• Hepatitis : Inflammation of liver, can be self-limiting or can progress to fibrosis (scarring), cirrhosis or liver cancer
  • Hepatitis viruses most common cause of hepatitis in world
  • 5 main hepatitis viruses, referred to as types A, B, C, D and E
  • Types B and C lead to chronic disease and together, most common cause of liver cirrhosis and cancer


  • Hepatitis B virus (HBV) infection: a global public health problem
  • An estimated 257 million people are living with hepatitis B virus infection (defined as HBs Ag +VE)
  • Globally, an estimated 71 million people have chronic hepatitis C infection
  • India has more than 37 million HBV carriers
  • India alone has an estimated burden of 8.6 million viraemic HCV carriers

Hepatitis B Virus

  • DNA virus belonging to the Hepadnaviridae family
  • cccDNA binds to histones to form a viral mini-chromosome, and is the template for all viral RNA transcriptions, including the viral pregenomic RNA (pgRNA). pgRNA is packed and reverse transcribed within the nucleocapsids, which are subsequently used for the formation of virions

or recycling to the nucleus for cccDNA maintenance DNA virus belonging to the Hepadnaviridae family

  • Viral persistence relies on a covalently-closed circular DNA (cccDNA) located within the nucleus of infected hepatocytes
  • Host immune responses required to control viral replication.
  • HBV has evolved mechanisms to evade both innate and adaptive immune responses

Approved Hepatitis B Drugs For Adults (US)

Oral Antivirals (Nucleos(t)ide Analogues):

  • Tenofovir disoproxil
  • Tenofovir alafenamide
  • Entecavir
  • Telbivudine
  • Adefovir Dipivoxil
  • Lamivudine

Immune Modulators (Interferons):

  • 1) Pegylated Interferon: injection once a week usually for 6 months  to  1 year (Approved in 2005)
  • 2) Interferon Alpha (Intron A): injection several times a week usually for 6 months to 1 year, can be longer, An older drug not used as often (Approved in 1991) 

Recently Approved Drugs- Hepatitis B

  • Tenofovir alafenamide;  Approved November 2016
  • Heplisav-B [Hepatitis B Vaccine (Recombinant), Adjuvanted] ; Approved November 2017

Heplisav-B [Hepatitis B Vaccine (Recombinant), Adjuvanted]

  • Approved November 2017
  • In February 2018, ACIP approved recommendations for Heplisav-B (HepB-CpG) vaccine as an option for previously unvaccinated or incompletely vaccinated persons, including:
  • Adults 18 years of age and older who have a specific risk, or lack a risk factor but want protection
  • Schedule: Administer 2 doses at least 4 weeks apart
  • Dose (volume): 0.5 mL each dose
  • Route: Intramuscular (IM) injection

Ribavirin à used to treat RSV infection, hepatitis C, and viral hemorrhagic fever

It is a guanosine (ribonucleic) analog used to stop viral RNA synthesis and viral mRNA capping, thus, it is a nucleoside inhibitor.

Ribavirin is a prodrug, which when metabolized resembles purine RNA nucleotides. In this form, it interferes with RNA metabolism required for viral replication

The medication has two FDA “black box” warnings: One raises concerns that use before or during pregnancy by either sex may result in birth defects in the baby, and the other is regarding the risk of red blood cell breakdown.

Ribavirin should not be given with zidovudine because of the increased risk of anemia; concurrent use with didanosine should likewise be avoided because of an increased risk of mitochondrial toxicity

Hepatitis C- Prevalence

  • Globally, an estimated 71 million people have chronic hepatitis C infection, which corresponds to a prevalence of 1.6%
  • At least six distinct HCV genotypes, which are genetically distinct groups ofvirus
  • Knowing strain  virus can help inform treatment recommendations
  • Predominant genotypes in India – genotype 3, followed by genotype 1
  • Genotypes 4, 6 and 2 in small proportions

3 CLASSES OF HEP C TREATMENT-  DAA direct-acting antiviral

  • main targets of the direct-acting antiviral agents are the HCV-encoded proteins that are vital to the replication of the virus
  • The infectious viral structure is comprised of envelope glycoproteins in a lipid bilayer that contain the viral core protein and RNA
  • Synthesis of new viral RNA occurs in a highly structured replication complex that consists of NS3, NS4A, NS4B, NS5A, and NS5B

SimeprevirNS3/4A inhibitor

  • In November 2013, the FDA approved Simeprevir capsules to be used in combination with peginterferon alfa and ribavirin or in combination with sofosbuvir
  • Its efficacy is established in patients with hepatitis c genotype 1
  • One 150 mg capsule taken once daily with food
  • Recommended treatment duration with peginterferon alfa and ribavirin is 12 weeks, followed by either 12 or 36 additional weeks of peginterferon alfa and ribavirin
  • Warnings: 1) Embryofetal Toxicity 2) Photosensitivity 3) Rash
  • Adverse reaction: rash, pruritus and nausea

DaclatasvirNS5A Inhibitor

  • Approved in July 2015 for use with sofosbuvir as the first 12-week, all-oral treatment option for patients with chronic hepatitis C virus genotype 3
  • Dosage: 60 mg taken orally once daily with or without food in combination with sofosbuvir
  • Recommended duration: 12 weeks
  • Dose modification: Reduce dosage to 30 mg once daily with strong CYP3A inhibitors and increase dosage to 90 mg once daily with moderate CYP3A inducer
  • Warnings: Bradycardia when Co-administered with Sofosbuvir and Amiodarone
  • Adverse reaction: headache and fatigue

SofosbuvirNS5B inhibitor

  • December 2013, the FDA approved Sofosbuvir tablets to be used in combination with ribavirin or with pegylated interferon
  • Its efficacy is established in patients with hepatitis c genotypes 1, 2, 3 or 4, including those with HCC awaiting liver transplant and those with hepatitis c/HIV co-infection
  • Duration of treatment is usually 12-24 weeks
  • One 400 mg tablet taken once daily with or without food
  • Not recommended in severe renal impairment or end stage renal disease
  • Warnings: Pregnancy- birth defects and fetal death
  • Pregnancy: Ribavirin may cause birth defects and fetal death and animal studies have shown interferons have abortifacient effects; avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to initiating therapy, use at least 2 effective  non-hormonal methods of contraception and have monthly pregnancy tests


Glecaprevir + Pibrentasvir

  • Glecaprevir, a HCV NS3/4A protease inhibitor, and Pibrentasvir,  HCV NS5A inhibitor
  • Approved in August 2017
  • Treatment-Naïve Patients – 8 week therapy for all HCV genotypes without cirrhosis and 12 weeks therapy with compensated cirrhosis for
  • Treatment-Experienced Patients- regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor, but not both
  • Recommended dosage: 3 tablets (total dose: Glecaprevir 300 mg and Pibrentasvir 120 mg) orally
  • Adverse reactions (greater than 10%) are headache and fatigue

Sofosbuvir + Velpatasvir +  Voxilaprevir

  • Approved- July 18, 2017
  • Indicated for treatment of adult patients with chronic HCV infection without cirrhosis or with compensated cirrhosis
  • Also for patients with genotypes 1-6 who have been previously treated with DAA drug sofosbuvir or other drugs for HCV that inhibit a protein called NS5A

Elbasvir + Grazoprevir

  • Approved: January 28th 2016
  • Elbasvir, a HCV NS5A inhibitor and Grazoprevir, a HCV NS3/4A protease inhibitor
  • Indicated with or without ribavirin for treatment of chronic HCV genotypes 1 or 4 infection in adults

Sofosbuvir + Velpatasvir

  • Approved: June 28th 2016
  • Sofosbuvir, a HCV nucleotide analog NS5B polymerase inhibitor and Velpatasvir, a HCV NS5A inhibitor
  • Indication:
  • 1) treatment of adults with genotype 1-6 chronic hepatitis C virus infection without cirrhosis or with compensated cirrhosis
  • 2) with decompensated cirrhosis for use in combination with ribavirin
  • After 12 weeks, 98 % of patients taking FDC achieved SVR and 94 % of patients with decompensated cirrhosis taking FDC with ribavirin achieved SVR

Guidelines- WHO 2018

When to start treatment in adults and adolescents

  • WHO recommends offering treatment to all individuals diagnosed with HCV infection who are 12 years of age or older (With the exception of pregnant women) irrespective of disease stage (Strong recommendation, moderate quality of evidence)

What treatment to use for adults and adolescents

WHO recommends the use of pangenotypic DAA regimens for the treatment of persons with chronic HCV infection aged 18 years and above

  • The Guidelines Development Group defined pangenotypic regimens as those leading to a sustained virological response, SVR rate >85% across all six major HCV genotypes.

For adults without cirrhosis, the following pangenotypic regimens can be used:

  • • Sofosbuvir/velpatasvir 12 weeks
  • • Sofosbuvir/daclatasvir 12 weeks
  • • Glecaprevir/pibrentasvir 8 weeks

For adults with compensated cirrhosis, the following pangenotypic regimens can be used:

  • • Sofosbuvir/velpatasvir 12 weeks
  • • Glecaprevir/pibrentasvir 12 weeks
  • • Sofosbuvir/daclatasvir 24 weeks
  • • Sofosbuvir/daclatasvir 12 weeks

Persons with HCV genotype 3 infection who have received interferon and/or ribavirin in the past should be treated for 16 weeks.

  • In children aged less than 12 years with chronic HCV infection, WHO recommends:
  • deferring (postpone) treatment until 12 years of age (conditional recommendation, very low quality of evidence)
  • treatment with interferon-based regimens should no longer be used – strong recommendation

The key reasons for the current conditional recommendation to defer HCV treatment in children aged less than 12 years were as follows:

The low frequency of HCV-related liver disease in childhood.

  1. Only a small number of children experience significant morbidity that would benefit from early treatment.

The only available and approved regimen for this age group is pegylated interferon/ ribavirin.

  • This regimen has an overall low efficacy, a prolonged treatment duration (6–12 months), an inconvenient administration route (via injection), significant side-effects and high costs.

New, highly effective short-course oral pangenotypic DAA regimens are likely to become available for children <12 years in 2019.

Treatment with interferon should not be used in children aged less than 12 years despite the very low quality of evidence were as follows:

1. The issues with interferon-containing regimens and ribavirin in children.

  • These include long duration of treatment, limited efficacy and burdensome side-effects, including high rates of flu-like symptoms and haematological complications (anaemia,  leukopenia and neutropenia), and several potentially irreversible side-effects, such as thyroid disease, type 1 diabetes, ophthalmological complications and impaired growth

Clinical considerations

  • The use of pangenotypic regimens obviates the need for genotyping before treatment initiation.
  • In resource-limited settings, WHO recommends that the assessment of liver fibrosis should be performed using non-invasive tests (e.g. aspartate/platelet ratio index (APRI) score or FIB-4 test, This can determine if there is cirrhosis before initiation of treatment.
  • DAAs are well tolerated, with only minor side-effects. Therefore, the frequency of routine laboratory toxicity monitoring can be limited to a blood specimen at the start and end of treatment.
  • Following completion of DAA treatment, sustained virological response (SVR) at 12 weeks after the end of treatment is used to determine treatment outcomes

HIV/HCV coinfection

  • Persons with HIV/HCV coinfection are at a higher risk for progression of fibrosis
  • Treatment for HCV infection needs to consider drug–drug interactions with antiretroviral medications.

HBV/HCV coinfection

  • Persons with HBV/HCV coinfection are at risk for HBV reactivation during and following HCV treatment.
  • An assessment for HBV treatment eligibility with initiation of HBV treatment for those eligible may prevent HBV reactivation during HCV treatment.

How to test for chronic HCV infection and monitor treatment response?

Nucleic acid testing for qualitative or quantitative detection of HCV RNA should be used as the test of cure at 12 or 24 weeks (i.e. sustained virological response [SVR12 or SVR24]) after completion of antiviral treatment.

* Persons with HCV genotype 3 infection who have received interferon and/or ribavirin in the past should be treated for

16 weeks.

** May be considered in countries where genotype distribution is known and genotype 3 prevalence is <5%.

*** Treatment in adolescents at this time still requires genotyping to identify the appropriate regimen.

AFP: alpha-fetoprotein, APRI: aspartate-to-platelet ratio index, FIB-4: fibrosis stage

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