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

Long-term persistence of HCV resistance-associated substitutions after DAA treatment failure

BACKGROUND & AIMS: Data on the long-term persistence of HCV resistance-associated substitutions (RASs) after treatment with direct-acting antivirals (DAAs) are limited. This study evaluated the persistence of NS3, NS5A, and NS5B RASs for up to 5 years after the end of treatment (EOT). METHODS: We included samples from 678 individuals with an HCV genotype (GT) 1 or 3 infection and virologic DAA treatment failure collected in the European Resistance Database. NS3, NS5A, and NS5B were sequenced, and clinical parameters were evaluated. RESULTS: A total of 242 individuals with HCV GT1a (36%), 237 with GT1b (35%), and 199 (29%) with GT3 and a DAA failure were included. After protease inhibitor failure, the frequencies of NS3 RASs were 40-90% after the EOT. NS3 RASs disappeared rapidly in GT1b and GT3 after follow-up month 3 but were stable (≥60%) in GT1a owing to Q80K. The SOF-resistant NS5B RAS S282T was only found in individuals with GT3a. Non-nucleoside NS5B RASs were frequent in GT1 (56-80%) and decreased to 30% in GT1a but persisted in GT1b. NS5A RASs were very common in all GTs after NS5A inhibitor failure (88-95%), and even after follow-up month 24, their frequency was 65% and higher. However, RASs in GT1b had a stable course, whereas RASs in GT1a and GT3 declined slightly after follow-up month 24 (GT1a, 68%; GT1b, 95%; and GT3, 65%), mainly because of the slow decline of high-level resistant Y93H. CONCLUSIONS: We found that low-to medium-level RASs persisted, whereas high-level resistant RASs disappeared over time. Different patterns of RAS persistence according to HCV subtype could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. IMPACT AND IMPLICATIONS: There are little data on the long-term persistence of HCV resistance-associated substitutions (RASs) after DAA treatment failure, and RASs could have an impact on the efficacy of a rescue treatment. Especially in countries with limited availability of VOX/VEL/SOF or G/P/SOF, different patterns of RAS persistence could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. The different patterns of RAS persistence identified in this study can be used to derive general rules regarding the persistence of RASs after DAA failure that could be applied by physicians in less developed countries to plan individualized HCV retreatment

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