In June 2004, Scotland’s Health Minister recognised that hepatitis C virus (HCV) was one of the country’s most challenging public healthconcerns.1This acknowledgement cameshortly after a Royal College of Physiciansof Edinburgh Consensus Conference onHepatitis C, which highlighted that‘services are already struggling to copewith the burden of infection,’ and that‘significant resources must urgently bedirected at improving prevention anddelivery of care’.2 Following an extensiveconsultation, the Health Minister and the Chief Medical Officer launched theHepatitis C Action Plan for Scotland in September 2006.3
Its aims were: �To prevent the spread of HCV,particularly among people who injectdrugs (PWID)
�To diagnose HCV-infected people,particularly those who would mostbenefit from treatment
�To ensure that those infected with HCV receive optimal treatment, care and support.The plan was in two phases. Phase I,undertaken from September 2006 toAugust 2008, involved gatheringevidence to inform proposals for thedevelopment of HCV services duringPhase II.4 Phase II, launched in May2008, saw serious commitment fromthe Scottish Government to tacklethe HCV challenge facing Scotland,
with an investment of approximately £43million (85% of which was allocated to NHSboards) over the three years of the plan.This was intended to deliver actionsdesigned to dramatically improveprevention, diagnosis and treatmentservices throughout the country. This article provides an overview of
the action plan in respect of the evidencethat informed actions, co-ordination andgovernance arrangements, as well asimplementation of, and progress made in, delivering actions.
evidence
Approaches adopted to generate theevidence involved analysis of existing dataheld on laboratory and clinical databases,5
questionnaire surveys and face-to-faceinterviews with service providers,systematic reviews of the scientificliterature,6,7 case-finding evaluations,8
record-linkage exercises9 and modellingstudies to estimate the impact ofinterventions in preventing infection and the burden of disease.10,11
By the mid-2000s, an estimated 50,000Scots (1% of the population) were livingwith HCV, and 75% of these were chroniccarriers.5 Around 90% of those infectedacquired their virus through injecting druguse and the majority remainedundiagnosed.5 It was estimated that only20% of those chronically infected had everbeen in specialist care, and only 5% had
Sharon Hutchinson PhD CStat Hon MFPH , Principal Research Fellow, University of Strathclyde; Epidemiologist, Health Protection Scotland, Glasgow; David Goldberg DSc FRCP (Gla, Ed, Lon) FFPH FFTM RCPS (Gla) Consultant in Public HealthMedicine, Health Protection Scotland, Glasgow; Gareth BrownHead of Health Protection Team, Scottish Government, Edinburgh; Nicola Rowan PhD Programme Manager (Hepatitis C Action Plan), NHS Health Protection Scotland; National Co-ordinator for Viral Hepatitis, Scottish Government, Edinburgh; John DillonMBBS MD FRCP Consultant Hepatologist, Ninewells Hospital, Dundee; Avril Taylor PhD FFPH Professor in Public Health, University of the West of Scotland, Paisley; Syed Ahmed MB ChB MRCP (UK) FFPH Consultant in Public Health Medicine, NHS Greater Glasgow and Clyde
In this issue ...
Comment
Strategic and immune responses 3Alastair Miller
Service provision
Practical difficulties in treating hepatitis C patients in prison 8Catriona Sykes, Karen Robertson and Nicholas Kennedy
Case study
How would you deal with this patient? 10Patrick Kennedy
Meeting report
The British Viral Hepatitis Group: the other hepatitisviruses 11Geoffrey Bowden
Viral hepatitis
w w w . v h i p . c o . u k
i n p r a c t i c e
NovemBer 2012 Volume 4 Number 2
Hepatitis C strategy
in Scotland
Printed with the support of an educational grant from Roche Products Limited. Roche has no editorial control of this publication.
Printed with the support of an educational grant from Gilead Sciences Ltd. Gilead has no editorial control of this publication.
received a course of antiviral therapy,while over 2,000 were living with cirrhosisand 1,000–1,500 PWID were becominginfected annually (see Table 1).10–12
Co-ordination and governanceThe plan aimed to put mechanisms inplace to ensure better co-ordination and accountability ofservices, and to raise awareness of HCVamong those responsible for the deliveryof services in NHS boards, local authorities,community health partnerships, and drugand alcohol action teams. HealthProtection Scotland (HPS) was responsiblefor co-ordinating the action plan
nationally, which involved establishingand maintaining national networks tosupport NHS boards and otherorganisations delivering different aspectsof the plan; employing a projectmanagement approach to monitorprogress and performance, to help ensurethe plan was delivered in a timely, effectiveand efficient way; and communicatingprogress to, and getting feedback from,
stakeholders through annual reports andconferences. NHS boards, through theirappointed hepatitis C executive leads,were responsible for co-ordinating theaction plan locally.In Phase I, a co-ordinating group, chaired
by HPS and comprising representatives ofstakeholder groups, was accountable tothe government for delivering actions, themost important of which was thegeneration of Phase II of the plan. In thisrespect, much of the work involved wasstrategic in terms of gathering andinterpreting evidence and then makingrecommendations. Phase II, in contrast,mostly concerned the development ofservices by NHS boards and otherorganisations, all of which received
2 VIRAL HEPATITIS IN PRACTICE 2012; Vol 4 No 2
Key evidence and issues Key actions (2008–11) OutcomesA) PreventionKey evidence (Scotland, mid-2000s) • About 90% of those infected with HCV have injected drugs • NHS boards will have, or be affiliated to, a network • Between 2008–09 and 2009–10, more than• Over 1,000 PWID are infected annually covering prevention of HCV and comprising fourfold increase in paraphernalia (filters &• Among PWID attending drug treatment services, 20% representatives of all stakeholder sectors spoons) distributed to PWID in Scotlandreport sharing N/S and 40% other injecting paraphernalia •National guidelines for services providing injection •Among PWID surveyed in Scotland who
•The estimated numbers of N/S distributed to each PWID equipment to PWID will be developed were susceptible to HCV (tested antibody ranged from 50–500 across drug action team areas • Services providing injection equipment (N/S and negative), the proportion with recently Major issues other injection paraphernalia) will be improved in acquired infection (tested RNA positive) reduced•Widespread variations in the provision and uptake accordance with guidelines. Improvements to be (although not significantly) from 2.1% in of injection equipment exist made in terms of the quantity, quality and nature of 2008–09 to 1.5% in 2010
• NHS boards do not have formal networks to facilitate the provision • Analysis of UK pooled data demonstrated that prevention of HCV, and national guidelines for services uptake of opiate substitute therapy and highproviding injection equipment do not exist levels of N/S (that is, at least sterile N/S for each
• The reuse/sharing of injection equipment is still highly injection) can achieve substantial reductions in prevalent and HCV transmission among PWID is common the risk of HCV transmission13
B) Testing, treatment, care and support Key evidence (Scotland, mid-2000s)• Over 60% of people living with HCV remain undiagnosed •NHS boards will have, or be affiliated to, a • A public and professional website•Only 20% of chronically infected cases had ever been in managed care network for HCV, comprising (www.hepcscotland.co.uk) was launched,specialist care and only 5% treated. Of 450 persons initiated representatives of all stakeholder sectors with further awareness campaigns in 2010on therapy each year, 4% were prison inmates • Testing/treatment services in NHS boards • New approaches implemented in getting
•Over 2,000 HCV-infected persons were living with cirrhosis, developed to increase numbers undergoing people tested for HCV (such as DBS testing)with over 100 developing liver failure each year therapy in Scotland, from 450/year to • 33% rise in the annual number of new
• It was estimated that if 2,000 persons per year received 1,500 in 2010–11 (since revised to 1,000 HCV diagnoses between 2003–08antiviral therapy over the next two decades, 5,200 cases of due to financial restraints) and 2009–11; 20% of new diagnoses in 2011HCV-related cirrhosis would be prevented in the future • Agreements between NHS boards and the Scottish were made in specialist drug services where DBS
•GPs and other service providers highlighted difficulties in Prison Service developed to promote the treatment testing has been introducedtaking blood from PWID as a barrier to HCV test uptake of HCV-infected inmates in prisons • Clinical services developed, leading to doublingMajor issues • Awareness-raising campaigns continue to be in numbers initiated on therapy (to 1,049 in•The majority of persons chronically infected with HCV developed and implemented to meet the 2010–11); 80% of initiates in 2010–11 had everremain undiagnosed and many of those diagnosed fail to information needs of professionals and promote injected drugsreach and stay within specialist care services HCV testing among those at risk of being infected •More than eightfold increase in the number
• Insufficient numbers of HCV-infected persons, including • Programme of work to evaluate approaches to HCV of inmates initiated on therapy betweenprisoners, receive antiviral therapy testing (for example, DBS) will be undertaken 2007–08 (17) and 2010–11 (143)
DBS = dried blood spot; HCV = hepatitis C virus; N/S = needles/syringes; PWID = people who inject drugs; RNA = ribonucleic acid
Table 1. Summary of evidence and issues, subsequent actions and outcomes in the areas of preventing hepatitis C virus infection and its treatment, care and support.
Development dlfkngjknwww.vhip.co.uk
By the mid-2000s, an estimated 50,000Scots ... were livingwith HCv
There are, indisputably, certain aspects of theScottish healthcare system that are envied by
those of us practicing south of the border. The ScottishGovernment launched the Hepatitis C Action Plan for Scotland in September 2006, with the aims ofpreventing, diagnosing and treating HCV. There was a specific focus on people who inject drugs. SharonHutchinson and colleagues give us an insight into thedevelopment, implementation and outcomes of thisplan, although they do not discuss how it will cope inthe face of the rapidly expanding availability, and cost,of the new direct-acting antiviral agents. Anecdotally,colleagues in Scotland seem to be experiencing lessdifficulty in accessing protease inhibitors, and this may be as a result of the Scottish plan.It is accepted that prisoners represent a particular
target group for identifying and treating HCV, and thispresents both opportunities and barriers. Many of ushave had experience of the HCV-infected prisonerattending our clinics in chains with prison guards andare aware of the constraints that this imposes on thedoctor/patient relationship. We are also familiar with thelarge number of missed clinic appointments, scans andliver biopsies among this group. Nick Kennedy, andcolleagues, have huge experience of the practicaldifficulties of treating HCV-infected prisoners. Theyemphasise the potential cost-effectiveness of theirstrategy and point out that incarceration should actually be seen as an enhanced opportunity fortreatment rather than an impediment.We now have two very potent antivirals (tenofovir
and entecavir) that seem to retain long-term controlover HBV replication, even when used in monotherapy.However, for most patients with established chronicHBV this means prolonged, possibly life-long,treatment. Clearance of HBV surface antigen anddevelopment of anti-HBV surface antibody is ‘as good asit gets’ in terms of a ‘cure, and this happens in relativelyfew cases. Mala Maini and team give us somefascinating insights into the way that disruptedimmunity allows for the establishment of chronic HBVand how the use of potent antiviral agents used incombination with immune modulation may increasethe cure rate.Patrick Kennedy presents an apparently
straightforward case of HCV infection and talks usthrough the decision-making process in approachingthis patient’s treatment. Finally, Geoffrey Bowdenprovides a summary of the recent British Viral HepatitisGroup meeting.I hope you enjoy this issue of VHIP and, again,
stress that the Editorial Board would love to hear from you with article suggestions.
Alastair miller, Editor
� Comment
Strategic andimmune responses
Editor
Alastair Miller MA FRCP DTM&H
Consultant in Infectious Diseases,Tropical and Infectious Disease Unit,Royal Liverpool University Hospital.
Consultant Editor
Geoffrey Dusheiko MB BCh FCP(SA) FRCP FRCP(Edin) Professor ofMedicine and Honorary Consultant,Centre for Hepatology, Royal FreeHospital, London.
Editorial Board
Anna-Maria GerettiMD PhD FRCPath
Professor of Virology and InfectiousDiseases and Honorary Consultant,Institute of Infection and GlobalHealth, University of Liverpool andLondon Centre for Nanotechnology,University College London
Sarah Knighton MPharmS IPresc
Pharmacy Team Leader, LiverServices, King’s College Hospital NHS Foundation Trust, London.
Kathryn Nash MRCP PhD
Consultant Hepatologist,Southampton General Hospital.
Julia Robathan DipHe RN BSc(Hons)
Hepatology Clinical Nurse Specialist,Salisbury District Hospital, Salisbury NHS Foundation Trust.
Stephen D Ryder DM FRCP
Consultant Gastroenterologist,Nottingham University HospitalsNHS Trust.
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funding for this purpose. Accordingly,these lead organisations were directlyaccountable to government and, thus,reported progress (including spend) onactions. A governance board, run by HPSand comprising representatives of leadorganisations, facilitated the reportingprocess, and an advisory board wasestablished to advise on progress with, and issues concerning, delivery.
Implementation
Each action within Phase II of the plan hada desired outcome, performance measure,timescales, lead organisation accountablefor delivering the action and a network tosupport the lead organisation. Generally,the actions were high-level in nature (seeTable 1), allowing NHS boards the freedomto develop services in the context of theirparticular circumstances, according toexisting arrangements for HCV serviceprovision and the epidemiology ofinfection in their area. Implementationinvolved representatives from all relevantdisciplines and organisations, and took agraduated approach, focusing first onestablishing the necessary infrastructuresprior to services being delivered anddeveloped. National guidelines weredeveloped to help ensure that approachestaken were effective, efficient and, whereappropriate, consistent. Local and nationalnetworks were established so thatexperience, best practice and progresscould be shared, and support, advice andguidance provided.
Progress
More than three years have elapsed sincethe launch of Phase II, and a considerableamount of data, permitting the earlyevaluation of the plan’s impact, are nowavailable (see Table 1). A range ofinformation-generating initiatives areproducing high-quality data. Theseinclude a national survey of PWID; national clinical, test and diagnosisdatabases; and a national survey ofinjection equipment providers.13
A considerable investment has beenmade to improve access to, and uptake of,injection equipment among PWID. One ofthe principal recommendations of theGuidelines for services providing injectingequipment: Best practice recommendationsfor commissioners and injecting equipmentprovision (IEP) services in Scotland is that
injection equipment paraphernalia(spoons, filters and so forth) should bemade available to PWID. Between 2008–09and 2009–10, a more than fourfold increasein the number of sets of such paraphernaliagiven to PWID was observed. Although it istoo early to say what impact theprevention investment has had, it isencouraging that anonymous survey datasuggest a downward trend in the incidenceof HCV infection among PWID in Scotlandbetween 2008–09 and 2009–10. From a diagnostic perspective, 2011 saw
the highest number of annual diagnosesever made, and provisional estimatesindicate that around half of all persons inScotland living with chronic HCV havenow been diagnosed. There is no questionthat awareness of HCV amongprofessionals (as a consequence of a widerange of action plan initiatives, includingthe establishment of numerous local andnational networks) is likely to have playeda major role in the promotion of HCVtesting and, therefore, diagnosis. However,the introduction of dried blood spottesting in the specialist drug servicesetting has arguably had the greatestimpact on the diagnosis effort.Accordingly, there is strong evidence thata real breakthrough has been made ingetting PWID tested for HCV.From a treatment perspective,
much has been achieved in developingclinical services throughout the country. It is highly satisfying that over the threeyears of Phase II, the annual number of initiates on to antiviral therapy hasincreased more than twofold (and more than eightfold among prisoners) to1,049 (and 143) in 2010–11. Of criticalimportance is the observation that, for the great majority of this group,injecting drug use was the principal riskfactor for HCV transmission. It is, therefore,evident that having a history of injectingdrugs per se is no barrier to receiving – and,indeed, fully benefitting from –combination therapy.
Summary and the futureScotland’s Hepatitis C Action Plan isregarded globally as a model of goodpractice.14 It is evident that a considerableamount of progress has been made inimproving HCV prevention, diagnosis andtreatment services. Much of theinfrastructure, including networks and
governance arrangements to ensure thatHCV is managed as a mainstreamcondition both within and outwith NHSsettings, has been embedded.The Scottish Government has
maintained funding for HCV during 2011–15 within the context of a national SexualHealth and Blood-Borne Virus Framework.15
The Framework recognises the strategiclinks that exist across sexual health andblood borne-virus service sectors inScotland, and the benefits that further
integration can afford. Such an approachwill provide resilience at a time ofincreasing financial pressure.While the Scottish Government should
be applauded for its investment in the HCV cause, the role of hundreds of keystakeholders, working in a wide range of spheres, in making things happenshould be acknowledged �
Declaration of interestNone declared.
References1. Chisolm M. Members’ Debate on Hepatitis C, ScottishParliament, Edinburgh, 30 June 2004. 2. Royal College of Physicians of Edinburgh. ConsensusStatement on Hepatitis C. Edinburgh: RCPE, 2004. 3.www.scotland.gov.uk/Resource/Doc/148746/0039553.pdf (last accessed 03/08/12)4. www.scotland.gov.uk/Resource/Doc/222750/0059978.pdf (last accessed 03/08/12)5. Hutchinson SJ, Roy KM, Wadd S et al.Hepatitis C virusinfection in Scotland: epidemiological review and publichealth challenges. Scott Med J 2006; 51: 8–15.6. Palmateer N, Kimber J, Hickman M et al. Evidence for theeffectiveness of sterile injecting equipment provision inpreventing hepatitis C and human immunodeficiency virustransmission among injecting drug users: a review of reviews.Addiction 2010; 105: 844–859.7. Gillies M, Palmateer N, Hutchinson S et al. The provision ofnon-needle/syringe drug injecting paraphernalia in theprimary prevention of HCV among IDU: a systematic review.BMC Public Health 2010; 10: 721.8. Cullen BL, Hutchinson SJ, Cameron SO et al. Identifyingformer injecting drug users infected with Hepatitis C: anevaluation of a general practice-based case-findingintervention. J Public Health (Oxf) 2011; 34: 14–23.9. McDonald SA, Hutchinson SJ, Bird SM et al. Hospitalization ofhepatitis C-diagnosed individuals in Scotland fordecompensated cirrhosis: a population-based record-linkagestudy. Eur J Gastroenterol Hepatol 2010; 22: 49–57.10. Hutchinson SJ, Bird SM, Goldberg DJ. Modeling the currentand future disease burden of hepatitis C among injection drugusers in Scotland. Hepatology 2005; 42: 711–723.11. Hutchinson SJ, Bird SM, Taylor A, Goldberg DJ. Modellingthe Spread of Hepatitis C Virus Infection among Injecting DrugUsers in Glasgow: Implications for Prevention. IJDP 2006; 17:211–221.12. www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1309969906418 (last accessed 03/08/12)13. Turner K, Hutchinson S, Vickerman P et al.The impact ofneedle and syringe provision and opiate substitution therapyon the incidence of Hepatitis C virus in injecting drug users:pooling of UK evidence. Addiction 2011; 106: 1978–1988.14. Morris K. Tackling hepatitis C: a tale of two countries. Lancet2011; 377: 1227–1228. 15. www.hivscotland.com/downloads/1314363132-Framework.pdf (last accessed 14/09/12)
4
� In 2004 it was recognised thathepatitis C virus (HCV) was one ofScotland’s most challengingpublic health concerns.
� Major issues were that HCVtransmission among people whoinject drugs (PWID) was commonand insufficient numbers of HCV-infected people were receivingantiviral therapy.
� The Hepatitis C Action Plan wasdesigned to improve prevention,diagnosis and treatment servicesthroughout Scotland and wassupported by serious investment.
� Considerable progress has beenmade, with evident increases inthe annual number of peoplediagnosed with HCV and initiatedon antiviral therapy, and anencouraging downward trend inthe incidence of HCV infectionamong PWID.
Key points
VIRAL HEPATITIS IN PRACTICE 2012; Vol 4 No 2
� Approximately 90% of HCV sufferersin Scotland acquired the virus throughinjecting drugs
Chronic hepatitis B (CHB) virus infectioncurrently affects more than 350 millionpeople worldwide. Despite theavailability of a preventive vaccine, theburden of liver disease carried by thosewho have chronic infection poses asignificant global health threat. Availableantiviral regimens are suboptimal; theyare expensive, rarely curative and proneto resistance. The observation that thevast majority of adults who are acutelyinfected go on to control the virussuggests that immunotherapeuticapproaches could be utilisedsynergistically with available drugregimens in chronic infection, to tip the balance in favour of viral clearance.Here, we summarise what is known, and what remains to be elucidated,before this becomes a possibility.
Immune responses in different clinicaloutcomes
The outcome of hepatitis B virus (HBV)infection depends on age and host–virusinteractions. Most adults (over 95%) willresolve HBV infection with co-ordinatedorchestration of different components ofthe immune response controlling viralreplication. This is associated with thedevelopment of antibodies againsthepatitis B e antigen (HBeAg) and hepatitisB surface antigen (HBsAg). However, it isnow widely accepted that HBV is containedby an efficient immune response, ratherthan completely eradicated.1 It can,therefore, reactivate in the setting ofsignificant immunosuppression.In the individuals who go on to develop
CHB, the weak immune response to thevirus perpetuates persistence byinefficiently controlling viral replication.2
There is a much higher risk of chronicity inperinatal infection, with 90% of children
infected under the age of five years olddeveloping CHB. Chronic infection followsa dynamic course that varies amonginfected individuals and can be broadlydistinguished into four phases, which havebeen referred to as the ‘immunotolerant’,‘immunoactive’, ‘inactive carrier’ and‘reactivation’ phases.3While thisnomenclature may be of some use forclinical categorisation, it is misleading from the immunological viewpoint.Experimental data do not support theconcept that the immune response is more tolerant in the immunotolerant than the immunoactive phase; T-cellresponses are, in fact, most vigorous in the inactive phase.4,5 It is important tostress that the disease process in CHB can fluctuate and progress from one stage to another in an unpredictablefashion, necessitating regular monitoring of HBV DNA and markers of liver inflammation.
Innate immuneresponses
Typically, acute viral infections lead to earlyinduction of type I interferons (IFNs),particularly IFN-alfa (∝). In acute HBV inhumans, however, this is not seen. Thiscorroborates similar findings in acutelyinfected chimpanzees6 and the clinicalobservation that acute HBV infection is notassociated with viraemic symptoms.Whether this is due to active suppressionof IFN responses or happens as a passiveresult of the virus being ignored by theimmune system is unclear, but it is incontrast to hepatitis C virus (HCV)infection, so is unlikely to be purely aneffect of the liver environment. Evidencefor active suppression of early immunitycomes from a cohort of patientsopportunistically sampled in the preclinicalphase of HBV, who showed a progressiverise in interleukin (IL)-10 coinciding with
5
Immune responses in hepatitis b: a brief overview
Mala K Maini PhD FRCP Professor of Viral Immunology and Honorary ConsultantNicholas EasomMRCP Academic Clinical Fellow Dimitra PeppaMRCP Clinical Research FellowAbhishek Das PhD Academic Clinical Fellow, Division ofInfection and Immunity, University College London
www.vhip.co.uk Investigation
VIRAL HEPATITIS IN PRACTICE 2012; Vol 4 No 2
�Natural killer cells constitute up to 40% of resident lymphocytes in the liver
the viral ramp-up phase.7 There remainscontroversy around whether the innateimmune system is capable of sensing HBVinfection, given the sequestration ofcovalently closed circular (ccc) DNA in thenucleus and the production of messengerribonucleic acid (mRNA) transcripts thatare similar to normal human mRNA. Also,studies in hepatoma cell lines suggest thatHBV polymerase and X protein may inhibitdownstream signalling of cytoplasmic DNAreceptors, thereby preventing activation ofthe type I IFN genes.2
Natural killer (NK) cells are importanteffectors of the innate arm of the immuneresponse, and are increasingly being seento bridge the gap between innate andadaptive immune responses.8 Theyconstitute up to 40% of residentlymphocytes in the liver and thisintrahepatic predominance highlights theirpotential role in HBV control and thepathogenesis of HBV-induced hepatitis. They express a range of germline-
encoded receptors, which provide eitheractivatory or inhibitory signals to triggercytotoxicity or cytokine production.8
Although HBV transgenic mouse modelshave demonstrated that NK cells have thepotential to contribute to the control ofHBV infection,9 their contribution in theearly stages of natural infection iscontroversial. In acute infection in humans,production of the antiviral cytokine IFN-gamma (g) by NK cells is impaired by thehigh levels of circulating IL-10 and, as thisfalls, IFN-g production is restored.7 In CHB,NK cells have defective antiviral potentialas a result of their impaired non-cytolyticcapacity.10 They overexpress tumournecrosis factor-related apoptosis-inducingligand, which may contribute tohepatocyte death and liver damage.11
Cytokine patterns in the course of chronicHBV infection, and particularly duringflares, can modulate NK cell effectorfunctions and may act in concert tomaximise liver damage.11 The cytokineenvironment in CHB may also influence therecruitment of the non-specific infiltrateinto the liver during flares.
Adaptive immuneresponsesT-cells play a critical role in the control ofnon-cytopathic viruses like HBV. In acuteinfection, HBV-specific cluster ofdifferentiation (CD)-8 T-cells, with a broadrange of specificities, are detectable; a
strong multi-specific response is associatedwith adequate viral clearance. This isdependent on early priming by CD4 T-cells;depletion of CD4 T-cells prior to viralinoculation in HBV-infected chimpanzeesimpairs CD8 T-cell survival and function.12
As shown in the transgenic mouse model,virocidal pathways can be initiated bycytokines, including IFN-g and TNF-∝,which potently abrogate HBV replication.13
Virus-specific CD8 T-cells mediate viralclearance by production of these cytokinesand, in addition, lyse a proportion of virus-infected hepatocytes, which contributes toliver inflammation. Hepatocyte damage islikely further potentiated by a non-specificlymphocytic infiltrate, recruited to the liverfollowing the initial HBV-specific response.5
In CHB, HBV-specific CD8 T-cellresponses are markedly attenuated, withboth deletion of HBV-specific cells andexhaustion of the remaining cells.14
Specificities also become much narrowerthan in acute infection. Mechanisms ofattenuation are difficult to elucidate in thecontext of established chronic infection,but a number of these have been clarifiedrecently (see Figure 1). They include up-regulation of the pro-apoptoticmolecule Bim in HBV-specific CD8 T-cells,and negative regulation by co-inhibitorymolecules, including programmed death(PD) 1 and cytotoxic T-lymphocyte antigen(CTLA) 4.15–17 Antigen presentation bytolerogenic liver-resident populations,such as liver sinusoidal endothelial cells,
Kupffer cells and hepatocytes, providesinadequate co-stimulation and an excessof co-inhibitory ligands such as PD ligand-1, thereby driving T-cell exhaustion.18
Non-specific effects on CD8 T-cells arealso observed; global CD8 T-cells inpatients with chronic HBV infection havepoor IL-2 production and proliferativepotential.19 This is likely to enhance thepro-apoptotic effects of Bim, especially inthe context of the low level of CD4 cell helpseen in chronic HBV. Arginase release bydying hepatocytes depletes L-arginine; T-cells starved of this amino acid exhibitthe hallmark down-regulation of the CD3-zeta chain and have defective effectorfunction.19 Also, the high levels of HBsAgand HBeAg synthesised in chronic HBVinfection are likely to drive tolerance. Therole of other T-cell populations is unclear.CD4 T-cells are poorly primed in the liverand also subject to tolerising mechanisms,therefore providing poor help and furtherexacerbating CD8 T-cell exhaustion.18
Regulatory T-cells can suppress HBV-specific T-cells in vitro, but this effect isnon-specific and of unclear significance invivo; their frequency correlates with alaninetransaminase levels, suggesting a role insuppression of inflammation.20
Immune manipulation
Pegylated IFN-a carries a much lower rate of viral clearance in HBV than in HCV,so current therapy largely relies on
6 VIRAL HEPATITIS IN PRACTICE 2012; Vol 4 No 2
Investigation dlfkngjknwww.vhip.co.uk
� Figure 1. Proposed mechanisms disabling T-cell immunity in chronic hepatitis B virus
Priming by non-professional APCs
Prolonged high-doseviraemia and solubleHBV antigens
Failure of CD4 T-cell help
Extrinsic regulationby other cellular subsets
Immunosuppressivecytokines: IL-10, TGF-ß
Hepatocyte damageleading to depletion ofnutrients (eg arginine)
suppression of viral replication with theantiretroviral drugs tenofovir or entecavir.21
These rarely produce HBsAgseroconversion or sustained off-treatmentresponses. However, by suppressingreplication they also cause somesuppression of HBV antigen production.This is slow, as the cccDNA is long-livedand continues to be transcribed in thepresence of drug treatment. CD8 T-cellrecovery is limited in this context and willneed to be boosted if viral clearance is tobe achieved.
One aim of future therapies is toenhance HBV-specific T-cell responses byincorporating a multifaceted approach oftargeted immunotherapeutic interventionwith a therapeutic HBV vaccine. Blocking ofco-inhibitory pathways, including PD-1,CTLA-4, 2B4, Tim-3 and others, hasdemonstrated the redundancy of thissystem, with varying patient responsesand, in some cases, improved responses tothe blockade of multiple pathways.18 Thiscomplicates any attempt at a therapeuticapproach, but it is possible to envisage asystem of ex vivo testing to establish whichmechanisms are most important in aparticular individual. Bim-mediatedapoptosis is another possible target thatremains to be explored, although anygeneralised anti-apoptotic strategy may have teratogenic potential. Analternative approach would be tomanipulate the liver cytokine environment;for example, by blockade of theimmunosuppressive cytokine IL-10. All of these approaches carry considerablerisk of unleashing over-exuberant T-cellimmunity in the liver and would need to becarried out in the setting of potentantivirals to suppress viraemia and, ideally,be targeted only to the HBV-specificcomponent of the response.18
Other proposed T-cell-based strategiesinclude the use of replication-deficient HBVpseudovirus-carrying influenza antigensthat are only expressed in HBV-infectedcells. This effectively recruits non-HBV-specific memory T-cells withpotent effector functions and proliferativecapacity. Alternatively, T-cell receptor (TCR)-redirected T-cells can be produced by thetransfection of memory T-cells of otherspecificities with a HBV-specific TCR. Thisapproach is technically difficult, but hasshown promise in cancer trials.2
Given the potential pathogenic role ofNK cells in CHB, further insights from theirstudy can be used to develop
short-term immunotherapeutic strategiesthat would augment cellular control of HBV with minimal liver damage.Stimulation of the poor innate immune response to HBV infectionis showing promising results. TLRactivation can suppress viral replication invitro and in transgenic mice, and TLRagonists are showing some efficacy inchimpanzees and woodchucks.2 It shouldbe possible to target these agonists to theliver using TCR-like monoclonal antibodies,specific for HBV-infected cells.2 Type I IFNscould, similarly, be targeted to the liver,although how much additional benefitwould result over that of pegylated IFN-ais uncertain.
Conclusion
HBV infection is either controlledspontaneously by the immune system or it establishes persistence, culminatingwith a series of immune defects that favour perpetuation of this state.Research into the precise nature of thesedefects has been hampered by the lack of
good experimental models, but this is nowimproving. Many immunotherapeuticapproaches have been postulated, and some are moving towards clinicaltrials. It seems likely that viral clearance or long-term control of cccDNA will require a series of interventions beginningwith potent drug suppression ofreplication, followed by redirecting apopulation of T-cells against HBV whilepreventing them becoming tolerised in the liver �
Declaration of interestNone declared.
References1. Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. Thehepatitis B virus persists for decades after patient’s recoveryfrom acute viral hepatitis despite active maintenance of acytotoxic T-lymphocyte response. Nat Med 1996; 2: 1104–1108.2. Bertoletti A, Ferrari C. Innate and adaptive immuneresponses in chronic hepatitis B virus infections: towardsrestoration of immune control of viral infection.Gut 2011(Epub ahead of print).3. Villa E, Fattovich G, Mauro A, Pasino M. Natural history ofchronic HBV infection: special emphasis on the prognosticimplications of the inactive carrier state versus chronichepatitis. Dig Liver Dis 2011; 43(Suppl 1): s8–s14.4. Webster GJ, Reignat S, Brown D et al. Longitudinal analysisof CD8+ T cells specific for structural and nonstructuralhepatitis B virus proteins in patients with chronic hepatitis B:implications for immunotherapy. J Virol 2004; 78: 5707–5719.5. Maini MK, Boni C, Lee CK et al. The role of virus-specificCD8(+) cells in liver damage and viral control duringpersistent hepatitis B virus infection. J Exp Med 2000; 191:1269–1280.6. Wieland S, Thimme R, Purcell RH, Chisari FV. Genomicanalysis of the host response to hepatitis B virus infection.Proc Nati Acad Sci U S A 2004; 101: 6669–6674.7. Dunn C, Peppa D, Khanna P et al. Temporal analysis of earlyimmune responses in patients with acute hepatitis B virusinfection. Gastroenterology 2009; 137: 1289–1300.8. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S.Functions of natural killer cells. Nat Immunol 2008; 9: 503–510.9. Kakimi K, Guidotti LG, Koezuka Y, Chisari FV. Natural killer Tcell activation inhibits hepatitis B virus replication in vivo. JExp Med 2000; 192: 921–930.10. Peppa D, Micco L, Javaid A et al. Blockade ofimmunosuppressive cytokines restores NK cell antiviralfunction in chronic hepatitis B virus infection. PLoS Pathog2010; 16: e1001227.11. Dunn C, Brunetto M, Reynolds G et al. Cytokines inducedduring chronic hepatitis B virus infection promote a pathwayfor NK cell-mediated liver damage. J Exp Med 2007; 204: 667–680.12. Asabe S, Wieland SF, Chattopadhyay PK et al. The size ofthe viral inoculum contributes to the outcome of hepatitis Bvirus infection. J Virol 2009; 83: 9652–9662.13. Guidotti LG, Ishikawa T, Hobbs MV et al. Intracellularinactivation of the hepatitis B virus by cytotoxic Tlymphocytes. Immunity 1996; 4: 25–36.14. Maini MK, Schurich A. The molecular basis of the failedimmune response in chronic HBV: therapeutic implications. JHepatol 2010; 52: 616–619.15. Lopes AR, Kellam P, Das A et al. Bim-mediated deletion ofantigen-specific CD8 T cells in patients unable to control HBVinfection. J Clin Invest 2008; 118: 1835–1845.16. Boni C, Fisicaro P, Valdatta C et al. Characterization ofhepatitis B virus (HBV)-specific T-cell dysfunction in chronicHBV infection. J Virol 2007; 81: 4215–4225.17. Schurich A, Khanna P, Lopes AR et al. Role of thecoinhibitory receptor cytotoxic T lymphocyte antigen-4 onapoptosis-Prone CD8 T cells in persistent hepatitis B virusinfection. Hepatology 2011; 53: 1494–1503.18. Protzer U, Maini MK, Knolle PA. Living in the liver: hepaticinfections. Nat Rev Immunol 2012; 12: 201–213.19. Das A, Hoare M, Davies N et al. Functional skewing of theglobal CD8 T cell population in chronic hepatitis B virusinfection. J Exp Med 2008; 205: 2111–2124.20. Manigold T, Racanelli V. T-cell regulation by CD4 regulatoryT cells during hepatitis B and C virus infections: facts andcontroversies. Lancet Infect Dis 2007; 7: 804–813.21. Papatheodoridis GV, Manolakopoulos D, Dusheiko G,Archimandritis AJ. Therapeutic strategies in the managementof patients with chronic hepatitis B virus infection. LancetInfect Dis 2008; 8: 167–178.
7VIRAL HEPATITIS IN PRACTICE 2012; Vol 4 No 2
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� While over 95% of adults resolveacute hepatitis B virus (HBV)infection, it is contained by anefficient immune response rather than eradicated, so can reactivate in the setting ofimmunosuppression.
� The inherent capacity of the immune response tosuccessfully control HBV provides a rationale forimmunotherapeutic boosting inpatients with chronic infection.
� A number of mechanisms havenow been elucidated thatcontribute to the ‘exhaustion’ ofthe T-cell response andperpetuate control in patientswith persistent infection.
� New approaches to restoringthese defective immuneresponses – for example,redirecting T-cells to recognise HBV – could, in future, be combined with potentantivirals to achieve bettertreatment paradigms.
Chronic viral hepatitis, particularlychronic hepatitis C virus (HCV), iscommon in incarcerated individuals. Inthe USA, 1–3.7% of prisoners tested hadchronic hepatitis B virus and 23–34% hadchronic HCV.1 In a UK study, 24.2% ofprisoners tested were anti-HCV antibody-positive and 13.9% anti-hepatitis B coreantibody-positive.2 Around one third ofthe total HCV-infected population in theUSA is estimated to pass through thepenal system each year.3
Incarceration can provide anopportunity for healthcare services toengage with a disadvantaged populationthat is difficult to reach. However, thisopportunity is frequently missed. Beforethe introduction of the Hepatitis C ActionPlan for Scotland, only 30 of 450 patientstreated annually for HCV in Scotlandinitiated their treatment in prison and, ofthose, only 12 completed treatment.4
Awareness of the importance of HCVhas increased in recent years. Initiativessuch as the Hepatitis C Action Plan forScotland4 and England5 have led tosignificant improvements in UK HCVservices, including those provided forincarcerated individuals. In this review, weaim to elucidate some of the challengesassociated with treating patients in prison.
Background
Substance misuse
In Scotland, 90% of new cases of HCV occurin drug users.6 This is comparable withother developed countries. Substancemisuse programmes are essential for theprevention of onward transmission of viralhepatitis. A survey from November 2011showed that 1% of prisoners in Scotlandhad injected drugs in prison in thepreceding month – despite having accessto methadone treatment programmes –and, of these, 69% had shared needles.7
From 1999–2000, a Scottish study showedan incidence of 26 HCV infections per 100
person-years among prisoners who hadshared injecting equipment in prison.7,8
Concerns around security have, so far,limited needle exchange programmes inprison in the UK, but successful schemesexist elsewhere.9
In the USA, around 38–45% of prisoners were alcohol dependent beforeincarceration.10 Scottish Prison Servicefigures suggest that one half of prisonerswere intoxicated at the time of theiroffence. Substance misuse complicatesengagement with healthcare. However,evidence suggests that outcomes oftreatment may be no worse in patientswho acquired their infection throughintravenous drug use, if their addictions are adequately addressed.11
Mental health
A disproportionate number of prisonersalso have mental health issues (see Table1).12 Interferon-based HCV treatment is wellknown to be associated with mooddisorders and, in one study, mental healthissues led to discontinuation of treatmentin 4.4% of prisoners.13
Educational attainment
Educational attainment among prisonersis lower than in the general population. A UK study in 2008 found that 52% ofmales in custody, and 71% of females, had no qualifications at all. Eighty per centhad a writing age of less than 11 and 50% had a reading age of less than 11.14
The issues around HCV investigation and treatment are complex and patientsmay struggle to understand the rationalefor their management. This could have an impact on their engagement with the process.
Where should HCv care be provided?
Security is generally the prime concern in prisons, rather than healthcare. Thiscomplicates many aspects of HCV care,particularly where the HCV care modelentails transport to a hospital-based clinicfor assessment and treatment. Externalclinics present resource issues for theprison service in relation to patienttransportation. In our experience, patientsfrequently expressed confidentialityconcerns, and many also said thatattending hospital in a prison uniform andhandcuffs was a degrading experience. With the NHS now assuming
responsibility for healthcare in prisons, theUK model for HCV care in prisons isincreasingly via HCV outreach clinics withinthe prison itself, provided by specialistclinicians (nurses and consultants). Wehave successfully operated a model of thiskind since 1999. In the USA, a model hasbeen used where primary care physiciansmanage viral hepatitis in the community(including prison) with support fromspecialists. Outcomes were equivalent tothe standard model of care.15
Treatment pathway
When planning an HCV service it is usefulto describe a patient pathway and toidentify the factors that may help orhinder a patient progressing through it.Figure 1 shows a simplified pathway forthe diagnosis, referral, assessment andtreatment of HCV-infected prisoners,along with a summary of the manypotential barriers to progression throughthis pathway.
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Mental health disorder Percentage in males (81%) Percentage in females (19%)Psychotic illness 3.7 4Major depression 10 12Personality disorder 65 42Antisocial personality disorder 47 21
Table 1.Percentage of mental health disorders in male/female
prisoners. Adapted from Fazel and Danesh, 200212
Practical difficulties in treating
hepatitis C patients in prison
Cartriona SykesMBChB MRCP Registrar (ST4) in Infectious Diseases Karen Robertson RGN MSc Blood-BorneViruses Specialist Nurse Nicholas Kennedy MBChB MDFRCP(Edin) FRCPSG Consultant Physician and Honorary SeniorLecturer, Area Infectious Diseases Unit, Monklands Hospital, Airdrie
Historically, there has been low uptake ofviral hepatitis testing, with only 2.4% ofprisoners between 2005–08 undergoingtesting for viral hepatitis in the UK.2 Thereare ongoing initiatives to expand access totesting in prison, but these tend to focuson prisoners identified as high risk. Arecent study has shown that universaltesting of prisoners in England is not cost-effective at present rates of transmissionand disease progression, but there arebenefits in education surroundinghepatitis C.16 Uptake has improved inScotland; by 2011, 48% of prisoners hadundergone a test during their sentence.7 Ithas been suggested that an opt-outapproach to testing may be beneficial.
Specialist referral
Hospital-based assessment clinics used topresent a major obstacle, as previouslydescribed. Even when a prison outreachclinic is provided, failure to attend orengage can be a significant issue. Previous liver biopsy-based algorithms
represented a major obstacle to HCVassessment and treatment.17 In ourexperience, this was a particular problemfor incarcerated patients. We now assessthe stage of liver fibrosis by transientelastography, rather than biopsy, forvirtually all patients.18
We have found monthly HCV outreachclinics, run by a consultant and a nursespecialist, to provide a good model for HCVassessment in prisons. They offer supportand education for clinicians and addictionworkers within prison services, allowingthem to take the lead on testing andsupporting patients through treatment.
HCV treatment within prison
Additional challenges in treating hepatitisC in prison are summarised below.
Continuity of care The continuity of care can be jeopardiseddue to the unexpected transfer of patientsfor security reasons. Healthcare workerscan make a case against transfer of apatient on treatment, but the eventualdecision is at the discretion of the prisonservice. Transfer of care between differentNHS regions can lead to delays. Parole mayalso occur at short notice.
NutritionNutrition can be a problem, particularly asprotease inhibitors have specific dietary
requirements. Food of the correct typemay not be available at the correct time.Also, dietary supplements may be neededto support nutrition during treatment.
PrivacyIn a shared cell it may be hard to hideongoing treatment from other inmates,and patients have cited fear of being seenwith blood-borne virus (BBV) nurses inprison, or with HCV literature in their cells.19
WorkPatients suffering adverse effects oftreatment may be accused of malingeringor be unable to work, therefore forfeitingincome. This makes treatment a lessattractive option.
CommunicationThere can be difficulties in contacting BBVnurses due to prohibitions on mobilephones within prison.
Prescribing Clinicians may be reluctant to prescribesedatives and anxiolytics due to theircapacity for abuse. This may makeadherence to treatment more difficult,especially if there are anxiety issuesassociated with interferon.
Education Further education of prison staff aroundissues surrounding new treatments(especially drug interactions) will beneeded with the new protease inhibitors.
From prison to community
On release, the patient is likely to beattempting to reintegrate into family life,look for employment and find housing.Attending healthcare appointments maybe a low priority. Social and psychologicalsupport contacts made in prison may notbe available on release, making adherenceto treatment harder. In some cases, there
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� Figure 1. Pathway for the diagnosis, referral, assessment and treatment of HCV-infected prisoners
Patient journey
Admission to prison• Lack of knowledge• Fear of diagnosis and disclosure• Lack of training for prison nurses and addiction sta!• Low priority compared with drug use and mental health issues• Variable operational arrangements for testing in prison
Testing for HCV
• Clinician’s lack of awareness of need to refer• Patient’s lack of awareness about treatment options and bene"ts• Stigma of attending clinics outwith prison environment• Con"dentiality concerns• Variable availability of HCV outreach teams• Security/prison sta#ng• Transport to clinics• Poor communication between prison and NHS• Poor clinic attendance (even in prison)
Treatment
• Lack of patient con"dence in prison-based treatment and care• Venous access/phlebotomy issues• Access to liver biopsy (less of an issue with non-invasive techniques)• Lack of adequate support; for example, mental health and nutrition• Patient moved or liberated before treatment being initiated• Issues as identi"ed above under ‘assessment’: con"dentiality; transport; outreach team availability; security/prison sta#ng; communication; poor attendance
may be resumption of alcohol or druguse with consequent discontinuationof therapy and disengagement fromhealthcare. Delays in follow-up canarise as patients may be incarceratedaway from their residence and needreferral to local specialist services.Re-infection, after a sustained
virological response (SVR) has beenachieved, remains a concern. In astudy in South Australia, re-infectionrates in prison were shown to be 17%over a mean follow-up of 1,243 days.20
This relates, in part, to ongoing druguse, but also other factors liketattooing in prison, which is associatedwith a significantly increased risk ofHCV transmission.21
Conclusion
All of the problems faced in themanagement of HCV in the non-prisonpopulation are also encountered when treating those in prison. Theseproblems may be more acute in the prison setting, with additionalissues to contend with, particularly theinfluence of the prison security regime.Despite this, high-quality care can bedelivered in a prison environment, andstudies in the USA have shown that SVR rates with pegylated interferon/ribavirin therapy in correctionalinstitutions can be comparable with the wider population – 47% SVR rate overall.13,15
The long-term sequelae of viralhepatitis are costly. A US study of male prisoners has shown a costbenefit of ribavirin/pegylatedinterferon treatment for HCV in nearlyall subsets of patients (the exceptionbeing young patients with genotype 1and no fibrosis on biopsy).22 In this
study, savings were greater ifno biopsy was performed, as isincreasingly the case.Prison remains an important
reservoir of infection for viral hepatitisworldwide, and treatment can bejustified as a public health measurealone. It is also a factor in reducinghealth inequalities in societies wherethe poorest people often do notengage with healthcare �
AcknowledgementThe authors would like to thank their clinical colleagues, as well as the staff within the Scottish Prison Service, for all their help and support in theprovision of the HCV prison outreach clinic.
Declaration of interestNone declared.
References 1. Fazel S, Baillargeon J. The health of prisoners. Lancet2011; 377: 956–965.2. Kirwan P, Evans B, Brant L. Hepatitis C and B testing inEnglish prisons is low but increasing. J Public Health(Oxf) 2011; 33: 197–204.3. Hammett TM, Harmon MP, Rhodes W. The burden ofinfectious disease among inmates of and releasees fromUS correctional facilities, 1997. Am J Public Health 2002;92: 1789–1794.4. Goldberg D, Brown G, Hutchinson S et al.Hepatitis Caction plan for Scotland: phase II (May 2008–March2011). Euro Surveill 2008; 13: pii:18876.5. www.dh.gov.uk/assetRoot/04/08/47/13/04084713.pdf (last accessed 30/07/12)6. Roy KM, Hutchinson SJ, Wadd S et al.Hepatitis C virusinfection among injecting drug users in Scotland: areview of prevalence and incidence data and themethods used to generate them. Epidemiol Infect 2007;135: 433–442.7. Scottish prisoner survey. www.sps.gov.uk/Publications/Publication-3696.aspx (last accessed30/07/12)8. Champion JK, Taylor A, Hutchinson S et al. Incidenceof hepatitis C virus infection and associated risk factorsamong Scottish prison inmates: a cohort study. Am JEpidemiol 2004; 159: 514–519.9. Ferguson L, Batey R. Prisons, prisoners, and hepatitisC. J Gastroenterol Hepatol 2010; 25: 1184–1186.10. http://bjs.ojp.usdoj.gov/ (last accessed 30/07/12)11. Jafferbhoy H, Miller MH, Dunbar JK et al. Intravenousdrug use: not a barrier to achieving a sustainedvirological response in HCV infection. J Viral Hepat 2012;19: 112–119.12. Fazel S, Danesh J. Serious mental disorder in 23000prisoners: a systematic review of 62 surveys. Lancet2002; 359: 545–550.13. Maru DS, Bruce RD, Basu S, Altice FL. Clinicaloutcomes of hepatitis C treatment in a prison setting:feasibility and effectiveness for challenging treatmentpopulations. Clin Infect Dis 2008; 47: 952–961. 14. www.literacytrust.org.uk (last accessed 30/07/12)15. Arora S, Thornton K, Murata G et al.Outcomes oftreatment for hepatitis C virus infection by primary careproviders. N Engl J Med 2011; 364: 2199–2207.16. Sutton AJ, Edmunds WJ, Sweeting MJ, Gill ON. Thecost-effectiveness of screening and treatment forhepatitis C in prisons in England and Wales: a cost-utilityanalysis. J Viral Hepat 2008; 15: 797–808.17. Booth JC, Foster GR, Levine T, Thomas HC, Goldin RD.The relationship of histology to genotype in chronicHCV infection. Liver 1997; 17: 144–151.18. Castera L. Transient elastography and othernoninvasive tests to assess hepatic fibrosis in patientswith viral hepatitis. J Viral Hepat 2009; 16: 300–314.19. Perrett SE. Prisoner health: assessing a nurse-ledhepatitis C testing clinic. Br J Nurs 2011; 20: 611–614.20. Bate JP, Colman AJ, Frost PJ, Shaw DR, Harley HA.High prevalence of late relapse and reinfection inprisoners treated for chronic hepatitis C. J GastroenterolHepatol 2010; 25: 1276–1280.21. Long JS, Allwright J, Barry J et al. 2001. Prevalenceof antibodies to hepatitis B, hepatitis C, and HIV andrisk factors in entrants to Irish prisons: a nationalcross sectional survey. BMJ 2001; 323: 1209–1213.22. Tan JA, Joseph TA, Saab S. Treating hepatitis C inthe prison population is cost-saving. Hepatology2008; 48: 1387–1395.
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� Incarceration should beviewed as an opportunity for healthcare services toengage with a hard-to-reachpopulation.
� There are many aspects that compromise hepatitis Cvirus care in prisons, such assecurity, nutrition, continuityand prescribing.
Key points
How would you deal with this patient?
A 29-year-old female is infected with hepatitis C – this wasprobably transmitted following a blood transfusion at the age of nine. She has had abnormal liver function tests (LFTs) for some time and has been formally investigated in the clinic, with the following results.�Hepatitis C virus antibody positive. Hepatitis B surface antigen
and HIV negative.�Viral load 1.6 x 106 IU/ml.�Genotype (G) 1b disease.�Abnormal LFTs, alanine aminotransferase 54, aspartate
aminotransferase 45.� IL-28B CC genotype.� Liver biopsy reported mild fibrosis and a Fibroscan® (EchoSens) reported
a median liver stiffness of 6.5. The patient is healthy and has no co-morbidities. Although previously
reluctant to have treatment, she believes this is the right time to considerit, with a view to clearing the virus before starting a family. She hasexcellent insight into her condition and is well read on the subject of HCVand its new treatments. She takes no medications and reports no knowndrug allergies. Physical examination is unremarkable with no stigmata ofchronic liver disease. These findings are consistent with her biochemical,radiological and histological parameters. Her liver biopsy demonstratesonly mild fibrosis (Ishak fibrosis stage 2/6).
TherapyWhat is the most appropriate therapy for this patient? I would discussresponse-guided therapy with the patient and would envisage a 24-weekcourse of treatment. This would comprise 12 weeks of triple therapy withtelaprevir, pegylated interferon (PEG-IFN) and ribavirin, followed by a 12-week tail of PEG-IFN and ribavirin. To have 24 weeks of therapy, shewould need to have undetectable HCV ribonucleic acid (RNA) at four weeksand 12 weeks into treatment (this is known as an ‘extended rapidvirological response’). If she has detectable virus, with an HCV RNA >1,000IU/ml at either four weeks or 12 weeks, she would need to stop all antiviralmedication. If she has detectable virus, but <1,000 IU/ml, she wouldrequire a 48-week treatment course. However, if the virus remainsdetectable at 24 weeks, treatment should be stopped.
The patient is well informed, so may have her own views on whichprotease inhibitor (PI) she would prefer. Of the two currently available PIs,telaprevir has a lower pill burden and, as the patient is well informed,educating her regarding diet and the strict eight-hourly dosing regimenwould be relatively easy. Telaprevir also has a shorter duration of tripletherapy. The importance of the viral hepatitis nurse and their role in patienteducation should not be overlooked. Patients need to be aware of the risk ofdrug resistance if they dose erratically. Similarly, they need to be aware ofthe importance of fatty food ingestion when dosing, and the possibility ofdrug interactions. Patients are usually advised to report any newmedications to their dedicated clinical nurse specialist before starting anynew treatment. Specifically, the necessity to report skin rashesimmediately, and education around good skin care, are essential. Patientsmust also be aware that antiviral drugs should not be altered in terms ofdosing unless specifically directed by the treating physician.
Outcome I would anticipate a >90% chance of achieving a sustained virologicalresponse in this patient. While we focused on the use of telaprevir here, theNational Institute for Health and Clinical Excellence has approved bothtelaprevir and boceprevir, and the 90-day consultation period is nowcomplete, so, theoretically, these drugs can be widely prescribed across theUK. Whether this is the case or not will be dependent on funding within theindividual patient’s NHS trust �
Declaration of interest The author has received educational grants, lecturing and consultancy fees from Roche, BMS and Gilead.
Patrick KennedyMB BCh BAO BMedSci MRCP MD
Senior Lecturer and ConsultantHepatologist, Centre for Digestive Diseases, Barts Health NHS Trust,
While much attention is paid to hepatitisB virus (HBV) and hepatitis C virus (HCV)genotype (G) 1, there are, of course, otherviruses that cause hepatitis. On 13 July2012, a British Viral Hepatitis Group(BVHG) meeting in Birmingham focusedon some of these.
Delta virus
Hepatitis delta virus (HDV), explained DrBelinda Smith (St Mary’s Hospital, London),is only present in people already infectedwith HBV; of some 350 million people withHBV, between 15–20 million will be co-infected with HDV. Globally, there arewide discrepancies in prevalence; withinEurope there is an increasing prevalence incountries with high immigration,including the UK. HDV is readilytransmissible, but can suppress HBVreplication. Clinical presentation can varyfrom mild to severe liver disease, withprogression to cirrhosis and hepaticdecompensation. The aim of long-termtreatment is slow surface antigenclearance, normally with pegylatedinterferon (IFN) alfa, which may be moreeffective in combination with ribavirin. DrEleni Nastouli (University College LondonHospital) explained the fascinating originof the virus and how further studies of itslife cycle, and the development of newtreatments and diagnostic tools, willadvance our knowledge of its naturalhistory and optimise patient follow-up.
Seronegative hepatitis
Dr Ahmed M Elsharkawy (Queen ElizabethHospital, Birmingham) presented anumber of case histories to illustrateseronegative hepatitis, the second most common cause of acute liver failure in Western countries and the most common indication fortransplantation in acute liver failure. Heexplained that it is a poorly characterisedentity. Clinical and laboratory featuresindicate immune activation or
dysregulation to a greater extent than seenin other causes of acute liver failure. Thecondition recurs or persists in somepatients post-transplant, but this ismodified by immunosuppression.
Hepatitis e virus
Dr Harry Dalton (Royal Cornwall HospitalsNHS Trust) explained that hepatitis E virus(HEV) is a major health issue in developingcountries. The main route is faeco-oral, viainfected water. It mostly affects youngadults and the mortality in pregnantwomen is 25%. In developed countriesthere are several routes of infection,including blood products. There issignificant morbidity and mortality. HEV G3has been found in retail pig meat and DrDalton showed evidence – including fromCornwall – suggesting that pig productconsumption may be a contributory factorin certain areas.
HIv and the liver
Dr Graham Cooke (Imperial CollegeLondon) described the factors involved inthe aetiology of end-stage liver disease inHIV patients. He told delegates that
specific causes of raised alanineaminotransferase in HIV patients includednon-cirrhotic portal hypertension, HIV-specific drugs, alcohol, acute HCVinfection and non-alcoholic fatty liverdisease. Dr Cooke also addressed the issueof thrombotic events, which occur amongHIV patients despite their relatively youngage. There is an increasing interest in therisk of atherosclerotic disease andinteraction with drugs.
HCv G4
Dr Ashley Brown (Imperial College London)updated delegates on the latest advancesin the management of HCV G4. Many ofthe antiviral drugs currently beingdeveloped for HCV G1 patients haveactivity in HCV G4, and forthcoming trialresults will guide optimal treatment. Fordifficult-to-treat patients, who may stillrequire quad therapy, newer IFNs may offer a more tolerable alternative. Over thenext five to ten years, short, once-dailyregimens with minimal side-effects andsustained viral response rates over 90% will be available for the majority ofpatients. Dr Brown emphasised theimportance of public education, caseidentification and prevention oftransmission to optimise the use of thesedrugs once they become available �
Declaration of interestNone declared.
11VIRAL HEPATITIS IN PRACTICE 2012; Vol 4 No 2
www.vhip.co.uk Meeting report
The british Viral Hepatitis Group:
the other hepatitis viruses
Geoffrey BowdenThe British Association for the Study of the Liver Secretariat, Brighton
Hepatitis e virus is amajor health issue indeveloping countries
� Professor Graham Foster,President of BASL (left)and Dr Ashley Brown, Chair of the BVHG (right)
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