HCV Flashcards by Emily Goldstein

What is the family and genus of HCV?

How many genotypes are there?

Flaviviridae family and hepacivirus genus

6 main genotypes but up to 8 GTs (further divided into subtypes a/b/c…)

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What are the main proteins of HCV?

Which have most sequence variability?

Structural proteins = core and envelope glycoproteins

Non-structural proteins = NS2, NS3, NS4A, NS4B, NS5A, NS5B

Most variability in env 2

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What proteins do NS3, NS5A and NS5B code for?

NS3 = serine protease/RNA helicase

NS5A = Phosphoprotein used for assembly

NS5B = RdRp

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How long does RNA and anti-HCV take to become detectable in HCV infection?

RNA = 1-3 weeks post infection

ALT rise = 8-10 weeks

anti-HCV = 12 weeks

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How does HCV exist in a patient?

What impact does this have on sequencing and RAS?

HCV exists as a quasispecies

This means that using Sanger sequencing only population sequencing is obtained, there can be RAS which are only in minority species which may or may not be detected

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How many people are estimated to have HCV worldwide?

> 70 million

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What are the possible outcomes of HCV infection?

1) Acute infection with viral clearance

2) Chronic infection which can lead to necro-inflammation > extensive fibrosis > cirrhosis > HCC

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What are risk factors for HCV acquisition?

IVDU
Blood products pre 1990
MSM (sexaul tranmission via heterosexual sex is rare)
Prisoners
Homelessness
Born in a high risk country

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What is the relevance of IL28B in HCV infection?

Patients with an IL28B genotype are more likely to clear the infection spontaneously and with IFN and ribavirin treatment

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What HCV genotype is most prevalent worldwide? Which is most common in the UK?

Genotype 1

Genotype 1 and 3 are most prevalent in UK

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What is the rate of symptomatic acute HCV infection?

What are the symptoms?

~20% have symptomatic HCV infection

Jaundice, nausea, malaise

Fulminant hepatitis is very rare

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What percentage of acute HCV infection clear?

~15% clear within 24 m

~85% become chronically infected

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What are extrahepatic manifestations of HCV?

Mixed cryoglobulinaemia

B cell non-Hodgkin lymphoma

Glomerulonephritis

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What is the limit of quantitation recommended by EASL for HCV RNA assays?

15 IU/ml

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What testing should be performed in patients with ?new HCV infection?

RNA testing at 12 and 24 weeks post risk of infection as during acute infection fluctuating viral loads occur and can be negative when tested

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What are contraindications to DAA treatment in HCV?

Limited life expectancy

Treatment with cytochrome P450/P-gp inducers

Age <3 years

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What are the three goals of HCV treatment?

1) Reduce liver damage

2) Improve quality of life

3) Prevent onward transmission

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What DAA is contraindicated in decompensated cirrhosis and why?

Protease inhibitors due to increased risk of toxicity in Child Pugh B or C

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What were the SVR rates in IFN/ribavirin treatment of HCV?

40-70%

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Which genotype was considered difficult to treat with:

a) IFN based regimens

b) DAAs

a) Genotype 1

b) Genotype 3

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In which patient groups might ribavirin be added to a DAA regimen?

Patients with increased risk of treatment failure

1) decompensated cirrhosis
2) GT3 with compensated cirrhosis
3) Pre-DAA treatment failure with RASs

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What tests are performed in patients pre-HCV treatment?

HBsAg, HBsAb, anti-HBc (vaccinate if not immune)

HIV

HAV IgG (vaccinate if not immune)

Assess liver damage with non-invasive methods (fibroscan, serum biomarkers)

Is genotyping required pre-DAA treatment?

What region is sequenced for genotyping?

No, pangenotypic regimens are available

However cheaper regimens may be available if genotype is known

5’ UTR plus core, NS5B sequencing may be required for the rarer genotypes

What are the two available pangenotypic DAA regimens? And what is the duration?

Sofosbuvir/velpatasvir - 12 weeks

Glecapravir/pibretasvir - 8 weeks
but if cirrhosis and treatment experienced then 12 weeks

What would you add to sof/velpatasvir in patients with cirrhosis, genotype 3 HCV and NS5A Y93H mutation?

Add in weight based ribavirin

When could you use grazeprevir/elbasvir?

In genotype 1b infection (12 weeks)

How would you treat a patient with genotype 1l, 4r, 3b, 3g, 6u or 6v? And why?

Sofosbuvir/velpatasvir/voxilaprevir - 12 weeks Due to these genotypes naturally harbouring NS5A RASs

What are the risks of treating HCV with DAAs in patients with HBsAg or past HBV infection? How should these patients be treated during DAA treatment?

HBV reactivation If HBsAg positive, patients should receive NA treatment for the duration of DAA treatment and until 12 months after stopping DAAs (and monitored monthly if NAs stopped) In HBsAg negative, anti-HBc positive patients, ALT should be monitored monthly

When should SVR be measured after DAA treatment? What else should be tested at this time? What other two tests should be monitored monthly in specific populations?

12 weeks (or 24 weeks) as these are >99% correlated (relapse after 24 weeks is rare - 0.2%) If acute HCV then test at 12 AND 24 weeks ALT should also be tested to ensure this has normalised ALT should be monitored monthly in patients at risk of HBV reactivation. Renal function should be monitored in those with reduced eGFR

In which populations should HCC monitoring be continued even after SVR?

Follow up with ultrasound every 6 month after treatment if METAVIR F3 or F4 as the risk of HCC after SVR is reduced but not eliminated

Is baseline resistance testing indicated pre-DAA in treatment naïve patients? And why?

No, baseline RASs in treatment naïve patients can be present and not impact treatment outcome

What are the two regions in NS5A that are important for resistance? Name two of the most important resistance mutations

aa 24-32 and aa 92-93 Q30H and Y93H

What are the two regions in NS3 that are important for resistance? Name two of the most important resistance mutations

aa 36-56 and aa 155-175 Q41K and Q80K

What level in a HCV population can Sanger and NGS detect? What level is clinically relevant?

Sanger ~20% NGS <1% Clinically relevant at 15%

What is a DAA regimen used in patients with RASs?

Sofosbuvir/velpatasvir/voxilaprevir - 12 weeks

What database can be used to determine drug resistance mutations to different DAAs?

HCV-Glue

What are three situations which could result in HCV RNA reoccurrence after 6 months?

1) Late relapse of majority variant 2) Persistence of minority variant 3) Reinfection with a different virus

What populations appear to have a higher rate of HCV clearance and what biological mechanism is responsible?

IVDU who have recurrent infections appear to clear acute infections more recently than baseline Patients who clear initial infections have high levels of broadly neutralising antibodies

What is the rate of mother to child transmission of HCV?

4-8% (higher in HIV coinfection)

What tests should be performed on an infant born to HCV infected mother?

anti-HCV tested at 18 m

What risk does HCV in pregnancy have?

Increased risk of preterm delivery IUD Small babies

What DAAs are licensed in pregnancy?

None, treatment in pregnancy is not recommended

What is the risk of HCV transmission via breastmilk?

None

Why is universal HCV screening not recommended in pregnancy?

Does not fulfil criteria for screening in pregnancy 1) Seroprevalence in pregnancy is unknown 2) Risk factors of MTC transmission are unknown 3) High false positivity rate in low prevalence 4) No treatment in pregnancy 5) No treatment in children

How does HCV usually present in children? What are the risks of HCC? What is the treatment regimen for DAAs in children?

Most infection in children is asymptomatic HCC is very rare Treatment is the same as in adults for 12 year olds (sof/vel or glev/pib) In 3-11 y treatment is the same but dose adjusted

When should HCV treatment be performed in: a) HCV infected patients due for urgent transplant b) HCV infected patients listed for non urgent transplant c) HCV naïve patients transplanted with an organ from a HCV RNA positive patient

a) Treat after transplant (as soon as possible after the patient is stable, ideally within 3 months) b) Treat before transplant c) Either immediately following transplant (pre-emptive) or on the first RNA positive result

Can the following be donated from HCV RNA positive donors: a) organs b) Tissues c) HSPC, TC, HESC d) Gametes and embryos

a) Relative contraindication b) absolute contraindication c) Relative contraindication d) absolute contraindication

When should recipients who receive a HCV positive organ be tested post transplant?

RNA testing at day 3-7 post transplant and then again at d 10-14. Final test at 6 weeks post transplant

Can the following patients donate blood? a) anti-HCV positive, RNA positive b) anti-HCV positive, RNA negative

a) No b) No, unable to donate unless anti-HCV negative

Are dedicated dialysis machines and segregation required for patients who are HCV RNA positive?

Dedicated machines and segregation not required for HIV or HCV infected patients

How often should dialysis patients be tested for HCV? And with what tests?

Every 3 months anti-HCV unless risk factors for HCV acquisition and then RNA testing required

When can a HCW who has HCV be cleared for EPPs?

Only when treated or spontaneously cleared and with an SVR at 12 weeks (confirmation of clearance required at 24 weeks)

What is the target for HCV elimination?

65% reduction in mortality and 90% reduction in new infections by 2030

What pangenotypic regimen can be used to treat HCV in decompensated disease?

Sofosbuvir and velpatasvir with weight based ribavirin for 12 weeks (or 24 weeks if ribavirin contraindicated)