Review the latest recommendations with

Ellie Carmody, MD, MPH

Dr. Carmody, an Infectious Diseases specialist, is an Assistant Professor at NYU Langone Health and Medical Director for the Outpatient Infectious Diseases and Viral Hepatitis Clinic at Bellevue Hospital in New York City

Learning Objectives:

• Identify the basic structural biology of hepatitis C and its relation to current DAA targets
• Describe the natural history of hepatitis C infection
• Identify current screening recommendations
• Describe current management of hepatitis C

CONTENTS:

• Overview of Hepatitis C
• Biology
• Natural History
• Screening and Diagnosis
• CDC HepC Test Interpretation Table
• Pre-Treatment Evaluation of HCV Infection
• Treatment Principles
• Monitoring
• Additional Management and Counseling Tips
• The Wrap-Up

THE CASE:

A 26-year-old woman presents to you for routine care after obtaining insurance with a new job

• History of injection drug use with heroin, first use age 23, most recent use 1 month ago
• Two ED visits for methicillin-resistant Staphylococcus aureus (MRSA) soft tissue abscess over past 3 years
• Lives in the basement of her mother’s home | Has boyfriend who sometimes uses heroin with her | They use different needles

SYNOPSIS:

Overview of Hepatitis C

Hepatitis C virus (HCV) is transmitted mainly through parenteral exposures to infectious blood or body fluids that contain blood. It results in chronic liver infection in more than half of people exposed, and over time, can lead to cirrhosis, end stage liver disease, and hepatocellular carcinoma (HCC). The epidemiology of HCV has shifted dramatically over the past decade, with a new wave of infections occurring in young people who inject drugs (PWID). Directly acting antivirals (DAA) have revolutionized treatment for HCV, and treatment has become easier, safer, and accessible to nearly all patients. Though patients with HCV who have had treatment failure, HIV or HBV co-infection or those with decompensated cirrhosis may need specialist care, the vast majority can be treated with 8 to 12 weeks of an antiviral with minimal monitoring by their primary care provider.

Biology

• Positive single stranded RNA hepacivirus in Flaviviridae family (West Nile, Dengue, yellow fever)
• Proteins that form virus particle
  • Structural proteins: Core | E1 | E2
  • Remaining nonstructural proteins: Roles in viral replication | Antivirals target nonstructural proteins to disrupt viral replication and assembly
• HCV has an affinity for hepatocytes, and has also been found in Kupffer, endothelial, gut and brain epithelial cells, and peripheral leukocytes
• Viral entry: E2 interacts with scavenger receptor class B type I and CD81
• Six genotypes in global circulation that vary between regions
  • Relevant in determining optimal DAA drug regimen in those with prior treatment failure

Natural History

Acute Infection

• Usually asymptomatic or mildly symptomatic
• Unlikely to prompt visit to medical care
• Symptom onset: On average 2 to 12 weeks after exposure
• Typical symptoms can include the following
  • Fever | Fatigue | Abdominal pain | Loss of appetite | Nausea | Vomiting | Joint pain | Jaundice | Dark urine | Clay-colored stool
• Nearly half of people who have HCV antibodies (anti-HCV) may have spontaneous clearance after acute infection (Seo et al. Clin Gastroenterol Hepatol, 2020)

Chronic Infection

• Slightly more than half of people with HCV antibodies go on to develop chronic infection
  • 5 to 25% will develop cirrhosis within 10 to 20 years | Percentage increases with duration of infection
• Risks for persons with cirrhosis
  • Hepatocellular carcinoma: 1 to 5% annual risk
  • Hepatic decompensation: 3 to 6% annual risk | Patients with hepatic decompensation have 15 to 20% annual risk of death (Thomas and Seef. Clin Liver Dis, 2005)

Screening and Diagnosis

• CDC, AASLD/IDSA and USPSTF
  • All recommend universal testing for HCV in all US adults ≥18 years at least once and all pregnant women during every pregnancy
• Annual screening: Indicated in PWID and HIV-infected men who have unprotected sex with men per AASLD/IDSA guidelines
• Periodic repeat HCV testing: Should be offered to all persons with behaviors, exposure or circumstances associated with increased risk of HCV exposure including
  • Injection drug use (current or ever)
  • Intranasal illicit drug use
  • Men who have sex with men
  • Persons on long-term hemodialysis (ever)
  • Persons with percutaneous/parenteral exposures in an unregulated setting
  • Healthcare, emergency medical, and public safety workers after needlestick, sharps, or mucosal exposure to HCV-infected blood
  • Children born to HCV-infected women
  • Prior recipients of a transfusion or organ transplant, including persons who
    • Were notified that they received blood from a donor who later tested positive for HCV
    • Received a transfusion of blood or blood components, or underwent an organ transplant before July 1992
    • Received clotting factor concentrates produced before 1987
  • Persons who were ever incarcerated
  • HIV infection
  • Sexually active persons about to start pre-exposure prophylaxis (PrEP) for HIV
  • Unexplained chronic liver disease and/or chronic hepatitis
  • Solid organ donors (living and deceased) 

Screening Algorithm

• Initial screening test: HCV antibody (anti-HCV)
  • If anti-HCV is reactive: Must be followed with qualitative HCV RNA or quantitative HCV RNA to confirm active infection
  • If HCV RNA is not detected: Indicates resolved infection and no further testing needed
• Labs offering “reflex testing” are preferred (positive anti-HCV samples sent reflexively for HCV RNA) to minimize need for patients to return for second test
• Negative anti-HCV but who may have been exposed to HCV within past 6 months
  • Test for HCV RNA or repeat anti-HCV

CDC HepC Test Interpretation Table

CDC HepC Test Interpretation Table

Pre-Treatment Evaluation of HCV Infection

Key Elements of HCV History

• Identify risk behaviors and risk exposures
  • Establish onset of risk factor (e.g. first injection drug use) to establish potential duration of infection
• Prior evaluation and HCV treatment and agents used
• Comorbidities
  • Other known liver diseases, HBV, hepatotoxic drugs, ETOH
  • HIV
  • Extrahepatic manifestations (glomerulonephritis, cryoglobulinemia, non-Hodgkin’s lymphoma, Porphyria cutanea tarda)
  • Diabetes mellitus
  • Injection/inhaled substance use (for re-infection counseling)
• Family history of liver disease
• Review of systems for symptoms of cirrhosis
• Medication review for drug interactions
  • Assess with candidate DAA with HEP Drug Interaction Checker (see ‘Learn More – Primary Sources’ below)

Liver Directed Physical Exam

• Eyes: Scleral icterus
• Breath: Fetor hepaticus (sweet, pungent)
• Thyroid: Enlarged or nodular thyroid
• Breast: Gynecomastia (men)
• Skin: Jaundice | Palmar erythema | Spider angiomata
• Lung: R hydrothorax
• Abd: Liver size | Texture | Spleen size | Masses | Caput | Ascites
• GU: Testicular atrophy
• Neuro: Tremor | Asterixis
• Extremities: Dupuytren’s contracture (ulnar, nodular fibrosing lesions) | Terry’s nails (white nails with thin pink band at tip)

Labs

• Hepatic function panel | Basic metabolic panel | CBC
• INR
• Hepatitis B
  • Surface antigen | Surface antibody | Core antibody
• Hepatitis A total antibody
• HIV 4th generation antigen/antibody
• HCV quantitative RNA
• HCV genotype if non pan-genotypic agent may be prescribed
• HCV-Fibrosure (blood test to establish METAVIR fibrosis staging and necroinflammatory grading) or liver elastography | If Fibrosure not available, calculate AST to Platelet Ratio Index (APRI) and Fibrosis-4 (Fib-4) (See ‘Learn More – Primary Sources’ below)
• Child-Turcotte-Pugh score in those with cirrhosis (See ‘Learn More – Primary Sources’ below)

Treatment Principles

• Treat all patients with acute or chronic HCV infection
  • Exception: Short life expectancy that cannot be changed by HCV therapy | Liver transplantation | Other directed therapy
• DAA regimens and pregnancy
  • Safety of DAA has not been assessed during pregnancy or in breastfeeding women
    • Offer counseling to women of childbearing age before beginning HCV treatment
    • Treatment should be deferred in pregnant women until after delivery and breastfeeding
    • For more on hepatitis and pregnancy, see ‘Related Topics’ below
• Drug combinations
  • Two or three DAA are combined into therapies to target two to three non-structural proteins, similar to antiretroviral therapy in HIV
  • Combination therapy leads to much higher rates of cure (now >90%) than monotherapy
• Resistance testing
  • Only indicated prior to use of certain DAAs | Refer to AASLD/IDSA HCV treatment guidelines Resistance Primer (see ‘Learn More – Primary Sources’, below)
• When to refer to a specialist
  • Infectious disease specialist: Refer treatment-experienced patients and patients with HIV, HBV co-infection to infectious diseases for treatment
  • GI/hepatology: Refer patients with decompensated cirrhosis, prior liver transplant or known HCC | Those with Model for End-Stage Liver Disease (MELD) score > 10, any history of bleeding varices, ascites, or hepatic encephalopathy should be referred to transplant center (see ‘Learn More – Primary Sources’ below for MELD calculation)
• Treatment approach for all other patients not directly referred to ID or GI
  • Before treating, ask: “Cirrhotic or non-cirrhotic?”
  • Then refer to AASLD/IDSA simplified treatment guidelines using pan-genotypic agent
  • Without cirrhosis: Simplified HCV Treatment for Treatment-Naive Patients Without Cirrhosis
  • With compensated cirrhosis: Simplified HCV Treatment Algorithm for Treatment-Naive Adults With Compensated Cirrhosis
  • The two pan-genotypic agents currently recommended in the simplified treatment guidelines are:
    • Glecaprevir (300 mg) / pibrentasvir (120 mg) to be taken with food for a duration of 8 weeks
    • Sofosbuvir (400 mg) / velpatasvir (100 mg) for a duration of 12 weeks

Monitoring

• Clinic or televisit recommended to ensure medication adherence, monitor for adverse events and potential drug-drug interactions
  • Without cirrhosis: No blood tests during therapy are needed
  • With cirrhosis: May check labs for liver injury
• Patients with diabetes on medication
  • Counsel and monitor for potential hypoglycemia
• Patients on warfarin
  • Counsel and monitor INR for potential changes in anticoagulation status
• Quantitative HCV RNA and hepatic function panel
  • Check 12 weeks or later following completion of therapy to confirm sustained virologic response (cure) and hepatic enzyme normalization
• Patients with cirrhosis
  • Obtain ultrasound q6 months with or without alpha-fetoprotein testing for HCC surveillance and continue post cure
  • Obtain esophagogastroduodenoscopy to screen for varices

Additional Management and Counseling Tips

• Assess for ETOH use (AUDIT-C and CAGE tools available in ‘Learn More – Primary Sources’, below)
  • Counsel abstinence from ETOH and refer for intervention as needed
• Assess for opiate use disorder and refer to/provide opiate replacement therapy
• Perform or refer for harm reduction and needle exchange
  • Counsel on clean injection techniques for injection drug users
  • Counsel on risk of re-infection: once cured of HCV: Persons remain susceptible to re-infection
• Vaccinate for
  • HAV | HBV if non-immune | 23-valent pneumococcal polysaccharide vaccine (PPV23) if cirrhosis is present
• Educate on how to avoid HCV transmission to others including counseling on refraining from sharing appliances that may come into contact with blood including
  • Syringes | Needles | Cookers | Toothbrushes | Razors | Nail clippers | Glucose monitors and lancet devices

The Wrap-Up

• The above patient would warrant HCV screening as do all adults
• She is at particularly high risk for HCV given injection drug use
• Her risk of cirrhosis is probably low given the relatively short duration of injection drug use
  • If she has HCV infection confirmed by detectable HCV RNA, she should be treated with a pan-genotypic agent after receiving a pre-treatment evaluation and assessment of liver fibrosis as above
  • Her boyfriend and any other injecting partners should be encouraged to be tested
  • She should be counseled not to share needles, syringes, cookers, or other appliances that may come into contact with blood of her boyfriend or others
  • She should be referred for harm reduction and for opiate replacement therapy if amenable
  • After cure, she should be counseled regarding risk of re-infection and re-tested with HCV RNA (she will always have anti-HCV) at least annually
• Key points
  • Directly acting antivirals target non-structural proteins of hepatitis C virus resulting in disruption of viral replication and cure >90% of patients
  • Universal screening for HCV in adults is recommended
  • All patients with acute or chronic HCV infection should be treated except those with short life expectancy not related to liver disease
  • Most patients can be treated with an 8 to 12-week course of a pan-genotypic agent by their primary care provider with minimal monitoring

RESOURCES:

Hepatitis C Online

USPSTF: Hepatitis C Virus Infection in Adolescents and Adults – Screening

CDC: Hepatitis C Questions and Answers for Health Professionals

AASLD & IDSA: HCV Guidelines

Project ECHO: Hepatitis C Virus

Prevalence of spontaneous clearance of hepatitis C virus infection doubled from 1998 to 2017 (Seo et al. Clin Gastroenterol Hepatol, 2020)

Natural history of hepatitis C (Thomas and Seef. Clin Liver Dis, 2005)

HEP Drug Interaction Checker

AST to Platelet Ratio Index (APRI)

Fibrosis-4 (Fib-4)

Child-Turcotte-Pugh Score

AASLD & IDSA: HCV Resistance Primer

Model For End-Stage Liver Disease (MELD) for ages 12 and older

UDIT Alcohol Consumption Questions (AUDIT-C)

CAGE Questionnaire for Detecting Alcoholism

Commercial Support

This educational activity is supported by an independent educational grant from Gilead Sciences

Faculty Disclosures

Dr. Carmody reports that she has no relevant financial relationships to disclose

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