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S I GN Scottish Intercollegiate Guidelines Network 92 Management of hepatitis C A national clinical guideline 1 Introduction 1 2 Testing 4 3 Prevention of secondary transmission 7 4 Referral 9 5 Children and hepatitis C 10 6 Acute hepatitis C 12 7 Assessment of liver disease 13 8 Progression of untreated disease 15 9 Treatment of chronic hepatitis C 18 10 Treatment of advanced infection 26 11 Nutrition, supportive care and complementary therapies 28 12 Information for discussion with patients and carers 31 13 Implementation, resource implications and audit 37 14 Development of the guideline 39 Abbreviations 43 References 44 December 2006 Copies of all SIGN guidelines are available online at www.sign.ac.uk KEY TO EVIDENCE STATEMENTS AND GRADES OF RECOMMENDATIONS LEVELS OF EVIDENCE 1++ High quality meta-analyses, systematic reviews of randomised controlled trials (RCTs), or RCTs with a very low risk of bias 1+ Well conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias 1- Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias 2++ High quality systematic reviews of case control or cohort studies High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal 2+ Well conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal 2- Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal 3 Non-analytic studies, eg case reports, case series 4 Expert opinion GRADES OF RECOMMENDATION Note: The grade of recommendation relates to the strength of the evidence on which the recommendation is based. It does not reflect the clinical importance of the recommendation. A At least one meta-analysis, systematic review of RCTs, or RCT rated as 1++ and directly applicable to the target population; or A body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results B A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 1++ or 1+ C A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 2++ D Evidence level 3 or 4; or Extrapolated evidence from studies rated as 2+ Good practice points  Recommended best practice based on the clinical experience of the guideline development group This document is produced from elemental chlorine-free material and is sourced from sustainable forests Scottish Intercollegiate Guidelines Network Management of hepatitis C A national clinical guideline December 2006 © Scottish Intercollegiate Guidelines Network ISBN(10) 1 905813 02 3 ISBN(13) 978 1 905813 02 5 First published 2006 SIGN consents to the photocopying of this guideline for the purpose of implementation in NHSScotland Scottish Intercollegiate Guidelines Network 28 Thistle Street, Edinburgh EH2 1EN www.sign.ac.uk 1 INTRODUCTION 1 Introduction 1.1 the need for a guideline The hepatitis C virus (HCV) was first identified in 19891 and HCV infection has become a major health problem worldwide. Approximately 0.8% of the Scottish population are thought to be chronically infected with HCV (around 37,500 individuals). The prevalence of infection varies between population groups ranging from 50% in injecting drug users (IDU) to less than 0.04% among new blood donors.1 Up to 80% of patients infected with HCV become chronically infected and most of these patients will show evidence of chronic hepatitis.2 Hepatitis C is usually slowly progressive over a period of many years. Five to 15% of patients with chronic hepatitis may progress to liver cirrhosis over 20 years.3 Four to nine per cent of patients with cirrhosis will develop liver failure, and two to five per cent of patients with cirrhosis will develop primary hepatocellular carcinoma. In the UK the two major routes of transmission of HCV have been sharing of drug injecting equipment by IDU and transfusion of infected blood or blood products. Virus inactivation treatment of blood products began in 1987 and from 1991 blood has been screened for hepatitis C, eliminating blood products as a source of HCV infection. HCV infection can be effectively treated with combination drug therapy (pegylated alfa interferon and ribavirin) with sustained viral response rates in 50-80% of patients. Although there are existing guidelines around the selection of patients for treatment4-7 there are no national guidelines for screening, testing, diagnosis, service configuration, care during treatment nor post-treatment follow up in adults or children. Presently wide variation exists across Scotland in the delivery of services to individuals infected with HCV. 1.2 remit of the guideline The guideline provides evidence based recommendations covering all stages of the patient care pathway; screening, testing, diagnosis, referral, treatment, care and follow up of infants, children and adults with, or exposed to, HCV infection. The remit encompasses prevention of secondary transmission of the virus but specifically excludes primary prevention of HCV infection. Primary prevention of hepatitis C infection is an important public health concern but is a difficult topic for an evidence based guideline to cover. The principles and evidence for the prevention of all blood borne viruses are generic and reviewing all of this evidence would have been beyond the capacity of any guideline development group, whilst reviewing the HCV evidence alone would have produced a distorted view. This guideline will be of interest to all health professionals in primary and secondary care involved in the management of people with hepatitis C infection. 1.3 definitions Acute hepatitis C There is no generally accepted definition of acute hepatitis C infection but for purposes of investigations and treatment of acute hepatitis C, the following criteria have been used; a clear point of exposure and a positive HCV RNA within six months or a significant rise in serum alanine aminotransferase or seroconversion in which antibody and/or HCV RNA is absent from a first and present in a second sample. 1 Management of hepatitis c Chronic hepatitis C Ongoing infection with hepatitis C virus beyond the acute phase. Mild disease is present when inflammation of the liver tissue is absent or largely confined to the portal tracts with no evidence of fibrous tissue extending between the portal tracts. Moderate liver disease is described when there is significant inflammation and/or liver cell damage associated with increased fibrous tissue extending beyond the portal tracts but not resulting in nodule formation. Severe disease occurs when patients have developed bridging fibrosis or cirrhosis (histologically proven or otherwise) of the liver, whether there are clinical signs of liver dysfunction or not. Genotypes Many different strains of HCV have been recognised by virological testing. These have been grouped into six categories known as genotypes 1 to 6. There are significant geographical variations in the prevalence of the different genotypes in different parts of the world. In the UK genotype 1 is the most common, followed by genotype 3 and then genotype 2. There are small numbers of patients in the UK infected with hepatitis C virus of genotypes 4, 5 and 6, most of whom acquired the infection overseas. Sustained viral response Sustained viral response (SVR) is defined as undetectable HCV RNA in the patient’s serum using sensitive nucleic acid detection techniques, six months after the end of a period of antiviral therapy. Early viral response Early viral response (EVR) is either a negative HCV RNA or a two log drop in quantitative HCV RNA levels after starting antiviral treatment. It is measured at 12 weeks for patients with genotype 1.8-10 Rapid viral response Rapid viral response (RVR) is a negative qualitative HCV RNA measured four weeks after antiviral treatment for patients with genotype 2 or 3. Non-responder A non-responder is a patient who after antiviral treatment for HCV has detectable HCV RNA at the end of treatment. Relapser A relapser is a patient who after antiviral treatment for HCV has no detectable HCV RNA at the end of treatment, but who does have detectable HCV RNA six months after the end of a period of antiviral therapy. Current and former injecting drug users Definitions of current and former injecting drug users vary between different therapeutic environments. Any definition must be considered in the continuum of a chronic, relapsing disease. Precise definition of former injecting drug users is for the most part arbitrary, and in the context of hepatitis C the issue is the potential risk of re-infection with HCV after successful treatment. For the purpose of this guideline an individual infected with HCV may be considered as not at risk of reinfection if they have been non-injecting for six months. Exposure prone procedures Exposure prone procedures (EPP) are those where there is a risk that injury to a healthcare worker may result in the exposure of a patient’s open tissues to the blood of the worker. These procedures include those where the worker’s gloved hands may be in contact with sharp instruments, needle tips and sharp tissues (spicules of bone or teeth) inside a patient’s open body cavity, wound or confined anatomical space where the hand or fingertips may not be completely visible at all times. 2 1 INTRODUCTION 1.4 Statement of intent This guideline is not intended to be construed or to serve as a standard of care. Standards of care are determined on the basis of all clinical data available for an individual case and are subject to change as scientific knowledge and technology advance and patterns of care evolve. Adherence to guideline recommendations will not ensure a successful outcome in every case, nor should they be construed as including all proper methods of care or excluding other acceptable methods of care aimed at the same results. The ultimate judgement must be made by the appropriate healthcare professional(s) responsible for clinical decisions regarding a particular clinical procedure or treatment plan. This judgement should only be arrived at following discussion of the options with the patient, covering the diagnostic and treatment choices available. It is advised, however, that significant departures from the national guideline or any local guidelines derived from it should be fully documented in the patient’s case notes at the time the relevant decision is taken. 1.5 review and updating This guideline was issued in 2006 and will be considered for review in three years. Any updates to the guideline in the interim period will be noted on the SIGN website: www.sign.ac.uk. 3 Management of hepatitis c 2 Testing 2.1 Clinical and cost-effective testing for HCV National and international guidelines recommend that individuals who have an excess risk of being infected and might benefit from knowing their HCV status should be offered an HCV test.5, 11-13 This recommendation is based primarily on the need to diagnose an often silent infection, allowing the initiation of prompt antiviral treatment if appropriate.14 Since treatment cannot be offered unless a diagnosis of chronic HCV infection is made, the offering, and uptake, of testing among populations at risk of HCV will convey a degree of clinical benefit. 4 Further benefits of diagnosing people infected with HCV include the opportunity to convey information aimed at slowing the rate of HCV disease progression (such as advice about the dangers of excess alcohol consumption) and reducing the chances of infection being transmitted to others. No robust, consistent evidence to indicate the effectiveness of these interventions was identified. UK guidelines consistently recommend that people who may convey an HCV risk to patients in the healthcare setting should undergo HCV testing.5, 11-13 Several instances of healthcare worker to patient and blood/organ donor to recipient transmission of HCV have been recorded.15, 16 Controlled trials or cohort studies to gauge the cost effectiveness of offering an HCV test to different population groups have not been undertaken. Limited evidence from economic modelling work, indicates that offering an HCV test to former injecting drug users in drug treatment and perhaps other settings would convey cost-effective clinical benefits.17 Former IDU are more likely to have a higher prevalence of HCV and comply with therapy than current IDU. Models of best practice for the identification and testing of former IDU have not been developed and evaluated. Expert opinion suggests that general practices, particularly those that serve areas with a high prevalence of drug use, may constitute environments where focused, well supported testing initiatives might be successful. Prisons may also offer similar opportunities.18 Targeted and generalised HCV awareness/ testing campaigns have been conducted but no evaluations of their success in encouraging people (including former IDU) at high risk of HCV to engage with services have been reported. In populations where the prevalence of HCV is low (eg genitourinary medicine clinic attendees), economic modelling indicates that universal testing does not convey cost-effective clinical benefit.17 4 D The following groups should be tested for HCV: ƒƒ blood/tissue donors ƒƒ patients on haemodialysis ƒƒ healthcare workers who intend to pursue a career in a specialty that requires them to perform exposure prone procedures. D The following groups should be offered an HCV test: ƒƒ patients with an otherwise unexplained persistently elevated alanine aminotransferase ƒƒ people with a history of injecting drug use ƒƒ people who are human immunodeficiency virus (HIV) positive ƒƒ recipients of blood clotting factor concentrates prior to 1987 ƒƒ recipients of blood and blood components before September 1991 and organ/tissue transplants in the UK before 1992 ƒƒ children whose mother is known to be infected with HCV ƒƒ healthcare workers following percutaneous or mucous membrane exposure to blood which is, or is suspected to be, infected with HCV ƒƒ people who have received medical or dental treatment in countries where HCV is common and infection control may be poor ƒƒ people who have had tattoos or body piercing in circumstances where infection control procedure is, or is suspected to be, suboptimal ƒƒ people who have had a sexual partner/household contact who is HCV infected. 4 4 4 2 TESTING 2.2 HCV Diagnostic testing 2.2.1 Principles of testing Detection of viral RNA by nucleic acid tests (NAT, usually using reverse transcription polymerase chain reaction; RT PCR) indicates current infection. Detection of antibodies indicates resolved or current infection. The testing algorithm suggested in Figure 1 is based on the following key principles: ƒƒ ƒƒ ƒƒ ƒƒ ƒƒ ƒƒ ƒƒ ƒƒ ƒƒ ƒƒ ƒƒ 2 diagnostic assays are most reliable when used on plasma or serum19 assays for antibody in saliva are very sensitive if optimum salivary collection devices and modified enzyme linked immunosorbent assays (ELISA) are used, but NAT for viral 2++ 19-21 RNA is unreliable limited testing of dried blood spots for detecting antibody has suggested it may be useful 2++ but further evaluation is needed for the detection of viral RNA19 nucleic acid testing sensitive enough to detect 50-100 IU/ml of virus must be performed 2+ to detect current infection22 viral RNA can be detected as early as one to two weeks after infection, whereas antibody 4 can be detected at seven to eight weeks after infection23 antibody to infection may not be generated particularly if the individual is immuno4 suppressed24 following acute infection, HCV RNA may oscillate between positive and negative for several months. Results from samples taken at this time may be misleading. 23 In an 4 individual positive for HCV antibody, but negative for HCV RNA, a second sample should be tested to confirm the initial diagnosis, especially as the date of infection is unknown in most cases individuals with a positive HCV antibody test and repeatedly negative RNA do not 4 require further active management of hepatitis C infection24 since hepatitis C is a serious communicable disease, after an initial laboratory diagnosis, a 4 second sample should be taken from the patient to confirm correct identification of the original sample25 genotyping of individuals with proven HCV infection is required to determine likely 1++ response to treatment. Those with genotype 1 infection require longer duration of treatment than those with genotype 2 and 3 (see section 9.1.2)7 expert guidance suggests that healthcare workers who have, or might have, sustained 4 an occupational exposure to HCV should be offered RNA testing at six, 12 and 24 weeks, with anti-HCV testing at 12 and 24 weeks.26 ++ B Diagnostic testing for HCV should be performed on serum or plasma where possible. D HCV genotyping should be undertaken if antiviral therapy is being considered. D Following an isolated acute percutaneous exposure to blood infected, or strongly suspected of being infected, with HCV, healthcare workers should be offered HCV RNA testing at six, 12 and 24 weeks and anti-HCV testing at 12 and 24 weeks.  The testing procedure outlined in Figure 1 should be followed. 5 Management of hepatitis c Figure 1: Initial laboratory diagnosis of hepatitis C infection (except infants) Serum or plasma sample ELISA for antibodies to HCV POSITIVE NEGATIVE HCV RNA (NAT) POSITIVE Ongoing HCV infection. If this is the first time this patient has been found positive for HCV confirm with a second sample. NEGATIVE If possible acute infection, immunosuppressed or a new haemodialysis patient Probable past resolved infection with HCV. Repeat once (at least six months later) to confirm viral RNA remains absent. POSITIVE Repeat NAT NEGATIVE Past resolved infection with HCV or false positive ELISA. 6 Not infected with HCV