Treatment

  Treatment Guidelines / Hepatitis Overview / Treatment

Treatment

Hepatitis A - General Care

  • 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
Partner Notification
  • Partner notification should be performed for at-risk sexual contacts (oral/anal, digital/rectal, & penetrative anal sex) w/in 2 wk before to 1 wk after the onset of jaundice
Other Antivirals
Inosine dimepranol acedoben (Inosine pranobex, Inosiplex, Methisoprinol)
  • Adverse Reactions:
    • Transient elevation of urine &/or serum uric acid levels; infrequent: Skin rashes &/or itching, Gl upsets, nausea, diarrhea, fatigue &/or malaise; rarely: Headache, vertigo, arthralgia, constipation, polyuria
  • Special Instructions:
    • Monitor serum uric acid levels in patients w/ gout, urolithiasis or renal dysfunction
    • Supervise administration to digitalized patients
  • Dosage Guidelines:
    • Hepatitis A & Acute Hepatitis B
      • 100 mg/kg/day PO in 4-6 divided doses
        • Maintenance dose: 50 mg/kg/day PO in 3-4 divided doses
          • Duration: 7-10 days

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Hepatitis B - General Care

    Acute Hepatitis B
    • Supportive care
      • Treatment w/ antivirals is generally not recommended
    • Consider hospitalization if there is vomiting, dehydration, signs of hepatic decompensation
      • Consider treatment w/ nucleoside or nucleotide analogs in severe acute hepatitis
    Partner Notification
    • Partner notification for at-risk contacts
      • Contact tracing should include any sexual contact (penetrative vaginal or anal or oral/anal) or needle-sharing partners w/in 2 wk before onset of jaundice until the patient becomes negative for HBsAg
    • All non-immune sexual & household contacts must be screened & vaccinated
    Chronic Hepatitis B
    • Vaccination against hepatitis A for non-immune patients
    • Periodic screening for HCC in high-risk carriers
      • HCC may have a long asymptomatic stage lasting 2 yr or longer
      • Carriers of HBV at high risk for developing HCC include men ≥40 yr, patients w/ cirrhosis, co-infected w/ HCV, w/ HBV genotype C, or persistent HBV DNA >2000 IU/mL, or those w/ family history of HCC
      • Screening methods are alpha-fetoprotein (AFP) determination & ultrasound
    • Liver biopsy
      • Purpose is to assess the degree of liver damage, to rule out other causes of liver disease & to help predict prognosis
      • Recommended for chronic hepatitis B patients who are candidates for antiviral therapy
    Partner Notification
    • Trace contacts as far back as any episode of jaundice or to the time when infection is thought to have been acquired
    Pharmacological Therapy
    Chronic Infection
    Patients For Whom Treatment is Not Recommended
    • W/o clinical evidence of cirrhosis, w/ 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
    • W/o clinical evidence of cirrhosis but w/ persistently abnormal ALT, HBV DNA >20,000 IU/ml, regardless of HBeAg status
    Goals of Treatment
    • Continued viral suppression is necessary to reduce or prevent hepatic disease & 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 & to decrease hepatic necroinflammation & fibrosis during & after therapy
      • Long-term goal of therapy is to avoid hepatic decompensation, reduce or prevent progression to cirrhosis &/or HCC & to prolong survival
    • Endpoints used to assess response:
      • Biological response: Normalization of serum ALT
      • Virological response: HBV DNA <104 copies/mL & sustained seroconversion from HBeAg to anti-HBe
      • Histological response: Decrease in histology activity compared to pretreatment liver biopsy
      • Complete response: Fulfill criteria of biochemical & virological response & 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 & complications
    • HBeAg-positive patients w/ elevated ALT levels & compensated liver disease should be observed for 3-6 mth 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 & 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 w/ Peginterferon w/ Ribavirin

    1. Interferons W/ or W/O Ribavirin
    Interferon alfa
    • Interferons have antiviral, antiproliferative & immunomodulatory effects
    • May be a preferred agent in the treatment of HBeAg-negative chronic hepatitis B & HBeAg-positive chronic hepatitis w/ elevated ALT
    • Suppresses HBV replication & 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 & lower levels of serum HBV DNA
    • Finite duration of therapy
    Interferons
    • Adverse Reactions:
      • Influenza-like symptoms (fatigue, fever, headache, myalgia, arthralgia); Neuropsychiatric symptoms (depression, mood swings, irritability, somnolence); Hematologic effects (granulocytopenia, thrombocytopenia); CV effects (chest pain, edema, hypertension); Misc effects (pain at inj site, dyspepsia, alopecia, thyroid function abnormalities)
      • May cause or aggravate fatal or life-threatening infectious or ischemic disorders
    • Special Instructions:
      • Contraindicated in patients w/ decompensated liver disease, autoimmune hepatitis
      • Use w/ caution in patients w/ hepatic or renal impairment, depression or psychiatric disorders, cardiovascular disease, arrhythmias, hypertension, pre-existing thyroid disease
      • Maintain adequate hydration during treatment
      • Withdraw drug if jaundice occurs
      • Monitor liver function test (LFT)
    Ribavirin
    • Adverse Reactions:
      • Hemolytic anemia, fatigue, itching rash, sinusitis, gout, birth defects
    • Special Instructions:
      • Do not give to patients w/ conditions that may be exacerbated by Ribavirin-induced hemolysis
      • Use w/ caution in patients w/ hepatic or renal impairment
      • Contraindicated in pregnancy & in patients who may become pregnant
    • Dosage Guidelines:
    1.1. Interferon alfa-2a
    • Chronic Hepatitis B
      • 3-4.5 MIU SC/IM 3x/wk
        • Duration: 6 mth
    1.2. Interferon alfa-2b
    • Chronic Hepatitis B
      • 5 MIU SC/IM 24 hrly or 3-10 MIU SC/IM 3x/wk
        • Duration:4-6 mth
    Other Considerations
    • Prednisone priming prior to Interferon alfa therapy is not recommended
    • Contraindicated in patients w/ decompensated cirrhosis & coexisting autoimmune diseases
    • Not recommended for patients w/ compensated cirrhosis because of risk of hepatic decompensation associated w/ Interferon alfa-related flares of hepatitis
    • Side effects include mood swings & 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 w/ another drug
    Peginterferon alfa
    • Approved in a number of countries for chronic hepatitis B for both HBeAg-positive & HBeAg-negative chronic hepatitis in adult patients w/ compensated liver disease, evidence of viral replication & 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 & HBsAg seroconversion
      • Longer half-life compared to Interferon alfa & appears to impart a clinical benefit over conventional Interferon alfa
    • Action: Inert Polyethylene glycol is added to Interferon, decreases the drug’s renal clearance & increases its half life
      • Provides sustained viral suppression w/ efficacy similar to or better than standard Interferon alfa
    • Finite duration of therapy, no reported resistance
    1.3. Peginterferon alfa-2a
    • Chronic Hepatitis B
      • 180 mcg SC once wkly
        • Duration: 12 mth
      1.4. Peginterferon alfa-2b
      • Chronic Hepatitis B
        • 1.0-1.5 mcg/kg/wk SC
          • Duration: HBe positive: 6 mth
          • Duration: HBe negative: 12 mth
      Other Considerations
      • Contraindicated in patients w/ decompensated cirrhosis
      • Side effects include mood swings & depression; patient’s mental health should be closely monitored by the clinician
      2. Nucleoside Reverse Transcriptase Inhibitors 
      2.1. Clevudine

      Daily dose of 30 mg for 24 wk has been shown to be associated w/ 59% undetectable HBV DNA (<300 copies/mL) & 7.6% HBeAg seroconversion in HBeAg-positive patients, w/ 92% undetectable HBV DNA in HBeAg-negative patients

      • Adverse Reactions:
        • GI effects (dyspepsia, abdominal pain); Misc effects (upper respiratory infections, asthenia, headache)
      • Special Instructions:
        • Contraindicated in patients w/ renal impairment
        • Use w/ caution in patients w/ lactic acidosis & severe hepatomegaly w/ steatosis
      • Dosage Guidelines:
        • Chronic Hepatitis B 30 mg PO 24 hrly
          • Duration: Not yet determined
      2.2. Entecavir
      • Approved by United States Food & Drug Administration (USFDA) for treatment of chronic hepatitis B virus infection in adults w/ evidence of active viral replication & 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 & serologic responses after 1 yr of treatment in nucleoside-treatment-naive & Lamivudine-resistant adult patients w/ HBeAg-positive or HBeAg-negative chronic HBV infection w/ compensated liver disease
      • Appears to be superior to Lamivudine based on histologic improvement, reduction in viral load & ALT normalization
      • Effective in the treatment of Adefovir & Tenofovir resistance
      • Inhibits the following HBV polymerase activities: Base priming, reverse transcription of the negative strand from the pregenomic messenger RNA, & synthesis of the positive strand of HBV DNA
      • Adverse Reactions:
        • CNS effects (headache, fatigue, dizziness, somnolence); GI effects (N/V, dyspepsia, increase in ALT that generally resolves w/ continued treatment); Misc effects (edema, ascites, hyperglycemia)
      • Special Instructions:
        • Use w/ caution in patients w/ renal impairment
        • May need to reduce dosage in patients w/ renal impairment
      • Dosage Guidelines:
        • Chronic Hepatitis B in nucleoside-treatment-naive: 0.5 mg PO 24 hrly
          • Duration: Not yet determined
        • Chronic Hepatitis B w/ history of Lamivudine resistance: 1 mg PO 24 hrly
          • Duration: Given x at least 1yr in clinical trials
      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 & hepatocellular carcinoma
        2.3. Lamivudine
        • Used for HBeAg-positive chronic hepatitis w/ elevated ALT but has a high rate of drug resistance during long-term treatment
        • Recommended in viremic patients (HBeAg-positive & HBeAg-negative patients) w/ ALT >5x ULN esp if there is concern regarding decompensation
        • Good safety profile & 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 & reduction in rate of development of hepatic fibrosis
        • Effects:
          • Pretreatment ALT is the most important predictor of response
          • Response is greatest in patients w/ an ALT 2-5x the normal value
        • Treatment may be discontinued in patients who have completed 1 yr of treatment & have persistent HBeAg seroconversion to anti-HBe & undetectable HBV DNA by PCR assay
        • Treatment may be continued in patients who have not achieved HBeAg seroconversion & have no evidence of breakthrough infection because HBeAg seroconversion may occur w/ continued treatment
        • Adverse Reactions:
          • GI disturbances (abdominal pain, N/V, diarrhea; mild increases in ALT levels that generally resolves w/ continued treatment); Resp effects (cough, nasal symptoms); CNS effects (malaise, fever); Musculoskeletal effects (arthralgia, musculoskeletal pain, peripheral neuropathy); Misc effects (rash, alopecia)
        • Special Instructions:
          • Use w/ caution in patients w/ hepatomegaly & hepatic impairment
        • Dosage Guidelines:
          • Chronic Hepatitis B
            • 100 mg PO 24 hrly
              • Duration: ≥1 yr
        Other Considerations
        • While on therapy, monitor LFTs & HBV DNA levels every 3 mth
        • Test for HBeAg & anti-HBe at the end of 1 yr of treatment & every 3-6 mth thereafter
        2.4. Telbivudine
        • Orally bioavailable w/ potent & specific anti-HBV activity
        • Clinical trials show that Telbivudine gave more potent HBV suppression than Lamivudine or Adefovir in both HBeAg-positive & negative patients & 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
        • Adverse Reactions:
          • CNS effects (dizziness, headache); GI effects (diarrhea, increased blood amylase, nausea; increased ALT levels that generally resolves w/ continued treatment); Other effects (rash, fatigue)
        • Special Instructions:
          • Use w/ caution in patients w/ renal impairment
        • Dosage Guidelines:
          • Chronic Hepatitis B
            • 600 mg PO 24 hrly
              • Duration: Optimal duration not yet determined

        3. Nucleotide Reverse Transcriptase Inhibitor
        3.1. Adefovir dipivoxil
        • Adefovir dipivoxil has shown to be beneficial in patients w/ HBeAg-positive chronic hepatitis B infection
        • May be a preferred agent for patients w/ negative HBeAg, HBV DNA >105 copies/mL & elevated ALT
        • Inhibits reverse transcriptase & DNA polymerase activity & 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% & lower risk of Adefovir resistance of 4-8% in 3-4 yr
          • 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 yr & confirmed HBeAg seroconversion but durability of response is unknown
          • Therapy may be continued in those who did not achieve HBeAg seroconversion but safety & efficacy has not been established
        • HBeAg-negative chronic hepatitis may need extended treatment (>1 yr) to maintain response
          • Further studies are needed to determine optimal duration of therapy
        • Adverse Reactions:
          • GI disturbances (nausea, flatulence, diarrhea, dyspepsia, abdominal pain); Dermatologic effects (skin rashes, pruritus); Resp effects (cough, pharyngitis, sinusitis); Misc effect (headache)
          • At high doses: Nephrotoxicity (renal tubular dysfunction resembling Fanconi’s syndrome, deterioration in renal function)
        • Special Instructions:
          • Use w/ caution in patients w/ hepatic or renal impairment
          • May need to reduce dosage in patients w/ renal impairment
        • Dosage Guidelines:
          • Chronic Hepatitis B
            • 10 mg PO 24 hrly
              • Durations: ≥1 yr
        Other Considerations
        • Renal function must be monitored every 3 mth for patients w/ predisposition to renal insufficiency & for patients on Adefovir dipivoxil for >1 yr
        3.2. 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 & as an alternative agent in patients w/ suspected or confirmed resistance to Adefovir, Entecavir, Lamivudine & Telbivudine
        • Adverse Reactions:
          • CNS effects (insomnia, dizziness, depression); GI disturbances (nausea, flatulence, diarrhea, dyspepsia, abdominal pain); Misc effects (increased triglycerides, weakness)
        • Special Instructions:
          • Use w/ caution in patients w/ hepatic or renal impairment
          • May need to reduce dosage in patients w/ renal impairment
          • Do not use concurrently w/ other nucleotide reverse transcriptase inhibitors
        • Dosage Guidelines:
          • Chronic Hepatitis B
            • 300 mg PO 24 hrly
              • Duration: ≥1 yr
        4. Other Antivirals
        4.1 Inosine dimepranol acedoben (Inosine pranobex, Inosiplex, Methisoprinol)
        • Adverse Reactions:
          • Transient elevation of urine &/or serum uric acid levels; infrequent: Skin rashes &/or itching, Gl upsets, nausea, diarrhea, fatigue &/or malaise; rarely: Headache, vertigo, arthralgia, constipation, polyuria
        • Special Instructions:
          • Monitor serum uric acid levels in patients w/ gout, urolithiasis or renal dysfunction
          • Supervise administration to digitalized patients
        • Dosage Guidelines:
          • Hepatitis A & Acute Hepatitis B
            • 100 mg/kg/day PO in 4-6 divided doses
              • Maintenance dose: 50 mg/kg/day PO in 3-4 divided doses
                • Duration: 7-10 days
        Lamivudine-resistant HBV
        • Emergence of Lamivudine-resistant HBV is increasingly common w/ prolonged treatment, together w/ a decreasing rate of remission
        • Associated w/ development of Lamivudine-resistant YMDD viral mutants, which appear to be less virulent than wild-type HBV, but have been associated w/ rapidly progressive liver disease in some patients
        • Lamivudine resistance is usually manifested as breakthrough infection w/ reappearance of HBV DNA in serum
        • There may be continued clinical benefit w/ continuation of treatment in spite of development of drug resistance
          • Benefits of continued treatment must be balanced against the risk of resistant mutants

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        Hepatitis C - General Care

        • Supportive care
        • Consider hospitalization if there is vomiting, dehydration, signs of hepatic decompensation
          • Evaluate for advanced fibrosis or other conditions that may hasten liver fibrosis (eg HBV & HIV infections) to help guide treatment
            • Monitor for HCC w/ AFP & liver ultrasound every 6 mth
        • Screen for other STDs in cases of sexually acquired hepatitis or if otherwise appropriate
        Partner Notification
        • Partner notification for at-risk contacts
          • Contact tracing to include any sexual contact (penetrative vaginal or anal sex) or needle-sharing partners from 2 wk before the onset of jaundice
          • If w/o acute infection, trace back to the likely time of infection eg blood transfusion, 1st needle sharing
        Pharmacological Therapy

        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 & hepatocellular carcinoma risk in patients w/ cirrhosis
        Principles of Treatment
        • Treatment is indicated for both treatment-experienced & treatment-naive patients w/ compensated & 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 & 6 mth later
        • Rapid virologic response (RVR) is achieved when HCV RNA becomes undetectable (<50 IU/mL) in serum after 4 wk of therapy
        • Early virologic response (EVR) is defined as 2-log drop or loss of HCV RNA 12 wk 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 & 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 & those w/ HCV genotype non-1 infection
        • Less likely to happen if infection lasts >12 wk

        Acute Hepatitis C
        • Treatment may be delayed for 8-12 wk to allow spontaneous resolution
        • Interferon (high-dose) or Peginterferon may be used
          • Treat HCV genotype 1 for 24 wk, genotype 2 , 3, or 4 for 12 wk
          • Patients unresponsive to monotherapy should be given Peginterferon/Ribavirin or a protease inhibitor-based triple therapy
        Chronic Hepatitis C
        HCV Genotype 1 w/o cirrhosis
        • Recommended treatments:
          • Daclatasvir/Sofosbuvir x 12 wk
          • Ledipasvir/Sofosbuvir x 12 wk & may be shortened to 8 wk, if the baseline HCV RNA is <6 million IU/mL 
        • Alternative treatments:
          • Simeprevir/Sofosbuvir x 12 wk & should not be given in patients positive for q80K variant of genotype 1a
          • Ombistavir/Paritapevir/Ritonavir/Dasabuvir w/ Ribavirin x 12 wk in genotype 1a
          • Ombistavir/Paritapevir/Ritonavir/Dasabuvir x 12 wk in genotype 1b

        HCV Genotype 1 w/ cirrhosis

        • Recommended treatments:
          • Daclatasvir/Sofosbuvir w/ or w/o Ribavirin x 12 wk or Ledipasvir/Sofosbuvir w/ or w/o Ribavirin x 12 wk 
        • Alternative treatments:
          • Simeprevir/Sofosbuvir w/ or w/o Ribavirin x 12 wk & should not be given in patients positive for q80K variant of genotype 1a
          • Ombistavir/Paritaprevir/Ritonavir/Dasabuvir w/ or w/o Ribavirin

        HCV Genotype 2 w/ or w/o cirrhosis

        • Recommended treatments:
          • Sofosbuvir/Ribavirin x 12 wk w/o cirrhosis & Sofosbuvir/Ribavirin x 16 wk w/ cirrhosis
        • Alternative treatments:
          • Daclatasvir/Sofosbuvir x 12 wk

        HCV Genotype 3 w/o cirrhosis

        • Recommended treatments:
          • Daclatasvir/Sofosbuvir or Sofosbuvir/Ribavirin x 12 wk

        HCV Genotype 3 w/ cirrhosis

        • Recommended treatments:
          • Daclatasvir/Sofosbuvir/Ribavirin x 12 wk
        • Alternative treatments:
          • Sofosbuvir/ Peginterferon/Ribavirin x 12 wk 

        HCV Genotype 4 w/o cirrhosis

        • Recommended treatments:
          • Daclatasvir/Sofosbuvir or Ledipasvir/Sofosbuvir x 12 wk
        • Alternative treatments:
          • Simeprevir/Sofosbuvir x 12 wk & should not be given in patients positive for q80K variant of genotype 1a
          • Ombistavir/Paritaprevir/Ritonavir/Ribavirin
        HCV Genotype 4 w/ cirrhosis
        • Recommended treatments:
          • Daclatasvir/Sofosbuvir w/ or w/o Ribavirin
          • Ledipasvir/Sofosbuvir w/ or w/o Ribavirin
        • Alternative treatments:
          • Simeprevir/Sofosbuvir w/ or w/o Ribavirin
          • Ombitasvir/Paritaprevir/Ritonavir/Ribavirin x 24 wk

        HCV Genotype 5 or 6 w/o cirrhosis

        • Recommended treatments:
          • Ledipasvir + Sofosbuvir x 12 wk
        • Alternative treatments:
          • Sofosbuvir/Peginterferon/Ribavirin x 12 wk

        HCV Genotype 5 or 6 w/ cirrhosis

        • Recommended treatments:
          • Ledipasvir + Sofosbuvir x 24 wk
        • Alternative treatments:
          • Sofosbuvir/Peginterferon/Ribavirin x 12 wk

        1. Interferons W/ or W/o Ribavirin
        Interferon alfa
        • Interferons have antiviral, antiproliferative & immunomodulatory effects
        • May be a preferred agent in the treatment of HBeAg-negative chronic hepatitis B & HBeAg-positive chronic hepatitis w/ elevated ALT
        • Suppresses HBV replication & 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 & lower levels of serum HBV DNA
        • Finite duration of therapy
        Interferons
        • Adverse Reactions:
          • Influenza-like symptoms (fatigue, fever, headache, myalgia, arthralgia); Neuropsychiatric symptoms (depression, mood swings, irritability, somnolence); Hematologic effects (granulocytopenia, thrombocytopenia); CV effects (chest pain, edema, hypertension); Misc effects (pain at inj site, dyspepsia, alopecia, thyroid function abnormalities)
          • May cause or aggravate fatal or life-threatening infectious or ischemic disorders
        • Special Instructions:
          • Contraindicated in patients w/ decompensated liver disease, autoimmune hepatitis
          • Use w/ caution in patients w/ hepatic or renal impairment, depression or psychiatric disorders, cardiovascular disease, arrhythmias, hypertension, pre-existing thyroid disease
          • Maintain adequate hydration during treatment
          • Withdraw drug if jaundice occurs
          • Monitor liver function test (LFT)
        Ribavirin
        • Adverse Reactions:
          • Hemolytic anemia, fatigue, itching rash, sinusitis, gout, birth defects
        • Special Instructions:
          • Do not give to patients w/ conditions that may be exacerbated by Ribavirin-induced hemolysis
          • Use w/ caution in patients w/ hepatic or renal impairment
          • Contraindicated in pregnancy & in patients who may become pregnant
        • Dosage Guidelines:
        1.1. Interferon alfa-2a
        • Chronic Hepatitis C
          • 3 MIU SC/IM 3x/wk
            • Alternative dose:
              • Duration: 12 mth
        • Induction therapy:
          • 6 MIU SC/IM 3x/wk followed by
            • Duration: 3 mth
        • Maintenance therapy:
          • 3 MIU SC/IM 3x/wk
            • Duration: 3 mth
        1.2. Interferon alfa-2a + Ribavirin
        • Chronic Hepatitis C in combination w/ Ribavirin
          • 3-4.5 MIU SC/IM 3x/wk +
          • Ribavirin
            • >75 kg: 600 mg PO 12 hrly
            • ≤75 kg: 400 mg PO in the morning & 600 mg PO in the evening
              • Duration: 6 mth
        1.3. Interferon alfa-2b
        • Chronic Hepatitis C
          • 3-10 MIU SC/IM 3x/wk
            • Duration:18-24 mth
        1.4. Interferon alfa-2b + Ribavirin
        • Chronic Hepatitis C in combination w/ Ribavirin
          • 3 MIU SC 3x/wk +
          • Ribavirin
            • >75 kg: 600 mg PO 12 hrly
            • ≤75 kg: 400 mg PO in the morning & 600 mg PO in the evening
              • Duration: 6-12 mth
        1.5. Interferon alfacon-1
        • Chronic Hepatitis C
          • 9 mcg SC 3x/wk (≥48 hr between doses)
            • Duration: 6 mth
          • Non-responders or have relapsed: 15 mcg SC 3x/wk
            • Duration: 6 mth
        Other Considerations
        • Prednisone priming prior to Interferon alfa therapy is not recommended
        • Contraindicated in patients w/ decompensated cirrhosis & coexisting autoimmune diseases
        • Not recommended for patients w/ compensated cirrhosis because of risk of hepatic decompensation associated w/ Interferon alfa-related flares of hepatitis
        • Side effects include mood swings & 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 w/ another drug
        Peginterferon alfa
        • Approved in a number of countries for chronic hepatitis B for both HBeAg-positive & HBeAg-negative chronic hepatitis in adult patients w/ compensated liver disease, evidence of viral replication & 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 & HBsAg seroconversion
          • Longer half-life compared to Interferon alfa & appears to impart a clinical benefit over conventional Interferon alfa
        • Action: Inert Polyethylene glycol is added to Interferon, decreases the drug’s renal clearance & increases its half life
          • Provides sustained viral suppression w/ efficacy similar to or better than standard Interferon alfa
        • Finite duration of therapy, no reported resistance
        1.6. Peginterferon alfa-2a
        • Chronic Hepatitis C
          • 180 mcg SC once wkly
            • Duration: 12 mth
        1.7. Peginterferon alfa-2a + Ribavirin
        • Chronic Hepatitis C in combination w/ Ribavirin
          • Genotype-1 or -4
            • 180 mcg SC once wkly + Ribavirin
              • >75 kg: 1200 mg PO 12 hrly
              • ≤75 kg: 1000 mg PO in the morning & 600 mg PO in the evening
                • Duration: 12 mth
          • Genotype-2 or -3
            • 180 mcg SC once wkly + Ribavirin
              • 800 mg/day PO
                • Duration: 6 mth  
        1.8. Peginterferon alfa-2b
        • Chronic Hepatitis C
          • 0.5-1 mcg/kg SC once wkly
            • Duration: 6-12 mth
        1.9. Peginterferon alfa-2b + Ribavirin
        • Chronic Hepatitis C in combination w/ Ribavirin
        • Genotype-1
          • 1.5 mcg/kg SC once wkly + Ribavirin
            • <65 kg: 800 mg PO divided 12 hrly
            • 65-85 kg: 1000 mg PO divided 12 hrly
            • 86-105 kg: 1200 mg PO divided 12 hrly
            • >105 kg: 1400 mg PO divided 12 hrly
              • Duration: Genotype-1: 12 mth
              • Duration: Genotype-2 or -3: 6 mth
        Other Considerations
        • Contraindicated in patients w/ decompensated cirrhosis
        • Side effects include mood swings & depression; patient’s mental health should be closely monitored by the clinician

        2. Antivirals

        2.1 Ombitasvir/Paritaprevir/Ritonavir/Dasabuvir

        • Adverse Reactions:
          • In combination w/ Ribavirin: Fatigue, nausea, pruritus, other skin reactions, insomnia, asthenia
          • Monotherapy (w/o Ribavirin): Nausea, pruritus, insomnia
        • Special Instructions:
          • Assess for laboratory & clinical evidence of hepatic decompensation prior to initiation of therapy
          • Use w/ caution in patients co-infected w/ HIV or hepatitis B, post liver transplant, HCV genotypes other than genotype 1, who have failed previous therapy w/ direct acting antivirals against HCV & those w/ risk of hepatic failure in patients w/ cirrhosis
          • Contraindicated in patients w/ moderate to severe hepatic impairment & in men whose female partners are pregnant, may be pregnant or planning to become pregnant
          • Should not be co-administered w/ additional Ritonavir or Ritonavir-containing regimens & direct-acting antivirals against HCV
        • Dosage guidelines:
          • 2 tabs (Ombitasvir 12.5 mg, Paritaprevir 75 mg, Ritonavir 50 mg) PO 24 hrly in the morning
          • 1 tab (Dasabuvir 250 mg) PO 12 hrly in the morning & evening
          • Duration:
            • 12 wk for genotype 1b w/o cirrhosis, or combined w/ Ribavirin in patients w/ genotype 1a w/o cirrhosis; combine w/ Ribavirin in patients w/ genotype 1b w/ cirrhosis
            • 24 wk for those combined w/ Ribavirin in patients w/ genotype 1a w/ cirrhosis & may be considered for some patients based on prior treatment history

        Sofosbuvir/Ledipasvir

        • Adverse Reactions:
          • Fatigue, nausea, diarrhea, insomnia, headache
        • Special Instructions:
          • Patients taking beta-blockers or those w/ underlying cardiac comorbidities &/or advanced liver disease may be at increased risk for symptomatic bradycardia w/ co-administration of Amiodarone
        • Dosage guidelines:
          • 1 tab (Ledipasvir 90 mg, Sofosbuvir 400 mg) PO 24 hrly
          • Duration:
            • For treatment naive patients w/ or w/o cirrhosis & treatment experienced patients w/o cirrhosis: 12 wk
            • For treatment experienced patients w/ cirrhosis: 24 wk
        3. Other Antivirals
        3.1. Daclatasvir
        • Adverse Reactions:
          • Daclatasvir + Sofosbuvir: Fatigue, headache, nausea
        • Special Instructions:
          • Use w/ caution in patients w/ decompensated liver disease, pregnancy & contraception requirement, pre-, peri- or post-liver transplant, HCV/HIV, HBV co-infection, rare hereditary problems
          • Avoid co-administration w/ strong inducers of CYP3A4
        • Dosage Guidelines:
          • Chronic Hepatitis C
            • 60 mg PO 24 hrly
              • Duration:
              • Genotype-1, 2, 3, & 4 (treatment experienced): W/ Sofosbuvir 12 wk
              • Genotype-3 or w/ cirrhosis: W/ Sofosbuvir 12-24 wk
              • Genotype-4 (treatment naive): W/ Peginterferon/Ribavirin 24 wk
              • If HCV RNA is undetectable at treatment wks 4 & 12, Peginterferon/Ribavirin should be continued up to 48 wk
        3.2. Sofosbuvir
        • Adverse Reactions:
          • CNS effects (fatigue, headache, insomnia, chills, irritability, myalgia); Dermatologic effects (pruritus, skin rash); GI effects (nausea, diarrhea, decreased appetite); Hematologic effects (anemia, neutropenia); Other effects (fever, flu-like symptoms)
        • Special Instructions:
          • Use w/ caution in patients w/ renal impairment, HCV/HBV co-infection, treatment-experienced patients w/ genotype 1, 4, 5 & 6 HCV infection; patients w/ genotype 5 & 6 HCV infection; interferon-free regimens for patients w/ genotype 1, 4, 5 & 6 HCV infection. Concomitant w/ other direct-acting antivirals against HCV. Concomitant w/ potent P-gp inducers in the intestine
        • Dosage Guidelines:
          • Chronic Hepatitis C
            • 400 mg PO 24 hrly
              • Duration:
              • Genotype-1, 3, 4: W/ Ribavirin/Peginterferon alfa 12 wk
              • Genotype-2: W/ Ribavirin 12 wk
              • Genotype-3: W/ Ribavirin for 24 wk
              • Genotype-1, 2, 3 or 4 awaiting liver transplantation: W/Ribavirin until liver transplantation
              • Genotype-1 ineligible to receive an interferon-based regimen: W/ Ribavirin 24 wk may be considered
        4. Protease Inhibitors
        • Eg Simeprevir
        • An NS3/4A protease inhibitor used for the treatment of genotype 1 & 4 chronic HCV infection in patients >18 years of age
        • Have been shown in clinical trials to be effective in inhibiting HCV genotype 1 replication & in providing improvement in the SVR rates in treatment-naive & treatment-experienced patients
          • Simeprevir + Peginterferon/Ribavirin are for infections w/ HCV genotype 1a w/o q80K polymorphism & HCV genotype 1b

        Boceprevir

        • Adverse Reactions:
          • GI effects (nausea, taste disturbance, decreased appetite), Dermatologic effects (rashes, pruritus, dry skin); Misc effect (headache, fatigue, blood dyscrasias, metabolic disturbances, palpitations, cough)
        • Special Instructions:
          • Should be taken w/ meals
          • Must not be used as monotherapy, used in combination w/ Peginterferon alfa & Ribavirin
          • Use w/ caution in patients at risk for prolongation of QT interval
          • Contraindicated in patients w/ auto-immune hepatitis & concurrent use of drugs that are inducers of or metabolized by cytochrome P450 isoenzymes
        • Dosage Guidelines:
          • Chronic Hepatitis C Genotype-1
            • 800 mg PO 8 hrly
            • Max dose: 2400 mg/day
              • Duration:
              • Patients w/ compensated cirrhosis: Initial 1 mth of Peginterferon alfa & Ribavirin therapy followed by 11 mth of Boceprevir w/ Peginterferon alfa & Ribavirin
              • Patients w/o cirrhosis & are not previously treated or those who have failed prior therapy w/ Peginterferon alfa & Ribavirin: Initial 1 mth of Peginterferon alfa & Ribavirin then Boceprevir added to regimen the course of which is determined by patient’s HCV-RNA levels

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        Hepatitis D - General Care

        • 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
        Partner Notification
        • Partner notification for at-risk contacts
        Pharmacological Therapy
        • Interferon alfa may have a role, Peginterferon alfa-2a given for 48 wk
          • Treatment is stopped after HBsAg seroconversion or if HDV RNA did not decrease w/ treatment of 6-12 mth
        1. Interferons W/ or W/O Ribavirin
        Interferon alfa
        • Interferons have antiviral, antiproliferative & immunomodulatory effects
        • May be a preferred agent in the treatment of HBeAg-negative chronic hepatitis B & HBeAg-positive chronic hepatitis w/ elevated ALT
        • Suppresses HBV replication & 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 & 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 w/ decompensated cirrhosis & coexisting autoimmune diseases
        • Not recommended for patients w/ compensated cirrhosis because of risk of hepatic decompensation associated w/ Interferon alfa-related flares of hepatitis
        • Side effects include mood swings & 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 w/ another drug
        Interferons
        • Adverse Reactions:
          • Influenza-like symptoms (fatigue, fever, headache, myalgia, arthralgia); Neuropsychiatric symptoms (depression, mood swings, irritability, somnolence); Hematologic effects (granulocytopenia, thrombocytopenia); CV effects (chest pain, edema, hypertension); Misc effects (pain at inj site, dyspepsia, alopecia, thyroid function abnormalities)
          • May cause or aggravate fatal or life-threatening infectious or ischemic disorders
        • Special Instructions:
          • Contraindicated in patients w/ decompensated liver disease, autoimmune hepatitis
          • Use w/ caution in patients w/ hepatic or renal impairment, depression or psychiatric disorders, cardiovascular disease, arrhythmias, hypertension, pre-existing thyroid disease
          • Maintain adequate hydration during treatment
          • Withdraw drug if jaundice occurs
          • Monitor liver function test (LFT)
        Ribavirin
        • Adverse Reactions:
          • Hemolytic anemia, fatigue, itching rash, sinusitis, gout, birth defects
        • Special Instructions:
          • Do not give to patients w/ conditions that may be exacerbated by Ribavirin-induced hemolysis
          • Use w/ caution in patients w/ hepatic or renal impairment
          • Contraindicated in pregnancy & in patients who may become pregnant
        • Dosage Guidelines:
        1.1. Interferon alfa-2b
        • Chronic Hepatitis D
          • 5 MIU/m2 SC 3x/wk
            • Duration: ≥3-4 mth

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        Hepatitis E - General Care

        • 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

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        6. Cholagogues, Cholelitholytics & Hepatic Protectors
        • Adverse Reactions:
          • Diarrhea
        • Special Instructions:
          • Should be taken w/ food
        • Dosage Guidelines:
        • Silymarin1
        • 200 mg PO 12-24 hrly or
        • Initially for severe disease: 140 mg PO 8 hrly x 4 wk
        • Maintenance dose: 70 mg PO 8 hrly

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        7. Immunoglobulins
        • Adverse Reactions:
          • Post-inj local reactions, hypersensitivity reactions
        • Dosage Guidelines:
        • a.Hepatitis B Immunoglobulin (Hepatitis B Ig)
          • Individualize dose based on manufacturer’s recommendations
        • b.Human Immunoglobulin
          • Single IM dose
          • Individualize dose based on manufacturer’s recommendations w/in 2 wk of exposure to Hepatitis A

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        8. Vaccines
        a. Hepatitis A vaccine
        • Adverse Reactions:
          • Post-inj local reactions; systemic symptoms (fever, headache, malaise); hypersensitivity reactions
        • Special Instructions:
          • Give by SC route in patients w/ bleeding disorders
        • Dosage Guidelines:
          • Individualize dose based on manufacturer’s recommendations & local immunization guidelines
        b. Hepatitis A & B vaccine
        • Adverse Reactions:
          • Post-inj local reactions; CNS effects (fever, headache, malaise, dizziness, sleep disturbance); GI effect (abdominal pain); hypersensitivity reactions
        • Special Instructions:
          • Give by SC route in patients w/ impaired immunity or w/ bleeding disorders
        • Dosage Guidelines:
          • Individualize dose based on manufacturer’s recommendations & local immunization guidelines
        c. Hepatitis B vaccine1
        • Adverse Reactions:
          • Post-inj local reactions; CNS effects (fever, headache, malaise, dizziness, sleep disturbance); GI effect (abdominal pain); hypersensitivity reactions
        • Special Instructions:
          • The deltoid region as a site for inj is recommended for adults & the anterolateral thigh for infants
          • Inj in the gluteal region has been associated w/ diminished response
        • Dosage Guidelines:
          • Individualize dose based on manufacturer’s recommendations & local immunization guidelines
        d. Thymosin alpha-1 (Thymalfasin)
        • Adverse Reactions:
          • Discomfort at injection site, redness, polyarthralgia w/ hand edema & rash
        • Special Instructions:
          • Use w/ caution in pregnant & lactating women
          • Monitor liver functions regularly
          • Contraindicated in patients w/ hypersensitivity to thymosin alpha-1 & those immunosuppressed following transplantation
        • Dosage Guidelines:
          • Chronic Hepatitis B
            • 1.6 mg SC 2x/wk for 6 mth
          • Chronic Hepatitis C
            • 1.6 mg SC 2x/wk for 12 mth

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