November 22, 2013

New in January 2014: Clinical Guidance for Hepatitis C

The AASLD/IDSA Clinical Guidance for Hepatitis C

Background
AASLD and the Infectious Diseases Society of America (IDSA) have initiated a joint-society effort to establish a consensus and dynamic HCV guideline and will partner with the International Antiviral Society-USA (IAS-USA) in this effort. IAS-USA is a not-for-profit educational organization that has provided state-of-the-art, balanced CME and published respected clinical guidelines for two decades. IAS-USA will provide structure (project management) and coordination as well as web development for the recommendations and their dissemination. Representatives from other societies with an interest in hepatitis C management (e.g. AGA, CDC) may designate a liaison already within the writing groups, with the approval of the chairs and vetting group.

The guidelines will be updated in a timely manner as developments in the field evolve rapidly over the next several years. Although the guideline will be published in HEPATOLOGY and Clinical Infectious Diseases in alternate years, frequent updates will appear online and be announced in the AASLD eNews. The target for the first edition of the guideline is January 2014.

Five chairs (two AASLD, two IDSA, and one IAS-USA) have been appointed from each society for a term of three to five years; one of whom from each society has no conflicts of interest.

AASLD: Donald Jensen, MD and Gary Davis, MD  
IDSA: David Thomas, MD and Henry Masur, MD  
IAS-USA: Michael Saag, MD     

The chairs will oversee the entire process of recommendation development and offer leadership in maintaining effective timelines and scientific credibility. The writing group is comprised of ten members each from AASLD and IDSA who are recognized as experienced experts in the field. The Institute of Medicine recommendation that at least 51 percent of writing group members be “non-conflicted” was adopted in principle. The GRADE system, commonly used for guideline development, was not felt to be suitable in this case as it would likely slow down the process in the rapidly evolving field and would delay the provision of timely and urgently needed guidance. Rather, the AASLD rating system used in the updated hepatitis C guideline published in 2011 will be used as the rating system for the quality of the evidence and strength of the recommendations.

Both the AASLD Governing Board and the IDSA Board of Directors have stated a commitment to generously fund this endeavor for three years, with terms for renewal as needed. This commitment will provide the necessary resources for the representatives of the respective societies to succeed in performing this important work and providing effective clinical guidance to clinicians who treat HCV.

Summary

The development of comprehensive HCV practice recommendations from two lead societies who are both highly regarded will be an important step in patient care management as numerous new therapeutic options become available. The web-based system, which has previously been so successful in HIV guidance, will ensure that the recommendations are both rapid and nimble to these changes. This system should prove to be highly valuable to providers, payers, and industry.

Source

International Journal for Equity in Health 2013, 12:92  doi:10.1186/1475-9276-12-92

Research

Julie Hepworth, Tanya Bain and Mieke van Driel

Author Affiliations

For all author emails, please log on.

Published: 18 November 2013

Abstract (provisional)

Introduction

Access to hepatitis C (hereafter HCV) antiviral therapy has commonly excluded populations with mental health and substance use disorders because they were considered as having contraindications to treatment, particularly due to the neuropsychiatric effects of interferon that can occur in some patients. In this review we examined access to HCV interferon antiviral therapy by populations with mental health and substance use problems to identify the evidence and reasons for exclusion.

Methods

We searched the following major electronic databases for relevant articles: PsycINFO, Medline, CINAHL, Scopus, Google Scholar. The inclusion criteria comprised studies of adults aged 18 years and older, peer-reviewed articles, date range of (2002--2012) to include articles since the introduction of pegylated interferon with ribarvirin, and English language. The exclusion criteria included articles about HCV populations with medical co-morbidities, such as hepatitis B (hereafter HBV) and human immunodeficiency virus (hereafter HIV), because the clinical treatment, pathways and psychosocial morbidity differ from populations with only HCV. We identified 182 articles, and of these 13 met the eligibility criteria. Using an approach of systematic narrative review we identified major themes in the literature.

Results

Three main themes were identified including: (1) pre-treatment and preparation for antiviral therapy, (2) adherence and treatment completion, and (3) clinical outcomes. Each of these themes was critically discussed in terms of access by patients with mental health and substance use co-morbidities demonstrating that current research evidence clearly demonstrates that people with HCV, mental health and substance use co-morbidities have similar clinical outcomes to those without these co-morbidities.

Conclusions

While research evidence is largely supportive of increased access to interferon by people with HCV, mental health and substance use co-morbidities, there is substantial further work required to translate evidence into clinical practice. Further to this, we conclude that a reconsideration of the appropriateness of the tertiary health service model of care for interferon management is required and exploration of the potential for increased HCV care in primary health care settings.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

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Gilead and GSK drugs for HCV and HIV win EU green light

LONDON Fri Nov 22, 2013 12:13pm EST

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The GlaxoSmithKline building is pictured in Hounslow, west London June 18, 2013.

CREDIT: REUTERS/LUKE MACGREGOR

(Reuters) - European regulators have recommended approval of a new drug from Gilead Sciences to treat hepatitis C and an HIV medicine from GlaxoSmithKline, both of which are expected to be major sellers.

The European Medicine Agency (EMA) said on Friday its committee of experts also gave the green light to a tuberculosis drug from Japan's Otsuka, following a review of an earlier rejection.

Recommendations for marketing approval by the EMA's Committee for Medicinal Products for Human Use (CHMP) are normally endorsed by the European Commission within a couple of months.

Analysts expect U.S.-based Gilead's sales to surge higher next year on the back of its treatment known as Sovaldi, or sofosbuvir, for people infected with the liver-destroying hepatitis C virus (HCV). The all-tablet treatment obviates the need for the injectable drug interferon, which can cause debilitating side effects.

Investors see the treatment as the crown jewel of Gilead's $11 billion purchase ofbiotechnology company Pharmasset and the market is expecting substantial revenues.

Shares in Gilead were up 4.4 percent at 11.32 a.m. EST following news of the European recommendation.

Analysts on average expect Gilead's drug to generate sales of $4.4 billion in 2015, according to Thomson Reuters Pharma.

The often-undiagnosed hepatitis C virus is transmitted through contaminated blood. While infection rates have dropped since the early 1990s - due in part to the introduction of blood and organ screening - many older adults remain at risk.

Two new antiviral drugs, Incivek from Vertex Pharmaceuticals and Victrelis from Merck & Co, have cured more HCV patients in recent years, but both are protease inhibitors and are still used in combination with injections.

Sovaldi was recommended by an expert advisory committee of the U.S. Food and Drug Administration last month and a final decision from the FDA is expected by December 8.

GSK's Tivicay, or dolutegravir, is also forecast to be a significant new product for the British drugmaker. It will be sold through the ViiV Healthcare business, in which GSK is the biggest shareholder, alongside Pfizer and Shionogi.

The once-daily drug belongs to a novel class known as integrase inhibitors that block the HIV virus from entering cells, and is designed to be used in combination with other HIV drugs. Consensus forecasts point to sales of $1.6 billion by 2018. GSK shares were up 0.18 percent.

In addition, the European agency recommended approval of a new two-in-one diabetes drug called Xigduo from Bristol-Myers Squibb and AstraZeneca.

(Reporting by Ben Hirschler; Editing by Kate Kelland and Mark Trevelyan)

Source

Progression of Liver Disease in Children with Chronic HCV Infection

Provided by NEJM Journal Watch

November 21, 2013

Atif Zaman, MD, MPH reviewing Mohan P et al. Hepatology 2013 Nov.

Histologic changes were slow overall but did include a significant increase in bridging fibrosis or cirrhosis.

The rate of liver disease progression with hepatitis C virus (HCV) infection is well characterized in adults but not in children. Although most study data from Asia and Europe suggest that liver disease progression in children with HCV infection is very slow, data from several U.S. studies indicate that it is still a risk.

In the current retrospective study, investigators compared histologic findings from repeat biopsies in 44 treatment-naive children with HCV infection who were enrolled in a larger randomized treatment trial. Data were from two biopsies taken at least 1 year apart (mean time interval, 5.8±3.5 years). HCV infection was contracted via vertical transmission in 57% of children and via blood transfusion in the rest (except for 2 participants with unknown mode of transmission). The prevalence of genotype 1 infection was 84%.

Analyses of the repeat biopsies showed the following:

  • Persistent minimal inflammation in 50% of patients

  • Persistent absence of fibrosis in 16% of patients

  • An increase in bridging fibrosis or cirrhosis from 11% to 20% (P=0.005)

  • No correlation between worsening fibrosis and mode of HCV infection acquisition or demographic, clinical, or laboratory variables

Comment

    This is the largest study to date evaluating the histologic progression of hepatitis C virus infection in the pediatric population. In general, histologic progression was quite slow during a 5-year time span in the majority of patients, but, similar to the adult population, a significant minority did have histologic progression. With the advent of more-effective, better-tolerated treatment regimens for HCV infection, considering HCV treatment in the pediatric population will be important, as these patients face many decades of infection and increased risk for histologic progression without treatment.

    Disclosures for Atif Zaman, MD, MPH at time of publication Speaker’s bureau Bristol-Myers Squibb; Genentech; Gilead; Kadmon; Merck; Salix; Vertex

    Citation(s):

    1. Mohan P et al. Evaluating progression of liver disease from repeat liver biopsies in children with chronic hepatitis C: A retrospective study. Hepatology 2013 Nov; 58:1580. (http://dx.doi.org/10.1002/hep.26519)

Source

Jerome Alex: Where to start? At my birth.

Jerome Alex

Where to start? At my birth.

I was born in MIami Beach of RH-Factor opposing parents who were not supposed to have kids.
They did, 3 of us, all girls. All born with defects and challenges.

Judith is now gone, lost to a horrific cancer that was activated by the sun- melanoma. Janice, who lived with epilepsy for the first 7 years- her teeth are still gray, she is still here and doing fine. Me- well- I just had to have all my blood immediately exchanged or I would die. I was among the first kids to get this procedure in 1953, it was the first year they could do this, and woah! Live I did- but I had many allergies and illnesses as a child. I guess it was nip and tuck. But I am a survivor! And a thriver, I have always had determination- perhaps a small lack of good direction, but I was determined!

I since discovered that HCV came over in tainted blood product from the Koreas, SW Asia is a huge viral vector point. After the Korean war, that was the blood product we purchased for transfusions because our supply was gone after WW2- Did I get some of that? Who knows? I like to think I am connected to some mysterious being, who in some way was my parent too.

From early childhood until my teen years I had several surgeries and I now think my mom might have had hep c! She died of complication from cirrhosis and possible HCC. With the lousy health care she had who knows? She was a shining light to me, though, as she quit drinking in 1980 and we got to have many more years together after I quit.

In my early teens I ran away from home and I did use the needle for the first time- I have to say I did not like it, so that was not a problem for me- but one dabble is enough, right?

I began to play in bands and started a tee-shirt printing company in 1979 and to afford my passion- music! I had to have money to pay for all my equipment- that hasn't changed much! I've always been self (un)employed. LOL

In 1991, I was saved from the demons alcohol and drugs, both my parents and most of my relatives are addicts of one kind or another. And I do mean saved- after a rough night with a suicidal friend I awoke the next day with all desire to use gone, gone, gone. For over 20 years I had used drugs and liquor to ease the pain I grew up with due to divorce, rapes, child abuse and having a genius of sorts with no healthy outlet. My dad was a rocket scientist and I was surrounded with all manner of incredible, cutting-edge science, math, astronaughts and motion. We never lived anywhere for more than a year until we moved to Texas in 1966. So you can see, this life I was given was a consortium of wild and crazy, so what were a few hits of LSD or better yet, cocaine and more cocaine?

I have now been clean and sober for over 23 years and I thank God every day that He bent down and pulled me out of that. I really do not think I did it on my own, but I imagine I was ready. This is all leading up to something: when I tell people I have the hep c, & they ask me, "How did you get it"? I can honestly say I don't know. Out of the top 6 risk factors, I guess i was exposed to them all, so who knows, who will ever know, and I don' think it matters now.

All that matters is that I advocate for others to avoid the mistakes I made and to live a healthy life. As another contributor noted, it takes a lot of my time just to stay above water- but more on that next time! There's more to share, but my focus wavers~

Healing, peace and strength to you all,
Ja

Also See: Jerome Alex: Where to start? At my birth … Part 2

OLYSIO™ is the first once-daily protease inhibitor approved for the treatment of chronic hepatitis C in a combination antiviral regimen for adults with compensated liver disease

TITUSVILLE, N.J., Nov. 22, 2013 /PRNewswire/ -- Janssen Therapeutics, Division of Janssen Products, LP (Janssen), announced today the U.S. Food and Drug Administration (FDA) has approved OLYSIO (simeprevir), an NS3/4A protease inhibitor, for the treatment of chronic hepatitis C infection as part of an antiviral treatment regimen in combination with pegylated interferon and ribavirin in genotype 1 infected adults with compensated liver disease, including cirrhosis. OLYSIOmay benefit patients with chronic hepatitis C, including those who are treatment naive or who have failed prior interferon-based therapy.

Chronic hepatitis C is a blood-borne infectious disease of the liver that affects approximately 3.2 million people in the United States.

OLYSIO works by blocking the viral protease enzyme that enables the hepatitis C virus (HCV) to replicate in host cells. The goal of treatment for chronic hepatitis C is cure, also known as sustained virologic response (SVR), which is defined as undetectable levels of HCV in the patients' blood 12 to 24 weeks after the end of treatment. For treatment-naive and prior-relapser patients, a fixed treatment regimen of 12 weeks of OLYSIO combined with 24 weeks of pegylated interferon and ribavirin is recommended. For prior partial- and null-responder patients, a treatment regimen of 12 weeks of OLYSIOcombined with 48 weeks of pegylated interferon and ribavirin is recommended.

"Given the complexity of the condition, OLYSIO was studied in a number of different patient populations, including individuals who have relapsed or failed to respond to previous treatments," said Douglas Dieterich, M.D., Professor of Medicine in the Division of Liver Diseases, Mount Sinai School of Medicine, and OLYSIO clinical trial investigator. "The FDA approval of OLYSIO is an important milestone for people living with chronic hepatitis C as it means that patients have a new treatment option with the potential to cure this challenging disease."

OLYSIO is a prescription medicine used with other antiviral medicines, pegylated interferon and ribavirin, to treat genotype 1 chronic hepatitis C in adults with stable liver problems. OLYSIO must not be taken alone. The efficacy of OLYSIO in combination with peginterferon and ribavirin is greatly decreased in patients who have genotype 1a Q80K. Please talk to your doctor about testing for genotype 1a Q80K and using a different therapy when genotype 1a Q80K is present. It is not known if OLYSIO is safe and effective in children under 18 years of age.

The New Drug Application (NDA) filed by Janssen Research & Development, LLC, for OLYSIO was based in part on efficacy and safety results from three pivotal Phase 3 studies – QUEST-1 and QUEST-2 in treatment-naive patients and PROMISE in patients who have relapsed after prior interferon-based treatment – as well as data from the Phase 2b ASPIRE study in prior non-responder patients. Each of the studies evaluated OLYSIO dosed once daily in combination with pegylated interferon and ribavirin versus treatment with placebo plus pegylated interferon and ribavirin.

Results from a pooled analysis of QUEST-1 and QUEST-2 demonstrated that 80 percent of treatment-naive patients in the group receiving OLYSIO achieved sustained virologic response 12 weeks after the end of treatment (SVR12), compared with 50 percent of patients in the placebo groups. In PROMISE, 79 percent of prior-relapser patients in the simeprevir group of the study achieved SVR12 compared with 37 percent of patients in the placebo group. Results from ASPIRE demonstrated that use of OLYSIO led to sustained virologic response 24 weeks after the end of treatment (SVR24) in 65 percent of prior partial-responder patients and 53 percent of prior-null responder patients compared with 9 percent and 19 percent of prior partial- and null-responder patients in the placebo groups, respectively.

In the QUEST-1 and QUEST-2 studies, among genotype 1a treatment-naive patients receiving OLYSIO who had the Q80K polymorphism (a naturally occurring variation in the HCV NS3/4A protease enzyme), 58 percent achieved SVR12 versus 84 percent of patients without the Q80K polymorphism. In the placebo arm, 52 percent of patients with the Q80K polymorphism achieved SVR12. In the PROMISE study, among prior-relapser patients with the Q80K polymorphism who received OLYSIO, 47 percent achieved SVR12 versus 78 percent of patients without the polymorphism. In the placebo arm, 30 percent of patients with the Q80K polymorphism achieved SVR12.

"As an advocate working with the hepatitis C community, I'm pleased to know that Janssen has been working to make sure OLYSIO will be reasonably priced and available to the patients who need it," said Sue Simon, President of the Hepatitis C Association. "It is notable that in addition to introducing a new treatment option for patients, Janssen is establishing comprehensive programs to support and assist patients in their treatment journey."

Janssen has launched OLYSIOSupport, a comprehensive support program designed in partnership with the HCV community to assist in the hepatitis C treatment journey so that patients and caregivers – and their healthcare providers – can focus on treatment. To register for OLYSIOSupport or for additional information, please visit OLYSIO.com.

About OLYSIO (simeprevir)
OLYSIO (simeprevir) is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB and indicated in the U.S. for the treatment chronic hepatitis C infection in combination with pegylated interferon and ribavirin in HCV genotype 1 infected subjects with compensated liver disease, including cirrhosis.

Janssen is responsible for the global clinical development of OLYSIO and has exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB will retain marketing rights for OLYSIO in these countries under the marketing authorization held by Janssen-Cilag International NV. The treatment was approved in September 2013 in Japan under the trade name SOVRIAD and in November 2013 in Canada under the trade name GALEXOS for the treatment of genotype 1 hepatitis C. A Marketing Authorisation Application was submitted to the European Medicines Agency (EMA) in April 2013 by Janssen-Cilag International NV seeking approval of OLYSIO for the treatment of genotype 1 or genotype 4 chronic hepatitis C. To date, more than 3,700 patients have been treated with OLYSIO in clinical trials.

For additional information about OLYSIO, please visit www.OLYSIO.com

Important Safety Information
What is OLYSIO?

  • OLYSIO (simeprevir) is a prescription medicine used with other antiviral medicines, peginterferon alfa and ribavirin, to treat genotype 1 chronic (lasting a long time) hepatitis C in adults with stable liver problems.
  • OLYSIO must not be taken alone. The efficacy of OLYSIO in combination with peginterferon and ribavirin is greatly decreased in patients who have genotype 1a Q80K.   Please talk to your doctor about testing for genotype 1a Q80K and using a different therapy when genotype 1a Q80K is present.
  • It is not known if OLYSIO is safe and effective in children under 18 years of age.

IMPORTANT SAFETY INFORMATION

What is the most important information I should know and who should not take OLYSIO?

  • OLYSIO, in combination with peginterferon alfa and ribavirin may cause birth defects or death of your unborn baby. If you are pregnant or your sexual partner is pregnant, or plans to become pregnant, do not take these medicines. You or your sexual partner should not become pregnant while taking OLYSIO with peginterferon alfa and ribavirin and for 6 months after treatment is over.
    • Females and males must use two effective forms of birth control during treatment and for 6 months after treatment with OLYSIO, peginterferon alfa, and ribavirin combination therapy. Talk to your healthcare provider about forms of birth control that may be used during this time.
    • Females must have a pregnancy test before starting treatment with OLYSIO, peginterferon alfa, and ribavirin combination therapy, every month while being treated, and every month for 6 months after your treatment with OLYSIO, peginterferon alfa, and ribavirin combination therapy is over.
    • If you or your female sexual partner becomes pregnant while taking OLYSIO, peginterferon alfa, and ribavirin combination therapy or within 6 months after you stop taking these medicines, tell your healthcare provider right away. You or your healthcare provider should contact the Ribavirin Pregnancy Registry by calling 1-800-593-2214. The Ribavirin Pregnancy Registry collects information about what happens to mothers and their babies if the mother takes ribavirin while she is pregnant.
  • OLYSIO in combination with peginterferon alfa and ribavirin may cause rashes and skin reactions to sunlight. These rashes and skin reactions to sunlight can be severe and you may need to be treated in a hospital. Rashes and skin reactions to sunlight are most common during the first 4 weeks of treatment, but can happen at any time during treatment with OLYSIO, peginterferon alfa, and ribavirin combination therapy.
    • Use sunscreen, and wear a hat, sunglasses, and protective clothing when you will be exposed to sunlight during treatment with OLYSIO.
    • Limit sunlight exposure during treatment with OLYSIO.
    • Avoid use of tanning beds, sunlamps, or other types of light therapy during treatment with OLYSIO.
    • Call your healthcare provider right away if you get any of the following symptoms:
      • burning, redness, swelling or blisters on your skin
      • mouth sores or ulcers
      • red or inflamed eyes, like "pink eye" (conjunctivitis)
  • Do not take OLYSIO alone. OLYSIO should be used together with peginterferon alfa and ribavirin to treat chronic hepatitis C infection.

What should I tell my healthcare provider before taking OLYSIO?

  • Before taking OLYSIO, tell your healthcare provider if you:
    • have liver problems other than hepatitis C virus infection
    • have taken the medicines telaprevir (Incivek®) or boceprevir (Victrelis®)
    • had a liver transplant
    • are receiving phototherapy
    • have any other medical condition
    • are of East Asian descent
    • are breastfeeding. It is not known if OLYSIO passes into your breast milk. You and your healthcare provider should decide if you will take OLYSIO or breastfeed. You should not do both.
  • Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
  • OLYSIO and other medicines may affect each other. This can cause you to have too much or not enough OLYSIO or other medicines in your body, which may affect the way OLYSIO or your other medicines work, or may cause side effects. Do not start taking a new medicine without telling your healthcare provider or pharmacist.
  • Especially tell your healthcare provider if you take any of the following medicines: amiodarone (Cordarone®, Pacerone®), amlodipine (Norvasc®), atazanavir (Reyataz®), atorvastatin (Lipitor®, Caduet®), carbamazepine (Carbatrol®, Epitol®, Equetro®, Tegretol®), cisapride (Propulsid®, Propulsid Quicksolv®), clarithromycin (Biaxin®, Prevpac®), cobicistat-containing medicine: (Stribild®), cyclosporine (Gengraf®, Neoral®, Sandimmune®), darunavir (Prezista®), delavirdine mesylate (Rescriptor®), dexamethasone (when administered by injection or when taken by mouth), digoxin (Lanoxin®),  diltiazem (Cardizem®, Dilacor XR®, Tiazac®), disopyramide (Norpace®), efavirenz (Sustiva®, Atripla®),  erythromycin (E.E.S.®, Eryc®, Ery-Tab®, Erythrocin®, Erythrocin Stearate®), etravirine (Intelence®), felodipine (Plendil®), flecainide (Tambocor®), fluconazole (when taken by mouth or when administered by injection) (Diflucan®), fosamprenavir (Lexiva®), indinavir (Crixivan®), itraconazole (when taken by mouth) (Sporanox®, Onmel®), ketoconazole (when taken by mouth) (Nizoral®), lopinavir (Kaletra®), lovastatin (Advicor®, Altoprev®, Mevacor®), mexiletine (Mexitil®), midazolam (when taken by mouth), milk thistle (Silybum marianum) or products containing milk thistle, nelfinavir (Viracept®), nevirapine (Viramune®, Viramune XR®), nicardipine (Cardene®),  nifedipine (Adalat CC®, Afeditab CR®, Procardia®), nisoldipine (Sular®), oxcarbazepine (Trileptal®), phenobarbital (Luminal®),  phenytoin (Dilantin®, Phenytek®), pitavastatin (Livalo®),  posaconazole (when taken by mouth) (Noxafil®), pravastatin (Pravachol®), propafenone (Rythmol SR®), quinidine (Nuedexta®, Duraquin®, Quinaglute®), rifabutin (Mycobutin®), rifampin (Rifadin®, Rifamate®, Rifater®), rifapentine (Priftin®), ritonavir (Norvir®), rosuvastatin (Crestor®),  saquinavir mesylate (Invirase®), sildenafil (Revatio®, Viagra®),  simvastatin (Zocor®, Vytorin®, Simcor®), sirolimus (Rapamune®), St. John's wort (Hypericum perforatum) or products containing St. John's wort,  tacrolimus (Prograf®), tadalafil (Adcirca®, Cialis®),  telithromycin (Ketek®), tipranavir (Aptivus®),  triazolam (when taken by mouth) (Halcion®),  verapamil (Calan®, Covera-HS®, Isoptin®, Tarka®), voriconazole (when taken by mouth or when administered by injection) (Vfend®),  warfarin (Coumadin®)
  • This is not a complete list of medicines that could interact with OLYSIO. Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above.
  • Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

What are the most common side effects of OLYSIO?

  • The most common side effects of OLYSIO when used in combination with peginterferon alfa and ribavirin include skin rash, itching, nausea.
  • Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
  • These are not all of the possible side effects of OLYSIO. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

About Janssen Therapeutics
At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in hepatitis C, HIV and other infectious diseases. Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world. Headquartered in Titusville, New Jersey, Janssen Therapeutics, Division of Janssen Products, LP, is one of the Janssen Pharmaceutical Companies of Johnson & Johnson. Visitwww.JanssenTherapeutics.com for more information and follow us on Twitter at @JanssenUS.

(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995.  The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events.  If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Therapeutics, Inc. and/or Johnson & Johnson.  Risks and uncertainties include, but are not limited to, general industry conditions and competition; economic factors, such as interest rate and currency exchange rate fluctuations; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; challenges to patents; impact of business combinations; changes in behavior and spending patterns or financial distress of purchasers of health care products and services; changes to governmental laws and regulations and domestic and foreign health care reforms; trends toward health care cost containment; and increased scrutiny of the health care industry by government agencies.  A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 30, 2012.  Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson.  None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertake to update any forward-looking statements as a result of new information or future events or developments.)

NOTE: Janssen Therapeutics, Division of Janssen Products, LP, provides support to the Hepatitis C Association for initiatives benefitting individuals living with hepatitis C.

Media Contact: Craig Stoltz
Mobile: +1 (215) 325-3612

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SOURCE Janssen Therapeutics

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Also See: FDA approves new treatment for hepatitis C virus --- Simeprevir

FDA approves new treatment for hepatitis C virus --- Simeprevir

FDA NEWS RELEASE

For Immediate Release: Nov. 22, 2013
Media Inquiries: Stephanie Yao, 301-796-0394, stephanie.yao@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

FDA approves new treatment for hepatitis C virus

The U.S. Food and Drug Administration today approved Olysio (simeprevir), a new therapy to treat chronic hepatitis C virus infection.

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. Most people infected with the hepatitis C virus have no symptoms of the disease until liver damage becomes apparent, which may take several years. Most of these people then go on to develop chronic hepatitis C. Some will also develop scarring and poor liver function (cirrhosis) over many years, which can lead to complications such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in the abdomen, infections or liver cancer. According to the Centers for Disease Control and Prevention, about 3.2 million Americans are infected with the hepatitis C virus.

Olysio is a protease inhibitor that blocks a specific protein needed by the hepatitis C virus to replicate. It is to be used as a component of a combination antiviral treatment regimen. In clinical studies, Olysio was evaluated in combination with peginterferon-alfa and ribavirin, two drugs also used to treat hepatitis C virus infection. Olysio is intended for adults with compensated liver disease (a diseased liver that is still functioning), including cirrhosis, who have not received treatment for their infection (treatment naïve) or for whom previous treatment has not been effective (treatment experienced).

“Olysio is the third FDA-approved protease inhibitor to treat chronic hepatitis C virus infection, and provides health professionals and patients with a new, effective treatment for this serious disease,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

In 2011, the FDA approved Victrelis (boceprevir) and Incivek (telaprevir) for the treatment of hepatitis C. Olysio was reviewed under the FDA’s priority review program, which provides for an expedited review of drugs that, if approved, would provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to available therapies.

The safety and effectiveness of Olysio were evaluated in five clinical studies of 2,026 treatment-naive and treatment-experienced participants randomly assigned to receive Olysio plus peginterferon-alfa and ribavirin or placebo plus peginterferon-alfa and ribavirin. The studies were designed to measure whether a participant’s hepatitis C virus was no longer detected in the blood at least 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s infection had been cured.

Results showed 80 percent of treatment-naive participants given Olysio plus peginterferon-alfa and ribavirin achieved sustained virologic response, compared to 50 percent of participants receiving peginterferon-alfa and ribavirin alone. In one of the studies with treatment-experienced participants whose infection returned (prior relapsers), 79 percent receiving Olysio plus peginterferon-alfa and ribavirin achieved sustained virologic response compared to 37 percent of participants receiving peginterferon-alfa and ribavirin alone.

Another study examined Olysio’s safety and effectiveness in treatment-experienced participants, including prior relapsers, those who partially responded to prior therapy (partial responders) and those who did not respond to prior therapy (null responders). Adding Olysio improved response rates in each of these subgroups compared to peginterferon-alfa and ribavirin alone.

A reduction in Olysio’s effectiveness was observed in participants infected with the genotype 1a hepatitis C virus with an NS3 Q80K polymorphism, a strain of the hepatitis C virus commonly found in the United States. Olysio’s drug label includes a recommendation to screen for the presence of the strain prior to beginning therapy and to consider alternative therapy if the strain is detected.

The most common side effects reported in clinical study participants treated with Olysio in combination with peginterferon-alfa and ribavirin were rash (including photosensitivity), itching (pruritis) and nausea. Serious photosensitivity reactions resulting in hospitalization were reported. Patients will be advised to limit sun exposure and to use sun protective measures during treatment with Olysio in combination with peginterferon alfa and ribavirin. Olysio should not be used alone to treat chronic hepatitis C infection.

Olysio is marketed by Janssen Pharmaceuticals, based in Raritan, N.J. Victrelis is marketed by Whitehouse Station, N.J.-based Merck, and Incivek is marketed by Cambridge, Mass.-based Vertex Pharmaceuticals.

For more information:

FDA: Approved Drugs: Questions and Answers

FDA: Drug Innovation

FDA: What’s New at FDA in Hepatitis

CDC: Hepatitis C Information for the Public

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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Source FDA

Also See: OLYSIO™ (simeprevir) Receives FDA Approval for Combination Treatment of Chronic Hepatitis C – Press Release

21 November 2013
EMA/CHMP/687741/2013
Committee for Medicinal Products for Human Use (CHMP)

Summary of opinion1 (initial authorisation)

Sovaldi
sofosbuvir

On 21 November 2013, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Sovaldi, 400 mg, film-coated tablet intended for the treatment of chronic hepatitis C (CHC). The applicant for this medicinal product is Gilead Sciences International Ltd. They may request a re-examination of any CHMP opinion, provided they notify the European Medicines Agency in writing of their intention within 15 days of receipt of the opinion.

The active substance of Sovaldi is sofosbuvir, a direct acting antiviral (ATC code not yet assigned). The active metabolite of sofosbuvir is a pangenotypic inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase.

The benefits of Sovaldi used in combination with other medicinal products is its ability to inhibit viral replication in infected host cells which can lead to the eradication of the virus, correlating to a cure of chronic hepatitis C virus infection. Sovaldi provides the first interferon-free treatment option for chronic hepatitis C. In patients where interferon is still needed for efficacy, Sovaldi enables a shortened treatment duration compared to current standard-of-care. Furthermore, when used before liver transplantation, Sovaldi can prevent graft reinfection with HCV.

The most common side effects when Sovaldi is used in combination with ribavirin, or in combination with ribavirin and peginterferon alfa, were fatigue, headache, nausea and insomnia. The safety profile of Sovaldi in combination with ribavirin +/- peginterferon alfa was consistent with the expected safety profile of ribavirin and peginterferon alfa treatment, without increasing the frequency or severity of the expected adverse drug reactions.

A pharmacovigilance plan for Sovaldi will be implemented as part of the marketing authorisation.

The approved indication is: "Sovaldi is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults (see sections 4.2, 4.4 and 5.1). For hepatitis C virus (HCV) genotype specific activity, see sections 4.4 and 5.1".

1 Summaries of positive opinion are published without prejudice to the Commission decision, which will normally be issued 67 days from adoption of the opinion.

It is proposed that treatment with Sovaldi should be initiated and monitored by a physician experienced in the management of CHC.

Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.

The CHMP, on the basis of quality, safety and efficacy data submitted, considers there to be a favourable benefit-to-risk balance for Sovaldi and therefore recommends the granting of the marketing authorisation.

Source

Also See: European CHMP Adopts Positive Opinion for Gilead Sciences’ Sovaldi® for the Treatment of Chronic Hepatitis C Infection (Press Release Gilead)

European Medicines Agency recommends approval of sofosbuvir for the treatment of chronic hepatitis C (EMA Press Release)

FOSTER CITY, Calif.--(BUSINESS WIRE)--Nov. 22, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA), has adopted a positive opinion on the company’s Marketing Authorisation Application (MAA) for Sovaldi® (sofosbuvir 400 mg tablets), an investigational once-daily oral nucleotide analogue polymerase inhibitor for the treatment of chronic hepatitis C virus (HCV) infection in adults. The CHMP opinion supports the approval of Sovaldi for the treatment of HCV in combination with other agents. The CHMP’s recommendation will now be reviewed by the European Commission, which has the authority to approve medicines for use in the 28 countries of the European Union (EU).

Chronic HCV is a major cause of liver cancer and liver transplantation in Europe and around the world. The current standard of care for HCV involves up to 48 weeks of therapy with a pegylated interferon (peg-IFN)/ ribavirin (RBV)-containing regimen. These regimens are not always effective and are associated with significant side effects and contraindications with other medicines. Many HCV patients in Europe are not considered appropriate candidates for current treatment options.

The CHMP opinion was adopted following an accelerated review procedure, which is reserved for medicinal products that are expected to be of major public health interest. This assessment does not guarantee marketing authorisation by the European Commission. However, if approved, Sovaldi could be available in the EU in the first quarter of 2014.

The MAA for Sovaldi is supported primarily by data from four Phase 3 studies, NEUTRINO, FISSION, POSITRON and FUSION in which 12 or 16 weeks of Sovaldi-based therapy was found to be superior or non-inferior to currently available treatment options or historical controls, based on the proportion of patients who had a sustained virologic response (were HCV undetectable) 12 weeks after completing therapy (SVR12). Patients who achieve SVR12 are considered cured of HCV. During the European review, data from two additional Phase 3 studies, VALENCE and PHOTON-1 were filed to the MAA. In the VALENCE study, patients with genotype 3 HCV infection were treated with Sovaldi and RBV for 24 weeks. The PHOTON-1 study evaluated Sovaldi and RBV for 12 weeks in patients with genotype 2 HCV infection co-infected with HIV-1 and for 24 weeks in patients with genotypes 1 or 3 HCV co-infected with HIV-1. In all Phase 3 studies of Sovaldi, no viral resistance to the drug was detected among patients who relapsed following completion of therapy.

To date, nearly 3,000 patients have received at least one dose of Sovaldi in Phase 2 or 3 studies. Sovaldi was well tolerated in clinical studies. Adverse events were generally mild and there were few treatment discontinuations due to adverse events. The most common adverse events occurring in at least 10 percent of patients were consistent with the safety profiles of peg-IFN and RBV and included fatigue, headache, nausea, insomnia, dizziness, pruritis (severe itching) and anemia.

In the United States, an expert advisory committee of the U.S. Food and Drug Administration (FDA) voted unanimously (15-0) on October 25, 2013 that the available data support approval of sofosbuvir. A final decision from the FDA is anticipated by December 8, 2013.

Sovaldi is an investigational product and its safety and efficacy have not been established.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors, including the risk of unfavorable results from ongoing and subsequent clinical trials of Sovaldi for HCV. The European Commission, FDA and other regulatory agencies may not approve Sovaldi in the currently anticipated timelines or at all, and any marketing approvals, if granted, may have significant limitations on their use. As a result, Sovaldi may never be successfully commercialized. Further, Gilead may make a strategic decision to discontinue development of Sovaldi if, for example, Gilead believes commercialization will be difficult relative to other opportunities in its pipeline. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2013, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

Sovaldi is a registered trademark of Gilead Sciences, Inc.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936 (Investors)
Cara Miller, 650-522-1616 (Media, U.S.)
Sonia Choi, 609-213-6015 (Media, Europe)

Source

Also See: European Medicines Agency recommends approval of sofosbuvir for the treatment of chronic hepatitis C

Press Release

22/11/2013

First-in-class medicine provides the first interferon-free treatment option

The European Medicines Agency's Committee for Medicinal Products for Human use(CHMP) has recommended granting a marketing authorisation for Sovaldi (sofosbuvir), for use 'in combination with other medicinal products for the treatment of chronic (long-term) hepatitis C in adults'.

Hepatitis C virus (HCV) infection is a major European public-health challenge. It occurs in between 0.4% and 3.5% of the population in different European Union (EU) Member States.

The current standard of care includes a combination of the medicines pegylated interferon and ribavirin, with or without an inhibitor of the viral NS3/4A protease enzyme. However, interferon-based therapies are associated with potentially serious side effects, which are sometimes difficult to manage and also make a considerable proportion of HCV patients ineligible for therapy. This includes patients with very advanced liver disease, as well as patients with psychiatric diseases, autoimmune disorders, etc. For these patients, there is a very clear unmet medical need for new HCV treatment regimens.

The treatment of hepatitis C is a rapidly moving therapeutic area, with several new classes of direct-acting antivirals now in advanced stages of development. The European Medicines Agency is actively supporting the development of these new treatment options for patients through provision of scientific advice and drafting of guidance to developers of these medicines.

Sovaldi is the first representative of a new class of antivirals that act as inhibitors of an essential enzyme of HCV, the NS5B ribonucleic acid polymerase. This medicine provides the first interferon-free treatment option for chronic hepatitis C.

In clinical trials where sofosbuvir was used in combination with ribavirin alone, it has convincingly shown efficacy with a good safety profile. A high proportion of patients had no detectable virus in their blood 12 to 24 weeks after the end of the treatment and could therefore be considered to be cured of their hepatitis C virus infection.

Furthermore, when Sovaldi is used in combination with pegylated interferon as well as ribavirin, shortened treatment duration down to 12 weeks (compared to 24-48 weeks with the current standard of care) is possible and provides high efficacy. This is of value considering the side-effect profile of interferon.

New treatment option for HCV patients undergoing liver transplantation

HCV infection is the most common single cause of liver transplantation in the EU. However, patients who do undergo liver transplantation due to hepatitis C have a worse prognosis than patients who do so for other reasons, because recurrence of the virus in the graft is near-universal and often aggressive. For many of these patients, there are currently no approved treatment options that are likely to be effective.

In clinical trials, Sovaldi in combination with ribavirin has shown its capacity to prevent reinfection of the graft, and thus provides a treatment option for patients with HCV infection who are on the waiting list for liver transplantation.

Advice on compassionate use of sofosbuvir

During its October 2013 meeting, the CHMP gave an opinion on the conditions under which early access to sofosbuvir, in combination with other medicines, could be given in compassionate-use programmes, for patients with chronic hepatitis C infection before or after liver transplantation.

Such programmes, set up at the national level, are intended to give patients with a life-threatening, long-lasting or seriously disabling disease who have no available treatment options access to treatments that are still under development and that have not yet been authorised.

During its November meeting, the CHMP also provided an opinion on the use of a combination of sofosbuvir with the antiviral daclatasvir in certain patients with chronic hepatitis C virus (HCV) infection, in a compassionate-use programme.

Notes

  • The marketing-authorisation applicant for Sovaldi is Gilead.
  • More information on the CHMP opinion on the use of the combination of sofosbuvir and daclatasvir in a compassionate-use programme is available in a separate press release.

European Medicines Agency recommends approval of sofosbuvir for the treatment of chronic hepatitis C (PDF) (English only) 22/11/2013

Source

Vertex sells overseas rights to drug

By Chris Reidy  |  GLOBE STAFF  NOVEMBER 21, 2013

incivek-1030-8086007

VERTEX PHARMACEUTICALS INC.

Telaprevir sales have declined faster than Cambridge-based Vertex anticipated. A second-generation hepatitis C drug is in the works.

With it sights set on solving a different illness, Vertex Pharmaceuticals Inc., is selling off royalty rights to the sale of its hepatitis C treatment in overseas markets to the Belgian drug company Janssen Pharmaceutica NV for $152 million.

The royalty exchange is another sign of how fast Vertex is moving on from the drug, telaprevir, after sales of the treatment plummeted in the face of new competition.

While Vertex has a second-generation hepatitis C drug in the works, its new focus is developing a treatment for cystic fibrosis.

The money from Janssen will be used to advance its work on drugs for cystic fibrosis and other conditions, Vertex said in a statement.

Last month, the Cambridge biotech said it would cut 17 percent of its workforce, including 175 jobs in Massachusetts, and return $4.4 million in state tax incentives it had received for promising to create jobs, partly because of an unexpected drop in the sales of telaprevir.

Vertex is preparing to relocate from Cambridge to a gleaming new $800 million headquarters on the South Boston Waterfront, for which it received government tax subsidies.

Telaprevir is marketed under two brand names: as Incivek in North America and as Incivo in Europe and other markets. The deal with Janssen involves only the rights for Incivo. Vertex will continue to sell Incivek in North America.

Janssen will make a single $152 million cash payment to Vertex in the fourth quarter of 2013.

Under a 2006 collaboration, Janssen agreed to develop and commercialize the hepatitis C drug in Europe and elsewhere and to pay Vertex royalties on sales of the drug in those regions.

The Vertex drug has treated over 100,000 patients worldwide and generated more than $2 billion in sales since it was introduced in May 2011.

But in recent months, sales have been falling much faster than the company had anticipated, because doctors are encouraging patients to wait for a new generation of treatments that work better and are easier to take.

Chris Reidy can be reached at reidy@globe.com.

Source

Clinical Gastroenterology and Hepatology
Volume 11, Issue 12 , Pages 1661-1666.e3, December 2013

Lei Yu, Chihiro Morishima, George N. Ioannou

published online 28 May 2013.

Abstract

Background & Aims

Little is known about whether dietary cholesterol affects disease progression in patients with chronic hepatitis C virus infection.

Methods

We analyzed data from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial, which included patients with advanced fibrosis and compensated cirrhosis. Cholesterol intake was determined for 608 participants on the basis of responses to food frequency questionnaires, administered at baseline and 1.8 years later. We investigated whether cholesterol intake was associated with clinical progression (death, variceal bleeding, encephalopathy, ascites, peritonitis, Child–Turcotte–Pugh score ≥7, or hepatocellular carcinoma) or histologic progression of disease (an increase in Ishak fibrosis score of 2 or more points in a second liver biopsy compared with the first).

Results

After adjustments for age, sex, race, presence of cirrhosis, body mass index, treatment with peginterferon, lifetime alcohol consumption, smoking, health status, and coffee and macronutrient intake, each higher quartile of cholesterol intake was associated with a 46% increase in the risk of clinical or histologic progression (adjusted hazard ratio [AHR], 1.46; 95% confidence interval [CI], 1.13–1.87; P for the trend = .004). Compared with patients in the lowest quartile of cholesterol intake (32–152 mg/day), those in the 3rd (224–310 mg/day; AHR, 2.83; 95% CI, 1.45–5.51) and 4th quartiles (>310 mg/day; AHR, 2.74; 95% CI, 1.22–6.16) had significantly increased risk of disease progression.

Conclusions

On the basis of analysis of data from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial, higher dietary cholesterol intake is associated with higher risk of disease progression in HCV-infected patients with advanced fibrosis or compensated cirrhosis.

Keywords: Diet, Cholesterol, Hepatitis C, Cirrhosis

Abbreviations used in this paper: AHR, adjusted hazard ratio, BMI, body mass index, CI, confidence interval, CTP, Child–Turcotte–Pugh,FFQ, food frequency questionnaire, HALT-C, Hepatitis C Antiviral Long-term Treatment Against Cirrhosis, HCC, hepatocellular carcinoma,HCV, hepatitis C virus, MTP, microsomal triglyceride transfer protein, TLR, Toll-like receptor

Source

Simeprevir for the treatment of chronic hepatitis C

Drug Evaluations

Expert Opin Pharmacother. December 2013, Vol. 14, No. 18 , Pages 2581-2589 (doi:10.1517/14656566.2013.850074)

David M You 1 & Paul J Pockros 2,3

1 Naval Medical Center San Diego, Division of Gastroenterology, Department of the Navy, CA, USA

2 Scripps Clinic, Division of Gastroenterology/Hepatology, 10666 N. Torrey Pines Road, La Jolla, CA 92037, USApockros.paul@scrippshealth.org

3 Scripps Translational Science Institute, La Jolla, CA, USA

Introduction: The addition of protease inhibitors such as telaprevir and boceprevir with PEGylated interferon and ribavirin has significantly improved cure rates for genotype 1 hepatitis C virus (HCV) infection. Simeprevir (TMC435) is a second-generation protease inhibitor that is in development for the treatment of genotype 1 HCV infection.

Areas covered: The authors present: i) an overview of Phases I – III clinical trials of simeprevir for HCV infection based on peer-reviewed literature and congress presentations and ii) an evaluation of the efficacy and safety of simeprevir in the treatment of HCV infection.

Expert opinion: Simeprevir is a once-daily oral medication that combined with PEGylated interferon and ribavirin appears to be a potent and safe agent to treat genotype 1 HCV infection for patients who are treatment-naïve and prior treatment-failures. Compared to telaprevir and boceprevir, simeprevir will likely be the protease inhibitor of choice for genotype 1 HCV infection based on ease of use, lower rates of adverse events, including rash and anemia, and no significant reported drug–drug interactions. Associated side effects inherent with interferon-based regimens may be problematic for patients. As HCV therapies evolve into interferon-free regimens, simeprevir may potentially be combined with other oral direct-acting agents without interferon to treat HCV infection.

Keywords chronic hepatitis C, genotype 1, protease inhibitor, simeprevir, TMC435

Source

World J Virol 2013 November 12; 2(4): 139-145

Published online 2013 November 12. doi: 10.5501/wjv.v2.i4.139.

Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.

Paul J Rowan.

Paul J Rowan, Division of Management, Policy, and Community Health, University of Texas Health Sciences Center at Houston School of Public Health, Houston, TX 77030, United States

Author contributions: Rowan PJ solely contributed to this paper.

Correspondence to: Paul J Rowan, PhD, MPH, Division of Management, Policy, and Community Health, University of Texas Health Sciences Center at Houston School of Public Health, 1200 Herman Pressler Drive, Houston, TX 77030, United States. prowan@uth.tmc.edu

Telephone: +1-713-5009183 Fax: +1-713-5009181

Received April 25, 2013; Revised August 13, 2013; Accepted August 20, 2013;

Abstract

Depression is often a side effect of interferon-alpha treatment for hepatitis C, and is recognized as a cause for treatment discontinuation. When detected, antidepressant treatment begins promptly. In contrast to this rescue approach, prophylactic antidepressant treatment has been considered as a superior approach. While studies indicate that depression is lower with prophylaxis, no study has prospectively evaluated the degree that treatment completion might be boosted by the prophylactic strategy. A structured literature search was conducted to discover all trials of antidepressant prophylaxis for patients undergoing antiviral treatment for chronic hepatitis C. Selection criteria included: antidepressant prophylaxis study; report of depression treatment outcome; report of numbers discontinuing and reason for discontinuation (including any of the following: discontinuation data for medical side effects (i.e., thrombocytopenia); discontinuation due to lack of antiviral response; discontinuation due to lack of antidepressant effect; discontinuation due to antidepressant side effects; discontinuation due to patient preference; discontinuation due to loss to follow-up; or unspecified discontinuation). Across the studies, total enrollees were determined for the prophylaxis arms and the rescue arms, and then, again across studies, those discontinuing for reasons other than lack of antiviral response or medical side effect were summed for each of these two arms. Twelve studies were discovered. One was a retrospective chart review, one was an uncontrolled trial, and ten were controlled trials. Discontinuation of antiviral therapy was not less common in the prophylaxis arms: of the 396 patients treated by the prophylaxis strategy, 47 (11.9%) discontinued; of the 380 patients in the rescue strategy, 45 (11.8%) discontinued. While the prophylaxis strategy seems to manage depression symptoms, it does not seem to boost treatment completion. Rescue was a very successful strategy when indicated. While antidepressant prophylaxis has benefit in antiviral treatment, it should not generally be valued for boosting the likelihood of treatment completion.

Keywords: Depression, Therapy, Clinical, Psychiatry

Core tip: To inform clinical practice, this narrative review summarizes existing evidence regarding the degree that antidepressant prophylaxis boosts hepatitis C antiviral treatment completion compared to a rescue approach.

INTRODUCTION

Although pegylated interferon-alpha may provide a sustained viral response from chronic hepatitis C infection[1,2], this lengthy regimen is challenging to tolerate. Depressive symptoms, one of the more difficult side effects, can lead to discontinuation. Discontinuation rates for factors other than antiviral non-response range from 10% in well-conducted clinical trials[1,2] to 30% or more in clinical settings[3]. If depressive symptoms emerge, they must be clinically managed, including suspension of antiviral treatment as a last resort. Direct-acting antiviral agents may eventually supplant interferon-alpha/ribavirin regimens as standard of care[4], but interferon-alpha-based regimens have recently been re-affirmed as standards of care[5,6].

To reduce the threat of treatment-related depression, the idea of prophylactic depression treatment emerged[7]: when beginning interferon-alpha (and ribavirin) treatment, the patient would be started on an antidepressant with the goal of preventing, or attenuating, depressive symptoms. Initial case studies and case series noted success of this strategy. For example, antiviral treatment was restarted in a cohort of eight chronic hepatitis C patients who previously had discontinued due to emergent depressive episodes; all eight were able to fully complete the second course of treatment[8]. A precedent for this strategy was noting the success of antidepressant prophylaxis for interferon-alpha treatment of malignant melanoma[8,9].

Compared to prophylaxis, traditional practice can be termed “rescue” when depressive symptoms emerge in a patient undergoing antiviral treatment, depression treatment is quickly initiated so that those symptoms can be managed. The advantage to the prophylactic strategy is that depression and the threat of discontinuation can be avoided; the advantage to the rescue strategy is that patients are not unnecessarily treated, and so are not experiencing the additional treatment burden and side effects. Antidepressants may have quite adverse side effects in some patients, including retinal or gastroenterological bleeding[10,11]. Thus, clinicians are faced with a challenging clinical management strategy where risks and benefits must be considered.

Can prophylactic antidepressant treatment boost interferon-alpha treatment completion in patients with chronic hepatitis C virus (HCV)? No study has prospectively answered this question. This review has been conducted to discern an answer by reviewing antiviral therapy discontinuation data reported in trials evaluating the efficacy of antidepressant prophylaxis for managing depression. This review is presented in order to enhance the evidence available for clinical decision-making.

LITERATURE SEARCH

A Pubmed literature search was designed to discover trials that might have the data necessary to assess relative treatment completion between prophylaxis arms and control arms. A set of search terms was developed to capture studies relevant to hepatitis C. This included: “hepatitis”, “HCV”, “Hep C”, “Hep-C” and “chronic hepatitis C”. This was crossed with each of two other sets. The first was a set to capture depression-related studies: “depression”, “depressed”, “depressive”, “psychiatric”, “mental”. The other was a set to capture prophylactic strategies: “prophylaxis”, “prophylactic” or “prevention”.

From this search, all study titles would be reviewed to detect promising abstracts. All promising abstracts would be read, and likely studies would be pulled and assessed for necessary information. References of those studies would be checked manually.

The necessary information for selection into this review was established as the following: patients with chronic hepatitis C who were candidates for interferon-alpha treatment (whether including ribavirin or not, as this treatment strategy emerged as the prophylactic strategy emerged); recognized treatment regimen (i.e., interferon-alpha with ribavirin); no concurrent treatment such as for human immunodeficiency virus, since symptoms and treatment side effects would be significant confounders; at least two study arms where one included prophylactic treatment with an antidepressant, whether open-label or blinded, and the other is a control arm, whether placebo-controlled or not; sustained treatment of at least 8 wk in order to observe emergence of depressive symptoms from interferon-alpha and assess differential depression response between arms; and data on the numbers of patients in each arm that discontinued, or were lost to follow-up, for reasons other than medical side effects (thrombocytopenia, etc.) or non-response to antiviral therapy. Thus, the discontinuation group of focus would be those who medically could have completed treatment but discontinued for a reason other than a medical reason. To the degree that discontinuation reasons, such as psychiatric side effects, would be specifically reported, these would be tabulated and compared between the intervention-arm participants and the control-arm participants. The reporting of discontinuation for psychiatric reasons, specifically, was thus not an inclusion criterion.

For each eligible study, the number of patients discontinuing would be noted for each of the arms of the study. A descriptive analysis would be developed based on those results. The goal would be to describe the degree, if any, that antiviral treatment completion might be superior for the prophylactic strategy, compared side-by-side with the rescue strategy. Since the data sources for this study consisted of previously-published research studies, ethics approval for this narrative review was not sought from an institutional review board.

SEARCH RESULTS

For the “prophylaxis” search term set, “pretreatment” was soon discovered as a synonym, so this was added to that set. The “prophylaxis” set returned 1302661 abstracts; the “hepatitis C” set returned 184063 abstracts; and the “depression” set returned 869174 abstracts. The intersection of these three sets returned 419 abstracts. Titles of all were reviewed, leading to a set of 38 abstracts to review. This led to a set of 12 studies[8,12-23] in which the prophylactic strategy was evaluated, and discontinuation data were reported.

These studies are listed, with relevant study characteristics, in Table 1. All but one were prospective trials; one was a retrospective chart review study that composed a cohort of patients who were taking an antidepressant before the initiation of interferon-alpha treatment, and composed a control group of patients who required some kind of psychiatric treatment during interferon-alpha treatment. For the sake of completeness, this chart review study was included. One of the 12 studies (Gleason et al[20], 2007), among the first chronologically, did not have a control group; this study simply investigated treatment completion when a prophylactic strategy was trialed. This was included for completeness. For one study, the manuscript reporting the preliminary study design was available, and results have just recently been presented as a poster at a scientific conference; it is assumed that a more complete analysis will be forthcoming. For the sake of completeness, results based on this conference poster were included.

table-icon

Table 1 Study characteristics and discontinuation data: Antidepressant prophylaxis for interferon-alpha treatment of hepatitis C virus

Clinical Interventions

All studies were conducted in the era of prescribing ribavirin along with interferon-alpha. Nearly all were conducted in the era of pegylated interferon, with the exception of some of the earlier-initiated participants in the Morasco et al[21] (2007) and Raison et al[22] (2007) studies. Likewise, antidepressant dosages were normative, with typical strategies for increasing or augmenting dosage when clinically indicated, and typical medication switching strategies when clinically indicated. All studies used antidepressants from the selective serotonin re-uptake inhibitor class, including paroxetine (one study), paroxetine or citalopram (one study), citalopram (five studies), and escitalopram (four studies). This usage followed the pattern of Food and Drug Administration approval and clinical adoption of these drugs, with paroxetine favored in earlier studies, citalopram favored in the studies conducted in the middle of this time span, and escitalopram favored in later studies. A range of strategies were used to assess depression level before and during treatment. These generally included: standardized clinical interview, clinical interview, a depression questionnaire, or combination. In some studies, patients could be started on antiviral therapy even if some level of depressive symptoms was present.

Clinical outcomes

The overwhelming majority of patients were able to complete interferon-alpha treatment. Sustained viral response results were in line with other well-managed intervention studies using interferon-alpha and ribavirin (e.g., approximately 40% sustained viral response for those with genotype 1, approximately 75% for those with genotypes 2 or 3). Some patients failed to show a treatment response, and so interferon-alpha was discontinued due to lack of response. Some patients had treatment-related adverse events, such as thrombocytopenia, requiring discontinuation of therapy. To the degree that these data were available, the current study did not include these patients in the denominator at risk of discontinuing due to psychiatric difficulties, since they had discontinued due to medical reasons. Patients who were lost to follow-up or discontinued for other preference or discretionary reasons, or for unidentified reasons, were included in the numbers of patients who discontinued treatment for some reason other than antiviral non-response or medical side effect. This strategy was chosen because it can be challenging, especially from limited data included in published studies, to determine the leading reason for discontinuation or loss to follow-up, and the clinical question is whether prophylaxis boosts study completion.

Generally, providing antidepressant treatment resulted in amelioration of depressive symptoms. For the groups receiving antidepressant treatment prophylactically, average levels of depressive symptoms, or the portion of patients with an emergent depressive disorder, were lower in those receiving prophylactic treatment vs rescue treatment. Generally, problems with depression were worse for those at baseline with any depressive disorder history, or with higher initial depression severity.

Despite the clinical efficacy of antidepressant prophylaxis in controlling depressive symptomatology, there seemed to be no indication that the prophylactic strategy boosted treatment completion rates compared to the rescue strategy. Table 1 presents these data by study, including a summation of the total number of patients in the denominator, at risk for discontinuation, for both prophylactic and rescue arms, and the number for both arms that discontinued therapy. Of 396 patients in the prophylaxis arms altogether, who did not discontinue due to medical adverse events or clinical non-response, 47 (11.9%) discontinued interferon treatment before a recognized stopping point (e.g., 24 or 48 wk); of 380 patients in the rescue arms, 45 (11.8%) discontinued interferon treatment. There was no overall statistical difference when tested by Chi-Squared test with Yates’ correction (c2 = 0.00, P = 0.99).

One study (Raison 2007) seemed to yield a desired effect for prophylaxis: none of the 18 prophylaxis patients discontinued, while 6 of the 18 rescue patients discontinued. A review of this study in the context of other studies did not reveal any clear aspect of study design, measurement, or sampling that would indicate an explanation for this divergent result from the other, similar studies.

The Liu et al[18] study (2010) had greater discontinuation in the prophylaxis arm, but the psychosocial intervention used in this study, close monitoring and various counseling modalities, and psychopharmacotherapy only in certain cases where this psychosocial intervention was not successful, was very different from the other studies. Aside from this differential in discontinuation, the psychosocial intervention used in the Liu et al[18] study otherwise was successful in managing psychiatric symptoms, and doing so with less dependence on psychopharmacotherapy, compared to the usual care arm with rescue psychopharmacology. In this Liu study, with a psychosocial strategy for prophylaxis rather than psychaopharmacotherapy, the number of patients experiencing severe psychiatric symptoms was lower in the intervention group, with five meeting this criterion, vs 17 in the control group. Psychiatric symptomatology at less severe levels, likewise, was less frequent for the intervention arm compared to the control arm, with only six of the intervention patients eventually receiving antidepressant treatment compared to 19 in the control arm.

There were nine studies with data that permitted a Fisher’s Exact Test to test whether the discontinuation rate differed between prophylaxis arm and rescue arm. Of these nine, only four had results that were statistically significant. Three modestly favored prophylaxis. These were: Diez-Quevedo et al[17] 2010 (7.8% discontinuation in prophylaxis arm, 12.5% rescue arm, Fisher’s P = 0.02), Neri et al[19] 2010 (8.5% discontinuation in prophlylaxis arm, 10.5% discontinuation in rescue arm, Fisher’s P = 0.02), and Raison et al[22] 2007 (0.0% prophylaxis arm, 33.3% rescue arm, Fisher’s P = 0.02). The one study favoring rescue was Liu et al[18] 2010 (47.8% discontinuation in prophylaxis arm, 8.0% discontinuation in rescue arm, Fisher’s P = 0.02). With five studies having no statistical difference in discontinuation, three favoring prophylaxis by varying portions, and one favoring rescue by a strong portion, there seems to be no consistent pattern favoring either strategy.

Since these studies were focused upon the presence and severity of depressive symptoms, but not on reasons for failure to complete a full course of therapy, reasons for not completing therapy were not systematically reported, and those reporting did not use consistent criteria. For those that did report, the stated reasons for discontinuation are listed in Table 2. Predominant reasons for not completing therapy included: Lost to follow-up, psychiatric side effects, and non-adherence. These reasons are likely quite overlapping, such as a person choosing to fail to continue in treatment due to psychiatric symptoms.

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Table 2 For studies reporting discontinuation data, number discontinuing interferon-alpha therapy, and reason for discontinuation, summed across studies

DISCUSSION

Emergence of depressive symptoms is a challenging side effect when treating chronic hepatitis C with interferon-alpha. Rates of depression may be as high as 30% or more. It has been established that monitoring patients for the emergence of depression, and rescuing those in whom depression emerges, is a successful strategy for limiting treatment discontinuation or poor adherence. Because of this high incidence of treatment-related depression, the idea of prescribing an antidepressant prophylactically to all patients at the initiation of antiviral therapy is attractive. This search revealed 12 studies that have evaluated the benefits of prophylactic treatment. From these studies, it is clear that prophylactic treatment serves to reduce the emergence of depression, and serves to manage the level of depressive symptomatology.

This review was undertaken to investigate the degree that the prophylactic strategy might boost treatment completion. There is no clear indication that the prophylactic strategy generally serves to boost treatment completion, compared to a monitor-and-rescue strategy. Where noted, nearly all patients in the rescue arms were successfully rescued from the emergence of depression. Review of study parameters does not suggest any treatment strategy or patient profile where prophylaxis yields a boost in treatment completion.

Advantages to prophylaxis are the superior management of depression during treatment in some portion of patients. This advantage needs to be weighed against the negatives of this strategy, which include the increased treatment burden on the patient, increased cost, and the risk of adverse events from the antidepressant. Two of the reviewed studies indicate some likely applications for prophylaxis. The study by Schaefer et al[12] (2005) demonstrated lower rates of treatment-related depression in the prophylactically treated arm, compared to the arm with no prophylaxis, in a cohort of patients with chronic hepatitis C who also had a history of a mental disorder (predominantly affective and dependence disorders) but with no active symptomatology and not currently receiving any psychiatric medication. The Kraus et al[13] (2005) study demonstrated successful interferon-alpha retreatment with antidepressant prophylaxis for a cohort of patients who had previously discontinued interferon-alpha treatment due to the emergence of depressive symptoms, while the control arm experienced, on average, even higher depressive symptom levels in the second attempt at interferon-alpha treatment (possibly due to the use, for all, of pegylated interferon-alpha in the second but not first treatment attempt). So, certain subgroups with recognized psychiatric difficulties may benefit from antidepressant prophylaxis.

While psychopharmacology is effective for managing depression in interferon-alpha treatment of hepatitis C, it is interesting to note the positive results of the Liu study, with a psychosocial intervention including individual counseling, family counseling, and couples counseling. The exact design of this intervention was not reported, such as how counseling needs were discovered, or data on the number of sessions delivered, or the specific clinical issues addressed, or whether any component included comprehensive chronic illness management training (disease education, treatment education, stress management, physician-patient communication skills, etc.), which has been shown to improve treatment adherence along with health-related quality of life.

Why didn’t the prophylaxis approach have superior treatment completion, along with superior depression management, compared to rescue approach? It is possible that, in these trials, the rescue strategy worked as well as prophylaxis because clinical trials often have clinical management practices (answering patient questions, establishing clear lines of communication, systematic symptom monitoring, recruitment of motivated patients) that is stronger than usual care. If this is the case, then those delivering interferon-alpha treatment for chronic hepatitis C should be sure to parallel the symptom monitoring strategy of these trials. The monitoring of depression is a topic that has already been covered well in the literature concerning antiviral therapy, and has long been incorporated into treatment guidelines. The results of the Neri et al[19] (2010) study support this possibility: strong psychosocial monitoring led to better affective symptom control, with only a small portion of that advantage due to the use of antidepressants. At the same time, it is valuable to note that, in the Liu et al[18] (2005) study, interferon-alpha treatment conclusion or discontinuation led to a reduction in the emergent depressive symptom levels seen, leading the authors to conclude that “depression was specifically related to IFN therapy”.

One indirect benefit of antidepressant treatment may be the management of treatment side effects other than psychiatric side effects. Raison et al[22] (2007) found stronger completion rates in the prophylaxis arm, and this was noted as being related to lower antiviral side effect difficulties. The study by Diez-Quevedo et al[17] (2010) also noted lower levels of antiviral side effects in those receiving antidepressants. Antidepressants are used in a range of clinical indications beyond depression, such as management of pain and management of fibromyalgia symptoms. In antiviral therapy, antidepressants may somehow reduce a range of symptoms. This could explain an unusual finding regarding depression in a larger hepatitis C study[24] that used a rescue strategy for emergent depression: while depression emerged for 90 patients in this study of nearly 400, discontinuation rates were lower for those patients (6%) than for those in whom no depression emerged (15%). The antidepressant intervention, or the related social support experienced in the course of clinical response, may have served to ameliorate the experience of treatment side effects. Data were not sufficient in the studies reviewed here to investigate more fully the possibility that antidepressant treatment in antiviral treatment may ameliorate antiviral-related side effects.

Another treatment characteristic suggesting that prophylaxis has limited clinical benefit was the necessity of monitoring and rescuing patients in the prophylaxis group, as well as the rescue group. In the de Knegt et al[15] study (2011), with 40 patients in the escitalopram group and 39 in the placebo group, four in the prophylaxis group needed rescue (increase or augmentation of dose, or new medication) while seven patients in the placebo group needed rescue depression treatment. In the Schaefer et al[23] (2012) study, three in the prophylaxis group needed rescue by another antidepressant, while 16 in the rescue arm required rescue. In the Morasco et al[21] (2010) study, approximately 30% in each arm had to have medication dosage adjusted, with some of those in the prophylaxis arm entering “rescue” treatment. This need to monitor and adjust pharmacotherapy is a limit to the treatment efficiency to be gained by prophylaxis; prophylaxis does not reduce the necessity of monitoring patients for the emergence of depression symptoms, and so does not greatly lighten the task of clinical care required to manage depression.

Because the influences of cytokines upon the central nervous system are quite varied, it is not quite clear how interferon-alpha causes depression in some patients. Pro-inflammatory cytokines can experimentally induce “sickness behavior” in non-human animals. It is hypothesized that this malaise might serve a valuable function: when the body needs to fight off infection, it is advantageous to have a healing period of increased sleep, lower activity level, and lower appetite; pro-inflammatory cytokines promote inflammatory responses, and also may simultaneously be registered in the brain, leading to the coincident sickness behavior[25]. Research in humans has revealed that interferon-alpha has an array of effects in the central nervous system, and elevated cytokine activity, especially tumor-necrosis factor-alpha and interleukin-6 can be noted in some portion of cases of major depression[26,27]. Further, serotonin-acting antidepressants have an effect upon tumor-necrosis factor-alpha and interleukin-6, as well as other inflammatory markers[28].

Providers should be clear about desired purpose when considering prophylactic antidepressant for hepatitis C patients about to begin antiviral therapy. Antidepressant prophylaxis does not seem to boost treatment completion, so other goals, such as managing depression, should be clarified when considering the strengths and weaknesses of this strategy. Discontinuation of interferon-alpha for chronic hepatitis C is a great treatment challenge, and anything that interferes with completion of treatment should be well investigated.

Footnotes

P- Reviewer: Heiser P S- Editor: Wen LL L- Editor: A E- Editor: Wang CH

REFERENCES

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