.jpg)
High Hepatitis C, Liver Cancer Rate In Queens, NYC
During a “State of the Hospital” presentation at New York Hospital Queens, Director of Surgical Oncology Dr. Mitchell Chorost subtly revealed a little-known reality within the borough.
The Borough At A Glance
“We’re seeing an unusually high rate of liver cancer as a result of Hepatitis C,” he said, citing ethnic factors as the main driving force behind the spike. “A lot of people don’t realize that the problem is out there.”
Chorost’s findings, coupled with the 15th Anniversary of Hepatitis Awareness Month this May, bring a new urgency to raising awareness about this communicable and deadly, yet treatable, disease.
Nearly 80 percent of all untreated cases of Hepatitis C are believed to lead to liver cancer, according to the State Dept. of Health. The cancer itself causes 10,000 deaths nationwide each year.
Cultural Concerns
According to Chorost, a growing population of first-generation Asian and Russian immigrants has driven an increase in the overall rate of Hepatitis C and liver cancer.
“These cultures are very close people,” he said. “They assimilate with each other and that’s how they spread these diseases within each other.”
It is a byproduct of a growing rate in their native countries, the doctor added.
“There is no vaccine against Hepatitis C. It’s a worldwide epidemic, effecting namely Far East countries like China and Korea,” he said. “These are patients who weren’t aware they had it in China and Russia and they came with it. They’re carriers.”
Cancer By The Numbers
On a state-wide level, liver cancer has an occurrence rate of about 7 per 100,000, according to the CDC. Our borough dwarfs those figures.
By nearly every available measure, Queens has a higher rate. Nearly 14 of every 100,000 Queens men have liver cancer, and 4.5 among females.
When broken down, the rate per 100,000 residents doubles among Asian and Pacific Islanders.
>From 2003 to 2007, the rate of liver cancer among male Asian and Pacific Islanders was nearly double the statewide level, at 24.1 per 100,000, according to State Dept. of Health statistics.
The numbers are highly prevalent in neighborhoods with a high Asian population. Flushing leads the borough with a rate of 19.1 per 100,000.
Side Effects
The deceptive symptoms and low profile of Hepatitis C leads to a higher rate of liver cancer.
With fairly common symptoms such as nausea, fever and fatigue, it remains easy to overlook the possibility of infection. It has led many cases to go untreated, according to Chorost, and put an additional burden on NYHQ.
Simply put: They need more livers.
“The need for liver transplantation far exceeds the amount available,” Chorost said.
Even with newer methods such as partial liver donations, the hospital is falling short of demand among patients in need of a liver transplant.
Reason For Hope
In spite of the figures, Chorost said Hepatitis C is very treatable when caught early.
“Pamela Anderson has Hepatitis C and she’s doing really well,” he said.
Sunday, May 23, 2010
Annual HCV Screening Recommended in NYS for HIV+ For At-Risk Individuals
Annual HCV Screening Recommended in NYS for HIV+ For At-Risk Individuals
Hepatitis and HIV: Update to Hepatitis C
Virus in HIV-Infected Patients
As part of Hepatitis Awareness Month, the Office of the Medical Director, New York State Department of Health AIDS Institute, is pleased to announce guidelines updates from the Medical Care Criteria Committee, chaired by Barry S. Zingman, MD.
CLINICAL GUIDELINES UPDATE: HEPATITIS C VIRUS
Significant revisions include the following:
* An annual HCV antibody test is now recommended for HIV-infected patients who have continued high-risk behaviors but are seronegative for HCV; such individuals include:
o Injection drug users
o Men who have sex with men without barrier protection
o Anyone with multiple sexual partners
* Quantitative HCV RNA viral load testing is now recommended for HIV-infected patients:
o To confirm a reactive HCV ELISA antibody screen
o To exclude HCV infection in those who are seronegative for HCV but have risk factors for HCV exposure and unexplained liver disease, including increased serum liver enzymes
* A table has been added that lists the tests for measuring HCV RNA (see Table 1)
* Figure 1. HCV Testing Algorithm for HIV-Infected Patients has been updated
* Assessment for anti-HCV therapy is now recommended for HIV-infected patients with acute HCV infection (see Section VI. B. Assessment for Treatment of Acute HCV Infection)
* Sections on assessment of mental health disorders and alcohol and substance use have been added (see Sections V. F. Assessment of Mental Health Disorders and G. Assessment of Alcohol and Substance Use)
* A new section has been added on ongoing evaluation of patients when anti-HCV therapy is deferred (see Section VII)
* A new section has been added that outlines baseline assessments and counseling at initiation of therapy (see Section VIII)
* Consultation with a psychiatrist is now recommended when prescribing anti-HCV therapy for HIV-infected patients with mental health disorders
* Figure 2. Initial Anti-HCV Therapy for HIV/HCV Co-infected Patients has been updated and now recommends determining whether or not to continue anti-HCV treatment after week 12 by assessing for virologic response according to quantitative HCV RNA
* A table has been added that outlines strategies for managing side effects of anti-HCV therapy (see Table 7)
CLINICAL GUIDELINES UPDATE: OCCUPATIONAL AND NON-OCCUPATIONAL EXPOSURES TO HEPATITIS B AND HEPATITIS C
These sections provide guidance on post-exposure management for hepatitis B and C virus, including the following:
* Initiation of prophylaxis and the hepatitis B vaccine series for non-HBV-immune persons who sustain a blood or body fluid exposure (see Table 8)
* Baseline tests to obtain following a potential hepatitis C exposure and management according to results (see Table 9)
* Post-exposure follow-up schedule for individuals exposed to hepatitis C
OTHER HIV AND HEPATITIS CLINICAL GUIDELINES FROM THE NYSDOH AIDS INSTITUTE
Hepatitis A Virus
These guidelines recommend that clinicians:
* Vaccinate all HIV-infected patients who are negative for HAV IgG
* Obtain post-vaccination antibody measurements in patients who are at increased risk for hepatitis A infection to verify vaccine efficacy and to identify patients who might benefit from vaccine boosting. Persons who are at increased risk are listed in Table 1.
Hepatitis B Virus
These guidelines include recommendations that address the following:
* The HBV serologies that should be obtained prior to vaccination and when to obtain serologies after vaccination (see Figure 3)
* When to initiate treatment active against HBV (see Section VI)
* When to initiate ARV therapy in HIV/HBV co-infected patients (see Section VI)
* Routine laboratory assessment and therapeutic monitoring considerations of HIV-infected patients with HBV (see Table 3)
Hepatitis and HIV: Update to Hepatitis C
Virus in HIV-Infected Patients
As part of Hepatitis Awareness Month, the Office of the Medical Director, New York State Department of Health AIDS Institute, is pleased to announce guidelines updates from the Medical Care Criteria Committee, chaired by Barry S. Zingman, MD.
CLINICAL GUIDELINES UPDATE: HEPATITIS C VIRUS
Significant revisions include the following:
* An annual HCV antibody test is now recommended for HIV-infected patients who have continued high-risk behaviors but are seronegative for HCV; such individuals include:
o Injection drug users
o Men who have sex with men without barrier protection
o Anyone with multiple sexual partners
* Quantitative HCV RNA viral load testing is now recommended for HIV-infected patients:
o To confirm a reactive HCV ELISA antibody screen
o To exclude HCV infection in those who are seronegative for HCV but have risk factors for HCV exposure and unexplained liver disease, including increased serum liver enzymes
* A table has been added that lists the tests for measuring HCV RNA (see Table 1)
* Figure 1. HCV Testing Algorithm for HIV-Infected Patients has been updated
* Assessment for anti-HCV therapy is now recommended for HIV-infected patients with acute HCV infection (see Section VI. B. Assessment for Treatment of Acute HCV Infection)
* Sections on assessment of mental health disorders and alcohol and substance use have been added (see Sections V. F. Assessment of Mental Health Disorders and G. Assessment of Alcohol and Substance Use)
* A new section has been added on ongoing evaluation of patients when anti-HCV therapy is deferred (see Section VII)
* A new section has been added that outlines baseline assessments and counseling at initiation of therapy (see Section VIII)
* Consultation with a psychiatrist is now recommended when prescribing anti-HCV therapy for HIV-infected patients with mental health disorders
* Figure 2. Initial Anti-HCV Therapy for HIV/HCV Co-infected Patients has been updated and now recommends determining whether or not to continue anti-HCV treatment after week 12 by assessing for virologic response according to quantitative HCV RNA
* A table has been added that outlines strategies for managing side effects of anti-HCV therapy (see Table 7)
CLINICAL GUIDELINES UPDATE: OCCUPATIONAL AND NON-OCCUPATIONAL EXPOSURES TO HEPATITIS B AND HEPATITIS C
These sections provide guidance on post-exposure management for hepatitis B and C virus, including the following:
* Initiation of prophylaxis and the hepatitis B vaccine series for non-HBV-immune persons who sustain a blood or body fluid exposure (see Table 8)
* Baseline tests to obtain following a potential hepatitis C exposure and management according to results (see Table 9)
* Post-exposure follow-up schedule for individuals exposed to hepatitis C
OTHER HIV AND HEPATITIS CLINICAL GUIDELINES FROM THE NYSDOH AIDS INSTITUTE
Hepatitis A Virus
These guidelines recommend that clinicians:
* Vaccinate all HIV-infected patients who are negative for HAV IgG
* Obtain post-vaccination antibody measurements in patients who are at increased risk for hepatitis A infection to verify vaccine efficacy and to identify patients who might benefit from vaccine boosting. Persons who are at increased risk are listed in Table 1.
Hepatitis B Virus
These guidelines include recommendations that address the following:
* The HBV serologies that should be obtained prior to vaccination and when to obtain serologies after vaccination (see Figure 3)
* When to initiate treatment active against HBV (see Section VI)
* When to initiate ARV therapy in HIV/HBV co-infected patients (see Section VI)
* Routine laboratory assessment and therapeutic monitoring considerations of HIV-infected patients with HBV (see Table 3)
World Hepatitis Day NYC 2010
World Hepatitis Day NYC 2010
Informing the public about the risks of viral hepatitis infection and the importance of prevention, early detection and disease management is critical to the health and well being of the estimated 232,000 New York City residents living with hepatitis B or C, as well as to their families and community.
Learn more about viral hepatitis: www.cdc.gov/hepatitis.
Get tested! See below for special free testing events today and this month, or call 311 for testing and vaccination information.
World Hepatitis Day Press Conference on the Steps of City Hall
Today! May 19th 2010 from 1-2 PM
Join Linda Gibbs, the Deputy Mayor of Health and Human Services, the NYC Hepatitis B Coalition, and the NYC Hepatitis C Task Force in announcing the 2010 NYC Mayoral Proclamation and NYS Gubernatorial Proclamation designating May as Viral Hepatitis Awareness Month, and May 19th as World Hepatitis Day in New York City .
Speaking at the event:
Linda Gibbs, NYC Deputy Mayor for Health and Human Services
Donald Gardenier, DNP, Clinical Program Director, Mt Sinai Primary Care Liver Clinic
Henry Pollack, MD, NYU School of Medicine, B Free CEED - Center of Excellence for the Elimination of Hepatitis B Disparities
Umut Sarpel, MD , Division of Surgical Oncology, NYU School of Medicine
Su Wang, MD, Director of Hepatitis B Services, Charles B Wang Community Health Center
Patient advocates
Community Hepatitis Awareness Month Events
Free Hepatitis B & C Screening/Testing Opportunities
* Weill Cornell & NY Harm Reduction Educators Hepatitis C Testing. May 19th - 3 Sites:
o Weill Cornell Medical College , (1PM - 7PM). 1305 York Avenue , 2nd Floor NY , NY 10021 . Contact: (646) 962-4372.
o NY Harm Reduction Educators Harlem , (10AM - 4PM). 1991 Lexington Avenue, NY 10035 (Corner of 121st Street ). Contact: (212) 828-8464.
o NY Harm Reduction Educators Bronx , (10AM - 5PM). 953 Southern Boulevard, Suite 302 , Bronx , NY 10459 . Contact: (718) 842-6050.
* Charles B Wang Community Heath Center Hepatitis B Testing. 4 dates and 2 sites:
o May 19th and 20th (10AM-3PM) Walk-ins welcome. 268 Canal Street , 2nd floor, Manhattan 10013. For more information contact: klo@cbwchc.org.
o May 18th (2-5PM) and May 21st (3-5PM). 136-26 37th Avenue , 2nd floor, Flushing . For appointment or more information contact: 718-886-1212, ext 513.
* Harlem United - FROST’D Hepatitis C Outreach & Testing & Hepatitis A & B Vaccination. May 19th (12-4PM). 2 sites:
o 290 Lenox Avenue
o Outside the state building at 125th and Adam Clayton Powell Boulevard . For more info contact: eroberts@frostd.org.
* Actors’ Fund Al Hirschfeld Free Clinic Hepatitis B & C Testing for uninsured working members of the entertainment & performing arts community. Week of May 17th (9:30AM -5PM). Al Hirshfeld Free Health Clinic, 475 West 57th St. NY 10019 . Sponsered by the Al D. Rodriguez Liver Foundation. By appointment only, contact: jpearl@actorsfund.org.
* Citiwide Harm Reduction Hepatitis C Testing & Awareness Event. May 19th (12PM-3). 226 E. 144th St. Bronx , NY 10451 . Hepatitis C Screenings, Hepatitis A & B Vaccinations, HIV Testing, and escorts to medical care. Food, Snacks and music will be provided! For more info, contact: SGuillaume@citiwidehr.org.
* Mount Sinai Hepatitis C Risk Factor Screening. May 20th (10am – 3pm). 17 East 102nd Street , lobby (between Madison and 5th). Contact: Natalie.Kil@mountsinai.org.
* American Cancer Society Hepatitis B Education & Testing Events. Two dates and sites:
o May 23rd Sunday (1:30-3:30 PM). New Town Church - 85-15 Broadway, Elmhurst , NY 11373 . Speaker: Dr. Sing Chan. Pre-registration is required, contact: 718-886-8890 ext.19.
o May 27th Thursday (1-3PM). Confucius Plaza Community Room - 33 Bowery, New York , NY . Speaker: Dr. Wuhua Jing. Pre-registration is required, contact: 718-886-8890 ext.19.
* Community Health Action of Staten Island Hepatitis C Testing. May 24th (1-5PM). 380 Van Duzer Street , Staten Island , 10304. For more information contact (718) 808–1355.
Community Education
* “Adherence to HCV Treatment” Lecture with Jeffrey Weiss, PhD, MS, Mount Sinai . May 19th (12:30 PM – 1:30 PM). Weill Cornell 402 East 67 Street, NY 10065, Level C1, Conference Center A. Provided by Weill Cornell Medical College, Department of Public Health’s Division of Community & Public Health Programs: Community & Public Health Research & Clinical Rounds. A CME Activity. Target Audience: Weill-Cornell physicians, residents, researchers, students and other interested physicians and health care providers who specialize in substance abuse treatment, addiction psychiatry, general psychiatry, family medicine, community and public health.
* Mount Sinai Division of General Internal Medicine Grand Rounds: "Overcoming Barriers to HCV Treatment for Drug Users" with Alain Litwin, MD, MPH, MS, Associate Professor of Clinical Medicine and Psychiatry, Albert Einstein College of Medicine. May 27th (8:30 – 9:30 AM). 1468 Madison Avenue , Annenberg Building , Dining Rooms A and B
* Viral Hepatitis Clinical Studies in Australia Lecture. June 10th (4 – 5PM), 125 Worth Street, 2nd floor Auditorium. Presenter: Pip Marks BSc, MPH, Clinical Trials Manager, Australia ’s National Centre in HIV Epidemiology and Clinical Research. Will present on Studies: ETHOS – HCV management in Opiate Substitution settings; RAMPT-C – risks and mechanisms of sexual transmission of HCV; Acute-C – natural history and treatment of AHC; InC3 – International collaboration of AHC databases; STREP – HCC epidemiology and prevention; and ACHOS – Australian HCV observational database. No registration required.
Informing the public about the risks of viral hepatitis infection and the importance of prevention, early detection and disease management is critical to the health and well being of the estimated 232,000 New York City residents living with hepatitis B or C, as well as to their families and community.
Learn more about viral hepatitis: www.cdc.gov/hepatitis.
Get tested! See below for special free testing events today and this month, or call 311 for testing and vaccination information.
World Hepatitis Day Press Conference on the Steps of City Hall
Today! May 19th 2010 from 1-2 PM
Join Linda Gibbs, the Deputy Mayor of Health and Human Services, the NYC Hepatitis B Coalition, and the NYC Hepatitis C Task Force in announcing the 2010 NYC Mayoral Proclamation and NYS Gubernatorial Proclamation designating May as Viral Hepatitis Awareness Month, and May 19th as World Hepatitis Day in New York City .
Speaking at the event:
Linda Gibbs, NYC Deputy Mayor for Health and Human Services
Donald Gardenier, DNP, Clinical Program Director, Mt Sinai Primary Care Liver Clinic
Henry Pollack, MD, NYU School of Medicine, B Free CEED - Center of Excellence for the Elimination of Hepatitis B Disparities
Umut Sarpel, MD , Division of Surgical Oncology, NYU School of Medicine
Su Wang, MD, Director of Hepatitis B Services, Charles B Wang Community Health Center
Patient advocates
Community Hepatitis Awareness Month Events
Free Hepatitis B & C Screening/Testing Opportunities
* Weill Cornell & NY Harm Reduction Educators Hepatitis C Testing. May 19th - 3 Sites:
o Weill Cornell Medical College , (1PM - 7PM). 1305 York Avenue , 2nd Floor NY , NY 10021 . Contact: (646) 962-4372.
o NY Harm Reduction Educators Harlem , (10AM - 4PM). 1991 Lexington Avenue, NY 10035 (Corner of 121st Street ). Contact: (212) 828-8464.
o NY Harm Reduction Educators Bronx , (10AM - 5PM). 953 Southern Boulevard, Suite 302 , Bronx , NY 10459 . Contact: (718) 842-6050.
* Charles B Wang Community Heath Center Hepatitis B Testing. 4 dates and 2 sites:
o May 19th and 20th (10AM-3PM) Walk-ins welcome. 268 Canal Street , 2nd floor, Manhattan 10013. For more information contact: klo@cbwchc.org.
o May 18th (2-5PM) and May 21st (3-5PM). 136-26 37th Avenue , 2nd floor, Flushing . For appointment or more information contact: 718-886-1212, ext 513.
* Harlem United - FROST’D Hepatitis C Outreach & Testing & Hepatitis A & B Vaccination. May 19th (12-4PM). 2 sites:
o 290 Lenox Avenue
o Outside the state building at 125th and Adam Clayton Powell Boulevard . For more info contact: eroberts@frostd.org.
* Actors’ Fund Al Hirschfeld Free Clinic Hepatitis B & C Testing for uninsured working members of the entertainment & performing arts community. Week of May 17th (9:30AM -5PM). Al Hirshfeld Free Health Clinic, 475 West 57th St. NY 10019 . Sponsered by the Al D. Rodriguez Liver Foundation. By appointment only, contact: jpearl@actorsfund.org.
* Citiwide Harm Reduction Hepatitis C Testing & Awareness Event. May 19th (12PM-3). 226 E. 144th St. Bronx , NY 10451 . Hepatitis C Screenings, Hepatitis A & B Vaccinations, HIV Testing, and escorts to medical care. Food, Snacks and music will be provided! For more info, contact: SGuillaume@citiwidehr.org.
* Mount Sinai Hepatitis C Risk Factor Screening. May 20th (10am – 3pm). 17 East 102nd Street , lobby (between Madison and 5th). Contact: Natalie.Kil@mountsinai.org.
* American Cancer Society Hepatitis B Education & Testing Events. Two dates and sites:
o May 23rd Sunday (1:30-3:30 PM). New Town Church - 85-15 Broadway, Elmhurst , NY 11373 . Speaker: Dr. Sing Chan. Pre-registration is required, contact: 718-886-8890 ext.19.
o May 27th Thursday (1-3PM). Confucius Plaza Community Room - 33 Bowery, New York , NY . Speaker: Dr. Wuhua Jing. Pre-registration is required, contact: 718-886-8890 ext.19.
* Community Health Action of Staten Island Hepatitis C Testing. May 24th (1-5PM). 380 Van Duzer Street , Staten Island , 10304. For more information contact (718) 808–1355.
Community Education
* “Adherence to HCV Treatment” Lecture with Jeffrey Weiss, PhD, MS, Mount Sinai . May 19th (12:30 PM – 1:30 PM). Weill Cornell 402 East 67 Street, NY 10065, Level C1, Conference Center A. Provided by Weill Cornell Medical College, Department of Public Health’s Division of Community & Public Health Programs: Community & Public Health Research & Clinical Rounds. A CME Activity. Target Audience: Weill-Cornell physicians, residents, researchers, students and other interested physicians and health care providers who specialize in substance abuse treatment, addiction psychiatry, general psychiatry, family medicine, community and public health.
* Mount Sinai Division of General Internal Medicine Grand Rounds: "Overcoming Barriers to HCV Treatment for Drug Users" with Alain Litwin, MD, MPH, MS, Associate Professor of Clinical Medicine and Psychiatry, Albert Einstein College of Medicine. May 27th (8:30 – 9:30 AM). 1468 Madison Avenue , Annenberg Building , Dining Rooms A and B
* Viral Hepatitis Clinical Studies in Australia Lecture. June 10th (4 – 5PM), 125 Worth Street, 2nd floor Auditorium. Presenter: Pip Marks BSc, MPH, Clinical Trials Manager, Australia ’s National Centre in HIV Epidemiology and Clinical Research. Will present on Studies: ETHOS – HCV management in Opiate Substitution settings; RAMPT-C – risks and mechanisms of sexual transmission of HCV; Acute-C – natural history and treatment of AHC; InC3 – International collaboration of AHC databases; STREP – HCC epidemiology and prevention; and ACHOS – Australian HCV observational database. No registration required.
Mixed Findings on Vitamin D and Metabolic Syndrome
Mixed Findings on Vitamin D and Metabolic Syndrome
MedPage Today
Published: May 18, 2010
PRAGUE -- Suggestions that vitamin D insufficiency may account for at least some cases of metabolic syndrome received support from a small study reported here but were refuted in a much larger study.
Action Points
* Explain to interested patients that low vitamin D levels have been reported to be associated with metabolic syndrome and some of its components, but it remains to be confirmed in large, rigorous analyses.
* Explain that such associations do not necessary mean that low vitamin D actually causes these conditions, although it is possible, nor do they suggest that vitamin D supplements will prevent them.
* Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.
Individuals with relatively severe vitamin D deficits, as measured by serum 25-hydroxyvitamin D (25-OH-D), were at significantly increased risk for components of metabolic syndrome in a 92-patient study, according to Viliam Mojto, MD, PhD, of Derer's University Hospital in Bratislava, Slovakia, and colleagues.
But Natielen J. Schuch and colleagues at the University of Saõ Paolo in Brazil found no relationship between vitamin D insufficiency and metabolic syndrome in a study of 405 people -- perhaps because some 85% of the entire sample had low levels of the vitamin.
Both studies were reported here at the World Congress on Controversies to Consensus in Diabetes, Obesity, and Hypertension.
Metabolic syndrome is a condition characterized by a constellation of major risk factors for both cardiovascular disease and type 2 diabetes: obesity, dyslipidemia, impaired glucose tolerance, or insulin insensitivity, and high blood pressure.
The Slovakian researchers measured serum 25-OH-D levels in 92 adults, ages 25 to 92 years, treated as inpatients or outpatients at Derer's University Hospital.
Prevalences of individual components of metabolic syndrome or related overt diseases in the entire sample were as follows:
* Dyslipidemia: 4.1%
* Hypertension: 21.8%
* Impaired glucose tolerance: <2%
* Diabetes mellitus: 9.5%
* Atherosclerosis: 7.3%
* Ischemic heart disease: 20.6%
* Renal insufficiency: 12.7%
Mojto and colleagues found that the median level of 25-OH-D was about 16 ng/mL, well below the 30-ng/mL level regarded as insufficiency, and near the 15-ng/mL standard for serious deficiency.
For men as well as women, analyzed separately, diagnoses of hypertension, diabetes, ischemic heart disease, and renal insufficiency were all more common in those with 25-OH-D levels below 16 ng/mL.
In women, the excesses in diagnoses, compared with participants having higher 25-OH-D levels, ranged from 19% for hypertension to 160% for diabetes. Excess diagnoses in men ranged from 40% for diabetes to 67% for ischemic heart disease (P not reported).
These associations persisted after adjusting for age and sex, Mojto and colleagues indicated.
But they were not confirmed in the much larger Brazilian study.
About 46% of the 405 people enrolled in the University of Saõ Paolo study qualified for a diagnosis of metabolic syndrome, according to criteria developed by the U.S.-based National Cholesterol Education Program, according to Schuch and colleagues.
The mean 25-OH-D level in the 187 individuals who fit the criteria for metabolic syndrome was 24.4 ng/mL (SD 7.2), compared with a mean of 21.2 ng/mL (SD 6.4) among the 218 participants without the full syndrome (P<0.05).
In other words, 78% of those with metabolic syndrome met the 30-ng/mL standard for vitamin D insufficiency, compared with 92% of those without the syndrome.
The researchers didn't report on the possible relationships between vitamin D and individual components of metabolic syndrome.
MedPage Today
Published: May 18, 2010
PRAGUE -- Suggestions that vitamin D insufficiency may account for at least some cases of metabolic syndrome received support from a small study reported here but were refuted in a much larger study.
Action Points
* Explain to interested patients that low vitamin D levels have been reported to be associated with metabolic syndrome and some of its components, but it remains to be confirmed in large, rigorous analyses.
* Explain that such associations do not necessary mean that low vitamin D actually causes these conditions, although it is possible, nor do they suggest that vitamin D supplements will prevent them.
* Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.
Individuals with relatively severe vitamin D deficits, as measured by serum 25-hydroxyvitamin D (25-OH-D), were at significantly increased risk for components of metabolic syndrome in a 92-patient study, according to Viliam Mojto, MD, PhD, of Derer's University Hospital in Bratislava, Slovakia, and colleagues.
But Natielen J. Schuch and colleagues at the University of Saõ Paolo in Brazil found no relationship between vitamin D insufficiency and metabolic syndrome in a study of 405 people -- perhaps because some 85% of the entire sample had low levels of the vitamin.
Both studies were reported here at the World Congress on Controversies to Consensus in Diabetes, Obesity, and Hypertension.
Metabolic syndrome is a condition characterized by a constellation of major risk factors for both cardiovascular disease and type 2 diabetes: obesity, dyslipidemia, impaired glucose tolerance, or insulin insensitivity, and high blood pressure.
The Slovakian researchers measured serum 25-OH-D levels in 92 adults, ages 25 to 92 years, treated as inpatients or outpatients at Derer's University Hospital.
Prevalences of individual components of metabolic syndrome or related overt diseases in the entire sample were as follows:
* Dyslipidemia: 4.1%
* Hypertension: 21.8%
* Impaired glucose tolerance: <2%
* Diabetes mellitus: 9.5%
* Atherosclerosis: 7.3%
* Ischemic heart disease: 20.6%
* Renal insufficiency: 12.7%
Mojto and colleagues found that the median level of 25-OH-D was about 16 ng/mL, well below the 30-ng/mL level regarded as insufficiency, and near the 15-ng/mL standard for serious deficiency.
For men as well as women, analyzed separately, diagnoses of hypertension, diabetes, ischemic heart disease, and renal insufficiency were all more common in those with 25-OH-D levels below 16 ng/mL.
In women, the excesses in diagnoses, compared with participants having higher 25-OH-D levels, ranged from 19% for hypertension to 160% for diabetes. Excess diagnoses in men ranged from 40% for diabetes to 67% for ischemic heart disease (P not reported).
These associations persisted after adjusting for age and sex, Mojto and colleagues indicated.
But they were not confirmed in the much larger Brazilian study.
About 46% of the 405 people enrolled in the University of Saõ Paolo study qualified for a diagnosis of metabolic syndrome, according to criteria developed by the U.S.-based National Cholesterol Education Program, according to Schuch and colleagues.
The mean 25-OH-D level in the 187 individuals who fit the criteria for metabolic syndrome was 24.4 ng/mL (SD 7.2), compared with a mean of 21.2 ng/mL (SD 6.4) among the 218 participants without the full syndrome (P<0.05).
In other words, 78% of those with metabolic syndrome met the 30-ng/mL standard for vitamin D insufficiency, compared with 92% of those without the syndrome.
The researchers didn't report on the possible relationships between vitamin D and individual components of metabolic syndrome.
Hepatitis Awareness Month --- May 2010 from the CDC
Hepatitis Awareness Month --- May 2010
from the CDC
May 7, 2010 / 59(17);514
May 2010 marks the 15th anniversary of Hepatitis Awareness Month in the United States, and May 19 is World Hepatitis Day. Globally, viral hepatitis is the cause of most (78%) primary liver cancer, the third leading cause of cancer deaths in the world (1). Prevention of hepatitis B and hepatitis C virus transmission and treatment for early disease can prevent primary liver cancer (2). This issue of MMWR includes a report describing vaccination of at-risk adults with hepatitis B vaccine in California and a report on continued increases in hepatocellular carcinoma incidence in the United States.
The Institute of Medicine (IOM) recently issued Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and Hepatitis C. The IOM strategy has four components: 1) accurate public health surveillance, 2) innovative approaches to community education, 3) immunization capacity to eliminate hepatitis B virus transmission, and 4) development of viral hepatitis services, including screening with referral for medical management. Taken together, these strategies can reduce morbidity associated with viral hepatitis, including primary liver cancer.
Additional information about viral hepatitis is available at http://www.cdc.gov/hepatitis. The IOM report is available at http://www.iom.edu
References
1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74--108.
2. Cardoso AC, Moucari R, Figueiredo-Mendes C, et al. Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: incidence and survival in hepatitis C patients with advanced fibrosis. J Hepatol 2010;52:652--7.
from the CDC
May 7, 2010 / 59(17);514
May 2010 marks the 15th anniversary of Hepatitis Awareness Month in the United States, and May 19 is World Hepatitis Day. Globally, viral hepatitis is the cause of most (78%) primary liver cancer, the third leading cause of cancer deaths in the world (1). Prevention of hepatitis B and hepatitis C virus transmission and treatment for early disease can prevent primary liver cancer (2). This issue of MMWR includes a report describing vaccination of at-risk adults with hepatitis B vaccine in California and a report on continued increases in hepatocellular carcinoma incidence in the United States.
The Institute of Medicine (IOM) recently issued Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and Hepatitis C. The IOM strategy has four components: 1) accurate public health surveillance, 2) innovative approaches to community education, 3) immunization capacity to eliminate hepatitis B virus transmission, and 4) development of viral hepatitis services, including screening with referral for medical management. Taken together, these strategies can reduce morbidity associated with viral hepatitis, including primary liver cancer.
Additional information about viral hepatitis is available at http://www.cdc.gov/hepatitis. The IOM report is available at http://www.iom.edu
References
1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74--108.
2. Cardoso AC, Moucari R, Figueiredo-Mendes C, et al. Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: incidence and survival in hepatitis C patients with advanced fibrosis. J Hepatol 2010;52:652--7.
Vitamin D Supplement improve SVR in Chronic Hepatitis C (Genotype 1) Naïve Patients treated with Peg Interferon and Ribavirin
at EASL in April researchers reported:
Vitamin D Supplement improve SVR in Chronic Hepatitis C (Genotype 1) Naïve Patients treated with Peg Interferon and Ribavirin - (04/20/10) they reported a doubling of SVR with vitamin D3 supplementation of 2000-4000 IU/d for 4 weeks and an associatin with race or darkness of skin pigmentation, in other words perhaps an association with low response to peg/rbv by African-Americans & Lstinos
Low Vitamin D Levels Associated with Genotype 1, Fibrosis, Inflammation, with SVR, with waist circumference, Low HDL
Hepatology April 2010
"1. Mean serum values of 25(OH)D in Genotype 1 CHC patients were significantly lower than in controls (25.1 ± 9.9 g/L versus 43.1 ± 10.2 g/L; P < 0.0001;.....
2. low vitamin D levels (<30 g/L) were independently associated with high necroinflammatory activity (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.16-3.42, P = 0.01)......
3. Another interesting finding of this study is the evidence that lower 25(OH)D serum levels were an independent negative risk factor for SVR......
4. Comparing patients with significant fibrosis (F2-F4) with subjects with no significant fibrosis (F1), we confirmed that low serum 25(OH)D levels were independently related to significant fibrosis.....
5. a significant association was found between a decreased expression of CYP27A1 and low 25(OH)D serum levels (P = 0.01) (Fig. 3A). Moreover, CYP27A1 expression was negatively associated with the degree of necroinflammatory activity (P = 0.031)......
6. Figure 4, showing the distribution of 25(OH)D serum levels according to the stage of fibrosis, highlighted a significant trend in 25(OH)D reduction among the four fibrosis stages (P < 0.0001). However, even patients with fibrosis F1 had mean serum 25(OH)D levels significantly lower than control subjects (29.5 ± 10.9 g/L versus 43.1 ± 10.2 g/L; P < 0.0001)......
7. High GGT, low cholesterol, low 25(OH)D, greater steatosis, and severe necroinflammatory activity were associated with lack of SVR (P < 0.10)......
8. In conclusion, this study, showing low levels of serum 25(OH)D and of their liver hydroxylating enzymes in G1 CHC patients, and suggesting a relation of vitamin D status with the severity of liver disease and response to therapy, opens a new area of research on the potential use of vitamin D in patients with CHCWe have shown that the biochemical profile of Genotype 1 CHC patients is characterized by lower-than-normal serum 25(OH)D levels, and that a low 25(OH)D level is independently related to severe fibrosis and a low likelihood of SVR after standard-of-care antiviral therapy..........
9. Our study shows that low 25(OH)D levels are independently associated with female sex and with severity of necroinflammatory activity.....
10. high waist circumference (P < 0.06), high ALT (P = 0.09), and low high-density lipoprotein levels (P = 0.01), the severity of necroinflammatory activity (P = 0.01), and the severity of fibrosis (P < 0.001) were associated with lower 25(OH)D levels in G1 CHC, though only female sex (P = 0.007), the severity of necroinflammatory activity (P = 0.04), and the severity of fibrosis (P = 0.009) were independent factors in multiple linear regression analysis.....
11. CYP27A1 liver expression was directly related to serum 25(OH)D levels, and inversely associated with the severity of necroinflammatory activity. Therefore, the hepatic necroinflammatory activity caused by the HCV infection could be responsible for 25 (OH)D levels reduction by different mechanisms, such as a selectively reduced liver expression of enzymes involved in liver hydroxylation of vitamin D3.....
12. This study also offers the first evidence that low 25(OH)D serum levels, together with known risk factors for fibrosis severity, such as older age, low cholesterol levels, and high necroinflammatory activity,[26] are independently associated with the presence of severe fibrosis.....
13. It is conceivable that a reduced 25(OH)D level might by itself favor progression of fibrosis.....By multivariate analysis, hepatic steatosis (OR, 0.971; 95%CI, 0.944-0.999), lower cholesterol (OR, 1.009; 95% CI, 1.000-1.018), and 25(OH)D levels (OR, 1.039; 95%CI, 1.002-1.077) were independently associated with no SVR. Conclusion: G1 CHC patients had low 25(OH)D serum levels, possibly because of reduced CYP27A1 expression. Low vitamin D is linked to severe fibrosis and low SVR on interferon (IFN)-based therapy"
Figure 4. Distribution of 25(OH)D serum levels according to different stages of fibrosis.
Picture 2.png
Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C
Hepatology April 2010
Salvatore Petta 1 2 *, Calogero Cammà 1 3, Concetta Scazzone 4, Claudio Tripodo 5, Vito Di Marco 1, Antonino Bono 4, Daniela Cabibi 5, Giusalba Licata 1, Rossana Porcasi 5, Giulio Marchesini 6, Antonio Craxí 1
1Cattedra ed Unità Operativa di Gastroenterologia, DiBiMIS, University of Palermo, Italy
2Dipartimento di Biopatologia e Metodologie Biomediche, University of Palermo, Italy
3IBIM Consiglio Nazionale delle Ricerche, Palermo, Italy
4Dipartimento di Biotecnologie Mediche e Medicina Legale Sezione Chimica e Biochimica Medica, University of Palermo, Italy
5Cattedra di Anatomia Patologica, University of Palermo, Italy
6Dipartimento di Medicina e Gastroenterologia, Alma Mater Studiorum, University of Bologna, Italy
email: Salvatore Petta (petsa@inwind.it)
*Correspondence to Salvatore Petta, Gastroenterologia & Epatologia, Piazza delle Cliniche, 2, 90127 Palermo, Italy
ABSTRACT
25-Hydroxyvitamin D (25[OH]D) can potentially interfere with inflammatory response and fibrogenesis. Its role in disease progression in chronic hepatitis C (CHC) and its relation with histological and sustained virological response (SVR) to therapy are unknown. One hundred ninety-seven patients with biopsy-proven genotype 1 (G1) CHC and 49 healthy subjects matched by age and sex were consecutively evaluated. One hundred sixty-seven patients underwent antiviral therapy with pegylated interferon plus ribavirin. The 25(OH)D serum levels were measured by high-pressure liquid chromatography. Tissue expression of cytochrome (CY) P27A1 and CYP2R1, liver 25-hydroxylating enzymes, were assessed by immunochemistry in 34 patients with CHC, and in eight controls. The 25(OH)D serum levels were significantly lower in CHC than in controls (25.07 ± 9.92 g/L versus 43.06 ± 10.19; P < 0.001). Lower levels of 25(OH)D were independently linked to female sex (P = 0.007) and necroinflammation (P = 0.04) by linear regression analysis. CYP27A1, but not CYP2R1, was directly related to 25(OH)D levels (P = 0.01), and inversely to necroinflammation (P = 0.01). Low 25(OH)D (odds ratio [OR], 0.942; 95% confidence interval [CI], 0.893-0.994) and cholesterol (OR, 0.981; 95%CI, 0.969-0.992) levels, older age (OR, 1.043; 95%CI, 1.002-1.085), high ferritin (OR, 1.003; 95%CI, 1.001-1.005), and necroinflammation (OR, 2.235; 95%CI, 1.014-4.929) were independently associated with severe fibrosis (F3-F4) by multivariate logistic analysis. Seventy patients (41%) achieved SVR. By multivariate analysis, hepatic steatosis (OR, 0.971; 95%CI, 0.944-0.999), lower cholesterol (OR, 1.009; 95% CI, 1.000-1.018), and 25(OH)D levels (OR, 1.039; 95%CI, 1.002-1.077) were independently associated with no SVR. Conclusion: G1 CHC patients had low 25(OH)D serum levels, possibly because of reduced CYP27A1 expression. Low vitamin D is linked to severe fibrosis and low SVR on interferon (IFN)-based therapy.
DISCUSSION
We have shown that the biochemical profile of G1 CHC patients is characterized by lower-than-normal serum 25(OH)D levels, and that a low 25(OH)D level is independently related to severe fibrosis and a low likelihood of SVR after standard-of-care antiviral therapy.
Lower levels of serum 25(OH)D have been previously reported in populations heterogeneous for cause and severity of chronic liver disease.[11][19] We confirmed a 25(OH)D reduction in a homogeneous cohort of patients with G1 CHC, at low prevalence of F4 fibrosis. Although a significant trend in 25(OH)D levels reduction was observed with increasing stage of fibrosis, a significant reduction was also observed in the subgroup of patients with mild fibrosis (F1), making it unlikely that low 25(OH)D levels could be entirely explained by reduced liver function.
Our study shows that low 25(OH)D levels are independently associated with female sex and with severity of necroinflammatory activity. Although the study was not designed to clarify the correlation between female sex and lower 25(OH)D levels, because of the observed reduction in women older than 55 years, but not in men of the same age range, and because of the significant interaction between sex and age, we can speculate that hormonal alterations in postmenopausal women likely modulate the vitamin D status. Our results also underline an inverse relationship between 25(OH)D and the severity of necroinflammatory activity. The cross-sectional design of our study is unable to dissect the temporal relation between changes in 25(OH)D and necroinflammation. However, CYP27A1 liver expression was directly related to serum 25(OH)D levels, and inversely associated with the severity of necroinflammatory activity. Therefore, the hepatic necroinflammatory activity caused by the HCV infection could be responsible for 25 (OH)D levels reduction by different mechanisms, such as a selectively reduced liver expression of enzymes involved in liver hydroxylation of vitamin D3.
This study also offers the first evidence that low 25(OH)D serum levels, together with known risk factors for fibrosis severity, such as older age, low cholesterol levels, and high necroinflammatory activity,[26] are independently associated with the presence of severe fibrosis. We were not able to confirm IR as a risk factor for fibrosis severity, as reported by others.[26][27] The lack of this association could be attributable to differences in the mean age, alcohol use, and prevalence of obesity and diabetes. In any case we confirmed the important effect of metabolic alterations in fibrosis severity, providing evidence for an association between severe fibrosis and high ferritin levels, a surrogate marker of IR and metabolic syndrome.[28]
Interestingly, considering only noninvasive parameters, the AUC of the model that includes vitamin D levels to predict severe fibrosis remains good. This suggests the potential use of serum 25(OH)D levels as a noninvasive marker of liver fibrosis, a use that needs to be tested and validated in large prospective cohort studies in patients with CHC of all genotypes, and in chronic liver disease of other origins.
It is conceivable that a reduced 25(OH)D level might by itself favor progression of fibrosis. Different experimental models showed that vitamin D, via interaction with vitamin D receptor, protects against oxidative stress production,[29] can influence the migration, proliferation, and gene expression of fibroblasts,[30][31] and reduces the inflammatory and fibrogenic activity of liver stellate cells.[32][33] However further prospective cohort studies will be needed to determine the causal association between vitamin D deficiency and fibrosis in patients with CHC.
Another interesting finding of this study is the evidence that lower 25(OH)D serum levels were an independent negative risk factor for SVR. Again, this observation will require further validation in different, large cohorts of patients, but is supported by experimental data that suggest a role of vitamin D in the modulation of the immune response,[32][33] and by recent clinical data[36] reporting higher early virological response rate in CHC treated with standard of care plus vitamin D, compared with those treated with standard of care only. Finally, in line with data from the literature, we found that steatosis[35] and lower cholesterol levels, a known surrogate marker of fibrosis severity,[26] were independently associated with lower SVR rate. We did not find any association between IR and SVR, in keeping the conflicting data reported in the literature on the role of IR as a predictor of SVR.[36]
The main limitation of this study lies in its cross-sectional nature and its inability to dissect the temporal relation between 25(OH)D and fibrosis. A further methodological drawback is the potentially limited external validity of the results for different populations and settings. Another limitation of this study is the lack of data on the potential confounders that may influence the levels of vitamin D, such as exposure to sunshine, dietary intake, and the prevalence of osteoporosis. However, all of the subjects involved in this study lived in Sicily, where sunshine is abundant, even if we cannot rule out differences in sun exposure between healthy controls and CHC patients. However, data on the prevalence of osteoporosis were not available, nor was the dietary intake of vitamin D, which, however, remains a rather crude measure of vitamin D status because of recall bias. The lack of these data in both cases and controls makes a systematic error very unlikely. Also, data on osteoporosis were not available in both groups. Lack of data on polymorphisms of vitamin D hydroxylating enzymes, and on other variables involved in vitamin D metabolism, such as parathyroid hormone, and in vitamin D signaling regulation also could affect the interpretation of our findings.
In conclusion, this study, showing low levels of serum 25(OH)D and of their liver hydroxylating enzymes in G1 CHC patients, and suggesting a relation of vitamin D status with the severity of liver disease and response to therapy, opens a new area of research on the potential use of vitamin D in patients with CHC.
RESULTS
Patient Features and Histology.
The baseline features of the 197 patients are shown in Table 1. Most of our patients were in the overweight to obesity range. One patient in four had fibrosis of at least 3 by Scheuer score, with a high prevalence of moderate/severe necroinflammation (grading 2-3). Half of the cases had histological evidence of steatosis, though of moderate/severe grade in only 23 cases (11.7%).
The control subjects (25 women and 24 men, mean age of 53.7 ± 12.8 years) were comparable for body mass index with the HCV population (26.1 ± 3.5 kg/m2). Six had arterial hypertension.
Serum 25(OH)D Levels.
Mean serum values of 25(OH)D in G1 CHC patients were significantly lower than in controls (25.1 ± 9.9 g/L versus 43.1 ± 10.2 g/L; P < 0.0001; Fig. 1). Accordingly, 25(OH)D serum levels of less than 30 g/L were found in 144 (73%) G1 CHC patients and in only three control subjects (6%, P < 0.001). Advanced age (P = 0.004), female sex (P < 0.001), high waist circumference (P < 0.06), high ALT (P = 0.09), and low high-density lipoprotein levels (P = 0.01), the severity of necroinflammatory activity (P = 0.01), and the severity of fibrosis (P < 0.001) were associated with lower 25(OH)D levels in G1 CHC, though only female sex (P = 0.007), the severity of necroinflammatory activity (P = 0.04), and the severity of fibrosis (P = 0.009) were independent factors in multiple linear regression analysis (Table 2). Figure 1 also shows the distribution of serum 25(OH)D levels in relation to sex. A significant difference was observed in CHC patients (27.60 ± 9.39 g/L in men versus 22.23 ± 9.77 g/L in women; P = 0.0001) (Fig. 1). Figure 2 shows the distribution of 25(OH)D according to necroinflammatory activity.
Interestingly, women 55 years of age or older had lower 25(OH)D serum levels than their counterparts of younger than 55 years (20.2 ± 9.5 versus 24.5 ± 9.7; P = 0.03). Conversely, in men we observed no difference in 25(OH)D serum levels between patients 55 or older and younger than 55 years of age (26.72 ± 9.08 versus 28.52 ± 9.72; P = 0.33). To account for possible interaction between sex and age, a term for the product of the two variables was included in the linear multivariate model, and showed that the interaction between the two risk factors was significant (P = 0.002).
Considering 25(OH)D as a categorical variable, low vitamin D levels (<30 g/L) were independently associated with high necroinflammatory activity (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.16-3.42, P = 0.01) and with the interaction term between sex and age (OR, 1.015; 95%CI, 1.005-1.026, P = 0.005).
CYP27A1 and CYP2R1 Liver Evaluation.
In a random sample of 34 patients (19 men [55%]; mean age, 50 ± 12.7 years; 13 (38%) with severe fibrosis; 23 (67%) with moderate-severe necroinflammatory activity; mean 25(OH)D levels 25.96 ± 9.90 g/L), with baseline features not significantly different from the entire group (data not shown), we evaluated the immunohistochemical expression of CYP27A1 and CYP2R1 with a four-grade semiquantitative scoring system. The same analysis was performed in eight control samples from subjects, without liver disease, who underwent cholecystectomy.
CYP27A1 was expressed, with a score of 3 in 75% (6/8) of controls versus 0% (0/34) of cases (P < 0.001), with a score of 2 in 25% (2/8) of controls versus 12% (4/34) of cases (P = 0.42), with a score of 1 in 0% (0/8) of controls versus 25% (12/34) of cases (P = 0.10), and with a score of 0 in 0% (0/8) of controls versus 53% (18/34) of cases (P = 0.04). Similarly, CYP2R1 was expressed with a score of 3 in 50% (4/8) of controls versus 0% (0/34) of cases (P < 0.001), with a score of 2 in 50% (4/8) of controls versus 15% (5/34) of cases (P = 0.10), with a score of 1 in 0% (0/8) of controls versus 50% (17/34) of cases (P = 0.05), and with a score of 0 in 0% (0/8) of controls versus 35% (12/34) of cases (P = 0.10). According to these data, the overall expression of both CYP27A1 and CYP2R1 was significantly down-modulated (P = 0.0001 for both CYP27A1 and CYP2R1) in G1 CHC samples (Supporting Document 1).
The degree of expression of CYP2R1 proved to be neither significantly related to 25(OH)D serum levels nor associated with biochemical, anthropometric, and histological features. Conversely, a significant association was found between a decreased expression of CYP27A1 and low 25(OH)D serum levels (P = 0.01) (Fig. 3A). Moreover, CYP27A1 expression was negatively associated with the degree of necroinflammatory activity (P = 0.031) (Fig. 3B). No significant associations were found between CYP27A1 expression and the various biochemical, anthropometric, and histological features, other than inflammation grade (data not shown).
Case and control samples showed an overlapping picture because CYP450 proved to be diffusely expressed with a moderate intensity in both groups (Supporting Document 2). This suggests a maintained expression of cytochromes other than those involved in vitamin D metabolism in G1 CHC samples.
Variables Related to Severe Fibrosis.
The univariate and multivariate comparison of variables between patients with and without severe fibrosis (F3-F4) are reported in Table 3. Older age, male sex, low platelet count, high baseline values of ALT, high GGT, low cholesterol, high ferritin, low 25(OH)D, steatosis, and high necroinflammatory activity were associated with severe fibrosis (P < 0.10). Multivariate logistic regression analysis showed that the following features were independently linked to severe fibrosis (Scheuer score 3): older age (OR, 1.043; 95% CI, 1.002-1.085, P = 0.03), low cholesterol (OR, 0.981; 95%CI, 0.969-0.992, P = 0.001), high ferritin (OR, 1.003; 95%CI, 1.001-1.005, P = 0.007), low 25(OH)D (OR, 0.942; 95%CI, 0.893-0.994, P = 0.02), and high necroinflammatory activity (grading) (OR, 2.235; 95%CI, 1.014-4.929; P = 0.04). The overall area under the curve (AUC) of this model was good (AUC, 0.870). Figure 4, showing the distribution of 25(OH)D serum levels according to the stage of fibrosis, highlighted a significant trend in 25(OH)D reduction among the four fibrosis stages (P < 0.0001). However, even patients with fibrosis F1 had mean serum 25(OH)D levels significantly lower than control subjects (29.5 ± 10.9 g/L versus 43.1 ± 10.2 g/L; P < 0.0001).
Excluding steatosis and grading from the model, older age (OR, 1.043; 95%CI, 1.004-1.083; P = 0.03), cholesterol (OR, 0.980; 95%CI, 0.968-0.991; P = 0.001), and ferritin (OR, 1.003; 95%CI, 1.001-1.005; P = 0.004) were the noninvasive predictors of severe fibrosis. The overall AUC of this model was similarly good (AUC, 0.854).
Comparing patients with significant fibrosis (F2-F4) with subjects with no significant fibrosis (F1), we confirmed that low serum 25(OH)D levels were independently related to significant fibrosis (data not shown).
The model having fibrosis as an ordinal dependent variable by multiple logistic regression analysis included older age (P = 0.001), low platelets (P = 0.03), low cholesterol (P = 0.001), high ferritin (P = 0.007), low 25(OH)D (P = 0.0006), and high necroinflammatory activity (=P = 0.0002).
Factors Associated with SVR.
One hundred sixty-seven patients underwent and completed the antiviral treatment program. SVR was achieved in 70 individuals (41.9%). Among 97 patients (58.1%) who did not achieve SVR, nine were lost to follow-up, and 14 withdrew from antiviral therapy because of side effects. High GGT, low cholesterol, low 25(OH)D, greater steatosis, and severe necroinflammatory activity were associated with lack of SVR (P < 0.10) (Table 4). By logistic regression, low cholesterol (OR, 1.009; 95%CI, 1.000-1.018; P = 0.04), low 25(OH)D levels (OR, 1.039; 95%CI, 1.002-1.077; P = 0.03), and greater steatosis (OR, 0.971; 95%CI, 0.944-0.999; P = 0.04) were the only independent negative predictors of SVR.
A per protocol analysis of 144 patients confirmed that low cholesterol (OR, 1.012; 95% CI 1.002-1.022; p=0.02) and low 25(OH)D levels (OR, 1.048; 95%CI, 1.008-1.080; P = 0.02), as well as greater steatosis (OR, 0.970; 95%CI, 0.941-1.000; P = 0.04), were negative independent predictors of SVR.
METHODS
Patients.
From January 2007 to December 2008, a total of 197 consecutive patients with G1 CHC, resident in Sicily and recruited at the Gastrointestinal and Liver Unit at the University Hospital in Palermo, fulfilling all inclusion and exclusion criteria detailed later, were assessed. Patients were included if they had a histological diagnosis of CHC (any degree of fibrosis, including cirrhosis) on a liver biopsy performed within 6 months before enrollment. G1 CHC patients were characterized by the presence of anti-hepatitis C virus (HCV) and HCV RNA, with persistently abnormal alanine aminotransferase (ALT), and by alcohol consumption of less than 20 g/day in the last year or more, evaluated by a specific questionnaire. Exclusion criteria were (1) advanced cirrhosis (Child-Pugh B and C); (2) hepatocellular carcinoma; (3) other causes of liver disease or mixed causes (excessive alcohol consumption, hepatitis B, autoimmune liver disease, Wilson's disease, hemochromatosis, 1-antitrypsin deficiency); (4) cancer or chronic intestinal diseases; (5) human immunodeficiency virus infection; (6) therapy with medications known to affect vitamin D3 metabolism, including vitamin/mineral supplements; (7) previous treatment with antiviral therapy, immunosuppressive drug, or regular use of steatosis-inducing drugs; and (8) active intravenous drug addiction.
Forty-nine randomly-selected, nondiabetic, healthy blood donors of the same ethnic group as CHC patients and living in Sicily, recruited from January 2008 to December 2008, matched for age and sex, were enrolled as controls. Alcohol consumption of more than 20 g/day during the previous year or therapy with medications known to affect vitamin D3 metabolism (calcium, vitamin D supplementation, hormonal therapy, alendronate) were additional exclusion criteria. All had normal ALT values (<30 UI/L), and no evidence of viral infection (anti-HCV, anti-human immunodeficiency virus, and hepatitis B surface antigen negative) or steatosis, verified by ultrasound scan.
The study was performed in accordance with the principles of the Declaration of Helsinki and its appendices. Approval was obtained from the hospital's Institutional Review Board and Ethics Committee, and written informed consent was obtained from all cases and controls.
Clinical and Laboratory Assessment.
Clinical and anthropometric data were collected at the time of liver biopsy. Body mass index was calculated on the basis of weight in kilograms and height (in meters). Waist circumference was measured at the midpoint between the lower border of the rib cage and the iliac crest. The diagnosis of arterial hypertension was based on the following criteria: systolic blood pressure at least 135 mm Hg or diastolic blood pressure 85 mmHg or more (measured three times within 30 minutes, in the sitting position and using a brachial sphygmomanometer), or use of blood-pressure-lowering agents. The diagnosis of type 2 diabetes was based on the revised criteria of the American Diabetes Association, using a value of fasting blood glucose at least 126 mg/dL on at least two occasions.[20] In patients with a previous diagnosis of type 2 diabetes, current therapy with insulin or oral hypoglycemic agents was documented.
A 12-hour overnight fasting blood sample was drawn at the time of biopsy to determine serum levels of ALT, gamma-glutamyltransferase (GGT), total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, triglycerides, ferritin, plasma glucose concentration, and platelet count. Serum insulin was determined by a two-site enzyme enzyme-linked immunosorbent assay (Mercodia Insulin ELISA, Arnika). IR was determined with the homeostasis model assessment method.[21]
The analysis of serum 25(OH) D was performed using a Chromosystem reagent kit and a chromatographic system equipped with a Waters 1525 Binary high-pressure liquid chromatography pump connected to a photo diode array detector, and detection was carried out at 265 nm. In accordance with the kit's instructions, a serum 25(OH)D concentration of 30 g/L was considered the threshold value for identifying low levels of vitamin D.
All patients were tested at the time of biopsy for HCV-RNA by qualitative polymerase chain reaction (Cobas Amplicor HCV Test version 2.0; limit of detection: 50 IU/mL). HCV RNA positive samples were quantified by Versant HCV RNA 3.0 bDNA (Bayer Co. Tarrytown, NY) expressed in IU/mL. Genotyping was performed by INNO-LiPA, HCV II, Bayer.
Histology.
Slides were coded and read by one pathologist (D.C.) who was unaware of the patient's identity and history. A minimum length of 15 mm of biopsy specimen or the presence of at least 10 complete portal tracts was required.[22] Biopsy specimens were classified according to the Scheuer numerical scoring system.[23] The percentage of hepatocytes containing macrovescicular fat was determined for each 10× field. An average percentage of steatosis was then determined for the entire specimen. Steatosis was assessed as the percentage of hepatocytes containing fat droplets (minimum 5%) and evaluated as a continuous variable. Steatosis was classified as mild at 5% to 30% or moderate-severe at 30% or more.
CYP27A1 and CYP2R1 Liver Immunohistochemical Evaluation.
Immunohistochemistry was performed on liver biopsy tissue sections by means of the streptavidin-biotin-peroxidase method. All samples were fixed for 24 hours with 10% buffered formalin, paraffin-embedded, and cut in serial sections of 3 g. Tissue morphology was evaluated by hematoxylin-eosin staining.
Immunohistochemical detection of CYP2R1 and CYP27A1 was performed using anti-human CYP2R1 (C-15) and CYP27A1 (P-17) (goat polyclonal antibody, Santa Cruz Biotechonology, Inc.). After dewaxing, the endogenous peroxidase activity was inhibited by the pretreatment of the tissue section with 3% hydrogen peroxide before incubation with the primary antibody. The sections were washed twice, after all incubation steps, in phosphate-buffered saline for 5 minutes. Then slides were microwave-oven heated three times for 5 minutes in Tris/ethylenediaminetetra-acetic acid pH 9.0 buffer (heat-induced epitope retrieval), and washed with phosphate-buffered saline. Sections were subsequentially incubated in the presence of the primary antibody overnight at -4°C. The specimens were then incubated with the LSAB HRP detection kit (Universal DakoCytomation LSAB+ System HRP) at room temperature, according to the manufacturer's instructions. As a chromogen, 3-amino-9-ethylcarbazole was used for 5 minutes at room temperature with subsequent nuclear counterstaining with hematoxylin. Normal mouse serum was used instead of primary antibodies as a negative control.
A four-grade semiquantitative scoring system (in other words, score 0-3), performed by one pathologist (C.T.) unaware of other variables, was adopted for the evaluation of CYP2R1 and CYP27A1 immunohistochemical expression. The score was graded according to the intensity of the staining: score 0 was defined as the absence of significant reactivity, scores 1 and 2 as slight and moderate reactivity, respectively, and score 3 as intense reactivity. Because a slight degree of variation could be observed in the immunohistochemical expression of CYP2R1 and CYP27A1 among different areas of the same sample, the most intense reactivity observed in the biopsy specimen was recorded as the summary score.
Immunohistochemical analysis of CYP450 was performed for control purposes using a specific primary monoclonal antibody (clone 1A2, Abcam, MA) and evaluated by the same four-grade semiquantitative scoring system adopted for CYP27A1 and CYP2R1 assessment.
Antiviral Treatment Schedule and Outcomes.
Patients were treated with pegylated interferon -2a (Pegasys, Roche, Basel, Switzerland) 180 g /week or pegylated interferon 2b (Peg-Intron, Schering) 1.5 g/kg/week plus ribavirin at a dosage of 1000 or 1200 mg/day according to body weight (1000 mg/day for a body weight of <75 kg, 1200 mg/day for a body weight of >75 kg) for 48 weeks. Patients were withdrawn from treatment if they did not achieve a virological response, defined as undetectable serum HCV RNA by polymerase chain reaction, within 24 weeks after start of treatment.[24] Sustained virological response (SVR) was defined as negative serum HCV RNA at polymerase chain reaction 6 months after stopping antiviral therapy.
Statistics.
Continuous variables were summarized as mean ± standard deviation, and categorical variables as frequency and percentage. The Student t test and analysis of variance were used when appropriate. Multiple linear regression analysis was performed to identify independent predictors of 25(OH)D serum levels as a continuous dependent variable. As candidate risk factors for low serum levels of 25(OH)D, we selected age, sex, body mass index, waist circumference, baseline ALT, platelet count, GGT, ferritin, total cholesterol, high-density lipoprotein cholesterol, triglycerides, blood glucose, insulin, homeostasis model assessment score, diabetes, arterial hypertension, HCV-RNA levels, steatosis, and activity score.
Multiple logistic regression models were used to assess the relationship of both fibrosis and SVR to the demographic, metabolic, and histological characteristics of patients. In the first model, the dependent variable was severe fibrosis coded as 1 = F3 to F4 in the fibrosis score versus 0 = F1 to F2. Because fibrosis grade is nonlinear, we also performed ordinal logistic regression with fibrosis F0 to F4 as the dependent variable. In the second model, the dependent variable was SVR coded 1 = present versus 0 = absent. As candidate risk factors we selected the same independent variables included in the 25(OH)D model and added 25(OH)D serum levels as an additional independent variable. In this model, we included all patients who received at least one dose of pegylated interferon (intention-to-treat analysis).
Variables associated with the dependent variable at univariate analyses (probability threshold, P 0.10) were included in the multivariate regression models.[25] Regression analyses were performed by SAS.
Vitamin D Supplement improve SVR in Chronic Hepatitis C (Genotype 1) Naïve Patients treated with Peg Interferon and Ribavirin - (04/20/10) they reported a doubling of SVR with vitamin D3 supplementation of 2000-4000 IU/d for 4 weeks and an associatin with race or darkness of skin pigmentation, in other words perhaps an association with low response to peg/rbv by African-Americans & Lstinos
Low Vitamin D Levels Associated with Genotype 1, Fibrosis, Inflammation, with SVR, with waist circumference, Low HDL
Hepatology April 2010
"1. Mean serum values of 25(OH)D in Genotype 1 CHC patients were significantly lower than in controls (25.1 ± 9.9 g/L versus 43.1 ± 10.2 g/L; P < 0.0001;.....
2. low vitamin D levels (<30 g/L) were independently associated with high necroinflammatory activity (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.16-3.42, P = 0.01)......
3. Another interesting finding of this study is the evidence that lower 25(OH)D serum levels were an independent negative risk factor for SVR......
4. Comparing patients with significant fibrosis (F2-F4) with subjects with no significant fibrosis (F1), we confirmed that low serum 25(OH)D levels were independently related to significant fibrosis.....
5. a significant association was found between a decreased expression of CYP27A1 and low 25(OH)D serum levels (P = 0.01) (Fig. 3A). Moreover, CYP27A1 expression was negatively associated with the degree of necroinflammatory activity (P = 0.031)......
6. Figure 4, showing the distribution of 25(OH)D serum levels according to the stage of fibrosis, highlighted a significant trend in 25(OH)D reduction among the four fibrosis stages (P < 0.0001). However, even patients with fibrosis F1 had mean serum 25(OH)D levels significantly lower than control subjects (29.5 ± 10.9 g/L versus 43.1 ± 10.2 g/L; P < 0.0001)......
7. High GGT, low cholesterol, low 25(OH)D, greater steatosis, and severe necroinflammatory activity were associated with lack of SVR (P < 0.10)......
8. In conclusion, this study, showing low levels of serum 25(OH)D and of their liver hydroxylating enzymes in G1 CHC patients, and suggesting a relation of vitamin D status with the severity of liver disease and response to therapy, opens a new area of research on the potential use of vitamin D in patients with CHCWe have shown that the biochemical profile of Genotype 1 CHC patients is characterized by lower-than-normal serum 25(OH)D levels, and that a low 25(OH)D level is independently related to severe fibrosis and a low likelihood of SVR after standard-of-care antiviral therapy..........
9. Our study shows that low 25(OH)D levels are independently associated with female sex and with severity of necroinflammatory activity.....
10. high waist circumference (P < 0.06), high ALT (P = 0.09), and low high-density lipoprotein levels (P = 0.01), the severity of necroinflammatory activity (P = 0.01), and the severity of fibrosis (P < 0.001) were associated with lower 25(OH)D levels in G1 CHC, though only female sex (P = 0.007), the severity of necroinflammatory activity (P = 0.04), and the severity of fibrosis (P = 0.009) were independent factors in multiple linear regression analysis.....
11. CYP27A1 liver expression was directly related to serum 25(OH)D levels, and inversely associated with the severity of necroinflammatory activity. Therefore, the hepatic necroinflammatory activity caused by the HCV infection could be responsible for 25 (OH)D levels reduction by different mechanisms, such as a selectively reduced liver expression of enzymes involved in liver hydroxylation of vitamin D3.....
12. This study also offers the first evidence that low 25(OH)D serum levels, together with known risk factors for fibrosis severity, such as older age, low cholesterol levels, and high necroinflammatory activity,[26] are independently associated with the presence of severe fibrosis.....
13. It is conceivable that a reduced 25(OH)D level might by itself favor progression of fibrosis.....By multivariate analysis, hepatic steatosis (OR, 0.971; 95%CI, 0.944-0.999), lower cholesterol (OR, 1.009; 95% CI, 1.000-1.018), and 25(OH)D levels (OR, 1.039; 95%CI, 1.002-1.077) were independently associated with no SVR. Conclusion: G1 CHC patients had low 25(OH)D serum levels, possibly because of reduced CYP27A1 expression. Low vitamin D is linked to severe fibrosis and low SVR on interferon (IFN)-based therapy"
Figure 4. Distribution of 25(OH)D serum levels according to different stages of fibrosis.
Picture 2.png
Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C
Hepatology April 2010
Salvatore Petta 1 2 *, Calogero Cammà 1 3, Concetta Scazzone 4, Claudio Tripodo 5, Vito Di Marco 1, Antonino Bono 4, Daniela Cabibi 5, Giusalba Licata 1, Rossana Porcasi 5, Giulio Marchesini 6, Antonio Craxí 1
1Cattedra ed Unità Operativa di Gastroenterologia, DiBiMIS, University of Palermo, Italy
2Dipartimento di Biopatologia e Metodologie Biomediche, University of Palermo, Italy
3IBIM Consiglio Nazionale delle Ricerche, Palermo, Italy
4Dipartimento di Biotecnologie Mediche e Medicina Legale Sezione Chimica e Biochimica Medica, University of Palermo, Italy
5Cattedra di Anatomia Patologica, University of Palermo, Italy
6Dipartimento di Medicina e Gastroenterologia, Alma Mater Studiorum, University of Bologna, Italy
email: Salvatore Petta (petsa@inwind.it)
*Correspondence to Salvatore Petta, Gastroenterologia & Epatologia, Piazza delle Cliniche, 2, 90127 Palermo, Italy
ABSTRACT
25-Hydroxyvitamin D (25[OH]D) can potentially interfere with inflammatory response and fibrogenesis. Its role in disease progression in chronic hepatitis C (CHC) and its relation with histological and sustained virological response (SVR) to therapy are unknown. One hundred ninety-seven patients with biopsy-proven genotype 1 (G1) CHC and 49 healthy subjects matched by age and sex were consecutively evaluated. One hundred sixty-seven patients underwent antiviral therapy with pegylated interferon plus ribavirin. The 25(OH)D serum levels were measured by high-pressure liquid chromatography. Tissue expression of cytochrome (CY) P27A1 and CYP2R1, liver 25-hydroxylating enzymes, were assessed by immunochemistry in 34 patients with CHC, and in eight controls. The 25(OH)D serum levels were significantly lower in CHC than in controls (25.07 ± 9.92 g/L versus 43.06 ± 10.19; P < 0.001). Lower levels of 25(OH)D were independently linked to female sex (P = 0.007) and necroinflammation (P = 0.04) by linear regression analysis. CYP27A1, but not CYP2R1, was directly related to 25(OH)D levels (P = 0.01), and inversely to necroinflammation (P = 0.01). Low 25(OH)D (odds ratio [OR], 0.942; 95% confidence interval [CI], 0.893-0.994) and cholesterol (OR, 0.981; 95%CI, 0.969-0.992) levels, older age (OR, 1.043; 95%CI, 1.002-1.085), high ferritin (OR, 1.003; 95%CI, 1.001-1.005), and necroinflammation (OR, 2.235; 95%CI, 1.014-4.929) were independently associated with severe fibrosis (F3-F4) by multivariate logistic analysis. Seventy patients (41%) achieved SVR. By multivariate analysis, hepatic steatosis (OR, 0.971; 95%CI, 0.944-0.999), lower cholesterol (OR, 1.009; 95% CI, 1.000-1.018), and 25(OH)D levels (OR, 1.039; 95%CI, 1.002-1.077) were independently associated with no SVR. Conclusion: G1 CHC patients had low 25(OH)D serum levels, possibly because of reduced CYP27A1 expression. Low vitamin D is linked to severe fibrosis and low SVR on interferon (IFN)-based therapy.
DISCUSSION
We have shown that the biochemical profile of G1 CHC patients is characterized by lower-than-normal serum 25(OH)D levels, and that a low 25(OH)D level is independently related to severe fibrosis and a low likelihood of SVR after standard-of-care antiviral therapy.
Lower levels of serum 25(OH)D have been previously reported in populations heterogeneous for cause and severity of chronic liver disease.[11][19] We confirmed a 25(OH)D reduction in a homogeneous cohort of patients with G1 CHC, at low prevalence of F4 fibrosis. Although a significant trend in 25(OH)D levels reduction was observed with increasing stage of fibrosis, a significant reduction was also observed in the subgroup of patients with mild fibrosis (F1), making it unlikely that low 25(OH)D levels could be entirely explained by reduced liver function.
Our study shows that low 25(OH)D levels are independently associated with female sex and with severity of necroinflammatory activity. Although the study was not designed to clarify the correlation between female sex and lower 25(OH)D levels, because of the observed reduction in women older than 55 years, but not in men of the same age range, and because of the significant interaction between sex and age, we can speculate that hormonal alterations in postmenopausal women likely modulate the vitamin D status. Our results also underline an inverse relationship between 25(OH)D and the severity of necroinflammatory activity. The cross-sectional design of our study is unable to dissect the temporal relation between changes in 25(OH)D and necroinflammation. However, CYP27A1 liver expression was directly related to serum 25(OH)D levels, and inversely associated with the severity of necroinflammatory activity. Therefore, the hepatic necroinflammatory activity caused by the HCV infection could be responsible for 25 (OH)D levels reduction by different mechanisms, such as a selectively reduced liver expression of enzymes involved in liver hydroxylation of vitamin D3.
This study also offers the first evidence that low 25(OH)D serum levels, together with known risk factors for fibrosis severity, such as older age, low cholesterol levels, and high necroinflammatory activity,[26] are independently associated with the presence of severe fibrosis. We were not able to confirm IR as a risk factor for fibrosis severity, as reported by others.[26][27] The lack of this association could be attributable to differences in the mean age, alcohol use, and prevalence of obesity and diabetes. In any case we confirmed the important effect of metabolic alterations in fibrosis severity, providing evidence for an association between severe fibrosis and high ferritin levels, a surrogate marker of IR and metabolic syndrome.[28]
Interestingly, considering only noninvasive parameters, the AUC of the model that includes vitamin D levels to predict severe fibrosis remains good. This suggests the potential use of serum 25(OH)D levels as a noninvasive marker of liver fibrosis, a use that needs to be tested and validated in large prospective cohort studies in patients with CHC of all genotypes, and in chronic liver disease of other origins.
It is conceivable that a reduced 25(OH)D level might by itself favor progression of fibrosis. Different experimental models showed that vitamin D, via interaction with vitamin D receptor, protects against oxidative stress production,[29] can influence the migration, proliferation, and gene expression of fibroblasts,[30][31] and reduces the inflammatory and fibrogenic activity of liver stellate cells.[32][33] However further prospective cohort studies will be needed to determine the causal association between vitamin D deficiency and fibrosis in patients with CHC.
Another interesting finding of this study is the evidence that lower 25(OH)D serum levels were an independent negative risk factor for SVR. Again, this observation will require further validation in different, large cohorts of patients, but is supported by experimental data that suggest a role of vitamin D in the modulation of the immune response,[32][33] and by recent clinical data[36] reporting higher early virological response rate in CHC treated with standard of care plus vitamin D, compared with those treated with standard of care only. Finally, in line with data from the literature, we found that steatosis[35] and lower cholesterol levels, a known surrogate marker of fibrosis severity,[26] were independently associated with lower SVR rate. We did not find any association between IR and SVR, in keeping the conflicting data reported in the literature on the role of IR as a predictor of SVR.[36]
The main limitation of this study lies in its cross-sectional nature and its inability to dissect the temporal relation between 25(OH)D and fibrosis. A further methodological drawback is the potentially limited external validity of the results for different populations and settings. Another limitation of this study is the lack of data on the potential confounders that may influence the levels of vitamin D, such as exposure to sunshine, dietary intake, and the prevalence of osteoporosis. However, all of the subjects involved in this study lived in Sicily, where sunshine is abundant, even if we cannot rule out differences in sun exposure between healthy controls and CHC patients. However, data on the prevalence of osteoporosis were not available, nor was the dietary intake of vitamin D, which, however, remains a rather crude measure of vitamin D status because of recall bias. The lack of these data in both cases and controls makes a systematic error very unlikely. Also, data on osteoporosis were not available in both groups. Lack of data on polymorphisms of vitamin D hydroxylating enzymes, and on other variables involved in vitamin D metabolism, such as parathyroid hormone, and in vitamin D signaling regulation also could affect the interpretation of our findings.
In conclusion, this study, showing low levels of serum 25(OH)D and of their liver hydroxylating enzymes in G1 CHC patients, and suggesting a relation of vitamin D status with the severity of liver disease and response to therapy, opens a new area of research on the potential use of vitamin D in patients with CHC.
RESULTS
Patient Features and Histology.
The baseline features of the 197 patients are shown in Table 1. Most of our patients were in the overweight to obesity range. One patient in four had fibrosis of at least 3 by Scheuer score, with a high prevalence of moderate/severe necroinflammation (grading 2-3). Half of the cases had histological evidence of steatosis, though of moderate/severe grade in only 23 cases (11.7%).
The control subjects (25 women and 24 men, mean age of 53.7 ± 12.8 years) were comparable for body mass index with the HCV population (26.1 ± 3.5 kg/m2). Six had arterial hypertension.
Serum 25(OH)D Levels.
Mean serum values of 25(OH)D in G1 CHC patients were significantly lower than in controls (25.1 ± 9.9 g/L versus 43.1 ± 10.2 g/L; P < 0.0001; Fig. 1). Accordingly, 25(OH)D serum levels of less than 30 g/L were found in 144 (73%) G1 CHC patients and in only three control subjects (6%, P < 0.001). Advanced age (P = 0.004), female sex (P < 0.001), high waist circumference (P < 0.06), high ALT (P = 0.09), and low high-density lipoprotein levels (P = 0.01), the severity of necroinflammatory activity (P = 0.01), and the severity of fibrosis (P < 0.001) were associated with lower 25(OH)D levels in G1 CHC, though only female sex (P = 0.007), the severity of necroinflammatory activity (P = 0.04), and the severity of fibrosis (P = 0.009) were independent factors in multiple linear regression analysis (Table 2). Figure 1 also shows the distribution of serum 25(OH)D levels in relation to sex. A significant difference was observed in CHC patients (27.60 ± 9.39 g/L in men versus 22.23 ± 9.77 g/L in women; P = 0.0001) (Fig. 1). Figure 2 shows the distribution of 25(OH)D according to necroinflammatory activity.
Interestingly, women 55 years of age or older had lower 25(OH)D serum levels than their counterparts of younger than 55 years (20.2 ± 9.5 versus 24.5 ± 9.7; P = 0.03). Conversely, in men we observed no difference in 25(OH)D serum levels between patients 55 or older and younger than 55 years of age (26.72 ± 9.08 versus 28.52 ± 9.72; P = 0.33). To account for possible interaction between sex and age, a term for the product of the two variables was included in the linear multivariate model, and showed that the interaction between the two risk factors was significant (P = 0.002).
Considering 25(OH)D as a categorical variable, low vitamin D levels (<30 g/L) were independently associated with high necroinflammatory activity (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.16-3.42, P = 0.01) and with the interaction term between sex and age (OR, 1.015; 95%CI, 1.005-1.026, P = 0.005).
CYP27A1 and CYP2R1 Liver Evaluation.
In a random sample of 34 patients (19 men [55%]; mean age, 50 ± 12.7 years; 13 (38%) with severe fibrosis; 23 (67%) with moderate-severe necroinflammatory activity; mean 25(OH)D levels 25.96 ± 9.90 g/L), with baseline features not significantly different from the entire group (data not shown), we evaluated the immunohistochemical expression of CYP27A1 and CYP2R1 with a four-grade semiquantitative scoring system. The same analysis was performed in eight control samples from subjects, without liver disease, who underwent cholecystectomy.
CYP27A1 was expressed, with a score of 3 in 75% (6/8) of controls versus 0% (0/34) of cases (P < 0.001), with a score of 2 in 25% (2/8) of controls versus 12% (4/34) of cases (P = 0.42), with a score of 1 in 0% (0/8) of controls versus 25% (12/34) of cases (P = 0.10), and with a score of 0 in 0% (0/8) of controls versus 53% (18/34) of cases (P = 0.04). Similarly, CYP2R1 was expressed with a score of 3 in 50% (4/8) of controls versus 0% (0/34) of cases (P < 0.001), with a score of 2 in 50% (4/8) of controls versus 15% (5/34) of cases (P = 0.10), with a score of 1 in 0% (0/8) of controls versus 50% (17/34) of cases (P = 0.05), and with a score of 0 in 0% (0/8) of controls versus 35% (12/34) of cases (P = 0.10). According to these data, the overall expression of both CYP27A1 and CYP2R1 was significantly down-modulated (P = 0.0001 for both CYP27A1 and CYP2R1) in G1 CHC samples (Supporting Document 1).
The degree of expression of CYP2R1 proved to be neither significantly related to 25(OH)D serum levels nor associated with biochemical, anthropometric, and histological features. Conversely, a significant association was found between a decreased expression of CYP27A1 and low 25(OH)D serum levels (P = 0.01) (Fig. 3A). Moreover, CYP27A1 expression was negatively associated with the degree of necroinflammatory activity (P = 0.031) (Fig. 3B). No significant associations were found between CYP27A1 expression and the various biochemical, anthropometric, and histological features, other than inflammation grade (data not shown).
Case and control samples showed an overlapping picture because CYP450 proved to be diffusely expressed with a moderate intensity in both groups (Supporting Document 2). This suggests a maintained expression of cytochromes other than those involved in vitamin D metabolism in G1 CHC samples.
Variables Related to Severe Fibrosis.
The univariate and multivariate comparison of variables between patients with and without severe fibrosis (F3-F4) are reported in Table 3. Older age, male sex, low platelet count, high baseline values of ALT, high GGT, low cholesterol, high ferritin, low 25(OH)D, steatosis, and high necroinflammatory activity were associated with severe fibrosis (P < 0.10). Multivariate logistic regression analysis showed that the following features were independently linked to severe fibrosis (Scheuer score 3): older age (OR, 1.043; 95% CI, 1.002-1.085, P = 0.03), low cholesterol (OR, 0.981; 95%CI, 0.969-0.992, P = 0.001), high ferritin (OR, 1.003; 95%CI, 1.001-1.005, P = 0.007), low 25(OH)D (OR, 0.942; 95%CI, 0.893-0.994, P = 0.02), and high necroinflammatory activity (grading) (OR, 2.235; 95%CI, 1.014-4.929; P = 0.04). The overall area under the curve (AUC) of this model was good (AUC, 0.870). Figure 4, showing the distribution of 25(OH)D serum levels according to the stage of fibrosis, highlighted a significant trend in 25(OH)D reduction among the four fibrosis stages (P < 0.0001). However, even patients with fibrosis F1 had mean serum 25(OH)D levels significantly lower than control subjects (29.5 ± 10.9 g/L versus 43.1 ± 10.2 g/L; P < 0.0001).
Excluding steatosis and grading from the model, older age (OR, 1.043; 95%CI, 1.004-1.083; P = 0.03), cholesterol (OR, 0.980; 95%CI, 0.968-0.991; P = 0.001), and ferritin (OR, 1.003; 95%CI, 1.001-1.005; P = 0.004) were the noninvasive predictors of severe fibrosis. The overall AUC of this model was similarly good (AUC, 0.854).
Comparing patients with significant fibrosis (F2-F4) with subjects with no significant fibrosis (F1), we confirmed that low serum 25(OH)D levels were independently related to significant fibrosis (data not shown).
The model having fibrosis as an ordinal dependent variable by multiple logistic regression analysis included older age (P = 0.001), low platelets (P = 0.03), low cholesterol (P = 0.001), high ferritin (P = 0.007), low 25(OH)D (P = 0.0006), and high necroinflammatory activity (=P = 0.0002).
Factors Associated with SVR.
One hundred sixty-seven patients underwent and completed the antiviral treatment program. SVR was achieved in 70 individuals (41.9%). Among 97 patients (58.1%) who did not achieve SVR, nine were lost to follow-up, and 14 withdrew from antiviral therapy because of side effects. High GGT, low cholesterol, low 25(OH)D, greater steatosis, and severe necroinflammatory activity were associated with lack of SVR (P < 0.10) (Table 4). By logistic regression, low cholesterol (OR, 1.009; 95%CI, 1.000-1.018; P = 0.04), low 25(OH)D levels (OR, 1.039; 95%CI, 1.002-1.077; P = 0.03), and greater steatosis (OR, 0.971; 95%CI, 0.944-0.999; P = 0.04) were the only independent negative predictors of SVR.
A per protocol analysis of 144 patients confirmed that low cholesterol (OR, 1.012; 95% CI 1.002-1.022; p=0.02) and low 25(OH)D levels (OR, 1.048; 95%CI, 1.008-1.080; P = 0.02), as well as greater steatosis (OR, 0.970; 95%CI, 0.941-1.000; P = 0.04), were negative independent predictors of SVR.
METHODS
Patients.
From January 2007 to December 2008, a total of 197 consecutive patients with G1 CHC, resident in Sicily and recruited at the Gastrointestinal and Liver Unit at the University Hospital in Palermo, fulfilling all inclusion and exclusion criteria detailed later, were assessed. Patients were included if they had a histological diagnosis of CHC (any degree of fibrosis, including cirrhosis) on a liver biopsy performed within 6 months before enrollment. G1 CHC patients were characterized by the presence of anti-hepatitis C virus (HCV) and HCV RNA, with persistently abnormal alanine aminotransferase (ALT), and by alcohol consumption of less than 20 g/day in the last year or more, evaluated by a specific questionnaire. Exclusion criteria were (1) advanced cirrhosis (Child-Pugh B and C); (2) hepatocellular carcinoma; (3) other causes of liver disease or mixed causes (excessive alcohol consumption, hepatitis B, autoimmune liver disease, Wilson's disease, hemochromatosis, 1-antitrypsin deficiency); (4) cancer or chronic intestinal diseases; (5) human immunodeficiency virus infection; (6) therapy with medications known to affect vitamin D3 metabolism, including vitamin/mineral supplements; (7) previous treatment with antiviral therapy, immunosuppressive drug, or regular use of steatosis-inducing drugs; and (8) active intravenous drug addiction.
Forty-nine randomly-selected, nondiabetic, healthy blood donors of the same ethnic group as CHC patients and living in Sicily, recruited from January 2008 to December 2008, matched for age and sex, were enrolled as controls. Alcohol consumption of more than 20 g/day during the previous year or therapy with medications known to affect vitamin D3 metabolism (calcium, vitamin D supplementation, hormonal therapy, alendronate) were additional exclusion criteria. All had normal ALT values (<30 UI/L), and no evidence of viral infection (anti-HCV, anti-human immunodeficiency virus, and hepatitis B surface antigen negative) or steatosis, verified by ultrasound scan.
The study was performed in accordance with the principles of the Declaration of Helsinki and its appendices. Approval was obtained from the hospital's Institutional Review Board and Ethics Committee, and written informed consent was obtained from all cases and controls.
Clinical and Laboratory Assessment.
Clinical and anthropometric data were collected at the time of liver biopsy. Body mass index was calculated on the basis of weight in kilograms and height (in meters). Waist circumference was measured at the midpoint between the lower border of the rib cage and the iliac crest. The diagnosis of arterial hypertension was based on the following criteria: systolic blood pressure at least 135 mm Hg or diastolic blood pressure 85 mmHg or more (measured three times within 30 minutes, in the sitting position and using a brachial sphygmomanometer), or use of blood-pressure-lowering agents. The diagnosis of type 2 diabetes was based on the revised criteria of the American Diabetes Association, using a value of fasting blood glucose at least 126 mg/dL on at least two occasions.[20] In patients with a previous diagnosis of type 2 diabetes, current therapy with insulin or oral hypoglycemic agents was documented.
A 12-hour overnight fasting blood sample was drawn at the time of biopsy to determine serum levels of ALT, gamma-glutamyltransferase (GGT), total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, triglycerides, ferritin, plasma glucose concentration, and platelet count. Serum insulin was determined by a two-site enzyme enzyme-linked immunosorbent assay (Mercodia Insulin ELISA, Arnika). IR was determined with the homeostasis model assessment method.[21]
The analysis of serum 25(OH) D was performed using a Chromosystem reagent kit and a chromatographic system equipped with a Waters 1525 Binary high-pressure liquid chromatography pump connected to a photo diode array detector, and detection was carried out at 265 nm. In accordance with the kit's instructions, a serum 25(OH)D concentration of 30 g/L was considered the threshold value for identifying low levels of vitamin D.
All patients were tested at the time of biopsy for HCV-RNA by qualitative polymerase chain reaction (Cobas Amplicor HCV Test version 2.0; limit of detection: 50 IU/mL). HCV RNA positive samples were quantified by Versant HCV RNA 3.0 bDNA (Bayer Co. Tarrytown, NY) expressed in IU/mL. Genotyping was performed by INNO-LiPA, HCV II, Bayer.
Histology.
Slides were coded and read by one pathologist (D.C.) who was unaware of the patient's identity and history. A minimum length of 15 mm of biopsy specimen or the presence of at least 10 complete portal tracts was required.[22] Biopsy specimens were classified according to the Scheuer numerical scoring system.[23] The percentage of hepatocytes containing macrovescicular fat was determined for each 10× field. An average percentage of steatosis was then determined for the entire specimen. Steatosis was assessed as the percentage of hepatocytes containing fat droplets (minimum 5%) and evaluated as a continuous variable. Steatosis was classified as mild at 5% to 30% or moderate-severe at 30% or more.
CYP27A1 and CYP2R1 Liver Immunohistochemical Evaluation.
Immunohistochemistry was performed on liver biopsy tissue sections by means of the streptavidin-biotin-peroxidase method. All samples were fixed for 24 hours with 10% buffered formalin, paraffin-embedded, and cut in serial sections of 3 g. Tissue morphology was evaluated by hematoxylin-eosin staining.
Immunohistochemical detection of CYP2R1 and CYP27A1 was performed using anti-human CYP2R1 (C-15) and CYP27A1 (P-17) (goat polyclonal antibody, Santa Cruz Biotechonology, Inc.). After dewaxing, the endogenous peroxidase activity was inhibited by the pretreatment of the tissue section with 3% hydrogen peroxide before incubation with the primary antibody. The sections were washed twice, after all incubation steps, in phosphate-buffered saline for 5 minutes. Then slides were microwave-oven heated three times for 5 minutes in Tris/ethylenediaminetetra-acetic acid pH 9.0 buffer (heat-induced epitope retrieval), and washed with phosphate-buffered saline. Sections were subsequentially incubated in the presence of the primary antibody overnight at -4°C. The specimens were then incubated with the LSAB HRP detection kit (Universal DakoCytomation LSAB+ System HRP) at room temperature, according to the manufacturer's instructions. As a chromogen, 3-amino-9-ethylcarbazole was used for 5 minutes at room temperature with subsequent nuclear counterstaining with hematoxylin. Normal mouse serum was used instead of primary antibodies as a negative control.
A four-grade semiquantitative scoring system (in other words, score 0-3), performed by one pathologist (C.T.) unaware of other variables, was adopted for the evaluation of CYP2R1 and CYP27A1 immunohistochemical expression. The score was graded according to the intensity of the staining: score 0 was defined as the absence of significant reactivity, scores 1 and 2 as slight and moderate reactivity, respectively, and score 3 as intense reactivity. Because a slight degree of variation could be observed in the immunohistochemical expression of CYP2R1 and CYP27A1 among different areas of the same sample, the most intense reactivity observed in the biopsy specimen was recorded as the summary score.
Immunohistochemical analysis of CYP450 was performed for control purposes using a specific primary monoclonal antibody (clone 1A2, Abcam, MA) and evaluated by the same four-grade semiquantitative scoring system adopted for CYP27A1 and CYP2R1 assessment.
Antiviral Treatment Schedule and Outcomes.
Patients were treated with pegylated interferon -2a (Pegasys, Roche, Basel, Switzerland) 180 g /week or pegylated interferon 2b (Peg-Intron, Schering) 1.5 g/kg/week plus ribavirin at a dosage of 1000 or 1200 mg/day according to body weight (1000 mg/day for a body weight of <75 kg, 1200 mg/day for a body weight of >75 kg) for 48 weeks. Patients were withdrawn from treatment if they did not achieve a virological response, defined as undetectable serum HCV RNA by polymerase chain reaction, within 24 weeks after start of treatment.[24] Sustained virological response (SVR) was defined as negative serum HCV RNA at polymerase chain reaction 6 months after stopping antiviral therapy.
Statistics.
Continuous variables were summarized as mean ± standard deviation, and categorical variables as frequency and percentage. The Student t test and analysis of variance were used when appropriate. Multiple linear regression analysis was performed to identify independent predictors of 25(OH)D serum levels as a continuous dependent variable. As candidate risk factors for low serum levels of 25(OH)D, we selected age, sex, body mass index, waist circumference, baseline ALT, platelet count, GGT, ferritin, total cholesterol, high-density lipoprotein cholesterol, triglycerides, blood glucose, insulin, homeostasis model assessment score, diabetes, arterial hypertension, HCV-RNA levels, steatosis, and activity score.
Multiple logistic regression models were used to assess the relationship of both fibrosis and SVR to the demographic, metabolic, and histological characteristics of patients. In the first model, the dependent variable was severe fibrosis coded as 1 = F3 to F4 in the fibrosis score versus 0 = F1 to F2. Because fibrosis grade is nonlinear, we also performed ordinal logistic regression with fibrosis F0 to F4 as the dependent variable. In the second model, the dependent variable was SVR coded 1 = present versus 0 = absent. As candidate risk factors we selected the same independent variables included in the 25(OH)D model and added 25(OH)D serum levels as an additional independent variable. In this model, we included all patients who received at least one dose of pegylated interferon (intention-to-treat analysis).
Variables associated with the dependent variable at univariate analyses (probability threshold, P 0.10) were included in the multivariate regression models.[25] Regression analyses were performed by SAS.
Vertex, Worth $7.5B, Eagerly Awaits Final Proof that Hepatitis C Drug Works
Vertex, Worth $7.5B, Eagerly Awaits Final Proof that Hepatitis C Drug Works
5/17/2010 Luke Timmerman
http://www.xconomy.com
Related Posts
* Vertex Hepatitis C Drug Passes Key Test With More Convenient, Twice-Daily Dose
* Vertex Hepatitis C Drug Wipes Out Virus For Toughest-to-Treat Patients
* Vertex Maps Out Combo Drug Game Plan for Treating Hepatitis C
* Vertex Fending Off Competitors By Treating the Toughest Patients With Hepatitis C
* Vertex Drug Poised for Pivotal Trial Among Patients Who Fail Prior Hepatitis C Treatments
Vertex Pharmaceuticals has been in business for more than 20 years, and burned through more than $2.8 billion on a quest to develop drugs that shake up the medical standards of care. Now in the coming weeks and months, it will get the first definitive evidence that will say whether its lead drug candidate for hepatitis C has achieved its goal.
Investors, looking at data from preliminary and mid-stage clinical trials, have already pumped up the market value of Vertex past $7.5 billion largely in anticipation that its drug, telaprevir, will transform the lives of patients with the chronic liver-damaging condition. But the operative word there is preliminary. Vertex, which is based in Cambridge, MA, and has significant operations in San Diego, is still waiting for its first proof from Phase III clinical trials, the final step of testing required by the FDA before a drug can go on sale in the U.S.
These pivotal trials began two years ago, and enrolled more than 2,000 patients combined in three studies. The results are completely blinded to doctors, patients, investors, and people at Vertex. To say all parties are in suspense for these results would be an understatement. They can’t wait to get their hands on the new data and start digging through it.
“This is a year of defining moments,” says Bob Kauffman, Vertex’s chief medical officer.
Vertex has generated the excitement around what could be a first-in-class protease inhibitor drug for hepatitis C. It has excited researchers because it has been able to double the cure rate while enabling patients to cut their standard course of treatment time in half. That means that many more of the 3 million Americans and 170 million people worldwide with chronic hepatitis C liver infections will be likely to seek out treatment, and be able to stand up to the side effects of standard therapy that causes flu-like symptoms. If Vertex can prove this idea once and for all in the three pivotal trials, Vertex could seek FDA approval later this year and bring telaprevir to the market in 2011. U.S. sales alone could amount to more than $2 billion after a couple years, analysts say.
To help our readers get ready for this data, I spoke to Kauffman for a refresher on what the three big Vertex trials were designed to ask and answer. The key point to watch for in all of these studies is what is called a “sustained viral response,” or SVR, which is recorded when researchers can’t find any sign of virus in a patient’s blood sample for a full 24 weeks after they completed their course of therapy. This is the gold standard measurement for all hepatitis C drugs, and is commonly known as a “clinical cure.”
The first study to watch for is called “Advance.” This trial, started in March 2008, enrolled 1,050 patients who had never been treated before for hepatitis C—a so-called “naïve” patient population. This study is essentially designed to confirm earlier trials called Prove 1 and Prove 2, Kauffman says. Patients either got the Vertex drug in combination with standard treatments for 24 weeks, or the standard treatments for the usual 48 weeks. The trial is designed to ask whether patients can stop treatment early with the Vertex drug, so they can avoid having to put up with the flu-like side effects of pegylated interferon alpha and ribavirin, Kauffman says. Results from that study should be available by the end of June, he says.
Not long after that data arrives, Vertex plans to hear results from two other key trials before the end of September. One of them, called “Illuminate,” is enrolling patients who have never before
been treated for hepatitis C infections, just like the earlier trial. The study, which enrolled 500 patients, is also looking to see how many clinical cures it can generate, and whether there’s any benefit in subjecting patients to the standard 48-week course of therapy, or whether they do just as well in half the time, Kauffman says. “It should validate that 24 weeks is enough,” Kauffman says.
The third study, called “Realize,” is important for strategic and competitive reasons. This trial enrolled 663 patients who had previously been treated for hepatitis C, but weren’t cured. Vertex has shown some promising results in this tough-to-treat patient population in the past, which is the sort of data that can really give physicians confidence in the drug’s punch. Vertex has taken care to stratify this study into three different kinds of patients—those who benefitted for a while but relapsed, those who only partially responded to prior therapy, and those who never really benefitted at all. Patients will get telaprevir in addition to the standard treatment, or just the standard stuff, for a total of 48 weeks.
As I described back in September 2008, this study is one of the key ways that Vertex seeks to differentiate itself from a competitors that are following fast—Merck’s boceprevir.
Kauffman declined to speculate on how high the clinical cure rates will need to be for Vertex to declare victory. Last October, Vertex presented results from patients who failed prior therapy, which demonstrated telaprevir could induce cure rates between 55 percent and 90 percent. Vertex said back in April 2008, before it invested in the pivotal round of telaprevir trials, that between 61 percent and 68 percent of treatment-naïve patients were clinically cured in the smaller trials (Prove 1 and Prove 2).
After the past two years of recruiting patients, supplying the clinical sites with experimental drugs, monitoring the sites to make sure they follow the study protocol, and gathering all the data, you could say the expectations are high for this study. Wall Street, after all, is giving Vertex that $7.5 billion market valuation on anticipation of telaprevir’s sales trajectory more than any other factor. If the pivotal studies confirm the smaller trials—which is never a given in drug development—you will probably hear the victory whoops skimming all the way across the Charles River from Vertex headquarters in Cambridge.
“Phase III is the ultimate confirmation,” Kauffman says. “They are the largest and most definitive studies. It’s a very important time for us at the company now.”
Luke Timmerman is the National Biotechnology Editor for Xconomy. You can e-mail him at ltimmerman@xconomy.com, call 206-624-2374, or follow him on Twitter at http://twitter.com/ldtimmerman.
5/17/2010 Luke Timmerman
http://www.xconomy.com
Related Posts
* Vertex Hepatitis C Drug Passes Key Test With More Convenient, Twice-Daily Dose
* Vertex Hepatitis C Drug Wipes Out Virus For Toughest-to-Treat Patients
* Vertex Maps Out Combo Drug Game Plan for Treating Hepatitis C
* Vertex Fending Off Competitors By Treating the Toughest Patients With Hepatitis C
* Vertex Drug Poised for Pivotal Trial Among Patients Who Fail Prior Hepatitis C Treatments
Vertex Pharmaceuticals has been in business for more than 20 years, and burned through more than $2.8 billion on a quest to develop drugs that shake up the medical standards of care. Now in the coming weeks and months, it will get the first definitive evidence that will say whether its lead drug candidate for hepatitis C has achieved its goal.
Investors, looking at data from preliminary and mid-stage clinical trials, have already pumped up the market value of Vertex past $7.5 billion largely in anticipation that its drug, telaprevir, will transform the lives of patients with the chronic liver-damaging condition. But the operative word there is preliminary. Vertex, which is based in Cambridge, MA, and has significant operations in San Diego, is still waiting for its first proof from Phase III clinical trials, the final step of testing required by the FDA before a drug can go on sale in the U.S.
These pivotal trials began two years ago, and enrolled more than 2,000 patients combined in three studies. The results are completely blinded to doctors, patients, investors, and people at Vertex. To say all parties are in suspense for these results would be an understatement. They can’t wait to get their hands on the new data and start digging through it.
“This is a year of defining moments,” says Bob Kauffman, Vertex’s chief medical officer.
Vertex has generated the excitement around what could be a first-in-class protease inhibitor drug for hepatitis C. It has excited researchers because it has been able to double the cure rate while enabling patients to cut their standard course of treatment time in half. That means that many more of the 3 million Americans and 170 million people worldwide with chronic hepatitis C liver infections will be likely to seek out treatment, and be able to stand up to the side effects of standard therapy that causes flu-like symptoms. If Vertex can prove this idea once and for all in the three pivotal trials, Vertex could seek FDA approval later this year and bring telaprevir to the market in 2011. U.S. sales alone could amount to more than $2 billion after a couple years, analysts say.
To help our readers get ready for this data, I spoke to Kauffman for a refresher on what the three big Vertex trials were designed to ask and answer. The key point to watch for in all of these studies is what is called a “sustained viral response,” or SVR, which is recorded when researchers can’t find any sign of virus in a patient’s blood sample for a full 24 weeks after they completed their course of therapy. This is the gold standard measurement for all hepatitis C drugs, and is commonly known as a “clinical cure.”
The first study to watch for is called “Advance.” This trial, started in March 2008, enrolled 1,050 patients who had never been treated before for hepatitis C—a so-called “naïve” patient population. This study is essentially designed to confirm earlier trials called Prove 1 and Prove 2, Kauffman says. Patients either got the Vertex drug in combination with standard treatments for 24 weeks, or the standard treatments for the usual 48 weeks. The trial is designed to ask whether patients can stop treatment early with the Vertex drug, so they can avoid having to put up with the flu-like side effects of pegylated interferon alpha and ribavirin, Kauffman says. Results from that study should be available by the end of June, he says.
Not long after that data arrives, Vertex plans to hear results from two other key trials before the end of September. One of them, called “Illuminate,” is enrolling patients who have never before
been treated for hepatitis C infections, just like the earlier trial. The study, which enrolled 500 patients, is also looking to see how many clinical cures it can generate, and whether there’s any benefit in subjecting patients to the standard 48-week course of therapy, or whether they do just as well in half the time, Kauffman says. “It should validate that 24 weeks is enough,” Kauffman says.
The third study, called “Realize,” is important for strategic and competitive reasons. This trial enrolled 663 patients who had previously been treated for hepatitis C, but weren’t cured. Vertex has shown some promising results in this tough-to-treat patient population in the past, which is the sort of data that can really give physicians confidence in the drug’s punch. Vertex has taken care to stratify this study into three different kinds of patients—those who benefitted for a while but relapsed, those who only partially responded to prior therapy, and those who never really benefitted at all. Patients will get telaprevir in addition to the standard treatment, or just the standard stuff, for a total of 48 weeks.
As I described back in September 2008, this study is one of the key ways that Vertex seeks to differentiate itself from a competitors that are following fast—Merck’s boceprevir.
Kauffman declined to speculate on how high the clinical cure rates will need to be for Vertex to declare victory. Last October, Vertex presented results from patients who failed prior therapy, which demonstrated telaprevir could induce cure rates between 55 percent and 90 percent. Vertex said back in April 2008, before it invested in the pivotal round of telaprevir trials, that between 61 percent and 68 percent of treatment-naïve patients were clinically cured in the smaller trials (Prove 1 and Prove 2).
After the past two years of recruiting patients, supplying the clinical sites with experimental drugs, monitoring the sites to make sure they follow the study protocol, and gathering all the data, you could say the expectations are high for this study. Wall Street, after all, is giving Vertex that $7.5 billion market valuation on anticipation of telaprevir’s sales trajectory more than any other factor. If the pivotal studies confirm the smaller trials—which is never a given in drug development—you will probably hear the victory whoops skimming all the way across the Charles River from Vertex headquarters in Cambridge.
“Phase III is the ultimate confirmation,” Kauffman says. “They are the largest and most definitive studies. It’s a very important time for us at the company now.”
Luke Timmerman is the National Biotechnology Editor for Xconomy. You can e-mail him at ltimmerman@xconomy.com, call 206-624-2374, or follow him on Twitter at http://twitter.com/ldtimmerman.
HCV-Related Death on the rise world wide
from Jules of NATAP: you can presume that this trend is occurring in Western Europe, Australia, the USA, and Canada, in Western countries. It's been 20-30 yrs since many were infected with HCV and that is driving this trend, they are progressing in large numbers to cirrhosis, HCC & death now & over the next 5-10 years. However, with newly discovered orally administered antiviral HCV drugs we can cure close to all these patients with proper screening/testing and healthcare programs, but without properly designed programs we may miss the boat for hard to reach & hard to treat patient populations. Over 25 orally administered HCV drugs are in develoment now. Future therapy will consist of a regimen of multiple drugs like in HIV.
HCV-Related Death Rose 52% in Scotland from 1997 to 2006; 65% Remain Undiagnosed.....
...it is predicted that deaths will increase 2.8-fold between 2000 and 2020 in the United States (US) [15: Davis G, Albright J, Cook S, Rosenberg D. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 2003;9(4):331-8], and increase 1.7-fold between 2005 and 2020 (78 increasing to 129) in current/former injecting drug users (IDUs) in Scotland [16]. In this study, we observed a 1.3-fold rise in the number of liver-related deaths of people diagnosed with HCV infection (71 to 92) from 2000 to 2005, a rate which, if maintained over a further 10 years, would be even steeper than the 2005–2020 projections for IDUs in Scotland. With mortality from liver disease becoming increasingly associated with HCV infection, the importance of offering tests to individuals (particularly those under 55 years of age) presenting to hospital with an unexplained liver-related condition cannot be overemphasised.
Link to study in USA published in Gastroenterology in Dec 2009 by Gary Davis, a noted HCV researcher:
Aging of Hepatitis C Virus (HCV)-Infected Persons in the United States: A Multiple Cohort Model of HCV Prevalence and Disease Progression - (03/11/10)....HCC has doubled in HCV+ persons HCV+ 65+ yrs old.....The proportion of cirrhotics with decompensation is expected to continue to rise......It is in the immediate best interest of patients, providers, insurers, and governments to promote guidelines and encourage better screening for infection and early antiviral treatment.....only a small proportion of those with CH-C are aware of their infection and, of these, just 10% to 27% are offered treatment......Cirrhosis accounted for just 5% of all cases (diagnosed and undiagnosed) of CH-C in 1989, 10% in 1998, and 20% in 2006, the proportion with cirrhosis is projected to reach 24.8% in 2010, 37.2% in 2020, and 44.9% in 2030.
"The growing contribution of hepatitis C virus infection to liver-related mortality in Scotland"
Eurosurveillance, Volume 15, Issue 18, 06 May 2010
S A McDonald () et al. Health Protection Scotland, Glasgow, United Kingdom
The growing contribution of hepatitis C virus infection to liver-related mortality in Scotland
"In conclusion, HCV infection constitutes a significant, growing, public health burden in Scotland in terms of mortality from liver disease. Mortality from HCV-related liver disease is anticipated to increase as the population infected in the 1970s and 80s ages, those infected in the 1990s enter their second or third decade after HCV infection, and the size of the chronically-infected population grows. A better understanding of the risk factors associated with developing HCV-related liver disease will improve treatment and survival."
"Mortality from severe liver disease, of which major contributing factors include excessive alcohol consumption and chronic infection with the hepatitis C virus (HCV), is increasing in Scotland [1,2] and in other developed countries, such as the United States of America....placing a growing clinical and economic burden on the Scottish healthcare system....cirrhosis develops in 5%-15% of these individuals within 20 years of infection [6] and in about 20% within 30 years.....goals of this study were therefore to estimate the contribution of HCV infection to liver-related deaths in Scotland and to examine trends in this contribution over time and by age group....The overall proportion of deaths linked to the HCV Diagnosis database was 3.2% (871/26,861). The median age at death for individuals identified as diagnosed HCV-positive was 47 years (IQR: 39–58)."
"Over the past 15 years, we have observed an increasing contribution from HCV infection to mortality due to liver-related causes in Scotland. Deaths increased steadily with time among the 35–54 years age group, and the largest percentage of deaths linked to the HCV Diagnosis database (31%) were of people born from 1950 to 1959. This is consistent with infection of young people in the 1970s and 1980s....The proportion diagnosed with HCV among people dying from a liver-related cause rose from 2.8% (1995-1997) to 4.4% (2004-June 2006)...The largest proportional increases over this time-span occurred in people who died aged 35-44 years (from 7% to 17%) and aged 45-54 years (from 2% to 6%)"
"A larger problem of underestimation exists because 60% to 70% of the chronically HCV-infected population in Scotland are estimated to remain undiagnosed"
"Underreporting of HCV on death certificates is a problem for many countries, such as England [17] and the US [3,18,19], undermining studies that aim to determine HCV infection’s contribution to mortality"
ABSTRACT
The large number of individuals in Scotland who became infected with the hepatitis C virus (HCV) in the 1970s and 1980s leads us to expect liver-related morbidity and mortality to increase in the coming years. We investigated the contribution of HCV to liver-related mortality in the period January 1991 to June 2006. The study population consisted of 26,861 individuals whose death record mentioned a liver-related cause (underlying or contributing). Record-linkage to the national HCV Diagnosis database supplied HCV-diagnosed status for the study population. The proportion diagnosed with HCV among people dying from a liver-related cause rose from 2.8% (1995-1997) to 4.4% (2004-June 2006); the largest increase occurred in those aged 35-44 years at death (7% to 17%). Among all deaths from a liver-related cause, an HCV-positive diagnosis was more likely in those who died in 2001 or later than those who died in 1995-1997 (2001-2003: odds ratio=1.4, 95% confidence interval: 1.1-1.7; 2004-June 2006: 1.6, 1.3-2.0), and in those who died at under 55 compared with at least 55 years of age. HCV infection represents a significant, growing, public health burden in Scotland in terms of early deaths from liver disease.
Introduction
Mortality from severe liver disease, of which major contributing factors include excessive alcohol consumption and chronic infection with the hepatitis C virus (HCV), is increasing in Scotland [1,2] and in other developed countries, such as the United States of America [3]. About 1,500 new HCV diagnoses are made each year in Scotland (population 5.1 million in 2006) [4], and projection models of HCV-related liver disease forecast significant rises in morbidity and mortality over the coming decades, placing a growing clinical and economic burden on the Scottish healthcare system [5]. Given the large number of individuals chronically infected with HCV, and the fact that cirrhosis develops in 5%-15% of these individuals within 20 years of infection [6] and in about 20% within 30 years [7], it is important to ascertain the contribution of chronic HCV infection to liver-related mortality.
The existence of high-quality national HCV diagnosis and mortality databases provided the opportunity to use record-linkage methods to investigate the prevalence of diagnosed HCV infection in people who died from liver disease. The goals of this study were therefore to estimate the contribution of HCV infection to liver-related deaths in Scotland and to examine trends in this contribution over time and by age group. Up-to-date information regarding the contribution of HCV to mortality from liver disease is required to inform public health intelligence and health service planning, and as a calibration check on projections.
Discussion
Over the past 15 years, we have observed an increasing contribution from HCV infection to mortality due to liver-related causes in Scotland. Deaths increased steadily with time among the 35–54 years age group, and the largest percentage of deaths linked to the HCV Diagnosis database (31%) were of people born from 1950 to 1959. This is consistent with infection of young people in the 1970s and 1980s – before HCV was identified – and the natural history of chronic HCV infection [12]. HCV plays a much smaller role in liver-related deaths in older age groups mainly because relatively few individuals acquired infection at a late enough age.
A relatively high percentage of the liver-related deaths (17%) in the 25–34 age group were HCV-diagnosed individuals; the majority (69%) of these death records mentioned an alcohol-related ICD code. High liver-related mortality in this group may reflect more rapid development of liver disease associated with combined HCV infection and excessive alcohol use [13].
This study is the first to our knowledge that links national HCV diagnosis data to national mortality data to chart the contribution, over time, of HCV to all liver-related deaths [14]. Recent modelling initiatives have predicted substantial rises in HCV-related mortality in the next decade – for example, it is predicted that deaths will increase 2.8-fold between 2000 and 2020 in the United States (US) [15: Davis G, Albright J, Cook S, Rosenberg D. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 2003;9(4):331-8], and increase 1.7-fold between 2005 and 2020 (78 increasing to 129) in current/former injecting drug users (IDUs) in Scotland [16]. In this study, we observed a 1.3-fold rise in the number of liver-related deaths of people diagnosed with HCV infection (71 to 92) from 2000 to 2005, a rate which, if maintained over a further 10 years, would be even steeper than the 2005–2020 projections for IDUs in Scotland. With mortality from liver disease becoming increasingly associated with HCV infection, the importance of offering tests to individuals (particularly those under 55 years of age) presenting to hospital with an unexplained liver-related condition cannot be overemphasised.
It is notable that 48% of the records for liver-related deaths that linked to the HCV Diagnosis database did not mention HCV as either the underlying or a contributing cause of death. This finding has strong implications for public health decision making regarding the HCV epidemic. Underreporting of HCV on death certificates is a problem for many countries, such as England [17] and the US [3,18,19], undermining studies that aim to determine HCV infection’s contribution to mortality from liver disease by using cause-of-death coding on death certificates.
Using record-linkage to HCV diagnosis data, we determined that 3.2% of all liver-related deaths were related to HCV infection. This proportion is substantially lower than in previous reports that have considered the role of hepatitis C in mortality from chronic liver disease – for example, 15% (of 30,933 deaths in 1998) [18] and 16% (56/233 deaths in 2000) [19] in two studies from the US. This difference may be due to a higher prevalence of problem alcohol use in the Scottish population [20], particularly for death at a relatively young age: we note that 45% of all liver-related deaths and 69% of liver-related deaths in the 25-34 years age group mentioned one or more alcohol-related ICD codes.
Our study has important strengths and limitations. The use of a national deaths register to identify liver-related deaths has provided considerable statistical precision. The main limitations relate to a lack of information about chronic, versus resolved, infection on the HCV Diagnosis database, and to record-linkage errors. We assumed that all individuals who died from a liver-related cause and were diagnosed with HCV were chronically infected. Given that about 26% of those ever diagnosed antibody-positive appear to achieve spontaneous viral clearance [21], we may have overestimated the proportion of liver-related deaths associated with chronic HCV infection, although this is likely to be offset by underestimation due to unrecovered linkages – for example, if critical identifiers were erroneous or missing.
A larger problem of underestimation exists because 60% to 70% of the chronically HCV-infected population in Scotland are estimated to remain undiagnosed [12]. Because these ‘missing’ HCV-related deaths have not been added to the known HCV-related deaths reported here, we have quantified only the lower bound of the true contribution of HCV infection to liver-related mortality. It is likely, however, that more than 60%-70% of people with HCV infection presenting with fatal liver disease will be tested and diagnosed. Related to this issue, we note that if, say, postmortem HCV testing increased over the study period this would account for part of the increasing trend in the proportion of HCV-diagnosed liver-related deaths. Similarly, if the majority of the 6% of HCV Diagnosis records that were excluded from analysis (because of insufficient identifiers) were from the early part of the database period, then the increasing trend observed in the proportion of deaths that were HCV-diagnosed might be overestimated. No indication of such a distribution was found, however.
Because injecting drugs is the commonest risk factor for acquiring HCV infection in Scotland, the adjusted odds ratios reported here for sex and social deprivation are partly capturing differences in IDU prevalence: a higher proportion of males than females are IDUs, and IDU prevalence is greatest for people who live in the most deprived areas [22].
As we lacked data regarding problem alcohol use, we have not been able to estimate the relative contributions of HCV infection and alcohol consumption to liver-related mortality in people diagnosed with HCV infection; this is of particular interest for cases in whom alcoholic liver disease was specified as the underlying cause of death. High levels of alcohol consumption have been implicated as contributing to premature death in people with chronic HCV infection [23], consistent with a synergistic effect of alcohol and chronic HCV infection on the development of liver disease [13]. IDUs – who comprise the majority of the chronically-infected HCV population in Scotland – have been reported to have a relatively high prevalence (37%–53%) of heavy alcohol consumption (defined as a score of eight or more on the Alcohol Use Disorders Identification Test [AUDIT] scale [24,25], or as two positive responses in the CAGE questionnaire [26]). Consequently, the increase over time in the proportion of liver-related deaths linked to the HCV Diagnosis database that we observed may be partly attributed to a rise in problem alcohol use, if alcohol consumption has increased in the HCV-diagnosed population over the study period.
In conclusion, HCV infection constitutes a significant, growing, public health burden in Scotland in terms of mortality from liver disease. Mortality from HCV-related liver disease is anticipated to increase as the population infected in the 1970s and 80s ages, those infected in the 1990s enter their second or third decade after HCV infection, and the size of the chronically-infected population grows. A better understanding of the risk factors associated with developing HCV-related liver disease will improve treatment and survival.
Results
Overall description
Between 1 January 1991 and 30 June 2006, a total of 26,861 people died in Scotland whose death record specified a liver-related condition as the underlying or a contributing cause of death (Table 1). The majority of liver-related deaths occurred in males (62%; 16,660/26,861), and the median age at death was 61 years (interquartile range (IQR): 51–71) (Table 2). The overall proportion of deaths linked to the HCV Diagnosis database was 3.2% (871/26,861). The median age at death for individuals identified as diagnosed HCV-positive was 47 years (IQR: 39–58).
We report on deaths from underlying or contributing liver-related causes (n = 26,861), but note that distributions of baseline characteristics and annual trends were similar if the data were restricted to deaths from underlying liver-related causes only (n=16,767; data not shown).
Mention of HCV in death records
Viral hepatitis C was listed as the underlying or a contributing cause of death in 1.6% (543/26,861) of all liver-related deaths, and in 52% (450/871) of liver-related deaths linked to the HCV Diagnosis database. This proportion remained the same: 292/563 (52%) when liver-related deaths occurring from 2000 onwards only (n=13,891) were considered (Table 3).
Alcohol (ICD-10 K70, ICD-9 571.0-3) was mentioned in 45% (12,018/26,861) of all liver-related death records (Table 1), but in 51% of the group aged 25–34 years at death (308/600). People on the HCV Diagnosis database accounted for 17% of the liver-related deaths (17%) in the 25–34 age group (Table 2) and 69% of these deaths mentioned an alcohol-related ICD code (data not shown).
Odds of being diagnosed HCV-positive
Of those whose cause of death included a liver-related condition (either underlying or contributing), the odds of being diagnosed HCV-positive were significantly higher for males than for females, and for those who died before the age of 55 years than those who died aged 55 or older. Compared with deaths occurring 1995-1997, the odds of being HCV-diagnosed were higher for deaths occurring in 2001. People who lived in the more deprived regions had significantly higher odds of being HCV-diagnosed than people who lived in the two least deprived quintiles (Table 2). Of the HCV-diagnosed individuals, 32% (278/871) were born between 1960 and 1979. The median interval between HCV diagnosis and death was 2.1 years (range -0.4 to 14.5 years).
Table 4 compares the number and proportion of HCV-linked deaths by age at death and year of death categories, between 1995-1997 and 2004-June 2006. A trend test showed that HCV-linked deaths formed an increasing proportion of liver-related deaths over time, from 2.8% in 1995–1997 to 4.4% in 2004–June 2006 (p=0.012). The largest proportional increases over this time-span occurred in people who died aged 35-44 years (from 7% to 17%) and aged 45-54 years (from 2% to 6%). A significant difference in the rate of change in the proportion of HCV-linked deaths over time across age groups was confirmed by an interaction test (p<0.0001).
Table 4. Numbers of deaths from liver-related conditions, proportions of those diagnosed hepatitis C virus-positive, cross-tabulated by age at death and year of death, Scotland, 1995–1997 to 2004–June 2006
The image “http://www.eurosurveillance.org/images/dynamic/EE/V15N18/HepC_Scotland_Tab4.jpg” cannot be displayed, because it contains errors.
Methods
Study population and data sources
Death registrations are held by the General Register Office for Scotland (GROS). The study population consisted of all those who died from 1 January 1991 to 30 June 2006, and whose death certificate specified a liver-related condition.
International Classification of Diseases (ICD) codes were used to extract all records from the deaths register in which a liver-related condition was listed as either the underlying cause (i.e. the disease or injury initiating the train of events leading directly to death) or a contributing cause of death (n=26,861). We obtained underlying and contributing cause-of-death codes from ICD’s ninth revision (ICD-9) for deaths between 1989 and 1999 and the tenth revision (ICD-10) for deaths between 2000 and 2006. The relevant cause-of-death categories were: liver cancer, alcoholic liver disease, nonalcoholic liver disease, viral hepatitis, and sequelae of viral hepatitis (Table 1). Specific mention of viral hepatitis C (ICD-10 B17.1, B18.2), unspecified viral hepatitis C (ICD-9 070.7), or other/unspecified viral hepatitis (ICD-9 070.4-6, 070.9) as a cause of death was also noted, to assess the frequency with which HCV is mentioned on the death certificate. Liver-related deaths among those diagnosed HCV antibody-positive (with or without mention of HCV on the death record) were determined through record-linkage between the GROS deaths registry and the HCV Diagnosis database (details below).
Carstairs social deprivation scores (coded as quintiles) were available for each death record; deprivation score is determined from postcode sector of residence and is based on 2001 census variables [8]. The highest quintile corresponds to the 20% most deprived localities.
The HCV Diagnosis database, maintained by Health Protection Scotland (HPS), is a database of all individuals who have been diagnosed HCV positive in Scotland since testing began in 1991 [9]; laboratory detection of hepatitis C antibody positivity is a requirement for inclusion. This database contains the following non-named information: surname Soundex (a consonant-only phonetic encoding), forename initial, date of birth, sex, and postcode district of residence, as well as data concerning risk activities and the date of the earliest positive specimen. The database contained records for 20,969 persons diagnosed HCV positive between 1 January 1991 and 30 June 2006 [4]. As no probabilistic linkages between the GROS deaths register and the HCV diagnosis database were achieved if the HCV diagnosis record was lacking date of birth and two or more other identifiers, records for 1,295 out of 20,969 HCV-diagnosed people (6%) were deemed to have insufficient identifiers for linkage. Of the records with sufficient identifiers, 68% were male, and 71% (14,018/19,674) were born between 1960 and 1979.
Linkage procedure
Linkage of records between the HCV Diagnosis database and the GROS deaths registry was carried out by the Information Services Division (a division of NHS National Services Scotland) using probabilistic record-linkage techniques [10] to determine the HCV-diagnosed status of all individuals whose cause of death included a liver-related condition. These methods allow for matches using incomplete identifiers. The linked dataset was anonymised (i.e. the only identifiers retained were, date of birth, sex and postcode district of residence) before transfer to HPS for analysis. Linkages were approved by the Privacy Advisory Committee, which oversees confidentiality issues involving data held on NHS Scotland patients.
Data analysis
Logistic regression was used to estimate the association between four epidemiological variables and diagnosed HCV status (i.e. whether or not linked to the HCV Diagnosis database). These were: sex, age at death, year of death (with 1995–1997 specified as the reference category, because HCV testing was more limited before this period), and Carstairs social deprivation quintile. We did not analyse trends in mortality rates because the HCV Diagnosis database has expanded since its inception and people in the later stages of HCV disease may have been over-represented in its earlier years. Statistical analyses were carried out using R version 2.4.0 [11].
To estimate the extent of underreporting of HCV on the death certificate, we computed the proportion of death records that were linked to the HCV Diagnosis database, but failed to list an HCV code as either the underlying or a contributing cause of death. This analysis was also conducted separately for the year range 2000-2006, as the change in cause-of-death coding to the ICD-10 classification in 2000 overcomes the imprecision in the ICD-9 codes for HCV. The main data analysis was based on the linked data only.
References
1. Leon DA, McCambridge J. Liver cirrhosis mortality rates in Britain from 1950 to 2002: an analysis of routine data. Lancet. 2006;367(9504):52-6.
2. Palmateer N, Hutchinson S, McLeod A, Codere G, Goldberg D. Comparison of deaths related to hepatitis C and AIDS in Scotland. J Viral Hepat. 2007;14(12):870-4.
3. Wise M, Bialek S, Finelli L, Bell B, Sorvillo F. Changing trends in hepatitis C-related mortality in the United States; 1995-2004. Hepatology. 2008;47(4):1128-35.
4. Health Protection Scotland (HPS). Surveillance of known hepatitis C antibody positive cases in Scotland: results to 30 June 2006. HPS Weekly Report. 2006;40(2006/38):202-6.
5. Hutchinson S, Bird S, Goldberg D. Modeling the current and future disease burden of hepatitis C among injection drug users in Scotland. Hepatology. 2005;42(3):711-23.
6. Freeman A, Dore G, Law M, Thorpe M, von Overbeck J, Lloyd A, et al. Estimating progression to cirrhosis in chronic hepatitis C virus infection. Hepatology. 2001;34(4 Pt 1):809-16.
7. Thein HH, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology. 2008;48(2):418-31.
8. Carstairs V, Morris R. Deprivation and health in Scotland. Health Bulletin. 1990;48(4):162-75.
9. Shaw L, Taylor A, Roy K, Cameron S, Burns S, Molyneaux P, et al. Establishment of a database of diagnosed HCV-infected persons in Scotland. Commun Dis Public Health. 2003;6(4):305-10.
10. Kendrick S, Clarke J. The Scottish Record Linkage System. Health Bull (Edinb). 1993;51:72-9.
11. R Development Core Team. R: a language and environment for statistical computing. Vienna; Austria: R Foundation for Statistical Computing; 2006.
12. Hutchinson S, Roy K, Wadd S, Bird S, Taylor A, Anderson E, et al. Hepatitis C virus infection in Scotland: epidemiological review and public health challenges. Scott Med J. 2006;51(2):8-15.
13. Hutchinson S, Bird S, Goldberg D. Influence of alcohol on the progression of hepatitis C virus infection: a meta-analysis. Clinical Gastroenterology and Hepatology. 2005;3(11):1150-9.
14. Bird S, Goldberg D, Hutchinson S. Projecting severe sequelae of injection-related hepatitis C virus epidemic in the UK. Part 1: Critical hepatitis C and injector data. J of Epidemiology and Biostatistics;2001(6):3.
15. Davis G, Albright J, Cook S, Rosenberg D. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 2003;9(4):331-8.
16. Hutchinson S, Bird S, Goldberg D. Review of models used to predict the future numbers of individuals with severe hepatitis C disease: therapeutic and cost implications. Expert Review of Pharmacoeconomics and Outcomes Research. 2006;6(6):627-39.
17. Mann AG, Ramsay ME, Brant LJ, Balogun MA, Costella A, Harris HE. Diagnoses of, and deaths from, severe liver disease due to hepatitis C in England between 2000 and 2005 estimated using multiple data sources. Epidemiol Infect. 2009;137(4):513-8.
18. Vong S, Bell B. Chronic liver disease mortality in the United States; 1990-1998. Hepatology. 2004;39(2):476-83.
19. Manos MM, Leyden WA, Murphy RC, Terrault NA, Bell BP. Limitations of conventionally derived chronic liver disease mortality rates: Results of a comprehensive assessment. Hepatology. 2008;47(4):1150-7.
20. Information Services Division (ISD). Alcohol Statistics Scotland. Edinburgh: ISD; 2007.
21. Micallef JM, Kaldor JM, Dore GJ. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies. J Viral Hepat. 2006;13(1):34-41.
22. Hay G, Gannon M, McKeganey N, Hutchinson S, Goldberg D. Estimating the national and local prevalence of problem drug misuse in Scotland: executive report. Edinburgh: ISD; 2005.
23. Chen C, Yoon Y, Yi H, Lucas D. Alcohol and hepatitis C mortality among males and females in the United States: a life table analysis. Alcohol Clin Exp Res. 2007;31(2):285-92.
24. Campbell J, Hagan H, Latka M, Garfein R, Golub E, Coady M, et al. High prevalence of alcohol use among hepatitis C virus antibody positive injection drug users in three US cities. Drug Alcohol Depend. 2006;81(3):259-65.
25. Watson B, Conigrave K, Wallace C, Whitfield J, Wurst F, Haber P. Hazardous alcohol consumption and other barriers to antiviral treatment among hepatitis C positive people receiving opioid maintenance treatment. Drug Alcohol Rev. 2007;26(3):231-9.
26. Graham L. Prison health in Scotland: a health-care needs assessment. Scottish Prison Service; 2007
HCV-Related Death Rose 52% in Scotland from 1997 to 2006; 65% Remain Undiagnosed.....
...it is predicted that deaths will increase 2.8-fold between 2000 and 2020 in the United States (US) [15: Davis G, Albright J, Cook S, Rosenberg D. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 2003;9(4):331-8], and increase 1.7-fold between 2005 and 2020 (78 increasing to 129) in current/former injecting drug users (IDUs) in Scotland [16]. In this study, we observed a 1.3-fold rise in the number of liver-related deaths of people diagnosed with HCV infection (71 to 92) from 2000 to 2005, a rate which, if maintained over a further 10 years, would be even steeper than the 2005–2020 projections for IDUs in Scotland. With mortality from liver disease becoming increasingly associated with HCV infection, the importance of offering tests to individuals (particularly those under 55 years of age) presenting to hospital with an unexplained liver-related condition cannot be overemphasised.
Link to study in USA published in Gastroenterology in Dec 2009 by Gary Davis, a noted HCV researcher:
Aging of Hepatitis C Virus (HCV)-Infected Persons in the United States: A Multiple Cohort Model of HCV Prevalence and Disease Progression - (03/11/10)....HCC has doubled in HCV+ persons HCV+ 65+ yrs old.....The proportion of cirrhotics with decompensation is expected to continue to rise......It is in the immediate best interest of patients, providers, insurers, and governments to promote guidelines and encourage better screening for infection and early antiviral treatment.....only a small proportion of those with CH-C are aware of their infection and, of these, just 10% to 27% are offered treatment......Cirrhosis accounted for just 5% of all cases (diagnosed and undiagnosed) of CH-C in 1989, 10% in 1998, and 20% in 2006, the proportion with cirrhosis is projected to reach 24.8% in 2010, 37.2% in 2020, and 44.9% in 2030.
"The growing contribution of hepatitis C virus infection to liver-related mortality in Scotland"
Eurosurveillance, Volume 15, Issue 18, 06 May 2010
S A McDonald () et al. Health Protection Scotland, Glasgow, United Kingdom
The growing contribution of hepatitis C virus infection to liver-related mortality in Scotland
"In conclusion, HCV infection constitutes a significant, growing, public health burden in Scotland in terms of mortality from liver disease. Mortality from HCV-related liver disease is anticipated to increase as the population infected in the 1970s and 80s ages, those infected in the 1990s enter their second or third decade after HCV infection, and the size of the chronically-infected population grows. A better understanding of the risk factors associated with developing HCV-related liver disease will improve treatment and survival."
"Mortality from severe liver disease, of which major contributing factors include excessive alcohol consumption and chronic infection with the hepatitis C virus (HCV), is increasing in Scotland [1,2] and in other developed countries, such as the United States of America....placing a growing clinical and economic burden on the Scottish healthcare system....cirrhosis develops in 5%-15% of these individuals within 20 years of infection [6] and in about 20% within 30 years.....goals of this study were therefore to estimate the contribution of HCV infection to liver-related deaths in Scotland and to examine trends in this contribution over time and by age group....The overall proportion of deaths linked to the HCV Diagnosis database was 3.2% (871/26,861). The median age at death for individuals identified as diagnosed HCV-positive was 47 years (IQR: 39–58)."
"Over the past 15 years, we have observed an increasing contribution from HCV infection to mortality due to liver-related causes in Scotland. Deaths increased steadily with time among the 35–54 years age group, and the largest percentage of deaths linked to the HCV Diagnosis database (31%) were of people born from 1950 to 1959. This is consistent with infection of young people in the 1970s and 1980s....The proportion diagnosed with HCV among people dying from a liver-related cause rose from 2.8% (1995-1997) to 4.4% (2004-June 2006)...The largest proportional increases over this time-span occurred in people who died aged 35-44 years (from 7% to 17%) and aged 45-54 years (from 2% to 6%)"
"A larger problem of underestimation exists because 60% to 70% of the chronically HCV-infected population in Scotland are estimated to remain undiagnosed"
"Underreporting of HCV on death certificates is a problem for many countries, such as England [17] and the US [3,18,19], undermining studies that aim to determine HCV infection’s contribution to mortality"
ABSTRACT
The large number of individuals in Scotland who became infected with the hepatitis C virus (HCV) in the 1970s and 1980s leads us to expect liver-related morbidity and mortality to increase in the coming years. We investigated the contribution of HCV to liver-related mortality in the period January 1991 to June 2006. The study population consisted of 26,861 individuals whose death record mentioned a liver-related cause (underlying or contributing). Record-linkage to the national HCV Diagnosis database supplied HCV-diagnosed status for the study population. The proportion diagnosed with HCV among people dying from a liver-related cause rose from 2.8% (1995-1997) to 4.4% (2004-June 2006); the largest increase occurred in those aged 35-44 years at death (7% to 17%). Among all deaths from a liver-related cause, an HCV-positive diagnosis was more likely in those who died in 2001 or later than those who died in 1995-1997 (2001-2003: odds ratio=1.4, 95% confidence interval: 1.1-1.7; 2004-June 2006: 1.6, 1.3-2.0), and in those who died at under 55 compared with at least 55 years of age. HCV infection represents a significant, growing, public health burden in Scotland in terms of early deaths from liver disease.
Introduction
Mortality from severe liver disease, of which major contributing factors include excessive alcohol consumption and chronic infection with the hepatitis C virus (HCV), is increasing in Scotland [1,2] and in other developed countries, such as the United States of America [3]. About 1,500 new HCV diagnoses are made each year in Scotland (population 5.1 million in 2006) [4], and projection models of HCV-related liver disease forecast significant rises in morbidity and mortality over the coming decades, placing a growing clinical and economic burden on the Scottish healthcare system [5]. Given the large number of individuals chronically infected with HCV, and the fact that cirrhosis develops in 5%-15% of these individuals within 20 years of infection [6] and in about 20% within 30 years [7], it is important to ascertain the contribution of chronic HCV infection to liver-related mortality.
The existence of high-quality national HCV diagnosis and mortality databases provided the opportunity to use record-linkage methods to investigate the prevalence of diagnosed HCV infection in people who died from liver disease. The goals of this study were therefore to estimate the contribution of HCV infection to liver-related deaths in Scotland and to examine trends in this contribution over time and by age group. Up-to-date information regarding the contribution of HCV to mortality from liver disease is required to inform public health intelligence and health service planning, and as a calibration check on projections.
Discussion
Over the past 15 years, we have observed an increasing contribution from HCV infection to mortality due to liver-related causes in Scotland. Deaths increased steadily with time among the 35–54 years age group, and the largest percentage of deaths linked to the HCV Diagnosis database (31%) were of people born from 1950 to 1959. This is consistent with infection of young people in the 1970s and 1980s – before HCV was identified – and the natural history of chronic HCV infection [12]. HCV plays a much smaller role in liver-related deaths in older age groups mainly because relatively few individuals acquired infection at a late enough age.
A relatively high percentage of the liver-related deaths (17%) in the 25–34 age group were HCV-diagnosed individuals; the majority (69%) of these death records mentioned an alcohol-related ICD code. High liver-related mortality in this group may reflect more rapid development of liver disease associated with combined HCV infection and excessive alcohol use [13].
This study is the first to our knowledge that links national HCV diagnosis data to national mortality data to chart the contribution, over time, of HCV to all liver-related deaths [14]. Recent modelling initiatives have predicted substantial rises in HCV-related mortality in the next decade – for example, it is predicted that deaths will increase 2.8-fold between 2000 and 2020 in the United States (US) [15: Davis G, Albright J, Cook S, Rosenberg D. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 2003;9(4):331-8], and increase 1.7-fold between 2005 and 2020 (78 increasing to 129) in current/former injecting drug users (IDUs) in Scotland [16]. In this study, we observed a 1.3-fold rise in the number of liver-related deaths of people diagnosed with HCV infection (71 to 92) from 2000 to 2005, a rate which, if maintained over a further 10 years, would be even steeper than the 2005–2020 projections for IDUs in Scotland. With mortality from liver disease becoming increasingly associated with HCV infection, the importance of offering tests to individuals (particularly those under 55 years of age) presenting to hospital with an unexplained liver-related condition cannot be overemphasised.
It is notable that 48% of the records for liver-related deaths that linked to the HCV Diagnosis database did not mention HCV as either the underlying or a contributing cause of death. This finding has strong implications for public health decision making regarding the HCV epidemic. Underreporting of HCV on death certificates is a problem for many countries, such as England [17] and the US [3,18,19], undermining studies that aim to determine HCV infection’s contribution to mortality from liver disease by using cause-of-death coding on death certificates.
Using record-linkage to HCV diagnosis data, we determined that 3.2% of all liver-related deaths were related to HCV infection. This proportion is substantially lower than in previous reports that have considered the role of hepatitis C in mortality from chronic liver disease – for example, 15% (of 30,933 deaths in 1998) [18] and 16% (56/233 deaths in 2000) [19] in two studies from the US. This difference may be due to a higher prevalence of problem alcohol use in the Scottish population [20], particularly for death at a relatively young age: we note that 45% of all liver-related deaths and 69% of liver-related deaths in the 25-34 years age group mentioned one or more alcohol-related ICD codes.
Our study has important strengths and limitations. The use of a national deaths register to identify liver-related deaths has provided considerable statistical precision. The main limitations relate to a lack of information about chronic, versus resolved, infection on the HCV Diagnosis database, and to record-linkage errors. We assumed that all individuals who died from a liver-related cause and were diagnosed with HCV were chronically infected. Given that about 26% of those ever diagnosed antibody-positive appear to achieve spontaneous viral clearance [21], we may have overestimated the proportion of liver-related deaths associated with chronic HCV infection, although this is likely to be offset by underestimation due to unrecovered linkages – for example, if critical identifiers were erroneous or missing.
A larger problem of underestimation exists because 60% to 70% of the chronically HCV-infected population in Scotland are estimated to remain undiagnosed [12]. Because these ‘missing’ HCV-related deaths have not been added to the known HCV-related deaths reported here, we have quantified only the lower bound of the true contribution of HCV infection to liver-related mortality. It is likely, however, that more than 60%-70% of people with HCV infection presenting with fatal liver disease will be tested and diagnosed. Related to this issue, we note that if, say, postmortem HCV testing increased over the study period this would account for part of the increasing trend in the proportion of HCV-diagnosed liver-related deaths. Similarly, if the majority of the 6% of HCV Diagnosis records that were excluded from analysis (because of insufficient identifiers) were from the early part of the database period, then the increasing trend observed in the proportion of deaths that were HCV-diagnosed might be overestimated. No indication of such a distribution was found, however.
Because injecting drugs is the commonest risk factor for acquiring HCV infection in Scotland, the adjusted odds ratios reported here for sex and social deprivation are partly capturing differences in IDU prevalence: a higher proportion of males than females are IDUs, and IDU prevalence is greatest for people who live in the most deprived areas [22].
As we lacked data regarding problem alcohol use, we have not been able to estimate the relative contributions of HCV infection and alcohol consumption to liver-related mortality in people diagnosed with HCV infection; this is of particular interest for cases in whom alcoholic liver disease was specified as the underlying cause of death. High levels of alcohol consumption have been implicated as contributing to premature death in people with chronic HCV infection [23], consistent with a synergistic effect of alcohol and chronic HCV infection on the development of liver disease [13]. IDUs – who comprise the majority of the chronically-infected HCV population in Scotland – have been reported to have a relatively high prevalence (37%–53%) of heavy alcohol consumption (defined as a score of eight or more on the Alcohol Use Disorders Identification Test [AUDIT] scale [24,25], or as two positive responses in the CAGE questionnaire [26]). Consequently, the increase over time in the proportion of liver-related deaths linked to the HCV Diagnosis database that we observed may be partly attributed to a rise in problem alcohol use, if alcohol consumption has increased in the HCV-diagnosed population over the study period.
In conclusion, HCV infection constitutes a significant, growing, public health burden in Scotland in terms of mortality from liver disease. Mortality from HCV-related liver disease is anticipated to increase as the population infected in the 1970s and 80s ages, those infected in the 1990s enter their second or third decade after HCV infection, and the size of the chronically-infected population grows. A better understanding of the risk factors associated with developing HCV-related liver disease will improve treatment and survival.
Results
Overall description
Between 1 January 1991 and 30 June 2006, a total of 26,861 people died in Scotland whose death record specified a liver-related condition as the underlying or a contributing cause of death (Table 1). The majority of liver-related deaths occurred in males (62%; 16,660/26,861), and the median age at death was 61 years (interquartile range (IQR): 51–71) (Table 2). The overall proportion of deaths linked to the HCV Diagnosis database was 3.2% (871/26,861). The median age at death for individuals identified as diagnosed HCV-positive was 47 years (IQR: 39–58).
We report on deaths from underlying or contributing liver-related causes (n = 26,861), but note that distributions of baseline characteristics and annual trends were similar if the data were restricted to deaths from underlying liver-related causes only (n=16,767; data not shown).
Mention of HCV in death records
Viral hepatitis C was listed as the underlying or a contributing cause of death in 1.6% (543/26,861) of all liver-related deaths, and in 52% (450/871) of liver-related deaths linked to the HCV Diagnosis database. This proportion remained the same: 292/563 (52%) when liver-related deaths occurring from 2000 onwards only (n=13,891) were considered (Table 3).
Alcohol (ICD-10 K70, ICD-9 571.0-3) was mentioned in 45% (12,018/26,861) of all liver-related death records (Table 1), but in 51% of the group aged 25–34 years at death (308/600). People on the HCV Diagnosis database accounted for 17% of the liver-related deaths (17%) in the 25–34 age group (Table 2) and 69% of these deaths mentioned an alcohol-related ICD code (data not shown).
Odds of being diagnosed HCV-positive
Of those whose cause of death included a liver-related condition (either underlying or contributing), the odds of being diagnosed HCV-positive were significantly higher for males than for females, and for those who died before the age of 55 years than those who died aged 55 or older. Compared with deaths occurring 1995-1997, the odds of being HCV-diagnosed were higher for deaths occurring in 2001. People who lived in the more deprived regions had significantly higher odds of being HCV-diagnosed than people who lived in the two least deprived quintiles (Table 2). Of the HCV-diagnosed individuals, 32% (278/871) were born between 1960 and 1979. The median interval between HCV diagnosis and death was 2.1 years (range -0.4 to 14.5 years).
Table 4 compares the number and proportion of HCV-linked deaths by age at death and year of death categories, between 1995-1997 and 2004-June 2006. A trend test showed that HCV-linked deaths formed an increasing proportion of liver-related deaths over time, from 2.8% in 1995–1997 to 4.4% in 2004–June 2006 (p=0.012). The largest proportional increases over this time-span occurred in people who died aged 35-44 years (from 7% to 17%) and aged 45-54 years (from 2% to 6%). A significant difference in the rate of change in the proportion of HCV-linked deaths over time across age groups was confirmed by an interaction test (p<0.0001).
Table 4. Numbers of deaths from liver-related conditions, proportions of those diagnosed hepatitis C virus-positive, cross-tabulated by age at death and year of death, Scotland, 1995–1997 to 2004–June 2006
The image “http://www.eurosurveillance.org/images/dynamic/EE/V15N18/HepC_Scotland_Tab4.jpg” cannot be displayed, because it contains errors.
Methods
Study population and data sources
Death registrations are held by the General Register Office for Scotland (GROS). The study population consisted of all those who died from 1 January 1991 to 30 June 2006, and whose death certificate specified a liver-related condition.
International Classification of Diseases (ICD) codes were used to extract all records from the deaths register in which a liver-related condition was listed as either the underlying cause (i.e. the disease or injury initiating the train of events leading directly to death) or a contributing cause of death (n=26,861). We obtained underlying and contributing cause-of-death codes from ICD’s ninth revision (ICD-9) for deaths between 1989 and 1999 and the tenth revision (ICD-10) for deaths between 2000 and 2006. The relevant cause-of-death categories were: liver cancer, alcoholic liver disease, nonalcoholic liver disease, viral hepatitis, and sequelae of viral hepatitis (Table 1). Specific mention of viral hepatitis C (ICD-10 B17.1, B18.2), unspecified viral hepatitis C (ICD-9 070.7), or other/unspecified viral hepatitis (ICD-9 070.4-6, 070.9) as a cause of death was also noted, to assess the frequency with which HCV is mentioned on the death certificate. Liver-related deaths among those diagnosed HCV antibody-positive (with or without mention of HCV on the death record) were determined through record-linkage between the GROS deaths registry and the HCV Diagnosis database (details below).
Carstairs social deprivation scores (coded as quintiles) were available for each death record; deprivation score is determined from postcode sector of residence and is based on 2001 census variables [8]. The highest quintile corresponds to the 20% most deprived localities.
The HCV Diagnosis database, maintained by Health Protection Scotland (HPS), is a database of all individuals who have been diagnosed HCV positive in Scotland since testing began in 1991 [9]; laboratory detection of hepatitis C antibody positivity is a requirement for inclusion. This database contains the following non-named information: surname Soundex (a consonant-only phonetic encoding), forename initial, date of birth, sex, and postcode district of residence, as well as data concerning risk activities and the date of the earliest positive specimen. The database contained records for 20,969 persons diagnosed HCV positive between 1 January 1991 and 30 June 2006 [4]. As no probabilistic linkages between the GROS deaths register and the HCV diagnosis database were achieved if the HCV diagnosis record was lacking date of birth and two or more other identifiers, records for 1,295 out of 20,969 HCV-diagnosed people (6%) were deemed to have insufficient identifiers for linkage. Of the records with sufficient identifiers, 68% were male, and 71% (14,018/19,674) were born between 1960 and 1979.
Linkage procedure
Linkage of records between the HCV Diagnosis database and the GROS deaths registry was carried out by the Information Services Division (a division of NHS National Services Scotland) using probabilistic record-linkage techniques [10] to determine the HCV-diagnosed status of all individuals whose cause of death included a liver-related condition. These methods allow for matches using incomplete identifiers. The linked dataset was anonymised (i.e. the only identifiers retained were, date of birth, sex and postcode district of residence) before transfer to HPS for analysis. Linkages were approved by the Privacy Advisory Committee, which oversees confidentiality issues involving data held on NHS Scotland patients.
Data analysis
Logistic regression was used to estimate the association between four epidemiological variables and diagnosed HCV status (i.e. whether or not linked to the HCV Diagnosis database). These were: sex, age at death, year of death (with 1995–1997 specified as the reference category, because HCV testing was more limited before this period), and Carstairs social deprivation quintile. We did not analyse trends in mortality rates because the HCV Diagnosis database has expanded since its inception and people in the later stages of HCV disease may have been over-represented in its earlier years. Statistical analyses were carried out using R version 2.4.0 [11].
To estimate the extent of underreporting of HCV on the death certificate, we computed the proportion of death records that were linked to the HCV Diagnosis database, but failed to list an HCV code as either the underlying or a contributing cause of death. This analysis was also conducted separately for the year range 2000-2006, as the change in cause-of-death coding to the ICD-10 classification in 2000 overcomes the imprecision in the ICD-9 codes for HCV. The main data analysis was based on the linked data only.
References
1. Leon DA, McCambridge J. Liver cirrhosis mortality rates in Britain from 1950 to 2002: an analysis of routine data. Lancet. 2006;367(9504):52-6.
2. Palmateer N, Hutchinson S, McLeod A, Codere G, Goldberg D. Comparison of deaths related to hepatitis C and AIDS in Scotland. J Viral Hepat. 2007;14(12):870-4.
3. Wise M, Bialek S, Finelli L, Bell B, Sorvillo F. Changing trends in hepatitis C-related mortality in the United States; 1995-2004. Hepatology. 2008;47(4):1128-35.
4. Health Protection Scotland (HPS). Surveillance of known hepatitis C antibody positive cases in Scotland: results to 30 June 2006. HPS Weekly Report. 2006;40(2006/38):202-6.
5. Hutchinson S, Bird S, Goldberg D. Modeling the current and future disease burden of hepatitis C among injection drug users in Scotland. Hepatology. 2005;42(3):711-23.
6. Freeman A, Dore G, Law M, Thorpe M, von Overbeck J, Lloyd A, et al. Estimating progression to cirrhosis in chronic hepatitis C virus infection. Hepatology. 2001;34(4 Pt 1):809-16.
7. Thein HH, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology. 2008;48(2):418-31.
8. Carstairs V, Morris R. Deprivation and health in Scotland. Health Bulletin. 1990;48(4):162-75.
9. Shaw L, Taylor A, Roy K, Cameron S, Burns S, Molyneaux P, et al. Establishment of a database of diagnosed HCV-infected persons in Scotland. Commun Dis Public Health. 2003;6(4):305-10.
10. Kendrick S, Clarke J. The Scottish Record Linkage System. Health Bull (Edinb). 1993;51:72-9.
11. R Development Core Team. R: a language and environment for statistical computing. Vienna; Austria: R Foundation for Statistical Computing; 2006.
12. Hutchinson S, Roy K, Wadd S, Bird S, Taylor A, Anderson E, et al. Hepatitis C virus infection in Scotland: epidemiological review and public health challenges. Scott Med J. 2006;51(2):8-15.
13. Hutchinson S, Bird S, Goldberg D. Influence of alcohol on the progression of hepatitis C virus infection: a meta-analysis. Clinical Gastroenterology and Hepatology. 2005;3(11):1150-9.
14. Bird S, Goldberg D, Hutchinson S. Projecting severe sequelae of injection-related hepatitis C virus epidemic in the UK. Part 1: Critical hepatitis C and injector data. J of Epidemiology and Biostatistics;2001(6):3.
15. Davis G, Albright J, Cook S, Rosenberg D. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 2003;9(4):331-8.
16. Hutchinson S, Bird S, Goldberg D. Review of models used to predict the future numbers of individuals with severe hepatitis C disease: therapeutic and cost implications. Expert Review of Pharmacoeconomics and Outcomes Research. 2006;6(6):627-39.
17. Mann AG, Ramsay ME, Brant LJ, Balogun MA, Costella A, Harris HE. Diagnoses of, and deaths from, severe liver disease due to hepatitis C in England between 2000 and 2005 estimated using multiple data sources. Epidemiol Infect. 2009;137(4):513-8.
18. Vong S, Bell B. Chronic liver disease mortality in the United States; 1990-1998. Hepatology. 2004;39(2):476-83.
19. Manos MM, Leyden WA, Murphy RC, Terrault NA, Bell BP. Limitations of conventionally derived chronic liver disease mortality rates: Results of a comprehensive assessment. Hepatology. 2008;47(4):1150-7.
20. Information Services Division (ISD). Alcohol Statistics Scotland. Edinburgh: ISD; 2007.
21. Micallef JM, Kaldor JM, Dore GJ. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies. J Viral Hepat. 2006;13(1):34-41.
22. Hay G, Gannon M, McKeganey N, Hutchinson S, Goldberg D. Estimating the national and local prevalence of problem drug misuse in Scotland: executive report. Edinburgh: ISD; 2005.
23. Chen C, Yoon Y, Yi H, Lucas D. Alcohol and hepatitis C mortality among males and females in the United States: a life table analysis. Alcohol Clin Exp Res. 2007;31(2):285-92.
24. Campbell J, Hagan H, Latka M, Garfein R, Golub E, Coady M, et al. High prevalence of alcohol use among hepatitis C virus antibody positive injection drug users in three US cities. Drug Alcohol Depend. 2006;81(3):259-65.
25. Watson B, Conigrave K, Wallace C, Whitfield J, Wurst F, Haber P. Hazardous alcohol consumption and other barriers to antiviral treatment among hepatitis C positive people receiving opioid maintenance treatment. Drug Alcohol Rev. 2007;26(3):231-9.
26. Graham L. Prison health in Scotland: a health-care needs assessment. Scottish Prison Service; 2007
DDW: Telaprevir Said to Benefit Hardest HCV Case
DDW: Telaprevir Said to Benefit Hardest HCV Case
MedPage Today
Published: May 08, 2010
Links to full slide/poster reports at EASL;
EASL: Telaprevir in Null-Responders & Non-Responders - (04/15/10)
EASL: VX-222 Vertex NNRTI Polymerase Inhibitor 3 Days Monotherapy - (04/15/10)
EASL: Discrepancies Between Definitions of Null Response to Treatment with Peginterferon Alfa-2a and Ribavirin: Implications for New HCV Drug Development - (04/18/10)
EASL: On-Treatment Response-Guided Therapy with Telaprevir q8h or q12h Combined with Peginterferon Alfa-2a or Alfa-2b and Ribavirin in Treatment-Naïve Genotype 1 Hepatitis C (Study C208) - (04/18/10)
EASL: Activity of Telaprevir Alone or in Combination with Peginterferon Alfa-2a and Ribavirin in Treatment-naïve, Genotype 2 and 3, Hepatitis C Patients: Final Results of Study C209 - (04/18/10)
Action Points
* Explain to interested patients that telaprevir is not FDA approved for any purpose and is available only in a clinical trial setting.
* Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.
NEW ORLEANS -- Adding an investigational protease inhibitor for hepatitis C virus (HCV) to standard treatment induced rapid and sustained virologic responses in many patients with poor responses to standard therapy alone, researchers said here.
In an open-label extension study, most patients with inadequate or no responses, or who showed renewed viral activity after an initial response to pegylated interferon and ribavirin, succeeded in achieving so-called sustained virologic responses to a second course of treatment that included telaprevir, reported Andrew Muir, MD, of Duke University.
Another analysis of one of these trials also showed that, among patients with inadequate initial responses to the standard regimen, even those with risk factors predicting especially poor responses did well when telaprevir was added, Muir said.
He presented the findings in two sessions here at Digestive Disease Week and at a press conference.
Telaprevir is one of two HCV protease inhibitors now in development, the other being boceprevir. These drugs are widely expected to be the first direct antiviral drugs made available for HCV, with FDA approval possible in 2011.
One of the studies Muir presented involved 117 participants in three earlier trials in the PROVE series who were in the standard-therapy arms and failed to show sustained virologic responses. They were categorized by the type of poor response: null responders (those with little or no change in viral loads), partial responders (initial decrease of at least two logs in HCV RNA but virus still detectable at week 24), and relapses and breakthroughs.
These patients underwent a second round of treatment with PEG-interferon and ribavirin at standard doses with the addition of telaprevir at 750 mg every eight hours. All three drugs were given for 12 weeks, with interferon and ribavirin continued for an additional 12 weeks.
Patients not showing complete responses at week 24 received an additional 24 weeks of interferon and ribavirin.
Muir said more than half of patients, 59%, had sustained virologic responses to the 12 weeks of telaprevir and 24 weeks of standard therapy.
Among the 35 who ended up taking interferon and ribavirin for the full 48 weeks, 52% had sustained responses.
The shorter regimen was not very effective in the subgroup with null responses to standard therapy during the PROVE studies. Only 13% of these patients developed sustained virologic responses during the first 24 weeks. But 57% of those who stayed on therapy for 48 weeks achieved sustained responses, according to Muir.
Among the other subgroups, response rates to the 24-week regimen ranged from 60% to 92%. Only seven patients in those subgroups received 48 weeks of treatment, of whom two obtained sustained responses.
The other study presented by Muir was a post hoc subgroup analysis of responses in "difficult to cure" patients in one of the earlier trials, PROVE3. These were patients who had one or more risk factors previously known to predict poor responses to interferon and ribavirin.
These included:
* HCV genotype 1
* Age
* High baseline viral load
* Male gender
* Obesity
* Bridging fibrosis in the liver
Participants in PROVE3 had all received prior unsuccessful treatment for HCV, so it was not surprising that, of the 342 patients included in the analysis, most had at least one of these risk factors.
PROVE3 was a randomized trial that assigned patients to interferon and ribavirin at standard doses for 48 weeks with or without 12 weeks of telaprevir, or to 24 weeks of the standard therapy plus 12 weeks of telaprevir. There was also a fourth arm, combining telaprevir and interferon without ribavirin, that was excluded from the new analysis.
Muir reported that, in each major risk-factor group, patients in both telaprevir arms did far better than those receiving the standard therapy alone.
Sustained viral responses were achieved in 44% to 61% of patients receiving telaprevir, compared with 10% to 15% of those receiving only the standard regimen (P<0.0001 for all comparisons), for the following subgroups: males, those older than 50, those with body mass index values of 25 to 30, those with BMI over 30, those with initial viral loads of more than 800,000 IU/mL, and those with bridging fibrosis or cirrhosis.
Patients with the risk factor associated with the worst outcomes -- those with no response at all to initial interferon and ribavirin treatment -- also did better with telaprevir, with 38% obtaining sustained responses.
Multivariate analysis indicated that adding telaprevir increased the chances of achieving a sustained response by nearly nine-fold (odds ratio 8.7, 95% CI 4.6 to 16.7).
In his presentations here, Muir spent little time addressing adverse effects. However, earlier reports from the PROVE series indicated that anemia and skin rashes and pruritus were relatively common with telaprevir.
Philip Schoenfeld, MD, of the University of Michigan in Ann Arbor, who moderated the press conference where Muir spoke, said the results with HCV protease inhibitors have been highly encouraging.
"These agents offer the opportunity for a revolution in the treatment of hepatitis C virus patients, achieving successful eradication of the virus in substantially more patients," he said.
In particular, Schoenfeld added, boceprevir and telaprevir offer "new hope for patients who have failed conventional therapies."
MedPage Today
Published: May 08, 2010
Links to full slide/poster reports at EASL;
EASL: Telaprevir in Null-Responders & Non-Responders - (04/15/10)
EASL: VX-222 Vertex NNRTI Polymerase Inhibitor 3 Days Monotherapy - (04/15/10)
EASL: Discrepancies Between Definitions of Null Response to Treatment with Peginterferon Alfa-2a and Ribavirin: Implications for New HCV Drug Development - (04/18/10)
EASL: On-Treatment Response-Guided Therapy with Telaprevir q8h or q12h Combined with Peginterferon Alfa-2a or Alfa-2b and Ribavirin in Treatment-Naïve Genotype 1 Hepatitis C (Study C208) - (04/18/10)
EASL: Activity of Telaprevir Alone or in Combination with Peginterferon Alfa-2a and Ribavirin in Treatment-naïve, Genotype 2 and 3, Hepatitis C Patients: Final Results of Study C209 - (04/18/10)
Action Points
* Explain to interested patients that telaprevir is not FDA approved for any purpose and is available only in a clinical trial setting.
* Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.
NEW ORLEANS -- Adding an investigational protease inhibitor for hepatitis C virus (HCV) to standard treatment induced rapid and sustained virologic responses in many patients with poor responses to standard therapy alone, researchers said here.
In an open-label extension study, most patients with inadequate or no responses, or who showed renewed viral activity after an initial response to pegylated interferon and ribavirin, succeeded in achieving so-called sustained virologic responses to a second course of treatment that included telaprevir, reported Andrew Muir, MD, of Duke University.
Another analysis of one of these trials also showed that, among patients with inadequate initial responses to the standard regimen, even those with risk factors predicting especially poor responses did well when telaprevir was added, Muir said.
He presented the findings in two sessions here at Digestive Disease Week and at a press conference.
Telaprevir is one of two HCV protease inhibitors now in development, the other being boceprevir. These drugs are widely expected to be the first direct antiviral drugs made available for HCV, with FDA approval possible in 2011.
One of the studies Muir presented involved 117 participants in three earlier trials in the PROVE series who were in the standard-therapy arms and failed to show sustained virologic responses. They were categorized by the type of poor response: null responders (those with little or no change in viral loads), partial responders (initial decrease of at least two logs in HCV RNA but virus still detectable at week 24), and relapses and breakthroughs.
These patients underwent a second round of treatment with PEG-interferon and ribavirin at standard doses with the addition of telaprevir at 750 mg every eight hours. All three drugs were given for 12 weeks, with interferon and ribavirin continued for an additional 12 weeks.
Patients not showing complete responses at week 24 received an additional 24 weeks of interferon and ribavirin.
Muir said more than half of patients, 59%, had sustained virologic responses to the 12 weeks of telaprevir and 24 weeks of standard therapy.
Among the 35 who ended up taking interferon and ribavirin for the full 48 weeks, 52% had sustained responses.
The shorter regimen was not very effective in the subgroup with null responses to standard therapy during the PROVE studies. Only 13% of these patients developed sustained virologic responses during the first 24 weeks. But 57% of those who stayed on therapy for 48 weeks achieved sustained responses, according to Muir.
Among the other subgroups, response rates to the 24-week regimen ranged from 60% to 92%. Only seven patients in those subgroups received 48 weeks of treatment, of whom two obtained sustained responses.
The other study presented by Muir was a post hoc subgroup analysis of responses in "difficult to cure" patients in one of the earlier trials, PROVE3. These were patients who had one or more risk factors previously known to predict poor responses to interferon and ribavirin.
These included:
* HCV genotype 1
* Age
* High baseline viral load
* Male gender
* Obesity
* Bridging fibrosis in the liver
Participants in PROVE3 had all received prior unsuccessful treatment for HCV, so it was not surprising that, of the 342 patients included in the analysis, most had at least one of these risk factors.
PROVE3 was a randomized trial that assigned patients to interferon and ribavirin at standard doses for 48 weeks with or without 12 weeks of telaprevir, or to 24 weeks of the standard therapy plus 12 weeks of telaprevir. There was also a fourth arm, combining telaprevir and interferon without ribavirin, that was excluded from the new analysis.
Muir reported that, in each major risk-factor group, patients in both telaprevir arms did far better than those receiving the standard therapy alone.
Sustained viral responses were achieved in 44% to 61% of patients receiving telaprevir, compared with 10% to 15% of those receiving only the standard regimen (P<0.0001 for all comparisons), for the following subgroups: males, those older than 50, those with body mass index values of 25 to 30, those with BMI over 30, those with initial viral loads of more than 800,000 IU/mL, and those with bridging fibrosis or cirrhosis.
Patients with the risk factor associated with the worst outcomes -- those with no response at all to initial interferon and ribavirin treatment -- also did better with telaprevir, with 38% obtaining sustained responses.
Multivariate analysis indicated that adding telaprevir increased the chances of achieving a sustained response by nearly nine-fold (odds ratio 8.7, 95% CI 4.6 to 16.7).
In his presentations here, Muir spent little time addressing adverse effects. However, earlier reports from the PROVE series indicated that anemia and skin rashes and pruritus were relatively common with telaprevir.
Philip Schoenfeld, MD, of the University of Michigan in Ann Arbor, who moderated the press conference where Muir spoke, said the results with HCV protease inhibitors have been highly encouraging.
"These agents offer the opportunity for a revolution in the treatment of hepatitis C virus patients, achieving successful eradication of the virus in substantially more patients," he said.
In particular, Schoenfeld added, boceprevir and telaprevir offer "new hope for patients who have failed conventional therapies."
Vertex Hepatitis Drug Seen Successful
Vertex Hepatitis Drug Seen Successful, But Numbers Are Key: Phase 3 ADVANCE and ILLUMINATE trials in treatment-naive patients fully enrolled
Wall St Jnl
MAY 13, 2010, 2:56 P.M. ET
- ADVANCE: Vertex and Tibotec completed enrollment in October 2008 in the global 3-arm pivotal Phase 3 ADVANCE trial that is focused on 24-week telaprevir-based response-guided regimens in genotype 1 treatment-naive HCV patients. In the ADVANCE trial, telaprevir is being dosed for 8 or 12 weeks. All patients are expected to have completed 8 or 12 weeks of dosing with telaprevir or placebo by the end of January 2009. Vertex expects to have sustained viral response (SVR) data from the ADVANCE trial in the first half of 2010. The ADVANCE trial enrolled approximately 1,050 patients.
- ILLUMINATE: Vertex today announced that the Company has completed enrollment in the global 2-arm ILLUMINATE trial that will include evaluation of 24-week and 48-week telaprevir-based regimens in genotype 1 treatment-naive HCV patients. In the ILLUMINATE trial, telaprevir is being dosed for 12 weeks. The Company expects to have SVR data from the ILLUMINATE trial in the first half of 2010, which will supplement SVR data obtained from the pivotal Phase 3 ADVANCE trial. The ILLUMINATE trial enrolled approximately 500 patients
NEW YORK (Dow Jones)--Vertex Pharmaceuticals Inc. (VRTX) will report late-stage data on its hepatitis C treatment in coming weeks from the first of three key studies, and Wall Street will be watching the numbers to gauge how telaprevir will fare in a competitive market.
Many expect the study to be positive, based on extensive prior clinical data on the drug, and the stock is pricing in a lot of success for telaprevir. But the data from the so-called Advance trial, due by the end of June, could provide further gains as confidence grows in the drug's role in the lucrative but increasingly competitive hepatitis C market.
"Expectations are relatively high, but I think there is a reasonable amount of money on the sidelines," said analyst Brian Abrahams of Oppenheimer & Co., projecting telaprevir sales of $1.47 billion by 2013. Abrahams said the study will reduce the perceived risk in developing telaprevir and help investors feel more comfortable in investing in the company.
Vertex plans to market the drug itself in North America. Johnson & Johnson (JNJ) will help sell telaprevir overseas, with Mitsubishi Tanabe Pharma Corp. (4508.TO) holding rights in Japan and some Asian countries.
Although it has several promising pipeline products, Vertex's $7.7 billion market valuation is primarily tied to the success of telaprevir.
The stock, recently trading at $38.64, has largely traded between $38 and $44 since early November when an earlier trial of the drug showed positive results. Analysts project the stock moving into the mid-$40s on positive data, but that reaction will depend on the nuances of the data.
Unlike many clinical trials, the issue with the Advance study--along with the other two trials coming later this year--is not whether it succeeds, but the level of the success. Failure is seen as highly unlikely because of the success of multiple earlier studies, but such a development would be a major setback.
Hepatitis C is a blood-transmitted virus that causes liver inflammation and can lead to cirrhosis, cancer and liver failure.
There is no cure for the disease, but sustained virologic response, or SVR--when the virus isn't detected in the blood for six months after treatment--is pretty close and relapse is rare.
Last year, Johnson & Johnson projected the hepatitis C market would grow from $3.3 billion in 2008 to $7 billion in 2013, driven by sales of drugs like telaprevir.
The standard therapy, a combination of interferon injections and ribavirin pills over 48 weeks, achieves an SVR in up to about 50% of patients, according to the Centers for Disease Control. When telaprevir is used with those drugs, which can have severe side effects, it can cut the length of therapy to 24 weeks in most patients.
In mid-stage clinical trials that use a similar treatment regimen to the coming data, telaprevir showed an SVR rate of 61% to 69%, compared to 41% to 46% among patients taking a placebo, said Vertex Chief Medical Officer Robert Kauffman.
Another midstage study had more than 80% of patients achieving an SVR. That study, dubbed C-208, included more measures to manage a rash that can occur in some patients and used "response-guided therapy" that assesses whether patients should use the drug for a longer duration based on their initial response.
The results may have also been boosted because that study occurred in Europe, where patients SVRs are higher for unknown reasons, Dr. Kauffman said.
The Phase III program includes response-guided therapy and rash-related changes, but are being conducted in both the U.S. and Europe. Those factors have analysts generally expecting the SVR rate in the Advance trial to exceed 70%.
"Above 75%, things start to get interesting," RBC Capital Markets analyst Jason Kantor said, noting that such a high level would give "the bears very little to talk about."
But if the rate comes in below 70% it could prove to be disappointing to investors, even though the approval process for the drug will be still be able to move forward. The company expects to file for approval by the end of the year, Dr. Kauffman said, and hopes to get a six-month review from the Food and Drug Adminstration.
"From a regulatory perspective and changing clinical practice...a 68% SVR rate would be a slam dunk; however, one of the issues with Vertex is future competition," Kantor said.
Telaprevir is likely to face competition from Merck & Co.'s (MRK) boceprivir, which is on a similar development time line, and many companies are developing hepatitis C treatments, including Bristol-Myers Squibb Co. (BMY), Gilead Sciences Inc. (GILD) and Roche Holding AG (RHHBY, ROG.VX).
Wall St Jnl
MAY 13, 2010, 2:56 P.M. ET
- ADVANCE: Vertex and Tibotec completed enrollment in October 2008 in the global 3-arm pivotal Phase 3 ADVANCE trial that is focused on 24-week telaprevir-based response-guided regimens in genotype 1 treatment-naive HCV patients. In the ADVANCE trial, telaprevir is being dosed for 8 or 12 weeks. All patients are expected to have completed 8 or 12 weeks of dosing with telaprevir or placebo by the end of January 2009. Vertex expects to have sustained viral response (SVR) data from the ADVANCE trial in the first half of 2010. The ADVANCE trial enrolled approximately 1,050 patients.
- ILLUMINATE: Vertex today announced that the Company has completed enrollment in the global 2-arm ILLUMINATE trial that will include evaluation of 24-week and 48-week telaprevir-based regimens in genotype 1 treatment-naive HCV patients. In the ILLUMINATE trial, telaprevir is being dosed for 12 weeks. The Company expects to have SVR data from the ILLUMINATE trial in the first half of 2010, which will supplement SVR data obtained from the pivotal Phase 3 ADVANCE trial. The ILLUMINATE trial enrolled approximately 500 patients
NEW YORK (Dow Jones)--Vertex Pharmaceuticals Inc. (VRTX) will report late-stage data on its hepatitis C treatment in coming weeks from the first of three key studies, and Wall Street will be watching the numbers to gauge how telaprevir will fare in a competitive market.
Many expect the study to be positive, based on extensive prior clinical data on the drug, and the stock is pricing in a lot of success for telaprevir. But the data from the so-called Advance trial, due by the end of June, could provide further gains as confidence grows in the drug's role in the lucrative but increasingly competitive hepatitis C market.
"Expectations are relatively high, but I think there is a reasonable amount of money on the sidelines," said analyst Brian Abrahams of Oppenheimer & Co., projecting telaprevir sales of $1.47 billion by 2013. Abrahams said the study will reduce the perceived risk in developing telaprevir and help investors feel more comfortable in investing in the company.
Vertex plans to market the drug itself in North America. Johnson & Johnson (JNJ) will help sell telaprevir overseas, with Mitsubishi Tanabe Pharma Corp. (4508.TO) holding rights in Japan and some Asian countries.
Although it has several promising pipeline products, Vertex's $7.7 billion market valuation is primarily tied to the success of telaprevir.
The stock, recently trading at $38.64, has largely traded between $38 and $44 since early November when an earlier trial of the drug showed positive results. Analysts project the stock moving into the mid-$40s on positive data, but that reaction will depend on the nuances of the data.
Unlike many clinical trials, the issue with the Advance study--along with the other two trials coming later this year--is not whether it succeeds, but the level of the success. Failure is seen as highly unlikely because of the success of multiple earlier studies, but such a development would be a major setback.
Hepatitis C is a blood-transmitted virus that causes liver inflammation and can lead to cirrhosis, cancer and liver failure.
There is no cure for the disease, but sustained virologic response, or SVR--when the virus isn't detected in the blood for six months after treatment--is pretty close and relapse is rare.
Last year, Johnson & Johnson projected the hepatitis C market would grow from $3.3 billion in 2008 to $7 billion in 2013, driven by sales of drugs like telaprevir.
The standard therapy, a combination of interferon injections and ribavirin pills over 48 weeks, achieves an SVR in up to about 50% of patients, according to the Centers for Disease Control. When telaprevir is used with those drugs, which can have severe side effects, it can cut the length of therapy to 24 weeks in most patients.
In mid-stage clinical trials that use a similar treatment regimen to the coming data, telaprevir showed an SVR rate of 61% to 69%, compared to 41% to 46% among patients taking a placebo, said Vertex Chief Medical Officer Robert Kauffman.
Another midstage study had more than 80% of patients achieving an SVR. That study, dubbed C-208, included more measures to manage a rash that can occur in some patients and used "response-guided therapy" that assesses whether patients should use the drug for a longer duration based on their initial response.
The results may have also been boosted because that study occurred in Europe, where patients SVRs are higher for unknown reasons, Dr. Kauffman said.
The Phase III program includes response-guided therapy and rash-related changes, but are being conducted in both the U.S. and Europe. Those factors have analysts generally expecting the SVR rate in the Advance trial to exceed 70%.
"Above 75%, things start to get interesting," RBC Capital Markets analyst Jason Kantor said, noting that such a high level would give "the bears very little to talk about."
But if the rate comes in below 70% it could prove to be disappointing to investors, even though the approval process for the drug will be still be able to move forward. The company expects to file for approval by the end of the year, Dr. Kauffman said, and hopes to get a six-month review from the Food and Drug Adminstration.
"From a regulatory perspective and changing clinical practice...a 68% SVR rate would be a slam dunk; however, one of the issues with Vertex is future competition," Kantor said.
Telaprevir is likely to face competition from Merck & Co.'s (MRK) boceprivir, which is on a similar development time line, and many companies are developing hepatitis C treatments, including Bristol-Myers Squibb Co. (BMY), Gilead Sciences Inc. (GILD) and Roche Holding AG (RHHBY, ROG.VX).
Subscribe to:
Posts (Atom)
.JPG)