Hepatitis C

Hepatitis C is a bloodborne viral infection of the liver caused by hepatitis C virus, a single stranded ribonucleic acid flavivirus.

It is transmitted predominantly through percutaneous exposure to infected blood, most commonly via injection drug use and, historically, unscreened blood products.

It has a striking tendency toward chronicity that distinguishes it markedly from hepatitis A and B.

The availability of highly effective, well tolerated direct acting antiviral therapy has transformed management from a chronic, difficult to treat infection into a curable disease.

Pathophysiology and natural history

• Following acute infection, spontaneous viral clearance occurs in only a minority of individuals, typically within six months.
• The large majority (approximately seventy five to eighty percent) progress to chronic infection, reflecting the virus's capacity for immune evasion through rapid mutation of surface epitopes.
• Chronic infection produces progressive hepatic fibrosis over years to decades. The mechanism is a combination of direct viral cytopathic effect and ongoing immune mediated inflammation.
• A substantial minority develop cirrhosis. Those with established cirrhosis carry an ongoing annual risk of hepatocellular carcinoma even following successful viral eradication.
• Multiple genotypes exist with differing global geographic distribution. They were historically relevant to treatment regimen selection, though this has become progressively less important with the advent of pangenotypic direct acting antiviral combinations effective across genotypes.

• Acute infection is asymptomatic in the large majority. Only a minority develop a mild, non specific illness (malaise, nausea, right upper quadrant discomfort, occasionally jaundice). The infection is therefore frequently entirely unrecognised at the time of initial acquisition.
• Chronic infection is similarly frequently asymptomatic for years to decades. It is often identified through incidental screening in at risk populations, or deranged liver function tests found on routine testing.
• In a proportion, presentation is with established complications of cirrhosis (variceal bleeding, ascites, encephalopathy) or hepatocellular carcinoma at a late stage.
• Non specific fatigue is a commonly reported symptom in chronic infection. Its relationship to the infection itself versus other contributing factors can be difficult to establish clinically.
• Extrahepatic manifestations occur in a meaningful proportion of chronic infection. They include mixed cryoglobulinaemia, porphyria cutanea tarda, and an association with type 2 diabetes and certain lymphoproliferative disorders.
• Mixed cryoglobulinaemia is associated with palpable purpura, arthralgia and, in more severe cases, glomerulonephritis, as detailed under cryoglobulinaemic vasculitis.

• Hepatitis C antibody testing is the initial screening test, indicating current or past exposure to the virus. It does not distinguish between active infection, spontaneously resolved infection, or successfully treated infection. A positive antibody result must therefore always be followed by confirmatory testing.
• Hepatitis C ribonucleic acid polymerase chain reaction testing confirms active, current infection where the antibody test is positive. A negative ribonucleic acid result in the context of a positive antibody indicates either spontaneous clearance of a prior infection or successful previous treatment.
• Genotype testing was historically essential for treatment regimen selection. It is now less critical given widespread availability of pangenotypic direct acting antiviral regimens. It may still be relevant in specific clinical circumstances or where resource constraints limit access to pangenotypic therapy.
• Assessment of liver fibrosis is essential at diagnosis. Use non invasive markers (such as the FIB 4 index, calculated from age, transaminases and platelet count), transient elastography, or, less commonly now, liver biopsy.
• It stages disease severity, identifies those with established cirrhosis requiring hepatocellular carcinoma surveillance, and guides overall management planning.
• Screening for hepatitis C is recommended for defined at risk groups. These are people who inject or have injected drugs, recipients of blood products or organ transplantation before widespread screening was introduced, individuals with HIV infection, men who have sex with men with high risk sexual behaviour, and infants born to hepatitis C positive mothers.
• Many jurisdictions are increasingly moving toward broader, universal one time screening. A substantial proportion of chronic infection remains undiagnosed through risk factor based screening alone.

• Direct acting antiviral therapy has transformed hepatitis C treatment. It achieves sustained virological response (considered a functional cure) in the large majority of treated patients. Treatment courses are generally short, at eight to twelve weeks, with minimal adverse effects compared with the historical interferon based regimens.
• Sofosbuvir with velpatasvir (400 mg with 100 mg, given as a single combination tablet once daily) for twelve weeks is a widely used pangenotypic first line regimen for patients without cirrhosis or with compensated cirrhosis. It is effective across all major genotypes without the need for genotype specific regimen selection.
• Glecaprevir with pibrentasvir (300 mg with 120 mg, given as three combination tablets once daily with food) for eight weeks in treatment naive patients without cirrhosis is a further widely used pangenotypic option. It offers a shorter treatment duration in this specific population. Extend it to twelve weeks in patients with compensated cirrhosis or in those who are treatment experienced.
• Regimen selection is individualised according to the presence and severity of cirrhosis, prior treatment history, renal function, and potential drug interactions. Decompensated cirrhosis requires specific regimens and specialist hepatology management, given contraindication to protease inhibitor containing regimens in this group.
• Review drug interactions carefully, given the significant interaction potential of several direct acting antiviral agents. This applies particularly to certain antiepileptic, antiretroviral and lipid lowering medications.
• Treatment response is confirmed by undetectable hepatitis C ribonucleic acid twelve weeks after completion of treatment (sustained virological response at twelve weeks). Achievement of this endpoint is considered a functional cure.
• It is associated with a substantially reduced risk of subsequent liver related complications. For those with pre-existing cirrhosis, the risk is not entirely eliminated.
• Continue hepatocellular carcinoma surveillance with six monthly liver ultrasound indefinitely in patients with cirrhosis, even following successful viral eradication. Risk remains elevated in this subgroup despite cure of the underlying viral infection.
• Harm reduction measures include needle and syringe exchange programmes and opioid substitution therapy where relevant. They are important both for individual patients, reducing reinfection risk following successful treatment in those with ongoing injection drug use, and at a population level for onward transmission reduction.
• Integrate harm reduction alongside antiviral treatment access for people who inject drugs. Do not withhold treatment in this population on the basis of ongoing drug use. Treatment efficacy is similar, and treatment as prevention brings substantial public health benefit in this group.
• There is no vaccine currently available for hepatitis C. Prevention relies entirely on harm reduction, blood product and donor organ screening, and infection control measures.
• Expanding treatment access is the primary strategy for reducing the overall burden and onward transmission of this infection at a population level.