatitis B, entecavir, tenofovir, and telbivudine are discussed as first-line therapies. For hepatitis C, new protease inhibitors and NS5A inhibitors in combination with interferon and ribavirin are highlighted for genotype 1. Sofosbuvir-based regimens are mentioned for genotypes 2, 3, and 4.

1. Recent advances in
management of viral
- Student: Dr Anup U Petare
- Guide: Dr Raakhi K Tripathi.
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2. Global Prevalence
Recent Advances in Hepatitis B
Recent Advances in Hepatitis C
Fixed Dose Combinations
HEV 239 Vaccine.
Conclusion
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Flow of Seminar

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Hepatitis B

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5. • Hepatitis B is one of the world’s most common and
serious infectious diseases
• HBV infection causes more than one million deaths
every year.
• HCC ranks among the top 3 causes of death in
males in South East Asia and HBV accounts for
around 45% of cases of HCC.
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6. First line therapy:
Second line therapy for treatment failure:
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 Potent guanosine nucleoside analogue that inhibits HBV DNA
replication at 3 different steps:
 Priming of HBV polymerase
 Reverse transcription of negative-strand HBV DNA
 Synthesis of positive-strand HBV DNA
 Inhibits both the wild type and lamivudine-resistant HBV
variants
 Initial US FDA Approval 2005: chronic hepatitis B in adults aged
≥ 16
 March 2014: US FDA approved use in paediatric patients ≥ 2 yrs
Entecavir
(Baraclude)

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 High genetic barrier for resistance
 Five-year follow-up data demonstrated low (1.2%) risk of
cumulative resistance
 Current Status: a first line agent in the treatment of
hepatitis B
 Dose: Treatment naïve – 0.5 mg OD
Patients with h/o of receiving lamivudine – 1 mg daily
Entecavir
(Baraclude)

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Entecavir
(Baraclude)
Effective in decompensated cirrhosis
Based on a systematic review of,
 13 trials (Entecavir vs Lamivudine) and
 7 trials (Entecavir vs Lamivudine + Adefovir)
Entecavir significantly improved,
 Advanced liver disease scores
 Improved undectectability of HBV DNA, HBeAg seroconversion
and drug resistance

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 Acyclic nucleotide analogue of adenosine
HBV reverse transcriptase inhibitor.
 US FDA approved in 2008 for chronic hepatitis B in adults &
paediatric patients ≥ 12 years
 First line agent for treatment naïve patients
 Preferred as additional therapy in patients resistant
to Lamivudine, Telbivudine or Entecavir
http://www.gilead.com/~/media/files/pdfs/medicines/liver disease/viread/viread_pi.pdf accessed on 17.9.2015
(VIREAD)
Tenofovir disoproxil
fumarate

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Patient profile Dose
Adults & paediatric patients
12 yrs (>35 kg )
300 mg OD
Creatinine clearance 30-49
mL/min
300 mg every 48 hours.
Creatinine clearance 10-29
mL/min:
300 mg every 72 to 96 hours.
Hemodialysis: 300 mg every 7 days or after
approximately 12
hours of dialysis

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 January 28, 2013, FDA revised label to
 include long-term safety (myopathy and myositis)
 Long term efficacy data
 (GLOBE and NV02B-015 trials).
 Dose: 600mg OD
 MOA: HBV nucleoside analogue reverse transcriptase inhibitor
 Indication: Chronic hepatitis B in adult patients with evidence
of viral replication & either evidence of persistent ↑ in serum
aminotransferases (ALT or AST) or histologically active disease.
Initial U.S. Approval: 2006
(Tyzeka)
Telbivudine
www.fda.gov/downloads/Drugs/DrugSafety/UCM135934.pdf accessed on 15.9.15

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 Easily phosphorylated to its active triphosphate form
 More potent and efficacious than Lamivudine
(GLOBE trial)
 Well tolerated and has no dose limiting side effects
× Resistance profile similar to Lamivudine:
× Overall rate of drug resistance development is 22%
in HBeAg-positive and 9% in HBeAg-negative carriers
× Cross-resistant with lamivudine

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Dose: 1.6 mg S.C. twice or three times per week
for 6 months.
MOA: Immune modulator.
(Zadaxin)
Thymosin alpha 1

17. Potential anti-viral drugs for future
treatment
Non nucleoside antivirals: Interfere with proteins involved in viral
reproduction
ARC – 520 RNAi gene silencer Phase II/III
NVR – 1221 Capsid inhibitor Phase IIa
SB 9200 Small molecule nucleic acid
hybrids
Phase II
Rep 2139 HBsAg release inhibitor Phase II
Birinapant SMAC inhibitor Phase I/IIa
Bay 41 – 4109 Inhibits viral nucleocapsid Phase I
TKM – HBV HBsAg inhibitor Phase I
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18. Non interferon immune enhancers: Boost T cell and natural interferon
production
ABX 203 Therapeutic vaccine Phase IIb/III
GS 4774 Therapeutic vaccine Phase II
GS 9620 TLR7 agonist Phase II
CYT 107(IL- 7) Immunomodulator Phase II
TG 1050 Immunotherapeutic Phase I
INO 1800 Therapeutic vaccine Phase I
Tenofovir
alafenamide
fumarate:
Prodrug of Tenofovir Phase III
CMX 157 and AGX
1009
Prodrug of Tenofovir Phase II
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https://www.centerwatch.com/clinical-trials/results/new-therapies/nmt-
details.aspx?CatID=777
Hepatera
(Myrcludex B)
Phase II Completed October 27,
2014
Heplisav Phase III trial completed August 11,
2008
Pradefovir
mesylate
Reported the
interim data on safety & Efficacy
from a Phase 2 study
November 21,
2005

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Hepatitis C

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http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/hepatitis-c
accessed on

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• Most common chronic virus infections in the developed world
If untreated hepatocellular injury with fibrosis and eventual
cirrhosis
• Major risk factor for hepatocellular carcinoma
• Chronic Hepatitis C affects over 185 million people worldwide
( 3% population)
• Each Year 7,00,000 people die from HCV- related causes
Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of
age-specific antibody to HCV seroprevalence. Hepatology. 2013 Apr;57(4):1333-42.

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Genotype 1 Combination of PEG-IFN, RBV
and a PI or nucleotide
polymerase inhibitor
Genotypes 2 & 3 PEG-IFN and RBV or
sofosbuvir with RBV
Genotype 4 Sofosbuvir, PEG-IFN
and RBV
WHO Current Treatment guidelines for
different genotypes

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NS3/4A inhibitors
(-previr)

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Must be used in combination
with peginterferon alfa & ribavirin.
MOA: Hepatitis C virus (HCV) NS3/4A protease inhibitor
Indication: Treatment of genotype 1 chronic hepatitis C
(CHC) in adult patients with compensated liver disease,
including cirrhosis, treatment-naïve or previously treated
with interferon-based treatment, prior null responders,
partial responders, and relapsers.
Approved by USFDA in May 2011
Dose: 1125 mg BD
(Incivek)
Telaprevir

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Landmark Trials: phase-III ADVANCE, ILLUMINATE, REALIZE, PROVE3.

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http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202258s014lbl.pdf?source=govdelivery&utm_medium=email&ut
m_source=govdelivery Accessed on 11th September 2015
Initial U.S. Approval: 2011
On February 24, 2014, FDA approved an update.
MOA: NS3/4A protease inhibitor
Dose: 800 mg TDS.
Indication: Same as in Telapravir
(Victrelis)
Boceprevir

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Discontinuation of therapy recommended:
1) HCV-RNA levels of greater than or equal to
1000 IU per mL at TW8 (treatment week 8);
or
2) HCV-RNA levels of greater than or equal to
100 IU per mL at TW12 (treatment week 12);
or
3) Confirmed detectable HCV-RNA levels at TW24
(treatment week 24).

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MOA: NS3/4A protease inhibitor
Indication: Genotype 1 infection as a component of a combination
antiviral treatment regimen.
Dose: 150 mg OD.
FDA approved Olysio (simeprevir)
in November 2013,
Landmark Trial: 3 randomized, double-blind, placebo
controlled clinical trials (C208, C216, and HPC3007)
Simeprevir

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NS5A inhibitors
(-asvir)

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 FDA approval on July 24, 2015
 Hepatitis C genotype 3 infections.
 Dose: 60mg OD with sofosbuvir 12 weeks
30mg with strong CYP 3A inhibitor &
90 mg with CYP3A inducers
 MOA: Inhibits the HCV non-structural protein NS5A
Targets viral replication process,
Rapid decline of HCV RNA
http://www.who.int/selection_medicines/committees/expert/20/reviews/memo-Director-HIV-AIDS-Global-Hepatitis_HCV-DAA_14-Apr-15.pdf?ua=1 Accessed on 11th
September 2015.
Daclatasvir

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”World Health Organization's List of Essential Medicines”*

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NS5B inhibitors
(-buvir)

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FDA approved Sovaldi (sofosbuvir) in December 2013
http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/sovaldi/sovaldi_pi.pdf
 Dose: 400 mg tablet OD
 MOA:(HCV) nucleotide analog NS5B polymerase inhibitor
 Indication: Treatment of genotype 1, 2, 3 or 4 HCV infection as a
component of a combination antiviral treatment regimen.
Sofosbuvir

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 Part of WHO List of Essential Medicines.
 Landmark Trial: NEUTRINO, SPARE, PHOTON.
In August 2015 USFDA made major changes in
contraindications and warning & precautions

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 July 24, 2015, FDA approved
 Dose: Two tablets OD taken orally 12 weeks.
 MOA:
(Ombitasvir) NS5A inhibitor;
(Paritaprevir), NS3/4A protease inhibitor;
(Ritonavir), a CYP3A inhibitor.
 Indication: Patients with genotype 4 chronic hepatitis C virus
(HCV) infection without cirrhosis.
Technivie
http://www.rxabbvie.com/pdf/technivie_pi.pdf accessed on 19.9.2015

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 first drug that has demonstrated safety and efficacy
to treat genotype 4 HCV infections without the need
for co-administration of interferon.
 Landmark Trial: PEARL-I study.

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Viekira Pak
 Contains three new drugs—
ombitasvir, paritaprevir and dasabuvir
 Viekira Pak’s efficacy was evaluated in clinical trials
(SAPPHIRE I,II,PEARL II, III) enrolling 2,308 participants
with chronic HCV infection with and without cirrhosis

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 Initial USFDA approval Harvoni (ledipasvir and sofosbuvir)
in October 2014.
 Dose: Fixed dose combination OD
One tablet (90 mg of ledipasvir and 400 mg of sofosbuvir)
 MOA : Ledipasvir: NS5A inhibitor
Sofosbuvir: Nucleotide analog NS5B polymerase inhibitor
 In March 2015 label major change suggested in label was in
warnings bradyacardia with amiodarone use .
Harvoni
(ledipasvir & sofosbuvir)

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Exposed Cirrhosis Duration
Rx naïve +/- 12 Weeks
Rx experienced - 12 Weeks
Rx experienced + 24 Weeks
Duration:
March 2015:

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Landmark Trial for approval:
 ION-3: noncirrhotic treatment-naïve subjects,
 ION-1: cirrhotic and noncirrhotic treatment-naïve
subjects
 ION-2: cirrhotic and noncirrhotic subjects who failed
prior therapy with an interferon-based regimen,
including regimens containing an HCV protease
inhibitor.

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Hepatitis E

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http://www.cdc.gov/hepatitis/hev/hevfaq.htm

48.  HEV was first identified in India
 30 000 cases were reported in New Delhi, India, (1955 -
1956) after the flooding of the river Yamuna and
contamination of the city's drinking water
 52 000 cases were reported in Kashmir, India, in 1978.
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Hecolin®
(HEV 239) is licensed for use in adults in China and is
undergoing further clinical evaluation
http://www.nature.com/nbt/journal/v30/n4/f
ull/nbt0412-300a.html
adults of 16 y old and above
HEV genotype 1
Zhu FC et al. Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3
trial. Lancet. 2010 Sep 11;376(9744):895-902.

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Conclusion
 Promising DAA candidates are in early‐phase development
 Focus should be directed towards working with affected com
munities, scaling up and linking prevention and treatment pro
grammes, building capacity among non‐specialist providers to
deliver these regimens
 Real challenge is no longer curing hepatitis but
getting treatment to the millions of people who need it, as so
on as possible.

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“Perfectovir should not become the enemy of Goodovir”.
‐Jennifer Cohn, Medical Director, MSF Access Campaign