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Association of Preexisting Drug-Resistance Mutations and Treatment Failure in Hepatitis B Patients.doc

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Association of Preexisting Drug-Resistance Mutations and Treatment Failure in Hepatitis B Patients

AssociationofPreexistingDrug-ResistanceMutations andTreatmentFailureinHepatitisBPatients JieMa1,2,YingchunZhang2,XinyueChen3,YiJin3,DexiChen1,YunWu2,JingCui2,HaitaoWang2, JiaLiu5,NingLi1,3,4*,FengGao6* 1Beijing Institute of Liver Disease, Beijing, China, 2Beijing Baihuirui Bio-Technologies Inc, Beijing, China, 3Department of Medicine, Beijing You’an Hospital, Capital Medical University, Beijing, China, 4Department of Surgery, Beijing You’an Hospital, Capital Medical University, Beijing, China, 5Department of Microbiology, Peking UniversityHealthScienceCenter,Beijing,China,6DepartmentofMedicine,DukeUniversityMedicalCenter,Durham,NorthCarolina,UnitedStatesofAmerica Abstract The role of preexisting minority drug-resistance mutations in treatment failure has not beenfully understood in chronic hepatitisBpatients.Tounderstandmechanismsofdrugresistance,weanalyzeddrug-resistancemutationsin46treatment- failure patients and in 29 treatment-na?¨ve patients and determined linkage patterns of the drug-resistance mutations in individualviralgenomesusingahighlysensitiveparallelallele-specificsequencing(PASS)method.Lamivudineresistance (LAMr)mutationswerepredominantintreatment-failurepatients,irrespectiveoftheinclusionofLAMintheregimen.The primaryLAMrmutationsM204VandM204Iweredetectedin100%and30%ofthetreatment-failurepatients,respectively. Two secondary LAMr mutations (L180M and V173L) were also found in most treatment-failure patients (87% and 78%, respectively). Thelinkagescontaining these threemutations dominatedtheresistant viruses. Importantly,minority LAMr mutationspresentin,2%oftheviralpopulationweredetectedin83%ofthetreatment-na?¨vepatients.Moreover,thelow- frequency same linked LAMr mutations (,0.15%) were detected in 24% of the treatment-na?¨ve patients. Our results demonstratethattheselectionofpreexistingminoritylinkedLAMrmutationsmaybeanimportantmechanismfortherapid development of LAM resistance, caution the continuous use of LAM to treat drug-experienced and -na?¨v