Hepatitis

Hepatitis C

The hepatitis C virus is a bloodborne virus: the most common modes of infection are through exposure to small quantities of blood. This may happen through injection drug use, unsafe injection practices, unsafe health care, transfusion of unscreened blood and blood products, and sexual practices that lead to exposure to blood. Readmore...

Introduction

  • The hepatitis C virus is a bloodborne virus: the most common modes of infection are through exposure to small quantities of blood. This may happen through injection drug use, unsafe injection practices, unsafe health care, transfusion of unscreened blood and blood products, and sexual practices that lead to exposure to blood.
  • Globally, an estimated 71 million people have chronic hepatitis C virus infection. 
  • A significant number of those who are chronically infected will develop cirrhosis or liver cancer.

Epidemiology

  • The most affected regions are the WHO Eastern Mediterranean Region and the WHO European Region, with an estimated prevalence in 2015 of 2.3% and 1.5% respectively. 
  • In countries where infection control practices are or were historically insufficient, HCV infection is often widely distributed in the general population. There are multiple strains (or genotypes) of the HCV virus and their distribution varies by region. However, in many countries, the genotype distribution remains unknown.

Route of transmission

  • Blood and blood products
  • Vertical transmission from mother to child.
  • I.V drug users.
  • Haemodialysis.
  • Health care workers
  • Organ transplantation- recipients of HCV positive organs (e.g.- Liver transplantation)

Viral heterogenicity

  • Polymerase enzyme in HVC lacks proof reading ability.
  • This has lead to copying errors during replication.
  • Many mutants perish, but others persist and these account for tremendous viral diversity characteristic for HCV.
  • QUASISPECIES- many closely similar viral strains develop in the same host over time.
  • This ability to form multiple variants may help HCV escape immunity and its ability to cause chronic or persistent infections.
  • GENOTYPES- More than 50 subtypes described.
    • The most common subtypes are 1a, 1b, 2a, and 2b
    • Genotype 1 is most common (60 to 75 percent of isolates) in the United States, Latin America, and Europe; genotypes 2 and 3 are less common in these areas, while genotypes 4, 5, and 6 are rare.
    • Genotype 3 is most common in India, the Far East, and Australia.
    • Genotype 4 is most common in Africa and the Middle East.
    • Genotype 5 is most common in South Africa.
    • Genotype 6 is most common in Hong Kong and Vietnam.

Clinical features

Acute infection-

  • Many patients are asymptomatic after acute HCV infection.
  • Some may have- jaundice, nausea, dark urine, upper quadrant abdominal pain.
  • Incubation period- 2 to 26 weeks after exposure. 
  • Acute illness lasts for 2 to 12 weeks.
  • Lab- Elevated aminotransferase levels (often greater than 10 to 20 times the ULN), elevated bilirubin.

Chronic infection-

  • After HCV infection, chronic infection occurs in 50 to 85 percent of cases.
  • Symptoms- fatigue and sleep disturbance, other symptoms like nausea, abdominal pain, diarrhoea etc.
  • Extra hepatic manifestations- 
  • Hematologic diseases – essential mixed cryoglobulinemia and lymphoma.
  • Renal disease – membranoproliferative glomerulonephritis.
  • Autoimmune disorders – thyroiditis.
  • Dermatologic conditions – porphyria cutanea tarda and lichen planus.
  • Diabetes mellitus.

Pathophysiology-

Viral replication-

  • The infectious viral structure is comprised of envelope glycoproteins in a lipid bilayer that contain the viral core protein and RNA.
  • Cell entry  viral RNA is translated using host machinery into 10 viral proteins and some nonstructural (NS) proteins  NS3, NS4A, NS5A, NS5B.
NS3Proteolytic activity
NS4AMembrane protein- acts as cofactor
NS4BPart of the replication complex
NS5ARegulates and organises replication complex
NS5BRNA dependent RNA polymerase

Serologic markers-

  • HCV RNA 
  • Anti- HCV antibody

Diagnostic approach-

Whom to screen-

  • All individuals above 18 years, at least once in their lifetime.
  • In high risk populations- MSM’s, HIV infected, HBV infected patients, Patients on haemodialysis.
  • Patients with liver disease or with features similar to extrahepatic manifestations of HCV. (eg, porphyria cutanea tarda, mixed cryoglobulinemia).

Acute hepatitis- presenting with elevated enzymes +/- jaundice, we perform HCV RNA and anti-HCV antibodies.

  • HVC RNA -ve –> acute HCV unlikely.
  • Only anti-HCV –> previously cleared HCV infection.
  • HCV RNA +ve and anti-HCV antibody negative –> acute HCV infection.
  • HCV RNA +ve and anti-HCV antibody +ve –> HCV infection (cannot differentiate acute or chronic, unless recent HCV RNA or anti-HCV was done).
  • Patients with exposure –> needle prick injury, recent I.V drug abuse –> can do HCV RNA and anti-HCV at base line. These should be negative if done within 2 days, if patient is not previously infected.
  • If baseline results are negative –> not previously infected –> repeat testing at 4 weeks (HCV RNA and enzymes), and then at 12 weeks (HCV RNA and anti-HCV) and then at 6 months (HCV RNA, anti-HCV, and enzymes).
  • If HCV RNA remains undetectable –> no acute HCV infection.

FOLLOWING EXPOSURE –> HCV RNA –> detectable in days to 8 weeks.

                                        –> anti-HCV –> in 2 to 6 months.

Chart

Description automatically generated
Figure 1 Timeline of HCV infection

Chronic Hepatitis C-

  • Anti-HCV is performed. (will be positive for more than 6 months if acute  chronic infection)
  • If anti-HCV is reactive/ indeterminate  HCV RNA test.
  • If HCV RNA  detectable  chronic HCV.
  • If HCV RNA  undatable  previous cleared infection.
  • Anti-HCV can be negative even in HCV infected patients if they are severely immunocompromised (post transplantation, HIV, and haemodialysis patients), so we perform HCV RNA testing in these patients.

Management-

Goals of treatment-

  • SVR (sustained virological response)- undetectable RNA levels 12 weeks after therapy.
  • Preventing HCV related liver and extra hepatic complications.
  • Improve quality of life and remove stigma.

Indications for treatment-

  • Treatment naïve and treatment experienced patients who acquired HCV or chronic HCV patients should be treated.
  • Treatment is urgently recommended in- all individuals with high risk of transmitting it to others (MSM’s, sex workers, patients on haemodialysis etc), Coinfected patients (HIV or HBV).
  • Treatment is urgently recommended in patients with advanced fibrosis (METAVIR F2 OR F3), cirrhosis, compensated or decompensated liver disease and in with extra hepatic manifestations.

Contraindications for treatment-

  • cytochromeP450/P-gp-inducing agents (such as carbamazepine, phenytoin and phenobarbital) contraindicates all HCV DAA regimens.
  • Decompensated cirrhosis or with previous history of decompensation- HCV protease inhibitors are contraindicated- e.g. grazoprevir, grecaprevir or voxilaprevir.

Drugs-

  • Direct-acting antivirals are inhibitors of the NS3/4A protease, the NS5A protein, and the NS5B polymerase.
Figure 2 Directly acting antiviral agents

NS3/NS4A inhibitors

  1. Protease inhibitors disrupt HCV by blocking the NS3 catalytic site or the NS3/NS4A interaction.
  2. Glecaprevir — pangenotypic protease inhibitor available in combination with the NS5A inhibitor pibrentasvir. 
  3. Simeprevir — Simeprevir was the first available second-generation protease inhibitor.
  4. Voxilaprevir — Voxilaprevir is a potent, pangenotypic protease inhibitor, available in combination with the NS5B inhibitor sofosbuvir and the NS5A inhibitor velpatasvir. 

NS5A inhibitors-

Velpatasvir – available as FDC with sofosbuvir.

Ledipasvir- FDC with sofosbuvir.

Pibrentasvir- FDC with sofosbuvir.

NS5B inhibitors-

Nucleot(s)ide polymerase inhibitors (NPIs) — activated through phosphorylation to nucleoside triphosphate in hepatocyte  competes with nucleotides chain termination during RNA replication of the viral genome.

Sofosbuvir – 400mg OD.

Non-nucleoside polymerase inhibitors (NNPIs) — Dasabuvir. 

ProductPresentationPosology
Pangenotypic drugs or drug combinations
SofosbuvirTablets containing: 400 mg SOF1 tablet QD
Sofosbuvir/velpatasvirTablets containing: 400 mg SOF, 100 mg VEL1 tablet QD
Sofosbuvir/velpatasvir/
voxilaprevir
Tablets containing: 400 mg SOF, 100 mg VEL, 100 mg VOX1 tablet QD
Glecaprevir/pibrentasvirTablets containing: 100 mg GLE, 40 mg PIB3 tablets QD
Genotype-specific drugs or drug combinations
Sofosbuvir/ledipasvirTablets containing: 400 mg SOF, 90 mg LDV1 tablet QD
Ombitasvir/
paritaprevir/ritonavir
Tablets containing: 75 mg PTV, 12.5 mg OBV, 50 mg RTV2 tablets QD
DasabuvirTablets containing: 250 mg DSV1 tablet BID (am & pm)
Grazoprevir/elbasvirTablets containing 100 mg GZR, 50 mg EBR1 tablet QD

Figure 3 Doses of DAA’s used for HCV

Treatment of patients without cirrhosis or with compensated cirrhosis: general considerations-

  • IFN-free, ribavirin-free, DAA-based regimens must be used in HCV-infected patients without cirrhosis or with compensated (Child–Pugh A) cirrhosis, including:

Treatment-naïve (TN) patients- never been treated for their HCV infection

Treatment-experienced (TE) patients- previously treated with PEG-IFN + RBV; 
PEG-IFN
 + RBV + SOF; or SOF + RBV

  • The same IFN-free treatment regimens should be used in HIV-coinfected patients as in patients without HIV infection.

Abbreviations: DSV, dasabuvir; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; HCV, hepatitis C virus; IFN, interferon; LDV, ledipasvir; OBV, ombitasvir; PIB, pibrentasvir; PTV/r, paritaprevir/ritonavir; RBV, ribavirin; SOF, sofosbuvir; TE, treatment-experienced; TN, treatment-naïve; VEL, velpatasvir; VOX, voxilaprevir.

  • TN and TE patients (without cirrhosis/with compensated cirrhosis)
    • Fixed-dose SOF/VEL for 12 weeks
    • Fixed-dose GLE/PIB (8 weeks without cirrhosis; 12 weeks with cirrhosis)

After failure of DAA (PI and/or NS5A inhibitor)-containing regimen

  • First-line retreatment
    • SOF/VEL/VOX for 12 weeks (without cirrhosis/with compensated cirrhosis)
    • SOF/VEL + RBV for 24 weeks (decompensated cirrhosis)
  • Patients with predictors of poor response, SOF + GLE/PIB for 12 weeks:
    • Advanced liver disease
    • Multiple courses of DAA-based treatment
    • Complex NS5A RAS profile
  • Very difficult-to-cure patients: SOF/VEL/VOX + RBV or SOF + GLE/PIB + RBV for 12 weeks or for 16 or 24 weeks.

References:

  1. EASL recommendations on treatment of hepatitis C: Final update of the series- published 2020. link
  2. UpToDate- management recommendations for hepatitis C virus. link

Visit EASL GUIDELINES for further reading.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: