hepatitis%20-%20viral
HEPATITIS - VIRAL
The majority of acute viral hepatitis infections are asymptomatic or they can cause an anicteric illness that may not be diagnosed as hepatitis.
Hepatitis A generally causes minor illness in childhood with >80% of infections being asymptomatic but more likely to produce clinical symptoms in adults. 
Hepatitis B, C, and D may also be asymptomatic.
Hepatitis A is predominantly transmitted through oral-fecal route.
Hepatitis B is transmitted through perinatal, percutaneous, or sexual routes or close person-to-person contact via open cuts and sores.
Hepatitis C infections are transmitted through perinatal, percutaneous, or sexual routes, blood transfusions, or organ transplants.
Hepatitis D's route of transmission is sexual or percutaneous, especially IV drug use.
Hepatitis E is transmitted primarily through contaminated drinking water and oral-fecal transmission.

Principles of Therapy

Chronic Infection of Hepatitis B

Patients For Whom Treatment is Not Recommended
  • Without clinical evidence of cirrhosis, with PNALT, HBV DNA <2,000 IU/mL, regardless of HBeAg status or age
Patients For Whom Treatment is Recommended
  • Evidence of compensated or decompensated cirrhosis regardless of HBeAg status or HBV DNA or ALT levels
  • Without clinical evidence of cirrhosis but with persistently abnormal ALT, HBV DNA >20,000 IU/mL, regardless of HBeAg status
  • Chronic HBV severe reactivation
Goals of Treatment
  • Continued viral suppression is necessary to reduce or prevent hepatic disease and disease progression
  • Primary goal of treatment is to permanently suppress HBV or to eliminate it
    • Short-term goal is the sustained suppression of HBV DNA, ALT normalization, to prevent decompensation and to decrease hepatic necroinflammation and fibrosis during and after therapy
    • Long-term goal of therapy is to avoid hepatic decompensation, reduce or prevent progression to cirrhosis and/or HCC and to prolong survival
  • Endpoints used to assess response:
    • Biochemical response: Normalization of serum ALT
    • Virological response: HBV DNA <104 copies/mL and sustained seroconversion from HBeAg to anti-HBe
    • Histological response: Decrease in histology activity compared to pretreatment liver biopsy or a reduction of at least 1 point in fibrosis by Metavir staging
    • Complete response: Fulfill criteria of biochemical and virological response and loss of HBsAg
  • Current treatments of chronic hepatitis B have limited long-term efficacy
Considerations Prior to Initiation of Treatment
  • Age of patient
  • Severity of liver disease
  • Likelihood of response
  • Potential adverse events and complications
  • HBeAg-positive patients with elevated ALT levels and compensated liver disease should be observed for 3-6 months for spontaneous seroconversion from HBeAg to anti-HBe prior to initiation of treatment
  • Choice of therapy will depend on availability, cost of medication, necessary number of clinic visits, expected duration of treatment and patient/clinician preference
Other Considerations in Pharmacological Therapy
  • There is no evidence that combination therapy of 2 direct antiviral agents results in better viral suppression compared to single agent
  • In treating concurrent infections such as hepatitis C virus, hepatitis D virus and HIV infection, it is important to identify the dominant virus as this will determine the therapeutic regimen
    • Concurrent hepatitis C infection may be treated with same antiviral therapy for HCV monoinfection
Hepatitis C

Antiviral therapy is currently widely accepted for the following Hepatitis C patient groups:
  • ≥18 years of age
  • Normal and abnormal ALT levels
  • Liver biopsy showing chronic hepatitis with significant fibrosis (stage F1 or above)
  • HCV genotype 2 or 3 regardless of stage
  • Compensated liver disease 
  • Acceptable hematological and biochemical indices
  • If there is a history of depression, the condition is well controlled
  • Willing to be treated and conform to patient requirements
  • Treated previously for HCV infection
Therapy should be individualized in patients with any of the following:
  • Failed prior treatment of either Interferon given alone or in combination with Ribavirin or Peginterferon given alone
  • Current illicit drug user or alcoholic but willing to participate in substance abuse program or alcohol support program
  • No or mild fibrosis on liver biopsy
  • Acute hepatitis C
  • Coinfected with HIV
  • <18 years
  • Chronic renal disease
  • Decompensated cirrhosis
  • Liver transplant recipient
Therapy is contraindicated in patients with any of the following1
  • Major, uncontrolled depressive illness
  • Renal, heart or lung transplant recipient
  • Autoimmune hepatitis or other condition known to be exacerbated by Interferon and Ribavirin
  • Untreated hyperthyroidism
  • <3 years of age
  • Pregnant or unwilling/unable to comply with adequate contraception
  • Severe concurrent disease (eg hypertension, HF, uncontrolled DM, etc)
  • Known hypersensitivity to drugs used to treat HCV
  • Hepatic decompensation

1 Patients have detectable HCV RNA

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
Principles of Treatment
  • Treatment is indicated for both treatment-experienced and treatment-naive patients with compensated and decompensated liver disease
  • 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 by a sensitive test at the end of treatment and 6 months later
  • 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
  • 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
  • Choice, course and duration of therapy are influenced by the HCV genotype
Individualize treatment based on the following:
  • Severity of liver disease
  • 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

Hepatitis B

Adefovir dipivoxil
  • Adefovir dipivoxil has shown to be beneficial in patients with HBeAg-positive chronic hepatitis B infection
  • May be a preferred agent for patients with negative HBeAg, HBV DNA >105 copies/mL and elevated ALT
  • Inhibits reverse transcriptase and DNA polymerase activity and is incorporated into HBV DNA causing chain termination; however, it has a low barrier to resistance that can lead to drug resistance
  • Effective as an add-on agent in suppressing Lamivudine-resistant HBV; resulted in HBV DNA suppression of 82-87% and lower risk of Adefovir resistance of 4-8% in 3-4 years
    • 10-mg dose has a more favorable risk-benefit profile compared to 30-mg dose
  • HBeAg-positive chronic hepatitis patients may discontinue therapy after 1 year and confirmed HBeAg seroconversion but durability of response is unknown
    • Therapy may be continued in those who did not achieve HBeAg seroconversion but safety and efficacy has not been established
  • HBeAg-negative chronic hepatitis may need extended treatment (>1 year) to maintain response
    • Further studies are needed to determine optimal duration of therapy
Other Considerations
  • Renal function and bone profile must be monitored every 3 months for patients with predisposition to renal insufficiency and for patients on Adefovir dipivoxil for >1 year
Clevudine
  • Daily dose of 30 mg for 24 weeks has been shown to be associated with 59% undetectable HBV DNA (<300 copies/mL) and 7.6% HBeAg seroconversion in HBeAg-positive patients, with 92% undetectable HBV DNA in HBeAg-negative patients
  • Monitor for muscle symptoms and muscle weakness during therapy
Entecavir
  • Approved by United States Food and Drug Administration (USFDA) for treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in ALT or AST or histologically active disease
  • Considered 1st-line agent for treatment of HBV infection
  • Use is based on histologic, virologic, biochemical and serologic responses after 1 year of treatment in nucleoside-treatment-naive and Lamivudine-resistant adult patients with HBeAg-positive or HBeAg-negative chronic HBV infection with compensated liver disease
  • Appears to be superior to Lamivudine based on histologic improvement, reduction in viral load and ALT normalization
  • Effective in the treatment of Adefovir and Tenofovir resistance
  • Inhibits the following HBV polymerase activities: Base priming, reverse transcription of the negative strand from the pregenomic messenger RNA, and synthesis of the positive strand of HBV DNA
Other Considerations
  • Studies in rodents exposed to high doses (ie 3-40x that given to humans) of Entecavir showed increased incidence of lung adenomas, brain gliomas and hepatocellular carcinoma
Interferon alfa
  • Interferons have antiviral, antiproliferative and immunomodulatory effects
  • May be a preferred agent in the treatment of HBeAg-negative chronic hepatitis B and HBeAg-positive chronic hepatitis with elevated ALT
  • Suppresses HBV replication and induces remission of liver disease
  • Efficacy is limited to a small percentage of highly selected patients
    • Relapse is a major problem in HBeAg-negative chronic hepatitis B
  • For HBeAg-positive chronic hepatitis B, important predictors of response to therapy are high pretreatment ALT and lower levels of serum HBV DNA
  • Finite duration of therapy
Other Considerations
  • Prednisone priming prior to Interferon alfa therapy is not recommended
  • Contraindicated in patients with decompensated cirrhosis and coexisting autoimmune diseases
  • Not recommended for patients with compensated cirrhosis because of risk of hepatic decompensation associated with Interferon alfa-related flares of hepatitis
  • Side effects include mood swings and depression; patient’s mental health should be closely monitored by the clinician
  • Pregnancy is discouraged during Interferon therapy
    • If patient becomes pregnant during therapy, Interferon should be replaced with another drug
Lamivudine
  • Used for HBeAg-positive chronic hepatitis with elevated ALT but has a high rate of drug resistance during long-term treatment
  • Recommended in viremic patients (HBeAg-positive and HBeAg-negative patients) with ALT >5x ULN especially if there is concern regarding decompensation
  • Good safety profile and ease of administration are its advantages over Interferon alfa
  • Action: Premature termination of viral DNA chain termination thereby inhibiting HBV DNA synthesis
    • Induces histologic improvement and reduction in rate of development of hepatic fibrosis
  • Effects:
    • Pretreatment ALT is the most important predictor of response
    • Response is greatest in patients with an ALT 2-5x the normal value
  • Treatment may be discontinued in patients who have completed 1 year of treatment and have persistent HBeAg seroconversion to anti-HBe and undetectable HBV DNA by PCR assay
  • Treatment may be continued in patients who have not achieved HBeAg seroconversion and have no evidence of breakthrough infection because HBeAg seroconversion may occur with continued treatment
Other Considerations
  • While on therapy, monitor LFTs, HBeAg and anti-HBe every 3 months
  • Test for HBV DNA at 3 and 6 months of therapy and every 3-6 months thereafter
Lamivudine-resistant HBV
  • Emergence of Lamivudine-resistant HBV is increasingly common with prolonged treatment, together with a decreasing rate of remission
  • Associated with development of Lamivudine-resistant YMDD viral mutants, which appear to be less virulent than wild-type HBV, but have been associated with rapidly progressive liver disease in some patients
  • Lamivudine resistance is usually manifested as breakthrough infection with reappearance of HBV DNA in serum
  • There may be continued clinical benefit with continuation of treatment in spite of development of drug resistance
    • Benefits of continued treatment must be balanced against the risk of resistant mutants
Peginterferon alfa
  • Approved in a number of countries for chronic hepatitis B for both HBeAg-positive and HBeAg-negative chronic hepatitis in adult patients with compensated liver disease, evidence of viral replication and liver inflammation
    • In many countries in Asia, Peginterferon alfa 2b is approved for use in the treatment of chronic hepatitis B
  • Appears to have superior efficacy compared to Lamivudine based on HBeAg seroconversion, HBV DNA suppression and HBsAg seroconversion
    • Longer half-life compared to Interferon alfa and appears to impart a clinical benefit over conventional Interferon alfa
  • Action: Inert Polyethylene glycol is added to Interferon, decreases the drug’s renal clearance and increases its half life
    • Provides sustained viral suppression with efficacy similar to or better than standard Interferon alfa
  • Finite duration of therapy, no reported resistance
Other Considerations
  • Contraindicated in patients with decompensated cirrhosis
  • Side effects include mood swings and depression; patient’s mental health should be closely monitored by the clinician
Telbivudine
  • Orally bioavailable with potent and specific anti-HBV activity
  • Clinical trials show that Telbivudine gave more potent HBV suppression than Lamivudine or Adefovir in both HBeAg-positive and negative patients and showed equal potency to Entecavir in HBV suppression in HBeAb-positive patients but has a high rate of resistance
  • Action: Competitively inhibits viral reverse transcriptase blocking DNA polymerase activity
  • Monitor for muscle symptoms and muscle weakness during therapy
Tenofovir
  • A very effective antiviral agent for hepatitis B (chronic HBeAg positive or HBeAg negative) that has minimal resistance rate
  • Used as a 1st-line agent for treatment of HBV infection and as an alternative agent in patients with suspected or confirmed resistance to Adefovir, Entecavir, Lamivudine and Telbivudine
  • Monitor renal function and bone profile every 3 months

Acute Hepatitis C

  • Treatment may be delayed for 8-12 weeks to allow spontaneous resolution
  • Interferon (high-dose) or Peginterferon may 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

HCV Genotype 1a treatment-naive patients without cirrhosis

  • Recommended treatments:
    • Elbasvir/Grazoprevir x 12 weeks and in patients with no baseline NS5A RAVs for Elbasvir1
    • Ledipasvir/Sofosbuvir x 12 weeks
    • Paritaprevir/Ritonavir/Ombitasvir plus twice-daily dosed Dasabuvir with weight-based Ribavirin x 12 weeks
    • Simeprevir plus Sofosbuvir x 12 weeks
    • Sofosbuvir/Velpatasvir 12 weeks
    • Daclatasvir plus Sofosbuvir x 12 weeks
  • Alternative treatment:
    • Elbasvir/Grazoprevir with weight-based Ribavirin x 16 weeks and in patients with baseline NS5A RAVs for Elbasvir1

HCV Genotype 1a treatment-naive patients with compensated cirrhosis

  • Recommended treatments:
    • Elbasvir/Grazoprevir x 12 weeks and in patients with no baseline NS5A RAVs for Elbasvir1
    • Ledipasvir/Sofosbuvir x 12 weeks
    • Sofosbuvir/Velpatasvir x 12 weeks
  • Alternative treatments:
    • Paritaprevir/Ritonavir/Ombitasvir plus twice-daily dosed Dasabuvir with weight-based Ribavirin x 24 weeks
    • Simeprevir plus Sofosbuvir with or without weight-based Ribavirin x 24 weeks and in patients with no Q80K polymorphism
    • Daclatasvir plus Sofosbuvir with or without weight-based Ribavirin x 24 weeks
    • Elbasvir/Grazoprevir with weight-based Ribavirin x 16 weeks and in patients with baseline NS5A RAVs for Elbasvir

1Includes G1a polymorphisms at amino acid positions 28, 30, 31, or 93

HCV Genotype 1b treatment-naive patients without cirrhosis

  • Recommended treatments: 
    • Elbasvir/Grazoprevir x 12 weeks
    • Ledipasvir/Sofosbuvir x 12 weeks
    • Paritaprevir/Ritonavir/Ombitasvir plus twice-daily dosed Dasabuvir x 12 weeks
    • Simeprevir plus Sofosbuvir x 12 weeks
    • Sofosbuvir/Velpatasvir x 12 weeks
    • Daclatasvir plus Sofosbuvir x 12 weeks

HCV Genotype 1b treatment-naive patients with compensated cirrhosis

  • Recommended treatments: 
    • Elbasvir/Grazoprevir x 12 weeks
    • Ledipasvir/Sofosbuvir x 12 weeks
    • Paritaprevir/Ritonavir/Ombitasvir plus twice-daily dosed Dasabuvir x 12 weeks
    • Sofosbuvir/Velpatasvir x 12 weeks
  • Alternative treatments:  
    • Daclatasvir plus Sofosbuvir with or without weight-based Ribavirin x 24 weeks
    • Simeprevir plus Sofosbuvir with or without weight-based Ribavirin x 24 weeks
    • Asunaprevir plus Daclatasvir2 x 24 weeks

2Screening for NS5A resistance-associated variants (RAVs) is recommended prior to starting therapy

HCV Genotype 2 treatment-naive patients without cirrhosis

  • Recommended treatment:
    • Sofosbuvir/Velpatasvir x 12 weeks
  • Alternative treatment: 
    • Daclatasvir plus Sofosbuvir x 12 weeks

HCV Genotype 2 treatment-naive with compensated cirrhosis

  • Recommended treatment: 
    • Sofosbuvir/Velpatasvir x 12 weeks
  • Alternative treatment: 
    • Daclatasvir plus Sofosbuvir x 16-24 weeks

HCV Genotype 3 treatment-naive patients without cirrhosis

  • Recommended treatments:
    • Daclatasvir plus Sofosbuvir x 12 weeks
    • Sofosbuvir/Velpatasvir x 12 weeks

HCV Genotype 3 treatment-naive  patients with compensated cirrhosis

  • Recommended treatments: 
    • Sofosbuvir/Velpatasvir x 12 weeks3
    • Daclatasvir plus Sofosbuvir x 24 weeks with or without weight-based Ribavirin

3RAV testing for Y93H is recommended for cirrhotic patients and Ribavirin should be included in the regimen, if present

HCV Genotype 4 treatment-naive patients without cirrhosis

  • Recommended treatments: 
    • Paritaprevir/Ritonavir/Ombitasvir and weight-based Ribavirin x 12 weeks
    • Sofosbuvir/Velpatasvir x 12 weeks
    • Elbasvir/Grazoprevir x 12 weeks
    • Ledipasvir/Sofosbuvir x 12 weeks

HCV Genotype 4 treatment-naive patients with compensated cirrhosis

  • Recommended treatments:
    • Paritaprevir/Ritonavir/Ombitasvir and weight-based Ribavirin x 12 weeks
    • Sofosbuvir/Velpatasvir x 12 weeks
    • Elbasvir/Grazoprevir x 12 weeks
    • Ledipasvir/Sofosbuvir x 12 weeks 

HCV Genotype 5 or 6 treatment-naive patients with and without cirrhosis

  • Recommended treatments: 
    • Sofosbuvir/Velpatasvir x 12 weeks
    • Ledipasvir/Sofosbuvir x 12 weeks

New HCV Fixed-dose Combination Agents

  • Sofosbuvir/Velpatasvir/Voxilaprevir  
    • For patients with chronic HCV infection without cirrhosis or with compensated cirrhosis who have:
      • Genotype 1, 2, 3, 4, 5, or 6 infection and have been treated previously with an HCV regimen containing an NS5A inhibitor
      • Genotype 1a or 3 infection and have been treated previously with an HCV regimen containing Sofosbuvir without an NS5A inhibitor
    • Treatment duration is 12 weeks
  • Glecaprevir/Pibrentasvir  
    • For patients with chronic HCV infection genotypes 1-6 without cirrhosis or with mild cirrhosis, including patients with moderate to severe kidney disease and those on dialysis
    • Also for genotype 1 infection that has been treated previously with an HCV regimen either containing an NS5A inhibitor or an NS3/4A protease inhibitor but not both
    • Treatment duration is 8 weeks for genotypes 1-6 treatment-naive patients without cirrhosis

Decompensated Cirrhosis

HCV Genotype 1 or 4 

With decompensated cirrhosis who are Ribavirin ineligible  

  • Recommended treatment:
    • Daclatasvir plus Sofosbuvir x 24 weeks

HCV Genotype 1, 4, 5 or 6

With decompensated cirrhosis who are Ribavirin eligible  

  • Recommended treatments:
    • Sofosbuvir/Velpatasvir with weight-based Ribavirin x 12 weeks
    • Ledipasvir/Sofosbuvir with low initial dose of Ribavirin (may be increased as tolerated) x 12 weeks

With decompensated cirrhosis who are Ribavirin ineligible  

  • Recommended treatments:
    • Sofosbuvir/Velpatasvir x 24 weeks
    • Ledipasvir/Sofosbuvir x 24 weeks

With decompensated cirrhosis and in whom previous Sofosbuvir- or NS5A-based treatment has failed

  • Recommended treatments:
    • Ledipasvir/Sofosbuvir with low initial dose of Ribavirin (may be increased as tolerated) x 24 weeks
    • Sofosbuvir/Velpatasvir with weight-based Ribavirin x 24 weeks 

HCV Genotype 2 or 3

With decompensated cirrhosis who are Ribavirin ineligible  

  • Recommended treatments:
    • Sofosbuvir/Velpatasvir x 24 weeks
    • Daclatasvir plus Sofosbuvir x 24 weeks

With decompensated cirrhosis and in whom previous Sofosbuvir- or NS5A-based treatment has failed  

  • Recommended treatment:
    • Sofosbuvir/Velpatasvir with weight-based Ribavirin x 24 weeks

Hepatitis D

  • Interferon alfa may have a role, Peginterferon alfa-2a given for 48 weeks
    • Treatment is stopped after HBsAg seroconversion or if HDV RNA did not decrease with treatment of 6-12 months

Non-Pharmacological Therapy

Hepatitis D

  • Aim of treatment is to eradicate or to achieve long-term suppression of both hepatitis D virus and hepatitis B virus
  • Supportive care
  • Consider hospitalization if there is vomiting, dehydration, signs of hepatic decompensation
  • Screen for other STDs in cases of sexually-acquired hepatitis or if otherwise appropriate
  • Consider expert referral

Surgical Intervention

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 HBV infection should be evaluated for liver transplantation despite antiviral therapy as development of liver failure cannot be predicted 
    • Combination therapy with hepatitis B immunoglobulin and nucleos(t)ide analogues helps prevent HBV recurrence in these patients undergoing liver transplantation
  • Recipient patients without anti-HBs should receive prophylaxis for HBV recurrence if transplanted liver is anti-HBc positive 
  • Patients with HCV infection should be treated prior to transplant to decrease the risk of HCV recurrence 
    • If with hepatitis C recurrence, 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 
  • HDV replication is not a contraindication for liver transplantation
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