This blog is all about current FDA approved drugs to treat the hepatitis C virus (HCV) with a focus on treating HCV according to genotype, using information extracted from peer-reviewed journals, liver meetings/conferences, and interactive learning activities.
Risk Of Developing Liver Cancer After HCV Treatment
KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the company has submitted a New Drug Application to the U.S. Food and Drug Administration (FDA) for grazoprevir/elbasvir (100mg/50mg), an investigational once-daily, single tablet combination therapy for the treatment of adult patients with chronic hepatitis C genotypes (GT) 1, 4 or 6 infection. Within 60 days of submission, the FDA will determine whether it will accept for review Merck's application as filed. The company plans to submit additional license applications in the European Union and other markets by the end of 2015.
“This submission to the U.S. FDA is an important milestone as we seek to provide patients with a new treatment option for this serious infection.”
“Merck's submission is based on evidence from our wide-ranging clinical program assessing the efficacy and tolerability profile of grazoprevir/elbasvir in populations with chronic hepatitis C,” said Dr. Roy Baynes, senior vice president of clinical development, Merck Research Laboratories. “This submission to the U.S. FDA is an important milestone as we seek to provide patients with a new treatment option for this serious infection.”
The FDA has previously granted Breakthrough Therapy designation status for grazoprevir/elbasvir for the treatment of patients infected with chronic HCV GT1 with end stage renal disease on hemodialysis, and for patients infected with chronic HCV GT4. Breakthrough Therapy designation is intended to expedite the development and review of a candidate that is planned for use, alone or in combination, to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.
The New Drug Application for grazoprevir/elbasvir (100mg/50mg) is based in part upon data from the pivotal C-EDGE clinical trials program, as well as the C-SURFER and C-SALVAGE trials, evaluating grazoprevir/elbasvir (100mg/50mg), with or without ribavirin, in patients with chronic hepatitis C infection. Data from these trials were presented at The International Liver CongressTM 2015 in April 2015.
About Grazoprevir/Elbasvir
Grazoprevir/elbasvir is an investigational, once-daily single tablet regimen consisting of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A replication complex inhibitor). As part of Merck’s broad clinical trials program, grazoprevir/elbasvir is being studied in multiple HCV genotypes and in patients with difficult-to-treat conditions such as HIV/HCV co-infection, advanced chronic kidney disease, inherited blood disorders, liver cirrhosis and those on opiate substitution therapy.
Large but unexplained variations in paracetamol (acetaminophen)-induced liver failure among European countries
Six-times higher risk in Ireland and a 2-fold higher risk in the UK highlighted in study
Wiley
A fifty-fold between-country difference in rates of paracetamol-induced acute liver failure that leads to liver transplant (ALFT) has been revealed by a study that compared patient data from seven countries at the request of the European Medicines Agency: France, Greece, Ireland, Italy, Netherlands, Portugal and the UK. Researchers discovered that this variation was even more pronounced on a per-capita basis, with a 200-fold difference in ALFT cases. Publishing these findings in the British Journal of Clinical Pharmacology, the authors call for further research to identify the underlying causes.
Paracetamol is used extensively to combat pain, but when taken above the recommended dose it can cause severe liver damage. On occasions the damage is so severe that it leads to complete liver failure and, when this occurs, patients are recommended to have a transplant. A Study of Acute Liver Transplantation (SALT) identified patients with paracetamol-linked liver failure between 2005-2007, and compared the rate of these events per person and also per tonne of paracetamol sold in the country.
Although the average event rate of ALFT in the seven participating European countries over three years was one case per 6 million inhabitants per year, the rate was the highest in Ireland (one case for every 286,000 inhabitants) and the lowest in Italy (one case for every 180 million people in Italy), with a 200-fold difference between these two countries. A similar variation was seen when looking at the frequency of events for each tonne of paracetamol sold: while there was one ALFT event in Ireland for every 20.7 tonnes of paracetamol sold, the value was only one for every 1,074 tonnes sold in Italy.
Furthermore, paracetamol overdose represented 20% of all causes of this type of ALFT across Europe, but rose to 52% in Ireland and 28% in the UK, but dropped to only 1% in Italy. There were no cases at all recorded in Greece. Intriguingly while France had the highest per-person use of paracetamol, it had the third-lowest ALFT rate.
"Overall, we found a six-times higher risk in Ireland and a two-fold higher risk in the UK compared to the average of the countries participating in the study," says lead researcher Sinem Ezgi Gulmez, the associate Professor of Pharmacology at the University of Bordeaux, France.
Gulmez also points out that the highest rates of overdose ALFT per metric ton of paracetamol sold or per inhabitant were found in the two English-speaking countries (Ireland and the UK) in the study: "Since we do not have event rates for overdoses not leading to liver failure, we cannot conclude anything about the rates of non-ALFT overdoses in the different countries, but indicators point to more common use of paracetamol for self-poisoning in these countries".
"The differences in the figures for harm caused by paracetamol within different countries in Europe are not marginal, and suggest that there are some underlying causes. Paracetamol overdose is a serious public health issue and we should start looking into hepatotoxicity associated with paracetamol at normal doses," says Gulmez.
Wide variability in organ donation rates: Midwest leads nation in highest rates of donations
Hundreds more lives could be saved with improved donation rates, say experts from Penn and the University of Kansas Hospital
University of Pennsylvania School of Medicine
IMAGE: David Goldberg is an assistant professor in the division of Gastroenterology at Penn. view more
Credit: Penn Medicine
PHILADELPHIA -More than 123,000 Americans are currently waiting for lifesaving organ transplants, but 21 patients die each day because there aren't enough organs to go around. New research shows wide variation in the number of eligible organ donors whose loved ones consent to organ donation across the country. Donation consent rates are highest in the Midwest and lowest in New York State, according to a study by researchers from the Perelman School of Medicine at the University of Pennsylvania and the University of Kansas Hospital in the new issue of the American Journal of Transplantation.
"These findings dispute the commonly held notion that the gap in donor supply in certain geographic areas is due to large populations of racial and ethnic minorities who are less likely to consent for donation, thus affecting the geography of available organs," said the study's lead author, David Goldberg, MD, MSCE, an assistant professor in the division of Gastroenterology at Penn.
The researchers examined data from the Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS), the nation's organ transplant network, on all reported "eligible deaths," - defined as potential brain-dead organ donors age 70 years or less without any medical conditions precluding donation - from 2008 to 2013. Of 52,571 eligible patient deaths reported to UNOS, consent for donation was obtained in 73 percent of cases. Consent rates were highest among potential donors under the age of 55, patients of white race, and when the referral from the local hospital was made in a "timely" manner.
Consent rates along racial lines echoed findings from earlier studies: lower among African Americans, Hispanics, and Asians, when compared to Caucasian patients. Yet these lower consent rates among racial and ethnic minorities did not explain the overall geographic variability in consent rates. Even after accounting for patient and geographic factors of the potential donors, the study found that the donor consent rates among the 58 donor service areas (DSA) ranged from a 64 percent to 90 percent. Although the average consent rate within each donor service area, when accounting for the race/ethnicity and other factors among the eligible deaths, was between 75 and 80 percent, the consent rates fell below 70 percent in nearly a quarter of the donor service areas. Even when examining only one racial group at a time, the researchers found wide variation in donation rates across the nation's donor service areas: consent rates among Caucasian patients, for example, ranged from 72 to 92 percent across the 58 donor service areas.
"These data demonstrate that although the underlying demographics of the donor population may contribute to geographic differences in organ consent rates, it clearly is not the major driving factor," Goldberg said. "Although there may be underlying cultural or religious differences leading to variable consent rates, the dramatic differences in consent rates among younger Caucasians clearly show that race alone cannot explain geographic differences in organ donor consent rates."
The authors note that if consent rates over five and a half years in the geographic areas with the lowest consent rates were to increase to the current level of the geographic area with the median level of donors identified, there could potentially be 773 more donors available. That pool could yield nearly 2,700 lifesaving kidney, liver, lung, heart, pancreas, and/or intestine transplants. "Importantly, nearly one third of these increased donors would come from the donor service areas in New York State," Goldberg said. "This is of critical importance to the liver transplant community, the OPTN, and HRSA, as there are proposals currently being evaluated to redraw the maps for how organs are distributed. Yet efforts to increase donation rates, most notably in New York, would save more lives, increase the number of transplants, and potentially cost much less than efforts to more broadly share organs across the nation."
"With over 10,000 patients a year dying on a transplant waiting list or becoming too sick to undergo a transplant, these data highlight the potential opportunity to save hundreds of more lives each year by increasing consent rates among potential organ donors," says senior author Richard Gilroy, MD, medical director of Liver Transplantation at the University of Kansas Hospital. "By increasing organ donor consent rates, and optimizing how we utilize a scarce resource, the transplant community can help OPTN achieve its highest priority of increasing the number of transplants each year in the US."
The researchers note that these data alone do not capture all potential deceased organ donors in the U.S., as the current definition of an eligible death excludes potential donors over age 70, and those classified as a "donation after cardiac death" donor, both of which broaden the pool of available donors. "However," Goldberg pointed out, "this group of patients represents the vast majority of actual organ donors in the United States."
The researchers conclude that the best way to boost organ donation rates is a multi-pronged approach that includes education and engagement with potential donors and their families, broader community engagement, concerted efforts by hospitals caring for potential donors, and optimized performance of organ procurement organizations who manage organ donation in this country. "Efforts to increase organ donor consent rates by all parties should be a major focus of the transplant community and the general public," Goldberg said. "This is the only mechanism that will allow us to prevent waitlist deaths while increasing the number of transplants."
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Additional Penn authors include Benjamin C. French, PhD and Peter Abt, MD.
This work was supported by the National Institutes of Health (K08 DK098272) and the Health Resources and Services Administration contract 234-2005-37011C.
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania<http://www.med.upenn.edu/> (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System<http://www.pennmedicine.org/>, which together form a $4.3 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2013 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2013, Penn Medicine provided $814 million to benefit our community.
The controversy over the new crop of hepatitis C treatments has taken yet another turn as consumers are starting to file lawsuits against insurers that deny them access to the medicines. Over the past two weeks, two different women alleged that Anthem Blue Cross refused to pay for the Harvoni treatment sold by Gilead SciencesGILD -1.77% because it was not deemed “medically necessary.”
Both lawsuits claim the insurer denied coverage for Harvoni, one of two hepatitis C treatments sold by Gilead, because the amount of liver damage sustained by the women was insufficient to warrant payment for the drug. In both cases, the insurer decided that Harvoni was not medically necessary, according to the lawsuits.
Will scrutiny press insurers into covering high-cost drugs?
Anthem has not publicly commented on the lawsuits, but told the Wall Street Journal that limited clinical data is an issue when it comes to approving hepatitis C treatments. A spokesman noted that the newest Hepatitis C drugs have been approved through the FDA breakthrough therapy process, and have therefore been tested among fewer people than in typical clinical trials, leaving knowledge more limited for these new drugs. May Updates
Reducing the cost of new hepatitis C drugs
Daclatasvir, Harvoni (ledipasvir/sofosbuvir)/Sovaldi/Viekira Pak.
An index of articles pointing the reader to the current controversy over the high price of Sovaldi, Harvoni (ledipasvir/sofosbuvir) and AbbVie Viekira Pak.
GlobeImmune, Gilead Hepatitis B drug fails in mid-stage study
(Reuters) - GlobeImmune Inc said its experimental hepatitis B drug did not meet the main goal of reducing infection in patients after 24 weeks, in a mid-stage trial.
However, the drug reduced HBsAg, an antigen that indicates the strength of hepatitis B infection, after 48 weeks, the company said on Wednesday.
GlobeImmune is developing the drug, GS-4774, with Gilead Sciences Inc.
The drug was tested in 178 patients who were already on oral antiviral treatment.
Hepatitis B is the most common liver infection affecting about 400 million people worldwide.
Left untreated, the infection can cause diseases such as liver scarring and cancer.
As drugs to treat hepatitis C flood the market, drugmakers are shifting focus to other liver diseases, including hepatitis B and fatty liver disease.
Companies developing hepatitis B drugs include Arrowhead Research Corp, Canada's Tekmira Pharmaceuticals Corp and Isis Pharmaceuticals Inc.
GlobeImmune's shares closed at $8.24 on Tuesday on the Nasdaq.
(Reporting by Amrutha Penumudi in Bengaluru; Editing by Kirti Pandey)
ABBVIE PRESENTS NEW DATA FOR ITS INVESTIGATIONAL HEPATITIS C TREATMENT IN JAPANESE PATIENTS WITH AND WITHOUT CIRRHOSIS
- NEW DATA FROM GIFT-I STUDY PRESENTED AT THE ANNUAL MEETING OF THE JAPAN SOCIETY OF HEPATOLOGY
- PRIMARY ENDPOINT OF 95 PERCENT AND SECONDARY ENDPOINT OF 91 PERCENT SVR12 ACHIEVED IN GENOTYPE 1B HEPATITIS C VIRUS INFECTED JAPANESE PATIENTS WITHOUT AND WITH COMPENSATED CIRRHOSIS, RESPECTIVELY(1)
- 98 PERCENT SVR12 ACHIEVED IN ADDITIONAL ANALYSIS OF PATIENTS WITHOUT CIRRHOSIS RECEIVING DOUBLE-BLIND PLACEBO FOR 12 WEEKS, FOLLOWED BY OPEN-LABEL THERAPY WITH ABBVIE'S INVESTIGATIONAL TREATMENT(1)
- ABBVIE'S RIBAVIRIN-FREE TREATMENT FOR GENOTYPE 1 HEPATITIS C JAPANESE PATIENTS CONSISTS OF A 12-WEEK, TWO DIRECT-ACTING ANTIVIRAL, FIXED-DOSED COMBINATION OF PARITAPREVIR/RITONAVIR WITH OMBITASVIR, DOSED ONCE DAILY
May 26, 2015
NORTH CHICAGO, Ill., May 26, 2015 /PRNewswire/ -- AbbVie (NYSE: ABBV) presented new results from the Phase 3 GIFT-I study of its investigational, all-oral, interferon (IFN)- and ribavirin (RBV)-free, two direct-acting antiviral treatment with ombitasvir/paritaprevir/ritonavir at the Annual Meeting of the Japan Society of Hepatology in Kumamoto, Japan.1 GIFT-I evaluated genotype 1b (GT1b) chronic hepatitis C virus (HCV) infected Japanese patients, with and without cirrhosis, who were either treatment-naïve or IFN (with or without RBV) treatment-experienced.1 The primary endpoint was achieved, demonstrating 95 percent (n=106/112) SVR12 in a sub-group of treatment-naïve, non-cirrhotic, adult GT1b HCV infected Japanese patients who were eligible for therapy with IFN and had a high viral load.1 In study results related to the secondary endpoint, GT1b HCV patients with compensated cirrhosis achieved 91 percent (n=38/42) SVR12.1
In an additional intent-to-treat (ITT) analysis, SVR12 was achieved in 98 percent (n=104/106) of the GT1b HCV infected patients without cirrhosis (Arm B) who were randomized to initially receive double-blind placebo for 12 weeks, followed by open-label treatment with ombitasvir/paritaprevir/ritonavir.1 The ITT population included every patient that was randomized to placebo and received at least one dose of active, open-label study drug.
"It is critical to address the burden of hepatitis C in Japan, with GT1b being the most prevalent sub-type of the disease in the country," said Kazuaki Chayama, M.D., Ph.D, professor and head of the Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University. "GIFT-I shows the potential of this treatment to achieve high SVR rates for Japanese patients with GT1b hepatitis C, including those with compensated cirrhosis."
Across all study arms, three patients (n=3/363) discontinued treatment due to adverse events.1 The most commonly reported adverse events (>5 percent in any arm) were nasopharyngitis, headache, peripheral edema, nausea, pyrexia and decreased platelet count.1
"We are pleased to present full results from GIFT-I, which provide further insight into our hepatitis C treatment currently under priority review by the Japanese health authorities," said Scott Brun, M.D., vice president, pharmaceutical development, AbbVie. "We know physicians weigh the risks and benefits of HCV treatments for their patients as they look for an option that offers a potential cure. These data will help guide clinicians in their decision making and support AbbVie's goal of bringing an interferon- and ribavirin-free treatment to people living with genotype 1 hepatitis C in Japan."
In Japan, approximately 1.5 to 2 million people are living with HCV.2 Genotype 1 is the most common HCV genotype inJapan with 60 to 70 percent of patients infected and, of those, about 95 percent are infected with the GT1b sub-type.3AbbVie studied its two direct-acting antiviral treatment regimen without RBV in Japan due to patient and viral characteristics specific to the Japanese population, including high prevalence of GT1b.
AbbVie's investigational, two direct-acting antiviral treatment consists of ombitasvir/paritaprevir/ritonavir and is currently under priority review by the Japanese Ministry of Health, Labour and Welfare.
About GIFT-I Study GIFT-I comprises 363 patients in two sub-studies. In sub-study 1, 321 genotype 1b (GT1b) patients without cirrhosis, both treatment-naïve and interferon (IFN) [with or without ribavirin (RBV)] treatment-experienced, were randomized to receive either ombitasvir/paritaprevir/ritonavir (Arm A) [OBV/PTV/r] or placebo (Arm B) [2:1 randomization ratio, stratified by treatment history, past response, viral load and IFN eligibility]. Patients initially randomized to placebo (Arm B) then received OBV/PTV/r for an additional 12 weeks of open-label treatment. Sustained virologic response was assessed 12 weeks post-treatment (SVR12) as a primary efficacy endpoint in a sub-group of previously untreated, non-cirrhotic GT1b patients who were eligible for therapy with IFN and had a high viral load, defined as an HCV RNA level ≥ 100,000 IU/mL and received at least one dose of the double-blind, active study drug.1
In sub-study 2, 42 GT1b treatment-naïve and IFN (with our without RBV) treatment-experienced patients with compensated cirrhosis received open-label treatment for 12 weeks (Arm C) with SVR12 and assessed as a secondary efficacy endpoint.1
One patient from each arm (n=3/363) experienced on-treatment virologic failure [Arm A, 0.5% (n=1/215); Arm B, 0.9% (n=1/106); Arm C, 2.4% (n=1/42)].1 Across all arms, eight patients (n=8/354) experienced post-treatment relapse [Arm A, 2.4% (n=5/209); Arm B, 1.0% (n=1/105); Arm C, 5.0% (n=2/40)].1
About AbbVie's Investigational Two Direct-Acting Antiviral HCV Treatment For the treatment of genotype 1 chronic hepatitis C virus (HCV) infection in Japan, AbbVie's investigational, two direct-acting antiviral treatment consists of the fixed-dosed combination of paritaprevir/ritonavir (150/100 mg) with ombitasvir (25 mg), dosed once daily.
AbbVie's chronic HCV treatment combines two direct-acting antivirals, each with a distinct mechanism of action that targets and inhibits specific HCV proteins of the viral replication process.
About AbbVie's HCV Clinical Development Program in Japan AbbVie's HCV clinical development program in Japan focuses on our investigational, two direct-acting antiviral treatment and is designed with the goal of achieving high SVR rates in chronic HCV infected patients, including additional genotypes and patients with compensated cirrhosis.
Paritaprevir was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. Paritaprevir has been developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of hepatitis C.
Ombitasvir/paritaprevir/ritonavir is an investigational product and its safety and efficacy have not been established inJapan.
Additional information about AbbVie's clinical development program in Japan can be found on www.clinicaltrials.gov.
Free HCV Peer-Reviewed PDF Bonanza!!!
Posted on May 25, 2015
From now until the end of the month only! Free HCV Peer-Reviewed PDF Bonanza!!!
Free HCV Peer-Reviewed PDF Bonanza!!! Gone by June 1!
To satisfy your educational needs, Elsevier Multimedia Publishing has made available approximately 40 new, peer-reviewed, full text articles for free! Please click here for a list of these articles, which can readily be accessed in our American Journal of Medicine Hepatitis C Resource Center (hepcresource.amjmed.com). ****Clinical trial highlights provided below.
Note that ALL currently available, free, full text HCV peer-reviewed articles will be removed from the Resource Center by the end of this month!
Highlights
Hepatitis C Clinical Trials Hepatitis C: only a step away from elimination?[No authors listed]
Lancet. 2015 Mar 21;385(9973):1045. doi: 10.1016/S0140-6736(15)60584-0. No abstract available.
Hepatitis C virus RNA levels at week-2 of telaprevir/boceprevir administration are predictive of virological outcome.
Cento V, Di Paolo D, Di Carlo D, Micheli V, Tontodonati M, De Leonardis F, Aragri M, Antonucci FP, Di Maio VC, Mancon A, Lenci I, Manunta A, Taliani G, Di Biagio A, Nicolini LA, Nosotti L, Sarrecchia C, Siciliano M, Landonio S, Pellicelli A, Gasbarrini A, Vecchiet J, Magni CF, Babudieri S, Mura MS, Andreoni M, Parruti G, Rizzardini G, Angelico M, Perno CF, Ceccherini-Silberstein F.
Dig Liver Dis. 2015 Feb;47(2):157-63. doi: 10.1016/j.dld.2014.11.010. Epub 2014 Nov 24.
STARTVerso1: A randomized trial of faldaprevir plus pegylated interferon/ribavirin for chronic HCV genotype-1 infection.
Ferenci P, Asselah T, Foster GR, Zeuzem S, Sarrazin C, Moreno C, Ouzan D, Maevskaya M, Calinas F, Morano LE, Crespo J, Dufour JF, Bourlière M, Agarwal K, Forton D, Schuchmann M, Zehnter E, Nishiguchi S, Omata M, Kukolj G, Datsenko Y, Garcia M, Scherer J, Quinson AM, Stern JO; on behalf of the STARTVerso1 study group.
J Hepatol. 2015 Jan 2. pii: S0168-8278(14)00953-2. doi: 10.1016/j.jhep.2014.12.024. [Epub ahead of print]
Benitec Biopharma (ASX:BLT) has entered into an agreement with Maryland-based Omnia Biologics to manufacture material for its current first-in-man clinical trial for its TT-034 hepatitis C treatment.
This ensures the company has enough clinical material to complete the current trial.
The company is also moving to establish its own scalable manufacturing process in collaboration with third parties to supply large markets it is targeting.
Hepatitis C Treatment
TT-034 is a ddRNAi-based therapeutic that is designed to treat and potentially cure hepatitis C with a single administration.
It targets the hepatitis C viral RNA at three separate, highly conserved sites, which minimises the ability of the virus to mutate and escape the therapy.
Once it reaches the liver cells, it enters the nucleus and produces three separate short hairpin RNAs continuously for the live of the cell.
This has the potential to guard against reinfection for months to years without the need to re-treat.
Proactive Investors Australia is the market leader in producing news, articles and research reports on ASX emerging companies with distribution in Australia, UK, North America and Hong Kong / China.
A week in review Here is a look back at this weeks headlines, including today's news with updates as the day progresses. May 23
Alternative Medicine 3 things people get completely wrong about vitamin supplements One myth I hear often is that natural substances can’t possibly be harmful. Clearly excess can be dangerous, but natural substances can also carry risks even in moderate doses. For example, kava, often used as a sleep aid or to reduce anxiety, has been linked to liver toxicity Covered California Votes To Cap What Patients Pay For Pricey Drugs
Retired California school teacher Mikkel Lawrence sits with his cat, Max. Lawrence has hepatitis C and has struggled to afford the medicine he needs to treat it.
When to Treat: Hepatitis C
Should all patients be treated as soon as possible or is it useful to wait in some /many/most cases?
Chris McGuigan: driving drug development
There has been debate about the cost of medicines to treat hepatitis C. Do you think they are priced excessively? Sofosbuvir is certainly aggressively priced. Hepatitis C is difficult to treat and the natural outcome of the disease in many cases is a liver transplant, which is expensive in itself and impractical for all 180 million people worldwide with the disease. Previous therapy with pegylated interferon and ribavirin didn’t work in all the serotypes, side effects were a problem and compliance was rather low. Protease inhibitors weren’t a panacea, so people looked for polymerase inhibitors. Sofosbuvir was the first and it’s a good drug – well tolerated and curative in many cases. Gilead did pay US$11bn for Pharmasset to get this one drug and it’s fair to think they should be compensated for bringing such an innovative drug through.
Is it fairly priced? That’s beyond my pay grade, but hopefully Gilead will follow the lead of other pharmaceutical companies with HIV drugs in reducing prices in poorer countries. In any case it’s vital that pharmaceutical innovation is adequately rewarded.
NHS England accused of interference over hepatitis C drug
Officials at NHS England have been accused of interfering in a process to decide whether a drug which can cure Hepatitis C should be made available to patients on the health service
Hepatitis C: Weighing the Price of a Cure
A new class of drugs has proven to be an exceptional clinical success, but it's their equally striking costs that are garnering more attention.
Cures for other viruses may follow Hep C
Working on the Hep C virus since 1987, Dr Lopez-Talavera believed at the time that researchers like himself would never be able to cure Hep C without interferon, and that one year of therapy would always be needed. “But as much as I knew, I didn’t know much. And I keep learning, learning more about the virus,” he said.
On what the shortest treatment duration was likely to be with these DAAs, he explained: “If you put just one Hep C virus, one single RNA, into the body of a patient it is going to go into the blood cells and to the liver where it uses the machinery inside the cell to replicate and produce new viruses, and all that takes around 80 days. So we thought that in order to be able to make sure you don’t have any virus in any of those steps…. you need at least 80 days of therapy....
The change means that daclatasvir (Daklinza/ Bristol-Myers Squibb) and sofosbuvir (Sovaldi/Gilead ) may now be given to patients who have hepatitis C infections with either advanced cirrhosis or infections that have come back after patients received a liver transplant.
Dasabuvir in hepatitis C: Indication of added benefit in certain patients
All ten groups were reflected in the dossier compiled by the drug manufacturer, but the data were informative for only three of these groups. The benefit assessment was based on two randomized controlled approval studies (MALACHITE I and II), in which dasabuvir in combination with ombitasvir/paritaprevir/ritonavir and/or ribavirin was directly compared with triple therapy consisting of telaprevir, pegylated interferon and ribavirin.
Series- Hot Topics In HCV MedPage Today HCV HOT TOPICS - 10 Day Video Series
MedPage Today invited specialists from leading medical institutions to weigh in on the latest advancements in hepatitis C with one question each day for 10 days.
May 19
New at Clinical Care Options Audio - HCV Experienced Patients: Resistance testing, Cirrhosis and Genotype 3 Infection
Topics In This Webinar Include;
HCV therapy in the setting of renal impairment, resistance testing in DAA experienced patients, and the best approach to treat patients with cirrhosis or experienced patients who have genotype 3 infection.
EASL- Delaying HCV therapy worsens treatment efficacy
VIENNA — Delaying treatment for hepatitis C virus infection until an increased fibrosis-4 score is reached negatively impacted the efficacy of the treatment among veterans, according to data presented at the 2015 International Liver Congress.
Hep C patient sues Blue Cross for blocking access to Harvoni
It had to happen: A patient denied the latest hepatitis C drugs has sued her insurance company. In this case, it's Anthem Blue Cross, and the California plaintiff says her plan blocked her from treatment because she's not sick enough to qualify under its rules.
In This Issue:
EASL 2015: Snapshots
Alan Franciscus, Editor-in-Chief
This year’s conference had many outstanding presentations about hepatitis C drugs in development—too many to cover in one edition of the HCV Advocatenewsletter. As a result, we will be covering EASL in this edition as well in the next Mid-Monthly edition. I have tried to pick out a couple of most interesting studies from the presentations from AbbVie, BMS, Gilead, and Merck.
Even though there are some wonderful, new medications on the market, some people with HCV will still need to consider going on disability at some time in the future. For most people, it is not always easy to know when the right time to leave is. Liver disease caused by HCV is often marked by a gradual progression toward disability. As well, the emotional issues involved around leaving work and "becoming disabled" further cloud the decision-making process.
The Five: May Is Hepatitis Awareness Month
Alan Franciscus, Editor-in-Chief
May is Hepatitis Awareness month. In this month's column, I will provide a brief overview of the five hepatitis viruses—prevalence, how they are transmitted, and how to prevent transmission. Important Note: This is a very brief overview of viral hepatitis. For detailed information about viral hepatitis see our Viral Hepatitis: The Basics.
Lucinda K. Porter, RN
Author, Hepatitis C Advocate, Health Educator
Last Entry: Tell Your Hep Story (2015-05-22 05:58:39)
Here is a big way that anyone with hepatitis C can do to raise hepatitis awareness - tell your hep story. click here to enter
Matt Starr
Hepatitis, Liver Disease Support Coach
Last Entry: Worry and Boredom in Hartland (2015-05-21 16:10:57)
I'm taking ribavirin and Harvoni, the newest, most successful treatment yet developed for the insidious hepatitis C virus, with a cure rate of over 90% for my genotype 1. The side effects from ribavirin are fatigue and anemia, which my body has resisted, but is slowly increasing. click here to enter
Grace Campbell
A pseudonym for a person living with hepatitis C on Viekira Pak + Ribavirin
Last Entry: Hepatitis C: Uh oh. Buckle up - blood tests happening soon (2015-05-21 04:05:38)
It's Week 8 Blood Test time. You know what that means don't you. It's where I attempt to keep my anxiety under control by spending about $200 at the bookshop. That's my excuse for the purchases, anyway. click here to enter
Greg Jefferys
My Hep C Travel Diary, Hepatitis C Advocate
Last Entry: 'The Medicine Is Out There But I Can't Afford It' (2015-05-20 10:50:27)
I am getting a lot of emails from folk with Hep C sharing their stories with me and their terrible frustration at not being able to access the medication that might cure them. click here to enter
Kyle Jacobs
A pseudonym for a person living with hepatitis C on Harvoni
Last Entry: SVR 21 Weeks Post Treatment with Harvoni (2015-05-19 14:43:42)
Great news to report on my HCV viral load test! I still have a Sustained Virologic Response (SVR) for 21 weeks post treatment from Harvoni and according to my doctor, the incidence of late relapse is very low (less than 1%). click here to enter
Rick Nash
Hepatitis C Advocate
Last Entry: I shall not die so easily. (2015-05-15 11:46:29)
I received the results from my 24 weeks of Harvoni. click here to enter
Hepatitis Australia Alert Important and Appropriate use of medicines for the Treatment of Hepatitis C
Hepatitis Australia has been made aware that some people living with hepatitis C are seeking to import medicines not yet available under the Pharmaceutical Benefits Scheme in Australia to treat their hepatitis C infection.
Hepatitis Australia understands the frustrations caused by the current lack of availability of new hepatitis C treatment drugs in Australia and we are working hard to address it. Anyone considering buying new hepatitis C treatment drugs from overseas should be aware of this alert
PHARMACY DAILY Hep C med imports
Hepatitis Australia is alerting people who are looking to purchase medicines from overseas for hepatitis C treatment, that due to poor quality checks, the practice is risky, as well as being potentially illegal. With new drugs now available in Australia (PD 12 May), Hepatitis Australia also says it should not be necessary to import from overseas, and it is important to have patients’ current status evaluated before starting new therapies.
THE ABOVE SNIPPET IS THE FIRST PART OF AN ARTICLE SENT TO SUBSCRIBERS IN PHARMACY DAILY'S ISSUE FROM 22 MAY 15
Established in 2007, Pharmacy Daily is Australia's leading pharmacy industry publication, and is sent as a free subscription to people across the industry as a PDF newsletter every weekday
A New Webcast with David Bernstein, MD, FACG and Mitchell Shiffman, MD, FACG on behalf of the American College of Gastroenterology
Mitchell Shiffman, MD, FACG
David Bernstein, MD, FACG
Dr. David Bernstein, North Shore Long Island Jewish Health System, and Dr. Mitchell Shiffman, Liver Institute of Liver, Bon Secours Health System, were invited by the ACG to review noteworthy abstracts from the European Association for the Study of the Liver (EASL) meeting in Vienna.
This Webcast features data from EASL on Hepatitis C selected by Dr. Bernstein and Dr. Shiffman and targeted for an audience of GI clinicians.This brief and informative presentation provides a review of data from EASL on current and future HCV therapies that are relevant to gastroenterologists in the United States. Dr. Bernstein and Dr. Shiffman review the latest clinical data, including patient reported outcome data on newer therapies. Access the Webcast.
The Webcast was produced in collaboration with the International Coalition of Hepatology Education Providers (IC-HEP).
From Jules: lets be clear - who is really to blame - if the CDC itself, The White House, Congress would fund HCV adequately & appropriately then the CDC Foundation would not have to take any funds from industry. The CDC desperately wants to address the HCV epidemic & I do not see any evidence they are not acting appropriately; without CDC Foundation funding the CDC Hepatitis Section could do nothing because the CDC director & The White House & Congress give them next to nothing in funding for HCV. HCV is a public health epidemic & newly developed HCV drugs can cure HCV up to 100% with safe, tolerable, effective 12-week time-limited duration therapy, the 1st time in history that we can cure a virus with time-limted duration no less. SO, where is Tom Frieden, the CDC director, on this, why has HE not redirected funds from his budget to HCV? For years I have publicly stated the CDC has budget flexibility, they could move funds over to HCV but they refuse. Congress & The White House also refuse to fund HCV adequately, they provide a completely inadequate amount of $31 million to the CDC Viral Hepatitis section & recently The White House recommended an additional $31 mill which Congress is reviewing and this additional $31 mill White House recommendation is a joke - it should be just for starters $150 mill, that is what the CDC needs merely to launch a national screening project; because, it is estimated 75% of individuals with HCV are undiagnosed! so how can we cure anyone if they are undiagnosed.....
Article
Centers for Disease Control and Prevention: protecting the private good?
BMJ 2015 (Published 15 May 2015)
After revelations that the CDC is receiving some funding from industry, Jeanne Lenzer investigates how it might have affected the organisation's decisions The Centers for Disease Control and Prevention (CDC) includes the following disclaimer with its recommendations: "CDC, our planners, and our content experts wish to disclose they have no financial interests or other relationships with the manufacturers of commercial products . . . CDC does not accept commercial support."
Changing the face of hepatitis C management – the design and development of sofosbuvir
Authors Noell BC, Besur SV, deLemos AS Published Date April 2015 Volume 2015:9 Pages 2367—2374 DOI http://dx.doi.org/10.2147/DDDT.S65255 Received 3 January 2015, Accepted 12 March 2015, Published 24 April 2015 Approved for publication by Professor Shu-Feng Zhou Bennett C Noell,* Siddesh V Besur,* Andrew S deLemos
Department of Medicine, Center for Liver Diseases and Transplantation, Carolinas Medical Center, Charlotte, NC, USA
*These authors contributed equally to this work
Abstract: The availability of direct-acting antiviral (DAA) therapy has launched a new era in the management of chronic hepatitis C. Sofosbuvir, a uridine nucleotide analog that inhibits the hepatitis C RNA-dependent RNA polymerase, is the backbone of chronic hepatitis C therapy. Acting at the catalytic site of the polymerase, sofosbuvir is highly potent in suppressing viral replication and has a high genetic barrier to resistance. Sofosbuvir is effective across all hepatitis C genotypes, and is a mainstay of interferon-free combination therapy. In Phase II and III studies, genotype 1 patients who took sofosbuvir in combination with another DAA such as the NS3-4A protease inhibitor, simeprevir, or the NS5A replication complex inhibitors, ledipasvir or daclatasvir, achieved a sustained virologic response rate of over 90%. Harvoni®, a combination tablet of sofosbuvir and ledipasvir, dosed once daily is recommended for 24 weeks for treatment-experienced genotype 1 patients with cirrhosis, but 12 weeks of therapy is sufficient for all other populations. While genotype 2 (12 weeks or 16 weeks) and treatment-naïve genotype 3 patients (24 weeks) have excellent response rates with sofosbuvir and ribavirin, treatment-experienced cirrhotic genotype 3 patients may need the addition of another DAA such as daclatasvir. Sofosbuvir is efficacious in special populations such as HIV–hepatitis C virus-coinfected patients and liver transplant recipients and has already made a profound impact in these groups. Since it is renally eliminated, patients with advanced kidney disease or on dialysis must await dosing recommendations. Sofosbuvir-based regimens appear to be well tolerated with headache and fatigue being the most common side effects. The opportunity to cure patients with hepatitis C with sofosbuvir combination therapy is likely to change the future for our patients, particularly if the emphasis shifts to identifying those patients unaware that they are infected and providing affordable access to treatment.
Chronic hepatitis C (CHC) infection is a worldwide health concern affecting approximately 185 million people, about 3.5–4.4 million of whom reside in the US.1,2 Eighty percent of patients infected with hepatitis C develop a chronic infection, which will progress to cirrhosis in 20% of patients. End-stage liver disease due to CHC is currently the leading indication for liver transplantation in the US. Approximately 350,000 people across the world died from complications related to hepatitis C cirrhosis in 2010, and in the US, one million hepatitis C virus (HCV)-infected patients will have cirrhosis by 2020.3
The tremendous human cost from sequelae of CHC infection is now beginning to be framed in a new light due to the availability of highly effective all-oral therapies to cure hepatitis C infection. Patients no longer require treatment with pegylated interferon (Peg-IFN), which caused innumerable side effects resulting in poor adherence to therapy. Moreover, the patients most in need of treatment, namely cirrhotics and post-liver transplant patients, had dismal sustained virologic response (SVR) rates with Peg-IFN and ribavirin (RBV). With all-oral direct-acting antiviral (DAA) therapy, these patients now have actual life-saving therapies available with outstanding SVR rates. At the moment, it is not an exaggeration to say that sofosbuvir serves as the fulcrum, providing the foundation on which the change in caring for CHC patients is possible.
DAA therapy refers to pharmacological targets that specifically inhibit hepatitis C viral proteins. Identification of the four structural and six nonstructural proteins of HCV was possible only after the HCV RNA genome was sequenced (Figure 1). An intense effort by industry to develop attractive drug targets ensued but was initially complicated by the nature of the virus itself. The RNA polymerase NS5B does not have proofreading capability, and therefore, sequence diversity in the HCV genome exists at all times, even within individual patients. As a result, the first-generation DAAs, the NS3-4A protease inhibitors, telaprevir and boceprevir, were ineffective as monotherapy due to naturally occurring drug resistance mutations and required coadministration with Peg-IFN and RBV. Another example, simeprevir, a once-daily NS3-4A inhibitor, approved only a year ago in combination with Peg-IFN and RBV, is not recommended for genotype 1a patients who harbor the baseline Q80K resistance mutation. Sofosbuvir circumvents this problem by targeting the catalytic site of the NS5B viral polymerase, thereby profoundly diminishing viral replication directly.4 Furthermore, resistance mutations in the active site would be predicted to confer a lack of viral fitness (see Resistance section). These two factors, in combination with sequence conservation in the NS5B active site across all six hepatitis C genotypes, are responsible for the exceptional efficacy data of sofosbuvir.
Mechanism of action
NS5B is one of six nonstructural proteins encoded on the HCV genome. It is an RNA-dependent RNA polymerase responsible for replicating the HCV RNA genome which is a vital step in the HCV life cycle. The RNA-dependent RNA polymerase exhibits a classic fingers, palm, and thumb structure where interactions between the finger and thumb subdomains create the catalytic site that ensures synthesis of positive- and negative-strand HCV RNA.5 There are currently two types of NS5B inhibitors, nucleos(t)ide inhibitors and non-nucleoside inhibitors. Nucleoside inhibitors bind to the catalytic site of the RNA polymerase causing chain termination. Non-nucleoside inhibitors bind to a less conserved site resulting in a conformational change that distorts the positioning of residues binding RNA, thus inhibiting polymerization. Sofosbuvir belongs to the class of β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methylribose nucleoside inhibitors (Figure 2).
A variety of β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methylribose nucleosides have been shown to be potent inhibitors of HCV NS5B polymerase in clinical studies.6–8 Ultimately, second-generation compounds of these agents were selected due to improved potency and enhanced pharmacokinetics with hopes of enabling once-daily dosing.9 Unfortunately, many of the second-generation preliminary agents were not phosphorylated effectively in vivo due to being poor substrates to cellular kinases. In order to circumvent this rate-limiting step, a phosphoramidate prodrug strategy was used to synthesize compounds with improved bioavailability and transport into hepatocytes, thus enhancing intracellular concentrations of the active nucleoside. Sofosbuvir is a phosphoramidate prodrug that is metabolized in the liver to β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine-5′-monophosphate.8 The conversion of the monophosphate form to the active triphosphate involves four enzymatic steps and one nonenzymatic chemical step.10 The first step involves hydrolysis of the carboxyl ester moiety by serine protease, cathepsin A (CatA), and serine esterase, carboxylesterase 1 (CES1). The second step involves a nonenzymatic rapid chemical activation resulting in an alanyl phosphate intermediate. The third step of metabolism involves deamination by the cellular enzyme histidine triad nucleotide-binding protein 1 (Hint1), and the final two steps leading to the active triphosphate form are phosphorylation events catalyzed by cellular kinases UMP-CMP kinase and nucleoside diphosphate kinase (NDPK). Once converted to the triphosphate form, the uridine nucleotide acts as a defunct substrate for the NS5B polymerase causing chain termination, therefore ceasing RNA replication.
The active site moiety of NS5B is found in all HCV genotypes, which accounts for sofosbuvir’s pangenotypic activity. A study utilizing a molecular modeling approach used several quantitative structure–activity relationship (QSAR) properties to evaluate the performance of sofosbuvir on genotypes 1a, 2b, 3b, and 4a. Genotypes 1a and 3b were found to have the best QSAR values compared to genotypes 2b and 4a, suggesting that sofosbuvir would have better activity against HCV genotypes 1a and 3b.4 Lam et al demonstrated that sofosbuvir inhibited enzymatic activity of NS5B polymerase in genotypes 1–4 with similar 50% inhibitory concentrations between all the groups.11
Pharmacokinetics/drug–drug interactions
Sofosbuvir reaches peak plasma concentrations within 0.5–2 hours following oral administration and is approximately 60% bound to human plasma proteins. Administration with a standardized high-fat meal did not substantially affect its peak or area under the curve (AUC); therefore, it can be administered with or without food. Sofosbuvir undergoes extensive metabolism by the liver as described above to form the active nucleoside triphosphate, GS-461203. Dephosphorylation of GS-461203 results in the formation of the inactive metabolite GS-331007. Following a single 400 mg dose, the terminal half-life was 0.4 hours for sofosbuvir and 27 hours for the GS-331007 metabolite. Approximately 78% of the inactive metabolite is renally eliminated with the rest eliminated through the feces or as unchanged drug.
Population pharmacokinetic analyses in HCV-infected subjects indicated that race, sex, or age (19–75 years) had no clinically relevant effect on the exposure of sofosbuvir and GS-331007.12 Pharmacokinetics of sofosbuvir in pediatric patients has not been established. The AUC of the inactive metabolite, GS-331007, was increased 55%, 88%, and 451% in a pharmacokinetic study of HCV-negative subjects with mild, moderate, and severe renal impairment, respectively. Grade 4 laboratory abnormalities were limited to those with severe renal impairment.13 Dose adjustment for patients with mild-to-moderate renal impairment is currently not necessary. The safety and efficacy of sofosbuvir are currently being studied in patients with severe renal impairment including end-stage renal disease patients requiring dialysis. Currently, use in these patients is not recommended. The AUC of sofosbuvir increased by 126% and 143% in patients with hepatic impairment with Child-Pugh classes B and C, respectively. There was no difference in tolerability or effect in these patients, and the presence of cirrhosis had no clinically relevant effect on exposure.14 Dosage adjustment is not necessary for patients with mild, moderate, or severe hepatic impairment.
Sofosbuvir is a substrate of P-glycoprotein (P-gp); therefore, inhibitors or inducers of P-gp may alter serum concentrations of sofosbuvir. For example, the potent intestinal P-gp inducers (rifampin and St John’s wort) should be avoided, since they can decrease the sofosbuvir plasma concentration and reduce its efficacy. Coadministration with anticonvulsants is also not recommended. There was no effect on pharmacokinetic parameters when cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, or rilpivirine was coadministered with sofosbuvir. Sofosbuvir is not affected by cytochrome P450 metabolism, thus reducing the number of potential drug–drug interactions.15,16
Resistance
In vitro studies using HCV replicons to characterize resistance found S282T to be the only mutation across various genotypes and subtypes resistant to sofosbuvir. The S282T mutation conferred a 9.5-fold increase in the 50% effective concentration (EC50) of sofosbuvir against HCV replicons.17 Sofosbuvir remained susceptible to HCV replicons with resistant mutations to RBV, protease inhibitors, and NS5A inhibitors.17,18 Svarovskaia et al performed an extensive resistance analysis of 1,645 patients from Phase II and III sofosbuvir clinical trials using both deep sequencing and phenotypic analysis.19 There was no S282T mutation or polymorphisms present at baseline that were associated with failure to achieve SVR. Out of the 282 patients who did not achieve SVR, no resistant variants were detected during treatment in patients receiving dual and triple therapy; however, one patient receiving sofosbuvir monotherapy in the ELECTRON trial developed the S282T mutation.20 The S282T variant was present in greater than 99% of the viral population at 4 weeks posttreatment. This decreased to 27% at 8 weeks posttreatment and ultimately became undetectable at weeks 12 and 24 posttreatment. Analysis of all NS5B sequences identified L159F and V321A as sofosbuvir-treatment emergent substitutions. However, neither variant was associated with resistance to sofosbuvir in the replicon system.19 Sofosbuvir has a high genetic barrier to resistance. This may be due to the limited replicative fitness of the S282T strain of HCV compared to the wild type as Svarovskaia et al found, or could be due to sofosbuvir’s ability to rapidly reduce viral replication, thereby limiting the time resistant strains have to develop.19 The high barrier to resistance in addition to lack of cross-resistance between sofosbuvir and other classes of HCV inhibitors makes it an ideal candidate for combination therapy.
Sofosbuvir/ledipasvir
One combination recently approved by the US Food and Drug Administration (FDA) is sofosbuvir plus the NS5A replication complex inhibitor ledipasvir (Figure 3). Pharmacokinetic properties of combined ledipasvir, sofosbuvir, and circulating metabolite GS-331007 were studied in healthy adult subjects and subjects with CHC. While sofosbuvir and GS-331007 AUC and maximum concentration (Cmax) were similar in healthy subjects and those with CHC, ledipasvir AUC and Cmax were 24% lower and 32% lower, respectively, in HCV-infected subjects. Ledipasvir undergoes a slow oxidative metabolism through an unknown mechanism and is eliminated as an unchanged drug through biliary excretion. There was no detectable metabolism of ledipasvir by Cytochrome P450 enzymes. Ledipasvir solubility decreases as pH increases; thus, medications that increase gastric pH may result in a decreased concentration of ledipasvir. Omeprazole at doses of 20 mg once daily given 2 hours prior to ledipasvir resulted in lower AUC and Cmax. Only small decreases in ledipasvir AUC and Cmax were observed when given simultaneously with ledipasvir/sofosbuvir combination; therefore, proton-pump inhibitors at doses comparable to omeprazole 20 mg or lower can be administered simultaneously under fasted conditions.21 Amino acid substitutions Y93H and Q30E have conferred high levels of reduced susceptibility to ledipasvir in cell culture for genotypes 1a and 1b. Ledipasvir is fully active against the sofosbuvir resistance-associated substitution S282T in NS5B, and ledipasvir resistance-associated substitutions in NS5A are fully susceptible to sofosbuvir.
Comparative effectiveness of sofosbuvir and current use in clinical practice
Genotype 1
Sofosbuvir (Sovaldi®) originally gained FDA approval on December 6, 2013, in combination with Peg-IFN and RBV for genotypes 1 and 4, and in combination with RBV for genotypes 2 and 3. This label was based upon five Phase III clinical trials in a total of 1,724 HCV-mono-infected subjects with genotypes 1–6 CHC (see package insert). NEUTRINO was a single-arm, open-label multicenter trial in treatment-naïve patients (n=327) with genotypes 1 and 4–6.22 Patients received 12 weeks of sofosbuvir (400 mg daily) with weight-based RBV (1,000 mg in patients <75 kg, 1,200 mg if >75 kg daily) plus weekly Peg-IFN alpha (180 μg). The majority of patients were Caucasian (79%), genotype 1 (89%), and non-cirrhotic (83%). The SVR rate at 12 weeks (SVR12) following treatment was 92% (genotype 1a) vs 82% (genotype 1b). The SVR12 in patients with cirrhosis was 80%, and 71% in patients with multiple predictors of poor response to Peg-IFN (genotype 1, advanced fibrosis [F3/F4], IL28B non-C/C, and baseline viral load >800,000 IU/ mL) (Table 1).
Shortly after the approval of Sovaldi® with Peg-IFN and RBV for genotype 1 CHC patients, Phase III clinical trials with the fixed-dose combination of sofosbuvir (400 mg) with the NS5A inhibitor, ledipasvir (90 mg), were completed. The anticipation for this combination was pronounced, particularly for genotype 1 CHC patients with cirrhosis, who were in need of a safe and effective all-oral DAA combination. A total of 1,518 subjects with genotype 1 CHC received sofosbuvir/ledipasvir (Harvoni®) in the ION trials. ION-323 enrolled treatment-naïve patients with early-stage or no fibrosis (Metavir F0–F2) to either 8 weeks or 12 weeks of Harvoni®. The SVR12 in the 8-week treatment group with or without RBV was 94%, and 96% in the 12-week treatment group. ION-124 compared 12 weeks vs 24 weeks in treatment-naïve patients with and without cirrhosis. The SVR12 in the 12-week arm was 99% (176/177) in patients without cirrhosis and 94% (32/34) in patients with cirrhosis, with again no difference with the addition of RBV. Lastly, ION-225 investigated the response rate of 12 weeks vs 24 weeks of Harvoni® in treatment-experienced patients with or without cirrhosis and included patients who had failed prior protease inhibitor therapy. These historically difficult-to-treat patients had outstanding response rates, and 24 weeks of therapy was superior to 12 weeks of therapy (99% vs 94% SVR). Based upon this compelling data, Harvoni® was approved by the FDA on October 10, 2014, for 12 weeks in treatment-naïve genotype 1 CHC patients with or without cirrhosis and 24 weeks or 12 weeks in treatment-experienced patients with or without cirrhosis, respectively.
A current alternative which was recommended by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (http://www.hcvguideline.org/) in 2014 prior to approval of Harvoni® for genotype 1 patients intolerant of or ineligible for Peg-IFN was sofosbuvir and the NS3-4A inhibitor, simeprevir (150 mg daily).26 While originally an off-label use, this combination was just recently added to simeprevir’s package insert based upon data from COSMOS.27 Ninety-five percent of non-cirrhotic patients attained an SVR following 12 weeks with this combination. The SVR12 was 96% after 24 weeks of simeprevir and sofosbuvir in patients with cirrhosis (n=23), and extending treatment is advised in this population.27 In Europe, the NS5A inhibitor, daclatasvir (60 mg daily, Daklinza®), is an additional DAA, which can be combined with sofosbuvir for genotype 1 patients with (24 weeks) or without (12 weeks) cirrhosis with SVR rates comparable to Harvoni® (see also daclatasvir package insert).28
Genotypes 2–4
Sofosbuvir is the backbone for genotypes 2–4 treatment as well. It should be given for 12–16 weeks in combination with weight-based RBV for genotype 2 patients with or without cirrhosis. Treatment-naïve patients do slightly better than treatment-experienced patients (SVR >90% vs >80%).29 Genotype 3 patients, however, require 24 weeks of therapy with sofosbuvir and RBV. Like genotype 2, treatment-experienced patients do not fare as well as treatment-naïve patients (SVR 77% vs 93%).30 In Europe, the addition of daclatasvir to sofosbuvir and RBV is an attractive option for genotype 3 and would be a combination to choose, particularly in treatment-experienced patients with cirrhosis (see also daclatasvir package insert).28 Lastly, like genotype 1, sofosbuvir was originally approved in combination with Peg-IFN and RBV for 12 weeks for genotype 4 patients. While this combination remains a viable option for interferon-eligible patients, 24 weeks of sofosbuvir and RBV or 12-weeks of Harvoni® is probably a better alternative (http://www.hcvguideline.org) (Table 1).
Hepatitis C treatment in special populations
Patients with HIV coinfection represent an important subset of CHC patients to target therapy. They are at high risk for fibrosis progression compared to mono-infected patients. Thus, sofosbuvir, which can be safely administered concomitantly with antiretroviral therapy, has been a blessing to coinfected patients. Twenty-four weeks of sofosbuvir and RBV are effective in genotype 1–3 patients.31 For genotype 1 coinfected patients, 12 weeks of Harvoni® therapy resulted in an SVR rate of 98%32 and appears to be preferable to 24 weeks of sofosbuvir/RBV. However, ledipasvir increases tenofovir levels and should be avoided in patients with a creatinine clearance below 60 mL/min (http://www.hcvguideline.org). Historically, post-liver transplant outcomes in patients transplanted for CHC were inferior to other indications for liver transplant due to allograft reinfection and recurrent hepatitis C infection.33 Moreover, an aggressive form of allograft reinfection, fibrosing cholestatic hepatitis C (FCH), contributed to early graft failure within the 1st year after liver transplant. The availability of sofosbuvir is poised to change the natural history of hepatitis C after transplant. In fact, a compassionate use program with sofosbuvir for patients with FCH and allograft cirrhosis was started prior to its FDA approval, and 59% (54/92) of patients achieved an SVR12.34 While exact guidelines on when to initiate therapy post-transplant in the DAA era are not clear, patients can now be treated before transplant35 to prevent allograft reinfection or after transplant36 with truly remarkable response rates and without the risk of immune graft dysfunction associated with Peg-IFN therapy.37
Safety profile of sofosbuvir
Sofosbuvir is used in combination with other DAAs, Peg-IFN, or RBV. Thus, attributing side effects directly to sofosbuvir should be considered with caution. Anemia due to Peg-IFN/RBV therapy is common and should be monitored closely in regimens containing these agents. In a pooled analysis of Phase III trials of patients who received a sofosbuvir/RBV regimen, 8% of patients had a Hgb <10 g/dL, and <1% had a Hgb <8.5 g/dL. The corresponding numbers from the FISSION study in which patients also received Peg-IFN were 14% and 2%, respectively.22 Not surprisingly, patients treated with interferon-sparing, sofosbuvir-based regimens had less treatment discontinuation rates and reported better health-related quality of life.
It is important to make note of adverse effects of sofosbuvir in combination with other DAAs. In the COSMOS trial, fatigue and headache were the most common adverse effects; however, simeprevir and sofosbuvir were also associated with pruritus (17%), rash (11%), and hyperbilirubinemia (7%). Sofosbuvir plus daclatasvir combination therapy was also associated with fatigue (11%) and headache (7.8%), as well as nausea. Only two patients required treatment discontinuation, which was likely unrelated to the study drug.28 Pooled data from Phase III trials using sofosbuvir in combination with ledipasvir revealed headache (11%–17%) and fatigue (13%–18%) as the most common side effects with very few patients (<1%) requiring treatment discontinuation due to side effects. Nausea, diarrhea, and insomnia were reported in 5%–10% of patients. Laboratory abnormalities with elevation in bilirubin and lipase levels were noted in ≤3% of patients, and may be a unique adverse effect of ledipasvir.
Conclusion and future challenges associated with the effective treatment of hepatitis C
The challenges in managing patients with CHC are in many ways different today in the era of highly effective DAA therapy. With the arrival of sofosbuvir ($1,000 per pill) and now Harvoni® ($1,125 per pill), concerns about cost have arisen. The cost of therapy must be further contemplated in the context of a strained US health care system where many patients with CHC are either uninsured or insured through government-sponsored plans.38 Insurance companies may decide to prioritize treating certain patients first over others (eg, those with more advanced fibrosis). Another factor both in the US and across the world involves identifying infected patients. In 2012, the US Centers for Disease Control and Prevention recommended one-time screening for CHC infection in persons born between 1945 and 1965.39 The implementation of this guideline is expected to identify a large number of previously undiagnosed patients who will require treatment. The public health mandate to find such patients is justified by our ability to now provide safe and effective therapy. While the cost of sofosbuvir or Harvoni® treatment today remains an issue, many providers feel that the real question is actually the relative cost of treating against the price paid by not treating – namely more patients at risk for complications from cirrhosis. In developing countries, where access and affordability are paramount, generic pharmaceutical companies, through licensing agreements with Gilead Sciences Inc., expect to be able to provide the drug at a fraction of the US cost. As a result, the main obstacle may become ensuring adherence to therapy.
Future challenges still exist for special patient populations, and guidelines for treating HIV–HCV-coinfected patients with Harvoni® will require updating once ongoing clinical trials are complete. The same can be said regarding the optimal timing and duration of therapy for post-liver transplant patients. Chronic kidney disease patients with CHC infection, including those on dialysis, must await dosing recommendations for sofosbuvir and Harvoni® or seek alternative DAA combinations that are not renal cleared. Finally, a small percentage of patients will not achieve an SVR with DAA therapy containing sofosbuvir, reflecting real-world outcomes where adherence is suboptimal. Retreatment with sofosbuvir should be possible, but the decision to change to a different combination of DAA and/or adding RBV therapy will need to be individualized. While these concerns are real, when placed in perspective, the chance to prevent patients from developing cirrhosis, liver cancer, and even in some cases the need for liver transplant is truly remarkable to envision.
Disclosure
Dr deLemos has received support for clinical trials from Vital Therapies. The remaining authors have no disclosures.
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PHILADELPHIA -More than 123,000 Americans are currently waiting for lifesaving organ transplants, but 21 patients die each day because there aren't enough organs to go around. New research shows wide variation in the number of eligible organ donors whose loved ones consent to organ donation across the country. Donation consent rates are highest in the Midwest and lowest in New York State, according to a study by researchers from the Perelman School of Medicine at the University of Pennsylvania and the University of Kansas Hospital in the new issue of the American Journal of Transplantation.
PHILADELPHIA -More than 123,000 Americans are currently waiting for lifesaving organ transplants, but 21 patients die each day because there aren't enough organs to go around. New research shows wide variation in the number of eligible organ donors whose loved ones consent to organ donation across the country. Donation consent rates are highest in the Midwest and lowest in New York State, according to a study by researchers from the Perelman School of Medicine at the University of Pennsylvania and the University of Kansas Hospital in the new issue of the American Journal of Transplantation.
