Incidence of natural resistance mutations in naïve chronic hepatitis B patients: a systematic review and meta-analysis

Background and aim: Studies focused on the naturally occurring resistance mutation rate in treatment-naïve chronic hepatitis B (CHB) patients have set off a furious dispute. We conduct this meta-analysis to appraise the pooled incidence of spontaneous hepatitis B virus resistance mutations worldwide and its distribution.

Methods: We searched PubMed, EMBASE, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure until December 31, 2013. Cross-sectional or case-control studies reporting incidence of natural resistance mutations in untreated CHB patients were included. Pooled incidence was performed in fixed- or random-effects models, and heterogeneity among studies was assessed.

Results: A total of 106 studies were included involving 12,212 naive CHB patients. The summarized incidence of natural mutations worldwide was 5.73% (95% confidence interval [CI]: 4.85-6.61%), primary mutation rate 5.39% (95%CI: 4.54-6.24%), and secondary mutation rate 2.94% (95%CI: 1.59-4.29%). The pooled incidence reached up to 8.00% (95%CI: 6.63-9.38%) in China, higher than that in other countries (1.88% [95%CI: 1.06-2.69%]). Mutation rtM204V/I had the highest incidence of 4.89% (95%CI: 4.13-5.65%), and other primary mutations seldom spontaneously occurred. In subgroup analysis, genotype C hepatitis B virus infection, male, and hepatitis B antigen (HBeAg) negative patients had a slightly higher natural mutation rate.

Conclusion: The resistance mutations occurred frequently in untreated CHB patients, especially in China. The lamivudine resistance had the highest natural prevalence rate, while other nucleos(t)ide analogues showed rarely spontaneous resistance. Detecting the spontaneous resistance mutations will benefit the clinical management of CHB patients.