Naturally occurring mutations in the reverse transcriptase region of hepatitis B virus polymerase from treatment-naïve Korean patients infected with genotype C2

Abstract

AIMTo report naturally occurring mutations in the reverse transcriptase region (RT) of hepatitis B virus (HBV) polymerase from treatment naïve Korean chronic patients infected with genotype C2.METHODSHere, full-length HBV reverse transcriptase RT sequences were amplified and sequenced from 131 treatment naïve Korean patients chronically infected with hepatitis B genotype C2. The patients had two distinct clinical statuses: 59 patients with chronic hepatitis (CH) and 72 patients with hepatocellular carcinoma (HCC). The deduced amino acids (AAs) at 42 previously reported potential nucleos(t)ide analog resistance (NAr) mutation positions in the RT region were analyzed.RESULTSPotential NAr mutations involving 24 positions were found in 79 of the 131 patients (60.3%). Notably, AA substitutions at 2 positions (rt184 and rt204) involved in primary drug resistance and at 2 positions (rt80 and rt180) that functioned as secondary/compensatory mutations were detected in 10 patients (1 CH patient and 9 HCC patients) and 7 patients (1 CH and 6 HCC patients), respectively. The overall mutation frequencies in the HCC patients (3.17%, 96/3024 mutations) were significantly higher than the frequencies in the CH patients (2.09%, 52/2478 mutations) (P = 0.003). In addition, a total of 3 NAr positions, rt80, rt139 and rt204 were found to be significantly related to HCC from treatment naïve Korean patients.CONCLUSIONOur data showed that naturally occurring NAr mutations in South Korea might contribute to liver disease progression (particularly HCC generation) in chronic patients with genotype C2 infections.

Naturally occurring hepatitis B virus reverse transcriptase mutations related to potential antiviral drug resistance and liver disease progression

“…The mutations rtA181T/V, rtM204I, and rtM204V also cause the simultaneous HBsAg mutations, sW172 stop, sW196S/L/Stop, and sI195M, respectively[ 17 , 72 ] (Table 1 ). Our literature based pooled incidence data showed that of primary drug resistance mutations, M204I/V is the most frequently encountered in treatment-naïve patients[ 14 , 28 , 33 ] (5.89%), which was far more than the pooled mutation rate of rtA181T/V, rtS202C/G/I and rtN236T (incidence: 1.16%, 0.85% and 0.81%, respectively). Mutation of rtI169T (0.12%), rtT184G (0.06%), rtA194T (0.07%), and rtM250V/L (0.20%) had a very low pooled incidence (Figure 1 ).…”

“…Among the 50 studies, 36[ 12 , 20 , 21 , 32 - 58 , 60 - 65 ] used direct PCR sequencing methods, 11[ 22 - 28 , 59 , 66 - 68 ] used the INNO-LiPA line assay, and 3[ 29 - 31 ] detected RT mutations by ultra-deep pyrosequencing (UDPS). Seventeen articles[ 21 , 26 , 27 , 30 , 31 , 34 , 35 , 37 - 39 , 42 , 43 , 46 - 48 , 53 , 58 ] included treatment-naïve patients infected with genotypes B and C, one study[ 32 ] with genotypes A and D, eleven studies[ 22 , 28 , 29 , 36 , 50 , 51 , 55 , 56 , 60 , 63 , 68 ] with genotype D, one study[ 33 ] with genotype C, and fifteen studies[ 20 , 23 - 25 , 40 , 41 , 44 , 45 , 52 , 54 , 57 , 61 , 64 , 65 , 67 ] with more than three genotypes ( e.g ., A, C, and D or A, B, C, and D). In five studies, genotypes of patients were not mentioned.…”

“…The rtL80I/V mutation also occurs frequently in treatment-naïve patients. Yamani et al[ 38 ], Kim et al[ 33 ], and Mirandola et al[ 25 ] found pre-existing rtL80I/V mutation frequencies of 1.07%, 3.82%, and 0.78%, respectively. Notably, Kim et al[ 33 ] reported that rtL80I/V was the most frequently encountered preexisting mutation of secondary drug resistance mutations in South Korea (3.8%, 5/131 patients), even higher than rtL180M frequency (2.3%, 3/131 patients).…”

“…Yamani et al[ 38 ], Kim et al[ 33 ], and Mirandola et al[ 25 ] found pre-existing rtL80I/V mutation frequencies of 1.07%, 3.82%, and 0.78%, respectively. Notably, Kim et al[ 33 ] reported that rtL80I/V was the most frequently encountered preexisting mutation of secondary drug resistance mutations in South Korea (3.8%, 5/131 patients), even higher than rtL180M frequency (2.3%, 3/131 patients). Another compensatory RT mutation, rtV173L, was also detected in several studies of treatment-naïve patients, where Zheng et al[ 20 ], Wang et al[ 39 ], and Mirandola et al[ 25 ] reported that it occurred in 0.6%, 0.56%, and 0.39% of their patients, respectively.…”

“…In addition, several studies have reported that treatment-naïve patients with only putative RT mutations, and without primary or secondary changes, developed drug resistance since treatment initiation[ 41 ]. Our literature based pooled incidence data showed that several putative or pretreatment mutations, including rtI91L, mutations in 6 positions of A-B interdomain (rtY124H, rtY126C/R/H, rtT128I/N, rtD134E/N, rtN139D/E/H/K/Q and rtW153Q/R/E), rtF221Y and rtI224V, were encountered with high frequency from the treatment naïve patients[ 20 , 21 , 33 , 38 , 39 , 42 ]. Of these, a RT mutation in the A-B interdomain, rtD134E/N, which also cause a simultaneous sI126N/S mutation of the HBsAg “a” determinant, was found to have the highest frequency in treatment-naïve patients (1.70%) (Figure 2 ).…”