Response to potent anti-HBV agents in chronic hepatitis B and combined effect of HBV reverse transcriptase mutations.
OBJECTIVE
Response to nucleos(t)ide analogue therapy against HBV infection depends on a number of factors. One of them is appearance of drug resistance mutations. The present study aimed to investigate the efficacy of ETV and TDF as anti-HBV agents and to analyze the role of HBV-RT mutations in reducing the efficacy of mentioned drugs.


METHODS
Sixty nine treatment naïve CHB patients (mean age 33.8 ± 11.9 years) were enrolled and treated with ETV or TDF for one year. Complete virological response (CVR) was defined as undetectable serum HBV DNA after 12 months of therapy. Amino acid and nucleotide sequence analyses of HBV-RT region were performed using Geno2pheno HBV drug resistance tool. The 3D model of HBV-RT protein was built by I-TASSER server and RMSD was calculated between wild type and mutated HBV-RT protein.


RESULTS
After 12 months of treatment, four CHB patients did not achieve CVR and all of them were with HBV genotype D. HBeAg seroconversion was achieved in 56% HBeAg positive patients after 12 months of antiviral therapy. The HBV-RT amino acid sequences from these four patients were used for in-silico analysis. It was found that the presence of many mutations in HBV-RT region of HBV isolated from these patients led to a high degree of variation in configuration of atoms of HBV-RT protein and also caused displacement of active site of this protein.


CONCLUSIONS
The efficacy of antiviral drugs in inhibiting HBV replication may be reduced by combined effect of many HBV-RT mutations; however, an in vitro study is needed to validate the findings.
Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
Bhupesh
B
Singla
Department of Biotechnology, Maharishi Markandeshwar University, Mullana, Ambala 133207, India.
Rajasri
R
Bhattacharyya
Department of Experimental Medicine & Biotechnology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
Anuradha
A
Chakraborti
Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
Bal Krishan
BK
Sharma
Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
Shweta
S
Kapil
Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India. Electronic address: chawlayogesh@yahoo.co.in.
Yogesh K
YK
Chawla
Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
Sunil K
SK
Arora
Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
Ashim
A
Das
Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
Radha K
RK
Dhiman
Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
Ajay
A
Duseja
D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use*; D006147:Guanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D006515:Hepatitis B virus / Q000201:enzymology*; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D009154:Mutation; D063065:Organophosphonates / Q000627:therapeutic use; D012194:RNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics*; D000068698:Tenofovir
D000998:Antiviral Agents; D063065:Organophosphonates; C413685:entecavir; D006147:Guanine; D000068698:Tenofovir; D012194:RNA-Directed DNA Polymerase; D000225:Adenine
Hepatitis B virus; I-TASSER; Mutations; Nucleos(t)ide analogues; Real time PCR; Reverse transcriptase