Treating Hepatitis C
Chicago Tonight
April 28, 2014 10:30 am
An estimated 3.2 million Americans live with hepatitis C. Traditional
treatments didn’t always cure the viral infection and often came with
severe side effects. Late last year, the Food and Drug Administration approved two new drugs, Sovaldi and Olysio,
for the treatment of hepatitis C. But the drugs come with a hefty price
tag, starting at $66,000 for Olysio and $84,000 for Sovaldi. Brandis
Friedman has more on the treatments and their costs.
Continue to article....
Wednesday, April 30, 2014
Gilead says its drug gives hepatitis C patients more cost-effective cure
Gilead says its drug gives hepatitis C patients more cost-effective cure
By Russ Britt
Patients who weren’t getting proper treatment for hepatitis C now are getting it thanks to Sovaldi, the controversial new hit drug from Gilead Sciences Inc., an official from the company said Wednesday.
Gregg Alton, executive vice president for Gilead’s /quotes/zigman/72849/delayed /quotes/nls/gild GILD +0.24% corporate and medical affairs, told an audience at the Milken Institute’s Global Conference in Beverly Hills, Calif., that the $84,000 price tag for Sovaldi is proving to be cheaper and more effective than past treatments for hepatitis C.
“We’re actually reducing the cost of therapy,” Alton said. He says that patients using older therapies would end up spending up to $150,000 or $200,000 for getting treatment over a longer period of time, when costs for drugs to treat the frequent side effects are put into the mix. Sovaldi treatment lasts three months, prompting shock from some in the medical community over its $1,000-a-day price tag.
While many insurers have yet to complain about the price tag, the nation’s biggest carrier UnitedHealth Group Inc. /quotes/zigman/258846/delayed /quotes/nls/unh UNH said the drug cut into its first-quarter earnings. Alton points out that pharmacy benefit manager Express Scripts /quotes/zigman/9438326/delayed /quotes/nls/esrx ESRX -0.02% has voiced concerns about the drug’s cost.
“The payers are saying, ‘I didn’t plan for this,’ ” he said. “The fact is, patients are getting the drug.”
Alton later added the price on the drug was right, considering how much it used to cost to treat the ailment, but acknowledged that at some point rival drugs that are being developed will hit the market, which may affect pricing. As well, the healthy margins for Gilead and other biotechnology companies — 20% to 30% in some cases — will become the subject for debate.
“I’m sure that’s going to be a conversation,” Alton said. “How much is enough?”
Follow Russ Britt @russbrittmktw.
Follow Health Exchange @MWHealthBlog.
http://blogs.marketwatch.com/
By Russ Britt
Patients who weren’t getting proper treatment for hepatitis C now are getting it thanks to Sovaldi, the controversial new hit drug from Gilead Sciences Inc., an official from the company said Wednesday.
Gregg Alton, executive vice president for Gilead’s /quotes/zigman/72849/delayed /quotes/nls/gild GILD +0.24% corporate and medical affairs, told an audience at the Milken Institute’s Global Conference in Beverly Hills, Calif., that the $84,000 price tag for Sovaldi is proving to be cheaper and more effective than past treatments for hepatitis C.
“We’re actually reducing the cost of therapy,” Alton said. He says that patients using older therapies would end up spending up to $150,000 or $200,000 for getting treatment over a longer period of time, when costs for drugs to treat the frequent side effects are put into the mix. Sovaldi treatment lasts three months, prompting shock from some in the medical community over its $1,000-a-day price tag.
While many insurers have yet to complain about the price tag, the nation’s biggest carrier UnitedHealth Group Inc. /quotes/zigman/258846/delayed /quotes/nls/unh UNH said the drug cut into its first-quarter earnings. Alton points out that pharmacy benefit manager Express Scripts /quotes/zigman/9438326/delayed /quotes/nls/esrx ESRX -0.02% has voiced concerns about the drug’s cost.
“The payers are saying, ‘I didn’t plan for this,’ ” he said. “The fact is, patients are getting the drug.”
Alton later added the price on the drug was right, considering how much it used to cost to treat the ailment, but acknowledged that at some point rival drugs that are being developed will hit the market, which may affect pricing. As well, the healthy margins for Gilead and other biotechnology companies — 20% to 30% in some cases — will become the subject for debate.
“I’m sure that’s going to be a conversation,” Alton said. “How much is enough?”
Follow Russ Britt @russbrittmktw.
Follow Health Exchange @MWHealthBlog.
http://blogs.marketwatch.com/
Watch: The discovery of HCV and why drugs like Gilead’s Sovaldi are the center of an economic debate
Profiles in Innovation:
The Discovery of HCV
Topic Description
Thirty years ago patients who received a blood transfusion had a 30% chance of contracting hepatitis infection, in this video Dr. Harvey Alter, whose research led to the discovery of hepatitis C will discuss his work and the history of HCV.
We also examine how Chiron’s secret six-year effort led to the tests that virtually eliminated the virus from the blood supply, why drugs like Gilead’s Sovaldi are the center of an economic debate on the treatment of HCV, and envision a world in which HCV has been eradicated.
And we talk with Dr. Steven Pearson , who led a health technology assessment of Sovaldi.
Click here to view video
Can-Fite Submits Protocol to U.S. FDA for Phase II Liver Cancer Study
Can-Fite Submits Protocol to U.S. FDA for Phase II Liver Cancer Study
Tufts University will be a clinical site for international trial of CF102 with Orphan Drug Designation
PETACH TIKVA, Israel, April 29, 2014 /PRNewswire/ -- Can-Fite BioPharma Ltd. (NYSE MKT:CANF) (TASE:CFBI), a biotechnology company with a pipeline of proprietary small molecule drugs that address inflammatory and cancer diseases, announced today that it has submitted a study protocol to the U.S. Food and Drug Administration for its Phase II clinical trial of CF102 for the treatment of advanced liver cancer. The FDA has granted Orphan Drug designation to CF102 in this indication. The protocol, which has already been approved by the Institutional Review Board (IRB) in Israel, will also be filed in Europe.
The planned Phase II study will be conducted in Israel, Europe and the U.S. with 78 subjects who will be dosed with CF102 as a second-line treatment of advanced hepatocellular carcinoma (HCC) with Child-Pugh Class B cirrhosis. The study will investigate the efficacy and safety of CF102 as compared to placebo.
Dr. Keith Stuart, MD, assisted in developing the study protocol. He is Chairman, Department of Hematology at Lahey Clinic and Oncology Professor of Medicine, Tufts University School of Medicine. Tufts University will participate as the study's U.S. clinical site.
The protocol submission is supported by strong, positive data from Can-Fite's Phase I/II HCC study published in The Oncologist, and presented at the 18th World Congress on Advances in Oncology. The Phase I/II study data demonstrated that the trial objectives were successfully achieved. CF102 had a very favorable safety profile with very encouraging median overall survival and one patient who has been treated for 4 years with CF102. The A3 adenosine receptor (A3AR), which is the target of CF102, was also found to potentially serve as a biomarker to predict patients' reaction to treatment with CF102.
"We are planning to initiate our Phase II trial for advanced liver cancer during the current quarter. Having already received IRB approval in Israel, we look forward to the FDA's response to the protocol. Advanced liver cancer is an indication that is a clear, unmet medical need and we believe the FDA's Orphan Drug Designation for CF102 will support our clinical development path," stated Can-Fite CEO Dr. Pnina Fishman.
According to Global Industry Analysts, the global liver cancer drug market is expected to exceed $2 billion by 2015.
About CF102
CF102 is a small orally bioavailable drug which binds with high affinity and selectivity to the A3 adenosine receptor. The latter is highly expressed in tumor cells whereas low expression is found in normal cells. This differential effect accounts for the excellent safety profile of the drug. In our pre-clinical and clinical studies, CF102 induces a robust anti-tumor effect via de-regulation of the Wnt signaling pathway, resulting in apoptosis of liver cancer cells.
About Can-Fite BioPharma Ltd.
Can-Fite BioPharma Ltd. (NYSE MKT: CANF) (TASE: CFBI) is an advanced clinical stage drug development company with a platform technology that is designed to address multi-billion dollar markets in the treatment of cancer and inflammatory diseases. The Company's CF101 is in Phase II/III trials for the treatment of psoriasis and the Company is preparing for a Phase III CF101 trial for rheumatoid arthritis. Can-Fite's liver cancer drug CF102 is in Phase II trials and has been granted Orphan Drug Designation by the U.S. Food and Drug Administration. CF102 has also shown proof of concept to potentially treat other cancers including colon, prostate, and melanoma. These drugs have an excellent safety profile with experience in over 1,200 patients in clinical studies to date. For more information please visit: www.can-fite.com
Tufts University will be a clinical site for international trial of CF102 with Orphan Drug Designation
PETACH TIKVA, Israel, April 29, 2014 /PRNewswire/ -- Can-Fite BioPharma Ltd. (NYSE MKT:CANF) (TASE:CFBI), a biotechnology company with a pipeline of proprietary small molecule drugs that address inflammatory and cancer diseases, announced today that it has submitted a study protocol to the U.S. Food and Drug Administration for its Phase II clinical trial of CF102 for the treatment of advanced liver cancer. The FDA has granted Orphan Drug designation to CF102 in this indication. The protocol, which has already been approved by the Institutional Review Board (IRB) in Israel, will also be filed in Europe.
The planned Phase II study will be conducted in Israel, Europe and the U.S. with 78 subjects who will be dosed with CF102 as a second-line treatment of advanced hepatocellular carcinoma (HCC) with Child-Pugh Class B cirrhosis. The study will investigate the efficacy and safety of CF102 as compared to placebo.
Dr. Keith Stuart, MD, assisted in developing the study protocol. He is Chairman, Department of Hematology at Lahey Clinic and Oncology Professor of Medicine, Tufts University School of Medicine. Tufts University will participate as the study's U.S. clinical site.
The protocol submission is supported by strong, positive data from Can-Fite's Phase I/II HCC study published in The Oncologist, and presented at the 18th World Congress on Advances in Oncology. The Phase I/II study data demonstrated that the trial objectives were successfully achieved. CF102 had a very favorable safety profile with very encouraging median overall survival and one patient who has been treated for 4 years with CF102. The A3 adenosine receptor (A3AR), which is the target of CF102, was also found to potentially serve as a biomarker to predict patients' reaction to treatment with CF102.
"We are planning to initiate our Phase II trial for advanced liver cancer during the current quarter. Having already received IRB approval in Israel, we look forward to the FDA's response to the protocol. Advanced liver cancer is an indication that is a clear, unmet medical need and we believe the FDA's Orphan Drug Designation for CF102 will support our clinical development path," stated Can-Fite CEO Dr. Pnina Fishman.
According to Global Industry Analysts, the global liver cancer drug market is expected to exceed $2 billion by 2015.
About CF102
CF102 is a small orally bioavailable drug which binds with high affinity and selectivity to the A3 adenosine receptor. The latter is highly expressed in tumor cells whereas low expression is found in normal cells. This differential effect accounts for the excellent safety profile of the drug. In our pre-clinical and clinical studies, CF102 induces a robust anti-tumor effect via de-regulation of the Wnt signaling pathway, resulting in apoptosis of liver cancer cells.
About Can-Fite BioPharma Ltd.
Can-Fite BioPharma Ltd. (NYSE MKT: CANF) (TASE: CFBI) is an advanced clinical stage drug development company with a platform technology that is designed to address multi-billion dollar markets in the treatment of cancer and inflammatory diseases. The Company's CF101 is in Phase II/III trials for the treatment of psoriasis and the Company is preparing for a Phase III CF101 trial for rheumatoid arthritis. Can-Fite's liver cancer drug CF102 is in Phase II trials and has been granted Orphan Drug Designation by the U.S. Food and Drug Administration. CF102 has also shown proof of concept to potentially treat other cancers including colon, prostate, and melanoma. These drugs have an excellent safety profile with experience in over 1,200 patients in clinical studies to date. For more information please visit: www.can-fite.com
Studies Offer Insight on How to Improve Kidney And Liver Transplantation
Studies Offer Insight on How to Improve Kidney And Liver Transplantation Published
April 28, 2014
By Wiley
The quality of kidney and liver donations is fundamentally important for the longevity of transplants and the health of recipients. That's why it's critical to know which organs are suitable for transplantation, as well as to use techniques that preserve an organ's function after donation. Several studies published in the BJS (British Journal of Surgery) address these issues and offer ways to maximize the use of donated organs.
In the first study, Rajeev Desai, MRCP, of NHS Blood and Transplant, in the UK, led a team that assessed transplants from 17,639 donors, including 61 donors with cancer who were considered to have an unacceptable/high risk of transmitting cancer through their donated organs. The researchers found no cancer transmission in 133 recipients of organs from these 61 donors. At 10 years after transplantation, the organs from donors with unacceptable/high risk provided each recipient with more than 7 additional years of survival on average.
"The findings of our research indicate that the perceived risk of certain organ donors to their recipients is likely to have been over-estimated. Organ donors with a history of certain types of cancers who are excluded from transplantation in fact pose very little risk of cancer transmission to their recipients," said Dr. Desai. "These organs can be transplanted with very little risk to their recipients, resulting in significant improvement in the survival and health of the recipients."
In another study, Olivier Detry, MD, PhD, of the University of Liège, in Belgium, and his colleagues revealed excellent results from liver transplants from deceased donors who were older than what is usually recommended. The study looked specifically at donation after circulatory death (DCD), in which circulation, heartbeat, and breathing have stopped (as opposed to brain death, in which all the functions of the brain have stopped). A total of 70 DCD liver transplants were performed at the investigators' institution: 32 from donors aged 55 years and younger, 20 from donors between 56 and 69 years, and 18 from donors aged 70 years and older.
Organ and patient survival rates were not different at one and three years after transplantation between the three groups. "The use of DCD donors over the age of 60 is highly controversial, but we showed that excellent results could be expected if the cold ischaemic time is limited to less than 6 hours," said Dr. Detry. Cold ischaemic time represents the time between the chilling of an organ after its blood supply has been cut off and the time it is warmed by having its blood supply restored. "As the population of Western countries is aging, we will have to consider older donors even more often in the future," said Dr. Detry.
In a third study, investigators uncovered the importance of reducing cold ischaemic time for donor organs after circulatory death to preserve the energy status of the organs. Thamara Perera, FRCS, of Queen Elizabeth Hospital Birmingham, in the UK, and his colleagues used microdialysis, a novel technique to study the differences in basic energy metabolism between organs from DCD and brain death donors. They found that livers from DCD had depleted energy reserves during cold storage and that livers that failed after being transplanted showed severe energy depletion. "The importance of these findings is the ability to predict possible organ failures and unwanted outcomes before performing the actual transplant," said Mr. Perera. "The study also questions the suitability of organ preservation techniques that are currently in place." Modified preservation techniques to minimize organ injury related to energy metabolism may improve the quality of donor organs after circulatory death.
April 28, 2014
By Wiley
The quality of kidney and liver donations is fundamentally important for the longevity of transplants and the health of recipients. That's why it's critical to know which organs are suitable for transplantation, as well as to use techniques that preserve an organ's function after donation. Several studies published in the BJS (British Journal of Surgery) address these issues and offer ways to maximize the use of donated organs.
In the first study, Rajeev Desai, MRCP, of NHS Blood and Transplant, in the UK, led a team that assessed transplants from 17,639 donors, including 61 donors with cancer who were considered to have an unacceptable/high risk of transmitting cancer through their donated organs. The researchers found no cancer transmission in 133 recipients of organs from these 61 donors. At 10 years after transplantation, the organs from donors with unacceptable/high risk provided each recipient with more than 7 additional years of survival on average.
"The findings of our research indicate that the perceived risk of certain organ donors to their recipients is likely to have been over-estimated. Organ donors with a history of certain types of cancers who are excluded from transplantation in fact pose very little risk of cancer transmission to their recipients," said Dr. Desai. "These organs can be transplanted with very little risk to their recipients, resulting in significant improvement in the survival and health of the recipients."
In another study, Olivier Detry, MD, PhD, of the University of Liège, in Belgium, and his colleagues revealed excellent results from liver transplants from deceased donors who were older than what is usually recommended. The study looked specifically at donation after circulatory death (DCD), in which circulation, heartbeat, and breathing have stopped (as opposed to brain death, in which all the functions of the brain have stopped). A total of 70 DCD liver transplants were performed at the investigators' institution: 32 from donors aged 55 years and younger, 20 from donors between 56 and 69 years, and 18 from donors aged 70 years and older.
Organ and patient survival rates were not different at one and three years after transplantation between the three groups. "The use of DCD donors over the age of 60 is highly controversial, but we showed that excellent results could be expected if the cold ischaemic time is limited to less than 6 hours," said Dr. Detry. Cold ischaemic time represents the time between the chilling of an organ after its blood supply has been cut off and the time it is warmed by having its blood supply restored. "As the population of Western countries is aging, we will have to consider older donors even more often in the future," said Dr. Detry.
In a third study, investigators uncovered the importance of reducing cold ischaemic time for donor organs after circulatory death to preserve the energy status of the organs. Thamara Perera, FRCS, of Queen Elizabeth Hospital Birmingham, in the UK, and his colleagues used microdialysis, a novel technique to study the differences in basic energy metabolism between organs from DCD and brain death donors. They found that livers from DCD had depleted energy reserves during cold storage and that livers that failed after being transplanted showed severe energy depletion. "The importance of these findings is the ability to predict possible organ failures and unwanted outcomes before performing the actual transplant," said Mr. Perera. "The study also questions the suitability of organ preservation techniques that are currently in place." Modified preservation techniques to minimize organ injury related to energy metabolism may improve the quality of donor organs after circulatory death.
Tuesday, April 29, 2014
Impact Of SVR On Liver Fibrosis and Cirrhosis
New Drugs Less Side EffectsThe liver conference this month was all about new and investigational HCV oral regimens, many even close to FDA approval.
The long awaited revolution in HCV treatment has arrived, we are seeing improved cure rates, safety, and tolerability across many different patient populations and HCV genotypes. Finally, treating HCV without interferon has spared some patients from those debilitating side effects, but more importantly should open the door to treatment for people who are unable to tolerate interferon, or on the fence about starting treatment.
Gilead's Sovaldi (sofosbuvir) was approved last year for HCV genotypes 1 and 4 in combination with PEG-IFN/ribavirin and the first approved interferon-free treatment regimen for people with HCV genotypes 2 and 3. Gilead remains high on the list of game-changers and has demonstrated astounding cure rates in 8 to 12 weeks with other sofosbuvir based regimens. AbbVie's new antiviral agents ABT-450/r–Ombitasvir and Dasabuvir is also showing high SVR rates among difficult to treat patients in 12 and 24 week regimens. Here is an excerpt from the original article published this month in the New England Journal Of Medicine; ABT-450/r–Ombitasvir and Dasabuvir with Ribavirin for Hepatitis C with Cirrhosis
"...this multitargeted approach combining ritonavir-enhanced ABT-450 with ombitasvir, dasabuvir, and ribavirin resulted in rates of sustained virologic response at post-treatment week 12 of 92% with a 12-week regimen and 96% with a 24-week regimen, with a low rate of treatment discontinuation, among both previously untreated and previously treated patients with HCV genotype 1 infection and compensated cirrhosis, a group at risk for liver-related illness and death."
Treatment Challenges
As the therapeutic landscape for hepatitis C is changing, treatment challenges for patients is improving. For instance just a few years ago some patients considered the side effects of treatment much more detrimental then the disease itself. Triple therapy which includes interferon and either boceprevir or telaprevir proved difficult, with new side effects reported, the most serious being telaprevir's rash.
Another huge challenge in past was getting people tested for the virus, still is. In 2012 HCV testing strategies were put in place by the CDC and according to the agency, out of the three million Americans living with hepatitis C close to 75 percent have no idea they are infected – placing them at serious risk for liver disease, cancer, and death. The problem is so serious that in June 2013, the US Preventive Services Task Force followed suit and endorsed that recommendation by giving the one-time test of baby-boomers a "B" rating, which allows for payment by Medicare and private insurers for testing with no copayment by patients. If you were born during 1945-1965, talk to your doctor about getting tested for hepatitis C. Baby boomers are five times more likely than other adults to be infected.
Impact Of SVR On Liver Fibrosis and Cirrhosis
With improved therapies and better awareness in place the virus is getting treated and not a moment too soon. As research continues to demonstrate achieving SVR can prevent liver cancer and improve or even reverse serious disease complications such as fibrosis, and cirrhosis. As seen in recent literature published in the Journal of Hepatology and Liver International investigating the effect of SVR (synonymous with virological cure) on disease progression.
We begin with this October 2013 study published in Journal of Hepatology; Slow regression of liver fibrosis presumed by repeated biomarkers after virological cure in patients with chronic hepatitis C
The aim of this study is to evaluate the impact of SVR on liver fibrosis over a 10-year period.
In the cohort of 933 patients;
415 patients had advanced fibrosis at baseline
108 attained SVR
219 were nonresponders and 88 were not treated.
The percentage with regression of fibrosis
49 in patients with SVR
23 in nonresponders and 45 in untreated
Cirrhosis regressed in 24 of the 43 patients with SVR, but 15 new cases with cirrhosis occurred out of 128 patients without cirrhosis at baseline.
Conclusions
In patients with chronic hepatitis C, and as presumed by FibroTest™, virological cure was associated with slow regression of fibrosis 10 years later, a disappointing 5% decrease in cirrhosis cases, and a remaining 5% risk of primary liver cancer.
Please click on the links for a more detailed information.
In a literature review published this month in Liver International; Cirrhosis Regression in Hepatitis C Patients with Sustained Virologic Response after Anti-Viral therapy: A Meta-analysis, researchers set out to find the association between SVR and cirrhosis regression.
A systematic literature search was performed to identify studies that assessed the association between SVR and cirrhosis regression. The main outcome studied was cirrhosis regression in patients with a SVR as compared to patients without a SVR.
Six studies totaling 443 patients were included;
Of the 443 patients with cirrhosis, 137 achieved a SVR.
The percentage with regression of cirrhosis
Of these 137 patients who achieved an SVR, 73 (53%) patients had regression of cirrhosis.
Conclusions;
Our results suggest that the majority of patients with cirrhosis who achieve a SVR develop cirrhosis regression. Time between biopsies appears to be an important determinant of the likelihood of cirrhosis regression.
Please click on the links for a more detailed information.
Stay hopeful my friends, with so many extremely effective new drugs moving quickly through the development process, "your" cure will be within reach, sooner than later.
Safe healthy and safe.
Tina
Monday, April 28, 2014
Video - Pricey Hepatitis C Pill Sovaldi Rattles Medicaid Programs
Pricey Hepatitis Pill Sovaldi Rattles Medicaid Programs
April 28th, 2014 by ABMN Staff
Medicaid health insurance programs for the poor are grappling with how to pay for the costly Hepatitis C treatment Sovaldi, which costs $1,000 a pill and is running up a huge tab for states already grappling with myriad health and general budgetary issues. The costs are hitting Medicaid programs extraordinarily hard because the population of patients in need of Sovaldi tend to have low incomes and wouldn’t be able to afford it without the government insurance.
“Pricey Hepatitis Pill Sovaldi Rattles Medicaid Programs” is categorized as “world”. This video was licensed from Grab Networks. For additional video content, click the “video” tab at the top of this page.
Pharmacists are the key to helping patients and payers get ROI on expensive Hepatitis C meds
April 28, 2014 6:02 am by Vickie Andros
These are exciting times in the treatment of hepatitis C virus infection. The outlook for patients with hepatitis C has greatly improved with available treatment options offering a cure for many.
Until 2011, the standard of care for patients with hepatitis C was combination treatment of pegylated interferon and ribavirin. Treatment with peginterferon and ribavirin has been associated with significant side effects, worsening fatigue and decline in health-related quality of life.(1) Nonadherence to peginterferon and ribavirin treatment for hepatitis C has been a major barrier to treatment success. (2)
The landscape of treatment for hepatitis C is rapidly changing with approval of oral agents that produce better cure rates, are better tolerated and provide shorter duration of treatment. Numerous new agents are also expected to become available in 2014 and 2015 that will offer more effective, simpler all oral, interferon-free treatment regimens. For these reasons, many patients will demand these newer treatments.
Studies examining adherence to hepatitis C combination treatment with peginterferon and ribavirin have shown an increased risk of virologic failure in poorly adherent patients. (3)
Due to the high cost of these new treatments, the possibility that the virus could become resistant if adherence is not optimal, and that good outcomes are dependent upon adherence (4), it is important to provide patient support to ensure adherence to treatment is maintained throughout the course of therapy.
Physicians may not be able to meet the current and future demands of increased access to care and there exists the lack of capacity of our system to provide comprehensive care to patients. Other health care providers are needed to support the physician and the patient.
Clinicians need to educate patients regarding disease progression, potential of long-term clinical consequences if treatment is postponed, and challenges of treatment-related side effects. Understanding factors associated with patient non-adherence is also important in identifying opportunities for education. Side effects, including fatigue, headache and depression, are the most common reason for discontinuing treatment.
Studies have shown that educational interventions with behavioral support through continued patient contact over several weeks or months were effective for several chronic diseases, including hypertension, hyperlipidemia, heart failure, and myocardial infarction. (5) Pharmacist delivered patient care services have also been shown to increase medication adherence in other chronic disease states. (6)
Pharmacists are in the ideal position to help with adherence in terms of explaining the purpose of medications, how to take them, and the importance of staying on them. They are in a sense the most accessible providers in the health care system, but often are underutilized as a resource for improving medication adherence.
Pharmacists who provide comprehensive medication therapy management (MTM) services for patients with hepatitis C have the opportunity to assess the patient’s functional status and understanding about his/her diseases and treatments. Through this process pharmacists may also identify which treatment factors matter most to the patient – especially the side effects that lead to patients missing doses or discontinuing treatment. In doing so, the pharmacist is able to provide patient specific education and a side effect management plan for the patient.
Routine pharmacist follow-up with the patient throughout the treatment period (12-24 weeks) to assess adherence, address any concerns from previous communications, and identify and resolve medication related issues that may lead to non-adherence is helpful in assisting the patient to adhere to therapy.
Individual counseling, support and patient education from a health care provider other than the physician can help increase treatment adherence that results in the cure of hepatitis C.
References
1. Fusfeld L, Aggarwal J, Dougher C, et al. Assessment of motivating factors associated with the initiation and completion of treatment for chronic hepatitis C virus (HCV) infection. BMC Infect Dis 2013;13:234.
2. Evon DM, Esserman DA, Bonner JE, et al. Adherence to PEG/ribavirin treatment for chronic hepatitis C: prevalence, patterns, and predictors of missed doses and nonpersistence. J Viral Hepatitis 2013;20(8):536-549.
3. Lieveld FI, van Vlerken LG, Siersema PD, van Erpecum KJ. Patient adherence to antiviral treatment for chronic hepatitis B and C: a systematic review. Ann Hepatology 2013;12(3):380-391.
4. Lo Re V III, Amorosa VK, Localio AR, et al. Adherence to hepatitis C virus therapy and early virologic outcomes. Clin Infect Dis 2009;48(2):186-193.
5. Viswanathan M, Golin CE, Jones CD, et al. Interventions to improve adherence to self-administered medications for chronic diseases in the United States: a systematic review. Ann Intern Med. 2012;157(11):785-795.
6. Lee JK, Grace KA, Taylor AJ. Effect of a pharmacy care program on medication adherence and persistence, blood pressure, and low-density lipoprotein cholesterol. JAMA 2006;296:2563-257.1
Read more: http://medcitynews.com/2014/04/pharmacists-key-helping-patients-payers-get-roi-expensive-hepatitis-c-meds/#ixzz30BIAm1sx
Laboratory-based algorithm predicts liver cancer in Hep C and cirrhosis
Laboratory-based algorithm predicts liver cancer in Hep C and cirrhosis
May's issue of Gastroenterology reports on a new laboratory-based algorithm to predict development of hepatocellular carcinoma in patients with Hepatitis C and cirrhosis.
Serum levels of α-fetoprotein (AFP) are influenced not only by the presence of hepatocellular carcinoma (HCC), but also by the underlying severity and activity of liver disease, which is reflected by liver function tests.
Dr Hashem El-Serag and colleagues from Texas, USA constructed an AFP-based algorithm that included these factors to identify patients at risk for HCC, and tested its predictive ability in a large set of patients with cirrhosis.
The team used used the national Department of Veterans Affairs Hepatitis C Virus Clinical Case Registry to identify patients with cirrhosis, results from at least 1 AFP test, and 6 months of follow-up.
The researchers' algorithm included data on age, levels of aspartate aminotransferase, alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, albumin, creatinine, and hemoglobin, prothrombin time, and numbers of platelets and white cells.
The team examined the operating characteristics (calibration, discrimination, predictive values) of several different algorithms for identification of patients who would develop HCC within 6 months of the AFP test.
 |
| The probabilities of HCC, based only on 120 ng/mL AFP, were 11% |
| Gastroenterology |
The team identified 11,721 patients with hepatitis C virus−related cirrhosis in whom 35,494 AFP tests were performed, and 987 patients developed HCC.
A predictive model that included data on levels of AFP, ALT, and platelets, along with age at time of AFP test, best discriminated between patients who did and did not develop HCC.
Using this AFP-adjusted model, the predictive accuracy increased at different AFP cutoffs compared with AFP alone.
At any given AFP value, low numbers of platelets and ALT and older age were associated with increased risk of HCC, and high levels of ALT and normal/high numbers of platelets were associated with low risk for HCC.
For example, the probabilities of HCC, based only on 20 ng/mL and 120 ng/mL AFP, were 4% and 11%, respectively.
However, the team noted that patients with the same AFP values who were 70 years old, with ALT levels of 40 IU/mL and platelet counts of 100,000, had probabilities of developing HCC of 8% and 29%, respectively.
Dr El-Serag's team concludes, "We developed and validated an algorithm based on levels of AFP, platelets, and ALT, along with age, which increased the predictive value for identifying patients with hepatitis C virus−associated cirrhosis likely to develop HCC within 6 months."
"If validated in other patient groups, this model would have immediate clinical applicability."
Gastroenterol 2014: 146(5): 1249-1255.e1
28 April 2014
Sunday, April 27, 2014
The cure for hepatitis C is upon us, but at a costly penny
The cure for hepatitis C is upon us, but at a costly penny
André Picard
The Globe and Mail
Published Sunday, Apr. 27 2014, 4:00 PM EDT
There is a revolution coming to the treatment of hepatitis C. But a big fat asterisk is required with that assertion.
In the coming months, a number of drugs are going to be rolled out that can essentially “cure” hepatitis C. (More on the C-word in a moment.) The most talked-about, by far, is Sovaldi, a product of Gilead Sciences Inc. It is a single pill that contains the drugs sofosbuvir and ledipasvir.
The clinical trials involving this drug have produced some eye-popping results. They show that treating people infected with HCV, the virus that causes hepatitis C, with a single pill a day for as little as eight weeks can reduce the virus levels in their bodies to undetectable levels. This is referred to as a “functional cure” or remission, because relapse is possible. But the relapse rate is only 5 per cent after eight weeks, and it drops to 2 per cent if the regime is followed for 12 weeks, and to 0.2 per cent after 24 weeks of treatment.
Although other companies have produced similarly effective regimes, they have generated a lot less media attention because they are using cocktails of drugs. For example, AbbVie has produced a three-drug combo – ritonavir, ombitasvir and dasabuvir – that has similar “cure” rates in the 95- to 99-per-cent range.
The reason these new approaches – pill-based treatments – have generated so much buzz is twofold: A lot of people are infected with HCV, and the current treatments are ineffective and horrible.
In Canada, an estimated 250,000 people are living with hepatitis C; in the United States, it’s 3.2 million; worldwide 180 million. In North America, more people die of hepatitis C than of AIDS, about 16,000 a year.
The hardest-hit demographic, by far, is baby boomers, many of whom were exposed to tainted blood or experimented with injection drugs in their libertine youth. The Canadian Liver Foundation urges that everyone born between 1945 and 1975 be tested.
Hepatitis C can be devastating. As many as one in five infected with the virus will develop cirrhosis (scarring of the liver) that can require a transplant, and 1 per cent to 5 per cent will die of liver cancer.
The current treatment for hepatitis C is a combination of interferon and ribavirin, both drugs that have to be dosed precisely and injected. The treatment can last up to 48 weeks and it’s only effective about half the time, and has some nasty side effects.
The idea of replacing that with a single pill with few side effects (at least in clinical trials), that works almost all the time, has patients and scientists giddy. Some are even talking about eradicating the liver-ravaging virus.
But here’s the catch: The new treatment costs a lot of money. Sovaldi sells for $1,000 a pill; that means a 12-week course of treatment costs $84,000. If every person in the U.S. who was eligible were treated, it would cost $227-billion; that is almost equivalent to annual spending of $260-billion on every other prescription drug combined.
Those kinds of numbers have the business world excited. Sovaldi has the potential to become the biggest-selling (read most profitable) drug in history.
But there is push back. What exactly is the justification for charging $1,000 a pill? Some activists have taken to protesting against what they have dubbed “Gilead greed.” To be fair, other regimes are not a lot less costly, about $66,000 for a 12-week treatment.
Some – mainly health economists – point out that most people infected with HCV have no discernible symptoms, so they don’t all need treatment. Still others – consumer groups and physicians among them – argue that the cost is worth it because the new treatment is far superior to the existing approach and because expensive liver transplants and liver-cancer cases can be avoided.
But the California Technology Assessment Forum (CTAF), a research group funded by the U.S. insurance industry, found that it would take more than 20 years to offset the up-front treatment costs. That’s because, in many instances, patients will continue to use the current treatments, which bolster the immune system in addition to killing the virus. (Most of the research was done comparing standard treatment with standard treatment plus Sovaldi; little research shows how well it would work taken alone.) This is rarely mentioned and it weakens the economic argument for universal treatment. In fact, the CTAF argued that the expensive new treatments should only be used in patients with severe complications like cirrhosis.
In Canada, Sovaldi has been approved for sale, but it has not yet been listed on any public formulary, meaning it is not paid for by provincial drug plans.
There is much pressure for governments to bust open the piggybank and pay for this miracle “cure.” But, despite the potential benefits of drugs like Sovaldi, governments would be wise to move ahead cautiously.
The first priority should be to negotiate a better price. The second is to digest the whole of the evidence – not just the headlines – and recognize that these drugs need to be used selectively, starting with patients with advanced fibrosis or cirrhosis of the liver.
Of course, it would be nice to “cure” everyone of hepatitis C, but we can’t afford to do so at the expense of patients with other conditions. Treating everyone who is infected is simply not cost-effective, especially at current prices.
The hepatitis C treatment revolution will come, but it can’t come in the form of a bomb that destroys health-care budgets.
Follow me on Twitter: @picardonhealth
Monday Medical: New treatments for hepatitis C
Rosie Kern/For the Steamboat Today
Sunday, April 27, 2014
William Robinson is thankful for recent developments in the treatment of hepatitis C. The Hayden resident just completed a three-month treatment program at the Yampa Valley Medical Center Outreach Clinic under the guidance of Dr. John R. Sharp, a Steamboat Springs gastroenterologist.
The treatment has been successful and now Robinson can get back to his normal work week at HLCC Construction.
“I’m happy to get back to a 40-hour work week again,” he said.
Robinson was diagnosed with hepatitis C in late 2013. Hepatitis C is a contagious liver disease that may range from a mild infection to a serious health condition. Other common types of hepatitis are hepatitis A and B.
According to the Centers for Disease Control and Prevention, hepatitis A appears as a newly occurring infection and does not become chronic.
Both hepatitis B and C can begin as an acute infection and progress to chronic disease and both are spread by the sharing of needles or can be acquired during sex.
Before 1992, when testing of donated blood began, individuals were infected through blood transfusions.
An estimated 3.2 million persons in the United States have chronic hepatitis C virus infection. Many people may be infected with hepatitis C and not be aware of it because they don’t look or feel sick. It may take decades for the virus to cause serious damage to the liver. Some people with chronic hepatitis C infection develop scarring and poor liver function (cirrhosis) throughout many years, which can lead to complications such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in the abdomen, infections or liver cancer
Although less than 20 percent of patients with hepatitis C ever progress to cirrhosis, the only treatment available would be liver transplantation.
Robinson found out about his disease because every year he has his blood tested during YVMC’s Community Health Fair. This past October, after his blood test, William visited with his primary care physician, Dr. Charlie Petersen. Based on the elevated levels in his liver, Petersen referred Robinson to Dr. Sharp.
Dr. Sharp knew that new drugs for treating hepatitis C were slated to be approved in early 2014 by the Federal Drug Administration. He encouraged William to wait a few months for the new treatment regime.
Before the new drugs were approved, treatment included injections of interferon. With interferon, patients experienced serious side effects including flu-like symptoms, depression and hair loss and were treated for as many as 48 weeks.
In November 2013, the FDA approved Olysio (simeprevir) for the treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen that still included interferon that often was poorly tolerated.
In December, the FDA approved Sovaldi (sofosbuvir) to treat the disease in combination only with Ribavirin tablets.
“These new drugs are game changers,” Sharp said. “First of all, they are taken as oral medication, not injections. Secondly, they have been found to be extremely effective in treating hepatitis C in a short period of time.”
The FDA recommends treatment periods as short as 12 to 24 weeks.
“These new drugs also have minimal side effects,” Sharp added.
Recent news articles have stressed the high cost of the new drugs. Robinson is very fortunate that his health insurance, covered by his employer, paid for the expensive medication.
During his treatment, Robinson experienced some fatigue and headaches.
“However, I was still able to work part-time while I was taking the medicine,” he said.
He looks forward to returning to work full-time. When not working, he plans on walking his new puppy, a German short-hair mix named Kiri.
“I’m happy to be done with treatment and thankful for the care I received from Dr. Sharp,” he said.
Dr. Sharp states that patients need to be checked by their physician for hepatitis C and, if positive, consider treatment. His office staff have been able, through relationships with the drug manufacturers and pharmacy benefits coordinators, to obtain the expensive drugs through financial assistance programs even in patients with limited financial means.
“There really isn’t any reason to wait any longer for hepatitis C treatment," Sharp said. “It is an entirely new day."
Rosie Kern is the manager of marketing and communications for Yampa Valley Medical Center. She can be reached at rosie.kern@yvmc.org.
Mother To Child HCV Transmission Among Three Brothers: A Long-Term Follow-Up
Case Report
Volume 5, Number 4, April 2014, pages 227-231
Transmission of Hepatitis C Virus From a Mother to a Child Carrying IL28B Heterozygote rs8099917 Among Three Brothers: A Long-Term Follow-Up
Takafumi Saitoa, c, Kei Mizunoa, Tomohiro Katsumia, Kyoko Tomitaa, Chikako Satoa, Kazuo Okumotoa, Yuko Nishisea, Hisayoshi Watanabea, Li Shaob, Yoshiyuki Uenoa aDepartment of Gastroenterology, Yamagata University School of Medicine, Yamagata 990-9585, Japan bPublic Health, Yamagata University School of Medicine, Yamagata 990-9585, Japan cCorresponding author: Takafumi Saito, Department of Gastroenterology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan
Manuscript accepted for publication March 4, 2014
Short title: Mother-to-Child HCV Transmission
doi: http://dx.doi.org/10.14740/jmc1736w
Abstract HTML PDF
Abstract
Three male children were born every 2 years by spontaneous delivery from a mother infected with hepatitis C virus (HCV) genotype 2b, and all have been followed up after birth. The viral load in the serum of the mother was high before their deliveries, and anti-HCV antibody immunoglobulin G, which is allowed to pass through placenta, was positive in the umbilical blood of all the children. Mother-to-child transmission of HCV was confirmed in the second son, who was positive for both anti-HCV antibody and serum HCV RNA when first examined 108 days after birth, but not in the other siblings. Persistent HCV genotype 2b infection with mild elevation of the serum alanine aminotransferase level has been established in the second son for more than 14 years. The interleukin 28B (IL28B) genotype (rs8099917) of the second son showed the TG heterozygote, which is unfavorable for viral clearance, and this may predict persistent HCV infection. Among the three brothers sharing the same delivery conditions with exposure to the same virus, as well as sharing the same environment after birth, HCV infection has not been consistent, and one of them possessing the TG genotype of the IL28B gene (rs8099917) has had chronic HCV infection. These cases suggest that maternal HCV transmission does not occur so often, even among multiple children who are exposed to the same HCV with a high viral load, and that this variation might be attributable to very minor events that can impact on viral exposure in the perinatal period.
Keywords: Hepatitis; HCV; Perinatal infection; Vertical infection; Interleukin 28B
Introduction
Mother-to-child transmission of hepatitis C virus (HCV) is a serious health problem, and no effective preventive vaccine has yet been developed. The mechanism and timing of mother-to-child HCV transmission are not understood, nor is the natural history of the infection in mothers and their children. The rate of HCV transmission from HCV-infected mother to child is reported to be approximately 4-10% [1-7], but the associated factors are not fully defined [8].
HCV infection leads to development of chronic hepatitis with a risk of progression to cirrhosis and liver cancer, but some individuals clear the virus spontaneously and the hepatitis resolves in a self-limiting manner in the acute phase of infection [9-11]. Recently, it has been reported that the host genetic single nucleotide polymorphism (SNP) in the region of the interleukin 28B (IL28B) gene encoding interferon-λ-3, rs12979860, is associated with spontaneous HCV clearance in adults [12, 13], and even in infants vertically infected with HCV from their mothers [14]. This SNP is in high linkage disequilibrium with rs8099917, as reported for Japanese subjects [15, 16]. Furthermore, upstream of the IL28B gene, a dinucleotide variant ss469415590 in the IFNL4 gene encoding interferon-λ-4 protein has been reported to be more strongly associated with HCV clearance, and this variant is in high linkage disequilibrium with the SNPs of IL28B [17]. Thus, these genetic markers are worth investigating further for their possible usefulness in predicting the outcome of maternal HCV infection in children.
The pattern of maternal HCV transmission in multiple children from the same mother is still unclear. There is little evidence to indicate whether mother-to-child transmission of HCV occurs evenly or unevenly in this situation. Such cases would be informative for understanding the risk of perinatal HCV infection. We have experienced three deliveries from the same HCV-monoinfected mother, and prospectively followed up the three children after birth. In all of them, the factors possibly related to maternal HCV transmission, namely, the gender of the children, birth weight, delivery conditions, a high viral titer in the mother before their births, positivity for anti-HCV antibody in their umbilical blood and their environment after birth were uniform.
Here, we report the results of HCV transmission in these three children born from the same mother infected with HCV, with special reference to both the natural course of HCV infection in the children and their genotypes of IL28B (rs8099917) and IFNL4 (ss469415590) associated with the outcome of infection.
Case Report
The mother has been followed up for hepatitis C at our hospital for 18 years. The long-term course of her HCV infection is shown in Fig. 1. The serum alanine aminotransferase (ALT) level was low, at under 30 U/L, during the follow-up period except for two occasions when it exceeded 30 U/L just after delivery of the first and second sons. She had been infected with HCV genotype 2b, and the viral load was always high before she received antiviral therapy. Both hepatitis B surface antigen and anti-immunodeficiency virus antibody were negative in her serum. Six years after the third delivery, she received antiviral therapy with pegylated interferon plus ribavirin for chronic hepatitis C according to the Japanese standard protocol [18], and the therapy was successful in achieving a sustained virologic response.
Figure 1. Clinical course and serum alanine aminotransferase (ALT) levels in the mother with chronic HCV genotype 2b infection. Positivity and negativity for serum HCV RNA are represented as plus (+) and minus (-), respectively. PegIFN/RBV: pegylated interferon plus ribavirin treatment.
The characteristics of the three children are summarized in Table 1 below.
All were boys who were born by normal spontaneous delivery 40 weeks after the start of pregnancy. All were healthy and their birth weight was almost the same, at approximately 3,400 g. Nothing in their history suggested any concern about contamination with HCV during their perinatal periods, namely, wounds, surgery or transfusion of blood products. Anti-HCV antibody in the umbilical blood was tested for at birth, and it was positive in all of them. The first and third sons had no evidence of HCV infection because neither anti-HCV antibody nor HCV RNA in serum was positive after birth. However, the second son was confirmed to be infected with HCV 108 days after the delivery showing positivity for both anti-HCV antibody and HCV RNA in serum by the first postnatal assay. HCV transmission to this child resulted in persistent infection. The long-term follow-up and clinical course of this HCV-infected child are shown in Fig. 2. The serum ALT level had been low, at under 30 U/L, for approximately the first 2 years after birth, but thereafter fluctuated above and below 30 U/L until approximately 14 years of age. The HCV genotype of this child was 2b, which was the same as the mother’s, and the high-level viremia has continued during the follow-up period. Although the factors possibly influencing maternal HCV transmission, namely, gender, birth weight, delivery conditions, the mother’s high viral titer and positivity for anti-HCV antibody in the umbilical blood, were the same among the three siblings, HCV transmission from the mother occurred only in the second child. The genetic polymorphisms of the IL28B gene (rs8099917) and IFNL4 gene (ss469415590) associated with spontaneous viral clearance were examined after obtaining written informed consent from their mother. The genotypes of the IL28B gene (rs8099917) and IFNL4 gene (ss469415590) in the second son, in whom persistent HCV infection had become established, were TG and ΔG/TT, respectively. Those in the other children who were not infected with HCV varied, being TG and ΔG/TT in the first child, and TT and TT/TT in the third child.
Table 1. Characteristics of Children Born From the HCV-Infected Mother
Figure 2. Long-term follow-up of serum alanine aminotransferase (ALT) levels in the second child with maternal HCV genotype 2b infection. Positivity for serum HCV RNA is represented as plus (+).
Discussion
In this study, we observed different outcomes of HCV transmission among three brothers who had been exposed to the same HCV strain from the mother during the perinatal period. Interestingly, maternal HCV genotype 2b transmission did not occur evenly in these three siblings, despite the fact that all had the same HCV exposure as well as upbringing environment, and only the second child was infected with HCV genotype 2b. This HCV transmission led to persistent infection in this child, in whom the genotypes of the IL28B gene (rs8099917) and IFNL4 gene (ss469415590) were TG and ΔG/TT, respectively, which are unfavorable for spontaneous viral clearance after the establishment of infection [13, 19].
It is still unclear how mother-to-child HCV transmission occurs in the perinatal period, and our present findings may help to shed some light on the route of infection. During the perinatal period, there are two possible major routes of HCV transmission from mother to child: placental infection and birth canal infection. Placental infection results from active transport of virus from mother to child, or from micro-transfusion of virus due to placental membrane damage. In all of the three brothers, blood exchange between the fetus and the mother through the placenta had been good, because anti-HCV antibody (immunoglobulin G) had been transferred to all fetuses and was detected in the umbilical blood at birth in all cases. However, only the second child had been infected with HCV. Negativity for HCV RNA in the umbilical blood of this child was different from the viral titer in the serum of his mother, which indicated a very high level of HCV RNA, as shown in Table 1. Thus placental infection by active transport of HCV from mother to fetus appeared to have been negligible. Placental membrane damage possibly induced by a small wound that goes unnoticed at delivery may result in maternal HCV infection. In cases of twin delivery, HCV transmission is more likely to affect the second child because possible partial placental separation upon delivery of the first baby increases the chance of exposing the second child to maternal blood [20]. Otherwise, any small wound in child, such as on the skin or in the mucosa of the oral cavity, or the bulbar conjunctiva, may allow micro-transfusion of HCV from mother to a child, and this may result in maternal HCV transmission in the birth canal. After birth, the present three brothers were brought up in the same environment, and were breast-fed. This kind of background carries little risk of HCV infection [21]. These findings suggest that maternal HCV transmission does not usually occur in the perinatal period, with only rare exceptions due to accidental exposure such as minor placental damage or micro-wounds in the child. The prevalence of maternal HCV infection seems to be relatively low even among children exposed to the same virus, although serologic tests for HCV in children should be carefully conducted during follow-up.
Most adults with HCV infection fail to clear the virus and develop chronic hepatitis, but some are known to show resolution of the infection in a self-limiting manner. The rate of spontaneous viral clearance in the acute phase of infection is reported to be approximately 15-40% of all HCV-infected adults [9-11], and a systematic review of 31 studies has estimated this rate to be 26% [11]. In a recent genome-wide association study, the SNPs in the region of the IL28B gene encoding interferon-λ-3 were shown to be associated with the virologic response of HCV to antiviral therapy [15, 22]. Patients carrying an IL28B homozygote for the major alleles of rs12979860 (CC genotype) [22] or rs8099917 (TT genotype) [15] show a greater propensity for achieving a sustained virologic response to pegylated interferon-α and ribavirin therapy than those carrying an IL28B heterozygote or homozygote for its minor allele. This SNP (rs12979860) also influences the outcome of HCV infection in the context of natural history; the CC genotype of rs12979860, which is in high linkage disequilibrium with the TT genotype of rs8099917, enhances the resolution of HCV infection with spontaneous clearance [12, 13]. Furthermore, upstream of the IL28B gene, a dinucleotide variant ss469415590 (TT or ΔG) has been reported to be more strongly associated with HCV clearance in individuals of African ancestry than the SNP of IL28B (rs12979860) [17].
The genotype of IL28B is also associated with the outcome of infection in maternal HCV transmission; self-limiting hepatitis or persistent hepatitis has been reported in a child infected with HCV genotype 1 during the perinatal period [14]. The three children in the present report were checked for the SNPs of both the IL28B (rs8099917) and IFNL4 (ss469415590) genes, and the second son in whom HCV genotype 2b infection had been established and led to persistent infection with mild fluctuation of the ALT levels was found to carry the TG (rs8099917) type and ΔG/TT (ss469415590) type in the IL28B and IFNL4 genes, respectively. Thus the SNPs in these two genes predicted the outcome of infection in the second son with chronic HCV genotype 2b infection.
In conclusion, our present findings suggest that the chance of maternal HCV transmission is not so high even in multiple children exposed to the same HCV strain with a high viral load, and that maternal HCV transmission might be attributable to very minor events that can potentially result in viral exposure during the perinatal period. Here, the multiple deliveries did not largely affect the serum levels of ALT and HCV RNA in the mother. The genotype defined by SNPs in the IL28B gene (rs8099917) and the IFNL4 gene (ss469415590) was able to predict the development of persistent infection in the child with established maternal HCV genotype 2b transmission.
Conflict of Interest
The authors have no conflict of interest.
References
1. Ohto H, Terazawa S, Sasaki N, Hino K, Ishiwata C, Kako M, Ujiie N, et al. Transmission of hepatitis C virus from mothers to infants. The Vertical Transmission of Hepatitis C Virus Collaborative Study Group. N Engl J Med. 1994;330(11):744-750.
doi pubmed
2. Matsubara T, Sumazaki R, Takita H. Mother-to-infant transmission of hepatitis C virus: a prospective study. Eur J Pediatr. 1995;154(12):973-978.
doi pubmed
3. Zanetti AR, Tanzi E, Paccagnini S, Principi N, Pizzocolo G, Caccamo ML, D'Amico E, et al. Mother-to-infant transmission of hepatitis C virus. Lombardy Study Group on Vertical HCV Transmission. Lancet. 1995;345(8945):289-291. doi
4. Resti M, Azzari C, Mannelli F, Moriondo M, Novembre E, de Martino M, Vierucci A. Mother to child transmission of hepatitis C virus: prospective study of risk factors and timing of infection in children born to women seronegative for HIV-1. Tuscany Study Group on Hepatitis C Virus Infection. BMJ. 1998;317(7156):437-441.
doi pubmed
5. Gibb DM, Goodall RL, Dunn DT, Healy M, Neave P, Cafferkey M, Butler K. Mother-to-child transmission of hepatitis C virus: evidence for preventable peripartum transmission. Lancet. 2000;356(9233):904-907. doi
6. Dal Molin G, D'Agaro P, Ansaldi F, Ciana G, Fertz C, Alberico S, Campello C. Mother-to-infant transmission of hepatitis C virus: rate of infection and assessment of viral load and IgM anti-HCV as risk factors. J Med Virol. 2002;67(2):137-142.
doi pubmed
7. Steininger C, Kundi M, Jatzko G, Kiss H, Lischka A, Holzmann H. Increased risk of mother-to-infant transmission of hepatitis C virus by intrapartum infantile exposure to maternal blood. J Infect Dis. 2003;187(3):345-351.
doi pubmed
8. Cottrell EB, Chou R, Wasson N, Rahman B, Guise JM. Reducing risk for mother-to-infant transmission of hepatitis C virus: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013;158(2):109-113.
doi pubmed
9. Di Bisceglie AM. Natural history of hepatitis C: its impact on clinical management. Hepatology. 2000;31(4):1014-1018.
doi pubmed
10. Gerlach JT, Diepolder HM, Zachoval R, Gruener NH, Jung MC, Ulsenheimer A, Schraut WW, et al. Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology. 2003;125(1):80-88. doi
11. 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.
doi pubmed
12. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, Kidd J, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009;461(7265):798-801.
doi pubmed
13. Hung CH, Chang KC, Lu SN, Wang JH, Chen CH, Lee CM, Hu TH. Spontaneous clearance of hepatitis C virus in an interleukin 28B favorable genotype highly prevalent area. Hepatology. 2013;57(5):2089-2090.
doi pubmed
14. Ruiz-Extremera A, Munoz-Gamez JA, Salmeron-Ruiz MA, de Rueda PM, Quiles-Perez R, Gila-Medina A, Casado J, et al. Genetic variation in interleukin 28B with respect to vertical transmission of hepatitis C virus and spontaneous clearance in HCV-infected children. Hepatology. 2011;53(6):1830-1838.
doi pubmed/
15. Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41(10):1105-1109.
doi pubmed
16. Balagopal A, Thomas DL, Thio CL. IL28B and the control of hepatitis C virus infection. Gastroenterology. 2010;139(6):1865-1876.
doi pubmed
17. Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, Hergott D, et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet. 2013;45(2):164-171.
doi pubmed
18. Guidelines for the Management of Hepatitis C Virus Infection: First edition, May 2012, The Japan Society of Hepatology. Hepatol Res. 2013;43(1):1-34.
doi pubmed
19. Saito T, Ueno Y. Transmission of hepatitis C virus: self-limiting hepatitis or chronic hepatitis? World J Gastroenterol. 2013;19(41):6957-6961.
doi pubmed
20. Boxall E, Baumann K, Price N, Sira J, Brown M, Kelly D. Discordant outcome of perinatal transmission of hepatitis C in twin pregnancies. J Clin Virol. 2007;38(2):91-95.
doi pubmed
21. Indolfi G, Resti M. Perinatal transmission of hepatitis C virus infection. J Med Virol. 2009;81(5):836-843.
doi pubmed
22. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461(7262):399-401.
doi pubmed
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Digital Object Identifier (DOI): http://dx.doi.org/10.14740/jmc1736w
About DOI and CrossRef
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Volume 5, Number 4, April 2014, pages 227-231
Transmission of Hepatitis C Virus From a Mother to a Child Carrying IL28B Heterozygote rs8099917 Among Three Brothers: A Long-Term Follow-Up
Takafumi Saitoa, c, Kei Mizunoa, Tomohiro Katsumia, Kyoko Tomitaa, Chikako Satoa, Kazuo Okumotoa, Yuko Nishisea, Hisayoshi Watanabea, Li Shaob, Yoshiyuki Uenoa aDepartment of Gastroenterology, Yamagata University School of Medicine, Yamagata 990-9585, Japan bPublic Health, Yamagata University School of Medicine, Yamagata 990-9585, Japan cCorresponding author: Takafumi Saito, Department of Gastroenterology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan
Manuscript accepted for publication March 4, 2014
Short title: Mother-to-Child HCV Transmission
doi: http://dx.doi.org/10.14740/jmc1736w
Abstract HTML PDF
Abstract
Three male children were born every 2 years by spontaneous delivery from a mother infected with hepatitis C virus (HCV) genotype 2b, and all have been followed up after birth. The viral load in the serum of the mother was high before their deliveries, and anti-HCV antibody immunoglobulin G, which is allowed to pass through placenta, was positive in the umbilical blood of all the children. Mother-to-child transmission of HCV was confirmed in the second son, who was positive for both anti-HCV antibody and serum HCV RNA when first examined 108 days after birth, but not in the other siblings. Persistent HCV genotype 2b infection with mild elevation of the serum alanine aminotransferase level has been established in the second son for more than 14 years. The interleukin 28B (IL28B) genotype (rs8099917) of the second son showed the TG heterozygote, which is unfavorable for viral clearance, and this may predict persistent HCV infection. Among the three brothers sharing the same delivery conditions with exposure to the same virus, as well as sharing the same environment after birth, HCV infection has not been consistent, and one of them possessing the TG genotype of the IL28B gene (rs8099917) has had chronic HCV infection. These cases suggest that maternal HCV transmission does not occur so often, even among multiple children who are exposed to the same HCV with a high viral load, and that this variation might be attributable to very minor events that can impact on viral exposure in the perinatal period.
Keywords: Hepatitis; HCV; Perinatal infection; Vertical infection; Interleukin 28B
Introduction
Mother-to-child transmission of hepatitis C virus (HCV) is a serious health problem, and no effective preventive vaccine has yet been developed. The mechanism and timing of mother-to-child HCV transmission are not understood, nor is the natural history of the infection in mothers and their children. The rate of HCV transmission from HCV-infected mother to child is reported to be approximately 4-10% [1-7], but the associated factors are not fully defined [8].
HCV infection leads to development of chronic hepatitis with a risk of progression to cirrhosis and liver cancer, but some individuals clear the virus spontaneously and the hepatitis resolves in a self-limiting manner in the acute phase of infection [9-11]. Recently, it has been reported that the host genetic single nucleotide polymorphism (SNP) in the region of the interleukin 28B (IL28B) gene encoding interferon-λ-3, rs12979860, is associated with spontaneous HCV clearance in adults [12, 13], and even in infants vertically infected with HCV from their mothers [14]. This SNP is in high linkage disequilibrium with rs8099917, as reported for Japanese subjects [15, 16]. Furthermore, upstream of the IL28B gene, a dinucleotide variant ss469415590 in the IFNL4 gene encoding interferon-λ-4 protein has been reported to be more strongly associated with HCV clearance, and this variant is in high linkage disequilibrium with the SNPs of IL28B [17]. Thus, these genetic markers are worth investigating further for their possible usefulness in predicting the outcome of maternal HCV infection in children.
The pattern of maternal HCV transmission in multiple children from the same mother is still unclear. There is little evidence to indicate whether mother-to-child transmission of HCV occurs evenly or unevenly in this situation. Such cases would be informative for understanding the risk of perinatal HCV infection. We have experienced three deliveries from the same HCV-monoinfected mother, and prospectively followed up the three children after birth. In all of them, the factors possibly related to maternal HCV transmission, namely, the gender of the children, birth weight, delivery conditions, a high viral titer in the mother before their births, positivity for anti-HCV antibody in their umbilical blood and their environment after birth were uniform.
Here, we report the results of HCV transmission in these three children born from the same mother infected with HCV, with special reference to both the natural course of HCV infection in the children and their genotypes of IL28B (rs8099917) and IFNL4 (ss469415590) associated with the outcome of infection.
Case Report
The mother has been followed up for hepatitis C at our hospital for 18 years. The long-term course of her HCV infection is shown in Fig. 1. The serum alanine aminotransferase (ALT) level was low, at under 30 U/L, during the follow-up period except for two occasions when it exceeded 30 U/L just after delivery of the first and second sons. She had been infected with HCV genotype 2b, and the viral load was always high before she received antiviral therapy. Both hepatitis B surface antigen and anti-immunodeficiency virus antibody were negative in her serum. Six years after the third delivery, she received antiviral therapy with pegylated interferon plus ribavirin for chronic hepatitis C according to the Japanese standard protocol [18], and the therapy was successful in achieving a sustained virologic response.
Figure 1. Clinical course and serum alanine aminotransferase (ALT) levels in the mother with chronic HCV genotype 2b infection. Positivity and negativity for serum HCV RNA are represented as plus (+) and minus (-), respectively. PegIFN/RBV: pegylated interferon plus ribavirin treatment.
The characteristics of the three children are summarized in Table 1 below.
All were boys who were born by normal spontaneous delivery 40 weeks after the start of pregnancy. All were healthy and their birth weight was almost the same, at approximately 3,400 g. Nothing in their history suggested any concern about contamination with HCV during their perinatal periods, namely, wounds, surgery or transfusion of blood products. Anti-HCV antibody in the umbilical blood was tested for at birth, and it was positive in all of them. The first and third sons had no evidence of HCV infection because neither anti-HCV antibody nor HCV RNA in serum was positive after birth. However, the second son was confirmed to be infected with HCV 108 days after the delivery showing positivity for both anti-HCV antibody and HCV RNA in serum by the first postnatal assay. HCV transmission to this child resulted in persistent infection. The long-term follow-up and clinical course of this HCV-infected child are shown in Fig. 2. The serum ALT level had been low, at under 30 U/L, for approximately the first 2 years after birth, but thereafter fluctuated above and below 30 U/L until approximately 14 years of age. The HCV genotype of this child was 2b, which was the same as the mother’s, and the high-level viremia has continued during the follow-up period. Although the factors possibly influencing maternal HCV transmission, namely, gender, birth weight, delivery conditions, the mother’s high viral titer and positivity for anti-HCV antibody in the umbilical blood, were the same among the three siblings, HCV transmission from the mother occurred only in the second child. The genetic polymorphisms of the IL28B gene (rs8099917) and IFNL4 gene (ss469415590) associated with spontaneous viral clearance were examined after obtaining written informed consent from their mother. The genotypes of the IL28B gene (rs8099917) and IFNL4 gene (ss469415590) in the second son, in whom persistent HCV infection had become established, were TG and ΔG/TT, respectively. Those in the other children who were not infected with HCV varied, being TG and ΔG/TT in the first child, and TT and TT/TT in the third child.
Table 1. Characteristics of Children Born From the HCV-Infected Mother
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||||||||||||||||||||||||||||||||||||||||||||||||
NSD: normal spontaneous delivery; n.t.: not tested; CI: cutoff index. **This assay was done using the preserved sample. HCV RNA was measured by *branched DNA assay, **real time PCR, ***qualitative PCR. |
Discussion
In this study, we observed different outcomes of HCV transmission among three brothers who had been exposed to the same HCV strain from the mother during the perinatal period. Interestingly, maternal HCV genotype 2b transmission did not occur evenly in these three siblings, despite the fact that all had the same HCV exposure as well as upbringing environment, and only the second child was infected with HCV genotype 2b. This HCV transmission led to persistent infection in this child, in whom the genotypes of the IL28B gene (rs8099917) and IFNL4 gene (ss469415590) were TG and ΔG/TT, respectively, which are unfavorable for spontaneous viral clearance after the establishment of infection [13, 19].
It is still unclear how mother-to-child HCV transmission occurs in the perinatal period, and our present findings may help to shed some light on the route of infection. During the perinatal period, there are two possible major routes of HCV transmission from mother to child: placental infection and birth canal infection. Placental infection results from active transport of virus from mother to child, or from micro-transfusion of virus due to placental membrane damage. In all of the three brothers, blood exchange between the fetus and the mother through the placenta had been good, because anti-HCV antibody (immunoglobulin G) had been transferred to all fetuses and was detected in the umbilical blood at birth in all cases. However, only the second child had been infected with HCV. Negativity for HCV RNA in the umbilical blood of this child was different from the viral titer in the serum of his mother, which indicated a very high level of HCV RNA, as shown in Table 1. Thus placental infection by active transport of HCV from mother to fetus appeared to have been negligible. Placental membrane damage possibly induced by a small wound that goes unnoticed at delivery may result in maternal HCV infection. In cases of twin delivery, HCV transmission is more likely to affect the second child because possible partial placental separation upon delivery of the first baby increases the chance of exposing the second child to maternal blood [20]. Otherwise, any small wound in child, such as on the skin or in the mucosa of the oral cavity, or the bulbar conjunctiva, may allow micro-transfusion of HCV from mother to a child, and this may result in maternal HCV transmission in the birth canal. After birth, the present three brothers were brought up in the same environment, and were breast-fed. This kind of background carries little risk of HCV infection [21]. These findings suggest that maternal HCV transmission does not usually occur in the perinatal period, with only rare exceptions due to accidental exposure such as minor placental damage or micro-wounds in the child. The prevalence of maternal HCV infection seems to be relatively low even among children exposed to the same virus, although serologic tests for HCV in children should be carefully conducted during follow-up.
Most adults with HCV infection fail to clear the virus and develop chronic hepatitis, but some are known to show resolution of the infection in a self-limiting manner. The rate of spontaneous viral clearance in the acute phase of infection is reported to be approximately 15-40% of all HCV-infected adults [9-11], and a systematic review of 31 studies has estimated this rate to be 26% [11]. In a recent genome-wide association study, the SNPs in the region of the IL28B gene encoding interferon-λ-3 were shown to be associated with the virologic response of HCV to antiviral therapy [15, 22]. Patients carrying an IL28B homozygote for the major alleles of rs12979860 (CC genotype) [22] or rs8099917 (TT genotype) [15] show a greater propensity for achieving a sustained virologic response to pegylated interferon-α and ribavirin therapy than those carrying an IL28B heterozygote or homozygote for its minor allele. This SNP (rs12979860) also influences the outcome of HCV infection in the context of natural history; the CC genotype of rs12979860, which is in high linkage disequilibrium with the TT genotype of rs8099917, enhances the resolution of HCV infection with spontaneous clearance [12, 13]. Furthermore, upstream of the IL28B gene, a dinucleotide variant ss469415590 (TT or ΔG) has been reported to be more strongly associated with HCV clearance in individuals of African ancestry than the SNP of IL28B (rs12979860) [17].
The genotype of IL28B is also associated with the outcome of infection in maternal HCV transmission; self-limiting hepatitis or persistent hepatitis has been reported in a child infected with HCV genotype 1 during the perinatal period [14]. The three children in the present report were checked for the SNPs of both the IL28B (rs8099917) and IFNL4 (ss469415590) genes, and the second son in whom HCV genotype 2b infection had been established and led to persistent infection with mild fluctuation of the ALT levels was found to carry the TG (rs8099917) type and ΔG/TT (ss469415590) type in the IL28B and IFNL4 genes, respectively. Thus the SNPs in these two genes predicted the outcome of infection in the second son with chronic HCV genotype 2b infection.
In conclusion, our present findings suggest that the chance of maternal HCV transmission is not so high even in multiple children exposed to the same HCV strain with a high viral load, and that maternal HCV transmission might be attributable to very minor events that can potentially result in viral exposure during the perinatal period. Here, the multiple deliveries did not largely affect the serum levels of ALT and HCV RNA in the mother. The genotype defined by SNPs in the IL28B gene (rs8099917) and the IFNL4 gene (ss469415590) was able to predict the development of persistent infection in the child with established maternal HCV genotype 2b transmission.
Conflict of Interest
The authors have no conflict of interest.
References
1. Ohto H, Terazawa S, Sasaki N, Hino K, Ishiwata C, Kako M, Ujiie N, et al. Transmission of hepatitis C virus from mothers to infants. The Vertical Transmission of Hepatitis C Virus Collaborative Study Group. N Engl J Med. 1994;330(11):744-750.
doi pubmed
2. Matsubara T, Sumazaki R, Takita H. Mother-to-infant transmission of hepatitis C virus: a prospective study. Eur J Pediatr. 1995;154(12):973-978.
doi pubmed
3. Zanetti AR, Tanzi E, Paccagnini S, Principi N, Pizzocolo G, Caccamo ML, D'Amico E, et al. Mother-to-infant transmission of hepatitis C virus. Lombardy Study Group on Vertical HCV Transmission. Lancet. 1995;345(8945):289-291. doi
4. Resti M, Azzari C, Mannelli F, Moriondo M, Novembre E, de Martino M, Vierucci A. Mother to child transmission of hepatitis C virus: prospective study of risk factors and timing of infection in children born to women seronegative for HIV-1. Tuscany Study Group on Hepatitis C Virus Infection. BMJ. 1998;317(7156):437-441.
doi pubmed
5. Gibb DM, Goodall RL, Dunn DT, Healy M, Neave P, Cafferkey M, Butler K. Mother-to-child transmission of hepatitis C virus: evidence for preventable peripartum transmission. Lancet. 2000;356(9233):904-907. doi
6. Dal Molin G, D'Agaro P, Ansaldi F, Ciana G, Fertz C, Alberico S, Campello C. Mother-to-infant transmission of hepatitis C virus: rate of infection and assessment of viral load and IgM anti-HCV as risk factors. J Med Virol. 2002;67(2):137-142.
doi pubmed
7. Steininger C, Kundi M, Jatzko G, Kiss H, Lischka A, Holzmann H. Increased risk of mother-to-infant transmission of hepatitis C virus by intrapartum infantile exposure to maternal blood. J Infect Dis. 2003;187(3):345-351.
doi pubmed
8. Cottrell EB, Chou R, Wasson N, Rahman B, Guise JM. Reducing risk for mother-to-infant transmission of hepatitis C virus: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013;158(2):109-113.
doi pubmed
9. Di Bisceglie AM. Natural history of hepatitis C: its impact on clinical management. Hepatology. 2000;31(4):1014-1018.
doi pubmed
10. Gerlach JT, Diepolder HM, Zachoval R, Gruener NH, Jung MC, Ulsenheimer A, Schraut WW, et al. Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology. 2003;125(1):80-88. doi
11. 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.
doi pubmed
12. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, Kidd J, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009;461(7265):798-801.
doi pubmed
13. Hung CH, Chang KC, Lu SN, Wang JH, Chen CH, Lee CM, Hu TH. Spontaneous clearance of hepatitis C virus in an interleukin 28B favorable genotype highly prevalent area. Hepatology. 2013;57(5):2089-2090.
doi pubmed
14. Ruiz-Extremera A, Munoz-Gamez JA, Salmeron-Ruiz MA, de Rueda PM, Quiles-Perez R, Gila-Medina A, Casado J, et al. Genetic variation in interleukin 28B with respect to vertical transmission of hepatitis C virus and spontaneous clearance in HCV-infected children. Hepatology. 2011;53(6):1830-1838.
doi pubmed/
15. Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41(10):1105-1109.
doi pubmed
16. Balagopal A, Thomas DL, Thio CL. IL28B and the control of hepatitis C virus infection. Gastroenterology. 2010;139(6):1865-1876.
doi pubmed
17. Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, Hergott D, et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet. 2013;45(2):164-171.
doi pubmed
18. Guidelines for the Management of Hepatitis C Virus Infection: First edition, May 2012, The Japan Society of Hepatology. Hepatol Res. 2013;43(1):1-34.
doi pubmed
19. Saito T, Ueno Y. Transmission of hepatitis C virus: self-limiting hepatitis or chronic hepatitis? World J Gastroenterol. 2013;19(41):6957-6961.
doi pubmed
20. Boxall E, Baumann K, Price N, Sira J, Brown M, Kelly D. Discordant outcome of perinatal transmission of hepatitis C in twin pregnancies. J Clin Virol. 2007;38(2):91-95.
doi pubmed
21. Indolfi G, Resti M. Perinatal transmission of hepatitis C virus infection. J Med Virol. 2009;81(5):836-843.
doi pubmed
22. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461(7262):399-401.
doi pubmed
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Digital Object Identifier (DOI): http://dx.doi.org/10.14740/jmc1736w
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Saturday, April 26, 2014
Scientists at the UA make critical end-stage liver disease discovery
Scientists at the UA make critical end-stage liver disease discoveryThe discovery of an unknown cellular pathway has helped scientists and physicians better understand end-stage liver disease and offers a potential target for new therapeutics
IMAGE: Zhang's research group studies the molecular mechanisms cells use to protect themselves from damage caused by toxicants and carcinogens.
A team of researchers in the University of Arizona's College of Pharmacy has discovered a molecular pathway that could be key to creating new therapeutics that would slow or even reverse the progression of end-stage liver disease.
Although cirrhosis of the liver is most commonly associated with alcohol or drug abuse, the condition – marked by scar tissue replacing healthy liver tissue – also can result from viral hepatitis, obesity and diabetes, as well as certain inherited diseases. According to the National Institutes of Health, cirrhosis is the 12th leading cause of death by disease in the U.S. As with many other human pathologic conditions, end-stage liver disease goes hand in hand with oxidative stress, which refers to damage inflicted to biological tissues by reactive oxygen molecules. Such molecules, also called free radicals, occur naturally as a byproduct of metabolic processes in the body and are associated with many chronic diseases including cancer, diabetes, neurodegenerative and cardiovascular diseases.
"Cells keep oxidative stress under control through various mechanisms," said Donna Zhang, a professor in the UA Department of Pharmacology and Toxicology, explaining that most of these mechanisms involve Nrf2, a protein present in virtually every cell that acts as a molecular switch. Nrf2 activates various biochemical mechanisms inside the cell that capture reactive oxygen molecules or dispose of damaged cellular components before they can cause more trouble. The antioxidants found in many fruits and vegetables exert their healthful benefits by capturing reactive oxygen molecules.
Under normal, healthy conditions, when no oxidative stress response is needed, an enzyme called Keap1 constantly chews up Nrf2, keeping its level low.
"Then, under stress from reactive oxygen molecules, or when you eat antioxidants from certain plants like broccoli sprouts, it prevents Keap1 from eating up Nrf2, allowing it to accumulate in the cell," explained Zhang, who is also a member of the UA BIO5 Institute. "Nrf2 then activates the cellular antioxidant response. That is how antioxidants work." According to conventional wisdom, our bodies turn on their Nrf2-mediated protection pathway when subjected to high oxidative stress to limit the damage from the destructive oxygen compounds. During liver cirrhosis, Nrf2 should be induced by oxidative stress, but for reasons unclear until this study, this does not happen.
"This was a puzzle before we did our study," she said. "Somehow the protective mechanism mediated by Nrf2 is compromised by another factor, other than Keap1, in liver cirrhosis." Adding to the mystery is the fact that drugs aimed at inhibiting Keap1 from chewing up Nrf2 have proven ineffective in a cirrhotic liver.
When Zhang and her colleagues studied tissue samples from a human cirrhotic liver, they discovered the reason behind the inexplicably low Nrf2 levels in the face of rampant oxidative stress.
It turned out that another enzyme chews up Nrf2 and prevents the much-needed antioxidant response, exacerbating the disease process. That protein, Hrd1, is part of the cells' garbage disposal – it specializes in destroying misfolded proteins before they can accumulate and damage cell components.
Under normal conditions, Hrd1 levels are low, so it does not interfere much with Nrf2, explained Zhang. As liver cirrhosis progresses, excessive inflammation triggers the garbage-mediated stress response and Hrd1 becomes very abundant and begins chewing up Nrf2.
The study is published in the April 1 issue of the journal Genes and Development. The first author of the report is Tongde Wu, a graduate of the UA Department of Pharmacology and Toxicology, who developed the project as part of her dissertation research. Fei Zhao and Eli Chapman, in the same department, also contributed to the research. The work resulted from a collaboration between Zhang's research group and Deyu Fang, Beixue Gao and Can Tan at Northwestern University Feinberg School of Medicine in Chicago. Other contributors are Naoko Yagishita and Toshihiro Nakajima of St. Marianna University School of Medicine in Kawasaki, Japan, and Pak K. Wong of the UA College of Engineering.
The discovery could change the way scientists develop therapeutics, as it provides a new target for future drugs. In laboratory experiments, Zhang and her colleagues were able to restore Nrf2 levels in cirrhotic liver tissue by inactivating Hrd1, effectively reversing liver cirrhosis in mice.
"Previous efforts only focused on the Keap1 protein and tried to prevent it from breaking down Nrf2," Zhang said. "Now we know there is a second player in the game – Hrd1 – that we need to inhibit in order to restore Nrf2 levels.
"Boosting Nrf2 is good for protection in general, which is why you should always eat your broccoli," she stressed.
http://www.eurekalert.org/pub_releases/2014-04/uoa-sat042514.php
HCV Weekend Reading- Fibromyalgia: A New Paradigm?
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Hello everyone, wishing you all a happy Saturday!
In this edition of "Weekend Reading" the focus is on an article published yesterday over at MedPage Today.
When I stumbled upon; "Fibromyalgia: A New Paradigm?" written by Nancy Walsh, I thought it was a good read for anyone battling both chronic hepatitis C and fibromyalgia syndrome (FMS). Although the subject matter in the MedPage piece made no mention of hepatitis C, it does investigate a burning pain which is common in FMS, and may resonate with some readers.
In fact the association between chronic hepatitis C and fibromyalgia still remains controversial, but we know that a high prevalence of fibromyalgia has been found in patients infected with hepatitis C, especially women.
As anyone with HCV knows, fatigue, muscle, and joint pain are familiar symptoms of the virus, these debilitating symptoms are also common in individuals living with fibromyalgia. According to an interesting 2012 article; The Hepatitis-Fibromyalgia Connection, written by Dr. Mark Borigini, a board-certified rheumatologist, some experts believe these common symptoms may not be a coincidence;
Fibromyalgia and chronic hepatitis C infection share many clinical features including prominent somatic complaints such as musculoskeletal pain and fatigue. In fact, some medical experts believe that the symptoms and presenting patterns in common between hepatitis C and fibromyalgia are not coincidental. There is the possibility that hepatitis C may be a trigger of fibromyalgia.
Fibromyalgia is a syndrome characterized by long-lasting widespread pain and tenderness at specific points on the body. The term “fibromyalgia” means pain in the muscles, ligaments and tendons. With sleep disturbances and fatigue also integral symptoms. Fibromyalgia has been estimated to affect more than 5 million Americans, read more over at arthritis.org.
Chronic Hepatitis C and Fibromyalgia
A study out of Ireland, published in Arthritis & Rheumatism, Volume 62, November 2010, set out to identify the observational factors which are associated with hepatitis C patients who have fibromyalgia syndrome (FMS) versus those who did not. The study recruited 185 hepatitis C patients, researchers recorded a wide array of factors such as gender, age, pain intensity, and functional impairment. The authors found the following factors to be risk factors for FMS among the patients with chronic HCV: age 45 years or more, female sex, living alone, history of depression, acquisition of HCV through blood transfusion, and presence of HCV genotype 1.
Table 1. Comparing HCV infected subjects with and without FMS
| Chronic HCV patients with FMS (n = 106) | Chronic HCV patients without FMS (n = 79) | t, p value | |
|---|---|---|---|
| Female | 82 (77%) | 28 (35%) | 17.6; 0.001 |
| age >= 45 years | 80 (73%) | 26 (33%) | 17.9; 0.001 |
| Wide spread pain | 106 (100%) | 20 (25%) | 25.7; 0.001 |
| Depression | 60 (57%) | 20 (25%) | 15.3; 0.001 |
| HCV acquisition via blood transfusion | 65 (61%) | 26 (33%) | 15.0; 0.001 |
| Genotype 1 | 82 (77%) | 20 (25%) | 20.4; 0.001 |
This study reveals a high prevalence of FMS (57%) among subjects with chronic HCV infection, one third of whom reported some degree of functional impairment. Quality of life can be improved with recognition and management. Chronic hepatitis C patients who show the corresponding risk factors may have a higher liklihood of having FMS.
Reference: Mohammad, Ausaf, Carey, John J., Storan, Eoin R., Scarry, Margaret, Keane, Mary B., Moore, Angela, et al; The Prevalence of Fibromyalgia in Patients with Chronic Hepatitis C Infection. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :817
DOI: 10.1002/art.28585
MedPage Today
Fibromyalgia: A New Paradigm?
Research into small fiber neuropathy is explored and its possible relation to pain associated with fibromyalgia. Symptoms of small fiber neuropathy consists of pain, burning, tingling, and numbness in the feet, legs and hands, a symptom people living with both HCV and FMS are all too familiar with, the article is provided below, or click here to view both the article and video online at MedPage Today.
Fibromyalgia: A New Paradigm?
Skin biopsies revealed lower mean epidermal nerve fiber density among patients with fibromyalgia compared with controls at both the calf (5.8 versus 7.4, P<0.0002) and thigh (9.3 versus 11.3, P<0.0007), according to Xavier J. Caro, MD, of Northridge Hospital Medical Center in Northridge, Calif., and Earl F. Winter, PhD, of North Central University in Prescott, Ariz.
This "surprisingly high prevalence" of decreased epidermal nerve fiber density suggested peripheral nervous system injury that could be contributing to pain, according to the authors.
There also was an inverse correlation between the epidermal nerve fiber density at the calf and interleukin (IL)-2R, which is an activation marker of T-cells and macrophages (r=-0.28, P=0.04), supporting the additional concept that this is an immune-mediated process, Caro and Winter reported online in Arthritis & Rheumatology.
"These observations indicate that the current operative paradigm in fibromyalgia, in which central sensitization is viewed as the prime mover in this disorder, requires modification," they wrote.
Neuropathy and Fibromyalgia?
Other experts urge caution, however.
Daniel J. Clauw, MD, of the University of Michigan in Ann Arbor, who has conducted extensive research into fibromyalgia and recently wrote a clinical review of the condition in JAMA, said, "We simply don't know yet what finding small fiber neuropathy means in fibromyalgia."
"Small fiber neuropathy has been found in multiple chronic pain conditions so the meaning of this finding is unclear. Also, many cardinal symptoms of fibromyalgia (fatigue, sleep, memory, and mood disturbances) cannot be explained by neuropathy, and the distribution of the pain in fibromyalgia (e.g., headaches, irritable bowel, interstitial cystitis) doesn't match that of small fiber neuropathy. So we need to be careful about drawing conclusions from these findings," Clauw told MedPage Today.
The underlying pathophysiology associated with fibromyalgia continues to be uncertain, at least in part because of the lack of a specific tissue lesion.
"As a result, the idea has developed that a central nervous system origin for fibromyalgia is the only viable explanation for its existence," Caro and Winter wrote.
They noted that their interest into a potential peripheral nervous system origin for fibromyalgia stemmed from their observation that many patients described their pain in terms similar to those used by patients with peripheral neuropathy.
They previously explored this by electrodiagnostic testing and sural nerve biopsies, but such biopsies are difficult and expensive. More recently, reports have suggested that skin biopsies to quantitate epidermal nerve fiber density could be a useful tool for the evaluation of peripheral neuropathy.
The Clinical Study
Between January 2007 and August 2011 Caro and Winter assessed 41 consecutive patients who met the 1990 American College of Rheumatology criteria for fibromyalgia, along with 47 controls.
Participants underwent sensory testing, laboratory analyses, physical examinations, and punch skin biopsies at the anterolateral proximal thigh and distal leg.
The majority were women. Mean ages were 61 years for patients and 48 for controls.
All patients showed a "stocking distribution" of diminished sensory perception.
Among other findings were:
A significant inverse correlation between age and calf epidermal nerve fiber density in patients (r=-0.29, P=0.03), though not controls
A trend toward a significant inverse correlation between epidermal nerve fiber density at the thigh and IL-2R in the fibromyalgia patients (r=-0.22, P=0.08)
A trend was toward significance between symptom duration and IL-2R (r=-0.24, P=0.07), though not with epidermal nerve fiber density at either calf or thigh
"As a signal, IL-2R has been thought reliable enough so that it has been used to monitor the course of some autoimmune diseases," Caro and Winter wrote.
In addition, patients' pain rating on a 10-point scale and physician global 3-point tenderness score correlated with each other (r=0.51, P=0.0005) although pain didn't correlate with nerve fiber density.
Pain and Immunity
Small fiber neuropathy is associated with both loss of sensation to the skin and peripheral pain, so the finding of the stocking distribution of diminished perception was "not unexpected," according to the authors.
"The painful peripheral symptoms of small fiber neuropathy, on the other hand, are thought to be due to a disproportionate hyperexcitability of the primary, lesioned -- but not altogether defunct -- small nerve fibers and a surrounding, structurally normal, but physiologically hyperexcitable group of secondary small nerve fibers responding collaterally," they wrote.
But small fiber neuropathy isn't an entirely new concept, according to Ali Askari, MD, of UH Case Medical Center in Cleveland.
"It has come to light in the last decade, and explains a lot of the uncomfortable feelings in the legs and hands and other parts of the body in fibromyalgia," Askari said in an interview.
The exact reason for decreased epidermal nerve fiber density in these fibromyalgia patients "is not entirely self-evident," Caro and Winter noted.
"Nevertheless, in the absence of data implicating any other known neuropathic disorder in the genesis of this lesion, we consider it likely that an immunopathogenic mechanism is at work in this patient population," they wrote.
"According to our data, this nexus between the immune system and fibromyalgia is likely to be influenced by a T-cell mediated arm. It may also involve factors within a system commonly referred to as neurogenic inflammation," they added.
Another View
An editorial accompanying the study described the understanding of fibromyalgia as still incomplete.
"What we call fibromyalgia may be at the crossroads of different pathophysiological situations with a common clinical background phenotype," wrote Piercarlo Sarzi-Puttini, MD, and Fabiola Atzeni, MD, PhD, of Sacco University Hospital in Milan.
"Where does fibromyalgia originate? Is it due to a genetic and/or familial predisposition, a stress-related personality disorder, a psychoaffective disorder, or a post-traumatic stress disorder? It may be all of these or none," Sarzi-Puttini and Atzeni commented.
"All we can do is continue to look for tissue abnormalities and central processing alterations in an attempt to discover which come first, and then develop the best therapeutic (or, even better, preventive) strategy for the 2% to 3% of the population who suffer from the disease," the editorialists concluded.
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