December 16, 2013

Sofosbuvir Has Come Out of the Magic Box

Hepatitis Monthly

Seyed Moayed Alavian 1, 2, *

1 Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallh University of Medical Sciences, Tehran, IR Iran

2 Middle East Liver Diseases Center (MELD), Tehran, IR Iran

*Corresponding Author: Seyed Moayed Alavian, Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Mollasadra St., Vanak Sq., P.O. Box: 14155/3651, Tehran, IR Iran. Tel/Fax: +98-2188945186, E-mail: editor@hepatmon.com.

Hepatitis Monthly. 13(12): e16916 , DOI: 10.5812/hepatmon.16916

Article Type: Editorial; Received: Dec 15, 2013; Accepted: Dec 15, 2013; epub: Dec 16, 2013;

Keywords: Hepatitis C; Treatment; Sofosbuvir

After the introduction of hepatitis B (HBV) vaccination, which leaded to a dramatically decrease of HBV prevalence in the communities (1), it is predicted that hepatitis C virus (HCV) will emerge as the most common chronic viral liver disease in the next decades (2, 3). The global prevalence of HCV is at least 3% with over 170 million infected cases (4). The treatment regimens for chronic hepatitis C (CHC) have progressed within the past decade. The current standard of care in our country consisting of pegylated interferon alpha (PegIFNα) and ribavirin (RBV), has significantly improved the sustained virological response (SVR) rates from 50% up to 80% in patients infected with different HCV genotypes (5, 6). Iranian patients respond well to antiviral therapies which may be related to more favorable distribution of IL28B SNP polymorphism (7). After the introduction of Boceprevir and Teleprevir as the standard therapy for HCV genotype 1 infections, the hope for eradication of infection grows significantly, but the costs imposed by the drug side effects were not satisfactory for both patients and scientists (8). Availability of these agents, protease inhibitors (PIs), which have been added to the current standard of care (SOC), has offered a new treatment option for patients infected with HCV, who are infected with GT1, and have not responded or relapsed to the previous therapies. It is reported that by adding these agents to the standard of care of patients who were infected with HCV genotype 1, non-responders or relapsers to the previous therapies, the response rate had increased. The therapy failure in patients infected with different HCV genotypes in Iran, depends on the liver fibrosis status, age and comorbidity (8). Chronic HCV infection and its treatment are significant health care economic burdens that should be reviewed according the rate of responses and should attract the attention of health policy makers and academics in many countries (9). The costs of PIs -based triple therapy for hepatitis C and adverse managements are very high per sustained viral response, which means that it is not cost effective to use these drugs in our practice at the present time.

1. Sofosbuvir Get Approval

Recently FDA advisory board approved the Sofosbuvir for the treatment of chronic hepatitis C patients which will open up new horizons toward noninterferon-based therapies in management of CHC patients. It is dreamed to treat these patients with one tablet daily! The FDA advisory board reviews the efficacy and safety data collected from the clinical trials and decided to register a new drug cautiously. Sofosbuvir is a nucleotide analogue inhibitor of HCV NS5B polymerase that is administered orally. It has a potent antiviral activity against all genotypes of HCV. FDA advisory board approved Sofosbuvir for treatment of naïve adults infected with genotypes 1 and 4 in combination with pegylated interferon alpha (PEG-IFN) plus ribavirin) and for treatment of naïve infected adults with genotypes 2 and 3 in combination with ribavirin which indicating that we can use the drug in protocol IFN-free therapy in genotypes 2 and 3. The drug can take orally at a single dose 400 mg daily.

The literature review showed Sofosbuvir has been studied in different populations in combination with PEG-INF and ribavirin or with other direct-acting antiviral agents for the treatment of naive patients with genotype 1 HCV infection (10-12). In ATOMIC multicenter study in naive cases with genotype 1 infection, the patients have shown good responses to the combined sofosbuvir 400 mg and PEG-IFN or ribavirin therapy within 12 weeks (12) and extension to 24 weeks did not add more virologic responses. The Sofosbuvir therapy was successful and the side effects including anemia were related to ribavirin not Sofosbuvir. Unfortunately, there is not any data about cirrhotic patients as it is difficult to treat these patients and the results of the ongoing studies will be reported soon. In contrast with the results of PIs -based triple therapy for hepatitis C, the virologic response is not depend on to the early virologic response or baseline characteristics such as IL28B CC versus non-CC genotype, high versus low baseline viral load, and genotype 1a versus genotype 1b (12). The Sofosbuvir was effective in all of these situations. One of the important findings of this study was the drug safety in responders and no resistance-associated mutations in patients with virologic failure, which is due to the high genetic barrier to HCV resistance of Sofosbuvir (12).

Numerous studies are ongoing and the preliminary reports revealed that Sofosbuvir in combination with other direct-acting antiviral agents caused significant virologic responses. In a phase 2 study on cirrhotic and null responder hepatitis C patients, the combination of sofosbuvir and simeprevir with and without ribavirin for 12 or 24 weeks in patients with HCV genotype 1 infections resulted in high (93 - 96%) SVRs (13). Perhaps in future we can use combined Simeprevir and ribavirin therapy for six months without interferon to treat different genotypes infections or Simeprevir plus ribavirin and Simeprevir for three up to six months without interferon to treat genotype 1 infections. The combination of Sofosbuvir and a second direct-acting antiviral agent such as NS5A inhibitor Ledipasvir is highly effective in treatment-naïve patients with genotype 1 HCV infection and in patients that did not respond to previous treatments (14).

2. Conclusion Remarks

The benefits of this new approach in eradication of HCV infection are shorter duration with safer and lower side effects reported in users in comparison with PIs -based triple therapy. Once daily oral regimen is well-tolerated without significant resistance development. Different clinical trials of Sofosbuvir on treatment-naive patients with genotypes 1 hepatitis C virus infection, through 6 months showed that patients with genotype 1 infection had higher virologic response than those underwent combination therapy and currently available triple therapies. In patients with genotypes 2 and 3 HCV infection, the efficacy was similar in both IFN-free Sofosbuvir and standard PEG-IFN/ribavirin regimens (15). Traditional predictors of treatment response, such as IL28B polymorphisms, baseline viral load, and early response did not affect the response rates.

Opening this magic box and the emerge of Sofosbuvir reveals a hopefully future with more discovering drugs, which directly target various aspects of HCV life cycle and lead to more effective combinations of new drugs in management of HCV infection within a shorter time. Introduction of this drug will reduce to the global burden of HCV and millions of HCV infected patients around the world will be treated, and it will prevent the HCV associated morbidity and mortality such as liver cirrhosis , hepatocellular carcinoma and the need for liver transplantation , in 2020 (16). I hope we can identify the role of these drugs for the treatment of cirrhotic patients from ongoing studies. In patients with genotype 1 including relapse or resistant to therapy with low degree of liver fibrosis, we should wait for availability of new drugs.

Acknowledgments

Thanks to Mr. Sharafi for providing the full texts.

Footnotes

Implication for health policy/practice/research/medical education: It helps the clinicians to better understand the new drugs for treatment of Hepatitis C.

Authors’ Contribution: All the study was conducted by Prof. Seyed Moayed Alavian.

Financial Disclosure: No financial interest or conflict is present.

Funding/Support: This study is supported by Baqiyatallah Research Center for Gastroenterology and Liver Diseases.

References

1. Alavian SM, Fallahian F, Bagheri-Lankarani K. The Changing Epidemiology of Viral Hepatitis B in Iran. J Gastrointestin Liver Dis. 2007;16(4):403-406.

2. Merat S, Rezvan H, Nouraie M, Jafari E, Abolghasemi H, Radmard AR, et al. Seroprevalence of hepatitis C virus: the first population-based study from Iran. Int J Infect Dis. 2010;14 Suppl 3:e113-6. [DOI] [PubMed]

3. Alavian SM, Adibi P, Zali MR. Hepatitis C virus in Iran: Epidemiology of an emerging infection. Arch Iran Med.2005;8:84-90.

4. Yan Z, Fan K, Wang Y, Fan Y, Tan Z, Deng G. Changing pattern of clinical epidemiology on hepatitis C virus infection in southwest china. Hepat Mon. 2012;12(3):196-204. [DOI] [PubMed]

5. Alavian SM, Jabbari H, Daryani NE, Torabi Nami M. Hepatitis C Virus: The Rising Concerns and Growing Hopes, Report From the HCV Symposium, Fourth Tehran Hepatitis Congress, november 2011, Tehran, Iran. Hepat Mon.2012;12(7):423-429.

6. Alavian SM, Tabatabaei SV, Keshvari M, Behnava B, Miri SM, Elizee PK, et al. Peginterferon alpha-2a and ribavirin treatment of patients with haemophilia and hepatitis C virus infection: a single-centre study of 367 cases. Liver Int.2010;30(8):1173-80. [DOI] [PubMed]

7. Sharafi H, Alavian SM. IL28B polymorphism, Explanation for Different Responses to Therapy in Hepatitis C Patients. Hepat Mon. 2011;11(12):958-9. [DOI] [PubMed]

8. Alavian SM, Lankarani KB, Aalaei-Andabili SH, Pouryasin A, Ebrahimi Daryani N, Nassiri Toosi M, et al. Treatment of Chronic Hepatitis C Infection: Update of the Recommendations from Scientific Leader’s Meeting-28th July 2011-Tehran, IR Iran. Hepat Mon. 2011;11(9):703-713.

9. Vahedi M, Pourhoseingholi A, Ashtari S, Pourhoseingholi MA, Karkhane M, Moghimi-Dehkordi B, et al. Using statistical models to assess medical cost of hepatitis C virus. Gastro Hepat FBB. 2012;5(Suppl1):S31-S36.

10. Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis. 2013;13(5):401-8. [DOI] [PubMed]

11. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878-87. [DOI] [PubMed]

12. Kowdley KV, Lawitz E, Crespo I, Hassanein T, Davis MN, DeMicco M, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet. 2013;381(9883):2100-7. [DOI] [PubMed]

13. Lawitz E, Ghalib R, Rodriguez Torres M, editor(s). COSMOS Study: SVR4 results of a once daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype 1 null responders. 20th Conference on Retroviruses and Opportunistic Infections; 2013; Atlanta, Georgia.

14. Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Subramanian GM, et al. Efficacy of Nucleotide Polymerase Inhibitor Sofosbuvir plus the NS5A Inhibitor Ledipasvir or the NS5B Non-nucleoside Inhibitor GS-9669 Against HCV Genotype 1 Infection. Gastroenterology. 2013. [DOI] [PubMed]

15. Jacobson I, Ghalib RH, Rodriguez-Torres M, editor(s). SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: The COSMOS study. 64th Annual Meeting of the American Association for the Study of Liver Diseases; 2013; Washington, DC..

16. Zidan A, Scheuerlein H, Schule S, Settmacher U, Rauchfuss F. Epidemiological pattern of hepatitis B and hepatitis C as etiological agents for hepatocellular carcinoma in iran and worldwide. Hepat Mon. 2012;12(10 HCC):ee6894 [DOI] [PubMed]

Source

Scientists Identify Molecular Biomarkers of Vaccine Immunity

Provided by Science Daily

Dec. 16, 2013 — Testing the efficacy of vaccines in clinical trials takes years, even decades. Yet challenging infections like HIV, malaria and dengue are striking today. To speed up vaccine testing, scientists at the Emory Vaccine Center have established a goal of creating a "vaccine gene chip."

This device could read the activity of all the genes in the genome in white blood cells within a few days of administration of a test vaccine. Reading such "molecular signatures" would rapidly help predict the ability of that vaccine to stimulate the immune system and protect against disease.

Now scientists led by Bali Pulendran, PhD have taken an important step toward making such a chip, by comparing the molecular signatures induced by five very different vaccines in the immune systems of human volunteers. The results are published online in Nature Immunology.

Pulendran, senior author of the paper, is Charles Howard Candler professor of pathology and laboratory medicine at Emory University School of Medicine and a researcher at Yerkes National Primate Research Center. Co-first authors of the paper are postdoctoral fellow Shuzhao Li, PhD, assistant professor of infectious diseases Nadine Rouphael, MD, and postdoc Sai Duraisingham, PhD.

Two of the vaccines they tested in the current study are aimed at stimulating immunity against Neisseria meningitidis, a bacterium that can cause life-threatening meningitis or sepsis.

Researchers immunized 30 healthy volunteers with two different types of meningococcal vaccines, now-standard MCV4 or an older version, MPSV4. They surveyed the activity levels of human genes in blood samples from the volunteers, and compared the patterns against previous results they obtained while investigating responses to yellow fever and the seasonal flu vaccines.

Pulendran, whose lab had pioneered the use of such a "systems" approach to predicting vaccine immunity in previous studies using the yellow fever and seasonal flu vaccines, says his team was asking whether there are universal molecular signatures of vaccine effectiveness that were capable of predicting antibody responses to any vaccine.

"Our results suggest that gene expression predictors of antibody response are unlikely to be 'universal', but are dependent on the type of vaccine," he says.

For example, similar signatures correlated with the antibody responses against the carbohydrate components of the two meningococcal vaccines, while a different signature correlated with recall antibody responses such as that to the seasonal flu vaccine.

"These results represent a first small step towards identifying molecular signatures that might predict immunity to different types of vaccines, but clearly more comparative work is needed to define robust and predictors of immunity that may be common to a broader range of vaccines," he says.

To fully analyze the gene activation responses against meningitis and compare them to other vaccine response data, Pulendran and his colleagues had to build gene networks that were customized for immunology called "Blood Transcription Modules." These resources are available to other scientists to use and share.

Despite its nascent state, the field has already begun to offer unexpected insights about the workings of the immune system. Recent work published in Science from Pulendran's lab has demonstrated an unappreciated link between immunity to vaccines and the cells' ancient starvation response, using a systems approach to study immunity to the yellow fever vaccine.

The MPSV4 vaccine, available since the 1970s, contains the polysaccharide outer coating of the bacterium. MCV4 was the first of several meningococcal conjugate vaccines introduced in the last decade. MCV4 links the polysaccharide coating with a toxin protein from diphtheria bacteria. MCV4 is preferred for children, adolescents and younger adults, while MPSV4 is used in adults over 55. Both are different in form from yellow fever (live attenuated virus) and influenza (live attenuated or inactivated virus) vaccines.

Story Source:

The above story is based on materials provided by Emory Health Sciences.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

  1. Shuzhao Li, Nadine Rouphael, Sai Duraisingham, Sandra Romero-Steiner, Scott Presnell, Carl Davis, Daniel S Schmidt, Scott E Johnson, Andrea Milton, Gowrisankar Rajam, Sudhir Kasturi, George M Carlone, Charlie Quinn, Damien Chaussabel, A Karolina Palucka, Mark J Mulligan, Rafi Ahmed, David S Stephens, Helder I Nakaya, Bali Pulendran. Molecular signatures of antibody responses derived from a systems biology study of five human vaccines. Nature Immunology, 2013; DOI: 10.1038/ni.2789

Source

PRESS RELEASE

Dec. 16, 2013, 1:04 p.m. EST

Walgreens and CDC to Evaluate HIV Care Model at More Than 700 HIV-Specialized Pharmacies

PR-Logo-Businesswire

DEERFIELD, Ill., Dec 16, 2013 (BUSINESS WIRE) -- In support of the more than 1.1 million people living with HIV in the U.S., Walgreens WAG -0.23% WAG -0.23% is collaborating with the Centers for Disease Control and Prevention (CDC) to develop and evaluate a model of HIV patient-centered care through a national project aimed at advancing clinical integration and medication therapy management. The program is another way Walgreens is extending its commitment to improve HIV prevention and treatment outcomes.

Walgreens is leveraging the expertise of its more than 700 HIV-specialized pharmacies and specially trained pharmacists to lead medication care plans and provide data evaluation and outcomes reporting for 1,000 HIV positive project participants. Walgreens pharmacists, who routinely provide pharmacy care and treatment for people living with HIV, will meet one-on-one with project participants to create care plans that focus on medication adherence and address other needs including health education for added chronic conditions.

"Our approach to improving HIV prevention and treatment is individualized care focused on the holistic needs of patients," said Glen Pietrandoni, senior manager, virology, Walgreens. "Beyond dispensing medication, our pharmacists are trained to provide testing, confidential wellness consultations, coordinate care and benefits with physicians and insurance providers, and to help patients access financial support programs to reduce medication costs. However, medication adherence remains our primary objective because we know that taking the right medication at the right time is key to improving health outcomes."

A Walgreens study of more than 15,000 HIV patients showed that those who received care through one of its HIV-specialized pharmacies, with expert-level trained pharmacists, were significantly more adherent to their medication (74 percent) than those receiving care through a traditional, non-specialized Walgreens pharmacy (69 percent).(1)Adherent HIV patients are more likely to achieve improved health outcomes and suppressed viral loads, which make the virus less likely to be transmittable.(1)However, the CDC estimates only 25 percent of Americans with HIV have the virus under control.(2)

Walgreens collaboration with the CDC supports the goals the National HIV/AIDS Strategy and underscores its commitment to support communities affected by HIV/AIDS. Its HIV-specialized pharmacies continue to cooperate with local health departments and AIDS service organizations to support HIV testing and community events, and work with local health care providers, government leaders and religious organizations to continually assess and meet the needs of individuals in select communities throughout the U.S.

About Walgreens

As the nation's largest drugstore chain with fiscal 2013 sales of $72 billion, Walgreens (www.walgreens.com ) vision is to be the first choice in health and daily living for everyone in America, and beyond. Each day, Walgreens provides more than 6 million customers the most convenient, multichannel access to consumer goods and services and trusted, cost-effective pharmacy, health and wellness services and advice in communities across America. Walgreens scope of pharmacy services includes retail, specialty, infusion, medical facility and mail service, along with respiratory services. These services improve health outcomes and lower costs for payers including employers, managed care organizations, health systems, pharmacy benefit managers and the public sector. The company operates 8,197 drugstores in all 50 states, the District of Columbia, Puerto Rico and the U.S. Virgin Islands. Take Care Health Systems is a Walgreens subsidiary that is the largest and most comprehensive manager of worksite health and wellness centers, provider practices, and in-store convenient care clinics, with more than 750 locations throughout the country.

1. Murphy P, Cocohoba J, Tang M, et al. Impact of HIV-specialized pharmacies on adherence and persistence with antiretroviral therapy. AIDS PatientCare and STDs, Volume 26, Number 9, 2012.

2. Hall HI, Frazier EL, Rhodes P, et al. Differences in human immunodeficiency virus care and treatment among subpopulations in the United States. JAMA Intern Med. 2013 Jul 22;173(14):1337-44. doi: 10.1001/jamainternmed.2013.6841.

SOURCE: Walgreens

Source

Journal of Viral Hepatitis

Early View (Online Version of Record published before inclusion in an issue)

Original Article

H. Leblebicioglu1,*, V. Arama2, X. Causse3, P. Marcellin4, R. Ozaras5, B. Postawa-Klozinska6, K. Simon7, A. I. Suceveanu8, M. Wiese9, S. Zeuzem10, I. Klauck11, E. Morais11, S. Bjork12,†, B. Lescrauwaet13,†,  D. Kamar14,  J. P. Zarski15, for The AI463-121 European Longitudinal Chronic Hepatitis B Study Group

Article first published online: 15 DEC 2013
DOI: 10.1111/jvh.12202
© 2013 John Wiley & Sons Ltd

Abstract

Keywords: adefovir;  antiviral treatment;  chronic hepatitis B;  entecavir;  lamivudine;   tenofovir

Summary

In Europe, healthcare systems differ between countries and different factors may influence Chronic hepatitis B (CHB) treatment choices in different counties. This analysis from a prospective, longitudinal, non-interventional study in five EU countries aimed to explore determinants associated with treatment initiation or switch in patients with CHB. A total of 1267 adult patients with compensated CHB in Germany, France, Poland, Romania and Turkey were prospectively followed for up to 2 years (March 2008–December 2010). Determinants of treatment initiation or switch were analysed using multivariate Cox proportional hazards regression. Median time since CHB diagnosis was 2.6 (0–37.7) years. Among 646 treatment-naïve patients, the probability of treatment initiation during follow-up was higher: in Germany (P = 0.0006), Poland (P < 0.0001) and Romania (P = 0.0004) compared with Turkey; in patients with alanine transaminase (ALT) 1–2 × upper limit of normal (ULN) (P = 0.0580) or >2 × ULN (P = 0.0523) compared with ALT ≤1 × ULN; and in patients with hepatitis B virus (HBV) DNA ≥2000 IU/mL (P < 0.0001) compared with HBV DNA <2000 IU/mL or undetectable. Among 567 treated patients, 87 switched treatment during follow-up. The probability of treatment switch was higher: in France (P = 0.0029), Germany (P = 0.0078) and Poland (P = 0.0329) compared with Turkey; and in patients with HBV DNA <2000 (P < 0.0001) or ≥2000 IU/mL (P < 0.0001), compared with undetectable. Viral load and ALT level were identified as the major drivers of treatment initiation. HBV DNA level was also a significant determinant of treatment switch. Results were statistically different across EU countries.

Source

New hepatitis C drug has higher cure rate

The Canadian Press

Sheryl Ubelacker, The Canadian Press at 17:47 on December 16, 2013, EST.

TORONTO - Health Canada has approved a once-daily tablet for the treatment of chronic hepatitis C that could transform treatment of the disease for thousands of Canadians.

The drug Sovaldi (sofosbuvir) is to be taken in combination with older medications to treat the main forms of hepatitis C, which is caused by a blood-borne virus. Left untreated, the disease can lead to liver failure, cirrhosis and cancer.

An estimated 250,000 Canadians are living with chronic hepatitis C. But because the disease can take many years to progress without causing noticeable symptoms — even up to two or three decades —about 35 per cent have no idea they are infected.

Baby boomers are disproportionately affected by hepatitis C: they are five times more likely than people of other age groups to have contracted the virus, often from sharing needles for IV drug use or having sex with an infected person during their youth.

The Canadian Liver Foundation recommends that all Canadians born between 1945 and 1965 be tested for the virus.

Current treatments for the hepatitis C virus (HCV), which can take up to a year to complete, involve weekly injections of a drug that causes flu-like side-effects and cures about three out of four patients.

In clinical trials, 90 per cent of patients taking a single daily Sovaldi pill in combination with an older drug cocktail were cured in 12 weeks. However, the length of treatment and specific drug combination used depends on which of several genetic subtypes of the virus has caused a person's infection.

The current standard of care for HCV in Canada involves up to 48 weeks of therapy with an interferon drug, which may not be suitable for certain patients.

“I believe sofosbuvir has the potential to transform HCV treatment in Canada as it addresses many unmet patient needs,” said Dr. Jordan Feld, a liver specialist at Toronto Western Hospital. “The high cure rates, shortened treatment duration and potential to eliminate or reduce interferon injections give us our best opportunity to successfully treat Canadians with hepatitis C.”

Sovaldi is made by Gilead Sciences Inc., based in Foster City, Calif., one of a half-dozen companies battling over the market for more effective hepatitis C treatments.

Gilead Sciences Canada said Monday the cost of Sovaldi to consumers won't be available until the prescription drug goes on sale in pharmacies in early January, as the company is currently finalizing the price with regulatory authorities.

In the U.S., where the drug was approved by the FDA about two weeks ago, the parent company said a 12-week supply of Sovaldi would cost $84,000. That price could as much as double for patients with a subtype of the disease that would require them to take the drug longer.

Gilead Sciences Canada said it will launch a program Jan. 6 to provide support services for patients and health-care providers, including access to case managers to help with insurance-related needs. Another program will provide financial assistance for eligible patients who need help paying for out-of-pocket medication costs.

Source

Also See: Health Canada Issues Notice of Compliance for Sovaldi™ (Sofosbuvir) for the Treatment of Chronic Hepatitis C

PLOS One

OPEN ACCESS PEER-REVIEWED

RESEARCH ARTICLE

Luciana G. S. Orsini, Marcelo M. Pinheiro, Charlles H. M. Castro mail, Antônio E. B. Silva, Vera L. Szejnfeld

Published: November 28, 2013 DOI: 10.1371/journal.pone.008165

Abstract

Introduction

The high prevalence of chronic hepatitis C (CHC) and its consequent cirrhosis has been associated with bone fragility. Whether CHC may cause bone and mineral abnormalities in the absence of hepatocellular dysfunction is still unknown. In this study we aimed to determine the prevalence of osteoporotic vertebral fractures and low BMD measurements in men with non-cirrhotic CHC. Risk factors for low BMD and fractures were also investigated.

Methods

Morphometric vertebral fractures and BMD measurements were performed in 60 non-cirrhotic untreated men with CHC and 59 healthy controls, matched for age and gender, weight and current smoking. Serum CTx, calcium, phosphate, intact PTH, alkaline phosphatase and vitamin D (25OHD) concentrations were measured in all participants. Clinical risk factors for low BMD and fractures were evaluated by a structured questionnaire as well as details regarding HCV infection.

Results

Trochanter and total femur BMD were significantly lower in CHC patients as compared to healthy men (p = 0.04). In men 50 years and older, the prevalence of osteoporosis was significantly higher among CHC patients (p = 0.01). Lower levels of physical activities and more often report of prolonged immobilization were observed among CHC patients (p<0.05). Liver inflammation and fibrosis, viral load and genotype did not correlate with BMD measurements. Bone markers and 25OHD concentrations were similar in both groups. Only a few vertebral fractures were observed.

Conclusions

Our results demonstrate that non-cirrhotic untreated CHC patients have lower BMD at the femur as compared to healthy men in spite of the absence of significant bone and mineral abnormalities.


itation: Orsini LGS, Pinheiro MM, Castro CHM, Silva AEB, Szejnfeld VL (2013) Bone Mineral Density Measurements, Bone Markers and Serum Vitamin D Concentrations in Men with Chronic Non-Cirrhotic Untreated Hepatitis C. PLoS ONE 8(11): e81652. doi:10.1371/journal.pone.0081652

Editor: Luc Malaval, INSERM U1059/LBTO, Université Jean Monnet, France

Received: June 10, 2013; Accepted: October 15, 2013; Published: November 28, 2013

Copyright: © 2013 Orsini et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was funded by a grant from the Rheumatology Division at the Universidade Federal de São Paulo/Escola Paulista de Medicina (Unifesp/EPM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

The World Health Organization (WHO) has estimated that about 3% of the world population has positive serology for hepatitis C virus (HCV) (approximately 170 million of people) [1]. Bone diseases are common complications of chronic hepatitis C (CHC), mainly related to the associated cirrhosis. Among the bone abnormalities reported, hepatitis C-associated osteosclerosis (HCAO) is a rare acquired condition characterized by generalized increase in bone mineral density (BMD), bone pain, elevated serum alkaline phosphatase, generalized cortical thickening and increased uptake on bone scan [2][4].

Bone loss has been described as a complication of viral cirrhosis [5][9] and its prevalence increases in more severe cases [5][7]. Higher levels of serum soluble tumor necrosis factor (TNF) receptor 55 [8] and lower levels of 25-hydroxy vitamin D (25OHD) [5], [7], [8], testosterone [5], [7] and IGF-I in more advanced Child-Pugh stages [7], [8] may all contribute to the lower BMD measurements observed among patients with more severe disease.

Bone disorders have been clearly associated with the presence of cirrhosis per se, regardless of its cause. In patients with CHC and other viral hepatitis, their treatment may also be considered as a confounder when evaluating bone complications. It has been reported that the combination therapy for patients with CHC consisting of interferon-α (INF-α) plus ribavirin resulted in bone loss after 12 months [10]. Increased BMD as well as no change have also been reported after treatment with INF-α in patients with CHC [11], [12].

On the other hand, BMD and bone metabolism abnormalities in non-cirrhotic hepatitis C patients have not been well investigated. Whether chronic HCV infection in the absence of cirrhosis or viral treatment is a risk factor for the development of bone disease has long been controversial.

Only a few studies have evaluated bone status in CHC patients [13][15]. Some methodological questions associated to current treatment in some of the patients and the absence of a healthy control group for comparison has limited the results of those studies. Considering the lack of solid evidence for an effect of chronic HCV infection on bone status, in the present study we evaluated BMD measurements, bone and mineral metabolism and the prevalence of vertebral osteoporotic fractures in non-cirrhotic men with untreated CHC infection as compared to healthy age-matched controls.

Materials and Methods

Ethics Statement

Ethical approval was obtained from the Universidade Federal de São Paulo's ethics committee and all participants gave written informed consent prior to their inclusion in this study.

Patients

Sixty men (mean age 41.5±10.9 years old) with CHC infection consecutively seen at the UNIFESP's outpatients clinics and fifty-nine healthy men (mean age 41.7±10.8 years) were invited to participate in the present study. Anti-HCV/HCV RNA-positive patients (N = 60) had been followed for at least 6 months with persistently positive serology for HCV and negative serological markers for hepatitis B and human immunodeficiency virus (HIV). Healthy men (N = 59) were selected from blood donators registered at our center.

CHC patients with any clinical, laboratorial or histological cirrhosis were excluded, as well as those previously or currently treated with interferon/ribavirin therapy. Other exclusion criteria for both CHC patients and healthy controls included alcoholism (defined as more than 2 drinks per day) [17], diseases or use of drugs that interfere with bone metabolism (corticosteroids, levothyroxine, calcium and vitamin D supplements, diuretics, bisphosphonates, anabolic agents), diabetes mellitus, lung diseases and autoimmune hepatitis.

Body weight was measured (after removal of shoes and heavy outer clothing) using a balance beam scale. Height was measured (after removal of shoes) using a Filizola stadiometer. Height and weight were used to calculate the body mass index (BMI; kg/m2). Data about smoking and drinking habits, physical activity, prolonged immobilization, familial history of osteoporosis and hip fracture were obtained using a structured questionnaire based on the European Vertebral Osteoporosis Study (EVOS) [18], [19] and validated for our language and culture [20][22]. Patients and controls were matched for age, gender, weight, current smoking and alcohol use.

Bone density measurements

BMD measurements were performed in all subjects at the lumbar spine (L1-L4) and proximal femur (neck, trochanter and total hip) using dual X-ray absorptiometry (DXA) (DPX MD+, GE-Lunar, Madison, WI, USA). The coefficient of variation for BMD measurements was 1.5% and 2% at lumbar spine and total hip, respectively. Long-term quality control of the instrument was assured by daily scan using a standard spine phantom as instructed by the manufacturer. All scans were performed in the same machine by the same operator and were analyzed by a physician blinded to the group the participant belonged. Consistent with the recommendations from WHO [23] and from the International Society of Clinical Densitometry [16], men 50 years and older were classified according to T-score as normal bone density (T-score above – 1.0 SD), osteopenia (−1.0< T-score <−2.5) or osteoporosis (T-score below – 2.5 SD). Z-score was used to classify younger men (less than 50 years old) as within the expected range for age (Z-score above – 2.0) or below the expected range for age and sex (Z-score below – 2.0). For comparison purposes, BMD measurements in both groups were adjusted for age and body weight.

Laboratory tests

Blood was drawn in the morning after an overnight fasting. Routine tests included total serum calcium, phosphate, and creatinine and total alkaline phosphatase using standard methods. Intact parathyroid hormone (iPTH) (Nichols Advantage® Chemiluminescence Intact Immunoassay; interassay coefficient of variation of 7%; normal range 10–65 pg/mL), 25-hydroxy vitamin D (25OHD) (radioimmunoassay technique, DiaSorin, Stillwater, MN, USA; intra- and inter-assay coefficients of variation were 9.5% and 15.2%, respectively) and type I collagen C-telopeptide (CTx) serum concentrations (Elecsys 2010 automated analyzer, Roche; interassay coefficient of variation of 6%; normal range 0.081–0.850 ng/mL) were also determined.

HCV viral load and genotype, liver biopsy classification and serum albumin were obtained from an extensive review of the patients' charts.

Vertebral fracture assessment

Radiographic lateral and posterior-anterior images of thoracic and lumbar spine were taken according to standard protocols aiming to evaluate asymptomatic vertebral fractures. Thoracic films were centered at T8 and lumbar films at L3. Focus film distance was 1.5 m. A semi-quantitative method [24] was used to determine the prevalence of vertebral deformities. Only grades II and III were considered as vertebral fractures. Intra and inter-observer coefficients of variation and kappa indexes for the method in our unit are 4.8% (concordance 95.2%) and 6.3% (concordance 93.7%) and 0.84 (95%CI 0.78–0.92) and 0.82 (95%CI 0.75–0.9), respectively[21].

Statistical analysis

Results were expressed as mean ± standard deviation. Chi-squared tests were used to evaluate the prevalence of osteoporosis, osteopenia, and low BMD as well as the vitamin D status between CHC men and their healthy controls. We compared the BMD, anthropometric variables, frequency of risk factors for osteoporosis and laboratorial tests between CHC patients and healthy controls using Student's t-tests. Two-way ANOVA analyzes were used to adjust vitamin D concentrations according to the season of the year. Pearson's and Spearman's coefficient of correlation were used to estimate association between clinical variables and BMD measurements with the prevalence of low bone mass and osteoporosis in CHC patients. Potential risk factors for low bone mass and osteoporosis were analyzed by backward stepwise regression analysis using variables identified in correlation analyzes. SPSS statistical package for Windows (version 15.0) was used to analyze the data. Significance level was set as p<0.05.

Results

Relevant demographic and clinical characteristics for both CHC patients and healthy men are shown in Table 1. CHC patients had lower physical activity and reported prolonged immobilization more often than healthy men (p<0.05). In spite of their similar weight and height, CHC patients had significantly higher BMI values as compared to the healthy controls (p = 0.04).

journal.pone.0081652.t001

Table 1. Demographic data and clinical characteristics of chronic hepatitis C (CHC) men and healthy controls.

Spine and femoral neck BMD did not differ significantly between HCV patients and healthy men, as demonstrated in Table 2. On the other hand, total femur and trochanter BMD values were significantly lower in CHC men as compared to healthy controls, even after adjustments for body weight (p<0.05).

journal.pone.0081652.t002

Table 2. Bone mass measurements in CHC patients and healthy controls.

For subjects younger than 50 years old, BMD measurements below the expected range for age and sex (Z-score below – 2.0) were found in 1 (at the femur) out of 41 CHC patients (3%) and 2 (one at the femur, one at the lumbar spine) out of 40 controls (5%). Again, no statistically significant difference was observed between groups. For men 50 years old or more, osteoporosis was detected in 36% of the CHC patients (two patients at both femur and lumbar spine, three patients at the femur and two other patients at the lumbar spine) and in only 4% of the healthy men (2 at the femur and two others at the lumbar spine). Osteopenia was observed in 32% of both groups (three patients at the femur and three others at the lumbar spine; five healthy controls had osteopenia at the lumbar spine and one of them had osteopenia at the femur). BMD classified as normal was found in 32% of the CHC patients and in 64% of the controls (p = 0.01).

Serum concentrations of biochemical bone markers were in the normal range for both CHC patients and controls as shown in Table 3. Total calcium, phosphate, alkaline phosphatase, iPTH, CTx and vitamin D did not differ significantly between HCV patients and controls. The mean serum albumin was also within the normal limits in CHC patients (4.25±0.4 mg/dL).

journal.pone.0081652.t003

Table 3. Biochemical bone markers and laboratory tests of bone and mineral metabolism in CHC men and healthy controls.

Using previously published criteria [25], 25OHD status was classified in patients and controls as follows: sufficiency (above 30 ng/mL), insufficiency (11–29 ng/mL) and deficiency (below 10 ng/mL). After adjustments for the season of the year, no statistically significant difference was observed between the groups in terms of 25OHD status (Table 4).

journal.pone.0081652.t004

Table 4. Classification of vitamin D status in CHC men and healthy controls.

Chi-squared test and linear backward stepwise regression analyses were performed to investigate potential determinants for low BMD in our sample. BMD measurements at all skeletal sites did not correlate with lifetime tobacco exposure (pack-years of smoking), alcohol consumption (drinks/week), physical activity [26], prolonged immobilization, time since diagnosis and contamination, viral load and genotype, degree of liver inflammation and fibrosis at the biopsy in CHC patients. Although CTx serum concentrations correlated negatively with lumbar spine BMD (r = −0.21; p = 0.04), no other significant correlation was found between BMD measurements and other biochemical markers. Multivariate analyzes performed did not allow to identify any parameter significantly associated with low BMD measurements in CHC patients.

Morphometric vertebral fractures were observed in three healthy men and one CHC patient. The CHC patient was a 57 years-old man with history of current smoking (40 pack-years) and alcohol use (10 drinks/week). BMD measurements, bone markers and vitamin D status were in the normal range for this patient. Due to the few number of vertebral fractures in the sample, correlation and regression analyzes were not feasible and so the study was not able to evaluate whether vertebral fractures are associated with HCV infection.

Discussion

Our results demonstrated that non-cirrhotic untreated CHC men have lower total hip and trochanter BMD when compared to healthy men. Only a few studies had evaluated BMD measurements in non-cirrhotic CHC patients and their results are conflicting due to methodological questions [13][15]. In our present sample we were able to demonstrate that HCV infection affects BMD at the proximal femur independently of liver function, current cirrhosis or anti-viral medication.

In spite of the lower BMD values in CHC patients when compared to healthy men, mean BMD at all skeletal sites were within normal range. It is interesting to note that both CHC patients and healthy controls exhibited high prevalence of overweight and that is well recognized as having a protective effect on bone density [27][30].

Total hip BMD is highly influenced by trochanteric BMD since the trochanter occupies the largest area of the proximal femur. The lower values for total hip BMD observed among CHC patients may be explained by the significantly lower BMD measurements at the trochanter in these subjects. In agreement with this finding, other authors have also observed a significant decrease in trochanter BMD in CHC patients, regardless of the liver function [14].

Reduced current physical activity associated with higher prevalence of prior prolonged immobilization were also observed among CHC patients as compared to healthy controls and that may also have influenced our results. Lower mechanical load could be related to the lower values for trochanteric BMD observed among CHC patients. Studies with hemiplegic patients[31] and cosmonauts [32] have demonstrated the association between reduced weight-bearing activities and lower femur BMD. The effect is probably due to an increase of the number of osteoclasts and a decrease in the osteoblast population [33].

Hepatic dysfunction with the intervenient vitamin D deficiency has been associated with low bone density. A direct correlation has been reported between the severity of liver fibrosis and low bone density in non-cirrhotic CHC patients [15]. The issue is however controversial and in CHC patients without cirrhosis the association with low BMD has not been confirmed in all studies. Hofmann et al [34] reported no correlation between non-cirrhotic hepatic disease and BMD measurements. They have also found no association between BMD measurements and disease duration, viral load and lifetime tobacco exposure. Our data have demonstrated no significant correlation between BMD measurements and the severity of liver inflammation and fibrosis at the biopsy, viral load, transmission model, estimated disease duration or alcohol intake. It is important to note that patients with alcoholism were excluded from our study.

Our results have also shown that non-cirrhotic CHC patients present no clinically relevant abnormalities in bone markers and calciotropic hormones, as previously observed [13][15],[34]. Mean serum 25OHD concentrations were considered sufficient in CHC patients, corroborating previous findings [14], [34]. To our knowledge this is the first study to classify non-cirrhotic CHC patients according to vitamin D status. No significant difference was observed in 25OHD status between CHC patients and healthy controls. That also suggests that liver injury in our patients was not important, at least in terms of vitamin D synthesis and hydroxylation.

The number of morphometric vertebral fracture was rather small in both groups precluding further analyzes. The absence of vertebral fractures may also result from the normal lumbar BMD values observed in both CHC patients and healthy controls.

Some limitations of the present study need to be pointed out. Our cross-sectional design prevented us of establishing a cause-effect relationship in our results as well as evaluating the long-term effect of HCV infection on bone metabolism and fracture risk. As observed earlier, the high prevalence of overweight in our population might also have influenced our results and could have positively impacted on BMD measurements in both groups. Results in women chronically infected with HCV might be somewhat different from those reported here for men.

This study is the first to evaluate BMD, bone metabolism and the prevalence of morphometric vertebral fracture in a significant number of men with CHC, without the classic confounding factors for low bone density (menopause, cirrhosis and antiviral therapy). Our results demonstrate that non-cirrhotic untreated CHC patients are at low risk for osteoporosis and fractures. We have also observed no significant abnormalities in bone and mineral metabolism and a vitamin D status similar to that seen for healthy men.

Author Contributions

Conceived and designed the experiments: CHMC VLS. Performed the experiments: LGSO MMP. Analyzed the data: LGSO CHMC AEBS VLS. Contributed reagents/materials/analysis tools: CHMC VLS. Wrote the paper: LGSO MMP CHMC VLS.

References

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Gilead

– Sovaldi Receives Marketing Authorization for Patients with Genotypes 1, 2, 3 or 4 HCV –

– High Cure Rates (SVR 12) and Therapy Shortened to Just 12 Weeks for Many Patients –

December 16, 2013 08:30 AM Eastern Standard Time

FOSTER CITY, Calif.--(BUSINESS WIRE)--Gilead Sciences, Inc. (Nasdaq: GILD) today announced that Health Canada has issued a Notice of Compliance for Sovaldi™ (sofosbuvir) 400 mg tablets, a once-daily oral nucleotide analog polymerase inhibitor for the treatment of chronic hepatitis C (CHC) infection. Sovaldi is indicated for use in adult patients with compensated liver disease, including cirrhosis, for the treatment of genotype 1 or 4 CHC in combination with pegylated interferon and ribavirin, and for the treatment of genotype 2 or 3 CHC in combination with ribavirin. The recommended dose and treatment duration for Sovaldi combination therapy is as follows:

         
    Treatment   Duration
Treatment-naïve patients with genotype 1 or 4 CHC   Sovaldi + peginterferon alfa

+ ribavirin

  12 weeks
Patients with genotype 2 CHC   Sovaldi + ribavirin   12 weeks
Patients with genotype 3 CHC   Sovaldi + ribavirin   16 weeks*

* Consideration should be given to extending the duration of therapy beyond 16 weeks and up to 24 weeks guided by an assessment of the potential benefits and risks for the individual patient (these factors may include cirrhosis status and treatment history).

Treatment regimen, duration and response to Sovaldi are dependent on viral genotype and patient population, and associated baseline factors. Sovaldi must not be administered as monotherapy. The Canadian Product Monograph is available at www.Gilead.ca.

Gilead submitted the marketing application for Sovaldi in Canada on May 17, 2013 and was granted Priority Review by Health Canada. Gilead is awaiting federal and provincial reimbursement review for Sovaldi under the Canadian Common Drug Review process. Gilead anticipates that Sovaldi will be available to patients in Canada early next year. Sovaldi was approved in the United States on December 6, 2013 and applications are pending in the European Union, Australia and New Zealand, Switzerland and Turkey.

“I believe sofosbuvir has the potential to transform HCV treatment in Canada as it addresses many unmet patient needs,” said Jordan Feld, MD, MPH, Staff Hepatologist, Toronto Western Hospital, Department of Medicine, Division of Gastroenterology. “The high cure rates, shortened treatment duration, and potential to eliminate or reduce interferon injections give us our best opportunity to successfully treat Canadians with hepatitis C.”

An estimated 250,000 Canadians are living with chronic hepatitis C virus (HCV), but because the disease can progress for many years without causing noticeable symptoms, about 35 percent of these individuals do not know they are infected. HCV disproportionately impacts “baby boomers,” individuals born between 1945 and 1965, and the Canadian Liver Foundation now recommends that all Canadian baby boomers be tested for the virus. The current standard of care for HCV in Canada involves up to 48 weeks of therapy with a pegylated interferon (peg-IFN)/ribavirin (RBV)-containing regimen, which may not be suitable for certain types of patients.

The marketing authorization is supported primarily by data from four Phase 3 studies, NEUTRINO, FISSION, POSITRON and FUSION, which evaluated 12 or 16 weeks of treatment with Sovaldi combined with either RBV or RBV plus peg-IFN. Three of these studies evaluated Sovaldi plus RBV in genotype 2 or 3 patients who were either treatment-naïve (FISSION), treatment-experienced (FUSION) or peg-IFN intolerant, ineligible or unwilling (POSITRON). NEUTRINO evaluated Sovaldi in combination with peg-IFN/RBV in treatment naïve patients with genotypes 1, 4, 5 or 6. Patients who achieve SVR12 are considered cured of HCV. Trial participants taking Sovaldi-based therapy achieved SVR12 rates of 50-90 percent. For full study details, see the Clinical Studies section of the Product Monograph.

Sovaldi combination therapy was well tolerated in clinical studies. Adverse events were generally mild and there were few treatment discontinuations due to adverse events. The most common adverse reaction occurring in at least 5 percent of patients receiving Sovaldi in combination with ribavirin was fatigue. Among patients receiving Sovaldi in combination with RBV and peg-IFN, the most common adverse reactions occurring in at least 5 percent of patients were fatigue, anemia, neutropenia, insomnia, headache and nausea. See below for Important Safety Information regarding contraindications, warnings and precautions, adverse reactions and drug interactions.

Patient Assistance Program in Canada

As part of its commitment to ensuring that people with hepatitis C can access Sovaldi, Gilead Sciences Canada has developed the Momentum Support Program™, which will launch on January 6, 2014. The program is designed to provide an integrated offering of support services for patients and healthcare providers, including:

  • Access to dedicated case managers to help patients and their providers with insurance-related needs, including identifying alternative coverage options such as federal and provincially-insured programs.
  • The Sovaldi Co-pay assistance program, which will provide financial assistance for eligible patients who need help paying for out-of-pocket medication costs.

For more information regarding Sovaldi or the Momentum Program in Canada, please call the Gilead Sciences Canada medical information line at 1-866-207-4267.

About Sovaldi

Sovaldi is an oral nucleotide analog inhibitor of the HCV NS5B polymerase enzyme, which plays an essential role in HCV replication. Sovaldi is a direct-acting agent, meaning that it interferes directly with the HCV life cycle by suppressing viral replication. Treatment regimen and duration for Sovaldi are dependent on both viral genotype and patient population. Treatment response varies based on baseline host and viral factors. Sovaldi must not be administered as monotherapy.

IMPORTANT SAFETY INFORMATION

Contraindications

Sovaldi combination treatment with ribavirin or with peginterferon alfa plus ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risk for birth defects and fetal death associated with ribavirin. Contraindications to ribavirin or with peginterferon alfa plus ribavirin also apply to Sovaldi combination treatment. Refer to the Product Monographs of peginterferon alfa and ribavirin for a list of their contraindications.

Warnings and Precautions

Sovaldi must not be administered as a monotherapy and must only be used in combination with either peginterferon alfa/ribavirin or ribavirin for the treatment of hepatitis C infection.

Pregnancy: Use with Ribavirin or Peginterferon Alfa/Ribavirin: Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Female patients of childbearing potential and their male partners must use two forms of non-hormonal contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. Refer to the prescribing information for ribavirin.

Use with Potent P-gp Inducers: Rifampin and St. John’s wort should not be used with Sovaldi as they may significantly decrease sofosbuvir plasma concentration, reducing its therapeutic effect.

Adverse Reactions

Most common (≥20%, all grades) adverse reactions for:

  • Sovaldi + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia, and anemia
  • Sovaldi + ribavirin combination therapy were fatigue and headache

Drug Interactions

In addition to rifampin and St. John’s wort, coadministration of Sovaldi is not recommended with carbamazepine, modinafil, oxcarbazepine, phenobarbital, phenytoin, and rifabutin. Such coadministration is expected to decrease the concentration of sofosbuvir, reducing its therapeutic effect.

About Gilead Sciences

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

About Gilead Sciences Canada, Inc.

Gilead Sciences Canada, Inc. is the Canadian affiliate of Gilead Sciences, Inc. and was established in Mississauga, Ontario in 2006.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk Sovaldi may not be available to patients in Canada in the currently anticipated timelines. In addition, physicians and patients may not see advantages of Sovaldi over other therapies and may therefore be reluctant to prescribe the product, and the risk that public payers may be reluctant to approve or provide reimbursement for the product. Further, pending marketing applications for Sovaldi in the European Union and other territories may not be approved in the currently anticipated timelines or at all, and marketing approval, if granted, may have significant limitations on its use. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2013, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

Canadian Product Monograph for Sovaldi is available at www.Gilead.ca.

U.S. full prescribing information for Sovaldi is available at www.Gilead.com.

Sovaldi is a trademark of Gilead Sciences, Inc., or its related companies.

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

Contacts

Gilead Sciences, Inc.
Patrick O’Brien, Investors
650-522-1936
or
Cara Miller, Media
650-522-1616

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Clin Infect Dis. 2013 Nov 21. [Epub ahead of print]

Pérez-Latorre L, Sánchez-Conde M, Rincón D, Miralles P, Aldámiz-Echevarría T, Carrero A, Tejerina F, Díez C, Bellón JM, Bañares R, Berenguer J.

Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Abstract

Background. Hepatic venous pressure gradient (HVPG) is the best indicator of prognosis in patients with compensated cirrhosis. We compared HVPG and transient elastography (TE) for the prediction of liver-related events (LRE) in patients with HCV-related cirrhosis with or without HIV coinfection. Methods. Retrospective review of all consecutive patients with compensated HCV-related cirrhosis who were assessed simultaneously using TE and HVPG between January 2005 and December 2011. We used receiver operating characteristic (ROC) curves to determine the ability of TE and HVPG to predict the first LRE (liver decompensation or hepatocellular carcinoma). Results. The study included 60 patients, 36 of whom were coinfected with HIV. After a median follow-up of 42 months, 6 patients died, 8 experienced liver decompensations, and 7 were diagnosed with hepatocellular carcinoma. The area under the ROC curve (AUROC) (95% confidence interval) of TE and HVPG for prediction of LRE in all patients was 0.85 (0.73-0.97) and 0.76 (0.63-0.89) (P=0.13); for HIV-infected patients, the AUROC was 0.85 (0.67-1.00) and 0.81 (0.64-0.97), (P=0.57); and for non-HIV-infected patients the AUROC was 0.88 (0.75-1.00) and 0.77 (0.57-0.97) (P=0.19). Based on the AUROC values, 2 TE cutoff points were chosen to predict the absence (< 25 kPa) or presence (≥ 40 kPa) of LRE, thus enabling correct classification of 82% of patients. Conclusions. Our data suggest that TE is at least as valid as HVPG for predicting LRE in patients with compensated HCV-related cirrhosis coinfected or not with HIV.

PMID: 24265358 [PubMed - as supplied by publisher]

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Eur J Gastroenterol Hepatol. 2014 Jan;26(1):52-8. doi: 10.1097/MEG.0b013e328362dc99.

Durability of the response to peginterferon-α2b and ribavirin in patients with chronic hepatitis C: a cohort study in the routine clinical setting

Giordanino C, Sacco M, Ceretto S, Smedile A, Ciancio A, Cariti G, De Blasi T, Picciotto A, Marenco S, Grasso A, Pirisi M, Smirne C, Colletta C, Traverso A, Mazzucco D, Ciccone G, Simondi D, Rizzetto M, Saracco G.

aDepartment of Oncology, Division of Gastroenterology bDepartment of Internal Medicine, Division of Hepatogastroenterology cDepartment of Infectious Diseases, Amedeo di Savoia Hospital dUnit of Cancer Epidemiology, Molinette Hospital and CPO Piemonte, University of Turin, Turin eDepartment of Internal Medicine, Division of Gastroenterology, University of Genoa, Genoa fDivision of Gastroenterology, San Paolo Hospital, Savona gDepartment of Translational Medicine, Università del Piemonte Orientale 'A. Avogadro', Novara hDivision of Internal Medicine, Ospedale Madonna del Popolo, Omegna iDivision of Infectious Diseases, Ospedale Umberto Parini, Aosta jDivision of Gastroenterology, Ospedale degli Infermi, Rivoli, Italy.

Abstract

OBJECTIVES: To evaluate whether, in chronic hepatitis C-positive naive patients recruited in the routine clinical setting and treated with pegylated-interferon-α2b (Peg-IFN) and ribavirin (RBV), the sustained virologic response (SVR) is durable over the long term and whether it is associated with a decrease in liver complications and incidence of glucose abnormalities.

PATIENTS AND METHODS: This was a prospective long-term follow-up study of 182 naive patients enrolled in 2001-2002 and treated with Peg-IFN and RBV and followed up to December 2010, with clinical, biochemical, and virological evaluations every 6-12 months.

RESULTS: None of the 115 (63.2%) sustained responders showed late viremic relapse during the follow-up. SVR was better defined at 24 weeks (16/16 relapsers, 100%) than at 12 weeks after the end of therapy (14/16 relapsers, 87.5%). On multivariable analysis, viral genotype (odds ratio 0.16, 95% confidence interval 0.07-0.36, P=0.0001) and a greater than 20% RBV reduction (odds ratio 5.21, 95% confidence interval 1.54-17.67, P=0.008) predicted long-term response (LTR) independently. The incidence of cirrhosis was significantly higher among nonresponders (21.3%) compared with long-term responders (0.9%, P≤0.0001), but the risk of developing glucose abnormalities was not significantly reduced in long-term responders (hazard ratio 1.36, P=0.363). Hepatocellular carcinoma occurred only in three cases.

CONCLUSION: SVR achieved in patients treated in the routine clinical setting with Peg-IFN and RBV is durable over the long term and LTR significantly reduces the risk of progression to cirrhosis; however, in a population with mild liver fibrosis, the clinical impact of LTR on the risk of glucose abnormalities seems negligible.

PMID: 23719564 [PubMed - in process]

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By Ben Hirschler 1 hour ago

2013-12-16T122940Z_1_CBRE9BF0YPL00_RTROPTP_2_HEPATITIS-PRICE

Professor Karl Oldhafer, chief physician of general and visceral surgery at the Asklepios Hospital Hamburg-Barmbek, (2nd L) and his team perform liver surgery, one of the first surgeries of its kind in Germany with the support of a tablet computer to access and visualize planning data, in Hamburg in this August 15, 2013 file photo.
CREDIT: REUTERS/FABIAN BIMMER/FILES

By Ben Hirschler

LONDON Mon Dec 16, 2013 7:29am EST

LONDON (Reuters) - A new battle is looming over access to antiviral medicines in developing countries - this time for treating hepatitis C - more than a decade after a global showdown over the price of AIDS drugs in Africa.

Modern pills being launched in western markets could cure the liver-destroying infection in tens of millions of people from China to Congo, or even eradicate the disease entirely. But that will only happen if the cost falls dramatically.

Drugmakers like Gilead Sciences, whose product Sovaldi won U.S. approval this month with a $1,000 a day price tag, are under mounting pressure to strike deals to avoid a rerun of the disputes that stalled early access to HIV therapy.

"Affordability is an urgent and pressing issue," World Health Organization (WHO) Director General Margaret Chan told Reuters during a visit to London.

"These drugs are very expensive. How can we address this? I hope we can learn from the lesson of HIV and find solutions without confrontations."

In the 1990s, HIV/AIDS drugs costing more than $10,000 per patient a year were simply out of reach for millions of people in the developing world. Today, thanks to cheap generics from India, the cost for the poor has been slashed to around $100.

Like HIV, hepatitis C (HCV) can be spread through blood, often via contaminated needles. The WHO estimates that 150 million people worldwide are chronically infected, putting them at risk of cirrhosis and liver cancer.

But whereas the burden of HIV is largely in sub-Saharan Africa, most cases of HCV are in middle-income countries like China, India and Russia, where drug companies are more reluctant to accept rock-bottom prices.

ENSURING ACCESS

Chan said options for maximizing use of the drugs could include granting licenses to low-cost generic drug manufacturers in India and other countries, as has happened with HIV drugs and also Roche's flu pill Tamiflu.

Gregg Alton, Gilead's head of corporate and medical affairs, said his company was working on plans to help ensure access to Sovaldi in resource-limited countries and aimed to set out details early in 2014.

Other companies developing all-oral treatment regimens for HCV - such as Johnson & Johnson, AbbVie, Bristol-Myers Squibb and Merck & Co - also recognize they need to tackle the issue.

"We are going to be responsible players to make sure that people get access," said Paul Stoffels, head of pharmaceuticals at J&J. "There is a lot of pressure on us to make this available."

Like Gilead, J&J is not yet ready to disclose its access plans and Stoffels said in an interview it would take a couple of years before really simple all-tablet regimens suitable for use in poorer nations were widely available.

While Gilead's Sovaldi has broken new ground as the first pill to treat some HCV patients without injections of interferon, which can cause severe flu-like symptoms, it is still supposed to be given alongside interferon in others.

There is little doubt the new drugs will transform HCV treatment - and prove hugely profitable. In the developed world, they are tipped to become major blockbusters, with consensus sales forecasts for Sovaldi alone standing at $6.8 billion in 2018, according to Thomson Reuters Pharma.

Healthcare campaigners expect corporate schemes for poorer countries will focus on price discounts in middle- and low-income markets - but they argue this as a poor substitute for full generic competition, which could send prices tumbling.

CHEAP COPIES

In a bid to force the issue and allow Indian generic manufacturers to make cheap copies of the drug for distribution at home and in some other poor countries, a legal group has filed a motion opposing the patenting of Sovaldi in India.

The New York-based Initiative for Medicines, Access and Knowledge, or I-MAK, which claims the science behind Gilead's drug is not new, says it is taking the action to push prices down massively from the $84,000 that 12 weeks of treatment will cost in the United States.

"We think it has to be below $500," said Tahir Amin, the group's co-founder. "We have seen with HIV that only when you really bring the price down do people really get access."

Medecins Sans Frontieres (MSF), a campaigning group which provides humanitarian care, has thrown its weight behind the I-MAK patent challenge and Leena Menghaney, MSF campaign manager for India, said a sub-$500 price was a prerequisite for many governments to start considering use of the new drugs.

Looking simply at the cost of production, Andrew Hill, a pharmacologist at the University of Liverpool, thinks such a price target is certainly achievable. In fact, he calculates that large-scale production is possible for just $1 a day - or one thousandth of the Sovaldi price tag.

For a three-drug combination, he estimates a target price of between $100 and $250 for 12 weeks of treatment is realistic, including a margin for profits.

Of course, drug prices take account of more than just the cost of goods. They also reflect the value that medicines can offer society and Gilead argues its price is fair based on the significant benefits it brings.

The total cost of the 12-week regimen is also not so different to current treatment, which requires 24 or 48 weeks of interferon-based therapy and is less effective. And Gilead has ploughed an awful lot of money into this new medicine after paying $11 billion in 2012 for Pharmasset, the company that initially developed Sovaldi.

Still, the $1,000-a-day price tag has raised concerns even among some healthcare providers in the United States.

"Obviously, drug companies need to make a return on investment," said Hill. "The question is how much?"

(Editing by David Holmes)

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