hepatitis%20c
HEPATITIS C

Hepatitis C can be transmitted through blood transfusions, organ transplants, percutaneous (especially IV drug use), sexual or perinatal route.

It has an incubation period of 14-180 days.

Goal of treatment is to prevent progression to chronic hepatitis C through antiviral treatment of acute hepatitis C. Also, it aims to prevent occurrence of liver-related complications through antiviral treatment of chronic hepatitis C.

Hepatitis%20c Treatment

Principles of Therapy

  • Treatment is indicated for both treatment-naive and treatment-experienced patients with compensated and decompensated cirrhosis
    • Treatment-naive patients are those who have never been treated for HCV infection; treatment-experienced patients are those who are previously treated with Interferon or Peginterferon with or without Ribavirin, or Sofosbuvir plus Ribavirin with or without Peginterferon 
    • Interferon-free, Ribavirin-free, direct-acting antiviral (DAA)-based regimens are the recommended treatment options
      • NS3/4A (protease) inhibitors: Glecaprevir, Grazoprevir, Paritaprevir, Simeprevir, Voxilaprevir 
      • NS5A inhibitors: Daclatasvir, Elbasvir, Ledipasvir, Ombitasvir, Pibrentasvir, Velpatasvir 
      • NS5B polymerase inhibitor (nucleotide analogue): Sofosbuvir 
      • NS5B polymerase inhibitor (non-nucleoside analogue): Dasabuvir
  • Choice, course and duration of therapy are influenced by the HCV genotype as well as the severity of liver disease which must both be identified before starting treatment 
    • In areas where virological tests are unavailable or are costly, or if to simplify therapeutic regimen, pangenotypic therapy may be considered 
  • Assess risk for a drug-drug interaction before starting HCV therapy or other medications during therapy in patients receiving DAAs and monitor for side effects during treatment 
    • Patients initiating DAA therapy should also be assessed for HBV or HIV coinfection and for the presence of resistance-associated substitutions (RASs) 
  • Treatment responses are usually characterized by HCV RNA testing
  • Eradication of infection is considered when there is sustained virologic response (SVR)
    • SVR is defined as the absence of HCV RNA in serum or plasma by a sensitive test at 12 weeks and 24 weeks after completing treatment
    • If HCV RNA assays are unavailable, undetectable HCV core antigen in serum or plasma 24 weeks after completing treatment can be an alternative endpoint of therapy
  • Rapid virologic response (RVR) is achieved when HCV RNA becomes undetectable (<50 IU/mL) in serum after 4 weeks of therapy
  • Early virologic response (EVR) is defined as 2-log drop or loss of HCV RNA 12 weeks into therapy
  • End of treatment response is defined as continued absence of detectable virus at end of treatment
  • Relapse is considered when HCV RNA becomes undetectable on treatment but is detected after discontinuation of therapy
  • Reinfection happens when HCV RNA or HCV core antigen reappears after an SVR in patients who have risk factors for infection, and that the infection is caused by a different genotype or a related strain of the same genotype from the prior infection
  • Patients in whom HCV RNA levels remain stable while on treatment are considered non-responders while those whose HCV RNA levels decline but never become undetectable are referred to as partial responders

Individualize treatment based on the following:

  • Severity of liver disease
  • Previous therapy
  • Potential of serious side effects
  • Likelihood of treatment response
  • Presence of comorbid conditions

Spontaneous Resolution in Acute Infection

  • Chance of spontaneous resolution is greater in female patients and those with HCV genotype non-1 infection
  • Less likely to happen if infection lasts >12 weeks

Pharmacotherapy

Goals of Treatment

  • Antiviral treatment for acute hepatitis C aims to prevent progression to chronic hepatitis C
  • Antiviral treatment of chronic hepatitis C aims to prevent occurrence of liver-related complications
    • HCV therapy reduces decompensation rate and hepatocellular carcinoma risk in patients with cirrhosis
  • Prevent transmission of HCV 

Acute Hepatitis C 

  • Treatment may be delayed for 8-12 weeks as there is a 20-50% chance of spontaneous resolution 
  • Consider pharmacotherapy to prevent progression to chronic hepatitis C, or to minimize transmission or loss to follow-up 
    • DAA therapy was shown to be cost effective and improved clinical outcomes in comparison to delaying treatment until the chronic phase 
    • Measure HCV RNA prior to starting therapy and SVR at 12 and 24 weeks after therapy 
  • Pending further data that will establish the start time of the ideal treatment regimen and its duration, acute hepatitis C patients may be treated with the following antiviral regimens for 8 weeks: 
    • Sofosbuvir/Velpatasvir (all genotypes)
    • Glecaprevir/Pibrentasvir (all genotypes)
    • Sofosbuvir/Ledipasvir (genotypes 1, 4, 5 and 6)
    • Grazoprevir/Elbasvir (genotypes 1b and 4)
    • Ritonavir-boosted Ombitasvir, Paritaprevir, and Dasabuvir (genotype 1b)
  • Interferon (high-dose) or Peginterferon may also be used
    • Treat HCV genotype 1 for 24 weeks, genotype 2, 3, or 4 for 12 weeks
    • Patients unresponsive to monotherapy should be given Peginterferon/Ribavirin or a protease inhibitor-based triple therapy

Chronic Hepatitis C

  • In limited-resource settings, Peginterferon/Ribavirin combination therapy may be considered in HCV genotypes 1, 4, or 6 treatment-naive patients with favorable IL28B genotypes and low viral load and in HCV genotypes 2 or 3 treatment-naive patients
    • For treatment-experienced patients, Peginterferon/Ribavirin can only be given in those who relapse with favorable IL28B genotype and without cirrhosis
  • Sofosbuvir with Peginterferon/Ribavirin for 12 weeks can be utilized as an alternative regimen in patients with genotypes 1, 3, 5 and 6

Pangenotypic Therapy

  • Having a high treatment efficacy across all 6 major genotypes, pangenotypic therapy is a simplified treatment regimen for chronic hepatitis C in treatment-naive and treatment-experienced patients without cirrhosis or with compensated cirrhosis
  • Reduces the need for genotyping to guide treatment decisions in limited-resource settings 
  • Makes treatment readily accessible at reduced cost
  • Prior to initiation of treatment, check for possible drug-drug interactions, and determine the presence of HCV replication (HCV RNA or HCV core antigen testing) and presence of fibrosis or cirrhosis (APRI or FIB-4 non-invasive testing) to see if patient would need post-treatment follow-up (eg surveillance for hepatocellular carcinoma) 
  • Pangenotypic regimens currently available include the following:
Regimen Treatment Experience Duration (weeks)
Glecaprevir/Pibrentasvir1 Treatment naive without cirrhosis or with compensated cirrhosis or treatment experienced without cirrhosis 8
Treatment experienced with compensated cirrhosis 12
Sofosbuvir/Daclatasvir2 HCV/HIV coinfection when antiretroviral regimen cannot be made to accommodate recommended regimens 12
Sofosbuvir/Velpatasvir Treatment naive or treatment experienced, without cirrhosis or with compensated cirrhosis 12
Sofosbuvir/Velpatasvir/Voxilaprevir3 DAA (protease inhibitor and/or NS5A inhibitor)-containing regimen failure, without cirrhosis or with compensated cirrhosis 12
1 Glecaprevir/Pibrentasvir plus Sofosbuvir and weight-based Ribavirin x 16 weeks can be given to patients with prior Glecaprevir/Pibrentasvir or Sofosbuvir/Velpatasvir/Voxilaprevir treatment failure regardless of cirrhosis.
2 Sofosbuvir/Daclatasvir x 12 weeks for compensated cirrhosis may be considered in areas where the genotype is known and prevalence of genotype 3 is <5%.
3 Sofosbuvir/Velpatasvir/Voxilaprevir with weight-based Ribavirin x 24 weeks can be given to patients with prior Sofosbuvir/Velpatasvir/Voxilaprevir treatment failure regardless of cirrhosis.
Modified from:
  • The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. https://www.hcvguidelines.org. 27 Aug 2020.
  • European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C: final update of the series. J Hepatol. 2020 Sep 14;1-49.

  • Genotype-specific Therapy

    • Identify the HCV genotype and genotype 1 subtype (eg 1a or 1b) before initiating treatment to determine the choice and duration of therapy
    • Genotype and subtype should be determined in areas or setting where subtypes of HCV are resistant to NS5A inhibitors, eg subtypes 1l, 3b, 3g, 4r, 6u, 6v
    Regimen Genotype Treatment Experience Duration (weeks)
    Daclatasvir plus Sofosbuvir with or without weight-based Ribavirin 1a, 1b Treatment naive and treatment experienced, without cirrhosis   12-24
    3 Treatment naive without cirrhosis or with compensated cirrhosis, treatment experienced without cirrhosis 12-24
    Elbasvir/Grazoprevir  1a, 1b, 4 Treatment naive and treatment experienced, without cirrhosis or with compensated cirrhosis   12 
    Glecaprevir/Pibrentasvir 1a, 1b, 4, 5, 6 Treatment naive without cirrhosis or with compensated cirrhosis, or Peginterferon/Ribavirin (PEG/RBV) experienced without cirrhosis  8
    2, 3 Treatment naive without cirrhosis or with compensated cirrhosis 8
    1a, 1b, 2, 4, 5, 6 PEG/RBV experienced with compensated cirrhosis 12
     1 NS3 protease inhibitor plus PEG/RBV experienced; or non-NS5A inhibitor, Sofosbuvir-containing regimen experienced, without cirrhosis  12
     2 Sofosbuvir plus Ribavirin experienced, without cirrhosis or with compensated cirrhosis
     12
     3 Treatment experienced, without cirrhosis or with compensated cirrhosis
     12-16
    Ledipasvir/Sofosbuvir 1a, 1b, 4, 5, 6
    Treatment naive and treatment experienced, without cirrhosis or with compensated cirrhosis 12
     Ombitasvir/Paritaprevir/Ritonavir plus Dasabuvir with or without weight-based Ribavirin  1 Treatment naive or PEG/RBV experienced without cirrhosis or with compensated cirrhosis    12
     Ombitasvir/Paritaprevir/Ritonavir with weight-based Ribavirin  4 Treatment naive or PEG/RBV experienced without cirrhosis or with compensated cirrhosis
     12
     Simeprevir plus Sofosbuvir  1 Treatment naive and treatment experienced without cirrhosis 
     12
    Treatment naive and treatment experienced with compensated cirrhosis
     24
     Sofosbuvir/Velpatasvir   1a, 1b, 2, 3*, 4, 5, 6 Treatment naive and treatment experienced, without cirrhosis or with compensated cirrhosis
     12
     Sofosbuvir/Velpatasvir/Voxilaprevir*  3 Treatment naive and PEG/RBV experienced, with compensated cirrhosis
     12
    Sofosbuvir plus RBV experienced (with or without PEG), without cirrhosis or with compensated cirrhosis
     12
    3, 4, 5, 6  DAA experienced, without cirrhosis or with compensated cirrhosis
    12 
     Subtypes 1l, 3b, 3g, 4r, 6u, 6v and other undetermined subtypes resistant to NS5A inhibitors Treatment naive and treatment experienced, without cirrhosis or with compensated cirrhosis   12
    * If resistance testing is performed at baseline, patients with NS5A Y93H RAS for Velpatasvir should be treated with Sofosbuvir/Velpatasvir/Voxilaprevir or Sofosbuvir/Velpatasvir plus Ribavirin for 12 weeks; patients without the Y93H RAS should be treated with Sofosbuvir/Velpatasvir only for 12 weeks.
    Modified from:
  • The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. https://www.hcvguidelines.org. 27 Aug 2020.
  • European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C: final update of the series. J Hepatol. 2020 Sep 14;1-49.

  • Decompensated Cirrhosis

    • Patients with genotypes 1-6 with decompensated cirrhosis and those with compensated cirrhosis with prior decompensation episodes should receive Sofosbuvir/Velpatasvir with weight-based Ribavirin for 12 weeks 
      • Ribavirin can be initiated at 600 mg/day with subsequent dose adjustments based on patient's tolerance 
      • If patient has contraindications to or is intolerant of Ribavirin, Sofosbuvir/Velpatasvir alone can be given for 24 weeks 
    • Sofosbuvir/Velpatasvir with weight-based Ribavirin for 24 weeks can be given as retreatment for patients with genotypes 1-6 with decompensated cirrhosis who failed treatment with a DAA (protease inhibitor and/or NS5A inhibitor)-containing regimen 
    • Treatment regimens that include an HCV protease inhibitor, eg Glecaprevir, Grazoprevir or Voxilaprevir, should not be given

    HCV Genotype 1, 4, 5 or 6

    • With decompensated cirrhosis who are Ribavirin eligible
      • Ledipasvir/Sofosbuvir with low initial dose of Ribavirin (may be increased as tolerated) x 12 weeks
    • With decompensated cirrhosis who are Ribavirin ineligible
      • Ledipasvir/Sofosbuvir x 24 weeks
    • With decompensated cirrhosis and in whom previous Sofosbuvir- or NS5A-based treatment has failed
      • Ledipasvir/Sofosbuvir with low initial dose of Ribavirin (may be increased as tolerated) x 24 weeks

    Liver Transplantation

    • Indicated in patients with end-stage liver disease (cirrhosis), hepatocellular carcinoma, and acute liver failure (ie caused by viruses, drugs and toxic agents)
      • Considered in patients with expected survival of ≤1 year without transplantation or if quality of life is unsatisfactory due to the liver disease
    • Patients with HCV infection can be treated prior to or after transplant on a case-by-case basis 
      • If with hepatitis C recurrence posttransplant, treatment with antivirals is done and is started early in patients with significant graft damage
    • HCV replication is not a contraindication for liver transplantation, though antiviral therapy should be given after transplant
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