Long-term Analysis Of The Prevalence Of Drug Resistant HBV In Patients With Antiviral Therapy Failure

Hepatitis B is a potentially life-threatening liver infection caused by the hepatitis B virus.Approximately 240 million people are chronically infected with HBV.HBV infection is estimated to be the primary cause of 30% of the cirrhosis and 53% of the liver cancer cases worldwide.Five nucleos(t)ide analogues(NAs),i.e.,Lamivudine(LAM),Telbivudine(LdT),Entecavir(ETV),Adefovir(ADV),and Tenofovir(TDF),have been approved for the treatment of hepatitis B.These drugs not only effectively suppress HBV replication,normalizing alanine aminotransferase(ALT)levels,and reducing hepatic inflammation,but can also reverse hepatic fibrosis and even cirrhosis.Moreover,NAs have the advantage of oral administration and being relatively free of adverse effects.The major drawback of NAs is the high rate of antiviral resistance in long-term treatments due to the natural selection of mutations in the reverse transcriptase(RT)gene,leading to a virus that is partially or completely resistant to specific antiviral drugs.To study the prevalence of drug resistant HBV in patients with therapy failure in a tertiary referral liver center in China,we investigated 1223 CHB patients between 2010 and 2014 and performed HBV sequencing using their serum samples to check HBV genotypic resistance.We found that LAM genotypic resistance was the most common phenotype(46.2%),followed by LdT(46.1%),ETV intermediate(37.5%),ADV resistant(14.1%),TDF intermediate(11.4%),and ETV resistant(1.6%)phenotypes.The resistant ratio of LAM has been continuously increasing until 2013(53.7%)before going down to 47.7% in 2014,which evidenced a lagging effect in L-Nucleoside consumption.M204 I,N236T,and L180M+M204V+V173l/S202 G were the most common substitutions for L-Nucleosides(LAM and LdT),ADV,and ETV genotypic resistant phenotypes,respectively.Resistant ratios of LAM,LdT,and ETV in hepatocellular carcinoma(HCC),liver cirrhosis(LC),and CHB patients showed a significant difference.Independent risk factors for resistance were age,HBV load,serum AST,genotype D,exposure of LAM,and for samples collected in 2010 and 2013.The ADV resistant ratio,both in total recruited and LAM+ADV-exposed populations,is still at a relative low level(14.1% and 18.6%,respectively),supporting the efficiency of ADV-based rescue therapy in LAM resistant CHB patients,and is a suitable option for patients with limited economic conditions.