Viral Hepatitis

Definition

• Natural history

  • Vertical transmission at birth

    • high HBV DNA for the first 20-30y of life with normal LFTs (immune tolerant phase)

  • HBV exposure

    • 95% of adults clear the virus

• Phases

  • Immune tolerant

    • high HBV DNA with normal LFTs

    • HBeAg positive due to active viral replication 

  • Immune clearance 

    • sharp spike in ALT and HBV DNA may decline

    • there can be seroconversion from HBeAg to HBeAb

  • Inactive carrier

    • occurs after seroconversion to HBeAb

    • low DNA levels and relatively normal LFTs

  • Pre-core mutant chronic hepatitis

    • also called HBeAg negative chronic hepatitis or HBeAg negative immune reactivation phase

    • ~20% of those who seroconvert from HBeAg to anti-HBe positive and up to 20% of those with inactive chronic HBV enter this phase

    • occurs in older patients when the virus is no longer able to produce HBeAg

    • may have more advanced liver disease 

• Treatment with IVIG is associated with passive exposure of HBV cAb from pooled plasma

  • cAb is expected to disappear from serum over time

  • no indication for antiviral therapy or vaccination

Screening

• Screen for HBV in chronic HCV prior to starting therapy

• Screen for HBV in all patients who receive immunosuppressant medications 

  • ex. rituximab (anti-CD20) and prednisone for treatment of lymphoma

    • high risk for HBV flare or reverse seroconversion 

    • due to combination of B and T cell suppression

    • HBV DNA remains dormant within hepatocytes 

    • should receive prophylaxis against reverse seroconversion before or concurrent with treatment start and for 12-18 mo afterwards due to long lasting effects on anti-B cell monoclonal antibodies (ex. rituximab)

    • reactivation of HCV in HCV ab pos, RNA neg patients has not been reported

  • treatment with anti TNF therapy (ex. infliximab) 

    • HBV recovered - carries a low risk (~1.7%) of reverse seroconversion

      • does not have bimodal B and T cell immunosuppression

    • Inactive carrier - increased risk of reactivation (~40%)

• Screen for HCC

  • HBV is unique as a risk factor for HCC in the absence of cirrhosis.  Screen for HCC in those with...

    • chronic HBV

    • long duration of infection

    • cirrhosis

    • family history of HCC

  • regardless of fibrosis status, pursue HCC surveillance in... 

    • black or Asian men >40 yo with chronic HBV

    • Asian women >50 yo with chronic HBV 

    • HBV/HDV co-infection

  • liver ultrasound every 6 mo with or without AFP

Treatment

• Current therapy is suppressive not curative

  • patients will need to remain on therapy for life

  • longer duration of therapy risks the development of resistance

  • rates of HBV sAg loss and HBV eAg seroconversion are low

  • using two drugs together will not lead to increased efficacy as all therapies act via the same mechanism inhibiting HBV DNA polymerase

• Indications for Treatment in Acute HBV infection

  • fulminant hepatitis (<1% of patients)

  • hepatic encephalopathy 

  • INR >1.6

  • protracted course (elevated bilirubin >10 mg/dL for >4 wk)

  • immunocompromised patients

  • coexisting HCV or other chronic liver disease

  • in general avoid interferons and treat with any of the oral antivirals

• Oral nucleoside/tide agents

  • tenofovir and entecavir preferred for high potency and minimal resistance

  • effective for viral suppression

  • but have low rate of HBeAg seroconversion

  • loss of HBsAg with  nucleoside/tide therapy alone is rare

  • telbivudine not preferred

    • 20% risk of resistance at 2 years

• Peginterferon alfa 2a

  • monotherapy for genotype A and B 

    • monotherapy given over 1 yr gives the best chance for HBeAg seroconversion and HBsAg loss in genotype A infection, high ALT, and low viral loads

    • poor response in genotype C and D

  • add to tenofovir therapy for 10.4% rate of HBsAg loss

    • given still low rate of seroconversion AASLD does not suggest combination therapy

  • avoid PEG-IFN in those with uncontrolled psychiatric disease, history of autoimmunity, cytopenias, cardiac disease, and decompensated cirrhosis  (avoid in cirrhosis in general given risk of decompensation)

• Immune tolerant phase (HBV DNA >20,000 IU/mL with normal LFTs)

  • monitor LFTs and HBV DNA every 6 mo

  • if ALT is abnormal or if HBV DNA is several logs higher, liver biopsy may be reasonable

• Chronic HBV

  • Treat immune active chronic HBV with ALT > 2x ULN and...

    • HBV DNA > 2000 IU/mL (eAg negative)

    • HBV DNA > 20,000 IU/mL (eAg positive)

  • Evidence for threshold of ALT > 2x ULN is weak

    • consider age >40 yo, degree of fibrosis, and family history of HCC if starting therapy with ALT < 2x ULN

• Chronic HBV with recent seroconversion eAg positive to eAb positive

  • those without cirrhosis should receive consolidation therapy for at least 12 mo prior to discontinuing antiviral therapy

• Inactive carrier 

  • no treatment required

• HBeAg negative chronic HBV (immune reactivation phase)

  • treat if ALT is >2x ULN and HBV DNA >2000 IU/mL

  • continue oral therapy indefinitely if treatment is well tolerated

  • loss of HBsAg is rare

  • consider treatment discontinuation if surface antigen clears, assuming close ongoing follow up

• HBV induced cirrhosis

  • Compensated cirrhosis with low level viremia (<2,000 IU/mL)

    • treat with antiviral therapy to reduce risk of decompensation regardless of ALT level

    • entecavir and tenofovir

      • optimal duration of therapy unknown

      • protects from flares of active hepatitis 

      • may have improvement in histology

    • avoid PEG-IFN in cirrhosis in general given risk of decompensation

  • signs of decompensated cirrhosis with detectable HBV DNA

    • requires therapy with an oral agent to prevent flare

    • transplant evaluation

    • use of interferon is contraindicated 

  • EGD to screen for varices

  • Ultrasound to screen for HCC

  • Screen relatives for HBV and vaccinate as appropriate

• HBV flare

  • check for HDV infection

• HBsAg negative, cAb positive treated with prednisone >20 mg daily or equivalent for 4 or more wks (or on chronic moderate dose  prednisone 10-20 mg daily)

  • moderate risk of reactivation (1-10%)

  • HBV prophylaxis (ex. tenofovir) during treatment and for at least 6 mo after stopping immunosuppression

  • May monitor instead if that is patient's preference, but not recommended

• HBsAg positive, cAb positive treated with prednisone >20 mg daily or equivalent for 4 or more wks (or on chronic moderate dose  prednisone 10-20 mg daily)

  • high risk of reactivation (>10%)

  • HBV prophylaxis (ex. tenofovir) during treatment and for at least 6 mo after stopping immunosuppression

• HBV in chronic HCV prior to starting therapy

  • HBV/HCV coinfected patients can develop reactivation or flare of chronic HBV during or after treatment with DAA therapy

  • If HBV DNA is >20,000 IU/mL, treat HBV concurrently with HCV DAA therapy through SVR12

  • If HBV DNA is low or undetectable, follow at regular intervals during HCV DAA therapy or treat with HBV prophylaxis

    • initiate HBV treatment if HBV DNA increases >10 fold or >1000 IU/mL from an undetectable level at baseline

  • If HBV sAg negative and cAb positive, insufficient evidence to recommend HBV treatment

• Decompensated liver disease, liver failure

  • Refer to a liver transplant center

  • Supportive care

  • Emerging data for the use of N-acetyl cysteine 

  • HBV antiviral therapy at the point of acute liver failure is not associated with a mortality benefit 

  • Interferon is contraindicated

• HBV infection in pregnancy

  • Measure HBV DNA prior to the third trimester

    • establish if the mother is an inactive carrier and does not meet criteria for treatment

    • high viral loads increase risk of vertical transmission

    • mothers with viral load 200,000 IU/mL at week 28 should be treated with oral nucleoside/tide drug (at 28-32 wk) to reduce viral load and risk of transmission

      • Tenofovir compounds - pregnancy class B, rapidly reduces viral load

      • Telbivudine - pregnancy class B

      • Entecavir - pregnancy class C, also with rapid viral kinetics

    • Interferon not recommended in pregnant women

  • hepatitis B immune globulin and vaccination for the infant to reduce risk of vertical transmission

  • no role for prophylactic antiviral therapy for infants

• HBV with HIV coinfection

  • tenofovir/emtricitabine

Vaccination

• High dose vaccine for patients with...

  • HIV

  • hemodialysis

Signs and Symptoms

• porphyria cutanea tarda

• mixed cryoglobulinemia 

  • purpura

  • arthralgias

  • weakness

  • active sediment in urine analysis

  • renal insufficiency

  • positive serum cryoglobulins

  • low complement level

  • can be cured with eradication of HCV

  • in some it is persistent even after eradication due to development of monoclonal B cell populations

  • treat with IV rituximab only in severe cases with end-organ damage (ex. acute renal failure requiring HD)

• B-cell non-Hodgkin lymphoma

  • treatment of HCV leades to decreased risk of lymphoma

• CKD

  • HCV is independently associated with 51% increased risk of proteinuria,  43% increased incidence of CKD

Risk Factors

• IV drug use, needle sharing

• Increased risk of disease progression

  • HIV co-infection

  • older age

  • fibrosis

  • prior transplantation

  • EtOH

  • obesity, insulin resistance

Lab Findings

• HCV Ab - may take 6 weeks to develop

• HCV RIBA - used to confirm a positive HCV Ab if there is concern for a false positive or prior exposure with spontaneous viral clearance

  • no longer recommended by the CDC due to a shortage of reagents and not available in many labs

• HCV RNA - acute HCV infection

  • check if exposure was < 6 mo ago

  • Versus: acute EBV - lower AST/ALT elevation and preceding viral prodrome with fever and sore throat

• fibrosing cholestatic HCV

  • high viral load

  • high bilirubin

  • following liver transplant

  • biopsy before treating for acute cellular rejection, will improve with DAA

Pathology Findings

• Liver biopsy 

  • chronic HCV hepatitis

    • lymphocytic infiltrate with piecemeal necrosis of hepatocytes

  • fibrosing cholestatic HCV

Treatment

• Immune mediated anti-HCV drugs

  • Interferon alpha

    • pegylated interferon prolongs half life, reduces clearance, extends therapeautic action

    • Side Effects

      • flu-like symptoms

      • neuropsychiatric disordered - depression, mood lability, irritability, anxiety

      • alopecia, thyroiditis, diarrhea, injection site reaction, nausea

      • neutropenia, anemia, thrombocytopenia

  • Ribavirin - synthetic nucleoside analogue

    • ineffective in eliminating HCV or improving hepatic histology alone

    • enchances viral clearance when combined with IFN or DAAs

    • Side effects

      • hemolytic anemia (dose-related)

      • lactic acidosis (watch for HIV patients treated with didanosine)

      • teratogen - pregnancy category X

        • 2 forms of birth control during therapy and for 6 months after

      • alopecia, pruritus, rash, fatigue, headache, nausea, vomiting

      • depression, mood swings

      • dose reduce in renal insufficiency

• Direct acting anti-HCV drugs (DAAs)

  • NS5B inhibitor

    • sofosbuvir

      • primary metabolite (GS-331007) is primarily eliminated via the kidney

      • Sofosbuvir regimens NOT approved for CKD 4-5 or those on HD even when dose reduced or given post-dialysis

      • Sofosbuvir has an interaction with amiodarone - absolute contraindication

        • may result in significant bradycardia

  • NS5A inhibitor

    • velpatasvir

    • ledipasvir

      • pharmacokinetics not significantly affected by renal impairment

    • pibrentasvir - pangenotypic

  • NS3/NS4A - pangenotypic protease inhibitor

    • glecaprevir

      • NOT approved for decompensated cirrhosis as this is a protease inhibitor

      • poorly tolerated in advanced cirrhosis due to risk of decompensation

• Sofosbuvir/velpatasvir 

  • ASTRAL-1 trial - cure rate of 99% in treatment experienced genotype 1 patients with compensated cirrhosis

    • 12 weeks of therapy in in cirrhosis

    • 8 wks of therapy in those without cirrhosis

  • ASTRAL-3 trial - cure rate 93% compared to 73% in sofosbuvir/ribavirin

  • Decompensated cirrhosis

    • 12 wks

    • ASTRAL-4 trial - genotype 1, 2, 3, 4, 6

  • solubility of NS5A inhibitors (velpatasvir and ledipasvir) decreases as pH increases 

    • PPI therapy decreases concentration and can impact efficacy of therapy

    • avoid antacids within 4 hr of administration  

    • take H2 blockers simultaneously or 12 hr apart

• Sofosbuvir/ledipasvir 

  • only approved for genotypes 1 and 4

  • must be dosed for 24 wk

  • Decompensated cirrhosis

    • Sofosbuvir/ledipasvir for 24 weeks

    • Sofosbuvir (400 mg)/ledipasvir (90 mg) and ribavirin (600 mg, increased as tolerated) for 12 wks 

    • for genotypes 1 and 4

    • SOLAR-1, SOLAR-2 - SVR rates 87% and 86% in CTP class B and C cirrhosis, respectively

  • solubility of NS5A inhibitors (velpatasvir and ledipasvir) decreases as pH increases 

    • PPI therapy decreases concentration and can impact efficacy of therapy 

    • avoid antacids within 4 hr of administration  

    • take H2 blockers simultaneously or 12 hr apart

    • Sofosbuvir/ledipasvir can be taken fasted with PPI equivalent to omeprazole 20 mg or lower

• Glecaprevir/pibrentasvir

  • the only regimen approved for shorter duration of therapy in treatment experienced patients

  • Pangenotypic

  • CKD stage 4  or 5 (eGFR <30 mL/min or ESRD) including HD

    • EXPEDITION-4 trial 

    • treat with 8 wk course (same duration of therapy in those without CKD)

  • daily fixed-dose

  • preferred if patient is concurrently being treated with amiodarone

  • concurrent treatment with HMG-CoA reductase inhibitors (ex. atorvastatin) is NOT recommended

    • risk of rhabdomyloysis from increased statin concentrations

  • protease containing regimen - NOT recommended in decompensated cirrhosis

• Grazoprevir/elbasvir

  • Genotype 1a, 1b

    • NS5A Resistance associated variant (RAV) testing for genotype 1a but not 1b

  • Genotype 4

  • compensated cirrhosis

    • C-EDGE trial - SVR12 rate 97% in genotype 1b and state 4 fibrosis

  • protease containing regimen - NOT recommended in decompensated cirrhosis

  • CKD/ESRD

    • hepaticaly metabolized with minimal renal elimination

    • C-Surfer trial - evaluated in genotype 1 with advanced renal disease including those on HD, cure rates 94-99%

  • Concurrent PPI use - does not have PPI interaction 

• Sofosbuvir/Daclatasvir

  • second line for genotype 3 with cirrhosis

• Relapse following Sofosbuvir/ledipasvir treatment

  • rare, can be due to...

    • poor adherence

    • viral resistance to NS5A/NS5B treatment combination

    • NS5A Resistance associated variant (RAV)

      • virus reverts to wild type after prior DAA therapy is discontinued

      • re-challenge with another NS5A containing regiment with addition of an NS3B/4A protease inhibitor

        • Sofosbuvir/velpatasvir/voxilaprevir for 12 wks approved for genotypes 1-6 with prior treatment failure

        • POLARIS-1 trial - SVR12 in genotype 1 was 97% 

        • can also use in compensated cirrhosis

        • cirrhosis was not predictive of treatment failure

        • baseline NS5A RAV testing prior to initiating therapy is not required

    • extended therapy with sofosbuvir/ledipasvir or addition of ribavirin does NOT increase cure rates after relapse

• DAA side effects

  • HBV reactivation - uncommon but can lead to liver failure or death

  • regimens with protease inhibitors can precipitate liver failure, avoid in those with Child class B or C cirrhosis

  • typically mild - headache, fatigue, nausea, insomnia

  • elevated bilirubin (>1.5x ULN) in <1-3%

  • asymptomatic lipase elevation (>3x ULN) in <1-3%

• Factors predictive of poor response to DAAs

  • HCV Genotype 3 (compared to 1, 2, 4, 5, 6) or 1a (compared to 1b)

    • in genotype 3 test for resistance (Y93H substitution) which would require treatment with...

      • sofosbuvir/velpatasvir/voxilaprevir

      • sofosbuvir/ledipasvir/ribavirin

  • high viral load

  • Cirrhosis

  • decompensated cirrhosis

  • previously treated 

• Drug interactions

  • CYP450 inducers

    • lower levels of DAA

  • CYP450 inhibitors

    • increased levels of DAA

• HBV co-infection (positive sAg with active replication)

  • treat for HBV during HCV therapy and for at least 12 wks after completion of HCV therapy with close monitoring

• Sustained virologic response (SVR)

  • negative viral load 12 weeks after therapy completion

  • no longer requires follow up

  • can be re-infected so should avoid risk factors

  • perform annual HCV PCR for those with persistent high risk behaviors

• Post transplant considerations

  • watch for medication interactions with cyclosporine (CYP3A inhibitor)

  • liver transplant from HCV viremic donor

    • start DAA within the first month if able

  • non-liver organ transplant from HCV viremic donor

    • start DAA immediately after transplant

    • do not wait for laboratory confirmation

Prevention

• Immunosuppression in chronic HCV may cause HCV RNA to increase, but fulminant flares do not occur

Vaccination

• no available vaccine

Pregnancy

• to avoid vertical transmission...

  • avoid fetal scalp monitoring during gestation and delivery

  • avoid C section

Pediatrics

• Ledipasvir/sofosbuvir

  • approved for treatment in patients ≥3 yo

• Sofosbuvir/velpatasvir

  • approved for treatment in patients ≥6 yo

• Glecaprevir/pibrentasvir

  • approved for treatment in patients ≥12 yo

Screening

• Screening for HCV infection

  • all patients >18 yo

• HCC screening in those with cirrhosis

  • annual incidence of HCC in those with HCV and cirrhosis is 1-5%

    • risk is significantly reduced in those achieving SVR, but the risk does persist after eradication in those with cirrhosis

  • VCTE cutoff of 12.4 kPa to detect cirrhosis in chronic HCV

    • screen for HCC even in the absence of clinical symptoms of cirrhosis

  • liver ultrasound every 6 mo with or without AFP

    • addition of AFP may increase the sensitivity of screening when combined with ultrasound 

    • AFP alone not recommended due to lack of sensitivity and specificity