Combination Of Daclatasvir Research Articles

SAT-105 - The Combination of Daclatasvir and Sofosbuvir for Curing Genotype 2 Patients who cannot Tolerate Ribavirin

SAT-105 - The Combination of Daclatasvir and Sofosbuvir for Curing Genotype 2 Patients who cannot Tolerate Ribavirin

Hepatitis C virus genotype 3: Meta-analysis on sustained virologic response rates with currently available treatment options.

To address the therapeutic efficacy of various treatment regimens in genotype 3 selecting randomized clinical trials and prospective National Cohort Studies. (1) PEG-INF-based therapy including sofosbuvir (SOF) + RBV for 12 wk vs SOF + RBV 24 wk; (2) SOF + RBV therapy 12 wk/16 wk vs 24 wk; and (3) the role of RBV in SOF + daclatasvir (DCV) and SOF + ledipasvir (LDV) combinations. This meta-analysis provides robust information with the intention of addressing treatment strategy for hepatitis C virus genotype 3. A combination treatment including SOF + RBV + PEG-IFN for 12 wk notes better SVR than with only SOF + RBV for 12 wk, although its association with more frequent adverse effects may be a limiting factor. Longer duration therapy with SOF + RBV (24 wk) has achieved higher SVR rates than shorter durations (12 or 16 wk). SOF + LDV are not an ideal treatment for genotype 3. Lastly, SOF + DCV combination is probably the best oral therapy option and the addition of RBV does not appear to be needed to increase SVR rates substantially.

Hepatitis C Treatment with Sofosbuvir and Daclatasvir in an 83 Year Old Patient with Ischemic Vasculitis and End Stage Renal Disease on Hemodialysis

Hepatitis C virus (HCV) was first identified just over 25 years ago, but in this timeframe we have moved from identifying the virus to being able to offer a cure for the infection, which represents a remarkable feat in clinical and scientific medicine. However, the path to today’s treatment regimens was not straightforward. Interferon (INF), followed by the co-administration of ribavirin and subsequently the pegylation of IFN represented the limited standard of care for many years; notable primarily for the significant systemic effects associated with IFN based therapy. The emergence of all-oral, IFN-free regimens with second generation direct acting antivirals (DAAs) in 2013 has revolutionized the hepatitis C treatment landscape with cure rates now exceeding 90% and significantly fewer side effects. Nevertheless, there remain difficult to treat cohorts, including those with end-stage renal disease (ESRD). Limited data exists on the optimal management of such individuals with DAAs; the current report presents the case of an 83-year-old female patient with refractory ischemic vasculitis and ESRD on hemodialysis with multiple other co-morbidities successfully treated with a 12- week combination of Sofosbuvir and Daclatasvir.

Rapid reductions in prices for generic sofosbuvir and daclatasvir to treat hepatitis C

ObjectivesNovel treatments for hepatitis C demonstrate high cure rates, but current high prices can be a barrier to rapid global treatment scale-up. Generic competition can rapidly lower drug prices. Using data on exports of raw materials in 2015, we calculated currently feasible generic prices of sofosbuvir and daclatasvir. MethodsData on per-kilogram prices of sofosbuvir and daclatasvir active pharmaceutical ingredients (API) exported from India were extracted from an online database. To the cost of the amount of API needed for a 12-week treatment course, we added cost estimates for formulation (40%), packaging (US$0.35/month), and a mark-up (50%). ResultsBetween 1 January and 15 October 2015, over 5 tons of sofosbuvir were exported, with prices decreasing by US$702/kg/month, and observed prices of US$2501/kg in early September. Over the same period, 84 kg of daclatasvir were exported, with prices decreasing by US$1664/kg/month to US$1897/kg. Using the price estimation algorithm, we estimated the price of a generic sofosbuvir–daclatasvir combination regimen at US$200 per patient for a 12-week treatment course. ConclusionThe costs of generic production of sofosbuvir and daclatasvir are rapidly decreasing. Sofosbuvir–daclatasvir combination treatment could be produced for US$200 per patient per 12-week course.

12 Weeks of Daclatasvir in Combination With Sofosbuvir for Human Immunodeficiency Virus/Hepatitis C Virus Coinfection (ALLY-2 Study): Efficacy and Safety by Black Race

12 Weeks of Daclatasvir in Combination With Sofosbuvir for Human Immunodeficiency Virus/Hepatitis C Virus Coinfection (ALLY-2 Study): Efficacy and Safety by Black Race

12 Weeks of Daclatasvir in Combination With Sofosbuvir for HIV/HCV Coinfection (ALLY-2 Study): Efficacy and Safety by HIV Combination Antiretroviral Regimens

In the United States and Europe, approximately one third of all human immunodeficiency virus (HIV)–infected individuals are coinfected with hepatitis C virus (HCV), and liver disease has become the most common cause of morbidity and mortality in HIV-HCV–infected patients [1–3]. Thus, successful treatment of HCV is a priority for HIV-HCV–coinfected individuals. Current HIV treatment guidelines recommend initiation of antiretroviral therapy (ART) in all HIV-HCV–coinfected patients [4, 5]. However, simultaneous treatment of HIV and HCV can be complicated by interactions between antiretroviral drugs and current all-oral direct-acting antivirals (DAAs) [4–9]. HIV-HCV–coinfected patients may require modification of their stable antiretroviral regimens before starting some current DAA regimens, which is neither desirable for patients with long-term HIV suppression on a specific regimen nor possible for some treatment-experienced patients with limited alternative antiretroviral options. Therefore, there is a need in HIV-HCV coinfection for all-oral DAA regimens that combine high efficacy with good tolerability, simple dosing, and few or easily manageable drug interactions with concomitant antiretrovirals. Daclatasvir (DCV, an NS5A inhibitor) and sofosbuvir (SOF, an NS5B polymerase inhibitor) are both oral, once-daily (QD), pangenotypic DAAs with limited potential for interactions with antiretroviral drugs [10, 11]. DCV is approved for use in the United States, Europe, Japan, and multiple countries across the Americas, Middle East, and Asia-Pacific region. SOF is approved for use in the United States, Europe, and other countries. After 12 weeks of DCV + SOF, 98% of HCV treatment-naive, monoinfected patients and 97% of HIV-HCV–coinfected patients achieved sustained virologic response 12 weeks after stopping therapy (SVR12) [12, 13]. However, following 8 weeks of treatment, SVR12 rates were 76% in HIV-HCV–coinfected patients [13], suggesting that 12 weeks of DCV + SOF therapy is preferred. To investigate the impact of antiretroviral regimens on DCV + SOF efficacy and safety, we evaluated 12 weeks of DCV + SOF in HIV-HCV–coinfected patients stratified according to antiretroviral regimen.

Daclatasvir for the treatment of chronic hepatitis C

Introduction: Following more than 20 years of Interferon (IFN)-based treatment for hepatitis C virus (HCV), the understanding of viral life cycle led to the development of new antiviral drugs directly targeting HCV replication steps. Daclatasvir (DCV) is a potent inhibitor of non-structural NS5A HCV protein with pangenotypic activity and low-moderate barrier to resistance suitable for IFN-free combination with other direct acting antivirals (DAAs).Areas covered: The present review summarizes DCV key pharmacokinetic features and results from Phase II and III trials, discussing also NS5A resistance. Main literature articles have been identified through Pubmed and Medline search; moreover, abstracts from recent international meetings on liver disease have been scrutinized.Expert opinion: DCV in combination with other DAAs has provided IFN-free regimens with increased efficacy and tolerability. However, suboptimal barrier to resistance and the rapid development of new second-generation NS5A inhibitors will probably make DCV a relatively short-lived drug.

The safety of daclatasvir for the treatment of hepatitis C

Introduction: The direct acting antiviral daclatasvir is an NS5A replication inhibitor active against the entire range of hepatitis C virus genotypes. It is a key step in establishing the goal of an all-oral, ribavirin-free, pan-genotypic regimen against hepatitis C. Areas covered: We review current literature including published abstracts and manuscripts. Evidence was obtained through PubMed/Medline search using listed keywords and through review of published abstracts. Expert opinion: Daclatasvir introduces a degree of pangenotypic potency currently lacking in other NS5A agents. Emerging literature suggests that daclatasvir in combination with other DAAs will represent a promising option in this difficult to treat populations including posttransplant, genotype 3 and HIV patients.

HCV Drug Resistance Challenges in Japan: The Role of Pre-Existing Variants and Emerging Resistant Strains in Direct Acting Antiviral Therapy.

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.

Daclatasvir plus simeprevir with or without ribavirin for the treatment of chronic hepatitis C virus genotype 1 infection

We evaluated the combination of daclatasvir (pan-genotypic NS5A inhibitor) and simeprevir (NS3/4A protease inhibitor), with or without ribavirin, in hepatitis C virus genotype 1-infected patients. This phase II, open-label study enrolled treatment-naive patients or prior null responders with genotype 1b (n=147) or 1a (n=21) infection. Genotype 1b-infected patients were randomized 1:1 to receive daclatasvir 30mg plus simeprevir 150mg once daily with or without ribavirin; those who completed the initial 12-week treatment were re-randomized 1:1 to stop treatment or continue treatment through to week 24. Genotype 1a-infected patients received daclatasvir plus simeprevir with ribavirin for 24weeks. The primary endpoint was the proportion of patients with sustained virologic response at posttreatment week 12 (SVR12). For genotype 1b, 84.9% (45/53) and 74.5% (38/51) of treatment-naive patients and 69.6% (16/23) and 95.0% (19/20) of prior null responders to peginterferon and ribavirin achieved SVR12 with daclatasvir plus simeprevir alone and with ribavirin, respectively. Treatment duration did not have a well-defined impact on response. For genotype 1a, daclatasvir plus simeprevir with ribavirin provided a 66.7% (8/12) response rate in treatment-naive patients and was not effective in prior null responders. Data suggest that baseline resistance polymorphisms influenced SVR12 rates. Daclatasvir plus simeprevir was well tolerated with or without ribavirin with low incidences of serious adverse events and adverse events leading to discontinuation. Daclatasvir plus simeprevir, with or without ribavirin, was effective with a 12- or 24-week duration in genotype 1b-infected patients and was well tolerated. ClinicalTrials.gov identifier: NCT01628692.

Daclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1

BackgroundThe combination of daclatasvir, a hepatitis C virus (HCV) NS5A inhibitor, and the NS5B inhibitor sofosbuvir has shown efficacy in patients with HCV monoinfection. Data are lacking on the efficacy and safety of this combination in patients coinfected with human immunodeficiency virus type 1 (HIV-1).MethodsThis was an open-label study involving 151 patients who had not received HCV treatment and 52 previously treated patients, all of whom were coinfected with HIV-1. Previously untreated patients were randomly assigned in a 2:1 ratio to receive either 12 weeks or 8 weeks of daclatasvir at a standard dose of 60 mg daily (with dose adjustment for concomitant antiretroviral medications) plus 400 mg of sofosbuvir daily. Previously treated patients were assigned to undergo 12 weeks of therapy at the same doses. The primary end point was a sustained virologic response at week 12 after the end of therapy among previously untreated patients with HCV genotype 1 who were treated for 12 weeks.ResultsPatients had HCV genotypes 1 through 4 (83% with genotype 1), and 14% had compensated cirrhosis; 98% were receiving antiretroviral therapy. Among patients with genotype 1, a sustained virologic response was reported in 96.4% (95% confidence interval [CI], 89.8 to 99.2) who were treated for 12 weeks and in 75.6% (95% CI, 59.7 to 87.6) who were treated for 8 weeks among previously untreated patients and in 97.7% (95% CI, 88.0 to 99.9) who were treated for 12 weeks among previously treated patients. Rates of sustained virologic response across all genotypes were 97.0% (95% CI, 91.6 to 99.4), 76.0% (95% CI, 61.8 to 86.9), and 98.1% (95% CI, 89.7 to 100), respectively. The most common adverse events were fatigue, nausea, and headache. There were no study-drug discontinuations because of adverse events. HIV-1 suppression was not compromised.ConclusionsAmong previously untreated HIV–HCV coinfected patients receiving daclatasvir plus sofosbuvir for HCV infection, the rate of sustained virologic response across all genotypes was 97.0% after 12 weeks of treatment and 76.0% after 8 weeks. (Funded by Bristol-Myers Squibb; ALLY-2 ClinicalTrials.gov number, NCT02032888.)

P0888 : Effect of baseline factors on response to the fixed-dose combination of daclatasvir (DCV), asunaprevir (ASV) and beclabuvir (BCV), with or without ribavirin (RBV), in patients with HCV genotype 1 infection and cirrhosis

P0888 : Effect of baseline factors on response to the fixed-dose combination of daclatasvir (DCV), asunaprevir (ASV) and beclabuvir (BCV), with or without ribavirin (RBV), in patients with HCV genotype 1 infection and cirrhosis

Daclatasvir: a review of its use in adult patients with chronic hepatitis C virus infection.

Daclatasvir (Daklinza®) is an inhibitor of hepatitis C virus (HCV) NS5A protein. It is a new, oral, direct-acting antiviral with potent pangenotypic activity. This article provides a narrative review of the efficacy and tolerability of daclatasvir in combination with other agents in the treatment of patients with chronic HCV infection and summarizes its pharmacological properties. Since daclatasvir has a different mechanism of action to other current direct-acting antivirals, it provides additive or synergistic antiviral activity when used in combination. It produces high sustained virological response rates when used in combination with peginterferon-α plus ribavirin in patients chronically infected with HCV genotypes 1-4, and provides even higher response rates when used in an interferon-free, all-oral combination with sofosbuvir, with or without ribavirin. Daclatasvir has a moderately high genetic barrier to resistance, is effective during short-term treatment over 12 weeks and has a tolerability profile similar to that of placebo. In conclusion, daclatasvir is a highly effective and well tolerated, oral, once-daily, direct-acting antiviral for use in combination therapy in adult patients chronically infected with HCV.

Asunaprevir plus daclatasvir for the treatment of chronic hepatitis C virus infection.

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.

Daclatasvir for the treatment of chronic hepatitis C virus infection.

Daclatasvir is a nonstructural protein 5A (NS5A) replication complex inhibitor that has shown potent in vitro activity against multiple hepatitis C virus (HCV) genotypes (GT). It is currently in advanced clinical development as a component of combination treatment regimens in a variety of HCV-infected patient populations. In studies conducted thus far, it has been generally well tolerated. It has been approved for the treatment of HCV GTs 1-4 in the European Union. The combination of daclatasvir and asunaprevir (an HCV NS3/4A protease inhibitor) has been approved in Japan for the treatment of patients with GT1 HCV infection. Here we review the available literature on daclatasvir, including its information on its discovery, mechanism of action, pharmacology, preclinical and clinical activity, resistance and safety.

New direct-acting antivirals for the treatment of chronic hepatitis C

The successful development of direct-acting antivirals (DAA) represents a breakthrough in the treatment of hepatitis C virus (HCV) infection. Pegylated interferon alpha and ribavirin combination therapy for 24-48 weeks was a longstanding standard therapy despite high rate of adverse events and relatively low efficacy, with a sustained virological response (SVR) rate of 60% in genotype 1 and 80% in genotype 2 HCV infected patients in South Korea. However, the treatment paradigm is rapidly shifting from interferon-based therapy to interferon-free, all-oral DAA combination therapy, which leads to SVR rates of 90% with minimal adverse events and a shorter duration of treatment (12-24 weeks). Quantitation of serum HCV RNA and genotyping of HCV are essential tests for treatment with DAA agents, and genotype 1b and genotype 2 are the two most common genotypes in Korea. The first DAA treatment approved in 2015 was daclatasvir and asunaprevir combination therapy for 24 weeks, which carries an expected SVR rate of 80-90%. It is indicated for genotype 1b patients in whom resistance-associated mutation is not detected in the NS5A region of the HCV genome (L31 or Y93 codon). The next treatment approved was the ledipasvir/sofosbuvir fixed dose combination for genotype 1 patients, with an expected SVR rate of 90%–99% using the 12–24 week regimen. For genotype 2 infection, sofosbuvir and ribavirin combination for 12–16 weeks is recommended, with an expected SVR rate of 95%. However, the high cost of DAA therapy, drug-drug interactions, and the development of resistance-associated mutants remain as problems to overcome.

Daclatasvir + asunaprevir: first global approval.

The combination of daclatasvir+asunaprevir [Daklinza(®)+Sunvepra(®) (Japan)], two direct-acting antiviral agents, has been developed by Bristol-Myers Squibb for the treatment of patients with chronic hepatitis C virus (HCV) genotype 1 infections, including those with compensated cirrhosis. Daclatasvir+asunaprevir has received its first global approval in this indication in Japan. Daclatasvir+asunaprevir is the first all-oral, interferon- and ribavirin-free regimen for this indication. This article summarizes the milestones in the development of daclatasvir+asunaprevir leading to this first approval for the treatment of chronic HCV genotype 1 infections.

Sofosbuvir plus daclatasvir for post-transplant recurrent hepatitis C: Potent antiviral activity but no clinical benefit if treatment is given late

BackgroundWe evaluated efficacy and safety of sofosbuvir and daclatasvir±ribavirin in liver transplant recipients with severe recurrent hepatitis C. MethodsPatients included in an international compassionate use programme for treatment with sofosbuvir and daclatasvir±ribavirin for 24 weeks were prospectively studied. Serum hepatitis C virus RNA was measured at treatment weeks 4, 12, and 24 and during follow-up at weeks 4, 8, and 12. ResultsTwelve patients (3 with fibrosing cholestatic hepatitis and 9 with cirrhosis; median model for end-stage liver disease score 20) received sofosbuvir 400mg/day+daclatasvir 60mg/day, and 6 patients (50%) also received ribavirin 200–800mg/day. Nine patients completed 24 weeks of treatment (75%), and all had undetectable hepatitis C virus RNA at week 24; 3 patients died (25%, liver failure, gastrointestinal bleeding and sepsis); 4 patients experienced severe liver disease-related adverse events. Post-treatment hepatitis C virus RNA was available for 5 patients (week 8, n=2; week 4, n=3) and was undetectable in all cases. Mean Child–Pugh score and albumin level improved significantly at week 24. No changes in immunosuppressant doses were needed. ConclusionAll-oral sofosbuvir plus daclatasvir combination shows high virological efficacy in liver transplant recipients and does not interact with immunosuppressants. All adverse events were unrelated to study drugs. These data strongly suggest that this combination must be initiated before decompensation.

763 All-Oral Therapy With Daclatasvir in Combination With Asunaprevir and Bms-791325 for Treatment-Naive Patients With Chronic HCV Genotype 4 Infection

763 All-Oral Therapy With Daclatasvir in Combination With Asunaprevir and Bms-791325 for Treatment-Naive Patients With Chronic HCV Genotype 4 Infection

HCV cure without interferon

The launch of first-generation protease inhibitors (PIs) was a major step forward in HCV treatment. However, this major advance was restricted to genotype 1 (GT-1) patients. This year the launch of Sofosbuvir a NS5B nucleotide inhibitor (Nis), Daclatasvir a NS5A inhibitor (NS5A.I) and Simeprevir a second wave PIs open new perspective for IFN-free regimen. Both Sofosbuvir and Daclatasvir have a pan-genotypic activity. Sofosbuvir has highly potent antiviral activity across all genotypes in association with pegylated interferon and ribavirin (PR), thus allowing shortened treatment duration. Moreover, Sofosbuvir in combination with Daclatasvir without ribavirin for 12 weeks was able to cure > 95% of naive GT-1 and for 24 weeks was able to cure 40 patients with treatment experienced, failure to triple therapy with first generation PIs, GT-1 patients. Sofosbuvir in combination with Simeprevir for 12 weeks without ribavirin was able to cure all GT-1 naive patients and over 90% of treatment experienced GT-1 patients. As the three drugs have potent antiviral activities against GT-4, such association must be potent in such patient but data are pending. For GT-2, Sofosbuvir and ribavirin for 12 weeks are able to cure > 90% of naive and treatment-experienced patients. For GT-3 patients, Sofosbuvir and ribavirin for 24 weeks are able to cure around 90% of naive and treatment experienced patients with the exception of treatment-experienced cirrhotic patients in whom SVR is around 60%. However the combination of Sofosbuvir and Daclatasvir for 24 week leads to more than 90% SVR in the naive GT-3 population and trials are on-going for treatment-experienced patients. All this data confirmed that HCV can be cure with interferon–free regimen and short duration of treatment. Other combination with higher efficacy and very good safety profile are under development and should be available within two years.