Saturday, August 31, 2013
Merck demand triggers expanding patent war with Gilead over sofosbuvir
UPDATED: Merck demand triggers expanding patent war with Gilead over sofosbuvir
August 31, 2013 | By John Carroll
Gilead is rolling out its big legal guns to defend its control of the experimental hepatitis C drug sofosbuvir, one of the most valuable therapies in the industry's late-stage pipeline.
On Friday the company fired over Merck's bow, filing suit in the Northern District of California after Merck contacted the company a few weeks ago to stake a claim to 10% of the revenue generated by sofosbuvir. Merck ($MRK) wants Gilead ($GILD) to sublicense two of its hep C-related patents, according to the lawsuit. The pharma giant sells Victrelis (boceprevir), its recently approved hep C drug, which is likely to be swept away as sofosbuvir and companion therapies make it to the market, offering a treatment less likely to trigger side effects and quicker to quell the virus.
In a letter filed with the lawsuit, Merck's Pamela Demain, the executive director of corporate licensing, explained on Aug. 5 that Merck was seeking the 10% royalty based on the two patents: '499 and '712. And she set an August 31 deadline for a response, drawing a line in the legal sand.
Merck's terms: "Gilead shall pay Merck a 10% royalty on the Net Sales of Licensed Product … by Gilead, its distributors or sublicensees, including sales of Licensed Product that is co-packaged with one or more other pharmaceutical products, from the first sale of sofosbuvir until the expiration of the last to expire patent within the Licensed Patent Rights."
And that's just one of several legal fights brewing as an FDA marketing decision on sofosbuvir looms in early December.
In its first-half financial report, Gilead also notes that Roche is claiming control of sofosbuvir based on a 9-year-old, $168 million partnership it struck with Pharmasset, which Gilead bought for a whopping $11 billion in order to seize full ownership of sofosbuvir while it was still in midstage development. According to the SEC filing, Roche ($RHHBY) believes that its 2004 deal to develop a nucleoside polymerase treatment with Pharmasset gives it an exclusive license on sofosbuvir, which Roche claims is a "prodrug (or precursor) of PSI-6130."
Gilead says the arbitration demand filed by Roche is without merit, noting that the deal ended about two years after it began--long before it acquired the company.
The Roche move follows an effort by Idenix ($IDIX) in 2012 to establish that it was the first to invent sofosbuvir. "Our patent covers metabolites of sofosbuvir and RG7128. Idenix is attempting to claim a class of compounds, including these metabolites, in its pending patent application," notes Gilead.
The growing flank attack on the sofosbuvir patent highlights the increasingly complex relationships among pharma companies as they become more likely to partner with academics and biotechs to broaden their pipelines. Big Phase III programs often attract litigation, like Medivation's ($MDVN) claim on Aragon's cancer therapy, ARN-509, since acquired by J&J ($JNJ). And sometimes they win, as we saw when Onyx ($ONXX) successfully laid claim to a 20% royalty of Stivarga from Bayer after bristling over its similarities to their partnered drug Nexavar.
Gilead will spare no expense in this fight. Analysts believe that sofosbuvir is an almost certain blockbuster, with peak sales estimates hovering around $4 billion to $5 billion. It's the leader in a pack of programs which are in the process of rewriting the standard of care for hepatitis C as AbbVie ($ABBV), Bristol-Myers Squibb ($BMY), J&J and other rivals hustle to catch up. And the prospect of gaining even a slice of that action is worth a considerable sum in legal costs to any company that thinks it has an actionable claim.
A spokesperson for Merck told FierceBiotech Saturday that the company has "nothing to add at this time."
Related Articles:
Gilead's sofosbuvir cures some of the toughest hepatitis C cases
Shunned Gilead/Bristol-Myers hep C combo may be too good for docs to ignore
Gilead races to FDA after hep C blockbuster hopeful scores 4th win in PhIII
Read more: UPDATED: Merck demand triggers expanding patent war with Gilead over sofosbuvir - FierceBiotech http://www.fiercebiotech.com/story/merck-triggers-rapidly-expanding-patent-war-gilead-over-sofosbuvir-rights/2013-08-31#ixzz2davfY0DE
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Gilead Sues Merck Saying New Drug Won’t Infringe Patents
Gilead Sciences Inc. (GILD), the world’s largest maker of HIV medicines, sued Merck & Co. (MRK) seeking a court order that the experimental hepatitis C drug sofosbuvir won’t infringe patents.
Merck, which sold $502 million of its Victrelis hepatitis C drug last year, contacted Gilead this month requesting it license two patents Merck says are related to sofosbuvir, Gilead’s attorneys said a complaint filed today in federal court in San Francisco.
Merck, based in Whitehouse Station, New Jersey, asked Gilead to pay a 10 percent royalty on the net sales of the medicine until the patents expire, a request “meant to threaten Gilead” on the eve of U.S. regulatory approval of sofosbuvir, according to the complaint. Gilead seeks a judge’s declarations that the patents aren’t enforceable or infringed so it won’t have to license them to sell the medicine.
Gilead, based in Foster City California, said June 7 that sofosbuvir will receive a priority marketing review by U.S. regulators with a target review date of Dec. 8.
Hepatitis C attacks the liver and can lead to liver cancer. The virus affects about 150 million people worldwide and the market for new pills such as sofosbuvir is estimated at $20 billion.
Lainie Keller, a Merck spokeswoman, didn’t immediately respond to an e-mail after regular business hours seeking comment on the lawsuit.
The case is Gilead Sciences v. Merck, 13-04057, U.S. District Court, Northern District of California (San Francisco).
To contact the reporter on this story: Karen Gullo in San Francisco at kgullo@bloomberg.net
To contact the editor responsible for this story: Michael Hytha at mhytha@bloomberg.net
http://www.bloomberg.com/news/2013-08-31/gilead-sues-merck-saying-new-drug-won-t-infringe-patents.html
Friday, August 30, 2013
Liver cancer due to chronic inflammation: tumour growth follows programmed cell death (apoptosis)
Liver cancer due to chronic inflammation: tumour growth follows programmed cell death (apoptosis)
Neuherberg, August 30, 2013.
The death of numerous liver cells in the context of chronic inflammation due to apoptosis, a form of programmed cell death, can promote the formation of tumour cells in the liver.
This insight significantly contributes to a better understanding of cellular processes in liver cancer development and thereby opens up new therapeutic approaches. A research team including scientists from the Helmholtz Zentrum München has reported this in the current issue of the scientific journal 'Cell Reports'.
Liver cancer (Hepatocellular Carcinoma, HCC) usually arises as the result of a chronic, inflammatory liver disease. The most common causes here are excessive alcohol consumption as well as a high-fat diet and also chronic infection with the hepatitis viruses B and C. In the course of the inflammatory process, the liver cells (hepatocytes) die more frequently due to programmed cell death. The result is increased cell growth, also referred to as compensatory proliferation, which can lead to tumour development.
A distinction is made between the two most important forms of self-induced cell death, namely apoptosis (programmed cell death) and necroptosis (programmed necrosis), which are based on different cellular mechanisms. Until now, it was not clear which form of cell death is decisive for the development of malignant liver tumours. The team working with Professor Dr. Tom Luedde from the RWTH Aachen University Hospital and Professor Dr. Mathias Heikenwälder from the Institute of Virology at the Helmholtz Zentrum München (HMGU) has now been able to verify that apoptosis precedes the development of abnormal liver cells. The scientists, including Florian Reisinger from the Institute of Virology (HMGU) and Dr. Kristian Unger from the Research Unit Radiation Cytogenetics (HMGU) showed this using mouse models. Moreover they discovered that in contrast, necroptosis prevents uninhibited cell proliferation and consequently the development of liver cancer.
These findings could form the basis for new approaches to therapy for liver cancer, which until now has been a form of cancer that cannot be adequately treated and that kills 800,000 patients around the world each year. "We now know which cellular signalling pathways are involved in liver tumour development", explains Heikenwälder. "In a further step we want to develop new treatment options, for example, by attempting to pharmaceutically block the apoptosis itself or its signalling pathways. But any new therapy can also cause undesirable effects: In our experiments, we saw that blocking apoptosis under inflammatory conditions can result in bililary obstruction (cholestasis) in the context of liver inflammation."
In upcoming investigations, the scientists want to verify their findings on the development of liver cancer and search for active substances that inhibit apoptosis while simultaneously causing the mildest possible side effects. The objective is to further develop the acquired knowledge in the sense of translational research in order to provide concrete benefits for society.
Further information
Original publication:
Vucur, M. et al. (2013), RIP3 inhibits inflammatory hepatocarcinogenesis but promotes cholestasis by controlling Caspase-8- and JNK-dependent compensatory cell proliferation. Cell Reports, doi: 10.1016/j.celrep.2013.07.035
Link to publication
http://www.helmholtz-muenchen.de/en/news/latest-news/press-releases-2013/press-release/article/22151/index.html
Neuherberg, August 30, 2013.
Immunohistochemical stainings of Ki67 and pancytokeratin (Ki67 is stained brown, pancytokeratin is stained pink) indicate proliferation of hepatocytes (arrowheads) and biliary epithelial cells (arrows) in TAK1/RIP3-deficient mice. (Image: Helmholtz Zentrum München
The death of numerous liver cells in the context of chronic inflammation due to apoptosis, a form of programmed cell death, can promote the formation of tumour cells in the liver.
This insight significantly contributes to a better understanding of cellular processes in liver cancer development and thereby opens up new therapeutic approaches. A research team including scientists from the Helmholtz Zentrum München has reported this in the current issue of the scientific journal 'Cell Reports'.
Liver cancer (Hepatocellular Carcinoma, HCC) usually arises as the result of a chronic, inflammatory liver disease. The most common causes here are excessive alcohol consumption as well as a high-fat diet and also chronic infection with the hepatitis viruses B and C. In the course of the inflammatory process, the liver cells (hepatocytes) die more frequently due to programmed cell death. The result is increased cell growth, also referred to as compensatory proliferation, which can lead to tumour development.
A distinction is made between the two most important forms of self-induced cell death, namely apoptosis (programmed cell death) and necroptosis (programmed necrosis), which are based on different cellular mechanisms. Until now, it was not clear which form of cell death is decisive for the development of malignant liver tumours. The team working with Professor Dr. Tom Luedde from the RWTH Aachen University Hospital and Professor Dr. Mathias Heikenwälder from the Institute of Virology at the Helmholtz Zentrum München (HMGU) has now been able to verify that apoptosis precedes the development of abnormal liver cells. The scientists, including Florian Reisinger from the Institute of Virology (HMGU) and Dr. Kristian Unger from the Research Unit Radiation Cytogenetics (HMGU) showed this using mouse models. Moreover they discovered that in contrast, necroptosis prevents uninhibited cell proliferation and consequently the development of liver cancer.
These findings could form the basis for new approaches to therapy for liver cancer, which until now has been a form of cancer that cannot be adequately treated and that kills 800,000 patients around the world each year. "We now know which cellular signalling pathways are involved in liver tumour development", explains Heikenwälder. "In a further step we want to develop new treatment options, for example, by attempting to pharmaceutically block the apoptosis itself or its signalling pathways. But any new therapy can also cause undesirable effects: In our experiments, we saw that blocking apoptosis under inflammatory conditions can result in bililary obstruction (cholestasis) in the context of liver inflammation."
In upcoming investigations, the scientists want to verify their findings on the development of liver cancer and search for active substances that inhibit apoptosis while simultaneously causing the mildest possible side effects. The objective is to further develop the acquired knowledge in the sense of translational research in order to provide concrete benefits for society.
Further information
Original publication:
Vucur, M. et al. (2013), RIP3 inhibits inflammatory hepatocarcinogenesis but promotes cholestasis by controlling Caspase-8- and JNK-dependent compensatory cell proliferation. Cell Reports, doi: 10.1016/j.celrep.2013.07.035
Link to publication
http://www.helmholtz-muenchen.de/en/news/latest-news/press-releases-2013/press-release/article/22151/index.html
Hey Grandma, Let's Get You Checked for Hep C
Medscape Family Medicine > Best Evidence Review
Hey Grandma, Let's Get You Checked for Hep C
Charles P. Vega, MD
Aug 30, 2013
Best Evidence Review of the USPSTF Screening Recommendations for Hepatitis C
The Study
Moyer VA; US Preventive Services Task Force. Screening for hepatitis C virus infection in adults: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2013 Jun 25.
[Epub ahead of print]
Introduction
The prevalence of chronic hepatitis C virus (HCV) infection in the United States may have peaked over a decade ago, but there is convincing evidence that middle-aged and older adults born between 1945 and 1965 are at increased risk for infection. The most significant risk factor for chronic HCV infection is prior injection drug use, but the majority of adults with infection do not have this risk factor. Therefore, in additional to regular screening among high-risk groups, the US Preventive Services Task Force (USPTSF) now recommends 1-time screening for chronic HCV infection for adults born between 1945 and 1965.
While this recommendation may seem preposterous when thinking of your own Nana, do you really know what she was up to in 1968? There is good merit for the recommendation, which is discussed below.
Background to the Study
HCV infection is one of the most common chronic infections in the United States. Data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002 indicated that the overall prevalence of HCV infection was 1.6% among adults aged 20-59 years.[1] This figure includes over 3 million adults with active infection, as defined by a positive HCV RNA test. Moreover, this testing probably underestimated the total prevalence of HCV infection because high-risk populations, including homeless and incarcerated adults, were not included in the research. In a study of over 400 homeless war veterans, the prevalence of HCV infection was 44.0%.[2]
Evidence of HCV infection is twice as common among women than men and among African Americans than white adults.[3] The most important risk factor for HCV infection is intravenous drug use. Nearly one half of the cohort that was positive for HCV infection in the NHANES study had this risk factor.[1] Other significant risk factors for HCV infection include receipt of blood transfusion before 1992, receipt of other blood products before 1987, and other drug use.[3] Sexual behavior is a less powerful risk factor HCV infection compared with HIV infection, but there is evidence that a history of multiple sexual partners is associated with a higher risk for HCV infection. Many individuals with HCV infection have overlapping risk factors for infection.
Why Screen All Baby Boomers?
Although the authors of the recommendations regarding screening for HCV infection note that the prevalence of HCV infection in the United States appeared to peak in 2001, there is another clear trend in the epidemiology of HCV infection that merits close attention. Persons born between 1945 and 1965 comprise approximately 27% of the total population of the United States, but they account for a disproportionate share of cases of HCV infection.[4] The prevalence of HCV infection in this age group is 3.25%, and approximately three quarters of active HCV infection cases are encountered among persons born between 1945 and 1965.
Moreover, and more important, persons who are currently in the fifth through seventh decades of life at this time are at the highest risk for complications from HCV infection. They account for 73% of mortality due to HCV infection, and this group is also at the highest risk for hepatocellular carcinoma and cirrhosis.[4] Therefore, the number of patients needed to treat with anti-HCV therapy in order to prevent additional cases of mortality is lower in this specific older cohort of adults compared with younger adults.
Therefore, it is not only the epidemiologic data that drive the new HCV screening recommendations from the USPSTF, but also an expectation that treatment of heretofore undiagnosed HCV infection can put a substantial dent in the broad clinical impact of HCV. The new recommendations call for 1-time screening for all adults born between 1945 and 1965 (B recommendation: high certainty that the net benefit is moderate, or moderate certainty that the net benefit is moderate to substantial). The anti-HCV antibody is test the best screening tool for these adults.
Limitations and Benefits of Age-Based Screening
Limitations
The authors identify the limitations of the new recommendations. Although age-based screening should identify more patients with HCV infection, they admit that this method may be less efficient than risk-based screening. The potential harms of screening include stigmatization, but also the more tangible and serious complications of the diagnostic work-up of liver disease.
The rate of major complications after percutaneous liver biopsy ranges between 0.09% and 2.3%, with a trend toward higher complication rates in older studies.[5] Use of ultrasonography to guide liver biopsy may reduce the risk for complications by 30%. However, the authors of the current review note that overall use of liver biopsy is declining with greater reliance on laboratory testing alone to guide treatment. This will reduce the potential harms of screening for HCV infection.
A more serious complication of a large screening campaign for HCV infection among older adults is overdiagnosis, meaning the discovery of infections which would have no impact on the course of the patient's life. Up to 25% of acute infections with HCV may be cleared and do not progress to chronic HCV infection.[6] Despite the high numbers of patients with chronic HCV infection, only 10%-15% develop cirrhosis. The mean interval from infection to cirrhosis is a matter of debate but is approximately 20 years, and patients without other cirrhosis risk factors, such as chronic alcohol misuse or hepatitis B infection, are less likely to develop cirrhosis.
Benefits of Screening
Nonetheless, acquiring HCV infection at an age older than 40 years is also associated with a higher risk for cirrhosis, making overdiagnosis less of an issue among older adults.[6] In addition, treatment of chronic HCV infection has resulted in significant improvements in morbidity and mortality outcomes.
In research from 5 large tertiary hospitals in which 530 patients were followed for over 8 years for mortality outcomes, patients with a sustained virologic response (SVR) experienced a 74% reduction in all-cause mortality and a 94% reduction in the risk for liver-related mortality or transplantation compared with patients who did not have an SVR to anti-HCV therapy.[7] The mean age of participants in this research was 48 years, meaning that many patients included in the new screening recommendation might receive these substantial benefits of anti-HCV treatment.
Furthermore, treatment of chronic HCV infection reduces the risk for hepatocellular carcinoma. In a meta-analysis of 18 studies, SVR reduced the relative risk for hepatocellular carcinoma to 0.24 compared with no SVR.[8] SVR was similarly effective in reducing the risk for hepatocellular carcinoma in an analysis confined to patients with advanced liver disease.
The new screening methods also appear to be cost-effective. In an analysis of the proposed birth-cohort HCV screening plan proposed by the USPSTF, researchers found that screening would result in over 800,000 new cases of HCV infection identified, at the cost of $2874 per case.[9] Subsequent treatment for HCV would result in costs of $15,000-$35,000 per quality-adjusted life-year gained, a favorable sum compared with other health interventions. In fact, another analysis found that age-based screening for HCV was more cost-effective than risk factor-based screening, although the authors stress that this is true only if all new cases receive standard triple therapy for their infection.[10]
Adding to the PCP Tasks
Primary care physicians are asked to do many things. The average number of patient requests of physicians per clinic visit was 5.5 in one study, and this information is now 14 years old.[11] These requests exclude other important elements of the office visit, such as addressing severe anemia or demonstrating empathy and patience when the patient bursts into tears upon being asked, "So, how's it going?"
Primary care physicians are also the stewards of preventive healthcare, which is a wonderful opportunity and distinct challenge. We need to get screening tests ordered on time for the right patients, and practice shared decision-making each step of the way as we do so.
At first glance, the new screening recommendations from the USPSTF may seem superfluous. However, after reviewing the epidemiology, treatment outcomes, and even cost-effectiveness data, this screening certainly appears to be prudent and beneficial. It should be embraced by primary care physicians. It should also evolve. As the demographics of HCV infection shift, the age-based screening approach will almost certainly need to change as well. An eventual move away from HCV screening will indicate a great victory for the public's health.
Clinical Pearls
• Between 1% and 2% of the adult population in the United States has been found to have chronic HCV infection, although this may be an underestimation once high-risk groups are added to the equation.
• Persons born between 1945 and 1965 bear a disproportionate share of the disease burden of chronic HCV infection, both in terms of higher prevalence and increased rates of complications.
• Treatment that results in SVR among patients with chronic HCV infection substantially reduces the risks for cirrhosis, hepatocellular carcinoma, and mortality.
• The new recommendations from the USPSTF support traditional screening for HCV among high-risk groups but also call for 1-time screening using anti-HCV antibody testing among adults born between 1945 and 1965. If used widely, this screening program should have a positive effect on morbidity and mortality among older adults.
Introduction
Background to the Study
Why Screen All Baby Boomers?
Limitations and Benefits
Clinical Pearls
Hey Grandma, Let's Get You Checked for Hep C
Charles P. Vega, MD
Aug 30, 2013
Best Evidence Review of the USPSTF Screening Recommendations for Hepatitis C
The Study
Moyer VA; US Preventive Services Task Force. Screening for hepatitis C virus infection in adults: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2013 Jun 25.
[Epub ahead of print]
Introduction
The prevalence of chronic hepatitis C virus (HCV) infection in the United States may have peaked over a decade ago, but there is convincing evidence that middle-aged and older adults born between 1945 and 1965 are at increased risk for infection. The most significant risk factor for chronic HCV infection is prior injection drug use, but the majority of adults with infection do not have this risk factor. Therefore, in additional to regular screening among high-risk groups, the US Preventive Services Task Force (USPTSF) now recommends 1-time screening for chronic HCV infection for adults born between 1945 and 1965.
While this recommendation may seem preposterous when thinking of your own Nana, do you really know what she was up to in 1968? There is good merit for the recommendation, which is discussed below.
Background to the Study
HCV infection is one of the most common chronic infections in the United States. Data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002 indicated that the overall prevalence of HCV infection was 1.6% among adults aged 20-59 years.[1] This figure includes over 3 million adults with active infection, as defined by a positive HCV RNA test. Moreover, this testing probably underestimated the total prevalence of HCV infection because high-risk populations, including homeless and incarcerated adults, were not included in the research. In a study of over 400 homeless war veterans, the prevalence of HCV infection was 44.0%.[2]
Evidence of HCV infection is twice as common among women than men and among African Americans than white adults.[3] The most important risk factor for HCV infection is intravenous drug use. Nearly one half of the cohort that was positive for HCV infection in the NHANES study had this risk factor.[1] Other significant risk factors for HCV infection include receipt of blood transfusion before 1992, receipt of other blood products before 1987, and other drug use.[3] Sexual behavior is a less powerful risk factor HCV infection compared with HIV infection, but there is evidence that a history of multiple sexual partners is associated with a higher risk for HCV infection. Many individuals with HCV infection have overlapping risk factors for infection.
Why Screen All Baby Boomers?
Although the authors of the recommendations regarding screening for HCV infection note that the prevalence of HCV infection in the United States appeared to peak in 2001, there is another clear trend in the epidemiology of HCV infection that merits close attention. Persons born between 1945 and 1965 comprise approximately 27% of the total population of the United States, but they account for a disproportionate share of cases of HCV infection.[4] The prevalence of HCV infection in this age group is 3.25%, and approximately three quarters of active HCV infection cases are encountered among persons born between 1945 and 1965.
Therefore, it is not only the epidemiologic data that drive the new HCV screening recommendations from the USPSTF, but also an expectation that treatment of heretofore undiagnosed HCV infection can put a substantial dent in the broad clinical impact of HCV. The new recommendations call for 1-time screening for all adults born between 1945 and 1965 (B recommendation: high certainty that the net benefit is moderate, or moderate certainty that the net benefit is moderate to substantial). The anti-HCV antibody is test the best screening tool for these adults.
Limitations and Benefits of Age-Based Screening
Limitations
The authors identify the limitations of the new recommendations. Although age-based screening should identify more patients with HCV infection, they admit that this method may be less efficient than risk-based screening. The potential harms of screening include stigmatization, but also the more tangible and serious complications of the diagnostic work-up of liver disease.
The rate of major complications after percutaneous liver biopsy ranges between 0.09% and 2.3%, with a trend toward higher complication rates in older studies.[5] Use of ultrasonography to guide liver biopsy may reduce the risk for complications by 30%. However, the authors of the current review note that overall use of liver biopsy is declining with greater reliance on laboratory testing alone to guide treatment. This will reduce the potential harms of screening for HCV infection.
A more serious complication of a large screening campaign for HCV infection among older adults is overdiagnosis, meaning the discovery of infections which would have no impact on the course of the patient's life. Up to 25% of acute infections with HCV may be cleared and do not progress to chronic HCV infection.[6] Despite the high numbers of patients with chronic HCV infection, only 10%-15% develop cirrhosis. The mean interval from infection to cirrhosis is a matter of debate but is approximately 20 years, and patients without other cirrhosis risk factors, such as chronic alcohol misuse or hepatitis B infection, are less likely to develop cirrhosis.
Benefits of Screening
Nonetheless, acquiring HCV infection at an age older than 40 years is also associated with a higher risk for cirrhosis, making overdiagnosis less of an issue among older adults.[6] In addition, treatment of chronic HCV infection has resulted in significant improvements in morbidity and mortality outcomes.
In research from 5 large tertiary hospitals in which 530 patients were followed for over 8 years for mortality outcomes, patients with a sustained virologic response (SVR) experienced a 74% reduction in all-cause mortality and a 94% reduction in the risk for liver-related mortality or transplantation compared with patients who did not have an SVR to anti-HCV therapy.[7] The mean age of participants in this research was 48 years, meaning that many patients included in the new screening recommendation might receive these substantial benefits of anti-HCV treatment.
Furthermore, treatment of chronic HCV infection reduces the risk for hepatocellular carcinoma. In a meta-analysis of 18 studies, SVR reduced the relative risk for hepatocellular carcinoma to 0.24 compared with no SVR.[8] SVR was similarly effective in reducing the risk for hepatocellular carcinoma in an analysis confined to patients with advanced liver disease.
The new screening methods also appear to be cost-effective. In an analysis of the proposed birth-cohort HCV screening plan proposed by the USPSTF, researchers found that screening would result in over 800,000 new cases of HCV infection identified, at the cost of $2874 per case.[9] Subsequent treatment for HCV would result in costs of $15,000-$35,000 per quality-adjusted life-year gained, a favorable sum compared with other health interventions. In fact, another analysis found that age-based screening for HCV was more cost-effective than risk factor-based screening, although the authors stress that this is true only if all new cases receive standard triple therapy for their infection.[10]
Adding to the PCP Tasks
Primary care physicians are asked to do many things. The average number of patient requests of physicians per clinic visit was 5.5 in one study, and this information is now 14 years old.[11] These requests exclude other important elements of the office visit, such as addressing severe anemia or demonstrating empathy and patience when the patient bursts into tears upon being asked, "So, how's it going?"
Primary care physicians are also the stewards of preventive healthcare, which is a wonderful opportunity and distinct challenge. We need to get screening tests ordered on time for the right patients, and practice shared decision-making each step of the way as we do so.
At first glance, the new screening recommendations from the USPSTF may seem superfluous. However, after reviewing the epidemiology, treatment outcomes, and even cost-effectiveness data, this screening certainly appears to be prudent and beneficial. It should be embraced by primary care physicians. It should also evolve. As the demographics of HCV infection shift, the age-based screening approach will almost certainly need to change as well. An eventual move away from HCV screening will indicate a great victory for the public's health.
Clinical Pearls
• Persons born between 1945 and 1965 bear a disproportionate share of the disease burden of chronic HCV infection, both in terms of higher prevalence and increased rates of complications.
• Treatment that results in SVR among patients with chronic HCV infection substantially reduces the risks for cirrhosis, hepatocellular carcinoma, and mortality.
• The new recommendations from the USPSTF support traditional screening for HCV among high-risk groups but also call for 1-time screening using anti-HCV antibody testing among adults born between 1945 and 1965. If used widely, this screening program should have a positive effect on morbidity and mortality among older adults.
NIH observes 20th anniversary of Women’s Interagency HIV Study
NIH observes 20th anniversary of Women’s Interagency HIV Study
The largest and longest-running study to investigate the impact of HIV on women in the United States marks its 20th anniversary this month. Findings from the Women’s Interagency HIV Study (WIHS) have helped define how best to treat HIV-infected women in the United States and globally.
The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, established the WIHS in 1993 in response to a dramatic increase in AIDS cases among women in the United States. Since then, the WIHS has enrolled a total of 4,137 women who were HIV-infected or at risk for acquiring HIV, and has published more than 550 scientific papers
. In so doing, the study has charted the course of HIV disease in treated and untreated women across the United States through detailed clinical, biological, neurocognitive, and behavioral assessments; comparisons of HIV-infected and uninfected women; and studies of HIV-infected women receiving treatment.The scientific accomplishments of the WIHS include assessing how genetic, metabolic, behavioral and other factors influence HIV disease progression. The study also has generated information on the health effects of other viruses in HIV-infected women, including herpes, hepatitis C and human papilloma viruses. These data have helped clarify how such co-infections impact the course not only of HIV disease, but also of cardiovascular, liver, and kidney disease; cervical cancer; diabetes; lipodystrophy (the redistribution of fat) and neurocognitive disorders. And the study has demonstrated that economically and socially disadvantaged women will volunteer to participate in intensive, long-term clinical studies and make important contributions to medical research.
Today, nearly 2,120 women participate in the WIHS. More than 1,100 volunteers died from AIDS or other causes and 917 dropped out of the study. About 70 percent of the current participants are infected with HIV, and nearly 90 percent of those infected have taken antiretroviral therapy. The women are largely from minority groups, with 58 percent black, 28 percent Hispanic and 14 percent white. Roughly half of the participants live in poverty. These demographics of the WIHS volunteers reflect those of the HIV epidemic among women in the United States.
Every six months since 1993, WIHS volunteers have made study visits to sites in Chicago, Los Angeles, New York City, San Francisco and Washington, D.C. New study sites were established this year in Atlanta; Birmingham, Ala.; Jackson, Miss.; Chapel Hill, N.C.; and Miami, while the Los Angeles site was closed. WIHS staff interview women about their health and behavior and conduct clinical and laboratory tests, and the data and specimens gathered during these visits are confidentially stored and managed in a central database in Baltimore and a repository in Frederick, Md.
Since 1993 NIAID has continuously funded the WIHS in partnership with the National Cancer Institute, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute on Drug Abuse, all part of NIH. The National Institute of Mental Health recently became a funding partner.
NIH thanks the WIHS staff, scientists, and most importantly the volunteers, whose commitment and dedication over the past two decades have made the accomplishments of the WIHS possible.
NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
NIH...Turning Discovery Into Health®
Hepatitis C: Gilead's experimental drug could flip current treatment paradigm on its head
Gilead's sofosbuvir clears another HCV hurdle
Full Text Available at NATAP
Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients With Unfavorable Treatment Characteristics: A Randomized Clinical Trial
Or Download the PDF here
Related: Gilead's Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 shows promise in NIH trial
Evidence continues to mount suggesting Gilead's experimental drug for hepatitis C virus could flip the current HCV treatment paradigm on its head.
Results of the Phase II trial, sponsored and led by the National Institutes of Health, suggest that a regimen of sofosbuvir and ribavirin was highly effective in clearing the virus and well tolerated in two difficult-to-treat groups—patients with severe liver damage and African Americans. Both groups were comprised of those with genotype-1 HCV, which accounts for 70% of all HCV infections.
The findings among patients with genotype 1, which appear in the current issue of JAMA, come on top of data showing strong efficacy for sofosbuvir in cohorts with genotypes 2 and 3. As such, analysts say the drug is poised to take the lion's share of the HCV market. A recent forecast from FactSet Research Systems put annual sales of sofosbuvir at $6.4 billion by 2017.
In the current study, of the 60 enrolled volunteers, 50 were African American (88% of whom suffer from genotype 1 and are known to be harder to treat with interferon-based therapies).
The bifurcated study broke out one group of 10 people with liver fibrosis. Fibrosis is part of the scarring process and represents the liver's response to injury.They received sofosbuvir and ribavirin. After 12 weeks of therapy, HCV was no longer present in all volunteers who completed therapy (nine out of 10).
The other group consisted of 50 volunteers, including 13 with serious liver damage. They received sofousbuvir and either a dose of ribavirin based on weight or a low-dose ribavirin. From that group, 17 patients had no detectable levels of the virus 24 weeks after treatment stopped. Of the 22 volunteers who received the low-dose ribavirin, 12 were considered cured after the end of treatment.
In an NIH press release, researcher Dr. Shyam Kottilil summed up the findings, saying, “We saw an overall cure rate of about 70% using regimens that did not include interferon. This is an encouraging result, especially considering the proportion of volunteers who had characteristics…that are recognized as predictors of poor response to treatment.”
The findings could make it harder for other prospective all-oral treatment regimens. Boehringer Ingelheim unveiled Phase II data earlier this month of its HCV combo of faldaprevir and deleobuvir, reporting high efficacy rates—85% in genotype 1b—but the sample did not include African Americans.
Gilead's new drug application for sofosbuvir was filed in April. This initial application, under priority review, is for use in genotypes 2 and 3, and in the treatment-naïve for types 1, 4, 5 and 6.
FDA expects to review the application by December 8, the agency said. The European Medicines Association, too, has given sofosbuvir an “accelerated assessment,” and if approved the drug could become available by the first half of next year.
ISI Group analyst Mark Schoenebaum, in an investor note issued around the time of the FDA filing, wrote that “Gilead should be ready to launch an oral genotype 1 regime around the end of 2014.”
http://www.mmm-online.com/gileads-sofosbuvir-clears-another-hcv-hurdle/article/309268/?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+MMMHome+%28MMM+Home%29
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Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients With Unfavorable Treatment Characteristics: A Randomized Clinical Trial
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Related: Gilead's Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 shows promise in NIH trial
Evidence continues to mount suggesting Gilead's experimental drug for hepatitis C virus could flip the current HCV treatment paradigm on its head.
Results of the Phase II trial, sponsored and led by the National Institutes of Health, suggest that a regimen of sofosbuvir and ribavirin was highly effective in clearing the virus and well tolerated in two difficult-to-treat groups—patients with severe liver damage and African Americans. Both groups were comprised of those with genotype-1 HCV, which accounts for 70% of all HCV infections.
The findings among patients with genotype 1, which appear in the current issue of JAMA, come on top of data showing strong efficacy for sofosbuvir in cohorts with genotypes 2 and 3. As such, analysts say the drug is poised to take the lion's share of the HCV market. A recent forecast from FactSet Research Systems put annual sales of sofosbuvir at $6.4 billion by 2017.
In the current study, of the 60 enrolled volunteers, 50 were African American (88% of whom suffer from genotype 1 and are known to be harder to treat with interferon-based therapies).
The bifurcated study broke out one group of 10 people with liver fibrosis. Fibrosis is part of the scarring process and represents the liver's response to injury.They received sofosbuvir and ribavirin. After 12 weeks of therapy, HCV was no longer present in all volunteers who completed therapy (nine out of 10).
The other group consisted of 50 volunteers, including 13 with serious liver damage. They received sofousbuvir and either a dose of ribavirin based on weight or a low-dose ribavirin. From that group, 17 patients had no detectable levels of the virus 24 weeks after treatment stopped. Of the 22 volunteers who received the low-dose ribavirin, 12 were considered cured after the end of treatment.
In an NIH press release, researcher Dr. Shyam Kottilil summed up the findings, saying, “We saw an overall cure rate of about 70% using regimens that did not include interferon. This is an encouraging result, especially considering the proportion of volunteers who had characteristics…that are recognized as predictors of poor response to treatment.”
The findings could make it harder for other prospective all-oral treatment regimens. Boehringer Ingelheim unveiled Phase II data earlier this month of its HCV combo of faldaprevir and deleobuvir, reporting high efficacy rates—85% in genotype 1b—but the sample did not include African Americans.
Gilead's new drug application for sofosbuvir was filed in April. This initial application, under priority review, is for use in genotypes 2 and 3, and in the treatment-naïve for types 1, 4, 5 and 6.
FDA expects to review the application by December 8, the agency said. The European Medicines Association, too, has given sofosbuvir an “accelerated assessment,” and if approved the drug could become available by the first half of next year.
ISI Group analyst Mark Schoenebaum, in an investor note issued around the time of the FDA filing, wrote that “Gilead should be ready to launch an oral genotype 1 regime around the end of 2014.”
http://www.mmm-online.com/gileads-sofosbuvir-clears-another-hcv-hurdle/article/309268/?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+MMMHome+%28MMM+Home%29
Thursday, August 29, 2013
Strong association of type 2 diabetes mellitus with HCV infection
Journal of Diabetes Research
Volume 2013 (2013), Article ID 539361, 7 pages
http://dx.doi.org/10.1155/2013/539361
Research Article
Prevalence of Type 2 Diabetes Mellitus in Hepatitis C Virus Infected Population: A Southeast Asian Study
Muhammad Sadik Memon, Zain Islam Arain, Farukh Naz, Madiha Zaki, Suresh Kumar, and Asif Ali Burney
Isra University Hospital, Hala Naka Road, Hyderabad, Pakistan
Received 16 April 2013; Revised 9 July 2013; Accepted 15 July 2013
Academic Editor: Åke Lernmark
Copyright © 2013 Muhammad Sadik Memon et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Advancing age, increased weight, and HCV genotype 3 are independent predictors of type 2 diabetes in HCV seropositive patients, and there is a statistically significant association of cirrhosis observed with type 2 diabetes mellitus.
Abstract
Purpose
The study was aimed to investigate the frequency of diabetes mellitus type 2 in patients infected with chronic hepatitis C virus and its association with cirrhosis.
Patients and Methods
This prospective case series was conducted at Section of Gastroenterology and Hepatology, Isra University Hospital, Hyderabad, over a period of 4 months from June 2009 to October 2009. Hepatitis C virus seropositive patients who were older than 18 years, diabetic or nondiabetic, were included. Basic demographic data collected by questionnaire and laboratory investigations including fasting blood glucose levels, serum cholesterol, and liver function tests were done. A logistic regression model was used to explore the association between diabetic and nondiabetic HCV seropositives and type 2 diabetes mellitus with cirrhosis.
Results
A total of 361 patients with hepatitis C were analyzed; the prevalence of type 2 diabetes mellitus in HCV patients was 31.5%. Out of the total number of the participants, 58.4% (n = 211) were cirrhotics, while 41.6% (n = 150) were noncirrhotic HCV seropositives. In multivariate analysis, cirrhotic patients appeared significantly more likely (P = 0.01) to be diabetic as compared with noncirrhotic patients (OR = 2.005, 95% CI: 1.15, 3.43).
Conclusion
Advancing age, increased weight, and HCV genotype 3 are independent predictors of type 2 diabetes in HCV seropositive patients, and there is a statistically significant association of cirrhosis observed with type 2 diabetes mellitus.
1. Introduction
Hepatitis C virus (HCV) has been identified as one of the leading causes of chronic liver disease with serious sequel as the end stage of cirrhosis and liver cancer [1]. According to recent statistics, the worldwide prevalence of HCV infection is ~3% and affects around more than 170 million people globally [2]. Chronic hepatitis C infection mainly affects liver but can be associated with various extrahepatic manifestations including cryoglobulinemia, sialadenitis, glomerulonephritis, and porphyria cutanea tarda [3, 4].
Diabetes mellitus is a chronic disease of metabolism causing abnormal glucose homeostasis [5]. More than 171 million people globally are affected by diabetes mellitus, and the figure is expected to rise up to 366 million by 2030 [6]. A systemic review and meta-analysis from South Asia by Jayawardena et al. (2012) showed burden of diabetes in Pakistan ranging from 3% to 7.2% in a general population [7]. Type 2 diabetes mellitus in South Asian, when comparing with European individuals, is 4- to 6-fold more prevalent [8].
Several studies reported that HCV infection may also contribute to the development of diabetes, and higher prevalence of type 2 diabetes mellitus has been observed in the developed world (2% to 9.4%) in patients with HCV infection than in those with other forms of chronic hepatitis [9–12]. This association between HCV infection and diabetes was for the first time made by Allison et al. in 1994 [13]. Since then, a number of observational studies have been published.
There are several organized factors which influence the development of diabetes among HCV-infected patients like age, sex, family history of diabetes, African-American race, and HIV coinfection [14, 15].
Insulin resistance (IR) and diabetes can develop at any stage of HCV infection. Multiple mechanisms have been accounted for insulin resistance and development of diabetes in patients with chronic hepatitis C. It promotes IR mainly through interfering with insulin signaling pathway in hepatocytes, increasing inflammatory response with production of cytokines such as TNF alpha and IL-6 and increasing oxidative stress [16, 17].
There are many studies in the past done on frequency of diabetes in HCV infection. One such study was conducted by Elhawary et al. (2011) [15] that shows 13.84% prevalence of type 2 diabetes mellitus in HCV seropositive patients and also linked association of cirrhosis with diabetes mellitus.
HCV infection and type 2 diabetes mellitus are two chronic conditions which contribute to a significant morbidity and mortality. The rationale behind this study is to find out the maximum number of type 2 diabetes in those patients who are infected with hepatitis C virus and also the relation between cirrhosis and type 2 diabetes mellitus seropositive patients; so in this way, we will establish a valid association between type 2 diabetes in HCV seropositive population.
2. Patients and Methods
This prospective study was conducted at Isra University Hospital (IUH), Section of Gastroenterology and Hepatology, Hyderabad. IUH is a 300-bedded private, tertiary care academic teaching hospital that largely serves the residents of Hyderabad (population 2 million) and the surrounding 6–8 districts of Sindh province. The study protocol was evaluated and approved by the hospital authorities, from where all the study participants were recruited, and the study was conducted in accordance with the Declaration of Helsinki Guidelines. All the individuals provided informed consent before their participation.
3. Inclusion Criteria
HCV seropositive patients, with or without presence of liver cirrhosis and/or diabetes mellitus type 2, between the age of 18 and 75 years, both males and females visiting the outpatient department or admitted in Gastroenterology and Hepatology Ward, were recruited consecutively during a period of 4 months from June 2009 to October 2009. Demographic information and all relevant data, such as area of residence and past medical history, were collected by trained nurses in a predesigned structured questionnaire.
4. Exclusion Criteria
Patients with liver cancer, on interferon therapy, having end stage renal disease or coexisting viral infection like hepatitis B surface antigen positive patients, and pregnant females were excluded from the research.
5. Sample Collection
Senior laboratory technologist drew 5 mL venous blood sample using a sterilized disposable syringe, and then the sample was used for the detection of hepatitis C virus by enzyme-linked immunosorbent assay (ELISA) and HCV genotyping determined by using polymerase chain reaction (PCR). Diagnosis of type 2 diabetes mellitus was done according to the American Diabetes Association guidelines (2013) [18]. Other laboratory investigations include complete blood picture, serum cholesterol, serum albumin, total bilirubin, prothrombin time, and serum creatinine levels. Liver cirrhosis was confirmed if the patient had previous recent reliable reports available or by using radiological investigations and liver biopsy where needed.
6. Statistical Analysis
For the comparison of participants of those with and without type 2 diabetes, Student’s -test was used for normality distributed continuous variables. Categorical variables were presented as frequency and percentage, and chi-square test was used for nominal categorical variables comparison. The prevalence of type 2 diabetes mellitus among seropositive patients was calculated and presented as percentage. Age was categorized in two groups (<40 years and ≥40 years); body mass index (BMI) was calculated by weight in kg/height meter squared and then categorized in two groups (<27 and ≥27). Multiple logistic regression model was introduced with the dependent variables such as age, gender, weight, BMI, family history of diabetes, and HCV genotype. Initially, in order to include important variables, factors having significance in univariate analysis were included in the multivariate analysis. The final model was selected using a forward method and . Data entry and analysis were done with Statistical Package for Social Sciences, version 16 (SPSS Inc, Chicago, IL, USA).
7. Results
The mean age of the study population (± standard deviation) was with a range of 18–75 years of age. Male and female proportions were almost equal in our study sample, 52.6% and 47.6%, respectively. The majority of the study populations were married (94.4%) as compared to the single ones (5.54%). Overall prevalence of type 2 diabetes mellitus among HCV seropositive patients was 31.5% (Table 1).
Statistically significant proportion of HCV seropositive patients with cirrhosis was ≥40 years old ( ). Other significant factors in HCV seropositive cirrhotics were male proportion, area of residence, marital status, and type 2 diabetes mellitus ( ) (Table 1).
Table 2 shows comparison of means between type 2 diabetics and nondiabetic seropositive patients. In univariate analysis, mean age difference (4.71 years), fasting blood sugar (71.2 mg/dL), albumin (0.22 mg/dL), serum cholesterol (70.4 mg/dL), and serum creatinine (0.24 mg/dL) were statistically significant ( ) as compared with nondiabetic HCV seropositive patients (Table 2).
On multivariate binominal analysis, age ≥40 years, weight ≥70 kg, family history of diabetes, and HCV genotype 3 were significantly more likely to be diabetic ( ). Likelihood of being type 2 diabetic in HCV seropositive cirrhotic patients was significant in univariate analysis ( ), and in multivariate analysis, this association was observed two times higher as compared with noncirrhotic patients (OR = 2.005, 95% CI: 1.15, 3.43) (Table 3).
We observed the prevalence of type 2 diabetes as 31.5% (114 cases) out of 361 hepatitis C seropositive patients. When we compared the prevalence of type 2 diabetes in HCV-infected population and noninfected population, a twice higher rate of type 2 diabetes was observed in our study as compared to noninfected population [19]. White et al. (2008) [20] analyzed 34 eligible retrospective and prospective studies, showing a significant risk of type 2 diabetes in HCV-infected group as compared to non-HCV-infected control group. On the other hand, recent data also suggest three times higher prevalence of type 2 diabetes in HCV seropositive patients [21]. In this way, data from the previous literature and from our study show a strong association between HCV and type 2 diabetes. Several reasons can explain the association of type 2 diabetes with HCV. One of the explanations is that the pathophysiology of HCV-associated type 2 diabetes mellitus consists of a defect in insulin secretion, increased hepatic tumor necrosis factor alpha, excessive hepatic glucose production, and insulin resistance, because the core-encoding region of HCV is sufficient to induce insulin resistance by the previously defined mechanism via either direct or indirect way [22]. Secondly, a major contribution of already present risk factors of diabetes such as positive family history and advancing age also plays an important role among HCV infected persons [23, 24].
Advancing age (≥40 years) in HCV seropositive patients was significantly associated with type 2 diabetes mellitus as compared to younger age group (≥18 to 40 years) on both univariate and multivariate analyses. The finding also agrees with another study conducted earlier on Mexican population [25].
It was observed in our study that positive cases of type 2 diabetes with respect to gender, education level, and marital status had insignificant relation. A study conducted by Elhawary et al., 2011, also revealed the same findings as in our study [15]; this could be because of the same number of patients attending the hospital, but this insignificant association between seropositive patients cannot be neglected, as in the general population, type 2 diabetes was more prevalent in males than in females [26, 27]; this relationship should be evaluated further on larger scale studies.
Fasting blood glucose levels and total serum cholesterol levels were significantly observed when diabetic compared with nondiabetic HCV seropositive patients. Substantial evidence from the previous literature shows significant association between these laboratory findings [15, 21]. Additionally, patients with HCV and type 2 diabetes may involve kidneys and patients may present with acute renal failure during its later stages [4] which can be observed through significant association of raised serum creatinine in diabetic HCV positive patients [28]. In our study, an increase in mean serum creatinine was significantly observed in HCV patients with type 2 diabetes as compared to HCV patients who were not diabetic.
The most common genotype in our study was genotype 3 which constituted >85% of the whole sample. Previous literatures from Pakistan favor our findings [29–32]; as HCV genotype 3 is more common in Pakistan [33]. Controversies regarding the presence of a specific genotype in HCV seropositive diabetic patient are still a part of scientific debate, and larger scale studies are required to find a conclusion regarding which genotype is more specifically affecting diabetic HCV seropositive patients [34–36]. However, our study observed that the HCV seropositive population with genotype 3 was significantly associated with type 2 diabetes mellitus. This significant association could be due to genotype 3 in our study comprises of more than third portion of whole HCV diabetic population.
Our study also observed that odds of being type 2 diabetics among HCV-infected patients with cirrhosis was doubled ( ) as compared to noncirrhotic HCV seropositive patients. Importantly, studies published in other areas also describe similar trends, in which type 2 diabetes mellitus is more frequently observed in patients with cirrhosis as compared to noncirrhotics, and it ranges from 19.5% to 50% [37–40]. This relationship proves that with advancing liver disease there will be increased susceptibility of HCV seropositive patients to develop type 2 diabetes mellitus.
9. Study Limitations
There are certain limitations of this study. The most important limitations in this study are small sample size, single-centered-hospital-based study, and only included HCV seropositives which may be unable to reflect the actual incidence of type 2 diabetes in HCV seropositives.
10. Conclusion and Recommendation
This study concludes that there is a strong association of type 2 diabetes mellitus with HCV infection. Odds of development of type 2 diabetes increases by twofolds if an HCV patient has cirrhosis. Advancing age, increased weight, and HCV genotype 3 are independent predictors of type 2 diabetes in HCV seropositive patients. It is necessary to screen and control earlier for the presence of type 2 diabetes mellitus and also rule out HCV infection among diabetic populations which is rarely done on population-based studies.
Authors’ Contribution
Muhammad Sadik Memon and Zain Islam Arain conceived the idea and the design of this study. Farukh Naz and Madiha Zaki were involved in the drafting of questionnaire and the collection of data. Muhammad Sadik Memon and Zain Islam Arain analyzed the data and wrote the initial draft of this paper. Asif Ali Burney, and Suresh Kumar were the principal supervisors during the data collection. All authors approved the final draft for publication.
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Volume 2013 (2013), Article ID 539361, 7 pages
http://dx.doi.org/10.1155/2013/539361
Research Article
Prevalence of Type 2 Diabetes Mellitus in Hepatitis C Virus Infected Population: A Southeast Asian Study
Muhammad Sadik Memon, Zain Islam Arain, Farukh Naz, Madiha Zaki, Suresh Kumar, and Asif Ali Burney
Isra University Hospital, Hala Naka Road, Hyderabad, Pakistan
Received 16 April 2013; Revised 9 July 2013; Accepted 15 July 2013
Academic Editor: Åke Lernmark
Copyright © 2013 Muhammad Sadik Memon et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Advancing age, increased weight, and HCV genotype 3 are independent predictors of type 2 diabetes in HCV seropositive patients, and there is a statistically significant association of cirrhosis observed with type 2 diabetes mellitus.
Abstract
Purpose
The study was aimed to investigate the frequency of diabetes mellitus type 2 in patients infected with chronic hepatitis C virus and its association with cirrhosis.
Patients and Methods
This prospective case series was conducted at Section of Gastroenterology and Hepatology, Isra University Hospital, Hyderabad, over a period of 4 months from June 2009 to October 2009. Hepatitis C virus seropositive patients who were older than 18 years, diabetic or nondiabetic, were included. Basic demographic data collected by questionnaire and laboratory investigations including fasting blood glucose levels, serum cholesterol, and liver function tests were done. A logistic regression model was used to explore the association between diabetic and nondiabetic HCV seropositives and type 2 diabetes mellitus with cirrhosis.
Results
A total of 361 patients with hepatitis C were analyzed; the prevalence of type 2 diabetes mellitus in HCV patients was 31.5%. Out of the total number of the participants, 58.4% (n = 211) were cirrhotics, while 41.6% (n = 150) were noncirrhotic HCV seropositives. In multivariate analysis, cirrhotic patients appeared significantly more likely (P = 0.01) to be diabetic as compared with noncirrhotic patients (OR = 2.005, 95% CI: 1.15, 3.43).
Conclusion
Advancing age, increased weight, and HCV genotype 3 are independent predictors of type 2 diabetes in HCV seropositive patients, and there is a statistically significant association of cirrhosis observed with type 2 diabetes mellitus.
1. Introduction
Hepatitis C virus (HCV) has been identified as one of the leading causes of chronic liver disease with serious sequel as the end stage of cirrhosis and liver cancer [1]. According to recent statistics, the worldwide prevalence of HCV infection is ~3% and affects around more than 170 million people globally [2]. Chronic hepatitis C infection mainly affects liver but can be associated with various extrahepatic manifestations including cryoglobulinemia, sialadenitis, glomerulonephritis, and porphyria cutanea tarda [3, 4].
Diabetes mellitus is a chronic disease of metabolism causing abnormal glucose homeostasis [5]. More than 171 million people globally are affected by diabetes mellitus, and the figure is expected to rise up to 366 million by 2030 [6]. A systemic review and meta-analysis from South Asia by Jayawardena et al. (2012) showed burden of diabetes in Pakistan ranging from 3% to 7.2% in a general population [7]. Type 2 diabetes mellitus in South Asian, when comparing with European individuals, is 4- to 6-fold more prevalent [8].
Several studies reported that HCV infection may also contribute to the development of diabetes, and higher prevalence of type 2 diabetes mellitus has been observed in the developed world (2% to 9.4%) in patients with HCV infection than in those with other forms of chronic hepatitis [9–12]. This association between HCV infection and diabetes was for the first time made by Allison et al. in 1994 [13]. Since then, a number of observational studies have been published.
There are several organized factors which influence the development of diabetes among HCV-infected patients like age, sex, family history of diabetes, African-American race, and HIV coinfection [14, 15].
Insulin resistance (IR) and diabetes can develop at any stage of HCV infection. Multiple mechanisms have been accounted for insulin resistance and development of diabetes in patients with chronic hepatitis C. It promotes IR mainly through interfering with insulin signaling pathway in hepatocytes, increasing inflammatory response with production of cytokines such as TNF alpha and IL-6 and increasing oxidative stress [16, 17].
There are many studies in the past done on frequency of diabetes in HCV infection. One such study was conducted by Elhawary et al. (2011) [15] that shows 13.84% prevalence of type 2 diabetes mellitus in HCV seropositive patients and also linked association of cirrhosis with diabetes mellitus.
HCV infection and type 2 diabetes mellitus are two chronic conditions which contribute to a significant morbidity and mortality. The rationale behind this study is to find out the maximum number of type 2 diabetes in those patients who are infected with hepatitis C virus and also the relation between cirrhosis and type 2 diabetes mellitus seropositive patients; so in this way, we will establish a valid association between type 2 diabetes in HCV seropositive population.
2. Patients and Methods
This prospective study was conducted at Isra University Hospital (IUH), Section of Gastroenterology and Hepatology, Hyderabad. IUH is a 300-bedded private, tertiary care academic teaching hospital that largely serves the residents of Hyderabad (population 2 million) and the surrounding 6–8 districts of Sindh province. The study protocol was evaluated and approved by the hospital authorities, from where all the study participants were recruited, and the study was conducted in accordance with the Declaration of Helsinki Guidelines. All the individuals provided informed consent before their participation.
3. Inclusion Criteria
HCV seropositive patients, with or without presence of liver cirrhosis and/or diabetes mellitus type 2, between the age of 18 and 75 years, both males and females visiting the outpatient department or admitted in Gastroenterology and Hepatology Ward, were recruited consecutively during a period of 4 months from June 2009 to October 2009. Demographic information and all relevant data, such as area of residence and past medical history, were collected by trained nurses in a predesigned structured questionnaire.
4. Exclusion Criteria
Patients with liver cancer, on interferon therapy, having end stage renal disease or coexisting viral infection like hepatitis B surface antigen positive patients, and pregnant females were excluded from the research.
5. Sample Collection
Senior laboratory technologist drew 5 mL venous blood sample using a sterilized disposable syringe, and then the sample was used for the detection of hepatitis C virus by enzyme-linked immunosorbent assay (ELISA) and HCV genotyping determined by using polymerase chain reaction (PCR). Diagnosis of type 2 diabetes mellitus was done according to the American Diabetes Association guidelines (2013) [18]. Other laboratory investigations include complete blood picture, serum cholesterol, serum albumin, total bilirubin, prothrombin time, and serum creatinine levels. Liver cirrhosis was confirmed if the patient had previous recent reliable reports available or by using radiological investigations and liver biopsy where needed.
6. Statistical Analysis
For the comparison of participants of those with and without type 2 diabetes, Student’s -test was used for normality distributed continuous variables. Categorical variables were presented as frequency and percentage, and chi-square test was used for nominal categorical variables comparison. The prevalence of type 2 diabetes mellitus among seropositive patients was calculated and presented as percentage. Age was categorized in two groups (<40 years and ≥40 years); body mass index (BMI) was calculated by weight in kg/height meter squared and then categorized in two groups (<27 and ≥27). Multiple logistic regression model was introduced with the dependent variables such as age, gender, weight, BMI, family history of diabetes, and HCV genotype. Initially, in order to include important variables, factors having significance in univariate analysis were included in the multivariate analysis. The final model was selected using a forward method and . Data entry and analysis were done with Statistical Package for Social Sciences, version 16 (SPSS Inc, Chicago, IL, USA).
7. Results
The mean age of the study population (± standard deviation) was with a range of 18–75 years of age. Male and female proportions were almost equal in our study sample, 52.6% and 47.6%, respectively. The majority of the study populations were married (94.4%) as compared to the single ones (5.54%). Overall prevalence of type 2 diabetes mellitus among HCV seropositive patients was 31.5% (Table 1).
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| Statistically significant value 0.05.DM: diabetes mellitus, BMI: body mass index. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Statistically significant proportion of HCV seropositive patients with cirrhosis was ≥40 years old ( ). Other significant factors in HCV seropositive cirrhotics were male proportion, area of residence, marital status, and type 2 diabetes mellitus ( ) (Table 1).
Table 2 shows comparison of means between type 2 diabetics and nondiabetic seropositive patients. In univariate analysis, mean age difference (4.71 years), fasting blood sugar (71.2 mg/dL), albumin (0.22 mg/dL), serum cholesterol (70.4 mg/dL), and serum creatinine (0.24 mg/dL) were statistically significant ( ) as compared with nondiabetic HCV seropositive patients (Table 2).
Click On Table 2 To Enlarge
On multivariate binominal analysis, age ≥40 years, weight ≥70 kg, family history of diabetes, and HCV genotype 3 were significantly more likely to be diabetic ( ). Likelihood of being type 2 diabetic in HCV seropositive cirrhotic patients was significant in univariate analysis ( ), and in multivariate analysis, this association was observed two times higher as compared with noncirrhotic patients (OR = 2.005, 95% CI: 1.15, 3.43) (Table 3).
Click On Table 3 To Enlarge
We observed the prevalence of type 2 diabetes as 31.5% (114 cases) out of 361 hepatitis C seropositive patients. When we compared the prevalence of type 2 diabetes in HCV-infected population and noninfected population, a twice higher rate of type 2 diabetes was observed in our study as compared to noninfected population [19]. White et al. (2008) [20] analyzed 34 eligible retrospective and prospective studies, showing a significant risk of type 2 diabetes in HCV-infected group as compared to non-HCV-infected control group. On the other hand, recent data also suggest three times higher prevalence of type 2 diabetes in HCV seropositive patients [21]. In this way, data from the previous literature and from our study show a strong association between HCV and type 2 diabetes. Several reasons can explain the association of type 2 diabetes with HCV. One of the explanations is that the pathophysiology of HCV-associated type 2 diabetes mellitus consists of a defect in insulin secretion, increased hepatic tumor necrosis factor alpha, excessive hepatic glucose production, and insulin resistance, because the core-encoding region of HCV is sufficient to induce insulin resistance by the previously defined mechanism via either direct or indirect way [22]. Secondly, a major contribution of already present risk factors of diabetes such as positive family history and advancing age also plays an important role among HCV infected persons [23, 24].
Advancing age (≥40 years) in HCV seropositive patients was significantly associated with type 2 diabetes mellitus as compared to younger age group (≥18 to 40 years) on both univariate and multivariate analyses. The finding also agrees with another study conducted earlier on Mexican population [25].
It was observed in our study that positive cases of type 2 diabetes with respect to gender, education level, and marital status had insignificant relation. A study conducted by Elhawary et al., 2011, also revealed the same findings as in our study [15]; this could be because of the same number of patients attending the hospital, but this insignificant association between seropositive patients cannot be neglected, as in the general population, type 2 diabetes was more prevalent in males than in females [26, 27]; this relationship should be evaluated further on larger scale studies.
Fasting blood glucose levels and total serum cholesterol levels were significantly observed when diabetic compared with nondiabetic HCV seropositive patients. Substantial evidence from the previous literature shows significant association between these laboratory findings [15, 21]. Additionally, patients with HCV and type 2 diabetes may involve kidneys and patients may present with acute renal failure during its later stages [4] which can be observed through significant association of raised serum creatinine in diabetic HCV positive patients [28]. In our study, an increase in mean serum creatinine was significantly observed in HCV patients with type 2 diabetes as compared to HCV patients who were not diabetic.
The most common genotype in our study was genotype 3 which constituted >85% of the whole sample. Previous literatures from Pakistan favor our findings [29–32]; as HCV genotype 3 is more common in Pakistan [33]. Controversies regarding the presence of a specific genotype in HCV seropositive diabetic patient are still a part of scientific debate, and larger scale studies are required to find a conclusion regarding which genotype is more specifically affecting diabetic HCV seropositive patients [34–36]. However, our study observed that the HCV seropositive population with genotype 3 was significantly associated with type 2 diabetes mellitus. This significant association could be due to genotype 3 in our study comprises of more than third portion of whole HCV diabetic population.
Our study also observed that odds of being type 2 diabetics among HCV-infected patients with cirrhosis was doubled ( ) as compared to noncirrhotic HCV seropositive patients. Importantly, studies published in other areas also describe similar trends, in which type 2 diabetes mellitus is more frequently observed in patients with cirrhosis as compared to noncirrhotics, and it ranges from 19.5% to 50% [37–40]. This relationship proves that with advancing liver disease there will be increased susceptibility of HCV seropositive patients to develop type 2 diabetes mellitus.
9. Study Limitations
There are certain limitations of this study. The most important limitations in this study are small sample size, single-centered-hospital-based study, and only included HCV seropositives which may be unable to reflect the actual incidence of type 2 diabetes in HCV seropositives.
10. Conclusion and Recommendation
This study concludes that there is a strong association of type 2 diabetes mellitus with HCV infection. Odds of development of type 2 diabetes increases by twofolds if an HCV patient has cirrhosis. Advancing age, increased weight, and HCV genotype 3 are independent predictors of type 2 diabetes in HCV seropositive patients. It is necessary to screen and control earlier for the presence of type 2 diabetes mellitus and also rule out HCV infection among diabetic populations which is rarely done on population-based studies.
Authors’ Contribution
Muhammad Sadik Memon and Zain Islam Arain conceived the idea and the design of this study. Farukh Naz and Madiha Zaki were involved in the drafting of questionnaire and the collection of data. Muhammad Sadik Memon and Zain Islam Arain analyzed the data and wrote the initial draft of this paper. Asif Ali Burney, and Suresh Kumar were the principal supervisors during the data collection. All authors approved the final draft for publication.
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