Study of Resistance in Hepatitis C Virus Prior to Treatment with Direct Acting Antivirals

Abstract: The rapid advancement of Hepatitis C (HCV) treatment presents a great challenge to clinicians in optimising therapy for their patients. Genotype (GT), efficacy, side-effects, drug combinations and treatment durations must be tailored to individual patients, considering comorbidities, degree of fibrosis, adherence and antiviral resistance.Resistance associated substitutions (RASs) may impair treatment response to direct-acting antiviral agents (DAA). Almost all patients who fail treatment acquire RASs that may persist for years. Even treatment-naïve patients can harbour naturally occurring RASs against currently approved DAAs, i.e. resistance at baseline. Prevalence of key NS3 and NS5A-RASs is relatively high (3-9%) at baseline for DAA-treatment-naïve GT1a and 3a patients with population sequencing at 20% cut-off in Sweden and Norway.The studies in this thesis comprise investigations on the prevalence and the effects of baseline RASs on treatment outcome in patients with HCV GT1 and GT3 receiving personalised treatment based on results from NS3 and NS5A resistance testing. We developed a pan-genotypic population sequencing method for detecting NS5A RASs (Paper I), which is certified and used in routine diagnostics at our laboratory together with our previously developed NS3 RAS sequencing method.  We acquired data on RAS prevalence and treatment outcome from the early DAA management and carried out a non-randomised, prospective real-life study seeking to examine the impact on treatment outcome in patients receiving treatment tailored to baseline resistance testing.The studies were carried out between 2011 and 2017, one retrospective study comprising patients in the Uppsala region (Paper II) and two prospective studies with patients in a multicentre study involving sites in both in Sweden and Norway (Paper III and IV).RAS prevalence data from the prospective studies was obtained from a total of 401 patients and was shown to be slightly lower than reported from previous studies. Still, although not statistically significant due to the low prevalence of RASs in the cohort, we could show that there was a trend toward tailoring treatment to baseline RAS testing has a favourable impact on treatment outcome over treatment according to standard recommendations, especially in patients with cirrhosis. The economical and best practise objectives were important factors to consider when treatment costs were high and adverse effects were challenging at the initiation of the studies.In summary, this doctoral thesis presents results from real-life studies that indicate that tailoring treatment based on baseline RAS-testing have beneficial impact on patients that are treatment experienced and/or patients with cirrhosis.