Systematic review with meta-analysis: impact of baseline resistance-associated substitutions on the efficacy of glecaprevir/pibrentasvir among chronic hepatitis C patients.

BACKGROUND: The effect of baseline resistance-associated substitutions (RAS) on the sustained virologic response at 12 weeks (SVR12) among chronic hepatitis C (CHC) patients receiving the second generation, pan-genotypic glecaprevir/pibrentasvir (G/P) regimen is unclear.

AIM: To assess the effect of RAS on the SVR12 in CHC patients treated with G/P regimen.

METHODS: The EMBASE, MEDLINE and Cochrane central register of controlled trials databases were searched for relevant studies published before 1 March 2019. The principal outcome was to compare the SVR12 in CHC patients with and without baseline RAS, particularly in genotype-1, genotype-3 and direct-acting anti-virals (DAAs) failure patients. The outcomes were pooled using a random-effects model and odds ratio (OR) was calculated. The risk of bias was assessed using the Cochrane risk of bias tools for randomised and nonrandomised interventional studies.

RESULTS: After initially identifying 410 studies, 3302 patients from 17 studies were included. Among 50 cases of virologic failures, 48% had genotype-3 infection, 44% genotype-1 infection and 36% DAA-failure patients. Baseline RAS were present in 44(88%) patients. The most common NS5a and NS3 mutations were Y93H and A166S respectively. The odds of SVR12 were significantly reduced in patients with any baseline RAS (NS3 and/or NS5a) (OR 0.32, 95%C I[0.15, 0.65], I2  = 0%) and NS5a substitutions (OR 0.36, 95%CI [0.18,0.73]). The impact of RAS on SVR12 was significant among genotype-3 patients, but not among genotype-1 or DAA-failure cases. The presence of Y93H and A30K mutations significantly impacted SVR12 rates in genotype-3 patients.

CONCLUSION: Baseline NS3 or NS5a RAS, especially the NS5a substitutions-A30K, Y93H, decrease the odds of achieving SVR12 in genotype-3 CHC patients.