Hepatitis C

Synonym: non-A, non-B (NANB) hepatitis

What is hepatitis C?

Hepatitis C virus (HCV) was first identified in 1989. It is an enveloped RNA virus in the Flaviviridae family and Hepacivirus genus, with a narrow host range (humans and chimpanzees).

• HCV is blood-borne and, based upon differences in molecular structure, a number of different strains (genotypes) have been described (see Epidemiology, below).

• The incubation period of hepatitis C is between four to twenty weeks.¹

• HCV infection causes both acute and chronic infection. Acute hepatitis C is often asymptomatic (only about 20% of patients experience symptoms) and frequently does not come to light until some years after infection. Between 15 to 45% of people with acute hepatitis C spontaneously clear the infection within six months without treatment; the remainder develop chronic infection.² Hepatitis C is often diagnosed after routine blood testing, with the onset of hepatic impairment, or when screening a person at risk or a blood donor.

How is hepatitis C transmitted? (Routes of transmission)

Hepatitis C is transmitted via:

• Sharing needles and/or syringes amongst people who use intravenous drugs.

• Unsafe healthcare practices. These are (now) exceptionally rare in many countries, including the UK, but are an important route of transmission globally. They include:

  • Re-use of unsterilised, contaminated needles and equipment; this may particularly affect people receiving dialysis, surgery, and dental care.

  • Transfusion with unscreened blood. In the UK, all blood used for transfusions has been screened for HCV since 1991 - but an estimated 26,800 people were infected with HCV through blood transfusions in the UK between 1970 and 1991.³

• Sexual transmission.

  • This is very rare in heterosexual relationships (the transmission risk over 10 years is <0.1% in long-term heterosexual relationships between a person with, and a person without, HCV), but is more likely if the person with HCV also has HIV.¹

  • Rates are higher amongst men who have sex with men; this is largely linked to HIV co-infection, but may also relate to the presence of other STIs (eg, syphilis and lymphogranuloma venereum), traumatic anal sex, fisting, shared sex toys, group sex, sero-sorting, communal lubricant and recreational drug use.¹

  • Sex workers also appear to have higher rates of infection.¹

• Needlestick injuries, in healthcare workers.

• Other exposures to contaminated needles, eg, tattooing and body piercing.

• Sharing razors with a person with HCV.

• Mother-to-child transmission, which may occur intrauterine, intrapartum, and postnatally.⁴

• Sharing banknotes and straws to snort drugs, such as cocaine or heroin.

  • HCV rates are higher in cocaine users who have never injected drugs;⁵ blood and HCV RNA have been detected in the nasal secretions and drug-sniffing implements of intranasal drug users with HCV infection.⁶

The risk of transmission increases when an individual is also infected with HIV.

How common is hepatitis C? (Epidemiology)⁷

• The most recent modelled estimates suggest that around 92,900 people in the UK had chronic HCV at the end of 2021.

  • HCV prevalence in the UK has reduced substantially (by 47%) since 2015, which may be due, largely, to better access to direct-acting antiviral treatment.

• In the UK, only about 28% of people with HCV who inject drugs were aware of their infection in 2021, although this may have been reduced by the impact of the Covid-19 pandemic on diagnosis and treatment.

• Deaths from HCV-related end-stage liver disease and hepatocellular carcinoma fell by 31% between 2015 and 2020 in the UK; again, this is likely to be due to better access to direct-acting antivirals.

• Worldwide, an estimated 56.8 million people had HCV infection in 2020.⁸

  • Only 12.9 million (just under a quarter) of those had a diagnosis of HCV.⁸

• There are seven major genotypes of HCV (although an eighth has also been described⁹ ). These genotypes have differences in prognosis and may influence treatment decisions.¹⁰
  

  • Genotypes 1 and 3 are the most common subtypes of hepatitis C in the UK.¹¹

  • Genotype 1 is the most common subtype globally, though there is significant regional variation. For example:¹²

    • Genotype 2 is prevalent in West Africa (about 63% of HCV infections).

    • Genotype 4 is highly prevalent in Egypt (93% of HCV infections).

    • Genotype 6 is relatively common in Southeast Asia (31% of HCV infections).

    • Genotype 7 has only been reported once, in four immigrants to Canada from the Democratic Republic of Congo.¹³

  • Patients can be infected by more than one genotype.

Chronic HCV infection²

• Between 55 to 85% of patients with hepatitis C will develop chronic infection.

• Chronic hepatitis C infection can lead to progressive liver fibrosis and cirrhosis.

• Cirrhosis develops in 15-30% of people with chronic hepatitis C after 20 years.

• Each year, around 1-3% of patients with cirrhosis develop hepatocellular carcinoma and 2-5% develop liver failure.

Risk factors

Risk factors for hepatitis C relate to exposure to routes of transmission; see "Routes of transmission", above.

In the UK, at-risk groups for HIV include:^{7 1}

• People who inject drugs (PWID). This is the most important risk factor for HCV infection in the UK. Over half of PWID in the UK have had HCV infection at some point.⁷

• Men who have sex with men.

• Sex workers.

• People from highly endemic countries.

• Children of women with HCV.

• Prisoners and former prisoners.

• Tattoo recipients (although the risk of contracting HCV from professional tattoo parlours using standard hygiene and sterilization procedures is very small, and probably zero¹⁴ ).

• People who snort cocaine.

• People with alcohol dependence and alcohol addiction.

• Recipients of blood transfusions pre-1991 in the UK, or recipients of unsafe blood transfusions in other countries.

Other routes of transmission:

Certain factors are associated with poorer prognosis and complications. They include:¹⁵

• HCV genotype: genotypes 1, 4, 5, and 6 are less responsive to antiviral treatments. However, genotype 3 has higher rates of steatosis, cirrhosis, and hepatocellular carcinoma.¹⁶

• Being over 40 years old at the time of infection.

• Heavy alcohol consumption.

• Male gender.

• Certain ethnicities. Black African-American and Hispanic people seem to have lower sustained viral response rates to antivirals, compared to White and Asian people.

• Overweight and obesity.

• Smoking.

• Co-infection with HIV or hepatitis B:
  

  • As many as a third of patients with HIV also have HCV.

  • With increased survival in patients with HIV, the major burden of disease is becoming end-stage liver disease secondary to HCV infection with rapidly progressive fibrosis and cirrhosis.

  • Co-infection leads to earlier and more severe liver disease.

• Immunosuppression for any reason, which increases the risk of cirrhosis and hepatocellar carcinoma.

Needlestick injury

Symptoms of hepatitis C (presentation)¹⁸

• People with HCV infection are often asymptomatic.

• Many people who are chronically infected will experience nonspecific symptoms, including malaise, weakness and anorexia.

• Clinical features are worse if there is a high alcohol intake or other liver disease.

Acute HCV infection^{19 18}

• The majority are asymptomatic. Around 20% or fewer patients have symptoms.

• If symptomatic, clinical features include jaundice, myalgia, low-grade fevers, right upper quadrant pain, nausea, and deranged liver enzymes.

• Acute hepatitis can occur 2-12 weeks after exposure (the average is 7 weeks).

• It lasts for 2-12 weeks.

• The time between acute infection and seroconversion is about 6-8 weeks, but it can be longer in patients infected via blood transfusion.

• Hepatitis C RNA is detectable before anti-HCV antibodies; therefore, the diagnosis of acute HCV can be confirmed with a positive HCV RNA test.

• 15-45% of patients appear to clear the virus without sequelae (no detectable virus and normal LFTs; however, the remainder develop chronic infection.

  • Detectable HCV RNA at 12 weeks after exposure predicts chronic infection.

Chronic HCV infection

• Chronic HCV is indicated by persistent viraemia, as measured by detectable HCV RNA.

• Chronic infection can easily go unrecognised, unless complications develop, viral serology is done for another reason (eg, blood donation), liver function tests are checked for another reason and are abnormal, or the patient is specifically screened for HCV.

Diagnosing hepatitis C (investigations)¹⁵

Investigations should include a full assessment for other possible causes of abnormal LFTs, hepatitis, cirrhosis or any other individual presentation.

Screening for HCV in general practice is recommended for unexplained abnormal LFTs and for any person in an at-risk group.²⁰

Patients with suspected HCV infection should be tested for anti-HCV serology. False negatives can occur in patients with acute infection, immunodeficiency or end-stage kidney disease. HCV serology is positive three months after exposure in 90% of cases but may take as long as nine months to become positive.

Testing for hepatitis C

• In immunocompetent people: antibodies to hepatitis C virus, indicating if a person has ever been infected with HCV.

• If the antibody test is positive, or in immunocompromised people: HCV RNA (to check if HCV infection is active) and genotype analysis.

• If the antibody test is negative, consider repeating it (especially if the person is at high risk of infection).

• Repeat the antibody test at an appropriate time if the last risk exposure occurred within the 3- to 6-month 'window period' of the test, as it can take at least three months for antibodies to become detectable.

• Seek specialist advice if there is uncertainty about the optimal time to repeat the test.

• Repeat HCV RNA after 6/12 if antibodies are positive but HCV RNA is negative.

  • If the repeat HCV RNA is negative, this indicates past (cleared) HCV infection; however, these individuals are not immune to re-infection, and should be counselled as such.

• Repeat HCV RNA if positive to confirm diagnosis.

Other initial baseline investigations
These should include:

• FBC, renal function and electrolytes, LFTs, clotting screen, HbA1c, TFTs, ferritin.

• Hepatitis A serology: hepatitis A immunoglobulin M (HAV-IgM).

• Hepatitis B serology: hepatitis B surface antigen (HBsAg) or antibody to hepatitis B core antigen (anti-HBc).

• HIV test.

• Also consider screening for other sexually transmitted infections, if hepatitis C infection is thought to have been sexually acquired.

Further investigations
Further specialist investigations to assess the state of infection and progression of liver disease may include:

• Blood tests: viral load to assess response to treatment; clotting studies; autoantibodies.

• Transient elastography (eg, FibroScan®) can be offered to diagnose cirrhosis. If this is not suitable, liver biopsy can be offered.

• Liver ultrasound is used in people with advanced fibrosis or cirrhosis to screen for hepatocellular cancer. Ultrasound cannot accurately assess the degree of inflammation or liver fibrosis, or predict the prognosis.

• Liver biopsymay be considered in individual cases - for example, to assess the extent of liver damage caused by inflammation, fibrosis, or cirrhosis; to identify iron overload; and to exclude other causes of liver damage. However, liver biopsy has largely been replaced by non-invasive investigations such as transient elastography (Fibroscan®).

Associated diseases

There is an increased risk of developing diabetes mellitus in patients with HCV infection. There is also an increased risk of developing the following conditions:

• Sjögren's syndrome.

• Depression.

• Essential mixed cryoglobulinaemia.

• Polyarteritis nodosa.

• Autoimmune hepatitis.

• Thyroiditis.

• Membranous glomerulonephritis.

• Porphyria cutanea tarda.

• Lichen planus.

• Immune thrombocytopenia.

Management of hepatitis C^{15 1}

Notify the local Health Protection Team of suspected cases of acute viral hepatitis by completing a notification form immediately. Provide sources of support and information about hepatitis C, including British Liver Trust and Hepatitis C Trust.

Acute HCV

• From general practice, arrange a same-day assessment or immediate specialist advice if suspected acute HCV (hepatitis C antibody positive with clinical features of acute hepatitis, and/or a likely recent source of transmission is identified).

• Further investigation, monitoring, and treatment should be undertaken by specialists.

Specialist treatment for acute HCV is an evolving area.

• The direct acting antivirals (see below) were originally trialled and licensed for chronic HCV only, and some have advocated waiting to see if chronic HCV develops before treating. However, evidence suggests that treatment of acute HCV reduces the risk of progression, chronicity, and transmission.^{21 1}

  • The 2017 BASHH guidelines recommend measuring HCV-RNA at 4 and 12 weeks post-presentation in acute HCV. If HCV-RNA levels do not fall sufficiently at 4 weeks, or are still detectable at 12 weeks, the patient should be referred to a specialist centre for treatment and consideration of clinical trial recruitment.¹

  • The 2020 European Association for the Study of the Liver (EASL) guidelines instead recommend treating all people with acute hepatitis C (or 'recently acquired' hepatitis C) with either sofosbuvir and velpatasvir, or glecaprevir and pibrentasvir, for eight weeks.²¹

Chronic HCV^{21 1}

• From general practice, arrange urgent specialist referral if a person has suspected chronic hepatitis C infection (hepatitis C antibody positive and RNA positive with no clinical features of acute hepatitis).

• Further investigation, monitoring, and treatment should be undertaken by specialists.

Direct acting antiviral therapy

Treatment of hepatitis C was revolutionised by the development of direct acting antivirals (DAAs). These became available from 2011 onwards, and are now the mainstay of HCV treatment.²²

Interferon and ribavirin combination therapy was previously the standard treatment for HCV. DAAs have supplanted these, having both greater efficacy and tolerability. In some situations, ribavirin may still be used in combination with DAAs, such as when resistance-associated substitutions are present.¹

• All patients with chronic HCV should be assessed for DAA treatment.¹

• The goal of treatment is to cure HCV infection and thereby prevent complications, improve quality of life, and prevent transmission.

• The specific endpoint of HCV treatment is a sustained virologic response (SVR), defined as undetectable HCV-RNA in serum or plasma 12-24 weeks after completing treatment.

• SVR corresponds to a definitive cure in the vast majority of cases.

• Greater access to DAA treatment is thought to be the main driver behind HCV prevalence, morbidity, and mortality falling in recent years.⁷

Choice of DAA depends on many factors, including the HCV genotype, patient comorbidities, interactions with other drugs (particularly HIV medications), and other special situations such as pregnancy. The EASL guidelines cover these in detail,²¹ as does the Infectious Diseases Society of America (IDSA) and American Association for the Study of Liver Diseases (AASLD)'s 'living guideline' online, which is updated regularly.²³

Liver transplantation

Chronic HCV infection can lead to end-stage liver disease, necessitating liver transplantation. If HCV-RNA is detectable at the time of transplantation, the infection will recur, potentially leading to fibrosing hepatitis and graft failure if not treated.

DAA treatment is therefore recommended in this group, but the timing of it in relation to the transplant is controversial. One consensus opinion is that, in patients with severe, high-risk decompensated cirrhosis, transplantation should occur first with DAA therapy afterwards. However, patients who are likely to be waiting 6 months or longer for a liver transplant should receive DAA treatment first.¹⁸

General advice for patients¹

• Reassure patients that hepatitis C is curable with treatment.

• Give advice, where applicable, to stop drinking alcohol and stop smoking. Patients should be advised that excess alcohol consumption appears to hasten the progression of disease. Moderating, and ideally ceasing, alcohol intake is therefore essential.

• Advise patients to maintain a healthy weight and diet - which reduces the risk of fatty liver disease.

• Give a detailed explanation of their condition, with emphasis on the long-term implications for their health and that of their partner(s), with clear and accurate written information.

• Advise patients of routes of transmission. In particular, advise patients:

  • Not to donate blood, semen, or organs.

  • Not to share razors, toothbrushes, or anything else that could be contaminated with blood.

  • Not to share drug paraphernalia for snorting, injecting, or smoking drugs. Consider signposting to needle exchange services and/or drug treatment clinics.

• Discuss the risk of sexual transmission with patients.

  • Consistent condom use should prevent transmission. However, outside of HIV co-infection, sexual transmission rates amongst monogamous heterosexual couples are very low, and some may choose not to use them. Note that anal sex has a higher risk of transmission.

  • Advise on measures for higher-risk sexual practices; for example, consistent condom use, use of gloves for fisting, not sharing sex toys, not sharing lube, and avoiding group sex situations.

• Encourage patients to notify their household, their sexual partner(s), and anyone their share injecting drug equipment with, so that they can come forward for testing.

• Offer hepatitis A and B vaccination.

• Advise the person that they may be eligible for financial compensation if they were alive on 29 August 2003, and have chronic hepatitis C that is attributable to NHS treatment with blood or blood products received before September 1991.

Further management

• After successful eradication of the virus, patients with substantial fibrosis or cirrhosis require long-term follow-up - eg, to monitor for complications such as hepatocellular carcinoma and oesophageal varices²⁰ .

• Individuals can become re-infected with HCV after curative treatment; HCV screening should continue if they remain at risk of HCV.²⁴

• Liver fibrosis often regresses after viral eradication. However, some patients (particularly those with heavy alcohol use or fatty liver disease) may still progress to worsening fibrosis and cirrhosis, and may require enhanced monitoring.²⁴

• Long-term outcomes after DAA treatment are substantially better than for untreated HCV, but there may still be a residual increased risk for hepatocellular carcinoma.²⁵

Complications of hepatitis C

Hepatitis C can lead to cirrhosis, end-stage liver failure, and death.

Patients who develop cirrhosis are at increased risk of hepatocellular carcinoma:

• Between 1% and 5% of those infected with HCV will develop primary liver cancer.

• Hepatocellular carcinoma is suggested by weight loss and raised alpha-fetoprotein level.

Extrahepatic manifestations (as detailed above) may also develop.

Prognosis

The rate of progression of the disease is slow but variable. Approximately 55-80% of patients infected with HCV become chronic carriers. The chronic carrier state rarely resolves spontaneously.

If untreated, about 15-30% of those who are infected develop cirrhosis within 20-30 years and a small percentage of these people are at a high risk of developing hepatocellular carcinoma. A third may never progress to cirrhosis or will not progress for at least 50 years.

DAA treatment leads to high rates of SVR (and therefore cure). People with HCV who achieve SVR have an 87% reduction in liver-related mortality, an 80% reduction in HCC incidence, and a 75% reduction in all-cause mortality, compared to people with HCV who do not reach SVR.² As detailed above, however, individuals cured of HCV may still have residual liver fibrosis or cirrhosis, which may lead to adverse sequelae in future.²⁵

Prevention of hepatitis C²

• WHO has set a goal of eliminating HCV as a public health threat by 2030 (defined as a reduction in HCV incidence of 90%, and HCV deaths by 65%).

• No vaccine is currently available for HCV.²⁶

• DAA treatment is not currently recommended as post-exposure prophylaxis for HCV.²¹

• Identification and prompt treatment of people with HCV has a high likelihood of cure, reducing onwards transmission rates. Screening at-risk groups for HCV may help to achieve this.

• Patients and at-risk groups should be counselled to minimise transmission.

• Prevention strategies target those groups at greatest risk of infection (eg, intravenous drug users and in prisons) and include:
  

  • Improving education on illicit drug use.

  • Reducing initiation of injecting drug use.

  • Helping intravenous drug users to quit injecting.

  • Minimising harm for those who continue to inject.

  • Promoting the use of condoms, especially for those with multiple partners.