NS5A Inhibitor Research Articles

Update on Current Evidence for Hepatitis C Therapeutic Options in HCV Mono-infected Patients.

Therapies for hepatitis C (HCV) are evolving rapidly with the advent of novel direct-acting antiviral agents (DAAs). We review evidence for currently or imminently available regimens to aide clinicians in understanding current therapeutic options. A number of DAA combinations have completed clinical trials and are available for use. Current combinations are often genotype-specific, and combine HCV protease inhibitors, NS5A inhibitors and/or NS5B inhibitors to suppress HCV replication, leading to eradication. Current potential combinations for genotype 1 infection include sofosbuvir-ledipasvir, paritaprevir/ritonavir-ombitasvir-dasabuvir, sofosbuvir with daclatasvir, and grazoprevir-elbasvir. These regimens have been associated with sustained virologic response (SVR) rates of over 95% for treatment naïve individuals after 12weeks of therapy regardless of cirrhosis, and some sub-groups of patients may be successfully treated with just 8weeks of sofosbuvir-ledipasvir. Regimens for genotype 2 and 3 include sofosbuvir with ribavirin, sofosbuvir with daclatasvir, or with velpatasvir, which may offer highest SVR rates when available. The development of HCV drug resistance, particularly against NS5A agents, may impact subsequent regimens. The need for baseline screening for resistant variants is unclear for most regimens, but likely would affect only a minority of patients. All-oral curative regimens for HCV are now possible for most patients.

Matched and mixed cap derivatives in the tetracyclic indole class of HCV NS5A inhibitors

A matched and mixed capping SAR study was conducted on the tetracyclic indole class of HCV NS5A inhibitors to examine the influence of modifications of this region on the overall HCV virologic resistance profiles.

Aryl or heteroaryl substituted aminal derivatives of HCV NS5A inhibitor MK-8742

Herein we describe our research efforts around the aryl and heteroaryl substitutions at the aminal carbon of the tetracyclic indole-based HCV NS5A inhibitor MK-8742. A series of potent NS5A inhibitors are described, such as compounds 45–47, 54, 56, and 65, which showed improved potency against clinically relevant and resistance associated HCV variants. The improved potency profiles of these compounds demonstrated an SAR that can improve the potency against GT2b, GT1a Y93H, and GT1a L31V altogether, which was unprecedented in our previous efforts in NS5A inhibition.

Biophysical Studies on HCV 1a NS3/4A Protease and Its Catalytic Triad in Wild Type and Mutants by the In Silico Approach.

The hepatitis C virus (HCV), of the family flaviviridae, is one of the major causes of chronic liver diseases. Until the year 2012, HCV infections were treated using PEG-interferon and ribavirin combinations, which have a low cure rate and severe side effects. Currently, many direct-acting antivirals (DAAs) are available, e.g. protease inhibitors, NS5A and polymerase inhibitors. These drugs have proven to be efficient in interferon-free treatment combinations and capable of enhancing the cure rate to above 90%. Unlike PEG-interferon and ribavirin combinations, DAAs select for resistance in HCV. The R155K mutation in the HCV was found to resist all the currently available protease inhibitors. Here, we studied biophysical parameters like pocket (cavity) geometries and stabilizing residues of HCV 1a NS3/4A protease in wild type and mutants. We also studied HCV 1a NS3/4A protease's catalytic residues: their accessibility, energy, flexibility and binding to Phase II oral protease inhibitor vedroprevir (GS-9451), and compared these parameters between wild type and mutant(s). All these studies were performed using various bioinformatics tools (e.g. Swiss-PdbViewer and Schrödinger's Maestro) and web servers (e.g. DoGSiteScorer, SRide, ASA-View, WHAT IF, elNémo, CABS-flex, PatchDock and PLIP). From our study, we found that introduction of R155K, A156T or D168A mutation to wild-type NS3/4A protease increases the pocket's volume, surface (in the R155K mutant, surface decreases), lipo surface and depth and decreases the number of stabilizing residues. Additionally, differences in catalytic residues' solvent accessibility, energy, root-mean-square deviation (RMSD) and flexibility between wild type and mutantsmight explain changes in the protease activity and the resistance to protease inhibitors.

Effectiveness and safety of daclatasvir plus asunaprevir for patients with hepatitis C virus genotype 1b aged 75years and over with or without cirrhosis.

The aim of this study was to evaluate the efficacy and safety of 24-week daclatasvir (NS5A inhibitor) plus asunaprevir (NS3/4A protease inhibitor) treatment for elderly patients with hepatitis C virus (HCV) genotype 1b infection. This prospective, multicenter study consisted of 321 Japanese HCV genotype 1b patients who were interferon-ineligible/intolerant or non-responders to interferon-based regimens, including 103 (32.1%) aged ≥75years and 127 (39.6%) with cirrhosis. Sustained virological response (SVR) at 24weeks after the end of treatment and adverse effects were analyzed according to age. The overall SVR rate was 90.3%. In terms of by age, 94.5% (69/73), 88.3% (128/145), and 90.3% (93/103) of the patients aged <65, 65-74, and ≥75years, respectively, achieved SVR. For the entire cohort, pre-existent NS5A resistance-associated variants and prior simeprevir failure were independently associated with treatment failure. According to the analysis of patients without these unfavorable pretreatment factors, 90.8% (89/98) aged ≥75years achieved SVR, although this was significantly lower than for those aged <65years (98.5%, 66/67) (P <0.05). The frequency of adverse effects was comparable for the <75 and ≥75 age groups, the most common being an elevated alanine aminotransferase level (>150U/L, 8.7%), however, no decompensating events were seen. Daclatasvir plus asunaprevir for HCV genotype 1b was well tolerated and effective for patients without pre-existent NS5A resistance-associated variants or simeprevir failure, irrespective of fibrosis status. However, it was less effective for very old patients aged ≥75years compared to those aged <65.

Impact of Pre-existing NS5A-L31 or -Y93H Minor Variants on Response Rates in Patients Infected with HCV Genotype-1b Treated with Daclatasvir/Asunaprevir.

The combination of daclatasvir (DCV, pan-genotypic NS5A inhibitor) plus asunaprevir (ASV; NS3 protease inhibitor) is approved in Japan, Korea and other countries for the treatment of chronic hepatitis C virus (HCV) genotype (GT)-1. A high (~90 to 100%) sustained virologic response (SVR) with DCV/ASV therapy has been achieved by excluding patients infected with HCV GT-1b with baseline NS5A resistance-associated variants (RAVs) at L31 or Y93H detected by direct sequencing (DS). We set out to determine whether patients with minor variants at NS5A-L31 or -Y93H, detected by next-generation sequencing (NGS), impacted SVR rates with DCV/ASV therapy. Baseline samples from 222 interferon (IFN)-ineligible/intolerant (N=135) and prior non-responder (N=87) patients infected with GT-1b who were treated with DCV/ASV for 24weeks in the Phase 3 clinical study AI447026 were prepared for NGS (Ion-Torrent platform). The prevalence of baseline NS5A RAVs and their impact on SVR when observed at ≥1% by NGS in a patient's virus population were examined. NGS and DS (sensitivity ≥20%) data were compared. The prevalence of baseline NS5A RAVs at L31 or Y93H was 29% (63/219) and 18% (39/214) by NGS and DS, respectively. SVR24 rates were comparable in patients without observed baseline L31 or Y93H polymorphisms whether assessed by NGS (96%; 148/154) or by the less sensitive DS platform (95%; 164/173). Optimal SVR rates (≥95%) to DCV/ASV treatment were achieved using DS to exclude patients infected with GT-1b with NS5A RAVs at L31 or Y93H representing ≥20% of their virus population. Exclusion by NGS of patients with minor variants in NS5A (<20%) did not enhance SVR rates. These results suggest that the presence of minor variants in NS5A does not appear to impact the overall SVR rate in patients with GT-1b treated with DCV/ASV. This study was sponsored by Bristol-Myers Squibb. ClinicalTrials.gov identifier: NCT01497834.

Interferon-free treatment for HCV-infected patients with decompensated cirrhosis.

Progress in interferon-free treatment against hepatitis C virus (HCV) has remained a challenge in patients with decompensated cirrhosis due to a paucity of information on efficacy and safety profiles. This review illustrates that interferon-free treatment could result in greater than 85% sustained virological response (SVR) rates in patients with HCV genotype 1 and decompensated cirrhosis. The combination of pangenotypic HCV NS5A inhibitor velpatasvir and HCV NS5B inhibitor sofosbuvir has demonstrated high SVR rates in patients with HCV genotypes 1, 2, 3, 4 or 6 and decompensated cirrhosis. Certain patients discontinued treatment due to adverse events, death or having liver transplantation. Taken together, interferon-free treatment could produce higher SVR rates in decompensated hepatic cirrhosis. However, as adverse events were occasionally observed, liver transplantation should always be considered as well. Further improvements in treatment are called for in patients with decompensated cirrhosis.

Efficacy of the Combination of Sofosbuvir, Velpatasvir, and the NS3/4A Protease Inhibitor GS-9857 in Treatment-Naïve or Previously Treated Patients With Hepatitis C Virus Genotype 1 or 3 Infections

We performed a phase 2 trial of the efficacy and safety of 4, 6, and 8 weeks of sofosbuvir, given in combination with the NS5A inhibitor velpatasvir and the NS3/4A protease inhibitor GS-9857, in patients with hepatitis C virus (HCV) infection. We enrolled 161 treatment-naïve or previously treated patients infected with HCV genotypes 1 or 3 with or without compensated cirrhosis at 2 centers in New Zealand, from September 2014 through March 2015. All patients received sofosbuvir (400 mg) and velpatasvir (100 mg) plus GS-9857 (100 mg) once daily. The primary efficacy end point was sustained virologic response at 12 weeks after therapy (SVR12). The duration of therapy was determined by baseline patient characteristics: 4 or 6 weeks for treatment-naïve patients without cirrhosis, 6 weeks for treatment-naïve patients with cirrhosis, and 6 or 8 weeks for treatment-experienced patients with or without cirrhosis. Four weeks of sofosbuvir, velpatasvir, and GS-9857 produced an SVR12 in 4 of 15 (27%) treatment-naïve patients with HCV genotype 1 without cirrhosis. Six weeks of this combination produced a SVR12 in 14 of 15 (93%) treatment-naïve patients with HCV genotype 1 without cirrhosis, in 13 of 15 (87%) treatment-naïve genotype 1 patients with cirrhosis, in 15 of 18 (83%) treatment-naïve patients with HCV genotype 3 with cirrhosis, and in 20 of 30 (67%) patients with HCV genotype 1 who had failed an all-oral regimen of 2 or more direct-acting antiviral agents. Eight weeks of the drug combination produced an SVR12 in 17 of 17 (100%) patients with HCV genotype 1, in 19 of 19 (100%) patients with HCV genotype 3 and cirrhosis who had failed pegylated interferon plus ribavirin, in 25 of 28 (89%) patients with HCV genotype 1 who had failed protease inhibitor-based triple therapy, and in 4 of 4 (100%) patientswith HCV genotype 3 who had failed an all-oral regimen of ≥2 direct-acting antiviral agents. The most common reportedadverse events were headache, nausea, and fatigue. Eight weeks of treatment with the combination of sofosbuvir, velpatasvir, and GS-9857 produced an SVR12 in most treatment-naïve or previously treated patients with HCV genotype 1 or 3 infections, including those with compensated cirrhosis. ClinicalTrials.gov, Number: NCT02202980.

Clinical Pharmacokinetics and Pharmacodynamics of Ledipasvir/Sofosbuvir, a Fixed-Dose Combination Tablet for the Treatment of Hepatitis C

Ledipasvir/sofosbuvir (Harvoni®), a fixed-dose combination tablet of an NS5A inhibitor ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved in the US, European Union, Canada, and other regions for the treatment of chronic hepatitis C virus infection in adults. Following absorption, ledipasvir reaches maximum plasma concentrations (T max) 4-4.5h post-dose and is eliminated with a terminal half-life (t 1/2) of 47h. Sofosbuvir undergoes intracellular activation to an active triphosphate GS-461203 (not detected in plasma) and ultimately to GS-331007, a predominant circulating metabolite, which is the primary analyte of interest in clinical pharmacology studies. Sofosbuvir is rapidly absorbed and eliminated from plasma (T max: 0.8-1h; t 1/2: 0.5h). The peak plasma concentrations for GS-331007 are achieved between 3.5 and 4h post-dose; the elimination t 1/2 for GS-331007 is 27h. Ledipasvir/sofosbuvir exhibits a favorable clinical pharmacology profile; it can be administered once daily without regard to food and does not require dose modification in hepatitis C virus-infected patients with any degree of hepatic impairment or mild to moderate renal impairment. The pharmacokinetic profiles of ledipasvir, sofosbuvir, and GS-331007 (predominant circulating metabolite of sofosbuvir) are not significantly affected by demographic variables; pharmacokinetic/pharmacodynamic analyses reveal no exposure-response relationships for efficacy or safety. The review summarizes the clinical pharmacokinetics, pharmacodynamics, and pharmacokinetic/pharmacodynamic analyses for ledipasvir/sofosbuvir.

Discovery of potent macrocyclic HCV NS5A inhibitors

HCV NS5A inhibitors have demonstrated impressive in vitro virologic profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed-dose combination (FDC) regimen for the treatment of HCV infection. Merck’s effort in this area identified MK-4882 and MK-8325 as early development leads. Herein, we describe the discovery of potent macrocyclic NS5A inhibitors bearing the MK-8325 or MK-4882 core structure.

Alkyl substituted aminal derivatives of HCV NS5A inhibitor MK-8742

HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein we describe our continued research efforts around the alkyl “Z group” modification of the tetracyclic indole-based NS5A inhibitor MK-8742, which led to the discovery of a series of potent NS5A inhibitors. Compounds 10 and 19 are of particular interests since they are as potent as our previous leads and have much improved rat pharmacokinetic profiles.

O2 - Prevalence and characterization of NS5A resistance associated variants (RAVs) in patients who relapsed following exposure to NS5A inhibitors

O2 - Prevalence and characterization of NS5A resistance associated variants (RAVs) in patients who relapsed following exposure to NS5A inhibitors

Discovery of fused tricyclic core containing HCV NS5A inhibitors with pan-genotype activity

HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein, we describe research efforts that led to the discovery of a series of fused tricyclic core containing HCV NS5A inhibitors such as 24, 39, 40, 43, and 44 which have pan-genotype activity and are orally bioavailable in the rat.

Viral genome imaging of hepatitis C virus to probe heterogeneous viral infection and responses to antiviral therapies

Hepatitis C virus (HCV) is a positive single-stranded RNA virus of enormous global health importance, with direct-acting antiviral therapies replacing an immunostimulatory interferon-based regimen. The dynamics of HCV positive and negative-strand viral RNAs (vRNAs) under antiviral perturbations have not been studied at the single-cell level, leaving a gap in our understanding of antiviral kinetics and host–virus interactions. Here, we demonstrate quantitative imaging of HCV genomes in multiple infection models, and multiplexing of positive and negative strand vRNAs and host antiviral RNAs. We capture the varying kinetics with which antiviral drugs with different mechanisms of action clear HCV infection, finding the NS5A inhibitor daclatasvir to induce a rapid decline in negative-strand viral RNAs. We also find that the induction of host antiviral genes upon interferon treatment is positively correlated with viral load in single cells. This study adds smFISH to the toolbox available for analyzing the treatment of RNA virus infections.

Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir With or Without Ribavirin in HCV-Infected Patients Taking Concomitant Acid-Reducing Agents.

OBJECTIVES:Acid-reducing agents (ARAs) and proton-pump inhibitors (PPIs) that increase gastric pH can alter the bioavailability of antiviral drugs, particularly relevant in patients with advanced liver disease caused by chronic hepatitis C virus (HCV) infection seeking therapy. Using integrated data from six phase 3 studies, we report the safety and efficacy of the 3-direct-acting antiviral (DAA) regimen containing ombitasvir (OBV, an NS5A inhibitor), ritonavir-boosted paritaprevir (PTV/r, an NS3/4A protease inhibitor), and dasabuvir (DSV, an NS5B polymerase inhibitor) with or without ribavirin (RBV) for HCV genotype 1 patients taking concomitant ARAs and PPIs.METHODS:Treatment-naïve or peginterferon/RBV treatment-experienced patients with or without compensated cirrhosis received OBV/PTV/r and DSV with or without weight-based RBV. Rates of sustained virologic response (SVR), defined as HCV RNA below the lower limit of quantification, 12 weeks post-treatment (SVR12) and safety were evaluated in patients who were receiving concomitant ARAs.RESULTS:Among 2,053 patients enrolled and dosed with study drug, 410 (20%) were receiving concomitant ARAs; of these, 308 (15%) were taking concomitant PPIs. Rates of SVR12 were 95.9% (95% confidence interval (CI) 93.5–97.4%) among patients receiving an ARA, and 96.3% (95% CI 95.3–97.2%) in patients not receiving a concomitant ARA. Similarly, among patients receiving a PPI or not, SVR12 was achieved in 95.1% (95% CI 92.1–97.0%) and 96.4% (95% CI 95.5–97.2%), respectively. Response rates were high regardless of treatment regimen (with or without RBV), and among patients receiving a standard or high dose of PPIs. Regarding safety, adverse events and serious adverse events were more frequently reported in patients taking concomitant ARAs, though baseline population differences may have played a role.CONCLUSIONS:In phase 3 trials of OBV/PTV/r plus DSV and RBV in HCV genotype 1-infected patients, SVR12 rates were high regardless of ARA/PPI use or PPI dose. These data support the co-administration of this regimen with ARAs including PPIs.

Antiretroviral Use in the CEASE Cohort Study and Implications for Direct-Acting Antiviral Therapy in Human Immunodeficiency Virus/Hepatitis C Virus Coinfection.

Background. Interferon-free direct-acting antiviral (DAA) regimens for hepatitis C virus (HCV) provide a major advance in clinical management, including in human immunodeficiency virus (HIV)/HCV coinfection. Drug-drug interactions (DDIs) with combination antiretroviral therapy (cART) require consideration. This study aimed to characterize the cART regimens in HIV/HCV-coinfected individuals and assess the clinical significance of DDIs with DAAs in a real-world cohort. Methods. This analysis included participants enrolled in CEASE-D, a prospective cohort of HIV/HCV-coinfected individuals in Sydney, Australia, between July 2014 and December 2015. A simulation of potential DDIs between participants' cART and interferon-free DAA regimens was performed using www.hep-druginteractions.org and relevant prescribing information. Results. In individuals on cART with HCV genotype (GT) 1 and 4 (n = 128), category 3 DDIs (contraindicated or not recommended) were noted in 0% with sofosbuvir/ledipasvir, 0% with sofosbuvir plus daclatasvir, 17% with sofosbuvir/velpatasvir, 36% with ombitasvir/paritaprevir/ritonavir ± dasabuvir, 51% with grazoprevir/elbasvir, and 51% with sofosbuvir plus simeprevir; current cART regimens were suitable for coadministration in 100%, 100%, 73%, 64%, 49%, and 49%, respectively. In individuals with HCV GT 2 or 3 (n = 53), category 3 DDIs were evident in 0% with sofosbuvir plus daclatasvir, 0% with sofosbuvir and ribavirin, and 13% with sofosbuvir/velpatasvir; current cART regimens were suitable in 100%, 100%, and 81%, respectively. Conclusions. Potential DDIs are expected and will impact on DAA prescribing in HIV/HCV coinfection. Sofosbuvir in combination with an NS5A inhibitor or ribavirin appeared to be the most suitable regimens in this cohort. Evaluation of potential DDIs is required to prevent adverse events or treatment failure.

Development of rare resistance-associated variants that are extremely tolerant against NS5A inhibitors during daclatasvir/asunaprevir therapy by a two-hit mechanism.

The virologic characteristics of resistance-associated variants (RAVs) developing in patients receiving dual oral therapy with daclatasvir/asunaprevir, including those with previous triple therapy with simeprevir, were evaluated. A total of 206 patients with genotype-1b HCV infection, including 5 patients with previous simeprevir therapy, were treated with daclatasvir/asunaprevir for 24weeks. Resistance-associated variants in the NS5A regions at baseline and during/after therapy were evaluated using cycling-probe real-time polymerase chain reaction combined with direct sequencing. The dynamics of rare RAVs were also assessed using ultra-deep sequencing. A sustained virologic response (SVR12) was achieved in 180 patients (87%); the rates were 95% in patients without baseline NS5A-RAVs and 83%, 59%, and 77% in those with hepatitis C virus (HCV) strains carrying NS5A-L31M, NS5A-Y93H/C, and NS5A-R30Q/H/L mutations, respectively. A multivariate analysis revealed baseline NS5A-R30Q/H/L mutation and NS5A-Y93H mutations as significant factors associated with SVR12. Virologic failure developed in all 5 patients with previous simeprevir treatment, and rare RAVs (HCV strains with NS5A-R30H, NS5A-A92K, NS5A-P29del, and NS5A-P32del) developed at virologic failure. Ultra-deep sequencing revealed that HCV strains with NS5A-P29del or NS5A-P32del were absent at baseline and emerged within 4weeks of dual oral therapy among the strains appearing after simeprevir administration. NS5A-R30Q/H/L and NS5A-Y93H mutations at baseline determined the therapeutic efficacy of dual oral therapy with daclatasvir/asunaprevir, but rare NS5A-RAVs developed frequently in patients with previous simeprevir treatment. Such RAVs may develop in a two-hit manner, with simeprevir altering the quasispecies of HCV strains in the NS5A regions, leading to the emergence of HCV strains with NS5A-P29del and NS5A-P32del during exposure to daclatasvir/asunaprevir.

Frequency of Natural Resistance within NS5a Replication Complex Domain in Hepatitis C Genotypes 1a, 1b: Possible Implication of Subtype-Specific Resistance Selection in Multiple Direct Acting Antivirals Drugs Combination Treatment.

Different HCV subtypes may naturally harbor different resistance selection to anti-NS5a inhibitors. 2761 sequences retrieved from the Los Alamos HCV database were analyzed in the NS5a domain 1, the target of NS5a inhibitors. The NS5a resistance-associated polymorphisms (RAPs) were more frequently detected in HCV G1b compared to G1a. The prevalence of polymorphisms associated with cross-resistance to compounds in clinical use (daclatasvir, DCV, ledipasvir, LDV, ombitasvir, and OMV) or scheduled to come into clinical use in the near future (IDX719, elbasvir, and ELV) was higher in G1b compared to G1a (37/1552 (2.4%) in 1b sequences and 15/1209 (1.2%) in 1a isolates, p = 0.040). Interestingly, on the basis of the genotype-specific resistance pattern, 95 (6.1%) G1b sequences had L31M RAP to DCV/IDX719, while 6 sequences of G1a (0.5%) harbored L31M RAP, conferring resistance to DCV/LDV/IDX719/ELV (p < 0.0001). Finally, 28 (2.3%) G1a and none of G1b isolates harbored M28V RAP to OMV (p < 0.0001). In conclusion, the pattern of subtype-specific resistance selection in the naturally occurring strains may guide the treatment option in association with direct acting antivirals (DAAs) targeting different regions, particularly in patients that are difficult to cure, such as those with advanced liver disease or individuals who have failed previous DAAs.

Grazoprevir + elbasvir for the treatment of hepatitis C virus infection

ABSTRACTIntroduction: Hepatitis C virus (HCV)-related liver disease is a cause of significant morbidity and mortality worldwide. Currently, direct-acting antiviral drugs (DAAs) are associated with an increased sustained virologic response (SVR) and are the gold standard for treating HCV infection.Areas covered: The new combination of grazoprevir, an inhibitor of HCV NS3/4A, and elbasvir, an inhibitor of HCV NS5A, once daily will be available for the treatment of HCV infection. This combination therapy has a high efficacy in HCV genotype 1 and 4 infections, inducing a SVR up to 95%, even in difficult to treat patients such as cirrhotic, HIV co-infected, or dialysis-dependent patients, and patients with stage 4–5 chronic kidney disease or those who failed previous therapy. The safety of grazoprevir combined with elbasvir is very good and without significant adverse effects in phase 2 or 3 studies. For patients who failed prior DAA therapy, in vitro and in vivo studies showed that the grazoprevir and elbasvir combination is fully active against resistance to NS3/4A protease inhibitors. Resistance to NS5B inhibitors is least susceptible to grazoprevir or elbasvir.Expert opinion: This new combination of gazoprevir with elbasvir offers an opportunity to cure HCV infection with short interferon-free therapy, even in difficult to treat patients.

Hemoglobin Decrease with Iron Deficiency Induced by Daclatasvir plus Asunaprevir Combination Therapy for Chronic Hepatitis C Virus Genotype 1b.

BackgroundDecreased hemoglobin (Hb) level has been supposed to be a relatively rare side effect of a combination therapy against hepatitis C virus that consists of the NS5A inhibitor daclatasvir (DCV) and the NS3/4A protease inhibitor asunaprevir (ASV).MethodsThe study was conducted in 75 patients with genotype 1b chronic hepatitis C virus infection who had started combination therapy with DCV and ASV at St. Marianna University School of Medicine Hospital between September 2014 and December 2014.ResultsAmong the patients examined, decreased Hb level by ≥1.5 g/dL from the values at treatment initiation was observed in 11 individuals. This was accompanied by decreased mean corpuscular volume, and iron and ferritin levels.ConclusionsThese findings suggest that the mechanism of the phenomenon is caused by iron deficiency. The underlying mechanism and clinical impacts will need to be further examined.