Efficacy of Retreatment After Failed Direct-acting Antiviral Therapy in Patients With HCV Genotype 1-3 Infections

Hepatitis C virus infection is causing chronic liver disease, cirrhosis, and hepatocellular carcinoma. By combining direct-acting antivirals (DAAs), high sustained virologic response rates (SVRs) can be achieved. Resistance-associated substitutions (RASs) are commonly observed after DAA failure, and especially nonstructural protein 5A (NS5A) RASs may impact retreatment options.$^{1-3}$ Data on retreatment of DAA failure patients using first-generation DAAs are limited.$^{4-7}$ Recently, a second-generation protease- and NS5A-inhibitor plus sofosbuvir (voxilaprevir/velpatasvir/sofosbuvir [VOX/VEL/SOF]) was approved for retreatment after DAA failure.$^{8}$ However, this and other second-generation regimens are not available in many resource-limited countries or are not reimbursed by regular insurance, and recommendations regarding the selection of retreatment regimens using first-generation DAAs are very important. This study aimed to analyze patients who were re-treated with first-generation DAAs after failure of a DAA combination therapy

Patterns of Resistance-associated Substitutions in Patients With Chronic HCV Infection Following Treatment with Direct-acting Antivirals

BACKGROUND & AIMS Little is known about substitutions that mediate resistance of HCV to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments. METHODS We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (NS3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naïve patients, infected with HCV genotypes 1-4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than 2-fold changed in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks antiviral treatment were included in the analysis. RESULTS RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed. CONCLUSIONS We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies

An analysis and reconstruction of transitive nominalization in Ch’olan languages

This paper reconstructs the transitive nominalizing suffix *-yaj (IPA */-jax/) in the Ch’olan branch of Mayan languages. I consider data from modern Chol, Chontal, and Ch’orti’ as well as colonial Ch’olti’ to reconstruct the phonological form and syntactic function of this morpheme. This suffix has been called nominalizing antipassive (e.g., Robertson et al. 2010:186-7), although it does not eliminate the object in all cases. Rather, I analyze it as a more general valency-reducing suffix. Each of the languages has undergone small phonological changes, and all of them allow truncation of the suffix to -aj in certain phonological contexts and in fast speech. This paper argues that the glide is underlying, rather than epenthetic, and that the final consonant reconstructs to the velar fricative /x/ rather than the glottal /h/. It also considers the distribution of these nominalizations in each of the languages, and the additional morphology that can appear on them. In particular, there has been a shift between colonial Ch’olti’ and modern Ch’orti’ in the preferred method for marking the thematic roles of the nominalized verb. Ch’olti’ requires a prepositional phrase to reference the patient or stimulus of the verb if it has been derived into an agentive, while Ch’orti’ uses the Set A possessor for the same function. When there is no agentive prefix in Ch'olti', the Set A proclitic can appear before the nominalization, as in Ch’orti’. Chol and Chontal use the *-yaj suffix very similarly to each other. Although there is some debate about the role of nominalizations in split-ergative languages like these, these particular forms act as syntactic nouns, taking nominal morphology including possessors and being incorporated into verbs like any other noun. Further fieldwork on the distribution of the allomorphs in these languages would be particularly useful, as would a closer study focused on the syntactic distributionLinguistic