451 EVALUATION OF PHARMACOKINETIC DRUG–DRUG INTERACTION (DDI) BETWEEN BMS-791325, AN NS5B NON-NUCLEOTIDE POLYMERASE INHIBITOR, DACLATASVIR AND ASUNAPREVIR IN TRIPLE COMBINATION IN HCV GENOTYPE 1-INFECTED PATIENTS
X. WangW. LiShu‐Pang HuangBiao HeEllen ChungA. GriffiesElizabeth CooneyEmma HughesHamza KandoussiKaren SimsDavid GardinerRichard BertzTimothy Eley
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AbstractDaclatasvir is a novel NS5A inhibitor of hepatitis C virus (HCV). Daclatasvir combined with peginterferon α-2a and ribavirin in Japanese patients infected with genotype 1b HCV achieved sustained virological response (SVR) in 100% of treatment-naïve patients, due to high rates of favorable IL28B allele and genotype 1b. SVR 24 was achieved by asunaprevir and daclatasvir in 87.4% of intolerant and 80.5% of nonresponder patients. Baseline NS5A-resistant variants were detected and they failed to achieve SVR. Most patients with genotype 1a experienced virological breakthrough by dual oral treatment, and should be treated QUAD or replaced by all oral regimens that are more potent and have fewer side effects. IFN-free regimens including daclatasvir and asunaprevir for genotype 1 null responders should be tailored to subtype, and preexisting NS5A-resistant variants should be evaluated carefully before choosing the drugs. This regimen alone is unlikely to move forward without additional agents.Keywords:: asunaprevirchronic hepatitis CDAAdaclatasvirgenotype 1 Financial & competing interests disclosureThis work was supported by a Grant-in-aid from the Japanese Ministry of Health, Welfare and Labor. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Key issuesDaclatasvir is a first-in-class, NS5A replication complex inhibitor with potent pan-genotypic antiviral activity in vitro, and once-daily dosing of 1–100 mg produced a rapid and substantial decrease in hepatitis C virus (HCV)-RNA levels in patients chronically infected with HCV genotype 1.Overall response treated by pegIFN and ribavirin plus daclatasvir is higher in Asian studies than in non-Asian studies.The dual oral combination treatment with daclatasvir and asunaprevir showed a sustained virological response (SVR) 24 rate from 63.6 to 90.5% in a Phase II study in Japan, but most patients with preexisting NS5A-Y93H polymorphisms did not achieve SVR and emergence of resistance mutations to both the NS5A inhibitor and the protease inhibitor was observed. Preexisting viral variants should be carefully evaluated.Dual therapy with daclatasvir plus twice-daily asunaprevir is effective for most genotype 1b patients, but the dual combination therapy was not effective for genotype 1a in Europe and the USA. When genotype 1a patients were treated with QUAD, the SVR 24 rate was reported to be as high as 95%, and the dual oral regimen should be tailored for the subtype.Daclatasvir in combination with sofosbuvir provided an SVR 12 rate of 98%. If they have resistant variants to NS5A inhibitors, they should wait treatment until more potent antiviral drugs.Notes
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Three hepatitis C virus (HCV) inhibitors, asunaprevir (ASV; BMS-650032), daclatasvir (DCV; BMS-790052), and BMS-791325, each targeting a different nonstructural protein of the virus (NS3, NS5A, and NS5B, respectively), have independently demonstrated encouraging preclinical profiles and are currently undergoing clinical evaluation. Since drug-resistant variants have rapidly developed in response to monotherapy with almost all direct-acting antiviral agents (DAAs) for HCV, the need for combination therapies to effectively eradicate the virus from infected patients is clear. These studies demonstrated the additive-synergistic effects on replicon inhibition and clearance of combining NS3 protease or NS5B RNA polymerase inhibitors with the first-in-class, NS5A replication complex inhibitor daclatasvir (DCV) and reveal new resistance pathways for combinations of two small-molecule inhibitors that differ from those that develop during monotherapy. The results suggest that under a specific selective pressure, a balance must be reached in the fitness costs of substitutions in one target gene when substitutions are also present in another target gene. Further synergies and additional novel resistance substitutions were observed during triple-combination treatment relative to dual-drug therapy, indicating that, in combination, HCV inhibitors can exert cross-target influences on resistance development. Enhanced synergies in replicon inhibition and a reduced frequency of resistance together lend strong support to the utility of combinations of DAAs for the treatment of HCV, and the identification of altered resistance profiles during combination treatment provides useful information for monitoring resistance in the clinic.
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In this series we draw attention to medicines that have entered the European market with an entirely new mechanism of action. Publication is not to be confused with endorsement of use in clinical practice. Copyright to the images belongs to Leiden University, but use of the images (also available at http://coo.lumc.nl/trc and the app stores) is free. Chronic hepatitis C infection is a major cause of chronic liver disease, cirrhosis and liver cancer as well as an important indication for liver transplantation. Sofosbuvir (Sovaldi®) 1 and daclatasvir (Daklinza®) 2 are new direct acting antivirals (DAAs) with a favourable safety and tolerability profile, which have significantly changed treatment for this condition. After entering hepatocytes, the viral genome of the hepatitis C virus (HCV) is translated into a single polypeptide. This polypeptide is subsequently cleaved into viral proteins, including non-structural (NS) proteins NS3, NS4A, NS5B and NS5B RNA dependent RNA polymerase (Figure 1) 3, 4. These viral proteins are essential for viral replication and assembly making them significant targets for therapy. Sofosbuvir is the first available inhibitor of NS5B RNA dependent RNA polymerase. Daclatasvir is an inhibitor of NS5B. Sofosbuvir has activity against all six major HCV genotypes and stops HCV from multiplying and infecting new cells 5-7. Daclatasvir is effective against genotype 1–4 7, 8. Sofosbuvir is used in combination with peginterferon and/or ribavirin but is also approved for use without interferon treatment, in combination with daclatasvir with or without ribavirin 5-8. The goal of HCV treatment is to obtain a sustained virologic response (SVR), classically defined as undetectable HCV RNA 12 weeks or more following treatment completion. Until 2011, HCV was treated by a combination of peginterferon and ribavirin. This dual therapy achieves SVR rates of 40–80%, but the response is genotype dependent and associated with significant side effects. The approval of sofosbuvir offered the first possibility for complete oral regimes of DAAs. Compared with the first generation protease inhibitors (telaprivir and boceprevir), sofosbuvir has easier dosing regimens, lower toxicity and fewer drug–drug interactions. It is highly effective and safe for the treatment of chronic hepatitis C infected patients, even those who are difficult to treat because of cirrhosis 5-7. However, DAAs should not be administrated as monotherapy because this may lead to drug-resistance. Several clinical trials with sofosbuvir in combination with peginterferon and ribavirin have demonstrated overall efficacy rates of 50–93% 5, 6, while patients with genotype 2 and 3 treated with a combination of sofosbuvir and daclatasvir demonstrated a SVR of 94–100% 8, 9. The approval of these compounds has led to significant revisions of the chronic hepatitis C treatment guidelines in the USA and Europe. Sofosbuvir and daclatasvir are generally well tolerated with only a few adverse effects reported. The most common side effects reported with sofosbuvir in combination with daclatasvir are fatigue, nausea, headache and insomnia. Sofosbufir is a substrate of the glycoprotein (P-gp) transporter and daclatasvir is a substrate of CYP3A4 and P-gp. Co-administration with enzymes which induce or inhibit these pathways may be best avoided or necessitate dose adjustments. All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.
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Daclatasvir is a non-structural protein 5A (NS5A) inhibitor with activity against hepatitis C virus (HCV) genotypes 1–6 in vitro, and asunaprevir is a non-structural protein 3 (NS3) protease inhibitor with activity against genotypes 1, 4, 5, and 6. This study evaluates potential options for the re-treatment of HCV genotype 1b-infected patients who have failed combination therapy with daclatasvir plus asunaprevir. The antiviral activity of drug combination regimens in HCV subgenomic replicon cell lines representing genotype 1b (Con1 strain) wild-type or a variant with specific NS5A and NS3 amino acid substitutions conferring resistance to daclatasvir and asunaprevir were compared using replicon elimination assays. Drug concentrations representing multiple 50% effective concentrations (EC50) derived in vitro and trough plasma concentrations observed in a clinical setting were utilized. At multiple EC50 values of each drug (3×, 10×, and 30× EC50), combinations of daclatasvir plus sofosbuvir, sofosbuvir plus ledipasvir, sofosbuvir plus simeprevir, and sofosbuvir plus either a next-generation NS3 or NS5A inhibitor demonstrated comparable activity in wild-type and daclatasvir/asunaprevir-resistant cell lines. At clinically relevant drug trough concentrations, combination regimens of daclatasvir plus asunaprevir plus beclabuvir (±ribavirin), and daclatasvir plus asunaprevir plus beclabuvir plus sofosbuvir efficiently cleared daclatasvir + asunaprevir-resistant replicons from cells within 5 days of treatment. Our in vitro results highlight a number of potential all-oral treatment options for patients who do not achieve a sustained virologic response following therapy with daclatasvir plus asunaprevir. These results require further evaluation in clinical studies.
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The first discovered and sequenced hepatitis C virus (HCV) genome and the first in vivo infectious HCV clones originated from the HCV prototype strains HCV-1 and H77, respectively, both widely used in research of this important human pathogen. In the present study, we developed efficient infectious cell culture systems for these genotype 1a strains by using the HCV-1/SF9_A and H77C in vivo infectious clones. We initially adapted a genome with the HCV-1 5'UTR-NS5A (where UTR stands for untranslated region) and the JFH1 NS5B-3'UTR (5-5A recombinant), including the genotype 2a-derived mutations F1464L/A1672S/D2979G (LSG), to grow efficiently in Huh7.5 cells, thus identifying the E2 mutation S399F. The combination of LSG/S399F and reported TNcc(1a)-adaptive mutations A1226G/Q1773H/N1927T/Y2981F/F2994S promoted adaptation of the full-length HCV-1 clone. An HCV-1 recombinant with 17 mutations (HCV1cc) replicated efficiently in Huh7.5 cells and produced supernatant infectivity titers of 10(4.0) focus-forming units (FFU)/ml. Eight of these mutations were identified from passaged HCV-1 viruses, and the A970T/I1312V/C2419R/A2919T mutations were essential for infectious particle production. Using CD81-deficient Huh7 cells, we further demonstrated the importance of A970T/I1312V/A2919T or A970T/C2419R/A2919T for virus assembly and that the I1312V/C2419R combination played a major role in virus release. Using a similar approach, we found that NS5B mutation F2994R, identified here from culture-adapted full-length TN viruses and a common NS3 helicase mutation (S1368P) derived from viable H77C and HCV-1 5-5A recombinants, initiated replication and culture adaptation of H77C containing LSG and TNcc(1a)-adaptive mutations. An H77C recombinant harboring 19 mutations (H77Ccc) replicated and spread efficiently after transfection and subsequent infection of naive Huh7.5 cells, reaching titers of 10(3.5) and 10(4.4) FFU/ml, respectively.Hepatitis C virus (HCV) was discovered in 1989 with the cloning of the prototype strain HCV-1 genome. In 1997, two molecular clones of H77, the other HCV prototype strain, were shown to be infectious in chimpanzees, but not in vitro. HCV research was hampered by a lack of infectious cell culture systems, which became available only in 2005 with the discovery of JFH1 (genotype 2a), a genome that could establish infection in Huh7.5 cells. Recently, we developed in vitro infectious clones for genotype 1a (TN), 2a (J6), and 2b (J8, DH8, and DH10) strains by identifying key adaptive mutations. Globally, genotype 1 is the most prevalent. Studies using HCV-1 and H77 prototype sequences have generated important knowledge on HCV. Thus, the in vitro infectious clones developed here for these 1a strains will be of particular value in advancing HCV research. Moreover, our findings open new avenues for the culture adaptation of HCV isolates of different genotypes.
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Since 2017, direct-acting antivirals (DAAs) are the first-line treatment for patients with chronic hepatitis C virus (HCV) infection. In hemodialysis (HD) patients, however, a small percentage of patients failed to respond, and the data for the treatment of DAAs for such patients with HCV are lacking. Herein, we report a 57-year-old Libyan female patient on regular HD therapy for 18 years who did not achieved HCV clearance 12 weeks after the treatment with sofosbuvir/daclatasvir. Later, she was treated with elbasvir/grazoprevir (EBR/GZR) for 12 weeks and achieved a sustained virological response at the end of the treatment (12 weeks) and 12 months after the end of the treatment. No obvious side effects were reported during the treatment. Thus, EBR/GZR was effective and safe in this hemodialyzed patient with HCV genotype 2b infection who was failed to respond to12 week-treatment with sofosbuvir/daclatasvir combination.
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Daclatasvir is a nonstructural protein 5A inhibitor of hepatitis C virus (HCV) replication. Asunaprevir is an NS3/4A complex inhibitor of HCV replication. The combination of daclatasvir and asunaprevir has been approved in Japan for the treatment of genotype 1 chronic HCV infection. In vitro studies have documented potent activity of these drugs, individually and in combination, against genotype 1 HCV. Results from completed and ongoing clinical studies have confirmed this potent activity in patients, with better responses noted in genotype 1b patients compared to patients with genotype 1a HCV. Response rates are also better in treatment-naive patients compared to those who are treatment-experienced; in these cases, the addition of interferon and ribavirin appears to enhance the treatment response. The combination of daclatasvir and asunaprevir is, in general, well tolerated. Daclatasvir and asunaprevir are substrates for cytochrome P450 3A4 enzymatic pathway; thus, there is a substantial potential for drug interactions.
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Objective The present study aimed to reveal the factors associated with virologic failure in sofosbuvir and ledipasvir (SOF/LDV)-treated patients, and identify baseline NS5A or NS5B resistance-associated substitutions (RASs). Methods Four hundred ninety-three patients with Hepatitis C Virus (HCV) genotype 1b infection were treated with SOF/LDV; 31 had a history of interferon (IFN)-free treatment with daclatasvir and asunaprevir. The effect of baseline RASs on the response to SOF/LDV therapy was analyzed. Results Overall, a sustained virologic response at 12 weeks (SVR12) was achieved in 476 patients (96.6%). The SVR12 rates in the patients with IFN-free treatment-naïve and retreatment were 97.6% and 80.6%, respectively. HCV elimination was not achieved in 17 patients, 11 (including 5 with IFN-free retreatment) of whom had virologic failure. Eight patients had coexisting NS5A RASs of Q24, L28 and/or R30, L31, or Y93 and one patient had coexisting NS5A RASs of P32L and A92K. Interestingly, 10 and 8 patients had NS5B A218S and C316N RAS respectively. According to a multivariate analysis, coexisting NS5A RASs, NS5A P32 RAS, NS5B A218 and/or C316 RASs, and γ-glutamyltranspeptidase were associated with virologic failure. In the naïve patients, all patients without NS5B A218 and/or C316 RAS achieved an SVR12. Notably, the SVR12 rates of patients with coexisting NS5A and NS5B RASs were significantly lower (83.3%). Conclusions Although SOF/LDV therapy resulted in a high SVR12 rate, coexisting NS5A and NS5B RASs were associated with virologic failure. These results might indicate that the coexisting baseline RASs influence the therapeutic effects of SOF/LDV.
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All-oral combination therapy is desirable for patients with chronic hepatitis C virus (HCV) infection. We evaluated daclatasvir (an HCV NS5A replication complex inhibitor) plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients infected with HCV genotype 1, 2, or 3.In this open-label study, we initially randomly assigned 44 previously untreated patients with HCV genotype 1 infection and 44 patients infected with HCV genotype 2 or 3 to daclatasvir at a dose of 60 mg orally once daily plus sofosbuvir at a dose of 400 mg orally once daily, with or without ribavirin, for 24 weeks. The study was expanded to include 123 additional patients with genotype 1 infection who were randomly assigned to daclatasvir plus sofosbuvir, with or without ribavirin, for 12 weeks (82 previously untreated patients) or 24 weeks (41 patients who had previous virologic failure with telaprevir or boceprevir plus peginterferon alfa-ribavirin). The primary end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) at week 12 after the end of therapy.Overall, 211 patients received treatment. Among patients with genotype 1 infection, 98% of 126 previously untreated patients and 98% of 41 patients who did not have a sustained virologic response with HCV protease inhibitors had a sustained virologic response at week 12 after the end of therapy. A total of 92% of 26 patients with genotype 2 infection and 89% of 18 patients with genotype 3 infection had a sustained virologic response at week 12. High rates of sustained virologic response at week 12 were observed among patients with HCV subtypes 1a and 1b (98% and 100%, respectively) and those with CC and non-CC IL28B genotypes (93% and 98%, respectively), as well as among patients who received ribavirin and those who did not (94% and 98%, respectively). The most common adverse events were fatigue, headache, and nausea.Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir. (Funded by Bristol-Myers Squibb and Pharmasset (Gilead); A1444040 ClinicalTrials.gov number, NCT01359644.).
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