Showing posts with label women. Show all posts
Showing posts with label women. Show all posts

Thursday, May 15, 2014

What Every Woman Needs to Know About Hepatitis B and C

What Every Woman Needs to Know About Hepatitis B and C



This webinar highlights the importance of our liver and the 500 vital functions it performs, viral hepatitis and how this disease can damage the liver; and the good news -- that a vaccine to prevent hepatitis B, treatments for hepatitis B and C, and a cure for hepatitis C -- are available!!

The Office of HIV/AIDS and Infectious Disease Policy (OHAIDP) and the Office of Women's Health (OWH) hosted a webinar with the following objectives:

Increase awareness and knowledge of viral hepatitis and its impact on women, especially among OWH grantees;

Encourage OWH grantees and others to share viral hepatitis information with their communities; and

Provide a woman's personal perspective on being diagnosed with and treated for hepatitis C.

Also See:
Women and HCV

http://www.scribd.com/fullscreen/216044755?access_key=key-ghxrelvh49ka8xbfivn&allow_share=false&escape=false&show_recommendations=false&view_mode=slideshow


The effect of hepatitis C on the female gender remains a controversial topic, literature into various aspects of infection, such as spontaneous clearance, progression of fibrosis, response to interferon-based therapy favor women but vary in different study cohorts, and have been found to be highly influenced by two female host factors; age and menopausal status.

In this slide-set we explore all of the above, HCV transmission and gender specific host factors that can influence disease progression using recent literature published in the Journal of Viral Hepatitis, and Hepatology, as well as the article; “Women With Chronic Hepatitis C Virus Infection Recommendations for Clinical Practice,” found in the July 2013 issue of Southern Medical Journal.

Begin Here........


Tuesday, October 29, 2013

Estrogen protects women with NASH from severe liver fibrosis

Estrogen protects women with NASH from severe liver fibrosis

New research suggests that estrogen protects women with nonalcoholic steatohepatitis (NASH) from severe liver fibrosis. According to the study published online in Hepatology, a journal of the American Association for the Study of Liver Diseases, men are at higher risk of more severe fibrosis compared to women prior to menopause, but liver fibrosis severity is similar in men and post-menopausal women.

Non-alcoholic fatty liver disease (NAFLD) includes a range of liver disorders from simple fatty liver to inflammation, fibrosis, and cirrhosis. With the rapid rise in obesity, diabetes and metabolic syndrome, the prevalence of NAFLD—the result of insulin resistance—has also steadily increased. In fact, studies suggest that the NAFLD prevalence is 10% to 30%, making it the most common liver disease in the U.S.

"While most NAFLD patients have a mild disease known as fatty liver or hepatic steatosis, some patients present with NASH, which is more severe and increases overall mortality," explains Dr. Ayako Suzuki with the Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences in Little Rock, the lead author of the present study. "Our study aim was to investigate whether gender and menopause significantly impact fibrosis severity among adult patients with NAFLD."

The research team analyzed data from 541 adults with NASH who were seen at Duke University Liver Clinics and the Duke Metabolic and Weight Loss Surgery Program. The mean age of subjects was 48 years, with 35% of the group being men, 28% pre-menopausal women and 37% post-menopausal women.

Findings indicate that 22% of the cohort had advanced fibrosis. After adjusting for known predictors of fibrosis, the risk for greater fibrosis severity in post-menopausal women and men vs. pre-menopausal women was 1.4-fold and 1.6-fold, respectively. Furthermore, when dividing the cohort at age 50, which is the average age at menopause in the US, the risk for greater fibrosis severity in men vs. women before age 50 was 1.8-fold, while after the age 50 the risk was reduced to 1.2-fold.

"Our findings suggest a protective effect from estrogen against development of severe fibrosis," concludes Dr. Suzuki. "Further study of the impact of estrogen on fibrosis progression in NASH patients is needed."
More information: "Gender and Menopause Impact Severity of Fibrosis Among Patients with Nonalcoholic Steatohepatitis." Ju Dong Yang, Manal F Abdelmalek, Herbert Pang, Cynthia D Guy, Alastair D Smith, Anna Mae Diehl and Ayako Suzuki. Hepatology; (DOI: 10.1002/hep.26761) Published online: October 1, 2013.
                        
Journal reference: Hepatology      
Provided by Wiley

This study was funded by grants from the National Institute on Alcohol Abuse and Alcoholism (5RC2 AA019399), and the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) (U01-DK57149 and K23-DK062116).

Photo Credit - health.msn.co.nz 

Monday, October 28, 2013

Hepatitis C - Pregnant women may pass heartier viral strain to newborns


Pregnant women with hepatitis C may pass heartier viral strain to newborns, study suggests

Infants who get hepatitis C from their mothers during childbirth may inherit a viral strain that replicates more quickly than strains found in non-pregnant hosts, according to a new study published Oct. 27 in Nature Medicine. The findings, from a team in The Research Institute at Nationwide Children's Hospital, are the first to describe how a virus that has infected 180 million people worldwide takes advantage of immune changes during pregnancy.

About 1 percent of all pregnant women worldwide have hepatitis C, caused by a highly adaptable virus known as HCV that infects liver cells. In 3 to 5 percent of these pregnancies, the virus is passed to the newborns, accounting for the majority of new childhood HCV infections. Between 15 and 45 percent of people infected with HCV are able to mount an immune response sufficient to eradicate the virus. But in most cases, the virus eludes immunity, leading to a chronic infection that increases the risk of liver failure or liver cancer.

As part of a larger study of HCV in pregnant women and infants, researchers at Nationwide Children's followed two women with hepatitis C over a five-year period. Both women had two children during this time, and researchers were able to track the virus before, during and after pregnancy. Their analysis revealed surprising changes in HCV genomes that not only allowed the virus to thrive, but also ensured that the strain passed on by one of the women during childbirth was particularly good at replication, says Jonathan R. Honegger, MD, an infectious disease specialist and principal investigator in the Center for Vaccines and Immunity at Nationwide Children's.

"We found that better replicating versions of the virus emerged during pregnancy, and these 'fit' viruses were passed to the babies." Dr. Honegger says. "The findings actually provide unique insight into the impact of pregnancy on the mothers' control of viral infections, and also a striking illustration of this virus' ability to adapt to changing environmental pressures."

HCV persists in the general population, in part, because the virus outwits the immune system with mutations that can render it undetectable to CD8+ T-cells, important weapons in the body's antiviral immune arsenal. Although these viral variations—called immune escape mutations—protect the virus from attack by T-cells, they sometimes slow the virus replication machinery.

During pregnancy, T-cells are restrained to prevent the body from attacking the fetus as foreign tissue. Viral levels of HCV have also been known to increase during pregnancy, but whether this was related to changes in T-cell function was unknown. Working closely with Chris Walker, director of the Center for Vaccines and Immunity, and colleagues at Emory University and the University of North Carolina, Dr. Honegger found that during pregnancy, certain T-cell escape mutations were lost, resulting in a virus that could replicate far more quickly.

"This surprised us because the virus' immune escape mutations are usually stable in a patient," Dr. Honegger says. "The loss of these immune escape mutations from HCV during pregnancy provided strong evidence that the immune changes of pregnancy, intended to protect the fetus, significantly impaired the ability of CD8+ T-cells to exert pressure on the virus."

Loss of the escape mutations also meant that the babies got a version of the virus that was optimized for viral replication, Dr. Honegger adds. In the children they studied, the virus persisted and did not mutate in a way to suggest that it was under significant attack by their CD8+ T-cells.

"We don't yet know whether getting the fast-replicating, immune-susceptible version of the virus would be an advantage for the baby or the virus," says Dr. Honegger, who also is an assistant professor of pediatrics at The Ohio State University. "We suspect that if the baby doesn't mount a swift and strong immune response, then fast viral replication may increase the risk of persistent infection in the baby."

On the other hand, viral loads in the mothers dropped more than 1,000 fold by 12 weeks after delivery and viral genetic analysis showed that immune escape mutations had returned. "We interpreted this to mean that T-cell activity against hepatitis C in the liver increased sharply after delivery," Dr. Honegger says.

Researchers now are following a larger group of pregnant women with HCV, hoping to learn more about how viral mutations affect the way the body controls hepatitis C in pregnant women and infants.

"We believe that better understanding of the natural history of the infection in these patients will be critical for designing rational strategies to treat or prevent HCV in these populations."

###

Full citation: Honegger JR, Kim S, Price AA, Kohout JA, McKnight KL, Prasad MR, Lemon SM, Grakoui A, Walker CM. Loss of Immune Escape Mutations During Persistent HCV Infection in Pregnancy Enhances Replication of Vertically Transmitted Viruses. Nature Medicine. 2013 Oct 27. doi: 10.1038/nm.3351 [Epub ahead of print]

Funding: This work was supported by the US National Institutes of Health (R37-AI47367 to C.W, R56-AI096882 and R01-AI096882 to C.W and J.H., RO1-DA024565 and R01-AI95690 to S.L., R01-AI070101 and R01-DK083356 to A.G., T32-HD043003 and K12-HD043372 to J.H., and the Yerkes Research Center Base Grant P51RR-000165 (A.G.)), The Research Institute at Nationwide Children's Hospital (C.W. and J.H.), and the University of North Carolina University Cancer Research Fund (S.L.).

Nationwide Children's Hospital
2013 Oct 27. doi: 10.1038/nm.3351. [Epub ahead of print]
 
Loss of immune escape mutations during persistent HCV infection in pregnancy enhances replication of vertically transmitted viruses.
 
 
Source
1] The Center for Vaccines and Immunity, Nationwide Children's Hospital, Columbus, Ohio, USA. [2] Department of Pediatrics, The Ohio State University School of Medicine, Columbus, Ohio, USA.

Abstract
Globally, about 1% of pregnant women are persistently infected with the hepatitis C virus (HCV). Mother-to-child transmission of HCV occurs in 3-5% of pregnancies and accounts for most new childhood infections. HCV-specific CD8+ cytotoxic T lymphocytes (CTLs) are vital in the clearance of acute HCV infections, but in the 60-80% of infections that persist, these cells become functionally exhausted or select for mutant viruses that escape T cell recognition. Increased HCV replication during pregnancy suggests that maternofetal immune tolerance mechanisms may further impair HCV-specific CTLs, limiting their selective pressure on persistent viruses. To assess this possibility, we characterized circulating viral quasispecies during and after consecutive pregnancies in two women. This revealed a loss of some escape mutations in HLA class I epitopes during pregnancy that was associated with emergence of more fit viruses. CTL selective pressure was reimposed after childbirth, at which point escape mutations in these epitopes again predominated in the quasispecies and viral load dropped sharply. Importantly, the viruses transmitted perinatally were those with enhanced fitness due to reversion of escape mutations. Our findings indicate that the immunoregulatory changes of pregnancy reduce CTL selective pressure on HCV class I epitopes, thereby facilitating vertical transmission of viruses with optimized replicative fitness.

Thursday, October 10, 2013

Human breast milk inactivates hepatitis C virus infectivity

Human breast milk inactivates hepatitis C virus infectivity

Wednesday Oct 09, 2013 | Reuters

Clinical

Last Updated: 2013-10-09 12:35:30 -0400 (Reuters Health)

By Will Boggs, MD

NEW YORK (Reuters Health) - A new study shows why breastfeeding is generally safe even when mothers are infected with the hepatitis C virus (HCV).

The reason is that human breast milk inactivates hepatitis C virus (HCV) infectivity by disrupting its envelope, researchers from Germany have found.

"This study provides a novel mechanism for the protective properties of human mother's milk against HCV," Dr. Eike Steinmann from the TWINCORE Center for Experimental and Clinical Infection Research in Hannover told Reuters Health by email. "A new finding is that lipases in human milk generate free fatty acids that damage the viral envelope and render them non-infectious."

In an editorial published with the paper online September 24 in The Journal of Infectious Diseases, Dr. Ravi Jhaveri from the University of North Carolina in Chapel Hill says "the results provide a plausible explanation for why breastfeeding is not a risk factor for HCV transmission. This is reassuring for us as practitioners when we counsel our HCV patients that it is safe for them to breastfeed."

Using breast milk from healthy HCV-negative women, the research team found that even short preincubation periods of HCV in the milk brought consistent reductions of HCV infectivity by 2 to 3 orders of magnitude.

The breast milk inactivated HCV infectivity independent of the viral genotype, and antiviral activity was concentration dependent. Concentrations between 4% and 6% milk were sufficient to reduce HCV infectivity, whereas higher dilutions abolished the antiviral effect.

The antiviral activity was specific to human milk. It was not found in milk from horses, cows, or commercial infant formula.

The anti-viral activity was not destroyed by heat treatment, the authors reported.

In a series of experiments, the researchers showed that lipases in human milk generated fatty acids that disrupted the viral envelope, resulting in the loss of viral infectivity.

"Similar processes concerning the release of free fatty acids take place upon digestion of human breast milk by the infant," the investigators note. "Therefore, milk digestion products, like free fatty acids, released in the stomach might be able to inactivate residual viral particles which otherwise could be transmitted upon breastfeeding."

Human breast milk also had significant antiviral effects against other enveloped viruses (influenza, herpes simplex, and vesicular stomatitis virus) but no pronounced effect on non-enveloped viruses (murine norovirus, rotavirus).

"As there are far more enveloped viruses known than tested in this study, further investigations are necessary," Dr. Steinmann said.

"Human breast milk efficiently inactivates HCV in vitro and neither the Centers for Disease Control nor the American Association for the Study of Liver Diseases argues against breastfeeding from HCV infected women unless they have cracked or bleeding nipples," Dr. Steinmann concluded.

Dr. Jhaveri's editorial concludes, "After reading this article, when we clinicians next encounter an HCV infected patient that just delivered a healthy infant and wants to breastfeed, we have yet another reason to say 'Breast is Best.'"

SOURCE: http://bit.ly/GGK0gJ

J Infect Dis 2013.

Copyright © 2013 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.

Thursday, August 1, 2013

The Safety of Chemotherapy for Breast Cancer Patients with Hepatitis C Virus Infection


2013 Jul 24;4(6):519-23. doi: 10.7150/jca.6231. Print 2013.
 
The safety of chemotherapy for breast cancer patients with hepatitis C virus infection.
 
 
Source
1. Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan.

Abstract
Background: Hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease, and more than 880,000 people are estimated to be infected with HCV in Japan. Little information is available on the outcomes of HCV during chemotherapy for solid tumors, and the impact of HCV infection on toxicity of chemotherapy is unknown.

Materials and methods: We performed a retrospective survey of 1,110 patients diagnosed with breast cancer between January 2006 and March 2011 at our institution. All patients had been screened for hepatitis C serology at diagnosis of breast cancer. We retrospectively investigated the change in HCV load and the toxicities of chemotherapy, based on review of their medical records.

Results: 23 patients were identified as having a positive test for anti-HCV antibodies. Ten of these patients received chemotherapy. Their median age was 66 years. No patient had decompensated liver disease at baseline. Eight patients received cytotoxic agents with or without trastuzumab, and two patients received trastuzumab alone. Four of eight patients who received cytotoxic chemotherapy developed febrile neutropenia and one developed transaminases elevation. Serum HCV-ribonucleic acid (RNA) level before and after chemotherapy was evaluated in six patients. Median serum HCV-RNA level at baseline and after chemotherapy was 6.5 and 6.7 logIU/ml, respectively.

Conclusion: Chemotherapy for breast cancer patients with HCV infection is feasible, and viral load doesn't change during the chemotherapy.

Keywords: HCV, HCV-RNA, febrile neutropenia, Child-Pugh criteria, liver cirrhosis, chemotherapy.

Introduction Only

Full Article Available Here

Hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease, and more than 880,000 people are estimated to be infected with HCV in Japan (1). The estimated number of HCV carriers increases with age, therefore, carriers aged from 40 to 69 years account for more than 80% of cases (1). Breast cancer is the most common cancer among Japanese women (2). Furthermore, the age-adjusted breast cancer incidence rate has been increasing since 1975, and the incidence rate of breast cancer is highest in the age group of 40-49 years in Japan (2).

Little information is available on the status of HCV during chemotherapy for solid tumors and the influence of HCV infection on toxicity of chemotherapy is also unknown. Although there are guidelines for management of patients with Hepatitis B virus during chemotherapy, there are no data to support the use of chemotherapy to treat HCV-positive patients with solid tumors (3, 4). Some reports have noted the reactivation of HCV in patients with lymphoma who have received rituximab and combination chemotherapy (5, 6). However, there are substantial differences in immunosuppressive mechanisms between rituximab-based chemotherapy for hematologic malignancies and conventional chemotherapy for solid tumor, because rituximab, an anti-CD20 antigen, mainly inhibits B-cell function. Therefore, it may not be appropriate to use the same management during chemotherapy for HCV carrier patients with solid tumors.

The purpose of this study was to evaluate the safety profile and the change in HCV viral load during chemotherapy for HCV-carrier patients with breast cancer

Miura Y, Theriault RL, Naito Y, Suyama K, Shimomura A, Iwatani T, Miura D, Kawabata H, Kumada H, Takano T. The Safety of Chemotherapy for Breast Cancer Patients with Hepatitis C Virus Infection. J Cancer 2013; 4(6):519-523. doi:10.7150/jca.6231.

Full Text Article Available from http://www.jcancer.org/v04p0519.htm

Received 2013-3-11
Accepted 2013-5-23
Published 2013-7-24


 

Wednesday, July 24, 2013

Updates: Women With Chronic Hepatitis C Virus Infection

 
 
Filter through the many July updates on the website by clicking on the links provided below. Topics include; liver health, updated research on current or new therapies in development to treat hepatitis C, videos and more.

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All Updates: Women and HCV
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The natural history of hepatitis C virus infection differs between women and men. Women demonstrate a slow rate of disease progression until menopause. Older women are more likely to develop fibrosis and are less responsive than younger women to pegylated interferon and ribavirin. Women of childbearing age have higher rates of sustained virologic response, but current therapies are contraindicated during pregnancy. Vertical transmission of hepatitis C virus  occurs, but data supporting recommendations for prevention of mother-to-infant transmission are limited...
 
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In draft guidance published today NICE recommends peginterferon alfa in combination with ribavirin as an option for treating chronic hepatitis C in children and young people.
 
Among pediatric patients with HCV infection the effectiveness of PEG-IFN/RBV therapy may be lower in the group with genotype-1 IL28B minor alleles than in other groups with IL28B major allele. Treatment strategy should be carefully implemented in patients with IL28B unfavorable type.

Peginterferon/ribavirin effective for children, adolescents with chronic HCV
Treatment of chronic hepatitis C with pegylated interferon and ribavirin is effective and relatively safe for children and adolescents, according to recent results. Researchers performed a systematic review and meta-analysis of eight trials assessing the use of pegylated interferon (PEG-IFN) alfa-2a or 2b with ribavirin (RBV) in patients aged 3 to 18 years with chronic HCV.
 
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All Updates: HCV In Elderly Patients
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Abstract: A pilot study of triple therapy with telaprevir, peginterferon and ribavirin for elderly patients with genotype 1 chronic hepatitis C.
Results suggest that 24-week triple therapy with telaprevir 1,500 mg seems safe and efficacious for elderly Japanese patients infected with HCV genotype 1b.....

Abstract: Various Predictors of Sustained Virologic Response in Different Age Groups of Patients With Genotype-1 Chronic Hepatitis C.
SVR rate was highest in patients younger than 45 years and lowest in patients older than 65 years even through propensity score matching analysis. As for the SVR predictors ....
 
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All Updates: Liver Health Articles and Research
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Liver Transplant Houston: Is There a Special Diet to Follow?
A common question I am asked daily is in regard to “what kind of diet do I need to be on while waiting for my liver  transplant?”. There is a great deal of misunderstanding surrounding this, that it deserves a few simple comments.

Fat in Liver, Muscle, and Blood Increases Osteoporosis Risk
A new US study has revealed that, in addition to excess stomach fat, high fat levels in the liver and blood are also dangerous. The study, which was published in "Radiology", showed that people with higher levels of fat in their liver, muscle tissue and blood also have higher amounts of fat in their bone marrow, which increases the risk for osteoporosis.

Miriam A. Bredella from the Harvard Medical School in Boston and her team used proton magnetic resonance spectroscopy (MRS) to examine 106 men and women, aged 19 to 45 years, who were obese based on body mass index measurements, but otherwise healthy.

The researchers discovered that people with more liver and muscle fat had higher levels of fat in their bone marrow, independent of body mass index, age and exercise status. HDL cholesterol, the "good" type of cholesterol, was inversely associated with bone marrow fat content. Triglyceride levels had a positive correlation with bone marrow fat.

"Obesity was once thought to be protective against bone loss. We have found that this is not true," said Bredella. "If you have a spine that's filled with fat, it's not going to be as strong."
Article Source
Study available @ Medscape

Binge eating has scarred my liver
By Claire Bates BBC Science
When actor Ricky Grover, 51, was asked to take part in a TV programme testing for three serious health conditions he had no qualms in signing up. And tests revealed Mr Grover was showing signs of two of them. A skin-prick test revealed he had Type 2 diabetes while an MRI scan showed scarring, known as fibrosis, on his liver.....

FDA Voice -Reminds Consumers to Use Acetaminophen Safely
To help avoid the risk of liver damage, make sure you understand the information provided on the medicine label or the directions given by your health care professional....

Cutting Back on Fat and Sugar (In the Diabetic Liver)
In a way, the diabetic liver is like a lot of us—too in love with fat and sugar. In type 2 diabetes, the liver floods the bloodstream with three times more glucose than does a healthy liver, while at the same time storing more and more fat that can lead to chronic liver disease, cirrhosis, and liver cancer.

Eating Raw Oysters - Vibrio Vulnificus Bacteria Lurks In Gulf Waters
Those with liver damage due to excessive drinking and individuals with liver disease, including Hepatitis C and cirrhosis, are most at risk for developing serious illness from Vibrio vulnificus

Video
Hepatitis A and Hepatitis B Vaccine: Dr. Joe Galati Explains
Viral hepatitis most common causes of both cirrhosis and liver cancer 

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All Updates: 2013-Hepatitis C Full Text Articles
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Management algorithm for genotype 1 hepatitis C virus
Hepatitis C virus (HCV) infection is the most common etiology of chronic liver disease in Western countries. Morbidity and mortality due to HCV-related end-stage liver disease are increasing, just as novel therapeutics arrive with the promise of better cure rates that prevent these complications.
However, substantial barriers to successful application of these novel treatments remain, including the lack of providers with sufficient knowledge to address this epidemic. To address these deficits, this article aims to provide a general framework with algorithms to guide initial management decisions for HCV genotype 1 infection, the most commonly found genotype, based on therapies approved as of 2013.

Patients with hepatitis C infection and normal liver function: an evaluation of cognitive function

Direct-Acting Antivirals for the Treatment of Chronic Hepatitis C: Open Issues and Future Perspectives

Of Interest
Management of Treatment-Naïve Genotypes 2 and 3 HCV Infection

Advanced fibrosis is not a negative pretreatment predictive factor for genotype 2 or 3 chronic hepatitis C patients

Aust Fam Physician - Hepatitis C - An update

Durability of SVR in HCV patients treated with peg/riba and a direct-acting anti-viral
To evaluate the long-term durability of viral eradication in patients treated with triple therapy, including direct-acting anti-virals.

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All Updates: Chronic hepatitis C: Treat or wait?
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Not Waiting for New Hepatitis C Treatment
by Lucinda Porter, RN on July 18, 2013 With new hepatitis C medications in the pipeline, I’ve heard people wonder if everyone should wait, or if there are reasons why patients might want to start treatment now. Here are some reasons why patients are starting treatment now, rather than waiting .....

Video Vignettes -Current Outlook On Hepatitis C Treatment
With rapid advancements in the field and new agents offering potential improvements in outcomes, shorter treatment durations, and unique adverse event profiles, clinicians must stay informed of the evolving data in order to counsel patients appropriately--in particular, those who may wish to discuss the benefits and risks of initiating therapy now vs delaying treatment. This program will consist of a series of four video vignettes presenting interviews with clinical experts who will explore some of the most pressing issues in the management of patients with HCV.

Janssen’s Simeprevir: Hep C Patients Hope It Is Worth the Wait
Simeprevir, a protease inhibitor developed by Janssen and Medivir, is 1 of the prospective agents that has been creating a stir in the HCV community The FDA recently granted the drug priority review, which may accelerate its journey to market and help close the treatment gap for patients in need. Janssen is seeking approval for simeprevir administered once daily along with pegylated interferon and ribavirin to treat adult patients with genotype 1 chronic
HCV with compensated liver disease.

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All Updates: Interferon Free Combinations
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Interferon-free Regimen for Hepatitis C Advances
The direct-acting antiviral combination, manufactured by AbbVie Pharmaceuticals, consists of the proteaseinhibitor ABT-450, the non-nucleoside NS5B polymerase inhibitor ABT-333, and the novel NS5A inhibitorABT-267. When used in combination with ribavirin, it reportedly produces sustained virologic response ratesof up to 99% in patients with hepatitis C.

Treatment Action Group 2013 Pipeline Report
"An impressive 26  new HCV drugs are being studied in phases II/III in at least28 interferon-free regimens, which are bringing the potential of  faster, all-oral HCVcures rapidly toward approval for the world’s 185 million people living with  HCV"

A brighter future in the fight against hepatitis  An interferon-free therapy for hepatitis C may also soon exist. In April, a triple combination of direct-acting antivirals without interferon showed efficacy in treatment-naive individuals and in nonresponders to standard of care

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All Updates: 2013 Stem Cell News and Research
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Perspectives on human micro-liver-like structures made from iPS cells

A Science First: Japanese researchers grow human liver using stem cells

Don’t market stem-cell products ahead of proof

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All Updates: HCV Triple-therapy Side Effects
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Renal impairment is frequent in chronic hepatitis C patients  under triple therapy with telaprevir or boceprevir

Health-related QOL poorer during early HCV treatment with addition of telaprevir

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All Updates: Drug To Drug Interactions in Triple Therapy 
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There were several presentations in Wednesday’s session on drug interactions with new HCV agents in development and one survey on drug interactions with the currently licensed DAAs, boceprevir and telaprevir.
 
A  review of data from clinical trials indicated that the anti-HCV protease inhibitors telaprevir (Incivek or Incivo) and boceprevir  (Victrelis) did not add to the psychiatric adverse-event profile of  existing HCV therapy. However, the investigators identified several significant interactions between the protease inhibitors and a number of antidepressants, benzodiazepines, anticonvulsants and antipsychotics. 

Drug interactions may compromise response to boceprevir and telaprevir
Concurrent use of drugs that alter concentrations of boceprevir (Victrelis) or telaprevir (Incivek or Incivo) in the body may contribute to poor response to interferon-based triple therapy for chronic hepatitis C virus (HCV), according to study findings presented at the Digestive Disease Week meeting (DDW 2013) last month in Orlando.

Few Quick Links - News Updates
News/Incivek (Telaprevir)
News/Victrelis (Boceprevir)
Sofosbuvir (GS-7977 and PSI-7977)
News/Fibrosis
News/Cirrhosis
News/Transplant
News/Liver Cancer

Monday, January 14, 2013

Reducing Risk for Mother-to-Infant Transmission of Hepatitis C Virus: A Systematic Review for the U.S. Preventive Services Task Force

View all Updates Here

Reducing Risk for Mother-to-Infant Transmission of Hepatitis C Virus: A Systematic Review for the U.S. Preventive Services Task Force

Erika Barth Cottrell, PhD, MPP; Roger Chou, MD; Ngoc Wasson, MPH; Basmah Rahman, MPH; and Jeanne-Marie Guise, MD, MPH

[+] Article and Author Information

Abstract
Background: Mother-to-infant transmission is the leading cause of childhood hepatitis C virus (HCV) infection, with up to 4000 new cases each year in the United States.

Purpose: To evaluate effects of mode of delivery, labor management strategies, and breastfeeding practices on risk for mother-to-infant transmission of HCV.

Data Sources: MEDLINE (1947 to May 2012), the Cochrane Library Database, clinical trial registries, and reference lists.

Study Selection: Randomized trials and observational studies on mode of delivery, labor management strategies, and breastfeeding practices and risk for mother-to-infant transmission of HCV.

Data Extraction: Investigators abstracted and reviewed study details and quality using predefined criteria.

Data Synthesis: Eighteen observational studies evaluated the association between mode of delivery, labor management strategies, or breastfeeding practices and risk for mother-to-infant HCV transmission. Fourteen studies (2 good-quality, 4 fair-quality, and 8 poor-quality studies) found no clear association between mode of delivery (vaginal versus cesarean delivery) and risk for transmission. Two studies (1 good-quality and 1 poor-quality study) reported an association between prolonged duration of ruptured membranes and increased risk for transmission. Fourteen studies (2 good-quality, 2 fair-quality, and 10 poor-quality studies) found no association between breastfeeding and risk for transmission.

Limitations: Only English-language articles were included. Studies were observational, and most had important methodological shortcomings, including failure to adjust for potential confounders and small sample sizes.

Conclusion: No intervention has been clearly demonstrated to reduce the risk for mother-to-infant HCV transmission. Avoidance of breastfeeding does not seem to be indicated for reducing transmission risk.

Primary Funding Source: Agency for Healthcare Research and Quality.


An estimated 40 000 children are born to hepatitis C virus (HCV)–positive women each year (1). Mother-to-infant (vertical) transmission is the main route of childhood HCV infection (2). Estimates for the rate of vertical transmission range from 3% to 10% (2 - 5). Risk for transmission is highest among women with a high viral load at delivery (2 - 6) and those co-infected with HIV (5,7). Although antiviral therapies are contraindicated in pregnancy because of teratogenic risks, prenatal HCV screening to identify HCV-infected women unaware of their status might lead to other interventions during labor and delivery or in the perinatal period that reduce risk for mother-to-infant transmission (8).

The purpose of this review was to synthesize the evidence on the effects of mode of delivery, labor management strategies, and breastfeeding practices on risk for mother-to-infant transmission. This review was performed as part of a larger report on HCV screening (9) and will be used by the U.S. Preventive Services Task Force (USPSTF) to inform its prenatal HCV screening recommendations.

Discussion Only
Full Text Available @ Annals Of Internal Medicine

Vertical transmission is the leading cause of childhood HCV infection, and identification of effective management strategies to reduce risk for transmission is an important clinical and public health concern. However, the primary finding of this review as summarized in the Table is that no perinatal management strategy has clearly been shown to reduce risk for HCV transmission. Observational studies consistently found no evidence of an association between breastfeeding and risk for vertical transmission, consistent with data suggesting that transmission typically occurs in utero (23,33). Evidence on the effects of labor management strategies and mode of delivery on risk for transmission was somewhat conflicting. Two studies (5,24) reported increased risk for HCV transmission with more prolonged duration of ruptured membranes, similar to findings for other infectious agents transmitted vertically (such as group B streptococcus and HIV). However, other studies did not find vaginal delivery associated with increased risk for vertical transmission versus cesarean delivery, and the largest single study (15) reported a non–statistically significant trend toward decreased risk, even though vaginal delivery is associated with longer duration of ruptured membranes. Possible explanations for the failure to find an association between vaginal delivery and increased risk for transmission could include threshold or modifying effects related to the duration of rupture, viral load, or other factors. Cohort studies that focus on women with longer rupture of membranes or high viral load and perform statistical adjustment on other potential confounding factors could help clarify the effects of mode of delivery on transmission risk. Randomized trials are less susceptible to confounding but would involve potential challenges related to the acceptability of randomly assigning HCV-infected women to elective cesarean delivery versus planned vaginal birth....

Full Text Available @ Annals Of Internal Medicine

Thursday, September 13, 2012

Severity of Fibrosis in Women with Hepatitis C

Also See:
Sept 2012 Raloxifene aids HCV therapy in some postmenopausal women
Aug 2012 Women & Hepatitis C


Reproductive Status Is Associated with the Severity of Fibrosis in Women with Hepatitis C

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Erica Villa1¶*, Ranka Vukotic1¶, Calogero Cammà2, Salvatore Petta2, Alfredo Di Leo3, Stefano Gitto1, Elena Turola1¶, Aimilia Karampatou1¶, Luisa Losi4¶, Veronica Bernabucci1¶, Annamaria Cenci5, Simonetta Tagliavini5, Enrica Baraldi5, Nicola De Maria1, Roberta Gelmini6, Elena Bertolini1¶, Maria Rendina3¶, Antonio Francavilla7 1 Department of Gastroenterology, Azienda Ospedaliero-Universitaria & University of Modena and Reggio Emilia, Modena, Italy, 2 Sezione di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Palermo, Italy, 3 Department of Gastroenterology, University of Bari, Bari, Italy, 4 Department of Pathology, Azienda Ospedaliero-Universitaria, Modena, Italy, 5 Department of Clinical Pathology, NOCSAE, Modena, Italy, 6 Department of General Surgery, Azienda Ospedaliero-Universitaria, Modena, Italy, 7 Istituto di Ricovero e Cura “Saverio de Bellis”, Castellana Grotte, Italy

Abstract
Introduction
Chronic hepatitis C is the main cause of death in patients with end-stage liver disease. Prognosis depends on the increase of fibrosis, whose progression is twice as rapid in men as in women. Aim of the study was to evaluate the effects of reproductive stage on fibrosis severity in women and to compare these findings with age-matched men.
 
Materials and Methods
A retrospective study of 710 consecutive patients with biopsy-proven chronic hepatitis C was conducted, using data from a clinical database of two tertiary Italian care centers. Four age-matched groups of men served as controls. Data about demographics, biochemistry, liver biopsy and ultrasonography were analyzed. Contributing factors were assessed by multivariate logistic regression analysis.
 
Results
Liver fibrosis was more advanced in the early menopausal than in the fully reproductive (P<0.0001) or premenopausal (P = 0.042) group. Late menopausal women had higher liver fibrosis compared with the other groups (fully reproductive, P<0.0001; premenopausal, P = <0.0001; early menopausal, P = 0.052). Multivariate analyses showed that male sex was independently associated with more severe fibrosis in the groups corresponding to premenopausal (P = 0.048) and early menopausal (P = 0.004) but not late menopausal pairs. In women, estradiol/testosterone ratio decreased markedly in early (vs. reproductive age: P = 0.002 and vs. premenopausal: P<0.0001) and late menopause (vs. reproductive age: P = 0.001; vs. premenopausal: P<0.0001). In men age-matched with menopausal women, estradiol/testosterone ratio instead increased (reproductive age group vs. early: P = 0.002 and vs. late M: P = 0.001)
 
Conclusions
The severity of fibrosis in women worsens in parallel with increasing estrogen deprivation and estradiol/testosterone ratio decrease. Our data provide evidence why fibrosis progression is discontinuous in women and more linear and severe in men, in whom aging-associated estradiol/testosterone ratio increase occurs too late to noticeably influence the inflammatory process leading to fibrosis.
 
Chronic hepatitis C (CHC) is the primary cause of death in patients with end-stage liver disease [1]. Its prognosis depends on the accumulation of fibrosis over time due to various mechanisms of tissue damage caused by viral infection, ultimately leading to the development of cirrhosis and related complications. The development of hepatic fibrosis is most directly correlated with necro-inflammation, and several other host and viral factors have been associated with the rate of fibrosis progression [2], including older age, alcohol consumption, duration of infection, viral co-infections, steatosis, insulin resistance, and vitamin D deficiency [3].
 
Studies of large cohorts of patients with CHC have also found that high levels of estrogens (as observed during pregnancy) [4] are associated with decreased inflammatory activity in HCV women and that the progression of fibrosis in CHC is twice as rapid in men as in women [5], [6]. This difference has been attributed to the protective role of estrogens and has been supported by experimental and clinical data. Experimentally, estrogens were shown to have a relevant fibrosuppressive role in a rat model of dimethylnitrosamine- or pig-serum-induced liver fibrosis [7], [8]. Clinically, Di Martino et al. [9] and Codes et al. [10] showed that the progression of fibrosis increased significantly in women after menopause, whereas prolonged periods of hormone replacement therapy (HRT) were able to maintain this progression at a level similar to that in premenopausal women. In women, menarche initiates a long period of estrogen exposure that begins to decline in the premenopausal period, often leading to undetectable estrogen levels in early and late menopause. In women with CHC, this reduction in estrogen levels is accompanied by consensual fluctuation in the levels of pro-inflammatory [11], [12] and anti-inflammatory [12] cytokines that could interfere with the course of necro-inflammation and the progression of fibrosis. Much less is known about this process in men: pro-inflammatory cytokines do not fluctuate in age subgroups corresponding to female reproductive stages [11], but it remains unknown whether a relationship exists with changes in sex hormone balance in men.
 
Thus, the aim of our study was to evaluate the effects of differential hormonal exposure on the severity of fibrosis in men and women: we therefore compared women with CHC in different reproductive phases (reproductive age, premenopause, early menopause, late menopause) with four age-matched groups of men and investigated the correlations between fibrosis and the respective Estradiol and Testostosterone levels.
 
Materials and Methods
Between January 2002 and December 2008, 1000 consecutive patients with CHC were recruited to receive standard antiviral treatment at the Gastrointestinal and Liver Units of the University Hospitals of Modena and Bari, Italy. Eligible patients were ≥18 years of age, had compensated liver disease due to chronic hepatitis C virus (HCV) infection (any fibrosis stage, including compensated cirrhosis), detectable plasma HCV RNA levels, and had received no previous treatment for hepatitis C. Patients were excluded if they were co-infected with human immunodeficiency virus or hepatitis B virus or had any other cause of liver disease, severe depression or psychiatric disorder, or active substance or alcohol consumption >20 g/day in the last five years, as evaluated by a questionnaire. Women who had been using hormone replacement therapy were not included in the analysis. The detailed demographic characteristics of this cohort of patients have been reported previously [11].
Within this cohort, four groups of women were selected according to reproductive stage:
Group 1: full reproductive age (i.e., regular menses); Group 2: premenopausal; women included in this group entered menopause (defined as no menstrual period for 12 consecutive months) within 5 years from enrollment in the study; Group 3: early menopausal (menopause was present at the time of enrollment for less than 5 years); Group 4: late menopausal (menopause was present at the time of enrollment for at least 10 years).
Four groups of men contained patients that were pair-matched by age (1:1) with the female cohort.
This study was approved by the institutional review boards of the two hospitals and was conducted in accordance with the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines (ClinicalTrials.gov identifier: NCT01402583).
 
Clinical and Laboratory Assessment
All patients had undergone liver biopsy within 1 year before enrollment. Portal vein diameter (mm) was determined by color Doppler ultrasonography before liver biopsy. The following data were collected at the time of liver biopsy: age, sex, weight, height, and body mass index (BMI); serum levels of alanine aminotransferase (ALT), γ-glutamyl transpeptidase (GGT), glucose insulin; and platelet count. Insulin resistance was determined using the homeostasis model assessment (HOMA). HCV RNA was quantified by Abbott RealTime HCV assay (Abbott Molecular Inc., Des Plaines, IL, USA) and genotyped by INNO-LiPA assay (Innogenetics, Gent, Belgium). All biopsy specimens were reviewed and scored according to Ishak et al. [13] by a single pathologist (LL) who was blinded to the patients’ identities and histories. The percentage of hepatocytes containing macrovesicular fat was determined for each 10× field, and steatosis was classified as absent, mild (<5%), moderate (5–20%), or severe (≥20%).
 
Hormone Assays
Estradiol and testostosterone.
Blood samples were obtained from all patients by venipuncture and processed within 2 h after withdrawal. Serum was stored at –20°C and assayed to determine estradiol and testosterone levels. Serum samples were subjected to chemiluminescent microparticle immunoassays (CMIA) to determine 17β-estradiol and testosterone levels using commercially available kits and a c4000 Architect system (Abbott Diagnostic Division, Abbott Laboratories, Abbott Park, IL, USA). Estradiol was additionally quantitated using the Abbott Architect Estradiol Assay 200 (rev. 2004) one-step CMIA. Assay sensitivity was <10 pg/mL for estradiol and 50 pg/mL for testosterone. The intra- and inter-assay coefficients of variation were 5.6% and 4.9% for estradiol, and 4% and 4.6% for testosterone.
 
Anti-Müllerian hormone.
Serum anti-Müllerian hormone (AMH) levels were assessed in female patients by enzyme-linked immunosorbent assay (AMH Gen II ELISA; Beckman Coulter, Inc., Brea, CA, US). The sensitivity of the assay was 0.08 ng/mL. Intra- and interassay coefficients of variation were <5% and <7%, respectively.
 
Statistical Analysis
Continuous variables are summarized as mean (SD) and categorical variables as frequency (%). Continuous variables within each group were compared by the nonparametric Mann–Whitney U-test. Categorical data were compared by the chi-square test. Multiple logistic regression models were used to assess the relationship between severe fibrosis (Ishak staging ≥3) and the demographic, metabolic, and histological characteristics of patients in the individual groups and in each male–female pair group. In the statistical models, dependent variables were coded as 1 (present) or 0 (absent).
Regression analyses were performed using PROC LOGISTIC, PROC REG, and subroutines in SAS (SAS Institute, Inc., Cary, NC) [14].
 
Results
The detailed epidemiological, virological, laboratorial, histological, and ultrasonographic results of each male–female pair group are presented in Tables S1 and S2. Women in each group were selected according to reproductive status (full reproductive age, premenopausal, early menopausal, late menopausal), and data from the female groups were compared with those from age-matched male groups (intragroup analysis, Mann-Whitney U test).
 
Characteristics of Reproductive Status–Stratified Female Groups
We identified 123 women of full reproductive age [mean (SD), 36.7 (6.9) years; range, 18–45 years], 38 premenopausal women [mean (SD), 47.6 (1.8) years; range, 46–50 years], 50 women in the early menopausal stage [mean (SD), 53.8 (3.6) years; range, 47–60 years], and 144 women of late menopausal stage [mean (SD), 62.3 (3.2) years; range, 55–73 years].
 
The detailed comparison between the various groups is reported in Tables S3 and S4. Women in the first two cohorts (full reproductive age, premenopausal) showed similar moderately severe disease states, as indicated by liver necro-inflammatory activity (P = 0.42; Table S3) and staging (P = 0.062; Table S3, Figure 1). No significant difference in mean BMI was observed between these two groups (P = 0.118). Severe steatosis was more prevalent in premenopausal women (3/38, 8.0%) than in women of full reproductive age (4/123, 3.2%) although the difference did not reach significance (Table S4). The presence of cirrhosis in both groups at the time of enrollment was negligible.
 
Figure 1. Mean necro-inflammation and fibrosis scores in the four subgroups of female and age-matched male patients with chronic hepatitis (Women: triangles; Men: squares).
Levels of significance of the intra- and inter-group comparison are reported in the text.
 
 
 
The comparison of reproductive-aged women (full reproductive age, premenopausal) with those in early menopause revealed significant differences in several variables. The estimated duration of HCV infection was significantly longer in early menopausal women than in fully reproductive (P<0.0001) or premenopausal (P = 0.017) women. All indicators of disease severity were significantly worse in early menopausal women in comparison with the two reproductive-aged groups (early menopause vs. full reproductive age: grading, P = 0.020; staging, P<0.0001; early menopause vs. premenopause: grading, P = 0.014; staging, P = 0.042; Figure 1, Table S3). BMI did differ significantly among women in early menopause vs. full reproductive age (P = 0.039) but not between early menopause vs. premenopausal women (P = 0.90). A significantly higher percentage of early menopausal women had cirrhosis compared with reproductive-aged women (P = 0.039, Table S3).
 
In the late menopausal group, grading did not differ significantly in comparison with the reproductive-aged and premenopausal groups, but was significantly lower than that in the early menopausal group (P = 0.004). Staging at the time of liver biopsy was significantly higher in late menopausal women than in full reproductive age and premenopausal groups (P<0.0001 for both) while it was of borderline significance vs. early menopause (P = 0.052) (Table S3, Figure 1). Accordingly, cirrhosis was more prevalent in late menopausal women than in fully reproductive (P = 0.004) or premenopausal (P = 0.026) women; however, prevalence was not significantly different between late and early menopausal women (P = 0.25; Table S3). BMI, insulin resistance, and presence of steatosis did not differ significantly between any pair of female groups.
 
Multivariate analysis showed that necro-inflammation (OR: 1.506; 95% confidence interval (CI), 1.181–1.922, P = 0.001), steatosis (0 vs. >20%) (OR: 3.029; CI 1.154–7.951, P = 0.024), circulating estradiol levels (OR: 0.973, CI 0.947–0.999), P = 0.041), ALT (OR: 1.011, CI 0.003–1.019, P = 0.009) and portal vein diameter (OR: 2.644, CI 1.657–4.220, P<0.0001) were independently associated with the severity of fibrosis (Table 1). Neither age nor estimated length of HCV infection or estimated age of acquisition of infection was significantly related with severity of fibrosis
 
Univariate and multivariate analysis for fibrosis in the women with chronic hepatitis C.
 
 
 
 
Comparison of Reproductive Status–Stratified Female and Male Groups
The results of the comparison of each male–female group pair are reported in Table S1. The estimated duration of HCV infection did not differ significantly between each male–female group pair. Men in groups paired with the first three female groups (reproductive age, premenopause, early menopause) showed remarkably more severe liver disease, as indicated by mean stage of fibrosis (P<0.0001 for all 3 groups; Table S1 and Figure 1), but no significant difference in fibrosis was found between women in the late menopausal group and age-matched men. Similarly, no significant difference in the presence of cirrhosis was observed between male–female pairs correlating with full reproductive age and late menopause, whereas the incidence of cirrhosis was significantly lower in the two intermediate groups of women than in age-matched groups of men (P = 0.003 for both; Table S1). In contrast, no difference in grading or steatosis was observed between male–female group pairs.
GGT levels were significantly lower in women than in men in all group pairs (full reproductive age, P<0.0001; premenopause, P = 0.001; early menopause, P = 0.007; late menopause, P = 0.017; Table S1). BMI differed significantly between men and women in all group pairs except the early menopause pair (full reproductive age, P<0.0001; premenopause, P = 0.045; late menopause, P = 0.0012; Table S1).
 
No difference in the severity of liver necro-inflammation was observed between men and women in each group pair (Table S1).
 
Multivariate analysis in the whole male and female cohort, reported in Table 2, showed that sex (OR: 0.460, CI 0.236–0.896, P = 0.023), necro-inflammation (OR: 1.401, CI 1.239–1.584, P<0001), circulating estradiol levels (OR: 0.980, CI 0.962–0.999, P = 0.040), platelets count (OR: 0.974, 0.967–0.981, P<0.0001) and portal vein diameter (OR: 1.903, CI 0.539–2.354, P<0.0001) were independently related with severe fibrosis.
 
Univariate and multivariate analysis for fibrosis in the whole cohort of patients with chronic hepatitis C.
 
 
 
Results of multivariate analysis in the whole cohort, stratified in the four reproductive subgroups, are reported in Table 3. Male sex was independently associated with the severity of fibrosis in the premenopausal [male as reference: odds ratio (OR), 0.074; 95% confidence interval (CI), 0.007–0.834; P = 0.048] and early menopausal (OR, 0.037; 95% CI, 0.004–0.344; P = 0.004) group pairs, but not in the reproductive-aged or late menopausal group pairs (Table 3).
 
Comparison of the baseline independent predictive factors for fibrosis in the four cohorts of patients with chronic hepatitis C.
 

 
 
Hormone Assays
Serum concentrations of AMH in the four female groups are shown in Figure 2. Mean values were 2.4 (1.8) ng/mL in reproductive-aged women and 0.5 (0.3) ng/mL in premenopausal women (Mann–Whitney U-test, P<0.0001). AMH levels were undetectable in early and late menopausal women.
 
Figure 2. 
Mean serum levels of anti-müllerian hormone (AMH) in women divided according to reproductive phases.

AMH levels were significantly lower in premenopausal women in comparison with women in full reproductive age (p<0.0001) and became undetectable in menopausal women (both early and late).
 
 
 
Serum concentrations of estradiol and testosterone in the four group pairs are shown in Figures 3A and 3B, respectively, and the estradiol/testosterone ratio [E2/T; estradiol (pg/mL)/testosterone (ng/mL)] is reported in Figure 3C. Estradiol concentrations changed significantly in both men and women with age, with a marked difference observed in both sexes at the age corresponding to female menopausal onset. In particular, estradiol levels were significantly higher in reproductive-aged and premenopausal women than in early (reproductive age: P<0.0001; premenopausal: P<0.0001) and late menopausal women (reproductive age: P<0.0001; premenopausal: P<0.0001), whereas males exhibited a significant change in the opposite direction at corresponding ages (reproductive vs. early menopause: P = 0.003, vs. late menopause: P = 0.05; premenopausal groups vs. early: P = 0.001, vs. late P = 0.005). Testosterone levels changed significantly only in women, who showed significantly higher levels in the full reproductive age group than in the other groups (reproductive vs. premenopausal P = 0.44; vs. early menopausal P = 0.006; vs. late menopausal P = 0.013). Although a decline in testosterone levels was observed in the two older groups of men, this difference was not significant. The E2/T ratio changed significantly with age in both men and women. In women, the E2/T ratio decreased markedly in early (vs. reproductive age: P = 0.002 and vs. premenopausal: P<0.0001) and late menopause (vs. reproductive age: P = 0.001 and vs. premenopausal: P<0.0001). The opposite change occurred in men (reproductive age group vs. early menopause group: P = 0.002 and vs. late: P = 0.001) (Figure 3C).
 
 Estradiol and Testosterone serum levels and E2/T ratio in men and women divided according to women’s reproductive phases as described in Methods.
 
 
 
Discussion
In this cross-sectional study comparing a large cohort of women with CHC who were grouped, according to reproductive status, with age-matched men with CHC, we found that hormonal phases were differently associated with the histological severity of liver disease.
 
A few clinical studies [8], [9] have found that estrogens exert a beneficial effect on liver disease by slowing the progression of fibrosis; however, this effect has previously been evaluated in terms of lifetime exposure, rather than according to different reproductive stages. To overcome this limitation, we divided a cohort of 355 women with CHC into four groups according to reproductive status. The allocation of patients to these groups was substantiated using AMH levels, because this glycoprotein is a more accurate indicator of ovarian reserve than is age or other conventional serum marker (follicle stimulating hormone, estradiol, inhibin B) [14][16]. The AMH levels obtained in our study were in agreement with those reported for reproductive age, premenopause, and established menopause [17], [18], and thus validated the composition of the four groups.
 
The results of our study support the concept that the progression of fibrosis in women is a discontinuous process: very slow during reproductive age and accelerating rapidly after menopause. We found that disease severity at the time of liver biopsy, as measured by the severity of liver necro-inflammation and fibrosis, was very low in women of reproductive age and in premenopausal ones while it became higher among early menopausal women; the severity of fibrosis was found to be even higher among late menopausal women. Further support for the protective role of estrogens toward development of fibrosis comes from the multivariate analysis of risk factors for severe fibrosis: neither estimated duration of HCV infection nor the age of acquisition of HCV infection was independently associated with fibrosis while levels of circulating estradiol was.
 
The impact of hormonal exposure on fibrosis became even more complex when the female groups were compared with their age-matched male counterparts. Although the estimated duration of HCV infection was similar in all group pairs and age was equivalent by definition, women had less severe fibrosis than men in all but the late menopausal group pair. Female sex appeared to be independently associated with a lower prevalence of severe fibrosis in the premenopausal and early menopausal group pairs [19].
 
These findings may be explained by the observed changes in hormone levels according to reproductive status. The high estradiol levels observed in the reproductive-aged groups (full reproductive, premenopause) likely provided protection against the development of severe liver injury. However, an independent correlation between fibrosis and sex was found only in the premenopausal and early menopausal group pairs, and not in the fully reproductive group pair. This finding may be due to the short duration of infection and to the very mild stage of disease present in both sexes in the reproductive-aged group pair.
 
In contrast, menopausal women exhibited greater disease severity than those in the reproductive-aged and premenopausal group pairs, probably due to the decline in estradiol levels that occurs rapidly with menopause development. We have already shown that a marked up-regulation of inflammatory cytokines, especially interleukin-6 (IL-6), occurs in close temporal relationship with the onset of menopause [11], [12], when for the first time in a woman’s life E2/T ratio dramatically decreases: this is associated with a sharp increase in necro-inflammatory activity and is eventually followed (as the change in fibrosis score between early and menopausal women shows) by a significant increase in fibrosis in late menopausal women. As the late menopausal male-female group comparison indicates, at this stage women lose the advantage that they had in earlier reproductive stages: fibrosis and percentage of cirrhosis are no longer significantly different from males and only subtle indicators of disease progression (like portal vein diameter and platelets count) are still better in females. A further element that may play a relevant role in reducing differences in disease severity between genders in the late groups is the significant increase of estradiol levels and E2/T ratio that was observed in males of the early and late menopausal groups. This increase did not result in a change in necro-inflammation, but was associated with a significant reduction in fibrosis severity in men in group 4 (group 4 vs. group 3, P = 0.010). This is in agreement with the recently reported positive correlation between testosterone levels and increased risk of both advanced hepatic fibrosis and advanced hepatic inflammatory activity in HCV-infected men [20]: although this study evaluated only absolute Testosterone levels and not Estradiol or the E2/T ratio, it is relevant that higher unopposed levels of Testosterone related with higher severity of disease. In our cohort, the late inversion of the E2/T ratio in males coincided with the first and only improvement in fibrosis score in males.
 
These findings not only reinforce the view that the lengthy period of exposure to estrogens in women plays a favorable role in the progression of chronic liver disease in comparison with men, but also suggest that this protective effect is reversible and strictly dependent on estrogen levels. When the process of hormonal aging leads to an inversion in the E2/T balance characteristic of full reproductive age, women lose the favorable estrogen effect and show patterns similar to those of men.
 
Accordingly, male sex is constantly and independently associated with a higher degree of fibrosis in cohorts whose mean age coincides with the full reproductive stage (i.e., <50 years of age) [5], [6]. In contrast, cohorts with higher mean ages (>50 years; a surrogate indicator of menopause in women) show similar patterns of fibrosis progression in men and women, and male sex is no longer a predictor of severe fibrosis progression [6], [21], [22].
 
Although our study was not designed to clarify the pathogenesis of the association between reproductive phase and the severity of fibrosis in women, previous studies have provided several hypotheses. Many experimental data have shown that estradiol inhibits transforming growth factor (TGF)-β1 expression and hepatic stellate cell (HSC) activation, thereby suppressing the induction of hepatic fibrosis [8], [23], [24]. Estradiol is also known to induce the down-regulation of tumor necrosis factor (TNF) alpha, IL-6, and IL-1β [25][27], mediators contributing to hepatic necro-inflammation and the activation of HSCs. The favorable role of estrogens in men has also been suggested by two case reports, in which different pathological conditions required prolonged estrogen treatment in two young men, one with hepatitis C [28] and the other with nonalcoholic steatohepatitis (NASH) [29]. In the first case, the addition of estradiol reduced disease activity and maintained viral loads at lower levels than observed before treatment [28]. In the second case, it reversed hepatic steatosis and insulin resistance [28].
 
In this study of a cohort of women with CHC classified by reproductive phase and compared with age-matched men with CHC, we found that the severity of fibrosis in women is strictly related with Estradiol levels and E2/T ratio. Progression of fibrosis follows the sharp rise of necro-inflammatory activity occurring in coincidence with estrogen deprivation in early menopause [11]. This finding explains the discontinuous rate of fibrosis progression in women and the more linear rate observed in men, in whom the modification of sex hormone balance determined by aging-associated Estradiol increase occurs very late in life and thus may have only a limited beneficial effect on hepatic condition.
 
Limitations
The main limitation of this study lies in its cross-sectional design, which prevented the evaluation of fibrosis progression in individual patients according to baseline reproductive status and reproductive transitions. A further methodological question is the potentially limited external validity of the results for different populations and settings, because our study included a cohort of Italian subjects enrolled at a tertiary care center.
 
Author Contributions
Conceived and designed the experiments: EV RV CC SP. Performed the experiments: RG LS AC ST EB. Analyzed the data: EV CC ADL NDM AF. Contributed reagents/materials/analysis tools: ADL SG AK ET LL VB AC ST EB MR. Wrote the paper: EV RV CC AF.
 
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