Minimum costs to produce Hepatitis C Direct Acting Antivirals for access programs in developing countries

Provided by NATAP

Reported by Jules Levin

64th Annual Meeting of AASLD, Washington DC, United States of America, November 2013 [Poster 1097]

Andrew Hill and Saye Khoo, Department of Pharmacology and Therapeutics, Liverpool University, UK
Bryony Simmons, Imperial College, London, UK
Nathan Ford, University of Cape Town, South Africa

(Click on images to enlarge)

Ribavirin (generic) is a nucleoside analogue, with a relatively simple chemical synthesis (conversion factor (CF) x1). The daily dose is 1000-1200mg, with an overall dose of 84-100g for 12 weeks of treatment. Production costs were estimated at $0.25 to $0.75 per gram, giving an estimated cost of $21 to $76 for a 12 week course of treatment.

Daclatasvir (patent expiry 2027) is an NS5A inhibitor, and has a straightforward synthesis given its symmetry and the availability of cheap starting materials to synthesise the side-chains (CF x1-3). The daily dose is 60mg, with a total dose of 5g for 12 weeks of treatment. Production costs were estimated conservatively at $2 to $6 per gram, giving an estimated cost of $10 to $30 for a 12 week course of treatment.

Sofosbuvir (patent expiry 2029) is a nucleotide which requires a 2'-fluro-2'-methylfuranose intermediate. This cost-limiting material complicates synthesis (CF x4). The daily dose is 400mg, with a total dose of 34g for 12 weeks of treatment. Production costs were estimated at $2 to $4 per gram, giving an estimated cost of $68 to $136 for 12 weeks of treatment.

Faldaprevir (patent expiry 2025) is a protease inhibitor which requires a tetra-substituted quinoline and a vinyl-cyclopropane amino acid : this complicates the chemical synthesis (CF x10). The daily dose is 120mg, with a total dose of 10g for 12 weeks of treatment. Production costs were estimated at $10 to $21 per gram, giving an estimated cost of $100 to $210 for 12 weeks of treatment.

Simeprevir (patent expiry 2026) , a protease inhibitor, is a medium-ring macrocycle that utilises a novel, ring-closing metathesis reaction in the late stages of API manufacturing. Novel raw material include a tetra-substituted quinoline and a vinyl-cyclopropane amino acid: this significantly complicates synthesis (CF x10). The daily dose is 150mg, with a total dose of 13g for 12 weeks of treatment. Production costs were estimated at $10 to $21 per gram, giving an estimated cost of $130 to $270 for 12 weeks of treatment.

REFERENCES

HCV epidemiology: Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011;17(2):107-15 doi: 10.111/j.1469-0691.2010.03432.x. http://www.ncbi.nlm.nih.gov/pubmed/21091831

Income classification: The World Bank income classifications, 2013. http://data.worldbank.org/about/country-classifications/country-and-lending-groups

Genotype prevalence: Alberti A, Negro F. The global health burden of hepatitis C virus infection. Liver International 2011;31(2) doi:10.1111/j.1478-3231.2011.02537.x. http://www.ncbi.nlm.nih.gov/pubmed/21651699

Costs of HIV drugs: Medecins Sans Frontières. Untangling the web of antiretroviral price reductions. 15th Edition - July 2012. http://utw.msfaccess.org/

Patent expiry dates of HCV drugs (all patents are subject to potential patent life extensions): Ribavirin: WHO, Application for inclusion of ribavirin in the WHO model list of essential medicines. Nov. 2006, page 2. http://archives.who.int/eml/expcom/expcom15/applications/newmed/ribaravin/ribavirin.pdf

Daclatasvir: Bristol-Myers Squibb Company, Form 10-K, year ending 2011, page 9. http://www.sec.gov/Archives/edgar/data/14272/000119312512066416/d302058d10k.htm

Sofosuvir: Pharmasset, Inc, Form 10-K, year ending 2011, page 26; Patent US7,429,572; composition of matter patent US7,964,580. http://quote.morningstar.com/stock-filing/Annual-Report/2011/9/30/t.aspx?t=:VRUS&ft=10-K&d=9038796906580b2535f464bf081028c1

Faldaprevir: Patents US7,585,845 (http://www.google.com/patents/US7585845 ) and US7,514,557 (http://www.google.com/patents/US7514557)

Simeprevir: Medivir annual report, 2012, page 18; Patent WO07/014926 http://www.medivir.se/v4/images/pdf/2013/Medivir-ENG-web_0403.pdf Retro-synthesis and identification of cost limiting materials

Witkowski JT, et al. Design, synthesis, and broad spectrum antiviral activity of 1-D-ribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides. J Med Chem. 1972; 15(11): 1150-4
Gao M, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010; 465(7294): 96-100.

Peng G, et al.; Bristol-Myers Squibb Company. Process for synthesising compounds useful for treating hepatitis C. Patent Application WO2009/020825 A1. Feb 12, 2009.

Chun BK, Wang P.; Pharmasset, Inc. Preparation of 2'fluro-2'-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives. Patent Application WO2006/031725 A3. Apr 16, 2009.

Chun BK, et al.; Pharmasset, Inc. Nucleoside phosphoramidates. Patent Appliation US2011/0251152 A1. Oct 13, 2011.

White PW, et al. Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease. Antimicrob Agents Chemother. 2010; 54(11): 4611-8.

Llinas-Brunet M, et al. Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335). J Med Chem. 2010; 53(17): 6466-76.

Horvath A, et al.; Janssen Pharmaceuticals, Inc. Improved process for preparing an intermediate of the macrocyclic protease inhibitor TMC435. Patent Application WO2013/061285 A1. May 2, 2013.

DAA combinations (interferon-free): i-Base/Treatment Action Group. 2012
Pipeline Report: HIV, HCV, and TB drugs, diagnostics, vaccines, and preventative technologies in development. July 2012.http://www.pipelinereport.org/toc

SOUND-C2: Zeuzem S, Soriano V, Asselah T, et al. Interferon (IFN)-free combination treatment with the HCV NS3/4A protease inhibitor faldaprevir (BI 201335) and the non-nucleoside NS5B inhibitor BI 207127 ± ribavirin: final results of SOUND-C2 and predictors of response (Abstract 232). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_20.htm

AI444-040: Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al.; AI444040 Study Group. High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5a inhibitor) plus sofosbuvir (nucleotide NS5b inhibitor) with or without ribavirin, in treatment-naive patients chronically infected with HCV GT 1, 2, or 3 (Abstract LB-2). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_06.htm

AI443-014: Everson GT, Sims KD, Rodriguez-Torres M, et al. An interferon-free, ribavirin-free 12-week regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 yielded SVR4 of 94% in treatment-naive patients with genotype (GT) 1 chronic hepatitis C virus (HCV) infection (Abstract LB-3). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_07.htm

AI447-011: Lok AS, Gardiner DF, Hezode C, et al. Sustained virologic response in chronic HCV genotype (GT) 1-infected null responders with combination of daclatasvir (DCV; NS5a inhibitor) and asunaprevir (ASV; NS3 inhibitor) with or without peginterferon alfa-2a/ribavirin (PEG/RBV) (Abstract 79). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_15.htm

ELECTRON: Gane EJ, Stedman CJ, Hyland RH, et al. Once daily sofosbuvir (GS-7977) regimens in HCV genotype 1-3: The ELECTRON trial (Abstract 229). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_31.htm

SPARE: Osinusi A, Heytens L, Lee JY, et al. High Efficacy of GS-7977 in Combination with Low or Full dose Ribavirin for 24 weeks in Difficult to Treat HCV Infected Genotype 1 Patients: Interim Analysis from the SPARE Trial (Abstract LB-4). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_08.htm

POSITRON: Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med; 2013;368:1867-1877. http://www.nejm.org/doi/full/10.1056/NEJMoa1214854

COSMOS: Lawitz E, Ghalib R, Rodriguez-Torres M, et al. SVR4 results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype 1 null responders. Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections; 2013 March 3-6; Atlanta, GA. http://www.natap.org/2013/CROI/croi_34.htm

Source

High price for Hep C drug sparks controversy

By Lou Chibbaro Jr. on December 23, 2013

Carl Schmid, deputy director of the AIDS Institute, said Sovaldi is expensive, ‘but this is remarkable progress and the cure rate is extremely high.’ (Photo courtesy of Schmid)

The pharmaceutical company Gilead Sciences received praise earlier this month for bringing to market a newly approved drug capable of curing the potentially fatal liver disease Hepatitis C without the serious and debilitating side effects caused by the existing drug used to treat the disease.

Experts say 20 percent of people with HIV are co-infected with Hepatitis C, which over a period of years can lead to death through liver cancer and liver failure. Physicians treating people with HIV, including Whitman-Walker Health’s medical director, Dr. Richard Elion, have called Gilead’s new drug a major breakthrough.

But at least two organizations that advocate for people with HIV and Hepatitis C have denounced Gilead for setting the wholesale price for its new drug Sovaldi at a level they consider exorbitant and which they say could lead to further escalating prices for AIDS drugs.

The AIDS Healthcare Foundation, the nation’s largest private organization providing medical services for people with HIV/AIDS, and the Fair Pricing Coalition, which advocates for affordable prices for prescription drugs for people with serious illnesses, called Gilead’s decision to set a wholesale acquisition cost of $84,000 for a 12-week treatment regimen of Sovaldi unprecedented.

“There can be no better example of the unbridled greed of the pharmaceutical industry than Gilead’s latest move: pricing its new hepatitis drug at $84,000 per 28-tablet bottle or $1,000 per pill,” said Michael Weinstein, president of AHF.

Lynda Dee, co-chair of Fair Pricing Coalition, called Sovaldi a “very safe and highly effective drug” but noted that it must be used in combination with other drugs to treat different Genotypes, or strains, of Hepatitis C.

She said that although the other drugs – pegylated interferon and ribavirin – are not as expensive as Sovaldi, the price tag for combination therapy with Sovaldi comes to $93,000 and $168,000 for various treatment regimens for a single person living with Hepatitis C.

“Gilead has set the bar dangerously high as other companies determine prices for similar Hepatitis C drugs as they enter the market,” Dee said.

In a statement released at the time the U.S. Food and Drug Administration approved Sovaldi for patient use on Dec. 6, Gilead said it had put in place a patient assistance program to ensure that people with Hepatitis C have access to Sovaldi regardless of their ability to pay for it.

The statement said the program provides assistance to “patients who are uninsured, underinsured or who need financial assistance to pay for the medicine.” The program, called Support Path, will provide Sovaldi “at no charge for eligible patients with no other insurance options,” according to the statement.

While praising Gilead for offering such a program, which is common within the pharmaceutical industry, critics say the high price for Sovaldi would likely prompt other companies to put in place similarly high pricing policies for other promising drugs about to be released for the treatment of both Hepatitis C and HIV/AIDS.

Some Wall Street analysts suggested Gilead’s price for Sovaldi may be justified when taking into consideration the amount it spent to bring such a beneficial drug to market. Bloomberg business news service reported that Gilead, which didn’t invent Sovaldi, paid $11 billion in 2011 to buy Pharmasset, Inc., the company that developed Sovaldi and other Hepatitis C drugs expected to be approved soon.

Bloomberg cited pharmaceutical industry observers who said the Hepatitis C drugs Gilead obtained through this purchase could pull in as much as $20 billion by 2020.

Clinical trials with patients monitored by the Food and Drug Administration demonstrated that Sovaldi had a cure rate of more than 90 percent for patients with the Genotype 2 strain of Hepatitis C following a 12-week regimen with the drug ribavirin. Patients with Genotype 3, another strain of Hepatitis C, had a similarly successful cure rate following a 24-week regimen of Sovaldi and Ribavirin, the trials showed.

For patients with Genotype 1 or 4 of the Hepatitis C infection, the Sovaldi treatment needed to be combined with pegylated alfa interferon, the drug of choice for Hepatitis C before the development of Sovaldi and other new drugs nearing completion of clinical trials, statements by Gilead and the FDA said. Interferon causes serious and debilitating side effects for most patients, forcing some to stop using it before the Hepatitis C virus can be eliminated, according to medical experts.

The good news, according to those monitoring Hepatitis C treatment developments, is that Gilead and other pharmaceutical companies are close to releasing other new drugs capable of effectively curing patients with the Genotype 1 and Genotype 4 strains without the need for Interferon.

“I believe that Sovaldi will have a major impact on public health by significantly increasing the number of Americans who are cured of Hepatitis C,” said Dr. Ira Jacobson, chief of the Division of Gastroenterology at Weill Cornell Medical College in New York City, who served as a principal investigator in the clinical trials of Sovaldi.

Carl Schmid, deputy director of the AIDS Institute, which advocates for people with HIV, said the ability of Sovaldi to actually cure patients with Hepatitis C makes it different from HIV drugs on the market, which keep most patients healthy but cannot cure HIV/AIDS.

“Yes, it’s expensive,” he said of Sovaldi. “But this is remarkable progress and the cure rate is extremely high.”

Source

Life-saving hepatitis C drug approved, but cost is high

Provided by IRIN

humanitarian news and analysis

a service of the UN Office for the Coordination of Humanitarian Affairs

Photo: Wikipedia

Life-saving: the sofosbuvir molecule has been approved in the US and Europe for the treatment of hepatitis C

New York, 23 December 2013 (IRIN) - Following approvals in the US and Europe this month of a new drug to treat hepatitis C, activists are pushing for the medication to be made available in poor countries, a development reminiscent of the activism that forced down HIV/AIDS drug prices a decade ago in Brazil, South Africa and Thailand.

The World Health Organization (WHO) estimates that as many as 185 million people are infected with hepatitis C, which is often called a “viral time bomb” because it can exist, undiagnosed, in a person’s body for many years without causing symptoms.

According to the Open Society Foundations (OSF), more than 350,000 people die every year from liver disease related to the virus, and every year an estimated three to four million more people are infected.

Many of these people are co-infected with HIV; the illnesses are both blood-borne and have shared routes of transmission, particularly injecting drug use.

Unlike HIV, hepatitis C can be cured. But current treatment options have serious side effects, do not always work and are unaffordable for most people. The existing treatment, pegylated interferon, which is manufactured by Roche and Merck, can cost as much as US$18,000 for a 48-week course.

Interferon, which must be injected, can, in combination with the drug ribavirin, cure 40-70 percent of patients who use it. But its high cost has kept it out of reach for most patients, except in Egypt and Thailand, where the governments were able to negotiate significant price reductions with drug manufacturers.

“How have we got to a global system where new drugs being developed are out of reach of most of the population?”

The new drug, sofosbuvir, released by pharmaceutical giant Gilead, promises a leap forward in the hepatitis C treatment. It is orally administered, reduces treatment time to 12 weeks, has fewer side effects, and, if used in combination with other drugs, can achieve a 90 percent cure rate. The hitch?

The price tag.

In the US, which has some of the highest drug prices in the world, Gilead is expected to charge $80,000 for one course of treatment - more than four times the cost of interferon. While the cost of the drug is likely to be lower elsewhere, healthcare advocates fear the price will remain beyond the reach of poor people.

Pricing

Médicins Sans Frontières’ director of policy and analysis, Rohit Malpani, says the drug has been priced so high because it cost the company $11 billion to acquire Pharmasset, the original maker of the drug.

According to one analyst, Gilead has to make $4 billion on the drug annually, to justify the high cost of the buyout.

This is not a reflection of the research and development costs; it is an assessment of how much the company can get for it, Malpani adds. “Companies will engage in extensive studies to determine what the market will bear, but that is not the way that life-saving commodities should be priced.”

Access strategy

MSF’s Access Campaign, which lobbies for affordable medicines for resource-strapped communities, is waiting for Gilead to finalize its “access strategy” for poor countries after having received input from a range of organizations.

A Gilead spokesperson told IRIN that it would announce the details of its access programme early next year. The company says it is “committed to making its medicines available to patients, regardless of where they live or their ability to pay”, and that it is “working very closely with advocates in communities that are affected by hepatitis C to develop an appropriate access and pricing strategy”.

The spokesperson said Gilead wanted to “help ensure access to Sovaldi [the brand name for sofosbuvir] in resource-limited countries, especially countries that have a high hepatitis C burden”.
However, Malpani is not optimistic that the reduced price will be low enough to make the drug widely accessible. Furthermore, MSF believes Gilead is likely to offer “middle-income” countries - like China, Iran and Ukraine - a higher pricing strategy than that given to poor countries.
Ironically, 75 percent of the world’s poor reside in middle-income countries, Malpani said. “Our concern with Gilead’s access strategy is that it is likely to be unaffordable and punitive to the countries in that category,” he said.

MSF would like to set a target price for the drug of less than $500. However, according to an OSF report, "Unfortunately, past experience with HIV suggests that drug companies are unlikely to voluntarily extend significant discounts to middle-income countries, even if they may be open to reducing the price for the world's poorest."

According to one study, a 12-week course of sofosbovir could cost as little as $62-$134 to produce.
Asked why the drug was so expensive in the US, the Gilead spokesperson said: “We believe that the price of Sovaldi in the United States is fair, based on the value it represents to a larger number of patients.” A special programme for those unable to afford it would be available, he added.
“But the starting point is so outrageous, not even halving it would make it accessible,” says Els Torreele, director of OSF’s Access to Essential Medicines Initiative.

“How have we got to a global system where new drugs being developed are out of reach of most of the population? It’s totally normal today to price drugs at $100,000. Something is wrong with a system where drugs that so many people need are costing so much. This is not sustainable for anyone,” she said.

Daniel Wolfe, director of the International Harm Reduction Development Program at OSF, said that because of its association with HIV and drug use, hepatitis C is still highly stigmatized. “The experience of HIV has shown us that the combination of expensive medication and social stigma is deadly,” he said.

He added that companies are pricing their drugs for profit rather than public health concerns. “When governments are confronted by high prices for a stigmatized population affected, they tend to look the other way,” Wolfe said.

Patent worries

In India a “patent opposition” has been filed by the Initiative for Medicines Access and Knowledge (I-MAK) to stop Gilead from obtaining a patent on the drug there, which would clear the way for low-cost generics to be manufactured.

India has long been at the forefront of manufacturing generic life-saving drugs. Under its Patent Act, medications that are not new do not qualify for patent protection; I-Mak argues that sofosbuvir is “old science” stemming from a long line of antiretroviral drugs.

The World Trade Organization’s 1995 Trade-related Aspects of Intellectual Property Rights (TRIPS) agreement laid down minimum standards for patent laws. There is, however, “some flexibility for countries to determine what is meant under the criteria of patentability”, says Torreele, citing I-MAK’s case against Gilead’s sofosbuvir patent.

Since social activism helped force down the cost of AIDS drugs with generic alternatives over a decade ago, “the world has changed,” says Torreele. “The solutions to making HIV drugs affordable are not there anymore.”

While TRIPS makes allowances for governments to override patent laws to protect public health, “there is lots of pressure by the pharmaceutical industry on them to avoid these measures”.

And negotiations, spearheaded by the US, are currently taking place with 11 other countries to finalize the Transpacific Partnership Agreement, a trade deal that some worry could undermine the flexibility allowed by TRIPS.

pg/rz

Theme (s): Aid Policy, Health & Nutrition, HIV/AIDS (PlusNews),

[This report does not necessarily reflect the views of the United Nations]

Source

MicroRNA profile before and after antiviral therapy in liver transplant recipients for hepatitis C virus cirrhosis

Journal of Gastroenterology and Hepatology

Volume 29, Issue 1, pages 121–127, January 2014

Hepatology

Fanni Gelley², Gergely Zadori², Balazs Nemes², Matteo Fassan⁴,Gabor Lendvai¹, Eniko Sarvary², Attila Doros²,  Zsuzsanna Gerlei², Peter Nagy³, Zsuzsa Schaff¹, Andras Kiss^1,*

Article first published online: 19 DEC 2013

DOI: 10.1111/jgh.12362

© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

Keywords: HCV receptors;  HCV; liver transplantation;  microRNA;  SVR

Abstract

Background and Aim

Management of hepatitis C virus (HCV) recurrence is a major challenge after liver transplantation. Significant dysregulated expression of HCV receptors (i.e. claudin-1, occludin, tetraspanin CD81, scavenger receptor type B1) has been shown recently during HCV infection. This might facilitate hepatocytic entry and reinfection of HCV. MicroRNAs (miRs) play role in the regulation of gene expression. We aimed to characterize miR expression profiles related to HCV infection and antiviral therapy in adult liver transplant recipients, with special emphasis on miRs predicted to target HCV receptors.

Methods

Twenty-eight adult liver transplant recipients were enrolled in the study. Paired biopsies were obtained at the time of HCV recurrence and at the end of antiviral treatment. MiRs for HCV receptors were selected using target prediction software. Expression levels of miR-21, miR-23a miR-34a, miR-96, miR-99a*, miR-122, miR-125b, miR-181a-2*, miR-194, miR-195, miR-217, miR-221, and miR-224 were determined by reverse transcription–quantitative polymerase chain reaction.

Results

miR-99a* and miR-224 expressions were increased in HCV recurrence samples, while miR-21 and miR-194 were decreased in comparison to normal liver tissue. Increased expressions of miR-221, miR-224, and miR-217 were observed in samples taken after antiviral therapy when compared with HCV recurrence samples. High HCV titer at recurrence was associated with higher level of miR-122.

Conclusions

Samples at recurrence of HCV and after antiviral therapy revealed distinct HCV-related miR expression profiles, with significant dysregulation of those miRNAs potentially targeting mRNAs of HCV receptors. In particular, miR-194 and miR-21 might be involved in the regulation of HCV receptor proteins' expression during HCV infection and antiviral therapy.

Source

HIV Life Expectancy Approaches That Of Average Young American, But At What Quality Of Life?

By Chris Weller | Dec 20, 2013 02:22 PM EDT

(Reuters)  People with HIV can now expect to live into their early 70s. But what kind of life will that longevity entail?

Thanks to antiretroviral therapy, a combination of drugs that suppresses the spread of HIV (human immunodeficiency virus) within the body, young patients who are HIV-positive now enjoy a life expectancy that rivals the average American, a new study finds.

Underlying this shining discovery, however, is the sobering question of what state these young patients will live out their remaining years in. Barring the potential development of a cure, HIV management comes with a mountain of side-effects, some of which are devastating conditions on their own. And since each patient’s case is unique, the combination of certain drug therapies, patient background, and interaction with other drugs and risk factors may make antiretroviral therapy (ART) the key to longevity but not necessarily to rejuvenation.

“[It is] nothing short of miraculous, given where we were 20 years ago,” Dr. Mark Smith, president of the California Health Care Foundation, not involved in the study, and who treats people with HIV, told Healthline. “It's a stunning success story for biomedical science and has contributed greatly to our understanding of other viruses and disease processes as well."

Researchers collected data on 23,000 patients as part of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), each aged 20 years and older. They took a look at death rates across various time periods, finding that life spans increased from 36.1 years in 2000 to 2002 to 51.4 in 2006 to 2007. Extrapolating for today’s advances and current treatment methods, the team estimated that people living with HIV could potentially live into their early seventies, or roughly the equivalent of the average American.

Unfortunately, the news isn’t all good. Whites were significantly more likely to outlive non-whites, and people with no prior drug use had much better chances than people who had used drug intravenously. While a young white HIV patient may live into his or her seventies, drug users typically lived until age 49 and non-whites until age 58. “Across the board, communities of color fare worse than their white counterparts,” Kyle Murphy, assistant director of communications for the National Minority AIDS Council, toldHealthline. “They are diagnosed much later and are less likely to be retained in care or to be virally suppressed.”

Meanwhile, HIV treatment remains a challenge for all. From minor abdominal pain and dizziness to renal failure and HIV-associated neurocognitive disorder, the side-effects of antiretroviral drugs depend on a raft of different factors. If patients don’t follow their drug therapy regimens, they raise their risk of transmitting the disease to others, as it is now less suppressed and can more easily do damage. And despite some theories of “hit hard, hit early” in order to minimize this damage, the costs of facilitating such treatment can run patients into enormous debt.

In the end, however, extending patient life spans is seen by many as a universal good. It means the drug therapies are working. Indeed, certain researchers are skeptical that a cure may never be found, as it means less profit from repeat medication buyers. But on a personal level, it means a great deal. Smith, for instance, has a patient with HIV who is 70 years old.

“He walks his grandkids to school," Smith explained. "The irony is that now I have to worry about the same things I worry about with any 70-year-old — lipids, blood pressure, etc. Five years ago, frankly, I didn't spend a lot of time on mildly elevated blood pressure in people with HIV.”

Source: Samji H, Cescon A, Hogg R. Closing the Gap: Increases in Life Expectancy among Treated HIV-Positive Individuals in the United States and Canada. PLoS One. 2013.

Source

FDA Hepatitis Update - Changes to the Baraclude (entecavir) package and label

You are receiving this message as a subscriber to the FDA hepatitis electronic list serve. The purpose of the list serve is to relay important information about viral hepatitis-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.
Please do not reply to this message.

Changes have been made to the Baraclude (entecavir) label to reflect a new protective outer cardboard carton added as secondary packaging for 0.5 and 1 mg tablets, intended to help avoid exposure to light.  The container has been updated with the wording "Protect from Light."

The label reflects the change under 16 HOW SUPPLIED/STORAGE AND HANDLING as follows:

Storage
BARACLUDE Tablets should be stored in a tightly closed container at 25° C (77° F); excursions
permitted between 15–30° C (59–86° F) [see USP Controlled Room Temperature]. Store in the
outer carton to protect from light.

BARACLUDE Oral Solution should be stored in the outer carton at 25° C (77° F); excursions
permitted between 15–30° C (59–86° F) [see USP Controlled Room Temperature]. Protect from light. After opening, the oral solution can be used up to the expiration date on the bottle. The bottle and its contents should be discarded after the expiration date.

The Patient Product Information similarly summarizes the storage information as follows:

How should I store BARACLUDE?

• Store BARACLUDE Tablets or Oral Solution at room temperature, between 59° F to 86° F (15° C to 30° C).

• Keep BARACLUDE Tablets in a tightly closed container.

• Do not store BARACLUDE Tablets in a damp place such as a bathroom medicine cabinet or near the kitchen sink.

• Store BARACLUDE Tablets or BARACLUDE Oral Solution in the original carton, and keep the carton out of the light.

The complete revised label will be posted at Drugs@FDA.

Baraclude is a nucleoside analogue indicated for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

Baraclude is a product of the Bristol-Myers Squibb Company

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

If you are interested in receiving information about a broader range of FDA topics, consider subscribing to the FDA Patient Network News, a twice monthly newsletter containing FDA-related information on a variety of topics, including new product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings, proposed regulatory guidances and opportunity to comment, and other information of interest to patients and patient advocates.

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Treating HCV Infection in Patients Receiving Hemodialysis

December 17, 2013

Atif Zaman, MD, MPH reviewing Liu CH et al. Ann Intern Med 2013 Dec 3.

Until next-generation drugs become approved for this population, adding low-dose ribavirin to standard peginterferon therapy improves sustained virologic response.

Although the next-generation regimens for hepatitis C virus (HCV) are effective, currently, the standard approved regimen for patients receiving hemodialysis is still peginterferon plus low-dose ribavirin (200 mg/day). The addition of low-dose ribavirin was approved by the FDA in August 2011. However, that approval was based on small studies that were very heterogeneous with regard to treatments, HCV genotypes, and endpoints. Therefore, the efficacy and safety of combination therapy compared with monotherapy in this population is unclear.

In the current open-label, randomized, controlled trial, 205 treatment-naive patients with genotype 1 HCV infection receiving hemodialysis were randomized to receive either peginterferon alone (135 µg weekly) or in combination with ribavirin (200 mg daily) for 48 weeks. Outcomes were sustained virologic response (SVR) rate and adverse event–related withdrawal rate.

SVR was significantly higher in the combination group compared with the monotherapy group (64% vs. 33%, respectively; P<0.001). As expected, significant anemia (hemoglobin level <8.5 g/dL) was higher among the patients receiving ribavirin (72% vs. 6%; P<0.001), who also required higher doses of erythropoietin (P=0.006) for a longer duration (P=0.004). Adverse event–related withdrawal rates were similar in the combination and monotherapy groups (7% and 4%).

COMMENT

In this large treatment study, sustained virologic response was higher with combination peginterferon and ribavirin compared with monotherapy in patients with genotype 1 hepatitis C virus infection receiving hemodialysis. Using the very low dose of 200 mg daily of ribavirin not only achieved an SVR rate comparable to that reported in patients who were not receiving hemodialysis, but also kept the discontinuation rate due to adverse events low. While we wait for the safety and efficacy data of the new HCV regimens in patients receiving hemodialysis, peginterferon plus low-dose ribavirin is a viable option.

Editor Disclosures at Time of Publication

CITATION(S):

1. Liu CH et al. Pegylated interferon-α2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 1 receiving hemodialysis: A randomized trial. Ann Intern Med 2013 Dec 3; 159:729. (http://dx.doi.org/10.7326/0003-4819-159-11-201312030-00005)

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Role of Magnetic Resonance Elastography in compensated and decompensated liver disease

Journal of Hepatology

Article in Press

Sumeet K. Asrani, Jayant A. Talwalkar, Patrick S. Kamath, Vijay H. Shah, Giovanna Saracino, Linda Jennings, John B. Gross, Sudhakar Venkatesh, Richard L. Ehman

Received 12 June 2013; received in revised form 27 November 2013; accepted 9 December 2013. published online 20 December 2013.
Accepted Manuscript

Abstract

Background and Aims

Non-invasive predictors identifying subjects with compensated liver disease at highest risk for transitioning to a decompensated state are lacking. We hypothesized that liver shear stiffness as measured by magnetic resonance elastography is an important non-invasive predictor of hepatic decompensation.

Methods

Among patients with advanced fibrosis undergoing magnetic resonance elastography (2007-11), a baseline cohort and follow up cohort (compensated liver disease) were established. Cause specific cox proportional hazards analysis adjusting for competing risks was utilized to determine the association between elevated liver shear stiffness and development of decompensation (hepatic encephalopathy, ascites, variceal bleeding).

Results

In the baseline cohort (n=430), subjects with decompensated liver disease had a significantly higher mean liver shear stiffness (6.8 kPa, IQR 4.9-8.5) as compared to subjects with compensated liver disease (5.2 kPa, IQR 4.1-6.8). After adjustment for Model for End Stage Liver Disease score, hepatitis C, age, gender, albumin, and platelet count, the mean liver shear stiffness (OR=1.13, 95%CI 1.03-1.27) was an independently associated with decompensated cirrhosis at baseline. Over a median follow up of 27 months (n=167), 7.2% of subjects with compensated disease experienced hepatic decompensation. In the follow up cohort, the hazard of hepatic decompensation was 1.42 (95% CI 1.16 -1.75) per unit increase in liver shear stiffness over time. The hazard of hepatic decompensation was 4.96 (95% CI 1.4-17.0, p=0.019) for a subject with compensated disease and meanLSS value greater then or equal to 5.8 kPa as compared to an individual with compensated disease and lower mean LSS values.

Conclusion

Baseline liver shear stiffness assessed by magnetic resonance elastography is independently associated with decompensated liver disease.

Abbreviations: LSS, Liver shear stiffness, MRE, magnetic resonance elastography, HCV, hepatitis C, MELD, model for end stage liver disease, CI, confidence interval, OR, Odds ratio

Keywords: Non invasive, Outcomes, Natural history, Prognosis, Cirrhosis

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Increased Long-Term Survival Among Patients with Hepatocellular Carcinoma After Implementation of Model for End-Stage Liver Disease Score

Clinical Gastroenterology and Hepatology

Article in Press

Robert J. Wong, Pardha Devaki, Long Nguyen, Ramsey Cheung, Cheryl Cho-Phan, Mindie H. Nguyen

Received 29 July 2013; received in revised form 14 November 2013; accepted 6 December 2013. published online 19 December 2013.
Accepted Manuscript

Abstract

Background & Aims

Assignment of model for end-stage liver disease (MELD) exception points to patients with hepatocellular carcinoma (HCC) who fall within Milan criteria, which began in 2003, increases their priority on liver transplantation waitlists. However, little is known about how this change affected survival of all patients with HCC (transplant eligible and ineligible). We compared long-term survival of HCC patients before and after this change.

Methods

We performed a large population-based cohort study using the Surveillance, Epidemiology, and End Results cancer registry to investigate survival times of patients with HCC before those who met the Milan criteria were given MELD exception points (1998–2003) and afterward (2004–2010), using Kaplan Meier methods. Multivariate Cox proportional hazards models evaluated independent predictors of survival.

Results

During 2004–2010, a significantly higher percentage of patients with HCC survived for 5 years compared to 1998-2003 (21.9% vs 13.0%, P<.001). This difference remained significant among all treatment groups (no therapy: 15.2% vs 10.2%, P<0.001; local tumor destruction: 37.6% vs 22.1%, P<0.001; resection: 55.5% vs 39.2%, P<0.001; transplantation: 77.2% vs 73.1%, P =0.12). Multivariate Cox proportional hazards models, inclusive of sex, age, ethnicity, Milan criteria, number and stage of tumor, and time period, showed increased survival of patients during 2004–2010 (hazard ratio [HR], 0.87; 95% confidence interval, 0.83–0.91; P<.001). Compared to non-Hispanic whites, Asians (HR, 0.81; 95% CI, 0.77–0.86; P<.001) and Hispanics (HR, 0.89, 95% CI, 0.84–0.95; P<.001) had longer survival times, whereas blacks had a trend toward shorter survival times (HR, 1.05; 95% CI 0.98–1.13; P=.16).

Conclusions

Patients with HCC who met Milan criteria had significantly longer survival times after implementation of the MELD exception points, regardless of sex or ethnicity. Blacks continued to have the lowest rates of 5 year survival.

Keywords: SEER, racial disparities, liver cancer, resource allocation

Abbreviations: CI, confidence interval, HCC, hepatocellular carcinoma, HR, hazard ratio, MELD, model for end stage liver disease, SEER,surveillance, epidemiology, and end results, TACE, transarterial chemoembolization, UNOS, United Network for Organ Sharing

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Similar Effectiveness of Boceprevir and Telaprevir Treatment Regimens for Hepatitis C Virus Infection, Based on a Nationwide Study of Veterans

Clinical Gastroenterology and Hepatology

Article in Press

George N. Ioannou, Lauren A. Beste, Pamela K. Green

Received 14 October 2013; received in revised form 18 November 2013; accepted 2 December 2013. published online 19 December 2013.
Accepted Manuscript

Abstract

Background

& Aims: We investigated the real-world effectiveness of triple therapy regimens against hepatitis C virus (HCV) and compared rates of sustained virologic response (SVR) between telaprevir- and boceprevir-based regimens in a population-based study.

Methods

We analyzed data on all patients in the Veterans Administration (VA) healthcare system who were infected with HCV genotype 1 and began treatment with pegylated interferon, ribavirin, and either boceprevir (n=3696, 83%) or telaprevir (n=759, 17%) from June 2011 through February 2013.

Results

Patients treated with telaprevir were more likely to have baseline characteristics associated with not achieving SVR than patients treated with boceprevir. Fewer than half of patients eligible for short-duration regimens (28 weeks for boceprevir, 24 weeks for telaprevir) successfully completed treatment (37% for boceprevir, 27.5% for telaprevir); ∼25% discontinued early and the remaining patients were treated for longer durations. Of patients who were supposed to complete 48-week regimens, only 35% of boceprevir- and 34% of telaprevir-treated patients completed >44 weeks. The rate of SVR was 51.5% overall, 42.7% among patients with cirrhosis, 56.8% among treatment-naïve patients, 64.2% among prior relapsers, 31.7% among prior partial-responders, and 29.8% among prior null responders. There were no significant differences in rate of SVR between patients given boceprevir or telaprevir, in the entire population or among subgroups. The most important predictors of failure to achieve SVR were IL28B genotype, high viral load, Black race, diabetes, high APRI or FIB-4 scores, low platelet counts, or low levels of low-density lipoprotein cholesterol. Erythropoietin use was not associated with SVR.

Conclusions

In a nationwide analysis of Veterans with HCV genotype 1 infection, rates of SVR are similar for those treated with boceprevir vs telaprevir. However, rates of treatment completion and SVR in real clinical practice are substantially lower than those in clinical trials.

Keywords: DAA, antiviral therapy, population, APRI, outcome, LDL

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Tulane researcher gets $2.6M in grants for hepatitis studies

THE ASSOCIATED PRESS  
December 22, 2013 - 9:35 am EST

NEW ORLEANS — Tulane University pathology professor Srikanta Dash has been awarded two National Institutes of Health grants totaling $2.6 million to study why some patients respond and other develop resistance to standard treatments for chronic hepatitis C.

The disease is the most common cause of end-stage liver disease.

Dash, director of Tulane's hepatitis research laboratory, received a $1.4 million, four-year grant from the National Institute of Allergy and Infectious Diseases to explore the mechanisms behind a gene that plays a critical role in whether a patient with hepatitis C responds to antiviral treatment.

The second award is a $1.2 million National Cancer Institute grant to study how chronic hepatitis C develop resistance to interferon therapies.

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CDC Viral Hepatitis Updates: CDC Guidance for Evaluating Health-Care Personnel for Hepatitis B Virus Protection and for Administering Postexposure Management

Centers for Disease Control and Prevention (CDC) sent this bulletin at 12/19/2013 01:50 PM EST

Viral Hepatitis Updates from CDC

MMWR - CDC Guidance for Evaluating Health-Care Personnel for Hepatitis B Virus Protection and for Administering Postexposure Management

The MMWR is an extension of the ACIP 2011 recommendations for evaluating hepatitis B protection among health-care personnel (HCP) and administering post-exposure prophylaxis. The MMWR emphasizes the importance of administering Hepatitis B vaccination for all health-care personnel and provides explicit guidance for evaluating hepatitis B protection among previously vaccinated health-care personnel (particularly those who were vaccinated in infancy or adolescence), and it clarifies recommendations for postexposure management of health-care personnel exposed to blood or body fluids. This new guidance can assist clinicians, occupational health and student health providers, infection-control specialists, hospital and health-care training program administrators, and others in selection of an approach for assessing Hepatitis B protection for vaccinated health-care personnel.
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6210a1.htm

Testing Asian Americans & Pacific Islanders for Hepatitis B – Clinical Summary

Studies have shown that while Asian Americans and Pacific Islanders (AAPI) represent 5% of the total U.S. population, they make up 50% of hepatitis B cases. Nearly 2 in 3 people living with chronic hepatitis B do not know they are infected. Testing for chronic hepatitis B plays an important role in the detection, classification, management and medical care for patients with hepatitis B. This fact sheet outlines who should be tested for Hepatitis B with an HBsAg test, the geographic distribution of chronic hepatitis B infection worldwide, recommended follow-up for a positive HBsAg, and interpretation of serologic tests.
http://www.cdc.gov/hepatitis/HBV/PDFs/HepB-API.pdf

Know Hepatitis B Campaign Materials

Know Hepatitis B a national communications campaign promoting Hepatitis B testing among Asian Americans and Pacific Islanders (AAPIs).  Four languages have been added:  Burmese , Hmong,  Khmer, and Lao to campaign materials already available in Chinese, Vietnamese, Korean, and English. English, Chinese, Korean, Vietnamese and multi-lingual posters are also now available for ordering.

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Roadmap of miR-122-related clinical application from bench to bedside

Expert Opin Investig Drugs. 2013 Dec 20. [Epub ahead of print]

Qiu Z, Dai Y.

Abstract

Introduction: microRNA (miRNA) regulates target gene expression to influence many physiological and pathophysiological processes. The liver-specific miRNA, miR-122, contributes to liver function and plays a very important role in hepatic diseases including the viral hepatitis C (HCV). For this reason, developing an miR-122-related clinical application could be very useful in managing or treating many hepatic disorders. Areas covered: This review introduces the basic concepts of miRNA and miR-122. It also discusses the possibility of miR-122 as a biomarker and summarizes the results of anti-miR-122 treatment from basic research to a Phase IIa clinical trial. Furthermore, the authors discuss the potential opportunities and challenges found in clinical trials with miravirsen. Expert opinion: miR-122 may be a useful biomarker as both a diagnostic and prognostic tool. Furthermore, miravirsen is a novel treatment with great potential for hepatic disease treatment, especially in HCV. However, there is certainly the need for future investigations to better determine whether miR-122 is really specific for liver. It is also important to elucidate whether miR-122 is actually specific for HCV genome and further investigate the therapeutic potential of miravirsen. Only once these studies have been completed can anti-miR-122 treatment potentially enter the clinical practice.

PMID: 24354366 [PubMed - as supplied by publisher]

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Self-Efficacy and Adherence to Antiviral Treatment for Chronic Hepatitis C

J Clin Gastroenterol. 2013 Dec 18. [Epub ahead of print]

Bonner JE, Esserman DA, Golin CE, Evon DM.

Abstract

GOALS:: To investigate the role of self-efficacy (SE) during hepatitis C virus (HCV) treatment.

BACKGROUND:: Adherence to chronic HCV treatment is critical. SE is an important predictor of medication adherence in a number of chronic disease populations and medication regimens, but its role during HCV treatment remains unknown.

STUDY:: Data from the prospective Virahep-C study were analyzed to examine relationships between SE and patient-driven deviations (ie, missed doses measured using electronic pill caps, and nonpersistence) from adherence to HCV antiviral treatment. SE was measured using the 17-item HCV Treatment Self-Efficacy scale. This measure provides a global estimate of a patient's confidence to undergo and adhere to HCV treatment, and can estimate SE in 4 underlying domains: communication SE (ie, confidence to communicate with health care provider), physical coping SE (ie, confidence to cope with physical side effects), psychological coping SE (ie, confidence to cope with psychiatric side effects), and treatment adherence SE (ie, confidence to take all medications as prescribed and attend doctor visits). Generalized estimating equations and Cox proportional hazards models were used to assess associations between SE and missed doses and nonpersistence, respectively.

RESULTS:: SE was associated with being in a relationship, educated, privately insured, and less depressed. Higher communication SE at TW24 reduced the risk of missed doses between TW24 and TW48. Higher baseline treatment adherence SE reduced the likelihood of nonpersistence between baseline and TW24.

CONCLUSIONS:: SE's relationship to HCV treatment adherence has promising clinical and research implications.

PMID: 24356458 [PubMed - as supplied by publisher]

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Once-daily simeprevir in combination with pegylated-interferon and ribavirin: a new horizon in the era of direct-acting antiviral agent therapy for chronic hepatitis C

J Gastroenterology
DOI 10.1007/s00535-013-0926-7

Shinya Maekawa • Nobuyuki Enomoto
Received: 7 December 2013 / Accepted: 10 December 2013
Springer Japan 2013

Hepatitis C virus (HCV) is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC), and it is estimated that infected individuals total 185 million people worldwide. In Japan, around 2 million are infected with HCV, and more than 20 thousand die from HCV-induced HCC annually. Though viral eradication with antiviral therapies is the most important and effective choice for decreasing HCC-related deaths induced by HCV, complete viral eradication has been quite difficult till recently, especially in patients with genotype-1 HCV infection because of the low response rate to interferon (IFN)-based therapy [1, 2].

In this background, development of novel direct-acting antiviral agents (DAAs) specific for HCV was truly a revolutionary event. In 2011, two first-generation NS3 protease inhibitors (PIs), telaprevir and boceprevir, were firstly approved among all the DAAs for clinical use in USA and Europe for genotype-1 HCV in combination with pegylated-interferon and ribavirin (PR), while telaprevir was approved in Japan in the same 2011 period. As expected, a regimen including telaprevir in combination with pegylated-interferon and ribavirin dramatically improved the sustained viral response (SVR) rate to as high as 80 % in genotype-1 HCV infection. On the other hand, telaprevir has several undesirable problems. Among all, adverse events (AEs) of anemia and skin rash are serious problems of telaprevir, and Grade 3/4 skin disorders, including Stevens–Johnson syndrome and drug rashes with eosinophilia and systemic symptoms, as well as Grade 3 anemia (\8.0 g/dL), might occur [3, 4]. Moreover, cumbersome frequent dosing three times a day (every 7–9 h) could induce poor medication adherence. Under the circumstances, it has been quite stressful for patients as well as clinicians to introduce and monitor this telaprevir-based regimen.

Simeprevir (SMV, TMC435) is classified as a second generation PI with the macrocyclic structure having an advantage in the binding affinity and specificity for NS3 protease compared to the first-generation PI with the linear structure. Due to the difference in the structure, the drugresistance profile is somewhat different from that of telaprevir. Though simeprevir shows cross-resistance with telaprevir at amino acid positions of 155 and 156, most of the resistant mutation occurs at the simeprevir-specific amino acid position of 168 [5]. Though simeprevir is effective in all viral genotypes (genotype 1–6), it has the strongest antiviral activity for genotype-1a and -1b HCV infection. In particular, low AE rate and its patient-friendly once-daily dosing are the important characters of simeprevir aside from its strong antiviral activity. In the international phase II trials of simeprevir in combination with PegIFNa-2a/RBV for treatment-naı¨ve (PILLAR study) [6] and treatment-experienced patients (ASPIRE study) [7] for HCV genotype 1-infected patients, it was demonstrated that simeprevir was generally well tolerated and had a pharmacokinetic profile supporting once-a-day (QD) dosing resulting in high virologic response rates.

In this issue of the Journal of Gastroenterology, Hayashi et al. [8] reported the important results of the phase II Dose and duration Ranging study of Antiviral agent TMC435 in Genotype One HCV treatment-Naı¨ve patients (DRAGON study; TMC435-C215) evaluating once-daily simeprevir with pegylated-interferon and ribavirin therapy for treatment- naı¨ve, high viral-loaded hepatitis C genotype 1-infected patients in Japan. Due to the result of previous phase I study that simeprevir plasma concentration was higher in Japanese healthy volunteers compared with Caucasian volunteers, simeprevir doses of 50/100 mg QD were selected for this study, while simeprevir doses of 150 mg QD were selected in western countries [9]. Through investigating five treatment groups (SMV12/PR24 50 mg, SMV12/PR24 100 mg, SMV24/PR24 50 mg, SMV24/PR24 100 mg, and PR48), it was disclosed that simeprevir-combined groups all achieved high SVR rate (77–92 % compared to 46 % for PR). As to the AEs, simeprevir was well tolerated, and the incidence of anemia and skin rash were similar in their frequency and their grade between all the SMV groups and the PR group. Due to low AEs, therapy discontinuation rate and ribavirin dose reduction was also similar in the SMV groups and the PR group. While an AE of bilirubin elevation was specific to simeprevir, and it reached to grade 3 (2.6–5.0 mg/dL) to 4 ([5.0 mg/dL) in four patients (5 %) leading to the discontinuation of simeprevir in these individuals, the bilirubin level returned to baseline after the end of simeprevir in those patients. Since bilirubin elevation is considered to result from the blockade of bilirubin clearance-associated OATP1B1 and MRP transporters by simeprevir [10], it is considered that the bilirubin elevation by simeprevir does not reflect deterioration of liver function.

Following the results of this phase II DRAGON study, treatment dosage of simeprevir was determined as 100 mg QD in Japan, and successive phase III CONCERTO studies for simeprevir/pegylated-interferon/ribavirin therapy have been conducted (CONCERTO-1 for treatment-naı¨ve, -2 for previous null responder, -3 for previous relapser, and -4 for naı¨ve, null responder and relapser). After the completion of those CONCERTO studies with favorable outcomes for simeprevir-based regimens, once-daily simeprevir with pegylated-interferon and ribavirin therapy for high viralloaded hepatitis C genotype 1-infected patients was just recently approved for clinical use in Japan.

Considering the history of HCV therapy, this new therapy of once-daily simeprevir with pegylated-interferon and ribavirin therapy is ideal in its high efficacy and low AEs. Of course, it is true that DAA combination therapies without IFN (IFN-free therapies) would appear in the near future, and that these IFN-free therapies are advantageous in that they are free from IFN-related AEs. However, in terms of DAA-resistant viral mutants, it is considered that these mutant HCVs generally have low replication fitness, and are sensitive to IFN. Therefore, it is speculated that IFN-based DAA therapies compared to IFN-free DAA therapies are safer in preventing the development of multidrug resistant HCVs.

Taken together, the new regimen of once-daily simeprevir with pegylated-interferon and ribavirin therapy would surely be an important milestone in the therapy for high viral-loaded hepatitis C genotype-1 infected patients in the era of DAA therapy.

References

1. Kim MN, Kim BK, Han KH. Hepatocellular carcinoma in patients with chronic hepatitis C virus infection in the Asia- Pacific region. J Gastroenterol. 2013;48(6):681–8.

2. Thomas DL. Global control of hepatitis C: where challenge meets opportunity. Nat Med. 2013;19(7):850–8.

3. Chayama K, Hayes CN, Ohishi W, Kawakami Y. Treatment of chronic hepatitis C virus infection in Japan: update on therapy and guidelines. J Gastroenterol. 2013;48(1):1–12.

4. Kumada H, Toyota J, Okanoue T, Chayama K, Tsubouchi H, Hayashi N. Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan. J Hepatol. 2013;56(1):78–84.

5. Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, et al. In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435. Antimicrob Agents Chemother. 2010;54(5):1878–87.

6. Fried MW, Buti M, Dore GJ, Flisiak R, Ferenci P, Jacobson I, et al. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naive genotype 1 hepatitis C: the randomized PILLAR study. Hepatology. 2013;58(6):1918–29.

7. Zeuzem S, Berg T, Gane E, Ferenci P, Foster GR, Fried MW, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology. 2013. doi:10.1053/j. gastro.2013.10.058.

8. Hayashi N, Seto C, Kato M, Komada Y, Goto S. Once-daily simeprevir (TMC435) with peginterferon/ribavirin for treatmentnaı ¨ve hepatitis C genotype 1-infected patients in Japan: the DRAGON study. J Gastroenterol. 2013. doi:10.1007/s00535-013- 0875-1.

9. Verloes R, Shishido A. Phase I safety and PK of TMC435 in healthy volunteers and safety, PK and short-term efficacy in chronic hepatitis C infected individuals. Kobe: Abstract O-32 presented at the Japanese Hepatology Congress; 2009. p. 4–5.

10. Huisman MT, Snoeys J, Monbaliu J, Martens M, Sekar V, Raoof A. In vitro studies investigating the mechanism of interaction between TMC435 and hepatic transporters. Poster 278 presented at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), Boston, USA, October 29– November 2, 2010.

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What a Year for Harm Reduction!

Provided by The Huffington Post

Hilary McQuie
Western Regional Director, Harm Reduction Coalition

Posted: 12/22/2013 9:16 am

Harm reduction is a movement for social justice built on a belief in, and respect for, the rights of people who use drugs. Harm reduction is also a set of practical strategies and ideas aimed at reducing negative consequences associated with drug use. Although those working in harm reduction believe that drug criminalization maximizes harm, the focus of most harm reduction policy and practice is in the borderlands between legalization and prohibition. To quote an old social justice slogan, harm reduction is the art of "building a new society in the vacant lots of the old." And those lots are filling up, due to the hard work of people around the world. Here are 10 of the most important harm reduction developments in North America in 2013:

1. "Needle Exchange" in the US Turns 25

A quarter of a century ago, public health activists started doing needle exchange in Tacoma, WA, San Francisco, CA, and New York, NY. These efforts, now referred to as 'syringe access programs', spread and continued and have been widely recognized as the single most successful HIV prevention intervention. To date, however, they are legally excluded from receiving access to the federal funding enjoyed by all other HIV prevention efforts. Perhaps in 2014, we can report that the federal funding ban for syringe access programs was finally lifted for good.

2. States Decriminalize Syringes to Increase Safe Syringe Access

Syringe access policy varies by state, and this year, community organizing led the Nevada legislature to finally pave the way for syringe access programs and over the counter pharmacy sales by fully decriminalizing syringes, making it one of the strongest state enabling laws for syringe access programming. North Carolina partially decriminalized syringes to protect law enforcement from needlestick injury, but without legalizing their existing syringe access programs, yet.

3. Laws Passed in Six States to End Overdose Epidemic by Providing Antidote

Opioid overdose has surpassed auto accidents as the leading cause of accidental death in the US. New laws were passed this year in six states to encourage health care providers and community programs to widely distribute naloxone to treat opioid overdose incidents. Additionally, new programs started providing naloxone access in Colorado, Vermont, North Carolina, Kentucky, Ohio, New Jersey, Minnesota, and Missouri this year. Naloxone is used in opioid overdoses to counteract life-threatening depression of the central nervous system and respiratory system, allowing an overdosing person to breathe normally. Although traditionally administered by emergency response personnel, naloxone can be administered by minimally trained laypeople, which makes it ideal for treating overdose in people who have been prescribed opioid pain medication and in people who use heroin and other illicit opioids.

4. Opioid Overdose Antidote Provided by Rhode Island Walgreens Pharmacists Directly to Patients

2013 saw a statewide scale up of a collaborative pharmacy practice agreement for naloxone, bringing naloxone to all 26 Walgreens stores in Rhode Island and training 80 Walgreens pharmacists in how to counsel patients on, train in, and dispense naloxone (without a prescription) to anyone who asks for it.

5. Federal Agencies Declare Support for Peer-Delivered Naloxone Distribution

Under the Bush Administration, officials in the Office of National Drug Control Policy (ONDCP) opposed peer-delivered naloxone. Then Deputy Director Bertha Madras said drug users "aren't likely to be competent to deal with an overdose emergency", and stated that "rescue programs might take away the drug user's motivation to get into detoxification and drug treatment". Obama's White House Office of National Drug Control Policy takes a position 180 degrees from Madras, supports overdose prevention and naloxone programs, and included them in the 2013 Drug Control Strategy. Also this year, the drug treament agency of the federal government, the Substance Abuse and Mental Health Services Administration (SAMHSA) published their long-awaited "Opioid Overdose Prevention Toolkit" which has five components targeting first responders, community members, patients, prescribers, and overdose survivors and their family members. The toolkit provides information on naloxone distribution and prescription and overdose prevention. Peer-delivered naloxone distribution has definitely gone from an underground movement to a mainstream-supported strategy in 2013. Next year, perhaps we can report some funding for this critical yet unfunded lifesaver.

6. Jail-Based Overdose Prevention and Naloxone Distribution Begins

Opiate overdoses are all too common among people released from jail due to decreased tolerance. In March 2013, the Harm Reduction Coalition's Drug Overdose Prevention and Education (DOPE) Project began providing naloxone to inmates of the San Francisco County Jail as they were discharged. The DOPE Project, in collaboration with SFDPH's Jail Health Services, conducts overdose prevention trainings inside the jail, and is able to put naloxone kits in the property of inmates who choose to participate for pick up when they are released. This is the first non-research study in the country to begin providing naloxone directly to inmates as they re-enter the community.

7. Good Samaritan Laws for People Witnessing Overdoses Gain Traction, Law Enforcement Support

Community activists have been working to get Good Samaritan laws passed to protect people from arrest and prosecution for drug possession when they call 911 to report an overdose. Fourteen states have now enacted these laws, as have ninety college campuses. The Florida effort in 2012 was notably initiated by Palm Beach police, a harbinger of change in law enforcement support for harm reduction measures.

8. Newly-Approved Hepatitis C Treatments Move Closer to Making Interferon-Free Cure a Reality for People Who Inject Drugs.

Hepatitis C remains endemic among people who inject drugs, with chronic infection rates of 70% or more among long-term injectors. While new infections have declined dramatically since peaking in the 1980s, due in part to the expansion of syringe access programs, several states report a new wave of hepatitis C infections among younger injectors. While hepatitis C is curable, treatment has traditionally required use of interferon, a drug with significant psychological and physical side effects that does not work for everyone and is difficult to tolerate for many, particularly current and former substance users. In December, the US Food and Drug Administration (FDA) approved a new hepatitis C medication sofosbuvir (Sovaldi, Gilead Sciences, Inc), which can be used without interferon for some people. Other therapies in development offer hope that all people with hepatitis C will have interferon-free treatment options available by the end of 2014.

9. Community Organizes to Mandate Hepatitis C Testing in New York

An estimated 3-4 million people are infected with the hepatitis C virus, and three quarters of them are unaware of it. Baby boomers - those born between 1945 and 1965 - make up over 70% of people with chronic infection, and are at highest risk of liver complications. Following CDC's 2012 recommendation of a one-time hepatitis C test for all baby boomers, a coalition of harm reduction workers, people who use drugs, and other allies passed a bill in New York mandating that doctors inform their patients and offer a hepatitis C test. As better-tolerated treatments with high cure rates become available, this legislation ensures that thousands of lives that may have been lost to liver cancer and other hepatitis C complications are diagnosed and treated.

10. Montreal Approved to Open Four Supervised Injection Sites

There are approximately 90 supervised injection sites worldwide in Europe and Australia, and only one in North America: InSite in Vancouver, British Columbia. After InSite's long legal fight with their conservative government, Canada's Supreme Court ruled in 2009 that the potential denial of health services and the correlative increase in the risk of death and disease to injection drug users outweigh any benefit that might be derived from maintaining an absolute prohibition on possession of illegal drugs on InSite's premises, allowing the facility to stay open indefinitely. In 2009, the site recorded 276,178 visits (an average of 702 visits per day) by 5,447 unique users; 484 overdoses occurred with no fatalities, due to intervention by medical staff. This month, Montreal was given permission to open four injection sites of their own, ensuring that Vancouver's InSite is the first but not the last legal supervised injection site in North America. Perhaps we finally succeed in opening one in the US in 2014.

Hilary McQuie is Regional Director of the Harm Reduction Coalition, and is based in Oakland, CA http://harmreduction.org/

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