(13.1)--小儿传染病学Diagnosisofviralhepatitis.pdf

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1、 Copyright 2017 Wolters Kluwer Health,Inc.All rights reserved.Copyright 2017 Wolters Kluwer Health,Inc.All rights reserved.CURRENTOPINIONDiagnosis of viral hepatitisPhilippa J.Easterbrooka,Teri Robertsb,Anita Sandsc,and Rosanna PeelingdPurpose of reviewChronic hepatitis B virus(HBV)and hepatitis C v

2、irus(HCV)infections and HIVHBV and HCV coinfectionare major causes of chronic liver disease worldwide.Testing and diagnosis is the gateway for access toboth treatment and prevention services,but there remains a large burden of undiagnosed infectionglobally.We review the global epidemiology,key chall

3、enges in the current hepatitis testing response,newtools to support the hepatitis global response(20162020 Global Hepatitis Health Sector strategy,and2017 WHO guidelines on hepatitis testing)and future directions and innovations in hepatitis diagnostics.Recent findingsKey challenges in the current h

4、epatitis testing response include lack of quality-assured serological and low-costvirological in-vitro diagnostics,limited facilities for testing,inadequate data to guide country-specific hepatitistesting approaches,stigmatization of those with or at risk of viral hepatitis and lack of guidelines on

5、 hepatitistesting for resource-limited settings.The new Global Hepatitis Health Sector strategy sets out goals forelimination of viral hepatitis as a public health threat by 2030 and gives outcome targets for reductions innew infections and mortality,as well as service delivery targets that include

6、testing,diagnosis and treatment.The 2017 WHO hepatitis testing guidelines for adults,adolescents and children in low-income and middle-income countries outline the public health approach to strengthen and expand current testing practices forviral hepatitis and addresses who to test(testing approache

7、s),which serological and virological assays to use(testing strategies)as well as interventions to promote linkage to prevention and care.SummaryFuture directions and innovations in hepatitis testing include strategies to improve access such as throughuse of existing facility and community-based test

8、ing opportunities for hepatitis testing,near-patient or point-of-care assays for virological markers(nucleic acid testing and HCV core antigen),dried blood spotspecimens used with different serological and nucleic acid test assays,multiplex and multi-disease platformsto enable testing for multiple a

9、nalytes/pathogens and potential self-testing for viral hepatitis.Keywordsdried blood spot,Global Hepatitis Health Sector strategy,hepatitis B virus,hepatitis C virus,nucleic acidamplification test,rapid diagnostic test,WHO testing guidelinesINTRODUCTIONEpidemiology and burdenHIV,hepatitis B(HBV)and

10、hepatitis C virus(HCV)infections are major global public health problems,withoverlappingmodesoftransmissionandaffected populations.It is estimated that 36.9million people are living with HIV 1,2,248 millionwith chronic HBV(CHB)infection defined as per-sistence of hepatitis B surface antigen(HBsAg)fo

11、r6 months or more 3&and 110 million persons areHCV antibody-positive,of which 80 million haveviraemic HCV infection 4.However,the estimatescommonly cited in the published literature varywidely 5.Hepatitis B virus and HCV infectionsareassociatedwithsignificantmorbidityandmortality due to chronic live

12、r disease.They accountfor approximately 57%of cirrhosis and 78%ofhepatocellular carcinoma(HCC)cases worldwide,and together they cause an estimated 1.4 milliondeaths annually 6.The burden of HBV and HCV isaGlobal Hepatitis Programme,HIV Department,World Health Organiz-ation,bMe decins Sans Frontie re

13、s,cDepartment of Essential Medicinesand Health Products,World Health Organization,Geneva,SwitzerlandanddLondon School of Hygiene and Tropical Medicine,London,UKCorrespondence to Philippa J.Easterbrook,Global Hepatitis Pro-gramme,HIV Department,World Health Organization,Avenue Appia20,1211 Geneva 27,

14、Switzerland.Tel:+41 22 791 4518;e-mail:easterbrookpwho.intCurr Opin HIV AIDS 2017,12:302314DOI:10.1097/COH.0000000000000370This is an open access article distributed under the terms of the CreativeCommons Attribution-Non Commercial License 4.0(CCBY-NC),whereit is permissible to download,share,remix,

15、transform,and buildup thework provided it is properly cited.The work cannot be used commerciallywithout permission from the journal.www.co-Volume 12?Number 3?May 2017REVIEW Copyright 2017 Wolters Kluwer Health,Inc.All rights reserved.Copyright 2017 Wolters Kluwer Health,Inc.All rights reserved.dispr

16、oportionatelyhighinlow-incomeandmiddle-incomecountries(LMICs),particularlyin Asia and Africa.Worldwide,the majority ofpersons with CHB were infected at birth or in earlychildhood,andperinatalorhorizontaltrans-mission predominates in sub-Saharan Africa(SSA)and Asia.In contrast,in high-income settings

17、,such as North America and Europe,transmissionis predominantly via injection drug use and high-risk sexual behaviours,especially in MSM 7.Inmiddle-income and high-income countries,mostHCV infections occur among persons who injectdrugs(PWID),whereas in low-income settings,HCVinfectionismostcommonlyas

18、sociatedwith unsafe injection practices and procedures inhealthcarefacilitieswithinadequateinfectioncontrol 8.HIVhepatitis B virus and hepatitis C viruscoinfectionAs HIV-infected persons continue to live longerdue to increased uptake of antiretroviral therapy(ART),liver disease has emerged as a lead

19、ingcause of morbidity and mortality in HIV-infectedpersons coinfected with HBV or HCV 914.Tworecentcomplementarysystematicreviewsandmeta-analyses have provided updated regionalestimates of HIVHBV and HIVHCV coinfectionacross five different population groups 15&,16&.There is an estimated global hepat

20、itis B surfanceantigen(HBsAg)prevalence of 7?4%interquartilerange(IQR)5.011.2%in HIV-infected persons,and a burden of 2.73 million(IQR 1.74.3 million;IQR1.34.4million)HIVHBsAgcoinfectedpersons,based on a systematic review 15&.The greatestburden is in SSA(71%of all cases;1.96 million),asit is the mos

21、t affected region for HIV infection(65%or22millionoftotalglobalHIVinfections),followedby Southeast Asia(10%of all cases;288816).There isan estimated global HCV antibody(anti-HCV)sero-prevalence of 6.2%IQR 3.411.9(IQR 5.011.2%)inHIV-infectedpersons,andaburdenof2.28million(IQR1.34.4million)HIVHCVantib

22、odycoinfectedpersons 16&,of which 1.36 million are in PWID.However,in contrast to HIVHBV infection,thegreatest HIVHCV burden is in Eastern Europe andCentral Asia(27%of all cases),because of the largeHIV-infected population of PWID,followed by SSA(19%of all cases).These recent global estimatesof HIVH

23、BV and HCV coinfection are lower thanthe previously reported prevalence of coinfection5,9,1720.Differences between epidemiology of HIVhepatitis B virus and HIVhepatitis C viruscoinfectionThe two companion reviews 15&,16&highlightfurther important distinctions between the epi-demiology of HIVHBV and

24、HIVHCV coinfection.Prevalence of HCV coinfection varies widely and ishighest in PWID 82.4%(95%confidence interval(CI)55.288.5),followed by MSM 6.4%(3.210.0),with much lower rates within the general popu-lation 2.4%(IQR 0.85.8).In contrast,HBsAgprevalence is similar across different HIV-infectedpopul

25、ation/exposuregroups,andinparticularbetween the general population(6.6%)and higherrisk behaviour groups such as PWID(7.0%)andMSM(6.1%).This overall lower HBsAg prevalence,even in very high-risk groups,is largely because themajority of HBV infection is acquired perinatally orin early childhood,many y

26、ears before HIV acqui-sition,in contrast to HCV,which is acquired gener-ally in adulthood,as for HIV.Globally,PWIDaccounted for only 7%of all HIVHBV but 59%of HIVHCV coinfections.Impact of HIV coinfection on naturalhistory of hepatitis B virus and hepatitis CvirusThe interaction with HIV affects the

27、 transmissionand natural history of HBV and HCV infections9,10,12,18.HBVcoinfectioninHIV-infectedKEY POINTS?There are an estimated 2.73 and 2.28 million personswith HIVhepatitis B surface antigen and HIVanti-HCVcoinfection globally.The greatest burden of HIVHBVcoinfection is in sub-Saharan Africa(71

28、%of all cases),and for HIVHCV is in Eastern Europe and central Asia(27%of all cases).The majority of HIV-HCV coinfection(59%of cases)are in persons who inject drugs.?The majority of HBV infections are acquired perinatallyor in early childhood,many years before HIVacquisition,in contrast to HCV,which

29、 is acquiredgenerally in adulthood.?The current low rate of viral hepatitis testing is a majorbarrier to scale-up of access to prevention,careand treatment.?Current viral hepatitis testing strategies include initialserological testing with assays in either rapiddiagnostic test or laboratory-based im

30、munoassay formatfollowed by virological testing for HBV DNA and HCVRNA to guide treatment decisions.?Future directions and innovations in testing includesimplified diagnostic algorithms,point-of-care virologicalassays,multi-disease platforms and self-testing foranti-HCV.Diagnosis of viral hepatitis

31、Easterbrook et al.1746-630X Copyright?2017 The Author(s).Published by Wolters Kluwer Health,Inc.www.co-303 Copyright 2017 Wolters Kluwer Health,Inc.All rights reserved.Copyright 2017 Wolters Kluwer Health,Inc.All rights reserved.personsisassociatedwithlessspontaneousclearance of HBsAg,higher rates o

32、f chronicityand occult HBV(HBV DNA detected in the absenceof HBsAg),accelerated fibrosis progression withincreased risk of cirrhosis and HCC and higherliver-related mortality 9,10,14,18.HIV infectionalso doubles the risk of HCV perinatal trans-mission in HIV-infected mothers 21,22 and isassociated w

33、ith less-spontaneous HCV clearance,higher HCV viral loads and more rapid HCVdiseaseprogression8,2325.AlthoughARTimproves outcomes in both and HCV coinfectedpatients,they may also increase the risk of hepa-toxicity from ART three-fold to five-fold 8,10,andcross-resistance between HIV and HBV drugs is

34、common 26.Strategies for controlHepatitis B virusUniversal infant and birth-dose hepatitis B vaccina-tion remains the key strategy for prevention andcontrol of the HBV epidemic 27.High levels ofcoverage have resulted in a substantial decrease innew cases of HBV infection in those aged under15 years

35、28.However,rates of adult vaccinationin vulnerable high-risk groups,such PWID,MSM,sex workersorprisoners,remainlow,andthese needto be specifically targeted for hepatitis B and Ctesting,catch up hepatitis B vaccination and otherpreventive interventions 29.As Tenofovir(TDF)isthe most effective drug fo

36、r long-term treatment ofHBV 30,the impressive global scale-up of HIVtesting and treatment 1 together with the increas-ing adoption of a TDF-based regimen as the pre-ferred first-line ART in adults and children agedmore than 3 years 31 represents a major globalopportunity to identify and effectively

37、treat thosewho also have HBV coinfection,as well as to reducemother-to-child transmission.Hepatitis C virusThe new era of highly curative short-course direct-acting oral antiviral therapies for HCV has revolu-tionized the treatment of chronic HCV infectionand offers the potential to not only improve

38、 indi-vidual clinical outcomes but also reduce trans-mission 32.There is a need to continue to scale-up HIV and HCV prevention interventions inhigherrisk populations,especially PWID with needle orsyringe exchange programmes,opiate substitutiontherapy and provision of ART.This is in addition tostrate

39、gies to improve injection safety both world-wide and especially in Eastern Europe and SoutheastAsia.GOALS OF HEPATITIS TESTINGTesting and diagnosis of CHB and HCV infection isthe entry point for access to both prevention as wellascareandtreatmentservices.Earlyidentificationofpersons with CHB or HCV

40、infection enables them toreceive the necessary care and treatment to preventor delay progression of liver disease.Knowledge ofHBV status is important to guide optimal selectionof ART regimens that include use of TDF,but also inmaintaining an agent active against HBV when atreatment switch is require

41、d as withdrawal can beassociated with liver flares and acute on chronicliver disease 33.Testing also provides an oppor-tunity to link to interventions that reduce trans-mission,such as counselling on risk behavioursandtheprovisionofpreventioncommodities(such as sterile needles and syringes)and hepat

42、itisB vaccination.CHALLENGES IN HEPATITIS TESTINGDespite the significant burden of disease due to HBVand HCV infections and HIVHBV and HCV coin-fection,and the advances and opportunities fortreatment,the majority of people coinfected withHBV or HCV remain undiagnosed and unaware oftheir infection 34

43、.It is estimated that less than 5%of people with CHB or HCV infection know theirstatus 34,35&,but in low-income and middle-income settings,this is even lower(1%).This isalso particularly poor in populations such as PWID,prisoners,sex workers and MSM,for whom access tocare and treatment are already c

44、hallenging 32.There are several key reasons for this low rate ofhepatitis testing 36.These include lack of aware-ness about hepatitis B and C disease and potentialtreatments among patients and healthcare workers;limited facilities or services for hepatitis testing,including those that can reach most

45、 affected andvulnerable populations,such as harm reductionservices;limited access to reliable and low-costHBV and HCV diagnostics,including rapid diagnos-tictests(RDTs)andvirologicalassaysthatarequalityassured by stringent regulatory authorities and/orWHO prequalified;poor laboratory capacity andlim

46、ited access to additional tests to stage liver dis-ease and guide treatment decisions,such as transi-ent elastography(e.g.FibroScan);weak hepatitissurveillance programmes and limited national andsubnational data on epidemiological situation toguide country-specific hepatitis testing approaches;high

47、levels of stigma,discrimination and socialmarginalization of those with or at risk of viralhepatitis,such as PWID,MSM,prisoners and sexworkers;lack of testing guidance for low-incomeand middle-income settings and a limited evidenceSpecial commentary304www.co-Volume 12?Number 3?May 2017 Copyright 201

48、7 Wolters Kluwer Health,Inc.All rights reserved.Copyright 2017 Wolters Kluwer Health,Inc.All rights reserved.base to guide hepatitis testing approaches;lack ofpolitical and financial commitment,including fromtraditional donors,and that few countries havedesignated hepatitis units and budgets within

49、theirhealth ministries to lead the development of ahepatitis strategy.Testing strategiesHepatitis B virus testingCHB infection is diagnosed by detection of HBsAgusing serological assays in either RDT or laboratory-basedimmunoassayformatsthatincludetheenzyme immunoassay(EIA),chemiluminescenceimmunoas

50、say(CLIA)andelectrochemilumines-cence assay(ECL)37&.Confirmation of the pres-ence of HBsAg may be carried out by performing aneutralization step using a specific anti-HBs-con-taining reagent in the same assay or by repeatingHBsAg testing using a different assay of similarsensitivity(i.e.two-assayser