ChronicinfectionwithhepatitisBvirus(HBV)afflicts~400millionpeopleworldwide,including1.5-2millionin theU.S.A.ChronichepatitisB(CHB)leadstoearlydeathfromcirrhosis,liverfailureandprimarylivercancer (HCC) in at least 1 million people annually. Current antiviral therapies (AVT) can suppress but rarely cure infection,emphasizingneedforfreshapproaches.Weproposeonehere. MostCHBpatientsreceivingAVTintheWesthave?earlyantigennegative(HBeAg-)?disease,causedbya futilehostimmuneresponseagainstamutatedformofHBV.Thecurrentstandard-of-careislifelongAVTwhich canpreventdiseaseadvancementandlikelylowerHCCrisk.However,indefiniteAVTincursfinancialburdento healthcaresystemsandpatients,raisessafetyconcernsandcarriesdrugresistancerisk. Newdatafrom33HBeAg?CHBpatientsinGreece,supportedbyourpilotstudy,suggestthatAVTwithdrawal after ?3.7 years (192 weeks) of viral suppression can be safe, benefit many and even stimulate protective immunity.Duringfollow-up,18(55%)achievedsustainedviralandbiochemicalresponses.Ofthese,13(39%of the original cohort) went on to clear HBV by generating neutralizing surface antibody (HBsAb). This seismic resultindicatedthatinHBeAg-CHB,AVTwithdrawalislikelysafeandcaneffect?closetocure?ofwhatwould otherwisebealifelong,life-threateningandindefinitelytreatedinfection.Seminally,italsoopensanewdoorfor understandinghowtotiltacurativehostimmuneresponseinCHB,whichwealreadystudy. Inthisgrant,weproposetestingthefindingsoftheGreekstudyinalarger,ethnicallydiverseSanFrancisco populationthatisnaturallyenrichedforAsianswhocomprisetheworld?sgreatestHBVreservoir.Inparallel,we willusecellularandmolecularstudiesonliverandbloodfromthepatientstodissectimmunologicalmechanisms ofseroclearanceversuspersistenceofHBVanditsantigens.Thetranslationalscientificcomponentwillinpart bedrivenbyhypothesesbasedonourpublishedandunpublisheddata;?anditwillalsocontainahostgenetic prospectingarmthatwillseekevidenceforsignaturegeneexpressionpatternsthatbothpredictoutcomeand couldpointtounsuspectedmechanismsofimmunity.Akeyobjectivewillbetoattempttodistinguishpatients whoaremostorleastlikelytobenefitfromthetreatmentwithdrawalintervention. METHODS: An IRB-approved, 2-center (CPMC & UCSF) multidisciplinary prospective study of clinical outcomes,geneticprofilesandimmuneresponsesin80adulthumanpatientswithHBeAg-CHB,duringandafter oralAVT,usingserialbloodsamplesandliverbiopsytissue.30adultHBeAg-controlswillalsobestudied. PATIENT OUTCOMES (PROJECTED) 31 patients are predicted to HBsAb seroconvert and clear circulating HBVDNAandantigens;?49arepredictedtoremaininfected:36withactive,and13withquiescent,CHB.Akey goalistodeterminewhichHBeAg-CHBpatientscansafelystopAVTandbenefit.Thisstudycouldhavemajor therapeutic,managementandhealth-carecostimplications. 1

Public Health Relevance

Chronic infection with hepatitis B virus (HBV) afflicts ~400 million people worldwide, including 1.5-2 million in the U.S.A. Chronic hepatitis B (CHB) leads to early death from cirrhosis, liver failure and primary liver cancer (HCC) in at least 1 million people annually. Current antiviral therapies (AVT) can suppress but rarely cure infection, emphasizing need for fresh approaches. We propose one here.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK103735-05
Application #
9982307
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
2016-09-01
Project End
2021-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
California Pacific Medical Center Research Institute
Department
Type
DUNS #
071882724
City
San Francisco
State
CA
Country
United States
Zip Code
94107