No abstract

Worldwide, 50-70 million subjects are infected with an hepatitis C virus (HCV) genotype 2, 3, 4, 5 or 6. In these patients, the combination of PEG-INF-α and ribavirin remains the currently approved standard-of-care treatment. The identification of different potential therapeutic targets in the HCV life cycle has led to the development of both direct antiviral agents (DAAs) and reagents targeting host functions essential for viral replication. DAAs comprise so far first-generation, second-wave and second-generation NS3/4A protease inhibitors (PIs), nucleos(t)ide (NIs) and non-nucleoside inhibitors of the NS5B RNA polymerase and NS5A complex inhibitors. The main host-protein-directed antiviral agents are cyclophilin inhibitors and silibinin. Whereas the launch of first-generation PIs was a major landmark in the management of genotype 1 (GT-1)-infected patients, these drugs are inactive in most non-GT-1-infected patients. Several of these and other drugs have now reached phase II and even phase III clinical stage development. The purpose of this article is to provide an overview of the clinical results recently reported for the treatment for non-GT-1 HCV infection with a focus on the most promising new compounds and combinations.

The standard of care (SOC) for the treatment of HCV genotype 2 (HCV‐2) was pegylated interferon alpha plus ribavirin (PEG‐IFN/RBV) at weight‐based doses for a response‐guided duration. The launches of sofosbuvir and daclatasvir in 2014 have resulted in new, better tolerated and shorter treatment. The combination of sofosbuvir and RBV for 12 weeks appears to be the new SOC in both European and American guidelines. The cost and therefore the access to this treatment remains a problem in many countries because of major economic constraints. For the few more difficult‐to‐treat patients, a combination of direct acting antivirals may be suitable and is being studied in ongoing trials. Because of rapidly changing treatment recommendations, the decision to treat HCV‐2 patients with currently approved drugs or to wait until a better option is available in the future, must be made according to the stage of fibrosis.

This study sets out to establish the suitability of saliva‐based whole‐genome sequencing (WGS) through a comparison against blood‐based WGS. To fully appraise the observed differences, we developed a novel technique of pseudo‐replication. We also investigated the potential of characterizing individual salivary microbiomes from non‐human DNA fragments found in saliva. We observed that the majority of discordant genotype calls between blood and saliva fell into known regions of the human genome that are typically sequenced with low confidence; and could be identified by quality control measures. Pseudo‐replication demonstrated that the levels of discordance between blood‐ and saliva‐derived WGS data were entirely similar to what one would expect between technical replicates if an individual's blood or saliva had been sequenced twice. Finally, we successfully sequenced salivary microbiomes in parallel to human genomes as demonstrated by a comparison against the Human Microbiome Project.