Resistance-associated substitutions (RASs) to HCV direct-acting antivirals (DAAs) at baseline of treatment in thalassemi
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ORIGINAL ARTICLE
Resistance‑associated substitutions (RASs) to HCV direct‑acting antivirals (DAAs) at baseline of treatment in thalassemia patients: a referral center study Fahimeh Safarnezhad Tameshkel1 · Mohammad Hadi Karbalaie Niya1,6 · Farhad Zamani1 · Nima Motamed2 · Hossein Ajdarkosh1 · Jamshid Vafaeimanesh1,3 · Mahmoodreza Khoonsari1 · Masood Reza Sohrabi1 · Sima Aten1 · Azita Azarkeivan4 · Masoumeh Sadat Eslami4 · Dhayaneethie Perumal5 · Mansooreh Maadi1 · Behrooz Ghanbari1 · Hossein Keyvani1,6 Received: 17 February 2020 / Accepted: 7 June 2020 © Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract Patients with thalassemia major are at high risk of hepatitis C through blood transfusion from donors infected by hepatitis C virus (HCV). The use of direct-acting antiviral (DAA) therapy against such HCV infections has increased in different populations. However, resistant viral variants can affect treatment outcomes, and therefore improved surveillance strategies are needed. Accordingly, we aimed to evaluate resistance-associated substitutions (RASs) to HCV DAAs at the baseline of treatment in thalassemia patients in a referral center. Out of 89 thalassemia patients who suffered from HCV infection and were referred to our center between 2016 and 2017, 43 underwent further analysis of the HCV nonstructural proteins NS5A and NS5B using polymerase chain reaction (PCR) sequencing methods. Unique primers were designed using bioinformatics software for separate detection of HCV subtypes 1a, 3a, and 1b. Detection of RASs was performed based on previously published literature. Statistical analysis was carried out using SPSS version 19. The participants, 60.4% (26/43) of whom were male, had a mean age ± standard deviation (SD) of 33.0 ± 5.0 years. HCV subtype 1a was found in 27 cases, 3a in 13, and 1b in three. In HCV subtype 1a there were 163 mutations in NS5A and 212 mutations in NS5B. The frequency of RASs was 20.9% (8 RASs in 9 patients), including M28V and H58P in subtype 1a, L28M, R30Q, C316N, and C316S in subtype 1b, and S24F in subtype 3a. Statistically, the subtype 1b and a higher mutation rate in NS5A were associated with RASs (p-value 90%), and minimal side effects have made these drugs popular worldwide [33]. These agents target three essential proteins of HCV encoded by nonstructural (NS) protein genes: NS3 (protease), NS5A, and NS5B (both RNA-dependent RNA polymerase (RdRp) subunits [16]. More than 20 DAAs are under investigation at advanced phases of clinical trials or have been approved and shown to have high efficacy. Nucleoside and non-nucleoside inhibitors (e.g., sofosbuvir [SOF] and dasabuvir [DAS], respectively) that target NS5B as well as NS5A inhibitors (e.g., daclatasvir [DCV], ledipasvir [LED], and ombitasvir [OMB]) [14, 35] are used either as part of interferon (IFN)-based or IFN-free regimens. Although combinations of DAAs have become the standard of care for patients with HCV infections, several limitations have been reported, including treatment failure due to HCV resistan
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