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
- Hematologic disorders
- Endocrine diseases
- Renal disease
- Dermatologic findings
- 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.
