August 20, 2013

Review

Magdalena Harris* and Tim Rhodes

* Corresponding author: Magdalena Harris magdalena.harris@lshtm.ac.uk

Author Affiliations

Centre for Research on Drugs and Health Behaviour, London School of Hygiene and Tropical Medicine, 15-17 Tavistock Place, London, WC1H9SH, UK

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Harm Reduction Journal 2013, 10:7 doi:10.1186/1477-7517-10-7

The electronic version of this article is the complete one and can be found online at: http://www.harmreductionjournal.com/content/10/1/7

Received: 6 August 2012, Accepted: 13 April 2013, Published: 7 May 2013

© 2012 Harris and Rhodes; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Evidence documents successful hepatitis C virus (HCV) treatment outcomes for people who inject drugs (PWID) and interest in HCV treatment among this population. Maximising HCV treatment for PWID can be an effective HCV preventative measure. Yet HCV treatment among PWID remains suboptimal. This review seeks to map social factors mediating HCV treatment access.

Method

We undertook a review of the social science and public health literature pertaining to HCV treatment for PWID, with a focus on barriers to treatment access, uptake and completion. Medline and Scopus databases were searched, supplemented by manual and grey literature searches. A two step search was taken, with the first step pertaining to literature on HCV treatment for PWID and the second focusing on social structural factors. In total, 596 references were screened, with 165 articles and reports selected to inform the review.

Results

Clinical and individual level barriers to HCV treatment among PWID are well evidenced. These include patient and provider concerns regarding co-morbidities, adherence, and side effect management. Social factors affecting treatment access are less well evidenced. In attempting to map these, key barriers fall into the following domains: social stigma, housing, criminalisation, health care systems, and gender. Key facilitating factors to treatment access include: combination intervention approaches encompassing social as well as biomedical interventions, low threshold access to opiate substitution therapy, and integrated delivery of multidisciplinary care.

Conclusion

Combination intervention approaches need to encompass social interventions in relation to housing, stigma reduction and systemic changes in policy and health care delivery. Future research needs to better delineate social factors affecting treatment access.

Keywords: Hepatitis C; Antiviral treatment; Treatment access; People who inject drugs; Social factors

Review

Worldwide 170 million people are estimated to live with chronic HCV [1], with annual mortality rates due to HCV-related liver diseases estimated at over 350 000 [2]. Global HCV antibody prevalence among people who inject drugs (PWID) is high. A recent systematic review, for instance, identified 24 countries where HCV antibody prevalence in PWID ranged from 40–60% (such as Australia, UK, Greece), 25 countries with a range of 60-80% (USA, Canada, Germany) and 12 (Mexico, Thailand, Russia, the Netherlands) where prevalence was 80% or higher [3]. The World Health Organisation identifies PWID as a key target group for HCV prevention and treatment [2].

HCV antiviral treatment with peginterferon alfa and ribavirin is the standard of care for chronic HCV, with a 50-85% cure rate depending on genotype [4]. Modelling studies indicate that scaling-up HCV treatment access to PWID, specifically current injectors, has the potential to reduce the pool of communicable disease in the population, acting as an effective preventative measure [5,6]. Qualitative [7,8] and quantitative research [9-12] shows that PWID are interested in assessing and commencing HCV treatment. PWID have rates of HCV treatment adherence and successful completion comparable to other populations [13-16]. Clinical guidelines in a number of countries (such as the UK, Australia, US, Canada, France) have been modified to remove current injecting drug use as HCV treatment exclusion criteria [17-20]. Yet HCV treatment uptake among PWID is suboptimal, and estimated to be in the order of 2-4% of those eligible [5,17,21,22]. Why might this be so? What interplay of factors mediate HCV treatment access for PWID? And what specifically, might be the role of social and structural factors?

Drawing upon published literature pertaining to HCV treatment as well as HCV among PWID, we seek to map the social factors potentially mediating HCV treatment access and uptake for PWID. This will assist in developing a descriptive typology of social factors and how they function potentially as ‘barriers’ and ‘facilitators’ to treatment access. This is necessary because there is a dearth of pooled evidence investigating the role of social factors affecting HCV treatment. We therefore draw upon previous work on the conditionality of HIV treatment access for PWID as a way of conceptualising ‘social factors’ and their relevance [23-25]. This work on HIV treatment maps the treatment access environment as a product of interplay between macro-level factors (such as the adverse impacts of criminalisation, social and material inequality, and health policy) and meso-level factors (such as related to systems of service administration, management and delivery) [26]. Given the absence of previous review on social factors affecting HCV treatment, this review takes a two step approach to two different literatures in an attempt to map the field. First, we draw upon literature specific to HCV treatment for PWID, generated through a Medline and Scopus search of published papers since the year 2000, selected for their relevance to barriers and facilitators to treatment access. Second, we draw upon literature specific to HCV among PWID, generated through a Medline and Scopus search of published papers since the year 2000, and selected for their relevance regarding ‘social factors’ linked to HCV risk, prevention or treatment. The first of these literatures (HCV treatment) focuses predominantly on clinical and individual level factors, and the second (HCV among PWID) focuses on social and system level factors with a heavier focus on qualitative studies.

Continue reading full article here …..

Wednesday, 21 August 2013, 2:07 pm
Press Release: Joint Press Release

From the 1st of September hepatitis C sufferers will have a new treatment option thanks to VICTRELIS ™ (boceprevir) being funded for people with chronic viral hepatitis C, genotype 1. This includes patients being treated for the first time as well as those who have not responded to previous therapy.

VICTRELIS is the first new hepatitis C treatment made available to New Zealanders in the last decade. Chronic hepatitis C (HCV) is a serious viral infection of the liver that affects around 50,000 New Zealanders.

Hepatitis C genotype 1 is the most common form of the condition affecting approximately 50% of all known sufferers. If left untreated, hepatitis C can cause serious liver disease including cirrhosis, liver cancer and even death.

Professor Ed Gane, chief hepatologist and deputy director of the New Zealand Liver Transplant Unit at Auckland City Hospital says, “VICTRELIS is a protease inhibitor and works directly on the hepatitis C virus to stop it replicating. It is used in combination with other drugs - peginterferon alfa and ribavirin – which prevent the virus from becoming resistant to VICTRELIS.”

When added to other hepatitis C drugs - peginterferon alfa and ribavirin; VICTRELIS dramatically increases the chances of being cured. In patients who have never been treated before, VICTRELIS can almost double cure rates and for patients who have already failed previous therapy, it can treble the cure rate. This can be life changing, especially for patients who have been the hardest to treat – those with cirrhosis and those who have previously failed treatment.

Another advantage of VICTRELIS is that in almost half of the patients, total treatment time can be shortened from 48 weeks to 28 weeks.

Today, hepatitis C cirrhosis is the leading cause of liver cancer and liver failure. By offering a new chance of a cure, we can help prevent progression of liver disease, thereby reducing the rate of liver cancer and the need for liver transplants in New Zealand.

New Zealand Hepatitis Foundation Chief Executive Officer, John Hornell, says “It is fantastic to be able to offer hepatitis C patients a treatment that improves their chances of being cured. Hepatitis C is a disease many people are unaware of and even if they do know about it, they are unsure of treatment options. This means patients often present late with severe complications making the disease more difficult to treat and cure.

“We estimate there are 50,000 New Zealanders who have contracted hepatitis C with less than 25% being diagnosed. However thanks to new and more effective treatment options, there is no reason why people should not be diagnosed, treated and cured. However it is important to identify if you have been at risk and to get tested.”

VICTRELIS has been developed by Merck & Co Inc., known in New Zealand as Merck Sharp & Dohme (MSD). MSD New Zealand Director, Paul Smith, says, "MSD is a global healthcare leader with a long standing heritage in the treatment of hepatitis C. Merck & Co researchers developed the first approved therapy for chronic hepatitis C in 1991 and the first combination therapy in 1998. In addition to ongoing studies with VICTRELIS, extensive research efforts are underway to develop additional innovative oral therapies for viral hepatitis treatment.”

For more information or questions about hepatitis C please contact your GP or the Hepatitis Foundation of New Zealand www.hepatitisfoundation.org.nz

VICTRELIS MPI
Use: In combination with two other medicines (peginterferon alfa and ribavirin) for the treatment of chronic hepatitis C (a viral infection of the liver) Type 1 in patients ( 18 years) who have compensated liver disease and who either have not previously received, or have failed, interferon alfa treatment (pegylated or nonpegylated). When VICTRELIS should not be taken: Hypersensitivity to any of the ingredients of VICTRELIS. Patients with autoimmune hepatitis or any other problem with your immune system; serious liver problems other than chronic hepatitis C; galactose intolerance (the body is unable to absorb galactose); Lapp lactase deficiency (the body is unable to digest milk and milk products); Glucose-galactose malabsorption (the small intestine's is unable to transport and absorb glucose and galactose). Co- administration with the following medicines: oral midazolam, oral triazolam (a sedative, when given by mouth); amiodarone (used for heart-beat problems); ‘ergot’ type medicines, such as dihydro-ergotamine mesylate or ergotamine tartrate; sildenafil, tadalafil (when used to treat pulmonary arterial hypertension); alfuzosin (used to treat an enlarged prostate); simvastatin, lovastatin (used to treat high cholestrol); pregnancy or planning pregnancy, male partners of pregnant women use contraception (including at least 6 months after treatment conclusion), breast-feeding. Precautions: Must be administered in combination with peginterferon alpha and ribavirin; VICTRELIS is not recommended for patients under 18 years or elderly; caution when using with the following medicines: rifampicin (used in the treatment of tuberculosis); carbamazepine (used in the treatment of epilepsy and bipolar disorder); phenobarbitalm, phenytoin (anti-seizure medication); digoxin (used to treat congestive heart failure); amiodarone, quinidine (used for heart-beat problems); methadone (pain killer); pentamidine (used to treat or prevent the development of a serious type of pneumonia); some neuroleptics (psychiatric medication); drospirenone-containing medications (alternative contraceptives should be considered). Side effects: Fatigue; anaemia; nausea; taste change; increase in infections; diarrhoea; vomiting; dry mouth; chills; fever; influenza like illness; irritability; weight decreased; decreased appetite; unusual weakness; painful and swollen joints; muscular ache and pain; headache; dizziness; insomnia; depression; anxiety; cough; shortness of breath; shortness of breath while exercising; hair loss; pruritus; dry skin; rash.

VICTRELIS (Boceprevir). Prescription Only Medicine.
Victrelis_Capsules_MPI_A120726_vNZ1.1

All medicines have risks and benefits. VICTRELIS is fully funded for those who meet specified criteria. A doctor's visit fee and prescription charge will apply. VICTRELIS is a Prescription Only Medicine. Use only as directed. If you have side effects see your doctor, pharmacist, or health professional.

Based on data sheet prepared 26 July 2012. Supplied by: Merck Sharp & Dohme (NZ) Limited, Newmarket, Auckland. For additional product information, consult the Data Sheet and/or Consumer Medicine Information (CMI), available on request (phone 0800 500 673) or at the Medsafe website www.medsafe.govt.nz. TAPS No: PP4194

About MSD
Today's MSD is a global healthcare leader working to help the world be well. MSD is a tradename of Merck & Co., Inc., with headquarters in Whitehouse Station, N.J., U.S.A. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.msd.com or connect with us on Twitter, Facebook and YouTube.

ENDS

Source

Lauran Neergaard, The Associated Press
Tue, 20 Aug 2013 10:37:00 CST

WASHINGTON - Where you live can affect your chances of getting a liver transplant, and your risk of dying while waiting. The nation's transplant network says it's time to make the system fairer — and it may take a cue from how politicians redraw voting maps.

"Gerrymandering for the public good" is how Johns Hopkins University transplant surgeon Dr. Dorry Segev describes a proposal to change the map that governs how donated livers are distributed around the country.

The problem: Some areas have fewer donated organs, and higher demand for them, than others. The sickest patients go to the top of the waiting list. But the geographic variation means that someone in California, among the toughest places to get a new liver, waits longer and is a lot sicker before getting transplanted than someone in Ohio or Florida — if they survive long enough.

"This should not be happening," Segev said.

Segev is advising the United Network for Organ Sharing, which runs the transplant network, as its liver specialists consider the novel idea of "redistricting" how livers are allocated — redrawing the nation's 11 transplant regions based on the distribution and demand for donated organs, much like lawmakers set political districts based on the party voting histories of different areas.

The ultimate goal: "That your chance of dying without a liver transplant doesn't depend on your ZIP code," said Dr. John Roberts, transplant chief at the University of California, San Francisco.

The geographic disparity adds another hurdle to the already dire shortage of livers. Just 6,256 patients received a liver transplant last year, all but a few hundred from deceased donors. Nearly 16,000 people are awaiting a liver. About 1,500 people die waiting every year.

Desperate patients sometimes travel across the country to get on a shorter waiting list, if they can afford it or even know it's possible. The best-known example is the late Apple CEO Steve Jobs, who lived in California but in 2009 had a transplant in Memphis, Tenn., which at the time had one of the shortest waits. That's harder for the less wealthy to do.

"I could have withered away here," said William Sherbert, 47, who temporarily moved from California to Florida for a faster transplant.

When hepatitis B caused liver failure, Sherbert spent a year awaiting a transplant from a Los Angeles hospital. He was getting steadily sicker, but was nowhere near the top of the transplant list when his frantic partner finally unraveled how the system works.

Patients who have the highest MELD score — a ranking, based on laboratory tests, that predicts their risk of death — move up the waiting list. But it's not a single national list. The 11 transplant regions are subdivided into local areas that form individual waiting lists, and there are wide variations in organ availability within regions as well as between them. Generally livers first are offered to the sickest patients locally and then regionally. Changes that began this summer will allow some of the sickest patients access to livers from other parts of the country, an initial step to address disparities.

United Network for Organ Sharing figures show that in three regions stretching from Michigan and Ohio down to Florida, adults receiving new livers over the past two years had median MELD scores of 22 to 23. But in the region that includes California, recipients were far sicker, with a median score of 33. Nearly as tough were regions that include New York, and the Dakotas and Illinois.

An Internet database, the Scientific Registry of Transplant Recipients, compares transplant centre wait times and success rates so people can choose where to go. They can get on more than one waiting list if they meet each hospital's qualifications, and if they can get to that centre within a few hours of being notified that an organ is available. Often, that means moving.

"It's really a shame" that people have to consider such a step, Sherbert said. But he's glad he switched to a Florida hospital's list, possible only because his health insurance paid for the transplant plus the couple's airfare and some living expenses during the seven-month wait. Sherbert is feeling well after his May 2012 transplant, and is back home in Garden Grove, Calif.

In a study published last month in the American Journal of Transplantation, Segev's team used computer modeling to redistrict the transplant regions, better balancing local areas' supply and demand. Segev said 28 per cent of Americans live in an area where they'd have a high risk of death before getting a new liver, and redistricting could drop that proportion to as little as 6 per cent.

The transplant network's liver committee is considering different map options as it debates how to improve fairness without having to fly organs too far around the country. One big challenge will be turf wars, as transplant centres with shorter waits understandably don't want them to lengthen, said committee chairman Dr. David Mulligan of the Mayo Clinic in Phoenix.

"Every doctor wants the best for their patients. The issue becomes stepping back and looking at the big picture and thinking about all the patients," said Mulligan, who hopes to have a proposal ready for public comment within two years. "Yes, your patient waits a little longer, but they can wait a little longer."

Smaller disparities exist for some other transplants, including kidneys, but the transplant network is focusing first on livers. It wouldn't be a problem if there were more organ donors, Mulligan noted, encouraging people to register: "It's the last chance we have to be a hero in our lives."

Source

Coffee: Good for us? Or bad for us? Two new studies disagree

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Two new reports disagree about the health benefits of coffee and caffeine. (Irfan Khan / Los Angeles Times / December 8, 2012)

By Rene Lynch

August 19, 2013, 3:00 p.m.

Drinking lots of coffee is good for you!! Drinking lots of coffee will kill you!!

These are the competing headlines pinging around the media universe Monday, causing whiplash among those of us who rely on a cup (or more) of the black stuff to fuel our day.

First up, a new study released by Mayo Clinic Proceedings found that, "Drinking large amounts of coffee may be bad" for people under the age of 55.

"A study of more than 40,000 individuals found a statistically significant 21% increased mortality in those drinking more than 28 cups of coffee a week," the report said.

"More than 28 cups of coffee a week" works out to be at least four cups of coffee a day. Admittedly, that's a lot of coffee. But not exactly unheard of, especially during crunch times such as studying for finals, or staring down work deadlines.

Counter that with another study, also making the rounds Monday, suggesting that drinking four cups of coffee a day could reduce the risk of non-alcoholic fatty liver disease, also known as NAFLD.

The study by Duke-NUS Graduate Medical School in Singapore found that increased caffeine intake could reduce the disease that affects an estimated 30% of American adults.

According to the analysis, slated to be published in the September issue of Hepatology: "[T]hese findings suggested that coffee and tea consumption (equivalent to the caffeine intake of four cups a day) may be beneficial in the prevention and protection against the progression of NAFLD in humans."

So, what gives?

Unfortunately, there's no easy answer.

Further confusing the issue is the acknowledgment in the first study that men and women who consumed higher amounts of coffee were more likely to smoke and "had lower levels of cardiorespiratory fitness."

According to the Mayo Clinic document, coffee is a complex mixture of chemicals and while it is a major source of antioxidants and has plenty of beneficial health effects, it also carries with it plenty of potential adverse effects because of caffeine’s ability to, among other things, inhibit insulin activity and increase blood pressure.

As might be suspected, more research is needed, the studies both suggest.

"There continues to be considerable debate about the health effects of caffeine, and coffee specifically," said Dr. Carl J. Lavie of the Department of Cardiovascular Diseases, Ochsner Medical Center, New Orleans, and a co-author of the study.

He told the Los Angeles Times that although more research is needed, it might be a good idea to trim back on the excess coffee intake. "All things in moderation," he said.

Source

A Notice by the Food and Drug Administration on 08/02/2013

This article has a comment period that ends in 14 days (09/03/2013)

Action

Notice; Reopening Of Comment Period.

Summary

The Food and Drug Administration (FDA) is reopening the comment period for the notice of public meeting entitled “Human Immunodeficiency Virus (HIV) Patient-Focused Drug Development and HIV Cure Research,” published in the Federal Register of May 21, 2013 (78 FR 29755). In that notice, FDA requested public comment regarding patients' perspective on current approaches to managing HIV, symptoms experienced because of HIV or its treatment, and issues related to HIV cure research. FDA is reopening the comment period to allow interested persons additional time to submit comments.

DATES

Submit either electronic or written comments to the docket by September 3, 2013.

ADDRESSES

Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT

Pujita Vaidya, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 1170, Silver Spring, MD 20993-0002, 301-796-0684, FAX: 301-847-8443, email: Pujita.Vaidya@fda.hhs.gov.

SUPPLEMENTARY INFORMATION

I. Background

In the Federal Register of May 21, 2013 (78 FR 29755), FDA announced the notice of public meeting entitled “HIV Patient-Focused Drug Development and HIV Cure Research.” In that notice, FDA requested public comment on specific questions regarding patients' perspective on current approaches to managing HIV, symptoms experienced because of HIV or its treatment, and issues related to HIV cure research. Interested persons were given until July 14, 2013, to comment on the questions. The Agency is reopening the comment period until September 3, 2013 to allow interested persons additional time to submit comments.

II. Specific Questions for Public Comment

As part of Patient-Focused Drug Development, FDA is gathering input from HIV patients and patient advocates on current approaches to managing HIV, symptoms experienced because of HIV or its treatment, and issues related to HIV cure research. FDA is interested in receiving patient input that addresses the following questions.

Topic 1: Patients' Perspective on Current Approaches to Managing HIV and on Symptoms Experienced Because of HIV or Its Treatment

1. What are you currently doing to help manage your HIV and any symptoms you experience because of your condition or other therapies? (Examples may include prescription medicines, over-the-counter products, and nondrug therapies such as diet modification.)

a. What specific symptoms do your therapies or treatments address?

b. How long have you been on treatment and how has your treatment regimen changed over time?

2. How well does your current treatment regimen treat any significant symptoms of your condition?

a. How well have these treatments worked for you as your condition has changed over time?

b. Are there symptoms that your current regimen does not address at all or does not treat as well as you would like?

3. What are the most significant downsides to your current therapies or treatments, and how do they affect your daily life? (Examples of downsides could include bothersome side effects, physical change to your body because of treatment, going to the hospital for treatment.)

4. Of all the symptoms that you experience because of your condition or because of your therapy or treatment, which one to three symptoms have the most significant impact on your life? (Examples could include diarrhea, insomnia, difficulty concentrating, etc.)

  • Are there specific activities that are important to you but that you cannot do at all or as fully as you would like because of your condition? (Examples of activities may include sleeping through the night, daily hygiene, driving, etc.)

5. Assuming there is currently no complete cure for your condition, what specific things would you look for in an ideal therapy or treatment to manage your condition?

Topic 2: Patients' Perspectives on HIV Cure Research

1. What do you believe are the benefits of participating in an HIV cure research study?

2. What would motivate you to participate or to not participate in an HIV cure research study?

3. What risks would you find unacceptable for participating in an HIV cure research study and why? (Examples of risks that may be associated with participation in an HIV cure research study include commonside effects such as nausea and fatigue, and less common but serious adverse events such as blood clots, infection, seizures, and cancer.)

4. In certain HIV cure research studies, you would be asked to stop any other HIV medications that you are currently taking. How would this affect your decision whether to participate in an HIV cure research study?

5. The process of informed consent is an important way for the researchers to communicate the purpose of an HIV research study, as well as its expected benefits and potential risks, so that people can make an informed decision whether to participate in the study.

a. How should the informed consent clearly communicate to you the purpose of an HIV cure research study, particularly when a study is designed only to provide scientific information that could guide future research and development of treatments?

b. How should the informed consent clearly communicate to you the potential benefits of an HIV cure research study? In particular, how should the informed consent describe benefit when we do not think that participants in the study may gain any direct health benefits?

c. How should informed consent communicate clearly to you the potential risks of participating in an HIV cure research study? In particular, how should the informed consent describe a study if there is very limited understanding about how the medications or interventions may affect participants or what are the potential risks of those interventions or medications?

d. Is there any other information that you would find helpful when deciding whether to enter an HIV cure research study?

6. What else do you want FDA to know about HIV Cure Research from your perspective?

III. How To Submit Comments

Interested persons may submit either electronic comments regarding this document to http://www.regulations.gov or written comments to the Division of Dockets Management (see ADDRESSES). It is only necessary to send one set of comments. Identify comments with the docket number found in brackets in the heading of this document. Received comments may be seen in the Division of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.

Dated: July 29, 2013.

Leslie Kux,

Assistant Commissioner for Policy.

[FR Doc. 2013-18630 Filed 8-1-13; 8:45 am]

BILLING CODE 4160-01-P

Source

Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

Provided by NATAP

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The New England Journal of Medicine
august 15, 2013

Stefan Zeuzem, M.D., Vincent Soriano, M.D., Ph.D., Tarik Asselah, M.D., Ph.D., Jean-Pierre Bronowicki, M.D., Ph.D., Ansgar W. Lohse, M.D., Beat Mullhaupt, M.D., Marcus Schuchmann, M.D., Marc Bourliere, M.D., Maria Buti, M.D., Stuart K. Roberts, M.D., Ed J. Gane, M.D., Jerry O. Stern, M.D., Richard Vinisko, M.A., George Kukolj, Ph.D., John-Paul Gallivan, Ph.D., Wulf-Otto Bocher, M.D., and Federico J. Mensa, M.D.

"Rates of a sustained virologic response 12 weeks after the completion of therapy were 56 to 85% among patients with genotype 1b infection versus 11 to 47% among patients with genotype 1a infection and 58 to 84% among patients with IL28B CC versus 33 to 64% with non-CC genotypes. Rash, photosensitivity, nausea, vomiting, and diarrhea were the most common adverse events."

(Click on table to enlarge)

table2

Background

Interferon-free regimens would be a major advance in the treatment of patients with chronic hepatitis C virus (HCV) infection.

Methods

In this phase 2b, randomized, open-label trial of faldaprevir (a protease inhibitor) and deleobuvir (a nonnucleoside polymerase inhibitor), we randomly assigned 362 previously untreated patients with HCV genotype 1 infection to one of five groups: faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, plus ribavirin, for 16, 28, or 40 weeks (TID16W, TID28W, or TID40W, respectively); faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg twice daily, plus ribavirin, for 28 weeks (BID28W); or faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, without ribavirin, for 28 weeks (TID28W-NR). The primary end point was a sustained virologic response 12 weeks after the completion of therapy.

Results

The primary end point was met in 59% of patients in the TID16W group, 59% of patients in the TID28W group, 52% of patients in the TID40W group, 69% of patients in the BID28W group, and 39% of patients in the TID28W-NR group. The sustained virologic response 12 weeks after the completion of therapy did not differ significantly according to treatment duration or dosage among ribavirin-containing regimens. This response was significantly higher with TID28W than with TID28W-NR (P=0.03). Rates of a sustained virologic response 12 weeks after the completion of therapy were 56 to 85% among patients with genotype 1b infection versus 11 to 47% among patients with genotype 1a infection and 58 to 84% among patients with IL28B CC versus 33 to 64% with non-CC genotypes. Rash, photosensitivity, nausea, vomiting, and diarrhea were the most common adverse events.

Conclusions

The rate of a sustained virologic response 12 weeks after the completion of therapy was 52 to 69% among patients who received interferon-free treatment with faldaprevir in combination with deleobuvir plus ribavirin. (Funded by Boehringer Ingelheim; SOUND-C2 ClinicalTrials.gov number, NCT01132313.)

The introduction of the direct-acting antiviral agents telaprevir and boceprevir (nonstructural protein 3/4A [NS3/4A] protease inhibitors) was a major advance in the management of chronic infection with hepatitis C virus (HCV) genotype 1, the most prevalent and difficult-to-cure genotype.1 However, these drugs are used in combination with pegylated interferon alfa and ribavirin, which are associated with a high rate of side effects and discontinuation.2 In addition, many patients cannot receive pegylated interferon because of contraindications.3 Host genetic factors are known to influence the response to treatment with pegylated interferon and ribavirin in patients infected with HCV genotype 1. Single-nucleotide polymorphisms in the promoter region of the IL28B gene result in three genotypes: CC, CT, and TT (rs12879860), and patients with the CT or TT genotype have a reduced response to interferon-based therapies.4 The influence of this host factor on a sustained virologic response in patients treated with interferon-free regimens is unknown.

Monotherapy with direct-acting antiviral agents is associated with rapid selection of viral variants that are resistant to the antiviral compound.4-7However, combinations of potent direct-acting antiviral agents targeting different stages of the HCV life cycle offer the possibility of interferon-free treatment. The results of phase 1 and 2 studies involving patients with HCV genotype 1 infection have been encouraging and provide support for further development of combination therapies.8-13 In the phase 1b Safety and Antiviral Effect of Oral Combinations without Interferon in Patients Diagnosed with Hepatitis C (SOUND-C1) study, patients who had not previously been treated for HCV infection received 4 weeks of treatment with faldaprevir (an NS3/4A protease inhibitor) and deleobuvir (formerly known as BI207127; a nonnucleoside inhibitor of nonstructural protein 5B [NS5B] polymerase) plus ribavirin. At week 4, 100% and 73% of patients who received faldaprevir plus ribavirin with 600 mg or 400 mg of deleobuvir, respectively, had HCV RNA levels that were lower than 25 IU per milliliter.12 Here we describe the phase 2b SOUND-C2 study, which assessed the efficacy and safety of the interferon-free combination of faldaprevir plus deleobuvir, with or without ribavirin, for 16, 28, or 40 weeks.

Methods

Patients

Patients were enrolled at 48 sites in Europe, Australia, and New Zealand. Eligible patients were 18 to 75 years of age, had chronic HCV genotype 1 infection (HCV RNA level ≥10,000 IU per milliliter), had compensated liver disease, and had not received treatment. Patients could have cirrhosis, which was determined either by means of biopsy (Metavir stage F4 on a scale from F0 to F4, with higher stages indicating a greater degree of fibrosis) or by means of transient elastography. The study protocol is available with the full text of this article at NEJM.org.

Study Design

The trial was a multicenter, randomized, open-label, phase 2b study. Although no formal hypotheses were stated, the study was designed to investigate the effect of treatment duration, deleobuvir dosage, and the absence or presence of ribavirin in treatment regimens on the virologic response. Patients were stratified at randomization according to viral subtype (1a or 1b, which was determined by means of the Trugene HCV genotyping assay [Bayer] or the Versant HCV Genotype 2.0 Assay [Siemens], if the Trugene result was inconclusive) and according to the IL28B(rs12979860) genotype (either CC or non-CC, which was determined by means of polymerase-chain-reaction TaqMan allelic discrimination assays14 [Applied Biosystems]). With the use of an interactive voice-response system, the patients were assigned in a 1:1:1:1:1 ratio to one of five treatment groups: faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, plus ribavirin, for 16 weeks (the TID16W group), 28 weeks (TID28W), or 40 weeks (TID40W); faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg twice daily, plus ribavirin, for 28 weeks (BID28W); and faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, without ribavirin, for 28 weeks (TID28W-NR). For the first dose of the study drugs, patients received a 1200-mg dose of deleobuvir (i.e., an additional 600-mg dose) and a 240-mg dose of faldaprevir (i.e., an additional 120-mg dose). The ribavirin dose was 1000 mg per day (for patients with a body weight of <75 kg) or 1200 mg per day (for those with a body weight ≥75 kg). Stepwise temporary reductions of the ribavirin dose and the use of erythropoietin were permitted to manage anemia.

Patients who had virologic breakthrough or a detectable level of HCV RNA at weeks 6 and 8 were switched to pegylated interferon plus ribavirin and were considered to have had treatment failure. Breakthrough was defined as a confirmed increase in the HCV RNA level in two consecutive measurements to 25 IU per milliliter or higher for patients with HCV RNA levels that were previously lower than 25 IU per milliliter or 1 log10 IU per milliliter or higher for those with HCV RNA levels that were previously 25 IU per milliliter or higher. Relapse was defined as an HCV RNA level that was higher than 25 IU per milliliter after an undetectable level of HCV RNA at the end of planned treatment.

In a protocol amendment that was effective as of December 2011 (2 months before the internal database was unblinded), the definition of a sustained virologic response was changed from an undetectable level of HCV RNA 24 weeks after completion of therapy to an undetectable level of HCV RNA 12 weeks after completion of therapy. This change was made on the basis of a meta-analysis of HCV clinical trials showing that a sustained virologic response 12 weeks after the completion of therapy had a positive predictive value of 98% for a sustained virologic response 24 weeks after the completion of therapy.15 Other protocol amendments are described in the study protocol.

Study Oversight

The study was approved by the ethics committee at each participating site and was carried out in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Guidelines for Good Clinical Practice. All patients provided written informed consent before enrollment.

The sponsor, Boehringer Ingelheim, designed and conducted the study in collaboration with the academic investigators. The sponsor monitored the study, collected data, and performed the statistical analysis. The academic investigators, participating institutions, and sponsor agreed to maintain confidentiality of the data. The first draft of the manuscript was prepared by the first author with support from a medical writer employed by the sponsor, and the first author made the decision to submit the manuscript for publication. All the authors had access to the data and assume responsibility for the integrity and completeness of the data and for the fidelity of this report to the study protocol.

Efficacy Assessments

The primary efficacy end point was a sustained virologic response (i.e., undetectable level of HCV RNA) 12 weeks after the completion of therapy. The secondary efficacy end points were the time to an undetectable level of HCV RNA, an undetectable level of HCV RNA at week 4 of treatment, and an undetectable level of HCV RNA 24 weeks after the completion of therapy.

Plasma HCV RNA levels were measured with the use of the quantitative COBAS TaqMan HCV High Pure System assay, version 2 (Roche), with a lower limit of quantification of 25 IU per milliliter and a lower limit of detection of 17 IU per milliliter. During treatment, HCV RNA levels were measured on days 1 and 4; at weeks 1, 2, 4, 6, and 8; and every 4 weeks thereafter. After the end of the treatment period, HCV RNA levels were measured at 4, 8, 12, and 24 weeks.

Safety Assessments

Biochemical and hematologic assessments were performed at each visit during the treatment period and 4 weeks after the last dose of the study drug was administered. Data on adverse events were obtained at each treatment visit and at the follow-up assessment. Physical examinations were performed at the screening visit, at the safety follow-up assessment, and as needed for the assessment and treatment of symptoms during treatment visits. An independent data and safety monitoring committee conducted regular planned reviews of the safety data.

Drug-Resistance Assessments

Plasma samples from all visits at which levels of HCV RNA were measured were stored for monitoring of drug resistance. HCV nonstructural protein 3 (NS3) and NS5B regions were sequenced in all patients at baseline and in patients who had virologic breakthrough during treatment or relapse of infection in order to identify viral variants associated with resistance to NS3/4A or NS5B inhibitors.

Statistical Analysis

The primary efficacy and safety analyses were based on the intention-to-treat population (all randomly assigned patients who received at least one dose of study medication). The proportion of patients with a sustained virologic response 12 weeks after the completion of therapy was calculated and compared among treatment groups with the use of a stratified Cochran-Mantel-Haenszel test to adjust for HCV and IL28B genotypes.16 Prespecified pairwise comparisons were made among the groups that received deleobuvir three times daily (to assess duration), between the BID28W and TID28W groups (to assess the deleobuvir dosage), and between the TID28W and TID28W-NR groups (to assess the effect of ribavirin). Post hoc pairwise comparisons of rates of a sustained virologic response 12 weeks after the completion of therapy were calculated within each treatment group for genotype 1a versus 1b (with adjustment for the IL28B genotype) and for IL28B CC versus non-CC (with adjustment for the HCV genotype 1 subtype). All P values reported for statistical comparisons are for descriptive purposes only; no significance threshold was prespecified, and no adjustments for multiple comparisons were performed. Ten post hoc subgroup comparisons were performed (the genotype 1 subtype and IL28B genotype within treatment groups). If there were no true differences between subgroups at a 0.05 significance level, the chance of at least one false positive result would be approximately 40%.

We also performed a multivariate logistic-regression analysis to evaluate the effects of covariates (age, sex, body-mass index, presence or absence of cirrhosis or diabetes, baseline alanine aminotransferase and γ-glutamyl transferase levels, viral subtype, IL28B genotype, and baseline HCV RNA level) on virologic response rates. This analysis was based on the per-protocol population, which excluded patients who prematurely discontinued the study therapy for reasons other than lack of efficacy (i.e., they had adverse events leading to discontinuation, were lost to follow-up, or withdrew consent).

Results

Patients

Of 469 patients who were screened, 362 underwent randomization and received at least one dose of the study drugs (Fig. S1 in the Supplementary Appendix, available at NEJM.org). Enrollment in the TID28W-NR group was discontinued on February 3, 2011, at the request of the Food and Drug Administration after other studies showed that virologic breakthrough was more common with interferon-free regimens that did not contain ribavirin than with those that did.13,17 Baseline demographic and clinical characteristics were similar in the five study groups.

Efficacy

Virologic response rates are shown in Table 2 and in Table S1 in the Supplementary Appendix. There were no significant differences among rates of a sustained virologic response 12 weeks after the completion of therapy according to treatment duration (59% in the TID16W group vs. 59% in the TID28W group, P=0.86; 59% in the TID16W group vs. 52% in the TID40W group, P=0.37; and 59% in the TID28W group vs. 52% in the TID40W group, P=0.46) or deleobuvir dosage (69% in the BID28W group vs. 59% in the TID28W group, P=0.15). Rates of a sustained virologic response 12 weeks after the completion of therapy were higher among patients who received ribavirin than among those who received the same regimen without ribavirin (59% in the TID28W group vs. 39% in the TID28W-NR group, P=0.03).

Rates of a sustained virologic response 12 weeks after the completion of therapy were higher among patients with HCV genotype 1b infection than among those with HCV genotype 1a infection, after adjustment for IL28B genotype, in all groups except the TID40W group (BID28W, P<0.001; TID16W and TID28W-NR, P=0.001; TID28W, P=0.03; and TID40W, P=0.38). Response rates were also higher among patients with the IL28B CC genotype than among patients with non-CC genotypes in the BID28W and TID28W-NR groups (P=0.05 and P=0.02, respectively) after adjustment for viral subtype.

Genotype 1b, IL28B CC genotype, female sex, treatment regimens containing ribavirin, and normal baseline γ-glutamyl transferase levels were associated with a higher rate of sustained virologic response 12 weeks after the completion of therapy in the multivariate analysis (Table S2 in the Supplementary Appendix).

Fifty of the 75 patients who had virologic breakthrough during the study had HCV genotype 1a infection. Relapse occurred in 19%, 2%, 2%, 0%, and 10% of patients in the TID16W, TID28W, TID40W, BID28W, and TID28W-NR groups, respectively. Nine of 11 patients with relapsed infection in the TID16W group had HCV genotype 1a infection (Table 2).

A total of 97% of patients with virologic breakthrough (73 of 75 patients) had variants that emerged with mutants in both NS3 and NS5B, whereas the variants from patients who had relapsed infection were most commonly associated with single mutants in NS3 or NS5B (Table S3 in the Supplementary Appendix).

Safety

The most common adverse events were nausea, diarrhea, vomiting, jaundice, pruritus, rash, photosensitivity reaction, dry skin, asthenia, and fatigue (Table 3. Across all groups, 340 patients (94%) had adverse events and 34 (9%) had severe adverse events (defined as events that were incapacitating or led to an inability to work or perform usual activities). Between 56 and 73% of all the episodes of vomiting in the five treatment groups occurred during the first week of treatment. A similar pattern was observed for other gastrointestinal adverse events. Rashes were generally maculopapular and were typical of drug-related rashes. Photosensitivity reactions were commonly reported as exaggerated sunburns. Serious adverse events (defined as events that resulted in death, were life-threatening, resulted in persistent or clinically significant disability or incapacity, required or prolonged hospitalization, or were deemed to be serious by the investigator for any other reason, as detailed in the protocol) occurred in 7% of all patients (27 of 362). Of the patients with the most frequently reported events categorized as serious, 7 patients had skin disorders, 3 had infections, and 2 had anemia (Table S4 in the Supplementary Appendix).

The mean reductions in hemoglobin levels were 1.0 g per deciliter in the TID28W-NR group and approximately 2.5 g per deciliter in all other groups (Table 4. Anemia was reported as an adverse event in up to 13% of patients in the groups that received ribavirin and was not reported in any of the patients in the TID28W-NR group. Mean platelet levels increased from baseline during treatment in all groups (Table 4).

Discussion

The rates of a sustained virologic response 24 weeks after the completion of therapy among patients with previously untreated chronic HCV genotype 1 infection who received the current standard of care (pegylated interferon, ribavirin, and telaprevir or boceprevir) ranged from 68 to 75% in phase 3 trials.18-22 In this phase 2b study involving patients who had not previously received treatment for HCV genotype 1 infection, the combination of faldaprevir, deleobuvir, and ribavirin resulted in rates of a sustained virologic response of 52 to 69% 12 weeks after the completion of therapy.

Overall response rates were not affected by the treatment duration. However, the rate of relapse among patients with HCV genotype 1a infection who were treated for 16 weeks was higher than the rates among patients treated for 28 or 40 weeks with the same regimen (41% vs. 0% and 6%). Relapse rates among patients with genotype 1b infection were consistently low among all treatment groups (0 to 6%); these findings suggest that 16 weeks of treatment may be sufficient for this population.

The difference in response rates according to the deleobuvir dosage was not significant in this study (69% in the BID28W group vs. 59% in the TID28W group, P=0.15). However, the rate of premature discontinuation among patients who did not have a sustained virologic response 12 weeks after the completion of therapy was higher in the TID28W group than in the BID28W group (15% vs. 4%).

The low response rate observed in the group of patients who did not receive ribavirin was associated with high rates of virologic breakthrough and relapse. This finding is consistent with results from other studies of interferon-free regimens without ribavirin.13,17

The higher rate of a sustained virologic response 12 weeks after the completion of therapy among patients infected with HCV genotype 1b than among those infected with genotype 1a may be due to the fact that deleobuvir is less active against genotype 1a.23,24 In addition, there may be a lower barrier to the emergence of resistant variants for genotype 1a virus.25 Similar results were observed with other interferon-free regimens, indicating that genotype 1a may be more difficult to treat than genotype 1b.26,27

The observation that the IL28B polymorphism (rs12879860) affected the rate of a sustained virologic response 12 weeks after the completion of therapy suggests that innate immunity may still be important in interferon-free regimens.

However, the effect of the IL28B genotype is unclear in other interferon-free regimens.11,28

Adverse events were common; overall, 94% of patients had adverse events, and 9% had severe adverse events. Gastrointestinal and dermatologic adverse events were the most frequently reported events in this study. Patients received loading doses of faldaprevir and deleobuvir on the first day of the study to ensure sufficient plasma levels of both drugs during the first days of treatment. These loading doses may have contributed to the higher frequency of gastrointestinal events during the first week of treatment than later in the treatment period. Jaundice due to increased levels of bilirubin from baseline levels was observed in this study. Faldaprevir inhibits bilirubin metabolism primarily through inhibition of UGT1A1,29 which can lead to increased plasma levels of unconjugated bilirubin. In all cases of grade 3 or 4 hyperbilirubinemia, no concurrent increase in the alanine aminotransferase level was observed. The lower rate of jaundice in the TID28W-NR group (4%) than in the other groups can be explained by the absence of hemolysis in a ribavirin-free treatment.

Substantial reductions in red-cell, white-cell, and platelet counts are the most prohibitive side effects of interferon-based treatments for HCV infection. In the Individualized Dosing Efficacy vs. Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) study,30 30% of patients treated with pegylated interferon alfa-2a and the same dose of ribavirin used in this study had hemoglobin levels of less than 10 g per deciliter (i.e., anemia). In this study, 10% of patients in the groups that received ribavirin had hemoglobin levels that were less than 10 g per deciliter. The lower rate of anemia in this study might be due to the absence of the myelosuppressive effects of pegylated interferon; however, without a comparative study, this observation should be interpreted with caution. The low rate of anemia and the absence of a detrimental effect of the interferon-free regimens on white-cell or platelet counts may be an advantage of these regimens over interferon-based therapy.

This study has some limitations. First, the open-label design may have biased the comparative evaluation of the duration of treatment, since the patients who received longer regimens may have been more prone to early discontinuation of treatment than the patients who received shorter regimens. This may have contributed to the higher rate of discontinuation in the TID40W group.

Furthermore, the lack of an interferon-based control group limits the interpretation of the results in relation to the current standard-of-care treatment.

In conclusion, the interferon-free combination of faldaprevir and deleobuvir with ribavirin for the treatment of HCV genotype 1 infection was effective. The presence of ribavirin was found to be a necessary component of these regimens. The BID28W regimen had a more favorable efficacy and safety profile than did the other regimens examined in this study. The HCV genotype 1 subtype and host factors were found to be significantly associated with a sustained virologic response 12 weeks after the completion of therapy.

Supported by Boehringer Ingelheim.

Source

Gilead HCV Program, GS-7977

Provided by NATAP

(All links open in new windows)

from Jules od NATAP: Gilead submitted to the FDA approval for the Gilead nucleotide GS-7977+Peg/Rbv 12 weeks for Gt1, and for GS7977+Rbv for Gt2/3 and I think 4/6. They have been studying HIV/HCV coinfection in Gt2 and I think Gt1. The FDA hearing for TMC435 & for GS-7977 appears to be Oct 24/25 2013. There is a lot of research & studies that have been conducted so there is a lot below, you can look at the phase 3 results presented at EASL 2013, link below. Gilead has a protease inhibitor & a non-nuc as well in clinical development, studies presented at EASL 2013. GS-7977 has been studied in combination with BMS' NS5A inhibitor in naives & telaprevir/boceprevir failures with 95-100% SVR rates. In 2014 by June Gilead is expected to submit phase 3 study results to the FDA for their fixed dose combination go GS-7977 + their 1st generation NS5A with and w/o RBV, 12 weeks therapy. At the same time Abbvie will be submitting their Phase 3 study results for their INF-free oral regimen which includes their protease inhibitor, NS5A inhibitor & their non-nuc with & w/o RBV, 12 weeks therapy; GS-7977 mono therapy data is reported in study links below.

GS-7977 & HIV ARTs PK - No Clinically Significant Pharmacokinetic Interactions Between Sofosbuvir (GS-7977) and HIV Antiretrovirals Atripla, Rilpivirine, Darunavir/Ritonavir, or Raltegravir in Healthy Volunteers
http://www.natap.org/2012/AASLD/AASLD_64.htm

GILEAD SUBMITS NEW DRUG APPLICATION TO U.S. FDA FOR SOFOSBUVIR FOR THE TREATMENT OF HEPATITIS C http://www.natap.org/2013/HCV/040813_01.htm

Antiviral Drugs Advisory Committee .........October 24-25 http://www.fda.gov/AdvisoryCommittees/Calendar/ucm153468.htm

Gilead Reports Interim Data From Phase 2 LONESTAR Study - (05/03/13)

EASL 2013
Gilead reported 7 studies results including 4 phase 3 studies and others including their HCV protease inhibitor, 1st & 2nd generation NS5A inhibitors and their non-nuc, ALL with links to each presentation within this report http://www.natap.org/2013/HCV/050313_02.htm

Clin Pharm Workshop at EASL Amsterdam 2013 - Clinical Pharmacology of DAA's for HCV:
What's New and What's in the Pipeline
Gilead Sciences A. Mathias Pres. DATA FROM PHASE 3 STUDIES OF GILEAD'S SOFOSBUVIR FOR HEPATITIS C TO BE PRESENTED AT 48TH ANNUAL EASL MEETING; FINDINGS PUBLISHED ONLINE TODAY IN THE NEW ENGLAND JOURNAL OF MEDICINE - Press Release http://www.natap.org/2013/EASL/EASL_02.htm

Sofosbuvir for Previously Untreated Chronic Hepatitis C Infection: 2 phase 3 studies - FISSION (gt2/3), NEUTRINO (gt1) http://www.natap.org/2013/EASL/EASL_32.htm

Gilead's HCV Pipeline Unveiled at EASL http://www.natap.org/2011/EASL/EASL_97.htm

EASL: Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) in Chronic HCV Genotype (GT) 1-Infected Patients Who Previously Failed Telaprevir (TVR) or Boceprevir (BOC) - (04/27/13) EASL/2012: Potent Viral Suppression With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) and GS-7977 (Nucleotide NS5B Inhibitor), +/- Ribavirin, in Treatment-Naive Patients With Chronic HCV GT1, 2, or 3 (100% SVR gt1, 91% gt2) - (04/19/12)

COSMOS Study: SVR4 results of a once daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype 1 null responders http://www.natap.org/2013/CROI/croi_34.htm

AASLD/2012: High Rate of Sustained Virologic Response With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) Plus Sofosbuvir (Nucleotide NS5B Inhibitor), With or Without Ribavirin, in Treatment-Naive Patients Chronically Infected With HCV GT 1, 2, or 3 - (11/13/12)

EASL: No S282T Mutation Detected by Deep Sequencing in a Large Number of HCV Patients Who Received Sofosbuvir With RBV and/or GS-0938: the Quantum Study - (04/29/13)

EASL: GS-5816, a Second-Generation HCV NS5A Inhibitor With Potent Antiviral Activity, Broad Genotypic Coverage, and a High Resistance Barrier - (04/29/13)

EASL: Healthy Volunteer First-in-Human Evaluation of GS-5816, a Novel Second Generation Broad-Genotypic NS5A Inhibitor With Potential for Once-Daily Dosing - (04/29/13)

GILEAD PROVIDES UPDATE ON HEPATITIS C DEVELOPMENT PROGRAMS - update on GS-7977+GS-5885+Rbv in null responders in Electron http://www.natap.org/2013/HCV/010713_02.htm

GS-7977 400 mg QD Safety and Tolerability in the Over 500 Patients Treated for at Least 12 Weeks http://www.natap.org/2012/EASL/EASL_55.htm

Once Daily Sofosbuvir (GS-7977) Regimens in HCV Genotype 1-3: The ELECTRON Trial http://www.natap.org/2012/AASLD/AASLD_31.htm

AASLD: Once Daily Sofosbuvir (GS-7977) plus PEG/RBV In Treatment-Na•ve Patients With HCV Genotype 1, 4, and 6 Infection: The ATOMIC Study http://www.natap.org/2012/AASLD/AASLD_21.htm
http://www.natap.org/2013/HCV/033113_02.htm

Nucleotide Polymerase Inhibitor Sofosbuvir (GS-7977) plus Ribavirin for Hepatitis C - new published study http://www.natap.org/2013/HCV/010413_04.htm

ONCE DAILY DUAL-NUCLEOTIDE COMBINATION OF PSI-938 AND PSI-7977 PROVIDES 94% HCV RNA < LOD AT DAY 14: FIRST PURINE/PYRIMIDINE CLINICAL COMBINATION DATA (THE NUCLEAR STUDY) http://www.natap.org/2011/EASL/EASL_07.htm

Pharmasset Announces Results of a 28-day Phase 2a Study with PSI-7977 for the Treatment of Chronic Hepatitis C Infection http://www.natap.org/2010/HCV/102810_04.htm

AASLD: PSI-7977: ELECTRON Interferon is not required for Sustained Virologic Response in Treatment-Na•ve Patients with HCV GT2 or GT3 - (11/07/11) Lack of Effect of the Nucleotide Analog Polymerase Inhibitor PSI-7977 on Methadone PK and PD http://www.natap.org/2011/AASLD/AASLD_104.htm

PSI-7977 Has No Effect on QTcF Intervals at Therapeutic or Supratherapeutic Doses http://www.natap.org/2011/AASLD/AASLD_103.htm

PSI-7977 with PEG/RBV Elicits Rapid Declines in HCV RNA in Patients with HCV GT-4 and GT-6 http://www.natap.org/2011/hepDART/hepDART_01.htm

High Rapid Virologic Response (RVR) with PSI-7977 Daily Dosing plus PEG-IFN/RBV in a 28-day Phase 2a Trial http://www.natap.org/2010/AASLD/AASLD_49.htm

Gilead Acquires Pharmasset $11 Billion http://www.natap.org/2011/HCV/112111_02.htm

TMC435+GS7977 (Rbv) New Study in Advanced Hepatic Fibrosis- Null Responders & Naives http://www.natap.org/2013/HCV/012213_03.htm

Combination of two complementary nucleotide analogues, PSI-7977 and PSI-938, effectively clears wild type and NS5b: S282T HCV replicons - Comparison with combinations of other antiviral compounds http://www.natap.org/2010/EASL/EASL_28.htm

 

TMC435, Janssen HCV Program

Provided by NATAP

(All links open in new window)

Janssen Submits New Drug Application to U.S. FDA for Simeprevir (TMC435) for Combination Treatment of Adult Patients with Genotype 1 Chronic Hepatitis C http://www.natap.org/2013/HCV/033013_01.htm

Janssen HCV Drug Research & Development - (07/30/13)

Janssen HCV Drug Research & Development 2 - (08/19/13)

The Pharmacokinetic Interactions of HCV Protease Inhibitor TMC435 with Rilpivirine, Tenofovir, Efavirenz or Raltegravir in Healthy Volunteers http://www.natap.org/2012/CROI/croi_05.htm

CROI: Simeprevir (TMC435) with peginterferon/ribavirin in patients co-infected with chronic genotype-1 HCV and HIV-1: Week-24 interim analysis of the TMC435-C212 study - (03/07/13)

COSMOS Study SVR4 results of a once daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype 1 null responders - (03/06/13)

CROI: First interim results from a phase IIa study evaluating an all-oral regimen of Simeprevir and Sofosbuvir in prior null responder Hepatitis C patients - press release - (03/04/13) press announcement

Primary Efficacy and Safety Findings from Four Phase 3 Japanese Studies of Simeprevir Administered Once Daily Demonstrate Sustained Virologic Response in Genotype 1 Chronic Hepatitis C Adult Patients http://www.natap.org/2013/HCV/062313_04.htm

Rapid HCV-RNA Decline With Once Daily TMC435: A Phase I Study in Healthy Volunteers and Hepatitis C Patients http://www.natap.org/2010/HCV/031110_01.htm

Pharmacokinetics of simeprevir (TMC435) in volunteers with moderate or severe hepatic impairment http://www.natap.org/2013/EASL/EASL_65.htm

Virologic analysis of genotype-1-infected patients treated with once-daily TMC435 during the Optimal Protease inhibitor Enhancement of Response to TherApy (OPERA)-1 study http://www.natap.org/2010/AASLD/AASLD_45.htm

Medivir announces TMC435 in an expanded clinical collaboration: TMC435+BMS NS5A, TMC435+INX189 http://www.natap.org/2012/HCV/053012_01.htm

BMS/Medivir Announces TMC435 in an Expanded Clinical Collaboration - press release http://www.natap.org/2012/HCV/041812_01.htm

The Pharmacokinetic Interactions of the HCV Protease Inhibitor Simeprevir (TMC435) With HIV Antiretroviral Agents in Healthy Volunteers http://www.natap.org/2012/IDSA/IDSA_04.htm

No clinically significant interaction between the investigational HCV protease inhibitor simeprevir (TMC435) and the immunosuppressive agents cyclosporine and tacrolimus http://www.natap.org/2012/AASLD/AASLD_61.htm

TMC435 & Drug Interactions: Evaluation of metabolic interactions for TMC435 via cytochrome P450 (CYP) enzymes in healthy volunteers http://www.natap.org/2010/EASL/EASL_37.htm

TMC435+GS7977 (Rbv) New Study in Advanced Hepatic Fibrosis- Null Responders & Naives http://www.natap.org/2013/HCV/012213_03.htm

TMC435 in patients infected with HCV genotype 1 who have failed previous pegylated interferon / ribavirin treatment: Virologic analyses of the ASPIRE trial http://www.natap.org/2012/EASL/EASL_25.htm

Treatment outcome and resistance analysis in HCV genotype 1 patients previously exposed to TMC435 monotherapy and re-treated with TMC435 in combination with PegIFNa-2a/ribavirin http://www.natap.org/2011/EASL/EASL_75.htm

Pharmacokinetic-pharmacodynamic (PK-PD) analyses of TMC435 in treatment-na•ve hepatitis C (HCV)-infected patients in the OPERA-1 study http://www.natap.org/2010/EASL/EASL_33.htm

Pharmacokinetics of TMC435 in subjects with moderate hepatic impairment http://www.natap.org/2011/EASL/EASL_115.htm

Phase II all-oral combination studies of Simeprevir (TMC435), TMC647055 (non nuc polymerase inhibitor) and IDX719 (NS5A) for the treatment of Hepatitis C to be initiated shortly - 4 articles below http://www.natap.org/2013/HCV/013113_02.htm

No pharmacokinetic interaction between the investigational HCV protease inhibitor simeprevir (TMC435) and an oral contraceptive containing ethinylestradiol and norethindrone http://www.natap.org/2012/AASLD/AASLD_60.htm

Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2 to 6: TMC435-C202, a phase IIa, open-label study - Article in Press http://www.natap.org/2012/HCV/021312_02.htm

Samples from HCV Genotype-1 Patients Treated for 5 Days with TMC435 Monotherapy and Subsequently Re-treated with TMC435 in Combination with PegIFNα-2a/Ribavirin - slide talk http://www.natap.org/2010/HCV/061410_01.htm

Hepascore predictive of mortality, morbidity in chronic HCV

Provided by Healio

Chinnaratha MA. Liver Int. 2013;doi:10.1111/liv.12306.

August 20, 2013

Hepascore, a noninvasive measurement of liver fibrosis, was similarly accurate to liver biopsy in predicting mortality and liver-related morbidity among patients with chronic hepatitis C in a recent study.

Researchers evaluated 406 patients with chronic hepatitis C (CHC) during a mean follow-up of 5.9 years. Hepascore, calculated from levels of hyaluronic acid, alpha-2-macroglobulin, bilirubin and gamma glutamyltransferase, was measured in all patients. FIB-4 and aspartate aminotransferase/platelet ratio index (APRI) values were determined in 216 cases, and 148 patients underwent liver biopsy. Patients with Hepascores greater than 0.5 were considered to have significant fibrosis.

Thirty-one percent of patients had significant fibrosis, and 15% had cirrhosis according to Hepascore, compared with 15% and 10%, respectively, according to APRI. Among those who underwent liver biopsy, 49% had significant fibrosis, and 11% had cirrhosis. Hepascore and fibrosis score were significantly correlated among these patients (r=0.53, P<.001).

Twenty-two patients (5.4%) died during follow-up, including 10 from liver-related causes, and four patients who required liver transplantation. Hepascore was predictive of overall survival (HR=24.4; 95% CI, 5.8-102), and significant fibrosis as indicated by Hepascore was associated with liver-related (HR=32.8; 95% CI, 4.3-250) and overall mortality (HR=6.7; 95% CI, 2.6-17.1), while FIB-4 and APRI were not.

AUROC analysis indicated that liver biopsy and Hepascore were similarly predictive of liver-related death (AUROC=0.87; 95% CI, 0.79-0.96 for biopsy; AUROC=0.86; 95% CI, 0.8-0.9 for Hepascore). Investigators said patients with a Hepascore below 0.5 had a 99% probability of no liver-related death within 5 and 10 years.

Liver decompensation occurred in 3.9% of the cohort. Hepascore (HR=27; 95% CI, 5.3-142) and fibrosis stage according to biopsy (HR=3.1; 95% CI, 1.8-5.3) were associated with risk for liver-related morbidity. No association was observed with FIB-4 or APRI.

“Hepascore independently predicted overall and liver-related mortality and liver-related morbidity in patients with CHC and is comparable to liver biopsy,” the researchers concluded. “Hepascore is noninvasive, inexpensive and can be repeated over time to monitor patients. Thus, Hepascore could be incorporated into the management algorithm of CHC patients as a prognostic tool.”

Disclosure: Researchers Gary Jeffrey, Enricco Rossi and Leon Adams are co-proprietors for the Australian Patent for Hepascore. University of Western Australia and PathWest, which employ the researchers, hold a licensing agreement for Hepascore with Quest Diagnostics.

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