Viral Hepatitis Lecture

to Viral Hepatitis PHAR 839 | Infectious Diseases II Marc Salvatus, PharmD, BCPS West Coast University, School of Pharmacy October 18, 2024 Hepatitis Overview • Swelling and inflammation of the liver • Etiologies: viral, bacterial, autoimmune, alcohol, medication-induced WE Hepatitis A Virus (HAV) Hepatitis B Virus (HBV) Hepatitis C Virus (HCV) Nucleic Acid RNA DNA RNA Enveloped? No Yes Yes Acute Chronic Chronic Fecal-oral Blood, bodily fluid Blood, bodily fluid Yes Yes Clinical Trials No (supportive) Yes Yes Acute vs Chronic Transmission Vaccine? Drug Therapy? 5 effectlived mm Hepatitis B American Association for the Study of Liver Diseases (AASLD) 2018 6 Epidemiology I 86 • Substantial global disease burden • 2015: 3.5% of the population (257 million people) had chronic HBV • Significant risk of death resulting from liver disease • CDC 2021: 650,000 people per year die as a result of complications from HBV • Affects low- and middle-income countries including sub-Saharan Africa, East Asia, Amazon, southern parts of Eastern and Central Europe • Chronic infection with HBV serves as a reservoir for continued HBV transmission • Most new HBV infections are in children in areas of high HBV prevalence (~45% of global population) 7 Epidemiology • In the US: • Highest rates of acute HBV are among White or Black non-Hispanic men between 30 to 49 years • Common risk factors include injection drug use and sexual contact • Transmitted sexually, parenterally, and perinatally (from mother to child at birth) • May be transmitted through reuse of contaminated needles, syringes, or sharp objects 8 MBS AG mo HBUSILKantigen Hepatitis Overview niet genotypedos Ir matter weDon'ttestforit Hepatitis A Virus (HAV) Hepatitis B Virus (HBV) Nucleic Acid RNA DNA Enveloped? No Yes Acute Chronic Fecal-oral Blood, bodily fluid Yesfor HBV Testing genotypes not Chronic recommended for clinical practice Blood, bodily fluid Yes Yes Clinical Trials No (supportive) Yes Yes Acute vs Chronic Transmission Vaccine? Drug Therapy? •Hepatitis At least C 10Virus HBV (HCV) genotypes (A-J) with distinct geographic and RNA ethnic distribution II • 10 miBiodtest HBsAg a to Active Serologic Testing • aim •I Hepatitis B Virus infection HBsAg is the most abundant of the 3 antigens I Detectable HBsAg = active infection • Detection past 6 months = chronic infection • Increased risk of cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC) • Goal of therapy: negative/non-reactive HBsAg • Presence of antibodies to HBsAg (anti-HBs) indicates recovery and immunity from HBV infection soliverconcer 13 Serologic Testing • HBeAg is a marker of HBV replication and infectivity • Present in acute infection • Associated with high levels of HBV DNA in serum and higher rates of transmission • Seroconversion from HBeAg to anti-HBe is usually associated with a decrease in serum HBV DNA and remission of liver disease give Hepatitis B Virus 14 IggondlgM Serologic Testing d long wooAntibodiesthathelpthebody fightinfections Binitialstage termigmenity Gia • HBcAg is not readily detectable by current laboratory techniques; therefore, antibodies to HBcAg (antiHBc) are used for diagnostic purposes • Total anti-HBc measures both IgM and IgG  indicates previous or ongoing HBV infection • Positive IgM anti-HBc indicates recent (<6 months) infection with HBV Hepatitis B Virus 15 Egoti m Serologic Testing • Interpretation of Hepatitis B Serologic Test Results | CDC 18M186 Interpretation HBsAg Anti-HBs Total anti-HBc IgM anti-HBc Acute Infection + - + + Chronic Infection + - + -* Resolved Infection - + + N/A Immune from vaccination - + - N/A *IgM anti-HBc may be positive in persons with chronic infection during severe HBV infection flares or reactivation Getimmunefrominfection 16 youcon'tfairy 3 D it eradicate Bevins Acute vs Chronic HBV Infection LI AE liverdamage DedineinAE a Emonth 17 Clinical Presentation Hepatitis A (HAV) Signs and symptoms • Common: Fever, jaundice, scleral icterus, hepatomegaly • Less common: splenomegaly, skin rash, arthralgia • Children <6 y/o typically asymptomatic jiger Hepatitis B (HBV) • >70% of patients are asymptomatic • Jaundice, dark urine, white stool, abdominal pain, fatigue, fever, chills, loss of appetite, pruritis Laboratory Findings in Acute Phase of Infection go Hepatitis C (HCV) • >70% of patients are asymptomatic • Jaundice, dark urine, white stool, abdominal pain, fatigue, fever, chills, loss of appetite, pruritis Aminotransferase (ALT, AST) Elevations • >1,000 IU/L • ALT > AST • 1,000-2,000 IU/L • ALT > AST • Highly variable, can be ~1,000 IU/L • ALT > AST Bilirubin Elevated and preceded by aminotransferase elevations Normal or elevated Elevated and preceded by aminotransferase elevations Virus Specific Tests • IgM anti-HAV for acute HAV • IgG anti-HAV for prior infection or vaccination IgM anti-HBc (+), HBsAg (+) HCV RNA (+); HCV antibody reactive within 12 weeks of exposure 18 Clinical Presentation a Hepatitis Chronic Acute Hepatitis • • Incubation period lasting 1-4 months Profuse HBV DNA replication with high levels of HBV DNA and HBeAg secretion Symptoms: anorexia, nausea, jaundice, right upper quadrant discomfort, fatigue Immune system response to HBV-infected hepatocytes may lead to liver injury and fibrosis Rate of progression to chronic infection depends on age (more common for perinatally acquired infections) big • • • • • • Detection of HBsAg 6 months after initial detection Typically asymptomatic unless decompensated cirrhosis is present (e.g. jaundice, splenomegaly, ascites, peripheral i edema, encephalopathy) fhidbuildudupinabderen laBraindusfunction Progressive, generally consists of 4 phases (see next slide) Before Birth 19 Complications of HBV Infection p Cirrhosis • Liver attempts to regenerate with ongoing inflammation • On imaging, presents as nodules of regenerating cells integrated with fibrous tissue IE • Risk of developing HCC; patients require routine surveillance 2 Hepatocellular Carcinoma (HCC)Melivercancer • Primary tumor of the liver that develops from chronic liver disease • Fourth leading cause of cancer-related deaths in the world 21 HBV Reactivation • Recurrence or abrupt rise in HBV replication (increase in serum HBV DNA of at least 1 log10 and increase in transaminases) • Loss of HBV immune control • May occur in anyone with a current or prior HBV infection • High risk of reactivation in patients being treated with cancer chemotherapy, steroids, and other immunosuppressive agents • Antiviral prophylactic therapy may be used to prevent reactivation 23 CDC Vaccination Recommendations • Adult Immunization Schedule – Healthcare Providers | CDC • All individuals age 59 years and younger should receive HBV vaccine • Adults 60 years of age and older are recommended for vaccination based on risk factors 24 CDC Vaccination Recommendations 68andolder we Risk factors for HBV virus infection • 1 Chronic liver disease • HIV infection • Sexual exposure risk • Current or recent injection drug use s • Percutaneous or mucosal ga risk for exposure to blood 98 • E.g. health care and public safety personnel with anticipated risk for exposure to blood or blood-contaminated body fluids; persons on dialysis; patients with diabetes • 6 Incarceration • jail logup 7 Travel in countries with high or intermediate endemic hepatitis B 25 Edi Hepatitis B Vaccinations Name Age (Years) Dose (mL) 0-19 0.5 >20 1 1-19 0.5 >20 1 Heplisav-B* >18 PreHevbrio* Engerix-B Recombivax Iit S Twinrix (HAV + HBV) No. of Doses Schedule 3 0, 1, 6 months 3 0, 1, 6 months 0.5 2 0, 1 months >18 1 3 0, 1, 6 months >18 1 3 0, 1, 6 months *Cannot be interchanged with other HBV vaccines 26 x ptwillneedlifetimetreatment Approach to Treatment • supp Goals of therapy: • Suppress HBV replication (e.g. undetectable HBV DNA, loss of HBsAg/HbeAg) • Normalization of LFTs • 3 Prevent disease progression to cirrhosis and HCC • u Prevent HBV reactivation in patients with inactive HBV infections ask.gg • Complete HBV virus eradication is not achievable due to persistence of closed, circular DNA in hepatocytes and lifelong risk for HBV reactivation; risk of transmission persists despite pharmacotherapy b x my • Not all persons with chronic HBV are candidates for treatment (see next slide) • Treatment guidelines: World Health Organization (WHO) 2015, American Association for the Study of Liver Diseases (AASLD) 2018, European Association for the Study of the Liver (EASL) 2017 27 ALTNOV MOINorge 7 56 V14 Approach to Treatment Generally Accepted Criteria for Treatment of HBV have must Anyone with HBeAg (+) or HBeAg (-) active HBV defined as: • HBV DNA >2,000 IU/mL • ALT 2 times upper limit of normal (ULN) and/or with evidence of moderate or greater fibrosis 050 with compensated or decompensated cirrhosis 3 Anyone Both la Anyone not fulfilling above criteria with ALT <2 times ULN and any detectable HBV DNA (<2,000 IU/mL), consider: • Patient’s age • Family history of HCC • Prior history of HBV treatment • Extrahepatic manifestations of HBV 28 Approach to Treatment Nonpharmacologic recommendations: • Counsel patients on prevention of disease transmission • Vaccinate sexual and household contacts against HBV • Barrier protection methods for sex partners who have not completed vaccination series • Lifestyle modifications: avoid alcohol use and smoking (potentiates liver disease) • Herbal medicines (e.g. milk thistle): Limited data demonstrating efficacy 29 Treatment Options a Drug Class Mechanism of Action Generic Drug Names Interferons (IFNs) Naturally-produced cytokines with antiviral, antiproliferative, and immunomodulatory effects IFN-alfa-2b Pegylated IFN-alfa-2a Nucleoside/Nucleotide Reverse 2 (NRTIs) Transcriptase Inhibitors Inhibits HBV DNA polymerase resulting in DNA chain termination Entecavir* Tenofovir alafenamide (TAF)* Tenofovir disoproxil fumarate (TDF)* Adefovir Lamivudine *First-line therapy; high barrier to resistance 30 Interferon Alfa • Boxed Warnings: may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders Generic (Brand) Indication Dosing Comments IFN-alfa-2b (Intron A) HBV, HCV, cancer IM or SubQ for 16 weeks: 5 million units daily, or 10 million units TIW Discontinued by manufacturer; limited availability in the US Pegylated IFN-alfa-2a (Pegasys) HBV, HCV 180 mcg SubQ once weekly for 48 weeks Addition of polyethylene glycol (PEG) prolongs half-life togoodforpt wAdherenceissue 31 Interferon Alfa • Efficacy: over 48 weeks, HBeAg seroconversion rates of 29-36%; HBV DNA suppression (<2000-40,000 IU/mL) of 30-42% • Contraindications: decompensated liver disease (cirrhosis), autoimmune hepatitis, infants/neonates • Additional warnings: Neuropsychiatric, cardiovascular events, endocrine disorders (hypo/hyperthyroidism, hypo/hyperglycemia), visual disorders • Side effects: CNS effects (e.g. fatigue, depression), GI upset, increased LFTs, myelosuppression, flu-like syndrome (fever, chills, headache; pretreat with acetaminophen and antihistamine) • Monitoring: CBC, LFTs, thyroid function tests completeBlood oath 32 metforminconcauselacticaadess Firstline therapy ptneedstobeadherenoetotheirmedication Nucleoside/Nucleotide Analogues 0Wh of HBV upon discontinuation, HIV resistance (test Warnings for all NRTIs: exacerbation all patients for HIV prior to starting HBV therapy), lactic acidosis and severe enlarged ashepatomegaly with steatosis breathing NYimusdepain • Light • cfatrggypins.pt abrapid May be used for a minimum of 48 weeks; indefinitely for advanced liver disease/HCC Generic (Brand) IEntecavir (Baraclude) Dosing • • • am or non-lamivudineTreatment-naïve resistant infections: 0.5 mg PO daily Lamivudine-experienced or decompensated cirrhosis: 1 mg PO daily Adjust dose in renal impairment (CrCl <50 mL/min) Comments • • • • Guanosine analogue Not recommended in patients with prior lamivudine experience Take on empty stomach AEs: ↑ ALT, ↑ SCr, fatigue, headache, N/V/D 33 Eton RE D Nucleoside/Nucleotide Analogues • M Warnings specific to TDF/TAF: Renal toxicity, Fanconi syndrome (impairment in proximal tubular function), osteomalacia, decreased bone mineral density Generic (Brand) d systemic ng 2Tenofovir disoproxil fumarate (TDF) (Viread) 3 Tenofovir alafenamide (TAF) (Vemlidy) softening ofboys Dosing Comments 300 mg PO daily; renal dose adjustment for CrCl <50 mL/min • • Dispense in original container AEs: N/V/D, abdominal pain, headache, dizziness, depression 25 mg PO daily • Not recommended in CrCl <15 mL/min • Prodrug (converted to active tenofovir); more efficient delivery of tenofovir to hepatocytes Associated with less renal and bone toxicity compared to TDF (less systemic exposure) Take with food Dispense in original container AEs: headache, abdominal pain, fatigue, increased LDL Is • • • 34 Alternative Nucleoside/Nucleotide Analogues • Low barrier to resistance; not preferred for treatment of HBV Generic (Brand) Dosing Comments Adefovir (Hepsera) 10 mg PO daily • • Adenosine nucleotide analogue Avoid concurrent use with tenofovir Lamivudine (Epivir HBV) 100 mg PO daily • • Cytosine analogue Do not use Epivir HBV for treatment of HIV (contains lower dose of lamivudine which may lead to HIV resistance) 35 Monitoring Detectliverdamage • ALT levels, monthly* we • HBV DNA levels, every 3 months* • HBeAg after HBV DNA level is undetectable • HBsAg after HBeAg is lost or seroconverted • Abdominal ultrasound to rule out HCC, every 6 months ow III p *May reduce frequency of monitoring when levels have normalized 36 Hepatitis C AASLD/IDSA 2023 37 Hepatitis Overview Hepatitis A Virus (HAV) Hepatitis B Virus (HBV) Hepatitis C Virus (HCV) Nucleic Acid RNA DNA RNA Enveloped? No Yes Yes Acute Chronic Chronic Fecal-oral Blood, bodily fluid Blood, bodily fluid Yes Yes Clinical Trials No (supportive) Yes Yes Acute vs Chronic Transmission Vaccine? Drug Therapy? 38 Epidemiology and Screening • Most common blood-borne pathogen • Since 2014: acute HCV cases increased by 71%, most were among people aged 20-39 • Injection drug use is a major factor for transmission and increase in new infections • Other routes of transmission: needlestick injuries, sexual transmission, infants born from HCV-infected women • Universal screening recommended for all persons 18 years and older, especially for: • All pregnant females • PWID • Sexually active MSM with HIV • MSM at initiation of HIV pre-exposure prophylaxis 39 Screening a 40 Etiology and Pathophysiology • Single-stranded RNA virus that undergoes frequent viral mutations  challenge for vaccine development • Virus replicates within hepatocytes (similarly to HBV) • Differentiated into six major genotypes further classified into subtypes • Most common in the US: GT1a and GT1b, followed by GT2 and GT3 as • Preferred therapies are pan-genotypic (active against all genotypes) • Up to 85% of acute HCV infections lead to chronic infections • Chronic HCV infection may lead to cirrhosis, end-stage liver disease (ESLD), or HCC • Resolved cases are defined by highly active T-cell, CD8, and CD4 cell response 41 S firstthen Clinical Presentation Hepatitis A (HAV) Signs and symptoms Hepatitis B (HBV) • Common: Fever, jaundice, scleral icterus, hepatomegaly • Less common: splenomegaly, skin rash, arthralgia • Children <6 y/o typically asymptomatic patients are • >70% HCVofRNA detectable asymptomatic within 1-2 weeks of • Jaundice, dark urine, white exposure stool, abdominal pain, fatigue, fever, chills, loss of • appetite, Chronicpruritis HCV is associated with extrahepatic • 1,000-2,000 IU/L (e.g. manifestations • ALT > AST vasculitis, cardiovascular Normal or elevated disease, diabetes, etc.) Hepatitis C (HCV) • >70% of patients are asymptomatic • Jaundice, dark urine, white stool, abdominal pain, fatigue, fever, chills, loss of appetite, pruritis Laboratory Findings in Acute Phase of Infection Ethel Aminotransferase (ALT, AST) Elevations • >1,000 IU/L • ALT > AST Bilirubin Elevated and preceded by aminotransferase elevations Virus Specific Tests • IgM anti-HAV for acute HAV • IgG anti-HAV for prior infection or vaccination IgM anti-HBc (+), HBsAg (+) • Highly variable, can be ~1,000 IU/L • ALT > AST Elevated and preceded by aminotransferase elevations HCV RNA (+); HCV antibody reactive within 12 weeks of exposure 44 Approach to Treatment • Goal: Virologic cure/sustained virologic response (SVR) defined as a nondetectable HCV RNA at least 12 weeks after completing HCV therapy • Treatment recommended for all persons with HCV • • Early treatment can prevent complications of liver disease and reduce rates of HCV transmission Preferred pharmacologic regimen: 2-3 direct acting antivirals (DAAs) with different mechanisms of action • Regimen may include ritonavir which increases levels of DAAs 45 Exod class Drug 3 a Drug dog 2 class pray Pharmacologic Therapy: Direct Acting Antivirals 46 Pharmacologic Therapy: Direct Acting Antivirals Drug Class Mechanism of Action Name Clue Examples NS3/4A Protease Inhibitors Inhibits HCV NS3/4A serine protease (enzyme involved in viral maturation) -previr (P for Protease inhibitor) Glecaprevir Grazoprevir Paritaprevir Voxilaprevir NS5B Nucleotide Polymerase Inhibitor Competitively inhibits nonstructural protein 5B (NS5B), an RNA-dependent RNA polymerase required for viral replication -buvir (B for NS5B) Sofosbuvir NS5B Non-Nucleotide Polymerase Inhibitor Binds to NS5B RNA-dependent RNA polymerase at sites other than the active site  act as noncompetitive inhibitors NS5A Replication Complex Inhibitors Binds to the N-terminus of NS5A and inhibits both viral RNA replication and virion assembly Dasabuvir -asvir (A for NS5A) Ledipasvir Ombitasvir Pibrentasvir Velpatasvir Pharmacologic Therapy: Direct Acting Antivirals Simplified Treatment (includes patients with HIV/HCV coinfection) 86001g I • Indicated for treatment-naïve patients without cirrhosis OR who have compensated cirrhosis (Child-TurcottePugh [CTP] score <6) • Agents used in these regimens are pan-genotypic (approved for all 6 HCV genotypes) • 2 • No need to test for specific genotype During treatment: No laboratory monitoring necessary •3 If compensated cirrhosis present: laboratory monitoring necessary every 4 weeks (e.g. AST/ALT) during treatment • a Repeat HCV RNA and LFTs 12 weeks after completing HCV therapy to assess for cure (SVR) and resolution of hepatic inflammation If decompensated cirrhosis is present: • • Not a candidate for simplified treatment HCV treatment is managed by clinicians with experience with ESLD due to potential for cirrhosis-related complications (e.g. ascites, encephalopathy) 48 is BetterHigh lowerscorescoreisthe Me worst Child-Pugh Classification of Liver Disease Severity Score Class Interpretation One- and Two-Year Survival 5-6 A Well-compensated 100%; 85% 7-9 B Significant functional compromise 80%; 60% 10-15 C Decompensated 45%; 35% 49 canuse Recommended Agents for Initial HCV Treatment Generic (Brand) y Glecaprevir/pibrentasvir (Mavyret) Sofosbuvir/velpatasvir (Epclusa) Dosing Three tablets (glecaprevir 100 mg/pibrentasvir 40 mg per tablet) PO daily with food for 8 weeks One tablet (sofosbuvir 400 mg/velpatasvir 100 mg) PO daily for 12 weeks Comments • • • • • • Boxed warning: HBV reactivation AEs: headache, fatigue, nausea, diarrhea Contraindicated with strong CYP3A4 inducers Separate from antacids (4h) and H2RAs (12h or simultaneously); avoid PPIs with Epclusa Sofosbuvir: avoid with amiodarone (bradycardia risk) Glecaprevir: avoid with atorvastatin, lovastatin, simvastatin (rhabdomyolysis) 50 Recommended Agents for Initial HCV Treatment Generic (Brand) Therapeutic Use Comments Ledipasvir/sofosbuvir (Harvoni) • • Approved for GTs 1, 4, 5, 6 Fixed-dose combination tablet once daily for 8 or 12 weeks • • AEs (>10%): Headache, fatigue Avoid concurrent use with amiodarone (symptomatic bradycardia with sofosbuvir) Elbasvir/grazoprevir (Zepatier) • Approved for GTs 1a (resistance testing required), 1b and 4 Fixed-dose combination tablet once daily for 12 weeks • • AEs (>10%): Headache, fatigue C/I in patients with decompensated cirrhosis (Child-Pugh class B or C) • 51 Alternative Agents for HCV Treatment Generic (Brand) Sofosbuvir/velpatasvir/ voxilaprevir (Vosevi) Therapeutic Use • • • Approved for all GTs Reserved for prior DAA failure Fixed-dose combination tablet once daily for 12 weeks Comments • • • Ribavirin • • • Synthetic guanosine analog Only used in combination with DAAs (e.g. sofosbuvir with velpatasvir) Ineffective as monotherapy • • • AEs (>10%): Headache, fatigue, diarrhea, nausea, increased bilirubin Sofosbuvir - avoid concurrent use with amiodarone inducer enzyme C/I with rifampin Major AE: hemolytic anemia (monitor CBC) Contraindicated in pregnancy; teratogenic Use two forms of contraception during HCV treatment and for 6 months after 52 Choice of DAA Regimen in Select Conditions Condition Decompensated cirrhosis (Child-Pugh class B or C) Preferred DAA Regimens • • • Comments Genotypes 1-6: Sofosbuvir/velpatasvir + ribavirin daily for 12 weeks Genotypes 1, 4, 5, or 6 only: Ledipasvir/sofosbuvir + ribavirin daily for 12 weeks If patient is ineligible for ribavirin, extend duration to 24 weeks • Avoid protease inhibitors and interferon (risk of further decompensation) • Refer to medical practitioner with expertise in managing decompensated cirrhosis Sofosbuvir/velpatasvir/voxilaprevir daily for 12 weeks If previously treated with glecaprevir/pibrentasvir: Sofosbuvir/velpatasvir/voxilaprevir + ribavirin daily for 12 weeks • Additional treatment regimens listed in guidelines Failed any course of DAA therapy • • HIV coinfection Once-daily regimens (durations vary): • Elbasvir/grazoprevir • Glecaprevir/pibrentasvir • Sofosbuvir/velpatasvir • Sofosbuvir/velpatasvir/voxilaprevir • Potential DDIs between DAAs and HIV antiretrovirals – use drug interaction checker Liverpool HEP Interactions (hepdruginteractions.org) 53 HCV Vaccine Clinical Trials 54