Hepatitis C virus

Background

Microbiology

• Enveloped single-stranded RNA virus in the genus Hepacivirus and family Flaviviridae
• NS5A and NS5B are important non-structural proteins

Life Cycle

• Involves protease, polymerase, and non-structural proteins (NS5A/NS5B)

Epidemiology

• Worldwide about 70 million cases
• Genotype varies by geography
  • Genotype 1 most common worldwide
  • Genotype 1a and 1b common in Canada
    • Disproportionate burden in Indigienous Canadian population in the North
    • Very high burden of disease in Canada, causing more years of life lost in Ontario than any other infectious disease
  • Genotype 3 more common south-east Asia and in injection drug use
  • Genotype 4 common in Egypt (15% prevalence); Egypt has the highest burden in the world
• In Canada, about 245,000 chronic hepatitis C, about half are undiagnosed
  • Risk factors: injection drug use (highest risk), prior transfusion, and hemophilia
  • Increasing burden of disease as patients age and progress to cirrhosis
• Modes of transmission
  • Injection drug use (most important population, highest risk)
  • Tattoos
  • Blood transfusions before 1992
  • Cocaine use from blood on the straws
  • Rarely, sexual transmission especially HIV-infected MSM
  • Vertical transmission rare (3-5%)
  • Iatrogenic or medical transmission, from multi-use vials

Pathophysiology

• In the acute phase, the viral load and liver enzymes fluctuate over months
  • Anti-HCV-Ab develops at 12 weeks
  • Acute phase lasts 6 months to 2 years
• Spontaneous clearance is rare after 2 years
  • Anti-HCV-Ab positive and HCV RNA negative
  • Repeat to confirm, but no need to follow it
  • No complications, though it is a surrogate for risk behaviours
  • Not protected from reinfection
• If it isn't cleared, it becomes chronic
  • Lifetime risk of cirrhosis is 50-60%, with 20% having cirrhosis at 20 years
  • Liver cancer develops in 1-4%

Clinical Manifestations

• After exposure, incubation period of 5 to 12 weeks
• Not all have symptoms of primary infection, but if they do they are typically non-specific fatigue and myalgias, and occasionally jaundice
  • Lasts 2 to 12 weeks
• About 25% have spontaneous viral clearance within 6 to 12 months, with the rest progressing to chronic infection
• Chronic infection progresses slowly and asymptomatically until they develop liver fibrosis, compensated cirrhosis, and finally decompensated cirrhosis
  • ~20-25% progress to end-stage liver disease within 20 years

Extrahepatic Manifestations

• Vasculitis
  • Mixed cryoglobulinemia
  • Cryoglobulinemic vasculitis
  • Sicca syndrome and Sjögren syndrome
  • Polyarteritis nodosa
• Hematologic disorders
  • B-cell lymphoma
  • Monoclonal gammopathies
  • Immune thrombocytopenia
  • Autoimmune hemolytic anemia
• Endocrine diseases
  • Type 2 diabetes mellitus
  • Hypothyroidism
• Renal disease
  • Membranoproliferative glomerulonephritis
  • Chronic kidney disease
• Dermatologic findings
  • Porphyria cutanea tarda
  • Lichen planus
  • Necrolytic acral erythema
  • Leukocytoclastic vasculitis
• Other
  • Arthralgias and myalgias are common
  • Cardiovascular disease
  • Neurologic disorders, including depression, fatigue, and neurocognitive impairment, as well as neuropathy
• Autoantibodies, including rheumatoid factor, ANA, anticardiolipin antibody, anti-thyroid antibodies, and anti-smooth muscle antibody

Diagnosis

• Screening with serology for anti-HCV antibodies followed by RNA PCR to confirm ongoing infection
  • The window period for serology is about 5 to 10 weeks before antibodies are detectable
  • Viral RNA detectable 2 to 14 days after exposure
• Anti-HCV antibodies appear to be lifelong but not protective against reinfection, so need to check RNA PCR to rule out reinfection
• In Ontario, serology is done with a two-tier algorithm (screening test and confirmatory test)
  • Screening test is chemiluminescent microparticle immunoassay (CMIA)
  • Confirmatory test is a second chemiluminescence assay
  • Interpretation:
    • Screening and confirmatory reactive: positive test
    • Screening non-reactive: negative test
    • Screening reactive (or indeterminate) and confirmatory non-reactive (or indeterminate): inconclusive
      • Submit HCV RNA with repeat serology
      • If RNA not detected, repeat serology at 6-8 weeks
      • If repeatedly inconclusive, discuss with microbiologist

Management

Decision to Treat

• All individuals should be considered for antiretroviral treatment
• Assess readiness for treatment, as good adherence is necessary
• Alcohol, drug use, and mental health disorders are not containdications to treatment

Initial Investigations

• Confirm active infection with HCV RNA then get genotype and subtype
  • Two positive HCV RNA tests 6 months apart documents chronic infection, only needed in Ontario
  • May need resistance testing
  • Genotype only actually matters for cirrhosis (since we can otherwise pick a pan-genotypic regimen)
• Baseline bloodwork, including CBC, liver enzymes (ALT, AST, ALP), liver function (bilirubin, INR, albumin), and creatinine
• Serology to exclude HIV and HBV (HBsAg, anti-HBs, anti-HBc)
• Transferrin saturation to exclude hemochromatosis
• IgG levels, which if elevated can be suggestive of cirrhosis or possibly autoimmune hepatitis
• Baseline liver ultrasound
• If not clearly cirrhotic, assess liver fibrosis
  • Bloodwork: AST:platelet ratio index (APRI), FIB-4, FibroTest
  • Imaging: FibroScan
  • Gold standard: biopsy

Antivirals

• Include nonstructural 3/4A (NS3/4A) serine protease (­-previr), the NS5B RNA­ dependent RNA poly­merase (-buvir) and the NS5A protein (­-asvir)
• Assess drug-drug interactions with www.hep­druginteractions.org
  • PPIs interact with Epclusa and Harvoni
  • Statins require dose reduction; avoid atorvastatin with Maviret
  • Notable interactions with most anti-epileptics, except leviteracetam
  • Sofosbuvir increases TDF levels
• Choice of treatment regimen depends on genotype, previously-failed treatments, and cirrhosis
  • All protease inhibitors (-previr) are contraindicated in decompensated cirrhosis, which refers to ascites, esophageal variceal hemorrhage, jaundice, or hepatic encepha­lopathy
  • Sofosbuvir/velpatasvir/voxilaprevir (Vosevi) is indicated for previously-treated patients
• Durations are typically between 8 and 12 weeks
  • Epclusa 12 weeks for most, now covered by ODB
  • Zepatier 12 weeks for G1 and G4
  • Maviret 8 weeks for most; 12 weeks for cirrhosis
  • Harvoni 8 weeks if uncomplicated

Treatment-Naive Patients Without Cirrhosis

Regimen	Duration by Genotype (weeks)							Notes
	1a	1b	2	3	4	5	6
Ledipasvir/sofosbuvir (Harvoni)	12 ± RBV	12	—	12 + RBV	12	12	12
Elbasvir/grazoprevir (Zepatier)	12-16 ± RBV	12	—	12 + SOF	12	—	—	rule out resistance first in G1a
Paritaprevir/ritonavir/ombitasvir + dasabuvir (Holkira Pak)	12 + RBV	12	—	—	—	—	—	add ribavirin for G1a
Paritaprevir/ritonavir/ombitasvir (Technivie)	—	—	—	—	12 + RBV	—	—
Sofosbuvir + daclatasvir	12	12	12	12	—	—	—
Sofosbuvir/velpatasvir (Epclusa)	12	12	12	12	12	12	12
Glecaprevir/pibrentasvir (Maviret)	8	8	8	8	8	8	8
Sofosbuvir/velpatasvir/voxilaprevir (Vosevi)	—	—	—	—	—	—	—	for treatment failure

Treatment-Naive Patients With Cirrhosis

Regimen	Duration by Genotype (weeks)							Notes
	1a	1b	2	3	4	5	6
Ledipasvir/sofosbuvir (Harvoni)	12 ± RBV	12	—	12 + RBV	12	12	12
Elbasvir/grazoprevir (Zepatier)	12-16 ± RBV	12	—	12 + SOF	12	—	—	rule out resistance first in G1a
Paritaprevir/ritonavir/ombitasvir + dasabuvir (Holkira Pak)	12 + RBV	12	—	—	—	—	—	add ribavirin for G1a
Paritaprevir/ritonavir/ombitasvir (Technivie)	—	—	—	—	12 + RBV	—	—
Sofosbuvir + daclatasvir	24	24	24	24 ± RBV	—	—	—
Sofosbuvir/velpatasvir (Epclusa)	12	12	12	12 ± RBV	12	12	12
Glecaprevir/pibrentasvir (Maviret)	12	12	12	12	12	12	12
Sofosbuvir/velpatasvir/voxilaprevir (Vosevi)	—	—	—	—	—	—	—	for treatment failure

Treatment-Experienced Patients

• Changes the options, mostly longer courses of treatment

Non-Pharmacologic Management

• Counsel to avoid sharing products like needles or razors, safe sex, avoid alcohol
• Vaccinate for hepatitis A and B

Follow-Up

• Need to confirm sustained virologic response (SVR), defined as negative PCR 12 weeks after completing therapy
• If they have achieved SVR
  • In patients without cirrhosis, no specific follow-up is necessary
  • In patients with cirrhosis, they should have biannual HCC screening with ultrasound
  • Annual HCV RNA in patients with ongoing risk factors
• If they have not achieved, then they should be evaluated for salvage therapy

Screening

• Majority of cases of chronic hepatitis C occur in baby boomers (born 1945 to 1975), though screening for this population appears to be controversial

Populations to Screen

• History of injection drug use, ever
• History of incarceration
• Received healthcare where there is a lack of IPAC
• Blood products or organ transplantation before 1992 in Canada
• Born or resided in a country where prevalence of HCV is >3%
  • Central, East and South Asia
  • Australasia and Oceania
  • Eastern Europe
  • Subsaharan Africa
  • North Africa or the Middle East
• Born to HCV positive mother
• History of sharing personal care items or sex with an HCV-positive person
• HIV infection
• Received hemodialysis
• Elevated ALT
• Born between 1945 and 1975 (baby boomers)
  • Recommended in the US and by CASL but not by CTFPHC

Opportunistic Screening

• Emergency rooms
• Hospital inpatients
• Substance use treatment clinics

Screening Procedure

• Anti-HCV antibody
  • Serum serology gold standard
  • There are some quick point-of-care tests, like from saliva
  • Also cheap options like dried blood spot testing, which can have RNA testing as well
• If positive, proceed to HCV RNA
  • May be able to do it as reflex testing
• Should be done annually in patients who have ongoing high-risk exposures

Further Reading

• Shah H, et al. The management of chronic hepatitis C: 2018 guideline update from the Canadian Association for the Study of the Liver. CMAJ. 2018;190(22):E677-E687.
• Hepatitis C Guidance 2018 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Clin Infect Dis. 2018;67(10):1477-92.