Arvind R. Murali, MDAssistant Professor of MedicineGastroenterology & Hepatology

Organ Transplant CenterUIHC, Carver College of Medicine

No financial disclosures

No conflicts of interest

No affiliations with any pharmaceutical company

Recommendations on HCV treatment regimens are based on AASLD/IDSA guidelines

Epidemiology of HCV infection

Who to screen for HCV infection?

Clinical Manifestations of HCV

Factors influencing treatment of HCV

Treatment of HCV

HCV in pregnancy

Acute HCV infection

56 yo male with past history of HCV infection is referred to you for evaluation. Hepatitis C antibody test is positive AND hepatitis C RNA test is negative. What is the next step?

a. Start Sofosbuvir-Ledipasvir for 12 weeksb. Start Sofosbuvir and ribavirin for 24 weeksc. Check hepatitis C genotype to help determine anti-viral

regimend. No evidence of current HCV infection and no treatment is

required

All but which of the following patients should be offered one-time HCV testing?

a. All persons born between 1965 and 1985b. 45-yo male using intravenous drugs c. 55 yo female on maintanence hemodialysisd. Child born to a HCV-infected mother

A 26 year old pregnant woman at 28 weeks gestational age is noted to have positive hepatitis C RNA. HCV genotype is 1b. What is your next step in management?

a. Start elbasvir/grazoprevir for 12 weeksb. Start glecaprevir/pibrentasvir for 8 weeksc. Start sofosbuvir/velpatasvir for 12 weeksd. Treatment is not recommended during pregnancy

You see a 55 yo old male with history of IVDU in your clinic. HCV antibody is positive and HCV PCR indicates high viral load. You obtain a liver ultrasound which shows a 2cm liver lesion. What do you do next?

1. Repeat Ultrasound in 6 months. 2. Start treatment for hepatitis C.3. Obtain MRI and if suggestive of HCC refer to a transplant

center.4. Start treatment for HCV, obtain MRI, and refer to a

transplant center.

HCV - One of the main causes of chronic liver disease worldwide

Long-term impact of HCV infection on liver disease is highly variable ranging from ◦ minimal histological changes ◦ extensive fibrosis and cirrhosis ◦ hepatocellular carcinoma (HCC)

About 180 million chronically infected persons worldwide

An estimated 3.5 million persons in the United States are HCV-infected2.7 million in the general non-institutionalized population800,000 - incarcerated, institutionalized, or homeless

Most people infected with HCV are unaware of their infection - In the US, about half of all infected people are unaware they are infected

In 2012, CDC recommended to offer a one-time HCV test to all persons born from 1945 through 1965, without prior ascertainment of HCV risk-factors.

Reasoning?

Persons in the 1945 to 1965 birth cohort accounted for nearly three-fourths of all HCV infections, a five-time higher HCV prevalence (3.25%)

All persons requiring HCV testing should first be tested for HCV antibody (anti-HCV) using an FDA-approved test

A positive test result for anti-HCV usually but not always imply current infection

Positive HCV antibody test indicates either◦ current (active) HCV infection (acute or chronic)◦ past infection that has resolved, or◦ a false-positive test result

All patients with HCV antibody positive◦ HCV nucleic acid test (NAT) to detect viremia to confirm

current (active) HCV infection

In patients with negative anti-HCV ab test but are◦ immunocompromised (HIV, chronic hemodialysis) ◦ exposure to HCV within the last six months

To detect re-infection in persons after previous spontaneous or treatment-related viral clearance◦ Get HCV RNA directly in these patients

An FDA-approved quantitative or qualitative NAT with a detection level of 25 IU/mL or lower should be used to detect HCV RNA

Positive HCV viral load confirms current infection

Positive anti-HCV test and negative HCV RNA PCR◦ No evidence of current (active) HCV infection, additional

HCV testing is typically unnecessary ◦ Only when there is a high index of suspicion for recent

infection, HCV RNA test can be repeated (3-6 months)

Hepatic • Acute hepatitis, cirrhosis, HCC

Non-hepatic manifestations• Mixed Cryoglobulinemic Syndrome• B-Cell Non-Hodgkins Lymphoma • Type 2 MPGN• Sicca Syndrome• Porphyria Cutanea Tarda• Lichen Planus• Moorens Corneal Ulcers

MCS is a small to medium vessel vasculitis characterized by production of cryoglobulins

Cryoglobulins - immune complexes of polyclonal immunoglobulin (Ig)G and monoclonal or polyclonal IgM with rheumatoid factor that precipitate at lower temperatures

Fix complement - lead to endothelial tissue damage and vasculitis

As high as 90 % of cases of MCS are associated with chronic HCV

Dermatological manifestations • palpable purpura

Other manifestations • Arthritis• Non-healing ulcers• Peripheral neuropathy• Central nervous involvement, and • Glomerulonephritis

Diagnosis confirmed by the presence of - cryoglobulins- elevated rheumatoid factor & - immunofluorescence of complement fixing IgM in tissues

HCV RNA viral load HCV genotype Co-existing HIV infection Co-existing Hepatitis B infection Presence or absence of cirrhosis If cirrhosis, compensated or decompensated Do they have CKD/ESRD Presence of HCC Transplant Candidate

There are currently 11 different genetic strains (genotypes) of hepatitis C virus (HCV) in the world

Highest prevalence is seen with genotypes 1 through 7

Testing for HCV genotype helps to guide selection of the most appropriate treatment regimen

Genotype 1 is the most common HCV genotype in North America and EuropeAccounts for nearly 80% of all infections in the U.S HCV genotype 1 - subtypes 1a, 1b, and 1c

Genotype 2 is the second most common HCV genotype in the U.S. About 10% of all infectionGenotype 2 - subtypes 2a, 2b, and 2c

Genotype 3 endemic to southeast Asia and some parts of Australia, and IndiaHCV genotype 3 - about 6% of AmericansGenotype 3 - two main subtypes: 3a and 3b

Genotype 4 - Africa, Middle East, EgyptGenotype 5 – Southern AfricaGenotype 6 – China, Hong KongGenotype 7 – Thailand, Congo

All patients considered for HCV treatment must have testing • hepatitis B surface antigen and surface antibody • hepatitis B core antibody

HbsAg positive – treat HBV prior to starting HCV treatment

HbsAg and HbsAb are negative but HBV core Ab positive“significant risk of re-activation of hepatitis B while on

treatment for HCV”

HBV re-activation can lead to liver failure and death. 24 cases of re-activation were identified by FDA – 2 deaths and 1 LT

Closely monitor liver enzymes and liver function tests while on HCV treatment

Severity of liver disease - A key factor in determining treatment and follow up evaluation of patients with HCV

Patients with advanced liver disease may have a lower response to HCV therapy – but they are the most likely to derive the greatest survival benefit

A liver biopsy is the gold standard in estimating the severity of liver inflammation/fibrosis but is rarely used due to risk of complications

Blood tests – platelet count, INR, APRI index

Liver imaging (eg, ultrasound, CT scan) – can be used to assess liver surface nodularity and spleen size

Serum fibrosis marker panels such as Fib4, Fibrospect

Liver Elastography measurement (Fibroscan/US/MRI)• provides instant information regarding liver stiffness• can reliably distinguish patients with a high versus

low likelihood of cirrhosis

***If there is a liver lesion on ultrasound and HCC is suspected, do not start treatment for HCV. Patients with suspected HCC should be referred to a transplant center for evaluation and management of HCC.

Sustained Virological Response (virologic cure)

“continued absence of detectable HCV RNA for at least 12 weeks after completion of therapy”

SVR – durable in more than 99% of patients followed-up for ≥5 years

Patients in whom SVR is achieved have HCV antibodies but no longer have detectable HCV RNA in serum, liver tissue, or mononuclear cells

SVR is associated with

Substantial improvement in liver histology, decrease in the risk of progression to cirrhosis

>70% reduction in the risk of liver cancer (hepatocellular carcinoma [HCC])

90% reduction in the risk of liver-related mortality and liver transplantation

Reduces symptoms from cryoglobulinemic vasculitis, a condition affecting 10% to 15% of HCV-infected patients

HCV-infected persons with non-Hodgkin lymphoma and other lymphoproliferative disorders achieve complete or partial remission in up to 75% of cases

Substantially improved quality of life, which spans their physical, emotional, and social health

Persons who have successfully achieved SVR (virologiccure) no longer transmit the virus to others

1. NS3/4A Protease Inhibitors - Inhibits cleavage of polyprotein - Ends with “previr”

2. NS5A Inhibitors - Blocks virus protein NS5A needed for virus reproduction and infection– Ends with “asvir”

3. NS5B polymerase Inhibitors - Inhibits RNA polymerase NS5B thus preventing virus replication - Ends with “buvir”

Elbasvir-Grazoprevir (Zepatier)Genotypes 1, 4 (12 weeks *no cirrhosis/comp cirrhosis)

Ledipasvir-Sofosbuvir (Harvoni)Geno 1, 4, 5, 6 (12 weeks *no cirrhosis/comp cirrhosis)

Glecaprevir-Pibrentasvir (Mavyret)Geno 1-6 (8 wks – no cirrhosis, 12 wks – comp cirrhosis)

Sofosbuvir-Velpatasvir (Epclusa)Genotypes 1-6 (12 wks *no cirrhosis/comp cirrhosis)

*All treatment naïve

Treatment experienced ◦ Peg-interferon/ribavirin experienced◦ NS3 protease inhibitor (telaprevir, boceprevir, simeprevir)◦ NS5B inhibitors (eg: sofosbuvir)◦ NS5A inhibitors (eg: ledipasvir, elbasvir, daclatasvir)

HCV/HIV co-infection

Post-Liver Transplant

Chronic Kidney disease

HCV in Pregnancy

Acute HCV infection - defined as presenting within 6 months of the exposure

Both HCV antibody and HCV RNA testing are recommended when acute HCV infection is suspected

Pre-exposure or post-exposure prophylaxis with antiviral therapy is not recommended

20% to 50% chance of spontaneous clearance of the infection in 6 months

Counsel patients with acute HCV infection to avoid hepatotoxicinsults - hepatotoxic drugs (eg, acetaminophen) and alcohol consumption

Counseling to reduce the risk of HCV transmission

Referral to an addiction medicine specialist is recommended for patients with acute HCV infection related to substance use

Repeat HCV RNA in 6 months to determine if spontaneous clearance of HCV has occurred

If HCV RNA is persistent beyond 6 months after diagnosis of acute HCV then patient has chronic HCV and needs to be treated

A vast number of people infected with HCV are unaware of their infection

Patients born between 1945 to 1965 should be screened for HCV even without any risk factors

Patients with anti HCV antibody positive should receive HCV RNA test to confirm current infection. No treatment indicated if HCV RNA is negative

Provide recommendations for counseling those with active HCV infection

Several DAA regimens are available to treat HCV.

Treatment should be based on HCV viral load, genotype, presence or absence of cirrhosis and if they treatment naïve or experienced

HCV treatment is recommended before considering pregnancy if possible, avoid during pregnancy

20-50% spontaneous clearance of HCV after acute infection, do not treat unless the HCV RNA is persistent at 6-12 months (chronic HCV)

56 yo male with past history of HCV infection is referred to you for evaluation. You obtain hepatitis C antibody test and it is positive but the hepatitis C RNA test is negative. What is the next step?

a. Start Sofosbuvir-Ledipasvir for 12 weeksb. Start Sofosbuvir and ribavirin for 24 weeksc. Check hepatitis C genotype to help determine anti-viral

regimend. Inform patient that there is no evidence of current HCV

infection and no treatment is required

All but which of the following patients should be offered one-time HCV testing?

a. All persons born between 1965 and 1985b. 45-yo male with history of intravenous drug

abusec. 55 yo female on hemodialysisd. Child born to a HCV-infected mother

A 26 year old pregnant woman at 28 weeks gestational age is noted to have positive hepatitis C RNA. HCV genotype is 1b. What is your next step in management?

a. Start elbasvir/grazoprevir for 12 weeksb. Start glecaprevir/pibrentasvir for 8 weeksc. Start sofosbuvir/velpatasvir for 12 weeksd. Inform patient that treatment is not recommended

during pregnancy due to lack of safety and efficacy data

You see a 55 yo old male with history of IVDU in your clinic. HCV antibody is positive and HCV PCR indicates high viral load. You obtain a liver ultrasound which shows a 2cm liver lesion. What do you do next?

1. Repeat Ultrasound in 6 months 2. Start treatment for hepatitis C and repeat Ultrasound in 3-6

months3. Obtain MRI and if suggestive of HCC refer to a transplant

center4. Start treatment for HCV, obtain MRI, and refer to a

transplant center

Alcohol – HCV patients be counseled regarding the deleterious effects of alcohol

Strong association between use of excess alcohol and the development of/progression of liver fibrosis and HCC in patients with HCV infection

Daily consumption of more than 50 grams of alcohol has a high likelihood of worsening fibrosis

Hepatitis B virus (HBV) infection and human immunodeficiency virus-1 (HIV) co-infection -associated with poorer prognosis of HCV

Persons with HCV should be tested for HIV antibody and hepatitis B surface antigen (HBsAg)/ core antibody using standard assays for screening

Counseled on how to reduce their risk of acquiring these infections, including through HBV vaccination

Patients with obesity and metabolic syndrome having underlying insulin resistance are more prone to have nonalcoholic fatty liver disease

NAFLD is a risk factor for fibrosis progression in HCV-infected persons

HCV-infected persons who are overweight (BMI> 25 kg/m2) or obese (BMI > 30 kg/m2) be

“counseled regarding strategies to reduce weight and improve insulin resistance via diet, exercise, and/or medical therapies”

Patients with HCV infection and hyperlipidemia or cardiovascular comorbidities may also benefit from various hypolipidemic drugs

Prospective studies - demonstrated the safety and efficacy of statins in patients with chronic HCV even in those with compensated cirrhosis

Statins and other hypolipidemic agents should not be withheld in HCV-infected patients

Persons with HCV infection should be counseled to avoid sharing toothbrushes and dental or shaving equipment, and be cautioned to cover any bleeding wound to prevent the possibility of others coming into contact with their blood.

Persons should be counseled to stop using illicit drugs and enter substance abuse treatment. Those who continue to inject drugs should be counseled to avoid reusing or sharing syringes, needles, water, cotton, and other drug preparation equipment; use new sterile syringes and filters and disinfected cookers; clean the injection site with a new alcohol swab; and dispose of syringes and needles after one use in a safe, puncture-proof container.

Persons with HCV infection should be advised not to donate blood and to discuss HCV serostatus prior to donation of body organs, other tissue, or semen.

Persons with HIV infection and those with multiple sexual partners or sexually transmitted infections should be encouraged to use barrier precautions to prevent sexual transmission. Other persons with HCV infection should be counseled that the risk of sexual transmission is low and may not warrant barrier protection.

Household surfaces and implements contaminated with visible blood from an HCV-infected person should be cleaned using a dilution of 1 part household bleach to 9 parts water. Gloves should be worn when cleaning up blood spills.