recent advances in mangement of viral hepatitis

05/01/2023 02:22 AM Recent advances in Management of Viral Hepatitis

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Recent advances in management of viral

- Student: Dr Anup U Petare- Guide: Dr Raakhi K Tripathi.


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Global Prevalence

Recent Advances in Hepatitis B

Recent Advances in Hepatitis C

Fixed Dose Combinations

HEV 239 Vaccine.

Conclusion

Flow of Seminar


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Hepatitis B


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• 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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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



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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 Entecavirhttp://www.gilead.com/~/media/files/pdfs/medicines/liver disease/viread/viread_pi.pdf accessed on 17.9.2015

(VIREAD) Tenofovir disoproxil

fumarate

http://www.gilead.com/~/media/files/pdfs/medicines/liver%20disease/viread/viread_pi.pdf





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Patient profile DoseAdults & 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

http://www.fda.gov/downloads/Drugs/DrugSafety/UCM135934.pdf%20accessed%20on%2015.9.15


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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


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Potential anti-viral drugs for future treatment

Non nucleoside antivirals: Interfere with proteins involved in viral reproduction

ARC – 520 RNAi gene silencer Phase II/IIINVR – 1221 Capsid inhibitor Phase IIaSB 9200 Small molecule nucleic acid

hybridsPhase II

Rep 2139 HBsAg release inhibitor Phase IIBirinapant SMAC inhibitor Phase I/IIaBay 41 – 4109 Inhibits viral nucleocapsid Phase ITKM – HBV HBsAg inhibitor Phase I


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Non interferon immune enhancers: Boost T cell and natural interferon productionABX 203 Therapeutic vaccine Phase IIb/IIIGS 4774 Therapeutic vaccine Phase IIGS 9620 TLR7 agonist Phase IICYT 107(IL- 7) Immunomodulator Phase IITG 1050 Immunotherapeutic Phase IINO 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

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

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


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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&utm_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

http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202258s014lbl.pdf?source=govdelivery&utm_medium=email&utm_source=govdelivery

http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202258s014lbl.pdf?source=govdelivery&utm_medium=email&utm_source=govdelivery


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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

http://www.who.int/selection_medicines/committees/expert/20/reviews/memo-Director-HIV-AIDS-Global-Hepatitis_HCV-DAA_14-Apr-15.pdf?ua=1

http://www.who.int/selection_medicines/committees/expert/20/reviews/memo-Director-HIV-AIDS-Global-Hepatitis_HCV-DAA_14-Apr-15.pdf?ua=1


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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

http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/sovaldi/sovaldi_pi.pdf


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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

http://www.rxabbvie.com/pdf/technivie_pi.pdf

http://www.rxabbvie.com/pdf/technivie_pi.pdf


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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 DurationRx naïve +/- 12 WeeksRx experienced - 12 WeeksRx 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




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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/full/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 communities, scaling up and linking prevention and treatment programmes, 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 soon as possible.


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

recent advances in mangement of viral hepatitis

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