Hepatitis C-Z: Recent Advances D Kelly, S Skidmore
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339 RECENT ADVANCES Arch Dis Child: first published as 10.1136/adc.86.5.339 on 1 May 2002. Downloaded from Hepatitis C-Z: recent advances D Kelly, S Skidmore ............................................................................................................................. Arch Dis Child 2002;86:339–343 In this review, recently identified hepatitis viruses Epidemiology of HCV infection (hepatitis C, hepatitis D, hepatitis E, hepatitis F, hepatitis Prior to the introduction of viral inactivation of blood products and screening of blood for G, transfusion transmissible virus) are described, and anti-HCV in 1991, infection with HCV was found the implications for paediatric liver disease discussed. in those who received blood products or trans- 7 .......................................................................... planted organs. Sporadic cases have also been described, as has nosocomial spread.8 Despite the obvious occupational risk from needle stick he rapid development of molecular tech- accidents, the prevalence of HCV among health niques has lead to the discovery of a number care workers in the UK is no higher than in blood Tof hepatotrophic viruses, but little clarity donors, which is related to the low prevalence of about their significance or long term outcome. HCV generally.910 Paediatricians now need an understanding of Currently the main source of infection is which hepatitis viruses are significant in clinical among intravenous drug abusers,11 which has practice, how to handle them, and when to refer particular relevance for paediatrics as the major- patients to a specialist unit. ity of new cases of hepatitis C are now in vertically infected infants. Although the prevalence may be falling in the drug abuser population, additional educational strategies are needed to reduce trans- HEPATITIS C mission further.12 Sexual transmission of HCV Hepatitis C (HCV) is a flavivirus which was cloned does occur,13 but with a transmission rate of 1 in 1989, when it was identified as the major approximately 5% (which is lower than with cause of post-transfusion hepatitis in adults and hepatitis B or HIV). It is often difficult to establish children. It is an RNA virus with a high degree of sexual transmission as the sole route of infection, heterogeneity, which results in the rapid accumu- since alternate risk factors such as intravenous lation of mutations so that many variants may drug abuse may coexist. Nevertheless, this topic coexist in a single patient. This genetic diversity needs to be highlighted for teenagers and young http://adc.bmj.com/ allows the virus to avoid immune surveillance, adults considering sexual relationships and ap- leading to chronic infection and difficulty in pro- propriate advice given. 2 ducing an effective vaccine. There are six major A number of recent studies have documented genotypes with different subtypes and a distinct the risk of vertical transmission of HCV, which 3 geographical distribution. Current evidence varies from 5% to 12%, depending on geographi- suggests that natural history and response to cal location. Transmission of infection is higher in treatment varies according to genotype. mothers with high titres of HCV RNA and those 14–18 who are HIV positive. The route of vertical on September 30, 2021 by guest. Protected copyright. Diagnosis of HCV infection transmission is unclear—it may be intrauterine, Diagnostic assays for HCV are now well estab- or related to maternal peripheral blood mono- lished and commercially available. In contrast to nuclear cell infection or perinatally via breast 19 early assays which suffered from a lack of specifi- feeding. There is no increased risk of transmis- 20 city, current tests are both sensitive and specific. sion in subsequent pregnancies, but all infants The most useful screening test is the detection of of HCV infected mothers should be screened (fig anti-HCV IgG in serum using an enzyme immu- 1). Maternal HCV antibodies may persist for up to noassay (EIA).4 However, detection of specific 9–10 months, and thus routine screening for HCV antibody does not differentiate between acute antibody should not take place before 12 months. and chronic infection, previous exposure, or HCV RNA is a reliable guide to infectivity; it may passive antibody transfer. IgM tests, which be performed at any time, if an early diagnosis is required (for adoption, for instance), but the See end of article for usually indicate acute infection, are not clinically authors’ affiliations useful for HCV. The so called “window period” infant should be followed up until 18 months of ....................... between infection and a serologically positive age. The role of breast feeding for HCV positive Correspondence to: antibody test can be addressed by detecting HCV Prof. D Kelly, The Liver RNA in serum, although the recently described mothers is controversial. HCV RNA has been 21 Unit, Birmingham HCV antigen assay may prove useful.5 The detec- detected in breast milk, but many large studies Children’s Hospital, tion of HCV RNA using nucleic acid amplification Steelhouse Lane, Birmingham B4 6NH, UK; tests, such as the polymerase chain reaction ................................................. Deirdre.Kelly@ (PCR) or branched DNA (bDNA) assays, reliably Abbreviations: bhamchildrens.wmids.nhs.uk identifies patients with persistent viraemia. The EIA, enzyme immunoassay; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E amount of HCV RNA detected by quantitation Accepted virus; HGV, hepatitis G virus; PCR, polymerase chain 22 January 2002 assays may be useful in determining infectivity reaction; RT, reverse transcriptase; TTV, transfusion ....................... and response to therapy.6 transmissable virus www.archdischild.com 340 Kelly, Skidmore Screen high risk patients Clinical Investigations Refer to Arch Dis Child: first published as 10.1136/adc.86.5.339 on 1 May 2002. Downloaded from presentation specialist unit Acute hepatitis Jaundice Hep A, B, C, E serology PT > 20 sec Anti HCV positive† Nausea FBC Rising bilirubin Vomiting LFT (> 100 µmol/l) Malaise PT, PTT Falling transaminases Onset 7–14 days Blood glucose Hepatic encephalopathy Measure HCV RNA Chronic hepatitis Asymptomatic Hep B, C, delta Prolonged jaundice Negative Positive Weight loss FBC Persistent abnormal Fatigue LFT transaminases Repeat 6 months Repeat 6 months Hepatosplenomegaly PTT HCV RNA positive Jaundice † Autoantibodies Hep B eAg positive † Immunoglobulins Hep D positive Negative Positive +/– elevated Copper hepatic transaminases Caeruloplasmin α ‡ 1 antitrypsin level Refer to specialised and phenotype liver unit Figure 2 Investigation and management of viral hepatitis. *Exclude Wilson’s disease. †Autoimmune liver disease. α Resolved infection/ Counselling/information ‡ 1 antitrypsin deficiency. passive transfer Liver biopsy m2) and oral ribavirin (15 mg/kg) indicates an initial response rate of 60%, while up to 37% of children have sustained viral clearance six months after completion of combination Hepatic inflammation therapy.33–36 Currently, treatment regimes are within the +/– fibrosis context of clinical trials in which only children over 3 years Consider for antiviral therapy have been included. Of particular interest for paediatrics, is within clinical trial the development of pegylated interferon which is given Figure 1 Proposed management and investigation of hepatitis C in weekly, and may be more effective than conventional childhood. *High risk patients include: recipients of multiple interferon.37 Although the National Institute of Clinical Excel- transfusions/pooled blood products/organ transplants pre-1990, lence (NICE) has issued guidelines for the treatment of hepa- infants of HCV positive mothers (at 12 months). †Anti-HCV by third titis C in adults, no specific guidance has been provided for generation assay; may be positive in infants of HCV positive mothers 9–12 months by passive transfer. children. It is essential therefore that further investigation and http://adc.bmj.com/ therapy of paediatric hepatitis C should only be carried out at specialised paediatric liver units and within the context of a have shown transmission only in mothers with high titres of multicentre clinical trial. HCV RNA,22 suggesting that it may be safe for most infants. NATURAL HISTORY OF HCV INFECTION HEPATITIS D (HDV/DELTA AGENT) The natural history, prognosis, and clinical significance of HDV is a defective virus which contains single stranded RNA. chronic hepatitis C is variable and poorly defined. Data from The outer coat consists of hepatitis B surface antigen and the on September 30, 2021 by guest. Protected copyright. virus requires the helper function of hepatitis B virus to estab- adult studies indicate a high degree of chronicity, with up to 38 50% developing progressive liver disease and 20% developing lish infection in humans. cirrhosis 20–30 years after infection. Although there is The diagnosis of HDV is based on the detection of HDV considerable variation in disease outcome, chronic liver antigen and IgM and IgG HDV antibodies. Molecular disease is more likely with genotype 1B.23 24 techniques to identify HDV RNA are being developed. HDV has 25 26 a worldwide distribution and is transmitted parenterally, with It seems likely that natural seroconversion does occur ;it 39 may be more common in children infected later in life as a high incidence in intravenous drug abusers. In general HDV recent studies have indicated that 20–40% of children infected does not need to be routinely