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Case Reports
. 2021 Apr 26;21(1):387.
doi: 10.1186/s12879-021-06080-0.

Resistance-associated substitutions and response to treatment in a chronic hepatitis C virus infected-patient: an unusual virological response case report

Fabián Aldunate #  1   2 , Natalia Echeverría #  1   2 , Daniela Chiodi  3 , Pablo López  4 , Adriana Sánchez-Cicerón  3 , Martín Soñora  1   5 , Juan Cristina  1 , Gonzalo Moratorio  1   2 , Nelia Hernández  3 , Pilar Moreno  6   7
Affiliations
Case Reports

Resistance-associated substitutions and response to treatment in a chronic hepatitis C virus infected-patient: an unusual virological response case report

Fabián Aldunate et al. BMC Infect Dis. .

Abstract

Background: Direct-Acting agents (DAAs) target and inhibit essential viral replication proteins. They have revolutionized the treatment of Hepatitis C virus (HCV) infection reaching high levels of sustained virologic response. However, the detection of basal resistance-associated substitutions (RASs) to DAAs in naïve patients could be important in predicting the treatment outcome in some patients exhibiting failures to DAA-based therapies. Therefore, the aim of this work was to evaluate the presence of RASs as minority variants within intra-host viral populations, and assess their relationship to response to therapy on a multiple times relapser patient infected chronically with HCV.

Case presentation: A male HCV infected-patient with a genotype 1a strain was evaluated. He had previously not responded to dual therapy (pegylated interferon-α plus ribavirin) and was going to start a direct-acting agent-based therapy (DAAs). He showed no significant liver fibrosis (F0). Viral RNA was extracted from serum samples taken prior and after therapy with DAAs (sofosbubir/ledipasvir/ribavirin). NS5A and NS5B genomic regions were PCR-amplified and the amplicons were sequenced using Sanger and next-generation sequencing (NGS) approaches. RASs were searched in in-silico translated sequences for all DAAs available and their frequencies were determined for those detected by NGS technology. Sanger sequencing did not reveal the presence of RASs in the consensus sequence neither before nor after the DAA treatment. However, several RASs were found at low frequencies, both before as well as after DAA treatment. RASs found as minority variants (particularly substitutions in position 93 within NS5A region) seem to have increased their frequency after DAA pressure. Nevertheless, these RASs did not become dominant and the patient still relapsed, despite perfect adherence to treatment and having no other complications beyond the infection (no significant fibrosis, no drug abuse).

Conclusions: This report shows that some patients might relapse after a DAA-based therapy even when RASs (pre- and post-treatment) are detected in very low frequencies (< 1%) within intra-host viral populations. Increased awareness of this association may improve detection and guide towards a personalized HCV treatment, directly improving the outcome in hard-to-treat patients.

Keywords: Case report; DAA therapy; Hepatitis C virus; RASs minority variants; Relapse.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Patient treatment timeline. Initial diagnosis, periods of therapies and responses to treatment are indicated on top of the time line, whereas type of treatment and samples used for RAS analyses in this study are indicated below
Fig. 2
Fig. 2
RASs found pre- and post-treatment with LDV/SOF + RBV detected as low frequency variants by NGS. 2a RASs conferring resistance to LDV detected within NS5A genomic region. 2b RASs conferring resistance to SOF detected within NS5B genomic region
See this image and copyright information in PMC

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