Hepatitis C virus: Difference between revisions

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== Microbiology ==
 +
==Background==
   
  +
===Microbiology===
−
* Enveloped single-stranded RNA virus
  
−
* NS5A and NS5B
  
   
  +
*Enveloped single-stranded RNA virus in the genus ''Hepacivirus'' and family ''[[Flaviviridae]]''
−
== Life Cycle ==
  
  +
*NS5A and NS5B are important non-structural proteins
   
  +
===Life Cycle===
−
* NS5A…...
  
−
* NS5B
  
   
  +
*Involves protease, polymerase, and non-structural proteins (NS5A/NS5B)
−
== Epidemiology ==
  
   
  +
===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
  
   
  +
*Worldwide about 70 million cases
−
== Pathophysiology ==
  
  +
*'''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%
  
   
  +
*In the acute phase, the viral load and liver enzymes fluctuate over months
−
== Clinical Presentation ==
  
  +
**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, may clear infection, but 70-80% become chronically infected
  
−
* Progresses slowly and asymptomatically until they develop liver fibrosis, compensated cirrhosis, then decompensated cirrhosis
  
−
** ~20-25% progress to end-stage liver disease within 20 years
  
   
  +
*After exposure, incubation period of [[Usual incubation period::5 to 12 weeks]]
−
== Management ==
  
  +
*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
   
−
=== Decision to treat ===
 +
=== Extrahepatic Manifestations ===
   
  +
* [[Vasculitis]]
−
* All individuals should be considered for antiretroviral treatment
  
  +
** [[Mixed cryoglobulinemia]]
−
* Assess readiness for treatment, as good adherence is necessary
  
  +
** [[Cryoglobulinemic vasculitis]]
−
* Alcohol, drug use, and mental health disorders are ''not'' containdications to treatment
  
  +
** [[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==
−
=== Initial investigations ===
  
   
  +
*Screening with serology for anti-HCV antibodies followed by RNA PCR to confirm ongoing infection
−
* Confirm active infection with HCV RNA then get genotype and subtype
  
  +
**The window period for serology is about 5 to 10 weeks before antibodies are detectable
−
** Two positive HCV RNA tests 6 months apart documents chronic infection
  
  +
**Viral RNA detectable 2 to 14 days after exposure
−
** May need resistance testing
  
  +
*Anti-HCV antibodies appear to be lifelong but not protective against reinfection, so need to check RNA PCR to rule out reinfection
−
* Baseline bloodwork, including CBC, liver enzymes, liver function, and creatinine
  
  +
*In Ontario, serology is done with a two-tier algorithm (screening test and confirmatory test)
−
* Serology to exclude HIV and HBV
  
  +
**Screening test is chemiluminescent microparticle immunoassay (CMIA)
−
* Transferrin saturation to exclude hemochromatosis, and IgG levels to exclude autimmune hepatitis
  
  +
**Confirmatory test is a second chemiluminescence assay
−
* Baseline liver ultrasound
  
  +
**Interpretation:
−
* If not clearly cirrhotic, assess liver fibrosis
  
  +
***Screening and confirmatory reactive: positive test
−
** Bloodwork: AST:platelet ratio index (APRI), FIB-4, FibroTest
  
  +
***Screening non-reactive: negative test
−
** Imaging: FibroScan
  
  +
***Screening reactive (or indeterminate) and confirmatory non-reactive (or indeterminate): inconclusive
−
** Gold standard: biopsy
  
  +
****Submit HCV RNA with repeat serology
  +
****If RNA not detected, repeat serology at 6-8 weeks
  +
****If repeatedly inconclusive, discuss with microbiologist
   
−
=== Antivirals ===
 +
==Management==
   
  +
===Decision to Treat===
−
* 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 [[https://www.hep­druginteractions.org/|www.hep­druginteractions.org]]
  
−
** PPI and Epclusa/Harvoni
  
−
** Statins require dose reduction; atorvastatin and Maviret is no-no
  
−
** Anti-epileptics except leviteracetam
  
−
* 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
  
   
  +
*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 [https://www.hep­druginteractions.org/ 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====
 
{| class="wikitable"
  
{| class="wikitable"
−
! Regimen
 +
! rowspan="2" |Regimen
  +
! colspan="7" |Duration by Genotype (weeks)
−
! 1a
  
  +
! rowspan="2" |Notes
−
! 1b
  
−
! 2
  
−
! 3
  
−
! 4
  
−
! 5
  
−
! 6
  
 
|-
  
|-
  +
!1a
−
| Ledipasvir/sofosbuvir (Harvoni)
  
  +
!1b
−
| 12 wk ± ribavirin
  
  +
!2
−
| 12 wk
  
  +
!3
−
| –
  
  +
!4
−
| 12 wk + ribavirin
  
  +
!5
−
| 12 wk
  
  +
!6
−
| 12 wk
  
−
| 12 wk
  
 
|-
  
|-
  +
|[[Ledipasvir]]/[[sofosbuvir]] (Harvoni)
−
| Elbasvir/grazoprevir (Zepatier)
  
−
| 12-16 wk ± ribavirin
 +
|12 ± RBV
−
| 12 wk
 +
|12
  +
|—
−
| –
  
−
| 12 wk + sofosbuvir
 +
|12 + RBV
−
| 12 wk
 +
|12
  +
|12
−
| –
  
  +
|12
−
| –
  
  +
|
 
|-
  
|-
  +
|[[Elbasvir]]/[[grazoprevir]] (Zepatier)
−
| Sofosbuvir/velpatasvir (Epclusa)
  
−
| 12 wk
 +
|12-16 ± RBV
−
| 12 wk
 +
|12
  +
|—
−
| 12 wk
  
−
| 12 wk
 +
|12 + SOF
−
| 12 wk
 +
|12
  +
|—
−
| 12 wk
  
  +
|—
−
| 12 wk
  
  +
|rule out resistance first in G1a
 
|-
  
|-
  +
|[[Paritaprevir]]/[[ritonavir]]/[[ombitasvir]] + [[dasabuvir]] (Holkira Pak)
−
| Glecaprevir/pibrentasvir (Maviret)
  
−
| 8 wk
 +
|12 + RBV
  +
|12
−
| 8 wk
  
  +
|—
−
| 8 wk
  
  +
|—
−
| 8 wk
  
  +
|—
−
| 8 wk
  
  +
|—
−
| 8 wk
  
  +
|—
−
| 8 wk
  
  +
|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====
  +
{| class="wikitable"
  +
! rowspan="2" |Regimen
  +
! colspan="7" |Duration by Genotype (weeks)
  +
! rowspan="2" |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====
−
* Epclusa 12 weeks for most, now OCB covered
  
−
* Zepatier 12 weeks for G1 and G4
  
−
* Maviret 8 weeks for most; 12 weeks for cirrhosis
  
−
* Harvoni 8 weeks if uncomplicated
  
−  
−
=== Experienced patients ===
  
   
−
* Changes the options, mostly longer
 +
*Changes the options, mostly longer courses of treatment
   
−
=== Non-pharmacologic management ===
 +
===Non-Pharmacologic Management===
   
−
* Counsel to avoid sharing products like needles or razors, safe sex, avoid alcohol
 +
*Counsel to avoid sharing products like needles or razors, safe sex, avoid alcohol
−
* Vaccinate for Hep A and B
 +
*Vaccinate for [[hepatitis A]] and [[Hepatitis B virus|B]]
   
−
=== Follow-up ===
 +
===Follow-Up===
   
−
* Need to confirm sustained virologic response (SVR)
 +
*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 ==
 +
==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
 +
*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 ===
 +
===Populations to Screen===
   
−
* '''History of injection drug use, ever'''
 +
*'''History of injection drug use, ever'''
−
* History of incarceration
 +
*History of incarceration
−
* Received healthcare where there is a lack of IPAC
 +
*Received healthcare where there is a lack of IPAC
−
* Blood products or organ transplantation before 1992 in Canada
 +
*Blood products or organ transplantation before 1992 in Canada
−
* Born or resided in a country where prevalence of HCV is >3%
 +
*Born or resided in a country where prevalence of HCV is >3%
−
** Central, East and South Asia
 +
**Central, East and South Asia
−
** Australasia and Oceania
 +
**Australasia and Oceania
−
** Eastern Europe
 +
**Eastern Europe
−
** Subsaharan Africa
 +
**Subsaharan Africa
−
** North Africa or the Middle East
 +
**North Africa or the Middle East
−
* Born to HCV positive mother
 +
*Born to HCV positive mother
−
* History of sharing personal care items or sex with an HCV-positive person
 +
*History of sharing personal care items or sex with an HCV-positive person
−
* HIV infection
 +
*HIV infection
−
* Received hemodialysis
 +
*Received hemodialysis
−
* Elevated ALT
 +
*Elevated ALT
−
* '''Born between 1945 and 1975''' (baby boomers)
 +
*'''Born between 1945 and 1975''' (baby boomers)
−
** Recommended in the US and by CASL but not by CTFPHC
 +
**Recommended in the US and by CASL but not by CTFPHC
   
−
==== Opportunistic screening ====
 +
====Opportunistic Screening====
   
−
* Emergency rooms
 +
*Emergency rooms
−
* Hospital inpatients
 +
*Hospital inpatients
−
* Substance use treatment clinics
 +
*Substance use treatment clinics
   
−
=== Screening procedure ===
 +
===Screening Procedure===
   
−
* Anti-HCV antibody
 +
*Anti-HCV antibody
  +
**Serum serology gold standard
−
* If positive, proceed to HCV RNA
  
  +
**There are some quick point-of-care tests, like from saliva
−
* Should be done annually in patients who have ongoing high-risk exposures
  
  +
**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 ==
 +
==Further Reading==
   
−
* Shah H, ''et al''. [https://doi.org/10.1503/cmaj.170453 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.
 +
*Shah H, ''et al''. [https://doi.org/10.1503/cmaj.170453 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.
−
* [https://doi.org/10.1093/cid/ciy585 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.
 +
*[https://doi.org/10.1093/cid/ciy585 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.
   
 
[[Category:Flaviviridae]]
  
[[Category:Flaviviridae]]

Latest revision as of 09:36, 15 September 2022

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

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

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

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