Hepatitis C virus （HCV） infection
Aetiology
An RNA virus in the flaviviridae family. It is endemic world-wide with high prevalence rates in South and East Asia and Eastern Europe. UK prevalence rates vary from 0.06% in blood donors to over 60% in IVDUs [128]. 5917 cases were reported in England and Wales in 2002 [129].
Transmission
·Parenteral spread accounts for the majority of cases through shared needles/syringes in IVDUs, transfusion of blood or blood products （pre-1990s）, renal dialysis, needle-stick injury or sharing a razor with an infected individual [130-135].
·Sexual transmission occurs at a low rate （approximately 0.2-2% per year of relationship, or 1-11% of spouses in long-term relationships） but these rates increase if the index patient is also HIV infected [136-143]. There is an increased rate of carriage （2%） in MSM attending GU clinics but this is largely linked to HIV co-infection [137, 138]. There is also evidence of increased rates of infection in female sex workers [61, 139], former prisoners, tattoo recipients and alcoholics [145-147].
·Vertical （mother to infant） spread also occurs at a low rate （5% or less in most studies）, but higher rates （up to 40%） are seen if the woman is both HIV and HCV positive [132, 136, 148-150]. Increased rates of transmission are seen in Japanese patients and in all groups transmission risk correlates with the presence of detectable HCV-RNA in the mother’s blood [149, 151, 152].
·Amongst blood donors, 50% of those with HCV infection do not admit to having risk factors [130, 153].
Clinical Features
Incubation period
Four to 20 weeks for the uncommon cases of acute hepatitis. HCV serology is usually positive （90%） three months after exposure but can take as long as nine months. Occasional cases of infection proven by RT-PCR （see “diagnosis”） do not result in positive antibody tests [131, 132, 154-156].
Symptoms [131, 132]
·The majority of patients （>80%） undergo asymptomatic acute infection.
·The uncommon cases of acute icteric hepatitis are similar to hepatitis A.
Signs
·Acute icteric hepatitis - see hepatitis A.
·Chronic hepatitis - see hepatitis B
Complications
·Acute fulminant hepatitis is rare （<1% of all hepatitis C infections）, but is particularly common after hepatitis A super-infection of chronic hepatitis C carriers [28, 131, 132, 157].
·Approximately 50-85% of infected patients become chronic carriers - a state which is normally asymptomatic but may cause non-specific ill health [159-160]. Once established, the chronic carrier state rarely resolves spontaneously （0.02%/year） [131-2]. Symptoms/signs are worse if there is a high alcohol intake or other liver disease [161-164]. Significant liver disease can be present in the 35% of carriers who have normal serum aminotransferase levels, [131, 132, 165, 166].
·Mortality in acute hepatitis is very low （<1%） but 1-30% of chronic carriers will progress to severe liver disease after 14-20 years infection, with an increased risk of liver cancer （approximately 1-4% of all patients and up to 33% of those with cirrhosis） [68, 69, 81, 131, 132, 177, 163, 168-170]. HIV co-infection worsens the prognosis [140, 171-173].
·Pregnancy- Complications of acute icteric hepatitis: as for hepatitis A [21]. For risk of vertical transmission see “transmission”.
Diagnosis （see also Sexually Transmitted Infection Screening and Testing Guidelines - Hepatitis A, B and C）
Serology
·A screening antibody test such as an Enzyme-linked immuno-assay （ELISA） or other immunoassay is initially performed and if positive a second test, such as a recombinant immuno-blot assay （RIBA）, third generation immunoassay or RT-PCR for RNA is used to confirm infection [23, 78, 79, 154-156, 174]. An antibody test may not become positive for three or more months after acute infection but a test for HCV-RNA will be positive after only two weeks. Chronic infection is confirmed if an HCV-RNA assay is positive six months after the first positive test. Patients with low-level viraemia may require HCV-RNA levels testing on two or more occasions to confirm infection. All patients being considered for therapy should have a viral RNA test to confirm viraemia and genotype assay （see below）.
Flow chart for hepatitis C testing using an ELISA Assay ___________________ELISA-II/III___________
↓ ↓
↓ Positive
↓ ↓
↓_________________________________Confirmation e.g RIBA ↓ ↓
←←Negative Positive ↓ ↓ ↓
↓ If in window period ↓
↓ or indeterminate result ↓
↓ ↓ ↓
↓ ↓ ↓ ↓ HCV- RNA____________ _______ HCV-RNA______
↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓
↓ Negative Positive Negative ↓→ Not infected. Confirms current Infection Past infection Other tests
·Acute infection - as for hepatitis A.
·Chronic infection - as for hepatitis B.
Management
General Advice
·Patients should be told not to donate blood, semen or organs and given advice on other routes of transmission （see below）（III, B） [128].
·Patients should be given a detailed explanation of their condition with particular emphasis on the long-term implications for the health of themselves and their partner（s）. This should be reinforced by giving them clear and accurate written information.
·Acute hepatitis C infection is a notifiable disease.
Further Investigations
Treatment
·Acute icteric hepatitis: There is firm evidence that high dose alpha interferon given during the acute phase will reduce the rate of chronicity to only 10% or less （IIb, B） [175-176]. Spontaneous resolution of acute hepatitis C is signified by a loss of HCV-RNA within the first month of symptoms. Only those HCV-RNA positive for more than a month need to be treated [177]. Otherwise manage as for hepatitis A.
·Chronic infection: Peginterferon alfa with ribavirin will abolish chronic infection in approximately 50% of patients and is the approved therapy of the National Institute for Clinical Excellence （NICE） （Ia, A） [178]. Treatment should be for 24 weeks for patients with genotypes 2 or 3. Other genotypes should be treated for 12 weeks and treatment only continued if there has been a reduction in HCV viral load to 1% of the level at the start of treatment. Patients achieving this 2 log10 reduction should be treated for 48 weeks in total. Patients are more likely to respond if they have less severe liver disease （low fibrosis index on liver biopsy）, low serum HCV-RNA levels （<2million RNA copies/ml）, if they are infected with certain HCV sub-types （types 2 and 3） or if they become HCV-RNA negative in the serum within 12 weeks （Ib, A） [178-182].
·HIV-positive patients respond to treatment, although not as well as HIV-negative patients, and should be considered for therapy （IIa, B） [47, 183-185]. Sustained virological response in those completing therapy is 11-29% for genotypes 1/4 and 43-73% for genotypes 2/3 （1b, A） [183-185]
·Patient selection for therapy depends on liver histology, HCV genotype and viral load [178-185]
·Given the high rate of fulminant hepatitis in co-infection hepatitis A &C and the worse prognosis of hepatitis B & C co-infection, patients with hepatitis C should be vaccinated against hepatitis A and B （III,B） [28, 157,158].
Pregnancy and Breast feeding
·There is at present no known way of reducing the risk of vertical transmission. Women should be informed of the potential risk of transmission in pregnancy （see transmission） （IV, C） [136].
·Breast feeding: there is no firm evidence of additional risk of transmission except, perhaps in women who are symptomatic with a high viral load （III,B）[148, 149, 186]
Sexual and Other Contacts
·Partner notification should be performed and documented and the outcome documented at subsequent follow-up. Contact tracing to include any sexual contact （penetrative vaginal or anal sex） or needle sharing partners during the period in which the index case is thought to have been infectious （IV,C） [37]. The infectious period is from two weeks before the onset of jaundice in acute infection. If there was no acute infection trace back to the likely time of infection （eg blood transfusion, first needle sharing） although this may be impractical for periods longer than two or three years. Consider testing children born to infectious women （IV, C） [136]. For other non-sexual contacts thought to be at risk, discuss with the CCDC or equivalent.
·There is currently no available vaccine or immunoglobulin preparation that will prevent transmission.
·Sexual transmission should be discussed. It seems likely that if condoms are used consistently then sexual transmission will be avoided, but given the very low rate of transmission outside of HIV co-infection （see above）, monogamous partners may choose not to use them （IV, C）.
Follow-up
·As for hepatitis B （IV, C）.
·Immunity is probably sub-type specific only - there are at least seven sub-types [154-156].
·Consider testing for hepatitis C in all IVDUs, especially if equipment has been shared, in haemophiliacs or other patients who received blood or blood products pre-1990 and in people sustaining a needle-stick injury if the donor HCV status is positive or unknown （III, B） [128, 130, 133-135, 138, 187]. Other groups to be considered for testing are sexual partners of HCV positive individuals, MSM, all HIV-positive patients, female sex workers, tattoo recipients, alcoholics and ex-prisoners （III, B） [61, 128, 137, 138, 141-146]. It may take three months or more for the anti-HCV test to become positive after exposure （see “incubation period”）.
·Since 1990 all donated blood in the UK has been screened for HCV and all blood products rendered incapable of transmitting infection （III, B） [188].
·Needle and syringe exchange schemes have led to a fall in parenterally transmitted infections including HCV, HBV and HIV, although not consistently （III, B） [189-191].
Qualifying statement
“The recommendations in this guideline may not be appropriate for use in all clinical situations. Decisions to follow these recommendations must be based on the professional judgement of the clinician and consideration of individual patient circumstances and available resources.”
“All possible care has been undertaken to ensure the publication of the correct dosage of medication and route of administration. However, it remains the responsibility of the prescribing physician to ensure the accuracy and appropriateness of the medication they prescribe.”
Auditable Outcomes
Acute hepatitis （A, B or C）
·Patients with acute hepatitis infection should be assessed clinically for severity, and have blood samples taken for serology, liver function, prothrombin time and renal function, all taken on the initial visit （target >90%）
·A clear treatment and follow-up plan should be stated in the notes （target 100%）.
Hepatitis A
·If the clinic policy is to test and vaccinate gay men, - test for immunity （target >90%）
- offer vaccination （target >90%）
·Provide written information on transmission and outcome of hepatitis A to infected patients （target >95%）
Hepatitis B
·Test patients in known at-risk groups for infection/immunity （target >90%）
·Offer vaccination to all non-immune patients at continuing risk （target >90%）
·In those offered vaccination, give a full course and test for post-vaccination response （target >50%）
·Provide written information on transmission and outcome of hepatitis B to infected patients （target >95%）
·Perform liver function tests once the diagnosis is known （target >80%）
·Write a clear long-term management plan in the notes of HBV-infected patients （target >95%）
Hepatitis C
·Ascertain the Hepatitis C and B status of intravenous drug users （target >80%）
·Provide written information on transmission and outcome of hepatitis C to infected patients （target >95%）
·Perform liver function tests once the diagnosis is known （target >80%）
·Write a clear long-term management plan in the notes of HCV-infected patients （target >95%）
Author and Centre
Gary Brook, Patrick Clements Clinic, Central Middlesex Hospital, London NW10 7NS.
Membership of the CEG
Clinical Effectiveness Group: Keith Radcliffe （Chairman）; Imtyaz Ahmad-Jushuf; David Daniels; Mark FitzGerald; Guy Rooney; Jan Welch.
Conflict of Interest
This guideline was commissioned and edited by the CEG of the BASHH, without external funding being sought or obtained.
The author is supervising treatment of patients with HIV and Hepatitis B in a clinical trail sponsored by Gilead Pharmaceuticals but is not receiving any personal funding.
