Hepatitis C virus (HCV) is a positive-stranded RNA virus which belongs to the family of flaviviruses, predominantly infecting liver hepatocytes. HCV infection is a major cause for morbidity worldwide. The primary objective of this study was to evaluate the comparative effectiveness of pan-genotypic therapies for the treatment of patients with HCV infection in Bulgaria (sofosbuvir/velpatasvir/voxilaprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir). The following databases were searched: MEDLINE, EMBASE, Cochrane Library, PubMed and clinicaltrials.gov to identify studies evaluating the therapeutic efficacy of sofosbuvir/velpatasvir/voxilaprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir for the treatment of HCV in treatment-naïve/experienced patients with genotypes GT1/2/3/4/5/6. The search was held using keywords: Hepatitis C virus (HCV), sofosbuvir/velpatasvir/voxilaprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir clinical trials, comparative, study. The research was mainly focused on the comparison of SVR in patients with genotype GT1b, since, according to local epidemiological data, 90% of HCV positive patients in Bulgaria are carriers of this genotype. The systematic literature review identified 11 studies which evaluated efficacy of pan-genotypic treatments. The range of SVR rates among all the genotypes, achieved after therapy with sofosbuvir/velpatasvir/voxilaprevir in treatment-naïve patients, was 92-100% (8-week therapy) and in experienced patients - 99-100% (12-week therapy), with glecaprevir/pibrentasvir was 91- 100% (12-week therapy), and with sofosbuvir/velpatasvir was 97-100% (12-week therapy). The highest SVR rates for patients with GT1b genotype was achieved in treatment experienced patients receiving 12-week sofosbuvir/velpatasvir/voxilaprevir therapy (99%). The SVR12 rate in patients, receiving sofosbuvir/velpatasvir/voxilaprevir for 8 weeks is comparable with the rate observed in patients treated with sofosbuvir/velpatasvir and glecaprevir/pibrentasvir for 12 weeks thus demonstrating that sofosbuvir/velpatasvir/voxilaprevir is a non-inferior therapy offering simple (administration once daily) and short-term (8- week) treatment regimen with high efficacy, favourable safety profile and good tolerability. This would result in improving the quality of life of patients and contribute significantly to the treatment of HCV infection in Bulgaria.