Synonyms: HCV; non-A, non-B (NANB) hepatitis

• HCV is blood-borne and, based upon differences in molecular structure, a number of different strains (genotypes) have been described.
• The incubation period of acute hepatitis C is usually between 6 and 9 weeks.¹
• HCV infection may be acute or chronic. Acute hepatitis C is usually asymptomatic and often does not come to light until some years after infection. 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.
• Individuals who do recover from acute infection are not at risk of long-term sequelae and do not need treatment, but only about 20% of those with acute infection will experience spontaneous viraemia resolution.²

Routes of transmission

Hepatitis C is transmitted via:

• Parenteral, especially by intravenous drug use, but also blood transfusion received before September 1991 (since 1991 all blood used in the UK has been screened for HCV).
• Haemodialysis.
• Sexual contact with an infected individual; sexual transmission is low (less than 1% per year of a relationship) but the rate increases when also infected with HIV.³
• Needle-stick injuries in the healthcare setting result in a 3% risk of HCV transmission.²
• Perinatal transmission from an infected mother.

Epidemiology⁴

• Current models suggest that there were about 191,000 people aged 15-59 years with antibodies to hepatitis C virus (HCV) in England and Wales in 2003 (which equates to about 142,000 people in this age group living with chronic hepatitis C infection).
• Deaths, transplants and hospital admissions for hepatitis-related end-stage liver disease continue to rise.
• Worldwide, 170 million people (3% of the world's population) are infected.
• However, there is a very large number of undiagnosed cases and estimates of true prevalence are much higher.
• Six major genetic types of HCV have been found:⁵
  • Genotype 1 is the most common in the UK, accounting for about 40-50% of cases.
  • Genotypes 2 and 3 make up another 40-50%.
  • Genotypes 4, 5 and 6 make up the remaining cases.
• Patients can be infected by more than one genotype.

Risk factors

• Drug misuse:
  • Injecting drug use remains the single most important reported risk factor for acquiring hepatitis C infection.
  • Transmission of hepatitis C may also be possible by nasal inhalation of drugs, e.g. cocaine.
  • In 2006, the prevalence of hepatitis C infection amongst those who have recently started injecting drugs within the last three years remained high at 22%.
  • In Northern Europe, about 70% of infected patients have been intravenous drug users.⁶
  • The major route of HCV transmission in the UK is by sharing equipment for injecting drug use, usually via blood-contaminated needles and syringes. Other drug injecting equipment (e.g. spoons and filters) may also transmit the infection if it is contaminated with infected blood.
• Blood transfusions:
  • Receiving a blood transfusion before September 1991 has since been shown to account for the majority of cases of post-transfusion NANB hepatitis.
• Pregnancy and breast-feeding:
  • Mother to baby (before or during birth); transmission rate from mother to child is about 6%.⁵ However, this is increased to around 14-17% when there is co-infection with HIV.
  • Breast-feeding is considered safe.
• Sexual intercourse:
  • Sexual transmission of HCV is possible but uncommon.⁷ Less than 5% of the regular sexual partners of people with HCV infection will become infected.
  • Studies have shown that individuals with multiple sexual partners have a slightly increased prevalence of hepatitis C compared with the general population.
• Other routes of transmission:
  • Needle-stick injury is a significant risk for healthcare workers and other groups such as police, prison staff and social workers. There is a 3% infection rate following needle-stick injury with an HCV-positive source.⁸
  • The use of medical and dental treatment with unsterile equipment.
  • Tattooing, ear piercing, body piercing or acupuncture when performed with unsterile equipment.
  • Sharing razors or toothbrushes which are contaminated with blood.
• Certain factors are associated with more rapid progression to severe liver disease. These include:
  • Being over 40 years old at the time of infection
  • Alcohol consumption
  • Male gender
  • Co-infection with HIV or hepatitis B:
    • As many as a third of patients with HIV also have HCV.⁹
    • 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.
  • Immuno-suppressive therapy

Presentation⁵

• People infected with hepatitis C virus (HCV) are often asymptomatic.
• Many people who are chronically infected will experience non-specific symptoms including malaise, weakness and anorexia.
• Clinical features are worse if there is a high alcohol intake or other liver disease³.
• About 80% of those exposed go on to develop chronic hepatitis.

Acute HCV infection

• The majority are asymptomatic. 20-30% present with jaundice or deranged liver enzymes - alanine aminotransferase (ALT); and 20-30% have non-specific symptoms such as anorexia, lethargy or abdominal pain.
• Average time from exposure to onset of symptoms is 6-7 weeks and, to seroconversion, 8-9 weeks (can take up to nine months).
• 15%-25% of patients appear to clear the virus without sequelae (no detectable virus and normal liver function tests (LFTs), but remainder develop chronic infection.

Chronic HCV infection

• 75-85% of patients.
• It is indicated by persistently elevated or fluctuating liver enzyme levels.
• Chronic infection often goes unrecognised for 10-20 years unless identified when a patient volunteers for blood donation or has LFTs performed (aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT).
• Cirrhosis develops in 10-20% after 20-30 years, and some develop hepatocellular carcinoma.

Investigations

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

• Screening for hepatitis C virus (HCV) in general practice is recommended for unexplained abnormal LFTs and for any person in an at-risk group.⁵
• 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 renal disease.
• HCV serology is positive three months after exposure in 90% of cases but may take as long as nine months to become positive.³
• Ongoing infection is confirmed in those with positive serology by testing for HCV RNA.⁵ A negative test, despite positive serology, suggests non-viraemic infection, transient absence of viraemia or recovered infection, a level of viraemia below the detection limit of the assay, or may reflect a non-specific ELISA result.
• The quantitative measurement of HCV RNA concentrations in serum and the determination of HCV genotype are recommended and should be used in helping to determine the duration of treatment.
• Spontaneous resolution of acute hepatitis C results in the loss of HCV RNA within the first two months. Only those HCV RNA positive for more than two months need to be treated.³
• Assessing severity of disease:⁵
  • Liver biochemistry is insensitive at predicting disease severity and normal results do not exclude progressive liver disease or cirrhosis.
  • Baseline ultrasound should be performed to look for focal lesions, splenomegaly (a marker of portal hypertension), or frank features of cirrhosis, although normal findings on imaging do not exclude cirrhosis.
  • Liver biopsy has limitations but is often used if treatment is to be deferred, if other cofactors may have contributed to liver disease (e.g. steatosis, iron overload, or alcohol), or if different non-invasive markers of fibrosis are discordant.
  • Non-invasive methods for assessing fibrosis are evolving and include using serum markers (e.g. macroglobulin, haptoglobin, apolipoprotein A1, GGT and total bilirubin) or with transient elastography, in which a shear wave is generated and tracked through the liver using ultrasound.
• Liver biopsy:
  • Is valuable to provide an histological assessment of the severity of liver inflammation, potential progression of fibrosis, and the presence or absence of cirrhosis (LFTs correlate poorly with both necro-inflammatory and fibrosis scores found on liver biopsy).
  • It may also be used to assess suitability for treatment (but the need for biopsy as a guide to treatment has been questioned).
  • Biopsy is recommended for patients found to be viraemic, whether or not liver function tests are abnormal. Standard histological scoring systems by a suitably experienced pathologist, should be used to encourage uniformity of histological reports.

HIV testing should be considered in all patients with HCV.¹⁰ Patients should also be tested for serological evidence of previous infection with hepatitis A or B, and immunisation offered to those without evidence of previous infection.⁵

Associated diseases

There is an increased risk of developing diabetes mellitus in patients with hepatitis C virus (HCV) infection.¹¹ There is also an increased risk of developing the following conditions:

• Sjögren's syndrome
• Essential mixed cryoglobulinaemia
• Polyarteritis nodosa
• Autoimmune hepatitis
• Thyroiditis
• Membranous glomerulonephritis
• Porphyria cutanea tarda
• Lichen planus
• Idiopathic thrombocytopenic purpura

Management

• Early diagnosis is essential for effective patient care. Refer to a specialist with a particular interest in hepatitis C virus (HCV).
• Arrange counselling from a health carer with knowledge and experience of chronic HCV infection - on the implications of HCV positivity, the risks of passing on the infection and risk reduction.
• Patients with HCV should not donate blood, organs, tissues or semen.
• The risk of sexual transmission is small - maximum of 5%, but possibly much less. There is insufficient evidence firmly to recommend barrier contraception in stable monogamous relationships but is strongly advised for HCV-infected patients with multiple sexual partners.
• Patients should be advised that excess alcohol consumption appears to hasten the progression of disease. Abstinence from alcohol is advisable.¹²
• Drug therapy should be considered for all patients with hepatitis C.¹

Drug treatment¹³

The effectiveness of treatment is related to the genotype of the virus. In trials for people with moderate or severe hepatitis C, about 75-85% of people with HCV genotype 2 or 3 had a sustained virological response six months after finishing a course of treatment with peginterferon alfa and ribavirin, compared with 40-50% of people with genotype 1, and somewhere in between these response levels for the three less common genotypes (4, 5 and 6).

• Peginterferon alfa-2a (or alfa-2b) and ribavirin can be prescribed in line with current NICE guidelines.^13,14
• Combination therapy with peginterferon alfa-2a (or alfa-2b) and ribavirin is recommended for the treatment of mild chronic hepatitis C.
• Monotherapy with peginterferon alfa-2a or peginterferon alfa-2b is recommended for the treatment of mild chronic hepatitis C for people who are unable to tolerate ribavirin, or for whom ribavirin is contra-indicated.
• A person with mild chronic hepatitis C can be treated immediately or wait until the disease has reached a moderate stage ('watchful waiting') depending on the views of the patient following a fully informed consultation with the responsible clinician.
• Current recommendations are to use combination therapy for varying times according to genotype:¹
  • Treatment of genotypes 1, 4, 5, and 6 requires 48 weeks of pegylated interferon and ribavirin and leads to sustained viral response rates of between 38 to 50%.
  • Treatment of genotype 2 and 3 requires 24 weeks of pegylated interferon and ribavirin and leads to sustained viral response rates of between 75 to 80%.
  • A minimum of a 100-fold drop in viral load is required to continue treatment beyond 12 weeks. If this is not achieved then treatment is stopped early as further therapy is likely to be futile.
• Second or subsequent courses of treatment are not recommended for people who have been treated with a first course of either combination therapy or monotherapy with peginterferon alfa if they have not had an early response (as indicated by reduction in viral load at 12 weeks).
• There is insufficient evidence to recommend combination therapy or monotherapy with peginterferon alfa for people with mild chronic hepatitis C who are under the age of 18 years, or those who have had a liver transplant.

Further management

• After successful eradication of virus, patients with substantial fibrosis or cirrhosis require long-term follow-up, e.g. to monitor for complications such as hepatocellular carcinoma and oesophageal varices.⁵
• Consideration should be given to entering patients with established cirrhosis into surveillance programmes for hepatocellular carcinoma (provided their general health is good enough that emerging cancers could be appropriately treated). SIGN recommends that all patients with HCV and cirrhosis should have a six-monthly ultrasound scan to screen for hepatocellular carcinoma.¹⁵
• Some people with end-stage liver disease or hepatocellular carcinoma may need liver transplantation.⁵

Complications

Acute fulminant hepatitis is rare (<1% of all hepatitis C infections), but is more common after hepatitis A superinfection of chronic hepatitis C carriers. Mortality in acute hepatitis is very low.
• Cirrhosis develops in about 20-30% of patients over a period of 20 to 30 years.²
• 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.

Prognosis⁵

• The rate of progression of the disease is slow but variable.
• Approximately 50-85% of patients infected with hepatitis C virus (HCV) become chronic carriers.
• Type 1 genotype is more likely to clear spontaneously but leads to more severe chronic infection.³
• The chronic carrier state rarely resolves spontaneously.
• About 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.
• Co-infection with both hepatitis B and alcohol seem to have an additional effect.

Prevention

• No vaccine is currently available for hepatitis C virus (HCV).
• Patients and at-risk groups should be counselled to minimise transmission.
• Prevention strategies target those groups at greatest risk of infection (e.g. intravenous drug users and in prisons), and include:
  • Improving education on drugs
  • 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

Document references

1. Guidance for the Prevention; Testing; Treatment & Management of Hepatitis C in Primary Care, Royal College of General Practitioners (2007)
2. Mukherjee S; Hepatitis C.; eMedicine, June 2009.
3. Management of the Viral Hepatitides A, B and C, British Association for Sexual Health & HIV (2008)
4. Hepatitis C, Health Protection Agency
5. Nash KL, Bentley I, Hirschfield GM; Managing hepatitis C virus infection. BMJ. 2009 Jun 26;338:b2366. doi: 10.1136/bmj.b2366.
6. Hope VD, Judd A, Hickman M, et al; Prevalence of hepatitis C among injection drug users in England and Wales: is harm reduction working? Am J Public Health. 2001 Jan;91(1):38-42. [abstract]
7. Balogun MA, Ramsay ME, Parry JV, et al; A national survey of genitourinary medicine clinic attenders provides little evidence of sexual transmission of hepatitis C virus infection. Sex Transm Infect. 2003 Aug;79(4):301-6. [abstract]
8. Department of Health; Guidance for clinical health care workers: protection against infection with blood-borne viruses (April 1998)
9. Bonacini M, Puoti M; Hepatitis C in patients with human immunodeficiency virus infection: diagnosis, natural history, meta-analysis of sexual and vertical transmission, and therapeutic issues. Arch Intern Med. 2000 Dec 11-25;160(22):3365-73. [abstract]
10. Management of co-infection with HIV-1 and hepatitis B or C virus, British HIV Association (2010)
11. Knobler H, Schihmanter R, Zifroni A, et al; Increased risk of type 2 diabetes in noncirrhotic patients with chronic hepatitis C virus infection. Mayo Clin Proc. 2000 Apr;75(4):355-9. [abstract]
12. Hepatitis C : quick reference guide for primary care, Department of Health (2009)
13. Hepatitis C - peginterferon alfa and ribavirin, NICE (2006); Peginterferon alfa and ribavirin for the treatment of mild hepatitis C
14. Hepatitis C - pegylated interferons, ribavarin and alfa interferon, NICE Technology Appraisal (2004); Interferon alfa and ribavirin for the treatment of chronic hepatitis C - part review of exisiting guidance no.14
15. Management of hepatitis C, SIGN (2006)

Internet and further reading

• Department of Health; Hepatitis C
• Department of Health; Hepatitis C infected health care workers
• Hepatitis C, Health Protection Agency

Acknowledgements