Abstract
Sustained virological response (SVR) rates have increased dramatically following the approval of direct acting antiviral (DAA) therapies. While individual DAAs have a low barrier to resistance, most patients can be successfully treated using DAA combination therapy. However, DAAs are vulnerable to drug resistance, and resistance-associated variants (RAVs) may occur naturally prior to DAA therapy or may emerge following drug exposure. While most RAVs are quickly lost in the absence of DAAs, compensatory mutations may reinforce fitness. However, the presence of RAVs does not necessarily preclude successful treatment. Although developments in hepatitis C virus (HCV) therapy in Asia have largely paralleled those in the United States, Japan’s July 2014 approval of asunaprevir plus daclatasvir combination therapy as the first all-oral interferon-free therapy was not repeated in the United States. Instead, two different combination therapies were approved: sofosbuvir/ledipasvir and paritaprevir/ritonavir/ombitasvir/dasabuvir. This divergence in treatment approaches may lead to differences in resistance challenges faced by Japan and the US. However, the recent approval of sofosbuvir plus ledipasvir in Japan and the recent submissions of petitions for approval of paritaprevir/ritonavir plus ombitasvir suggest a trend towards a new consensus on emerging DAA regimens.
Highlights
A recent open-label, phase II, randomized clinical trial was conducted in Japan to evaluate dual therapy with 12 or 24 weeks of ombitasvir (NS5A inhibitor) and paritaprevir/ritonavir (PI) in 101 patients with genotype 1b or 2 who failed to respond to prior peg-interferon plus ribavirin combination therapy [59]
Interferon lambda might have played a larger role in treatment of hepatitis C virus (HCV) were it not for the timely introduction of direct acting antiviral (DAA), but interferons may continue to play a useful role in treating or conditioning patients with DAA resistance, as interferon’s broad antiviral activity may help to clear resistant strains, improving the chance of successful re-treatment with DAA therapy
Treatment guidelines for patients with emergent resistance-associated variants (RAVs) have not been fully established, DAA therapy should be discontinued in such patients
Summary
Hepatitis C virus (HCV) is an enveloped virus in the hepacivirus genus of the Flaviviridae family. Direct Acting Antiviral Agents Because HCV does not integrate into the human genome and must replicate continuously to maintain infection, it should be possible to eradicate the virus by blocking replication at one or more stages of the life cycle. This approach to treating HCV was implemented in the form of direct acting antiviral (DAA) therapy, in which high-throughput methods are used to screen drugs that directly target HCV proteins (Table 1 and Figure 1). Simeprevir (TMC-435) Faldaprevir (BI-201335) Asunaprevir (BMS-650032) Paritaprevir (ABT-450/r) Danoprevir (ITMN-191, RG 7227) Sovaprevir (ACH-1625) Vedroprevir (GS-9451) Vaniprevir (MK-7009). Mosottrhtrheevmdeawuwarrioiinoanrrnsgesttvttschecanheasrasieaenv,p,estyshe.leceoMcowoanobnedssdrtaeavrnfiryacytrneimmaeonsufustttstaharhteetiaiolodavnntresiusvlmgoem.watCaeyoyrrocwfcsoiotsimnlm‐drepepsessteynirnspsetsaleaatnteaecivneffeodoartmroaffirowitetnnigelqedsusDstsiyAcllopkoAselsysssaianlasondnhsddtai,graaehblll,uqloowutwwiiictntkhthlhtyreheelevsoviassawrttr,iaoiabnanruncsttetttittncoooase, secoronenmdeaaridynreumvguentoafittnieontnhsecomanbfaseyernrcicnoegmofpatehnleesaadstrteugpfo.arCrtfiriaotlnsser‐esrsseisslitosastnascneacnetdoamaolotlhonewgr DtdhAreuAgvssairsiinhanitgthhet,owsraiemthmeraeicsnliassetsav.neScneoimtnoethe abseornnecseeisdtoarnfucgteh‐aeosfstdeorncuiagcto.endfCevrraroriinsasgn-rtsaetsdiselettaeacnstceedpaainrmtitaorlenargtemsDiesnAtatA‐nncsaeivisteo hpoaigthihee,nrtwsdairtpuhpgseraeirsnitsottahbneecaessasmtooceioacntleeadssdw. riuSthogmthoeeften conrfpeeasrirtsiietnangnt’csaet‐IaFlsNesaoLsc3tiagpteandrotvitayalprireae,nswtisshtdaicenhtceemcteitgodhiotntihntrdeeriactadmtreuesngetsl‐enicantivotenhepdaustaeiemtnotesincanlpaapstes.airmStomombueneearsresesosicpsitaoatnnesdceesw-ainisthstohtcehiseaeted varipapanatttiiesenndtt’est[Ie1Fc0Nt,e1Ld13].ginentorteyaptem, ewnhti-cnhaimveighptaitniednictasteapsepleecatriotnodbuee taosisnoncaiateteidmmwuitnhe rtehsepopnasteisenint’stheIFseNL3 genpoatytipene,tsw[1h0i,c1h1]m. ight indicate selection due to innate immune responses in these patients [10,11]
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