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Hepatitis C (HCV) (diagnostic criteria and testing (quantitative…
Hepatitis C (HCV)
diagnostic criteria and testing
recommendations for HCV screening
anti-HCV or antibody test
pts who are anti-HCV positive but who do not have a detectable HCV RNA do not have a current HCV infection and no further workup is required
the presence of antibody does
not
infer immunity, just exposure!
test interpretation
quantitative amplification assays for HCV RNA
performed to confirm chronic HCV infection
can serve to identify candidates for a shortened duration of therapy
used to monitor virologic response once tx is initiated
some insurances require 2 tests 6 months apart to determine spontaneous clearance of virus before tx
genotyping
duration of therapy varies depending on the infecting GT classification
AST-to-platelet ratio index (APRI) or fibrosis-4 (FIB-4) index
can help identify pts with advanced fibrosis or cirrhosis
not very specific or sensitive
transient elastography (FibroScan)
less invasive test to stage liver disease than biopsy
liver hardness is evaluated by measuring the velocity of a vibration wave ("shear wave") generated on the skin
kinda expensive
complete blood count (SCr, LFTs)
epidemiology
HCV is the most common indication for liver transplant in the US
~3.2 million people are chronically infected with HCV in the US
since 2010, the number of acute HCV cases increased by over 151%, due to both improved surveillance and increase in incidence
infection is prevalent in high-risk populations such as prisoners, IV drug users, and the homeless, which are generally excluded from most surveys
~45-85% of infected people may not be identified
HCV is the most common blood-borne pathogen, and is about 5x as common as HIV
impact of undiagnosed/untreated HCV is expected to increase dramatically over next 40-50 years
1.76 million persons developing cirrhosis, 400,000 developing hepatocellular carcinoma (HCC), and 1 million persons dying from HCV-associated complications
the number of HCV-related deaths among adults between ages 55 and 64 years continues to increase
targeted testing for HCV of persons born between 1945 and 1965 attempts to address this rising epidemic
development of HCV cirrhosis poses a 30% risk over 10 years for the development of end-stage liver disease (ESLD)
treatment options
pharmacological
direct acting antivirals (DAAs)
recommended tx regimens for treatment-naïve pts w/ HCV
comparison of different DAAs for HCV
NS3/4A inhibitors
NS3 is a multifunctional enzyme with N-terminal protease activity
NS4A is a noncovalently bound cofactor that enhances protease activity and anchors complex to the ER membrane
NS5A inhibitors
NS5A is a multifunctional protein involved in HCV replication and assembly
NS5B inhibitors
NS5B is the RNA-dependent RNA polymerase of HCV
sofosbuvir has a very high barrier to resistance and pangenotypic activity
treatment is ~95% effective
proteins encoded by HCV genome as targets for DAAs
pegylated interferon (peg-IFN)
use has diminished greatly since the approval of the DAAs due to substantial toxicities and AEs
only recommended in pts with HCV GT3 as part of a combination therapy with sofosbuvir and ribavirin
AEs: anemia, depression, anxiety/irritability, flu-like symptoms (headache, muscle aches, fatigue, fever), nausea, weight loss, dry mouth, SOB, insomnia
up to 50% of pts will spontaneously clear an HCV infection within the first 6 months of exposure (reasonable to defer HCV treatment for 6 months)
non-pharmacological
all chronic HCV pts should be vaccinated against hepatitis A and B (can be given during pharm tx)
lifestyle changes to reduce disease progression
stop continued alcohol use (no established lower limit of alcohol consumption at which disease progression is not seen)
eat a balanced diet and exercise regularly to maintain a normal weight
IV drug, tobacco, and daily marijuana smoking cessation
be cautious about body piercing and tattooing
practice safe sex
safe handling and disposal of sharps and waste
liver transplant
contraindicated in pts with active SUD
viral suppression for at least 28 days prior to transplantation was associated w/ SVR
monitoring and follow-up
acute HCV
monitor ALT, AST, bilirubin levels and INR at 2-4 week intervals until levels normalize
monitor HCV-RNA level every 4-8 weeks for 6-12 months until undetectable
if ALT and/or HCV-RNA levels remain elevated, consider treatment versus deferral options and continue to monitor accordingly
chronic HCV
obtain CBC, SCr, and LFTs after 4 weeks of therapy
d/c therapy if ALT levels rise 10-fold, or if a lesser rise is accompanied by certain symptoms (eg, N/V, jaundice)
for pts on elbasvir with grazoprevir, repeat LFTs every 4 weeks during treatment
quantitative HCV-RNA test (or HCV core antigen level) 4 and 12 weeks into therapy or 24 weeks after completion of therapy
If HCV-RNA is detectable after 4 weeks of therapy, repeat testing in 2 weeks
d/c therapy if HCV-RNA if level has increased 10-fold
for pts with cirrhosis, use baseline endoscopy to assess for presence of varices
no or small varices = repeat in 2 to 3 years
more significant varices = treat (with β-blockers and/or band ligation) and repeat endoscopy in 6-12 months
treatment goals
eradicate HCV infection (duh)
prevent development of chronic HCV infection sequelae including ESLD, HCC, and death
decrease the risk of transmission
reduce hepatic inflammation and necrosis
complications of HCV infection
progression to cirrhosis (primary concern in pts infected with HCV for ≥20 years)
cryoglobulinemia
- a local deposition of immune complexes that cause vasculitis
hepatocellular carcinoma (HCC)
signs and symptoms
most acute infections are asymptomatic and the course of the infection is insidious!
acute
jaundice
fatigue/weakness
abdominal pain
dark urine
anorexia
if infection is self-limiting, symptoms last several weeks as ALT and HCV RNA levels subside
chronic
hepatomegaly
poor appetite
right upper quadrant pain
nausea
etiology and pathophysiology
transmission of HCV occurs through percutaneous exposure
risk factors: IV drug use, tattoos received in a nonregulated setting, needle stick injuries, sexual transmission (esp. among HIV-positive MSM), infants born to HCV-infected women ("vertical transmission"), imprisonment, birth between 1945 and 1965
HCV is a ssRNA virus notable for lacking a proofreading polymerase, enabling frequent viral mutations
virus replicates within hepatocytes and, like hepatitis B, is not directly cytopathic
HCV replicates copiously posing an immense challenge for host immune control
the implications of viral mutations on direct-acting antiviral (DAA) therapy for HCV is not well understood
differentiated into six major GTs, which are further classified into subtypes (a, b, c, etc).
In the US, most infections are caused by GT1a and GT1b, followed by GT2 and GT3
historically GT1 infections were least likely to respond to therapy, but with the release of DAAs, major advances in response are now possible (GT3 continues to pose a therapeutic challenge)
most widely distributed GTs are 1 and 2, with GT1 the most common
no HCV vaccine available due to rapid mutation ability
resolved cases of HCV are defined by a vigorous T-cell response
CD8 activity mediates protective immunity but requires the aid of CD4 cells to maintain the response during viral mutations
up to 85% of acutely infected pts will develop chronic HCV infection (persistently detectable HCV RNA for ≥6 months)
special populations
pts w/ decompensated cirrhosis
the level of underlying cirrhosis limits the use of the DAAs
no dose adjustments for hepatic impairment are needed for ledipasvir/sofosbuvir, sofosbuvir, or daclatasvir
ombitasvir/paritaprevir/ritonavir with or w/o dasabuvir is not recommended in Child-Pugh Class B, and is contraindicated in Child-Pugh Class C
treatment-experienced pts
pts w/o cirrhosis who've failed a previous course of peg-IFN and ribavirin can be retreated similarly to treatment-naïve pts
pts w/ cirrhosis require either an extended duration of therapy, addition of ribavirin, or both
limited data on the retreatment of pts who failed a prior course of therapy with the DAAs
pts who failed a prior sofosbuvir-regimen may be retreated with ledipasvir/sofosbuvir and ribavirin for 12 weeks if no cirrhosis present, and for 24 weeks if cirrhosis is present
IV drug users
access to HCV therapies is limited, as many insurers refuse coverage of HCV therapies in the setting of active drug use
treat even if pt is actively using IV drugs to prevent further transmission
pts w/ HIV coinfection
ledipasvir increases tenofovir levels and may increase the risk of tenofovir-associated renal toxicity
potential DDIs between DAAs and HIV antivirals merit careful scrutiny and may necessitate antiretroviral drug changes
HIV antivirals which also use ritonavir are not recommended or require dosing without ritonavir
HIV and HCV therapies can be coadministered with the exception of didanosine and zidovudine
combining ribavirin and didanosine can result in fatal lactic acidosis
ribavirin causes hemolytic anemia and when combined w/ zidovudine can result in severe anemia
pregnancy
testing pregnant women at the initiation of prenatal care is recommended
DAA therapy is not FDA approved for pregnant women due to lack of safety and efficacy data
Cesarean delivery is not recommended for the prevention of vertical transmission
if mother is HCV+, do not test children until at least 18 months old
children
all children born to HCV-infected women should be tested for HCV infection after 18 months of age
repetitive testing by HCV RNA is not recommended
children who are anti-HCV positive after 18 months of age should be tested with an HCV-RNA assay after age 3 to confirm chronic HCV infection
siblings of children with vertically-acquired chronic HCV should be tested for HCV infection, if born from the same mother
