A Review of Daclatasvir Drug-Drug Interactions

Review article
A Review of Daclatasvir Drug-Drug Interactions.
Garimella T, et al. Adv Ther. 2016

Adv Ther. 2016 Sep 23. [Epub ahead of print]

Download - Full text review article

Abstract
The treatment of hepatitis C virus (HCV) infection has been revolutionized in recent years by the development of direct-acting antiviral regimens that do not contain peginterferon (pegIFN) and/or ribavirin (RBV). While direct-acting antiviral-based regimens have been shown to be greatly superior to pegIFN/RBV-based regimens in terms of efficacy and safety, they have a greater susceptibility to drug–drug interactions (DDIs).

Daclatasvir (DCV)—the benchmark pangenotypic nonstructural protein 5A inhibitor—has been shown to be efficacious and generally well tolerated in partnership with other HCV direct-acting antivirals, including sofosbuvir, asunaprevir (ASV), and ASV plus beclabuvir. DCV may be the object of a DDI via the induction or inhibition of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein (P-gp) by the concomitant medication, or the precipitant of a DDI via DCV-based induction/inhibition of CYP 3A4 or inhibition of P-gp, organic anion transporting polypeptide 1B1/B3, and/or breast cancer resistance protein.

This article presents an overview of the drug interaction studies conducted during the clinical development of DCV, the findings of these studies that led to the guidance on concomitant medication use and dosage along with any required DCV dose modifications, and the use of the known metabolic pathway of DCV to guide concomitant dosing where direct drug–drug studies have not been conducted. The robust characterization of the DCV clinical pharmacology program has demonstrated that DCV has few or no clinically relevant DDIs with medications with which it is likely to be co-administered, and the majority of DDIs that do occur can be predicted and easily managed.

Funding: Bristol-Myers Squibb.

KeywordsConcomitant medications Daclatasvir Drug–drug interactions Hepatitis C virus Infectious diseases

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UK patients who have liver transplants abroad get poorer management

UK patients who have liver transplants abroad get poorer management      
News Type: Clinical News
     
A small number of UK citizens are undergoing liver transplants abroad but their management is of a lower standard than in the UK.

These were the conclusions of researchers at Sheffield’s Royal Hallamshire Hospital, who sent questionnaires to all seven UK liver transplant units enquiring about liver patients receiving transplant abroad. Six of the seven centres responded.

A total of 12 patients were identified as having undergone liver transplantation overseas. The top destinations were India, China and Egypt.

Four units responded to questions regarding pre-transplant screening. One unit reported HBV and HCV screening not taking place. Four units responded to questions regarding post-transplant antimicrobial therapy. This revealed examples of patients inappropriately not receiving valganciclovir, co-trimoxazole, anti-fungal treatment and HBV immunoglobulins.

The researchers add that information transfer between overseas and UK based transplant teams is poor.

Reference
A questionnaire based assessment of numbers, motivation and medical care of UK patients undergoing liver transplant abroad. Winter BK, Odedra A, Green S. Travel Med Infect Dis. 2016 Sep 14 [Epub ahead of print]

Abstract
A questionnaire based assessment of numbers, motivation and medical care of UK patients undergoing liver transplant abroad.
Travel Med Infect Dis. 2016 Sep 14. pii: S1477-8939(16)30122-3. doi: 10.1016/j.tmaid.2016.09.004. [Epub ahead of print]

A questionnaire based assessment of numbers, motivation and medical care of UK patients undergoing liver transplant abroad.
Kerr Winter B1, Odedra A2, Green S2.

1Department of Infection and Tropical Medicine, Royal Hallamshire Hospital, Sheffield, S10 2JF, England, UK. Electronic address: Ben.kerrwinter@gmail.com.
2Department of Infection and Tropical Medicine, Royal Hallamshire Hospital, Sheffield, S10 2JF, England, UK.

Abstract
BACKGROUND:
Medical tourism, where patients travel abroad intentionally to access medical treatment, is a growing trend. Some of these patients travel to undergo organ transplantation. This study aims to quantify the number of UK patients who undergo liver transplantation abroad, assessing their motivations and management.

METHODS:
Questionnaires were sent to all seven UK liver transplant units enquiring about liver patients receiving transplant abroad. Included were questions on destination, motivation, and pre and post-transplant care.

RESULTS:
Responses were received from six of the seven transplant centres (86%). A total of 12 patients were identified as having undergone liver transplantation overseas. The top destinations were India, China and Egypt. Four units responded to questions regarding pre-transplant screening. One unit reported Hepatitis B and C screening not taking place. Four units responded to questions regarding post-transplant antimicrobial therapy. This revealed examples of patients inappropriately not receiving valganciclovir, co-trimoxazole, anti-fungal treatment and Hepatitis B immunoglobulins.

CONCLUSIONS:
UK patients are undergoing liver transplant abroad, albeit in small numbers. Pre and post-transplant management of these patients is of a lower standard than that provided to those undergoing transplantation in the UK. Information transfer between overseas and UK based transplant teams is poor.

Copyright © 2016. Published by Elsevier Ltd.

KEYWORDS:

Hepatology; Infectious diseases; Medical tourism; Transplantation
PMID: 27640117 DOI: 10.1016/j.tmaid.2016.09.004

Drugmakers racing each other on treatment for liver disease

Drugmakers racing each other on treatment for liver disease

By CAROLINE CHEN and JARED S. HOPKINS BLOOMBERG NEWS

Nonalcoholic steatohepatitis occurs when fat accumulates in the liver along with inflammation and damage, and as much as a quarter of the U.S. population may have a precursor condition called nonalcoholic fatty liver disease. The ailment develops slowly, and patients often don't show symptoms until their livers are heavily damaged. It's most common in people who are overweight or have diabetes, and doctors mainly prescribe diet changes and weight loss.

While doctors need to perform a biopsy to diagnose nonalcoholic steatohepatitis, between 6 and 15 million people in the U.S. alone are estimated to have the condition, and about 20 percent of them will go on to develop life-threatening cirrhosis. It will be the leading cause of liver transplants by 2020, according to Allergan. Drugs that treat it will likely command high prices, said Elizabeth Krutoholow, an analyst at Bloomberg Intelligence.

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We should aim to achieve complete elimination of hepatitis C

We should aim to achieve complete elimination of hepatitis C
Clinical Pharmacist
26 SEP 2016

Chair of the British Viral Hepatitis Group and Consultant in Infectious Diseases, North Manchester General Hospital

I read the letters from Charles Gore (Clinical Pharmacist 2016;8:232) and Anja St. Clair Jones (Clinical Pharmacist 2016;8:264) on the therapies and new services for hepatitis C with interest. The points made are valid and important.

The key issues highlighted by Gore were related to the fact that there are real restrictions placed on accessing the newer therapies for this infection that have not been imposed in other disease areas, with other medicines, in other patients. Resources are limited; however, denying individuals timely access to National Institute for Health and Care Excellence-approved, evidence-based, cost-effective therapies is, indeed, exceptional.

New Perspectives in HCV Infection

October 2016 Volume 65, Issue 1, Supplement, S1-S156
Journal Of Hepatology

New Perspectives in HCV Infection
Edited by Thomas Berg, Xavier Forns

Highlights

Assessment of HCV Disease
Benjamin Maasoumy, Johannes Vermehren
DOI: http://dx.doi.org/10.1016/j.jhep.2016.07.023
S67–S81
Published in issue: October 2016

Treatment and Remaining Challenges
Reversion of disease manifestations after HCV eradication
Adriaan J. van der Meer, Marina Berenguer
DOI: http://dx.doi.org/10.1016/j.jhep.2016.07.039
S95–S108
Published in issue: October 2016

Norah A. Terrault, Tarek I. Hassanein
DOI: http://dx.doi.org/10.1016/j.jhep.2016.08.001
S120–S129
Published in issue: October 2016

HCV Perspectives
Jordan J. Feld, Graham R. Foster
DOI: http://dx.doi.org/10.1016/j.jhep.2016.07.007
S130–S142
Published in issue: October 2016
Full-Text HTML PDF

Future landscape of hepatitis C research – Basic, translational and clinical perspectives
Darius Moradpour, Arash Grakoui, Michael P. Manns
DOI: http://dx.doi.org/10.1016/j.jhep.2016.07.026
S143–S155
Published in issue: October


Epclusa - NICE says yes to another hepatitis C drug

Also read - NICE backs Gilead’s hepatitis C drug Epclusa published today by The Pharma Letter.

NICE says yes to another hepatitis C drug

A new drug which effectively treats more genotypes of hepatitis C has been recommended for use in the NHS.

NICE has published new draft guidance which recommends sofosbuvir-velpatasvir – an anti-viral drug that offers patients with chronic hepatitis C a potential cure.

Sofosbuvir-velpatasvir – a tablet taken once daily – works by blocking the virus from multiplying and infecting new cells. Trials of the drug showed cure rates of 89% and above for all genotypes.

People who have genotype 3 are currently treated with an older type of anti-viral drug, which can cause unwanted side effects. Sofosbuvir-velpatasvir will be the first drug that offers more effective treatment to this group of patients – who make up 44% of the patient population with chronic hepatitis C.

The NICE appraisal committee concluded that sofosbuvir-velpatasvir was clinically and cost-effective, and should be routinely available on the NHS.

Professor Carole Longson, director of the NICE centre for health technology evaluation, said: “The decision by the independent NICE appraisal committee to recommend sofosbuvir-velpatasvir is great news. The drug provides considerable health benefits to patients with hepatitis C, in particular, those with genotype 3 who can become very ill, very quickly.

“Sofosbuvir-velpatasvir, a newer type of direct acting anti-viral medicine, can be used to treat all genotypes of hepatitis C. Other drugs currently available treat only certain genotypes or can cause unwanted side effects if they have to be taken in combination with earlier anti-viral treatments.”

“Our positive recommendation of sofosbuvir-velpatasvir means that more tolerable treatment options will become available to all patients with hepatitis C.”

Sofosbuvir-velpatasvir costs £38,980 for a 12 week treatment course. The drug may also be taken in combination with ribavirin costing around £40,000 – also for a 12 week course of treatment. But the NHS will pay less than these prices because a confidential discount has been agreed with the company.

The draft guidance recommends that decisions to treat patients with sofosbuvir-velpatasvir are made by multidisciplinary teams in the operational delivery networks put in place by NHS England, and to prioritise treatment for people with the highest unmet clinical need.

The preliminary recommendations are now out for public consultation. Consultees, including the company, healthcare professionals and members of the public can comment until 14 October 2016.

https://www.nice.org.uk/news/article/nice-says-yes-to-another-hepatitis-c-drug

Watch Summary Presentation - EASL Recommendations on Treatment of Hepatitis C 2016

EASL- AASLD Special ConferenceNew perspectives in hepatitis C virus infection - The roadmap for cure

Source - EASLEurope

Online now - EASL Recommendations on Treatment of Hepatitis C
Download 2016 - Update of the HCV EASL recommendations

Watch the livestreamed EASL updated  HCV recommendations with a follow-up Q&A session.

Epidemiology and Outcomes of Hepatitis C Infection in Elderly US Veterans

Epidemiology and Outcomes of Hepatitis C Infection in Elderly US Veterans

Patients with hepatitis C infection are getting older in the United States, yet are underrepresented in clinical trials. How does age impact outcomes with and without antiviral treatment?
The chronic hepatitis C (CHC) cohort in the United States is getting older. Elderly patients with CHC may be at a high risk of cirrhosis and hepatocellular carcinoma (HCC), but also other nonhepatic comorbidities that negatively impact their likelihood of receiving or responding to antiviral treatment. There is little information on the clinical epidemiology or outcomes of CHC and its treatment in the elderly.

We conducted a retrospective cohort study of 1 61 744 patients with a positive Hepatitis C virus RNA in the Veterans Health Administration Hepatitis C Clinical Case Registry to examine the association between age subgroups (20–49, 50–64, 65–85 years) and risk of cirrhosis, HCC or death using Cox proportional hazards models. We also examined the effect of treatment with a sustained viral response (SVR) on these outcomes in each age subgroup.

The age distribution was 36.8% 20- to 49-year-olds, 57.6% 50- to 64-year-olds and 5.6% 65- to 85-year-olds (i.e. elderly). Risk of cirrhosis, HCC and death was significantly elevated in elderly patients [HR cirrhosis = 1.14 (1.00–1.29), HR HCC = 2.44 (1.99–2.99); HR death 2.09 (1.98–2.22)] compared with younger patients. The incidence of HCC was than 8.4 per 1000 PY in the elderly compared with 2.6 per 1000 PY and 5.7 per 1000 PY, among the 20–49 and 50–64 age groups, respectively. Elderly patients were significantly less likely to receive antiviral treatment (3.8% vs 14.8% and 19.1%, P < 0.0001), but among those who received treatment SVR was not different among the age groups (33.5% vs 33.2% and 32.1%).

In an analysis limited to those who received treatment, SVR compared to treatment receipt with no SVR was associated with a reduction in risk of developing cirrhosis (HR = 0.34; 0.18–0.66) and HCC (HR = 0.60; 0.22–1.61) and all-cause mortality risk (HR = 0.52, 0.33–0.82).

Elderly patients with CHC are more likely to develop HCC than younger patients but have traditionally received less antiviral treatment than younger patients. However, receipt of curative treatment is associated with a benefit in reducing cirrhosis, HCC and overall mortality, irrespective of age.

  • Methods
  • Results
  • Discussion

  • Free registration is required

    AbbVie Presents Data on Eight-Week Treatment of VIEKIRAX® for Genotype 1b

    Online now EASL Recommendations on Treatment of Hepatitis C
    Download 2016 - Update of the HCV EASL recommendations

    AbbVie Presents Data on Eight-Week Treatment of VIEKIRAX® (ombitasvir/paritaprevir/ritonavir tablets) + EXVIERA® (dasabuvir tablets) in Patients with Genotype 1b Chronic Hepatitis C

    - 98 percent of previously untreated genotype 1b (GT1b) chronic hepatitis C virus (HCV) infected patients without cirrhosis achieved SVR12 in Phase 3b GARNET study1

    - First study evaluating 8 weeks of VIEKIRAX (ombitasvir/paritaprevir/ritonavir tablets) + EXVIERA (dasabuvir tablets)1

    - GT1b is the most common subtype globally,2 accounting for 47 percent of the nine million people infected with chronic HCV in Europe alone3,4

    - GARNET study results on 8-week treatment duration included in newly published 'EASL Recommendations on Treatment of Hepatitis C'

    NORTH CHICAGO, Ill., Sept. 23, 2016 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced new data showing high response rates with just eight weeks of VIEKIRAX® (ombitasvir/paritaprevir/ritonavir tablets) + EXVIERA® (dasabuvir tablets) treatment. In the Phase 3b GARNET study, 98 percent (n=160/163) of previously untreated patients with genotype 1b (GT1b) chronic hepatitis C virus (HCV) infection without cirrhosis achieved sustained virologic response rates at 12 weeks post-treatment (SVR12).1 These data were presented today at the 2016 EASL Special Conference: New Perspectives in Hepatitis C Virus Infection – The Roadmap for Cure, in Paris, France and included in the newly published 'EASL Recommendations on Treatment of Hepatitis C.' VIEKIRAX + EXVIERA is currently approved in the European Union for GT1b patients without cirrhosis or with compensated cirrhosis for 12 weeks.

    "VIEKIRAX + EXVIERA has already achieved high cure rates with 12 weeks of treatment," said Stefan Zeuzem, M.D., study author and Chief of the Department of Medicine at the J.W. Goethe University Hospital in Frankfurt, Germany. "These results now show the potential for cure in just eight weeks with VIEKIRAX + EXVIERA in HCV genotype 1b infected patients without liver cirrhosis. The efficacy in this population is particularly important as GT1b is the most common subtype of hepatitis C virus globally."

    Approximately 160 million people worldwide are infected with HCV.5 Genotype 1 is the most prevalent of the six major HCV genotypes, affecting an estimated 83 million people worldwide.6 In Europe, GT1b is the most predominant subtype accounting for 47 percent of the nine million people infected with chronic HCV.3,4,6

    "AbbVie remains focused on continuing to explore and understand the expectations of HCV care, including a shorter treatment duration with VIEKIRAX + EXVIERA in GT1b patients," said Rob Scott, M.D., Vice President, Development and Chief Medical Officer, AbbVie.

    In the GARNET study, the most commonly reported adverse events (≥5 percent) were headache (21 percent), fatigue (17 percent), nasopharyngitis (8 percent), pruritus (8 percent), nausea (6 percent) and asthenia (5 percent). These adverse events were mostly mild, with one patient discontinuing treatment due to adverse events.1

    About the GARNET Study1
    The Phase 3b GARNET study is a multicenter, open-label, single-arm study, investigating the safety and efficacy of eight weeks of treatment with VIEKIRAX + EXVIERA without ribavirin in treatment-naïve patients with GT1b chronic HCV infection without cirrhosis.1 The study enrolled 166 patients across 20 sites around the world. Of the 166 patients enrolled, 163 patients had GT1b chronic HCV infection without cirrhosis and three patients with other HCV genotypes were excluded from the efficacy analysis. The primary endpoint is the percentage of patients who achieved a sustained virologic response 12 weeks after treatment (SVR12).

    Two patients experienced post-treatment relapse and one subject discontinued due to noncompliance. Less than one percent of patients experienced serious adverse events or clinically significant (Grade ≥3) laboratory abnormalities. One patient discontinued treatment on Day 45 due to an adverse event but achieved SVR12.

    Additional information about the GARNET study can be found on www.clinicaltrials.gov.

    VIEKIRAX® + EXVIERA®
    VIEKIRAX + EXVIERA is approved in the European Union for the treatment of genotype 1 (GT1) chronic hepatitis C virus (HCV) infection, including patients with compensated cirrhosis. VIEKIRAX is approved in the European Union for the treatment of genotype 4 (GT4) chronic HCV infection.

    VIEKIRAX tablets consist of the fixed-dose combination of paritaprevir 150mg (NS3/4A protease inhibitor) and ritonavir 100mg with ombitasvir 25mg (NS5A inhibitor), dosed once daily. EXVIERA tablets consist of dasabuvir 250mg (non-nucleoside NS5B polymerase inhibitor) dosed twice daily. VIEKIRAX + EXVIERA are taken with or without ribavirin (RBV), dosed twice daily based on patient type. VIEKIRAX + EXVIERA is taken for 12 weeks with or without RBV, except in genotype 1a patients with compensated cirrhosis (Child-Pugh A), who should take it for 24 weeks with RBV.

    Paritaprevir was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for hepatitis C protease inhibitors and regimens that include protease inhibitors. Paritaprevir has been developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of chronic hepatitis C.

    Additional information about AbbVie's hepatitis C development program can be found on www.clinicaltrials.gov.

    EU Indication
    VIEKIRAX is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults. EXVIERA is indicated in combination with other medicinal products for the treatment of CHC in adults.

    Important EU Safety Information
    Contraindications:
    VIEKIRAX + EXVIERA are contraindicated in patients with severe hepatic impairment (Child-Pugh C). Patients taking ethinyl estradiol-containing medicinal products must discontinue them and switch to an alternative method of contraception prior to initiating VIEKIRAX + EXVIERA. Do not give VIEKIRAX with certain drugs that are sensitive CYP3A substrates or strong inhibitors of CYP3A. Do not give VIEKIRAX and EXVIERA with strong or moderate enzyme inducers. Do not give EXVIERA with certain drugs that are strong inhibitors of CYP2C8.

    Special warnings and precautions for use:
    VIEKIRAX and EXVIERA are not recommended as monotherapy and should be used in combination with other medicinal products for the treatment of hepatitis C infection.

    Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis
    VIEKIRAX and EXVIERA are not recommended in patients with moderate hepatic impairment (Child-Pugh B). Patients with cirrhosis should be monitored for signs and symptoms of hepatic decompensation, including hepatic laboratory testing at baseline and during treatment.

    ALT elevations
    Transient elevations of ALT to >5x ULN without concomitant elevations of bilirubin occurred in clinical trials with VIEKIRAX + EXVIERA and were more frequent in a subgroup who were using ethinyl estradiol-containing contraceptives.

    Pregnancy and concomitant use with ribavirin
    Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients when VIEKIRAX with or without EXVIERA is taken in combination with ribavirin, see section 4.6 and refer to the Summary of Product Characteristics for ribavirin for additional information.

    Use with concomitant medicinal products
    Use caution when administering VIEKIRAX with fluticasone or other glucocorticoids that are metabolized by CYP3A4. A reduction in colchicine dosage or interruption in colchicine is recommended in patients with normal renal or hepatic function. VIEKIRAX with or without EXVIERA is expected to increase exposure of statins so certain statins need to be discontinued or dosages reduced. Low dose ritonavir, which is part of VIEKIRAX, may select for PI resistance in HIV co-infected patients without ongoing antiretroviral therapy. HIV co-infected patients without suppressive antiretroviral therapy should not be treated with VIEKIRAX.

    Adverse Reactions
    Most common (>20 percent) adverse reactions for VIEKIRAX + EXVIERA with RBV were fatigue and nausea.

    Full summary of product characteristics is available at www.ema.europa.eu