Women's Health; Treating Hepatitis C
Estrogen Modulating Therapy for HCV Infection in Postmenopausal Women
Adding raloxifene hydrochloride to standard therapy significantly increased response, but only among women with IL28B genotype TT.
Studies of hepatitis C virus (HCV) infection treatment have shown that response to interferon-based therapy is lower in postmenopausal
women than in premenopausal women. This could be caused by declining estrogen levels in menopause. To test that hypothesis, investigators evaluated whether the addition of raloxifene hydrochloride (RLX) — a selective estrogen receptor modulator — improved the efficacy of standard therapy with peginterferon and ribavirin in this group.
Investigators randomized 123 postmenopausal Japanese women
aged 50 to 73 years with genotype 1b HCV infection to receive 60 mg of RLX daily plus standard therapy with 180 µg of peginterferon weekly and 600 to 1000 µg of ribavirin daily or standard therapy only for 48 weeks. The primary end point was
sustained virologic response (SVR), defined as undetectable serum HCV RNA after 24 weeks of treatment. The mean length of time since menopause was 10.2 years (range, 2–22 years). Baseline characteristics of the two groups did not differ.
SVR was significantly higher in the RLX group than the standard therapy group overall (61.3% vs. 34.4%; P=0.005) and in a subgroup with IL28B genotype TT (72.5% vs. 39.2%; P=0.001), but not in patients with IL28B genotype CC or TC. Only one patient discontinued RLX after developing a rash during week 2 of treatment.
Comment: These results suggest that the addition of RLX as adjuvant therapy to peginterferon and ribavirin in postmenopausal women with genotype 1b HCV infection significantly improves SVR. The improvement was
limited to women with IL28B genotype TT. The mechanism by which RLX improves SVR is unclear but could involve the improvement of estradiol levels and reduction of oxidative stress or inhibition of inflammatory
cytokine production. Regardless, further study of the use of RLX and other, similar agents as adjuvant therapy to HCV regimens is warranted.
— Atif Zaman, MD, MPH
Published in Journal Watch
Gastroenterology December 14, 2012
Furusyo N et al. Raloxifene
hydrochloride is an adjuvant antiviral treatment of postmenopausal women with
chronic hepatitis C: A randomized trial. J Hepatol
2012 Dec; 57:1186. (http://dx.doi.org/10.1016/j.jhep.2012.08.003)
Medline abstract (Free)
Severity of Fibrosis in Women with Hepatitis C
Raloxifene aids HCV therapy in some postmenopausal women
Women & Hepatitis C
Liver disease tends to progress more slowly in women than in men. Women are less likely to die from HCV than men are. Many factors influence
prognosis, such as the age at which HCV was acquired or presence of another infectious disease. Avoiding alcohol is one of the most important steps you can take in order to help your liver. The amounts of alcohol for healthy women (without HCV) are lower than the amounts for men. Women are more susceptible to alcohol-related health problems.
Add in hepatitis C and you have a recipe for disaster.....Continue Reading
FAQs About Womens Health-Protecting Yourself Against HBV and HCV
Sep 2012 Issue Of J Viral Hepat
Peginterferon-Α_2B plus ribavirin is more effective than peginterferon-Α_2A plus ribavirin in menopausal women with chronic hepatitis C
Villa E, Cammà C, Di Leo A, Karampatou A, Enea M, Gitto S, Bernabucci V, Losi L,
De Maria N, Lei B, Ferrari A, Vukotic R, Vignoli P, Rendina M, Francavilla A
J Viral Hepat 2012 Sep; 19(9):640-649.
Summary. Under-enrolment of women to randomized clinical trials, including chronic hepatitis C, has long been recognized. The aim of this study was to identify factors predictive of sustained virological response (SVR) to PEG IFN/Ribavirin antiviral therapy in relation to gender and reproductive status of female patients involved.
Seven hundred and forty-six treatment-naïve patients (431 men, 315 women) treated with Peg-IFNα-2a (180 μg/week) or
Peg-IFNα-2b (1.5 μg/kg/week) plus ribavirin (800–1400 mg/day) for 24 or 48 weeks were studied between 2006 and 2010. Differences in SVR rate, overall and by gender were assessed after adjustment and propensity score matching.
SVR was obtained in 44.2% of Peg-IFNα-2a-treated patients and in 51.2% of Peg-IFNα-2b-treated patients (intention-to-treat; P = 0.139). Age, fibrosis stage and genotype 2 and 3 were independently associated with SVR by multivariate analysis. Analysing by gender, the difference in SVR between PEG-IFNα types was not significant in men but highly significant in women (Peg-IFNα-2a:39.1%vs Peg-IFNα-2b:54.4%, P = 0.007).
This was attributable to a higher SVR rate with Peg-IFNα-2b in the difficult postmenopausal population (26.9% Peg-IFNα-2a vs 46.0% Peg-IFNα-2b, P = 0.040). In women, absence of menopause, genotype 2 hepatitis C virus infection and use of Peg-IFNα-2b were independently associated with SVR.
In conclusion, predictive factors for SVR are different in men and women.
Factors differing between genders are menopause, severe steatosis and peg-interferon used. The higher SVR rate with Peg-IFNα-2b in menopausal women is likely attributable to more favourable pharmacokinetics that allows Peg-IFNα-2b
to reach visceral fat and oppose the increased cytokine production and enhanced inflammatory status in menopause.
Phenotypes of Interferon-α-Induced Thyroid Dysfunction among Patients Treated for Hepatitis C Are Associated with Pretreatment Serum TSH and Female Sex.
Mammen JS, Ghazarian SR, Pulkstenis E, Subramanian GM, Rosen A, Ladenson PW. J
Clin Endocrinol Metab. 2012 Jun 11. [Epub ahead of print]
[PubMed - as supplied by publisher]
Nov 24 2011
Association between Chronic Viral Hepatitis Infection and Breast Cancer Risk: a Nationwide Population-based Case-control Study
HCV infection, but not HBV infection, appears to be associated with early onset risk of breast cancer in areas endemic for HCV and HBV. This finding needs to be replicated in further studies.
Early menopause is associated with lack of response to antiviral therapy in women with chronic hepatitis, finds March's publication of Gastroenterology. .
Chronic hepatitis C and liver fibrosis progress more rapidly in men and menopausal women than in women of reproductive age.Professor Erica Villa and colleagues from Italy investigated the associations among menopause, sustained virologic response, and liver damage in patients with chronic hepatitis C. . The research team performed a prospective study of 1000 consecutive, treatment-naïve patients 18 years of age and older with compensated liver disease from chronic hepatitis C.Liver biopsy samples were analyzed before patients received standard antiviral therapy. Baseline levels of liver inflammation were higher among postmenopausal womenGastroenterologyThe research team collected data from 442 women on the presence, type, and timing of menopause, associated hormone and metabolic features, serum levels of interleukin-6, and hepatic tumor necrosis factor-α. . Postmenopausal women achieved sustained virological response less frequently than women of reproductive age, but as frequently as men. By multivariate regression analysis, an independent significant predictor for women to not achieve a sustained virological response was early menopause.In addition, levels of γ-glutamyl transpeptidase, infection with hepatitis C virus genotype 1 or 4, and cholesterol levels were independent significant predictor for women to not achieve a sustained virological response. . Early menopause was the only independent factor that predicted lack of a sustained virological response among women with genotype 1 hepatitis C virus infection.The team observed that baseline levels of liver inflammation, fibrosis, steatosis, serum interleukin-6, and hepatic tumor necrosis factor-α were significantly higher among postmenopausal women than women of reproductive age.Professor Villa and colleagues conclude, "Among women with chronic hepatitis C, early menopause was associated with a low likelihood of sustained virological response, probably because of inflammatory factors that change at menopause." . Gastroenterol 2011: 140(3): 818-829 11 March 2011-
Also See ; Early Menopause is Associated with Lack of Response to Antiviral Therapy in Women with Chronic Hepatitis C: "This suggests that CHC in women should be treated early, disregarding the fact that liver disease is milder in women of reproductive age, as this condition will last only as long as the estrogen-exposed period."
Hormones: A Potential Explanation for Differences in Response Rates to Therapy for Chronic Hepatitis C Infection
Kimberly A. Forde
AffiliationsReprint requests Address requests fore reprints to: Kimberly A. Forde, MD, MHS, Division of Gastroenterology and Hepatology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, 3400 Spruce Street, 3 Ravdin, Philadelphia, Pennsylvania 19104,K. Rajender Reddy
published online 25 January 2011.Article
See “Early menopause is associated with lack of response to antiviral therapy in women with chronic hepatitis C,” by Villa E, Karampatou A, Cammà C, et al, on page 818.
Chronic hepatitis C (CHC) infection remains an important cause of morbidity and mortality worldwide. Although the incidence of infection has declined, corresponding to recognition of the major modes of hepatitis C virus (HCV) transmission and the establishment of preventative programs,1 the prior rate of acute infection informs and ultimately shapes the burden of disease observed currently.2 Because HCV exposure results in chronic infection in up to 85% of those individuals infected acutely3, 4 and the long-term sequelae of CHC5 take 20–30 years to manifest, the morbidity and mortality of CHC is projected to peak in the current decade.4, 6 ..
Therefore, although prevention of new infections is of utmost importance, treatment of individuals with chronic infection, where readily available, will impact greatly and attenuate the development of the untoward consequences of CHC.The current standard therapy for CHC continues to be pegylated interferon paired with ribavirin. Although many clinical factors including viral genotype, viral load, race, ethnicity, insulin resistance, and obesity affect response,7, 8, 9, 10 a sustained virologic response (SVR) is obtained in approximately 42%–53% of those with genotype 1 or 4 infection and 78%–82% in those with genotype 2 or 3 infection.11, 12 More recently, polymorphisms near the IL28B gene, which encodes interferon-λ-3, in the host have been demonstrated to have a strong impact on response to interferon-based therapy and on spontaneous clearance of acute infection.13, 14, 15 In addition to the insight we have gained into the viral life cycle, viral mechanics, and predictors of treatment response, the near future promises the approval of specifically targeted antiviral therapy for CHC that will increase rates of SVR in naïve and previously exposed CHC cohorts.16, 17, 18 ..
Although it is clear that CHC must be treated to interrupt the natural history of infection, the time at which the treatment of infection should be instituted often depends on a panoply of clinical and viral factors, including hepatic histopathologic features, viral genotype, and viral load. In this month's issue of Gastroenterology, Villa et al19 examine the effect of gender on treatment response rates in CHC and demonstrate some interesting findings that may ultimately affect the timing of the institution of CHC therapy for women based upon their menopausal status. In this prospective cohort study of 1000 consecutive treatment-naïve patients with CHC who underwent therapy, SVR was achieved less frequently in postmenopausal women compared with premenopausal women, but was comparable to that of men in the cohort.
Additionally, early menopause, defined as the presence of menopause for a period of ≤5 years, was an independent predictor of not achieving an SVR in the entire cohort of women and the single predictor of nonresponse in the cohort of women with genotype 1 infection. Although not a study of the pathogenesis of antiviral resistance, the measurement of inflammatory cytokines in the context of the study, namely tumor necrosis factor (TNF)-α and interleukin (IL)-6, lends credence to the shift in the inflammatory milieu that occurs at the time of menopause and how such changes might influence the ability of standard antiviral therapy to evoke an SVR. .
The effect of female gender on the course and outcomes of CHC infection remains a controversial topic in the available literature and broaches various aspects of infection, such as spontaneous clearance, progression of hepatic fibrosis, response to standard therapy, development of sequelae of infection, and post-liver transplant outcomes. In population-based cohorts, including the National Health and Nutrition Examination Survey, differences were not found in persistence of chronic infection between men and women.20
By contrast, in an Egyptian cohort, females were more likely to have spontaneous viral clearance.21 Poynard et al22 found the mean stage of fibrosis in chronic infection was higher in men than in women even after accounting for age and duration of infection. This finding, supported by work from Wright et al,23 was not demonstrated in an HCV cohort from the United Kingdom.24 Furthermore, with respect to treatment response in the setting of CHC, female gender has been identified as an independent predictor of SVR in several classic CHC treatment trials.25, 26, 27 However, such a finding was not substantiated in other well-designed clinical trials.12, 28
Additionally, emerging data suggest that women transplanted for HCV have accelerated hepatic fibrosis and increased mortality, the cause of which remains elusive.29When contemplating the role of gender associations in the context of CHC, one must examine the potential mechanisms or explanations underlying such gender differences. Estrogen has been the focus of limited, but informative, basic science research in this specific topic. Using dimethylnitrosamine-based injury as a model for hepatic fibrosis in rats, the role of estrogen in hepatic fibrosis was explored by Yasuda et al.30 In this model, estradiol administered to male rats resulted in a decrease in hepatic mRNA for procollagens and tissue inhibitor of metalloproteinase-1 (TIMP-1) as well as malondialdehyde, markers of hepatic fibrosis and lipid peroxidation, respectively. The administration of antibodies directed against estradiol or oophorectomy in female rats induced the opposite phenomena, namely up-regulation of procollagens, TIMP-1, and alpha smooth muscle actin–positive cells.30 .
Furthermore, hepatic stellate cells cultured with estrogen or progesterone substantiate the findings noted in the rat model.31 Specifically, exposure of hepatic stellate cells to estrogen resulted in the inhibition of reactive oxygen species generation, proliferation and activation of the cells, and attenuation of transforming growth factor-β expression. Progesterone, by contrast, had a stimulatory effect on these processes, an effect that could be reversed with the addition of estradiol in cell culture.31 Furthermore, the relative balance of these hormones is implicated in the production of inflammatory cytokines, with a notable up-regulation of IL-1, IL-6, and TNF-α at the time of menopause.32
These cytokines have been suggested to be mediators of the underlying host inflammatory response to CHC infection and modulate the likelihood of virologic response to currently available CHC therapy.33, 34
Clearly, these findings have important implications for the rate of hepatic fibrosis in women as well as their response to therapy, with a relatively “fibrosuppressive” state being evident potentially in the premenopausal period and a pro-fibrogenic state potentially in the postmenopausal period. Such a hypothesis has been explored in the context of 2 distinct observational studies. In the first study, Di Martino et al35 surveyed 472 HCV-infected women regarding estrogen exposure throughout their reproductive life cycles, including timing of menopause, exposure to exogenous estrogens, and pregnancies.35
These authors had liver biopsy specimens available for review and were able to correlate clinical factors with hepatic fibrosis. They found that postmenopausal women had a higher rate of fibrosis progression and that among postmenopausal women, exposure to hormone replacement therapy resulted in a fibrosis progression rate lower than that of their untreated counterparts but comparable with that of premenopausal women. These findings were subsequently replicated by Codes et al,36 demonstrating that menopausal status was associated with more advanced hepatic fibrosis and that the reported use of hormone replacement therapy was correlated with a lower rate of hepatic fibrosis progression. Unfortunately, neither study examined the effect of hormone replacement therapy on response to currently available CHC therapies nor the potential for adverse events associated with hormone replacement therapy, including an increased risk of cardiovascular events and/or breast cancer.Villa et al19 are the first to perform a comprehensive study examining response rates to CHC therapy based on gender as well as menopausal status within the female cohort included in the study. .
Additionally, the study highlights the changes of important cytokines including IL-6 and TNF-α throughout the reproductive life cycle in females as well as in males of varying ages. The sentinel observations in this study will undoubtedly lead to a further exploration of the effect of both estrogen and progesterone on the clearance of acute infection, establishment of CHC infection, and modulation of treatment response with new therapeutics. It also offers the opportunity for a candid discussion of the timing of therapy for CHC infection because rates of response seem to be affected by the transition of the premenopausal to postmenopausal state.Future study of antiviral response rates in women and the effect of menopausal status should include the consideration of additional key predictors of response to interferon-based treatment regimens. The first is the inclusion of a measure of tolerance and adherence to therapy. Reddy et al,37 using data from 569 genotype 1 CHC patients receiving pegylated interferon and ribavirin in the context of 2 phase III studies, investigated factors associated with SVR in patients >50 years of age. In this study, cumulative drug exposure and absence of cirrhosis were significantly predictive of SVR.
Although not assessed in the Villa study, intolerance to the interferon-based regimen secondary to side effects with advancing age, and hence dose reduction or treatment cessation, may have provided another potential reason for the SVR reduction observed in the postmenopausal cohort. .. Furthermore, an interaction between age and gender may be an important clinical predictor that merits examination. In a study of 311 subjects undergoing interferon monotherapy for CHC, Hayashi et al38 determined that not only traditional factors such as genotype and HCV RNA level, but also gender and an interaction between age and gender, were important predictors of treatment response in multivariate modeling.
Additionally, newly identified predictors of response, including vitamin D deficiency, acknowledged by the authors, and IL28B genotype, will be important to analyze in future studies, both of which may have a differential prevalence in men and in women as well as in premenopausal and postmenopausal women.13, 14, 39In summary, Villa et al19 present compelling evidence that menopausal status, perhaps as a consequence of a shift in the balance of inflammatory cytokines and/or changes in estrogen status, affects response rates in women undergoing therapy for CHC infection.
Such research should certainly encourage further studies exploring gender differences in CHC epidemiology, chronic infection, response to future therapies and occurrence of disease sequelae. Although a great first step in the exploration of this clinical question, further work must be done to explore not only the pathophysiology underlying this finding but also potential interactions between cumulative dose exposure, stage of hepatic fibrosis, age and gender, and newly emerging predictors of CHC treatment response. Although these observations will undoubtedly lead to an exploration of the use of hormone replacement therapy in women with CHC, the enthusiasm for such an intervention must be tempered by the potential risks of such therapy, such as adverse cardiovascular and breast cancer outcomes.
Back to Article Outline References,. .
Updated : December 22, 2010 ,
Researchers from Kobe University, Center for Infectious Diseases detail findings in hepatitis C virus
By NewsRx.com ,
New research, '17-estradiol inhibits the production of infectious particles of hepatitis C virus,' is the subject of a report. According to recent research from Kobe, Japan, "Persistent infection with hepatitis C virus causes serious liver diseases, such as chronic hepatitis, hepatic cirrhosis and hepatocellular carcinoma. The male gender is one of the critical factors in progression of hepatic fibrosis due to chronic HCV infection; thus female hormones may play a role in delaying the progression of hepatic fibrosis." ,
"It has also been reported that women are more likely than men to clear HCV in the acute phase of infection. These observations lead the present authors to the question: do female hormones inhibit HCV infection? In this study using HCV J6/JFH1 and Huh-7.5 cells, the possible inhibitory effect(s) of female hormones such as 17??-estradiol (the most potent physiological estrogen) and progesterone on HCV RNA replication, HCV protein synthesis and production of HCV infectious particles (virions) were analyzed. It was found that E2, but not P4, significantly inhibited production of the HCV virion without inhibiting HCV RNA replication or HCV protein synthesis. E2-mediated inhibition of HCV virion production was abolished by a nuclear estrogen receptor (ER) antagonist ICI182780. .
Moreover, treatment with the ERa-selective agonist 4, 4', 4?-(4-propyl-[1H]-pyrazole-1, 3, 5-triyl)trisphenol (PPT), but not with the ER??-selective agonist 2, 3-bis (4-hydroxyphenyl)-propionitrile (DPN) or the G protein-coupled receptor 30 (GPR30)-selective agonist 1-(4-[6-bromobenzo 1, 3 dioxol-5-yl]-3a, 4, 5, 9b-tetrahydro-3H-cyclopenta [c] quinolin-8-yl)-ethanone (G-1), significantly inhibited HCV virion production," wrote K. Hayashida and colleagues, Kobe University, Center for Infectious Diseases (see also Hepatitis C Virus) .
The researchers concluded:
"Taken together, the present results suggest that the most potent physiological estrogen, E2, inhibits the production of HCV infectious particles in an ERa-dependent manner." ,
Hayashida and colleagues published their study in Microbiology and Immunology (17??-estradiol inhibits the production of infectious particles of hepatitis C virus.
Microbiology and Immunology, 2010;54(11):684-90).
For additional information, contact K. Hayashida, Center for Infectious Diseases, Division of Microbiology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Publisher contact information for the journal Microbiology and Immunology is: Blackwell Publishing Inc., 350 Main St., Malden, MA 02148, USA.
Copyright 2010, Women's Health Weekly via NewsRx.com.
To see more of the NewsRx.com, or to subscribe, go to http://www.newsrx.com . .
Menopause and Obesity Linked to HCV Relapse after Interferon-based Treatment
SUMMARY: Obesity, fatty liver, and having hard-to-treat hepatitis C virus (HCV) genotype 1 predicted a greater likelihood of relapse after treatment, and thus failure to achieve sustained virological response, according to a French study presented at the recent American Association for the Study of Liver Diseases "Liver Meeting" (AASLD 2010) in Boston.
Among women, however, the only independent predictor was being menopausal. .
By Liz Highleyman .
Christiane Stern and colleagues from Beaujon Hospital in Clichy, France, evaluated factors associated with post-treatment relapse among chronic hepatitis C patients -- particularly women -- treated with pegylated interferon plus ribavirin.
Response to hepatitis C treatment is typically assessed at week 4 (rapid virological response, or RVR), week 12 (early virological response, or EVR), the end of treatment, and then 24 weeks after completing treatment to ensure that HCV viral load remains undetectable (sustained virological response, or SVR).
A significant number of patients relapse after finishing therapy.A total of 249 previously untreated chronic hepatitis C patients were given pegylated interferon alfa-2a (Pegasys) or pegylated interferon alfa-2b (PegIntron) -- about half each -- plus 800-1200 mg/day weight-adjusted ribavirin. .
Patients with HCV genotypes 2 or 3 were treated for 24 weeks, while those with genotypes 1 or 4 were treated for 48 weeks.The participants' average age was 47 years and 10% were classified as obese. About one-third were women, of whom 59% were menopausal (started at age 48, on average). One third had HCV genotype 1, 24% had advanced liver fibrosis (stage F3 or higher), and 27% had marked steatosis, or fat accumulation in liver cells.
34% of participants experienced HCV relapse after the end of treatment.
In the study population as a whole, factors significantly associated with relapse in a logistic regression analysis were:
HCV genotype 1;
Pegylated interferon dose reduction.
To assess the influence of menopause on relapse in women, the investigators compared patients older and younger than 50 years according to sex.
Among 165 men, 22% of those younger than 50 years and 25% of those older that 50 experienced relapse, not a significant difference.
Among 84 women, however, 14% of those under age 50 and 37% of those above 50 years experienced relapse, which did reach statistical significance.
Among women, factors significantly associated with relapse in a univariate analysis were menopause, obesity, high baseline viral load, HCV genotype 1, and moderate-to-severe liver necro-inflammation (stage A2 or higher).
In a logistic regression analysis accounting for multiple factors, however, only menopause was independently associated with relapse. .
Based on these findings, the investigators concluded, "Chronic hepatitis C patients infected with genotype 1 and presenting obesity and marked steatosis have higher rates of relapse.""[Pegylated interferon] reduction, but not ribavirin reduction, is associated with relapse," they continued. "In female patients, menopause has a negative impact on SVR rates."Prior research has tended to find that older patients on average to do respond as well to treatment as younger individuals. But in may cases such analyses did not take sex into account. The fact that this analysis saw an age difference for women but not men adds to the evidence that estrogen levels play a role in hepatitis C outcomes. .
Investigator affiliation: Service d'Hépatologie, Hôpital Beaujon, Clichy, France. 12/10/10
ReferenceC Stern, M Martinot-Peignoux, M Ripault, and other. Menopause is Associated with Relapse in Chronic Hepatitis C Patients Treated with Pegylated Interferon Plus Ribavirin. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract 969. . .
.Division of Gastroenterology, Federal University of São Paulo, São Paulo, SP vol.43 no.3 Uberaba published in May/June 2010
Gender influence on treatment of chronic hepatitis C genotype 1
Although various studies have been published regarding the treatment of chronic hepatitis C (CHC) with peginterferon (Peg-IFN) and ribavirin, little is known regarding the real impact of gender on the characteristics that influence the effectiveness and safety of antiviral treatment for CHC patients. The objective of this study was to evaluate the influence of gender on HCV treatment outcomes.
A retrospective analytical study was conducted among selected carriers of CHC genotype 1, who were treated with Peg-IFN α-2b at a dose of 1.5 μg/kg or Peg-IFN α-2a at a dose of 180 μg/week plus a ribavirin dose of 1,000-1,250 mg/day, according to weight, between 2001 and 2007. l
How many patients in the study ? 181 patients .
46.4 ± 11.0 years
How Many Women ?.
Out of 181 patients 46% were women .;
How Much Liver Damage?
At baseline, 32% of the patients had advanced fibrosis (F3-F4 Scheuer),
What Does F3 or F4 Mean? .
Table 2 Scheuer classification for grading and staging of chronic hepatitis
F1 Enlarged, fibrotic portal tracts
F2 Periportal or portal-portal septa, but intact architecture
F3 Fibrosis with architectural distortion, but no obvious cirrhosis
F4 Probable or definite cirrhosis ,
Viral Load 83% of the subjects had viral load more then 400,000 IU/ml, without significant difference between the genders . /
How High Is That?
.below 200.000 very low
above 25,000,000 very high
.When compared with men, women had higher incidence of many adverse events such as anemia and higher need for dose reduction, for both Peg-IFN and ribavirin . However, the rate of sustained virological response (SVR) did not differ between the genders: 45% (female) vs 41% (male) .
CONCLUSIONS: This study suggests that women and men react differently to combined therapy, especially in relation to the incidence of adverse events and the need for dose modification. Nevertheless, these differences do not influence the SVR rate. Key-words: Hepatitis C. Pegylated interferon. Ribavirin.
Gender. Women The Full Study ,
,Article From HCV Advocate From 2009
December 2009 HCV Advocate
HEALTWISE: Hepatitis C Update
Lucinda K. Porter, RN
It’s a tradition. Every November, I scan the HCV Advocate website for the latest news from the American Association for the Study of Liver Diseases (AASLD) meeting. This year there were some juicy morsels, six of which I will review.
In the first study, Hepatitis C and Menopause: Interplay of Age, Gender, HCV Replication and Activity in Progression and Consequence for Therapy, Trépo, Bailly, Moreno, Lemmers, Adler, and Pradat investigate the differences in fibrosis progression among HCV patients. Previous studies revealed the possibility that estrogen may have anti-fibrogenic effects, so researchers specifically looked at fibrosis development in the light of gender, age, and menopause.
They looked at 163 enrollees, ages 23 to 84 years with a mean age of 55; 56% were male. Slightly more than half (55%) had progression of fibrosis, measured by a METAVIR fibrosis score of at least F3. Overall, males had higher progression rates at 66% versus 41% for women. However, for those under the age of 50, fibrosis progression was 51% for males versus 11% for females. Over age 50, the rate jumps to 77% for males versus 61% for females.
These data show a strong relationship between gender and fibrosis progression. The researchers surmise that estrogen may have a protective benefit for younger women with HCV. They recommend the use of estrogen replacement therapy for menopausal women.
Another interesting discovery appeared in this study. In general, viral loads dropped with age except in the group of post-menopausal women. There was no explanation for this.
The second study examined similar issues. Early Loss of Exposure to Estrogens is Critical in Determining Entity of Fibrosis and Response to IFN in Women with Hepatitis C is the title of a poster presented by Karampatou, Pazienza, Lei, Di Leo, Francavilla, and Villa. After observing that post-menopausal women with HCV had increased progression of fibrosis, these researchers wondered whether the correlation was due to aging and/or longer durations of infection or to menopause.
They analyzed data from 945 HCV-treatment patients of evenly-distributed genotype—541 men and 404 women. In the female group, 252 were menopausal. Most of these were spontaneously menopausal although 50 were surgical. Body weight was lower in pre-menopausal women; however histological steatosis (fatty liver) was not significantly different between the two groups.
Pre-menopausal women had the highest response to HCV-therapy. The sustained virologic response (SVR) was 63% versus 51% of males and post-menopausal women. In short, post-menopausal women responded similarly to treatment as men did.
The researchers concluded that menopause plays a significant role in determining the progression of fibrosis along with response to treatment. Estrogens have a powerful role in the regulation of inflammation and immunity. They recommended that interferon-based therapy be initiated at the youngest possible age, preferably prior to menopause.
The third item to catch my attention appeared in a 2009 supplement published by Hepatology and is also pertinent to women with HCV. Hepatitis C Virus (HCV) Infected Females Are at Higher Risk of Graft Loss after Liver Transplantation was presented by Jennifer Lai, MD and team of the University of California San Francisco. Data showed that women who had HCV-related liver transplantation have poorer long-term survival rates than men do. Women are also more likely to reject the donor liver. Lai also reported that women had a greater risk of advanced recurrent HCV after liver transplantation.
More research is needed to understand the reasons for the differences. Although she confirmed the need for further studies, Lai speculated that the differences may be due to:
Aging differences between genders
Gender mismatching of organs between donors and recipients
Higher risk of kidney impairment in women prior to liver transplantation
Women and HCV
by Liz Highleyman
In the past decade, chronic hepatitis C has become a widespread health concern, and this is true for women as well as for men. The U.S. federal government estimates that about four million Americans are infected with hepatitis C. More men than women have the disease; most experts believe this is because men are more likely to have risk factors for exposure to the hepatitis C virus (HCV), not because they are more susceptible than women to infection. In the U.S., African-Americans and Latinos have higher hepatitis C rates than whites.
Many people remain unaware that they have HCV. Before 1992, people often contracted HCV through blood transfusions. In 1992, an accurate test for donated blood came into wide use, and today transfusions are considered safe. In the 1970s and 1980s, before HCV was identified, women often received blood transfusions when they underwent Cesarean delivery (C-section); some of these women remain unaware that they received donated blood. Some experts suggest that women who had a C-section before 1992 should be tested for HCV.
HCV Risk Factors
The risk factors for contracting HCV are similar for women and men. Sharing needles for injection drug use is a major risk, and most studies show that a majority of people who have injected drugs are HCV-positive. Nurses and others who work in healthcare settings may contract HCV when they come into contact with blood, for example through accidental needlesticks. Other methods of transmission include shared equipment used for non-injection drugs (for example, cocaine straws and crack pipes); re-use of needles for acupuncture, tattooing, or body piercing; and shared personal items such as razors, manicure tools, and toothbrushes. Be sure to cover any cuts or sores to prevent contact with blood, and properly dispose of used tampons and sanitary napkins. Hepatitis C is not spread through casual contact such as sneezing, coughing, hugging, or sharing drinking glasses. For as many as 10% of people with HCV, no specific risk factors can be identified.
Sexual Transmission of HCV
Sexual transmission of HCV is uncommon. Most studies show that only a small percentage of people – estimated at 0-3% -- contract HCV through unprotected heterosexual intercourse with a steady, monogamous HCV-positive partner. People who have multiple sex partners have a higher risk of contracting HCV. According to the National Institutes of Health (NIH), people in long-term, monogamous relationships do not need to change their current sexual practices, although they should discuss safer sex if either partner is concerned about transmission. The NIH recommends that people who have multiple sexual partners should practice safer sex, in particular using latex condoms. There are no known cases of HCV being transmitted through oral sex on a woman (cunnilingus) or on a man (fellatio); however, it is theoretically possible that the virus could be transmitted this way if a person has mouth sores, bleeding gums, or a throat infection. Some studies indicate that sexual transmission from men to women is more efficient than transmission from women to men, as is also the case with HIV. As with HIV, HCV may be more efficiently transmitted through anal sex than through vaginal intercourse. The risk of HCV transmission through woman-to-woman sexual activity has not been studied. Because HCV is spread through blood, it is more likely to be sexually transmitted when a woman is having her menstrual period.
HCV Progression & Symptoms in Women
Various studies have shown that hepatitis C progression is slower and liver damage tends to be less severe in women than in men. For one thing, it appears that women are more likely to completely clear HCV from their bodies after infection and never develop chronic disease. It is usually estimated that 80-85% of all people infected with HCV will go on to develop chronic hepatitis C, but the rate is lower for women. A German study of 1,018 young women infected with HCV in 1978-9 through contaminated immunoglobulin transfusions found that after 20 years, about 45% had cleared the virus. Researchers do not know why the HCV clearance rate is higher in women than men.
Women who do have chronic hepatitis C (that is, they still have HCV after six months) tend not to develop liver cirrhosis (scarring), liver cancer, or liver failure as rapidly as men. For all people with chronic HCV, disease progression is usually slow. A majority of people with chronic hepatitis C never develop serious liver damage. Among those who do, the process usually takes years or even decades; the usual estimate is 10-40 years, and may be longer for women. In the German study, only four of the 1,018 women had developed cirrhosis after 20 years. Some experts believe that the female hormone estrogen protects women from liver damage; if this is the case, the protective effect may diminish after menopause, as women’s bodies produce less of the hormone.
Many people with HCV have no symptoms and lead normal lives. Those who do develop symptoms may experience prolonged fatigue (tiredness), fever, headache, loss of appetite, nausea, pain in the abdomen, or pain in the muscles or joints. The types of symptoms are similar in women and men, but women may develop symptoms later or may experience more mild effects.
Several autoimmune conditions, in which the immune system attacks the body’s own tissue, are associated with HCV (for example, cryoglobulinemia, glomerulonephritis, and Sjogren’s syndrome). Because women in general are much more likely than men to have autoimmune conditions, it is not surprising that women with HCV seem to be at greater risk than HCV-infected men for developing these conditions. However, according to Norah Terrault, MD, MPH, of the University of California at San Francisco Division of Gastroenterology, while women with HCV may be more predisposed than men to autoimmune conditions, this does not necessarily mean that these conditions are directly associated with HCV; women may simply be more likely to have co-existing autoimmune conditions that may not be caused by HCV. More study is needed in this area.
HCV Diagnosis & Monitoring
Doctors use various tests to determine if a person has hepatitis C. One type of test measures antibodies in the blood, indicating that a person been exposed to HCV; the two most common antibody tests are called ELISA and RIBA. Viral load tests measure how much HCV genetic material is present in the blood; the two most common viral load tests are called PCR and bDNA. There are several different types of hepatitis C virus called genotypes. Genotype tests can help determine how well HCV treatment might work. Genotypes 1a and 1b, which are most common in the U.S., are more difficult to treat. Current research does not indicate that women are likely to have different HCV genotypes than men.
Liver function tests, which measure levels of liver enzymes and other substances in the blood, indicate how well the liver is working. Changes in liver enzyme levels can help to determine whether the liver is damaged and whether HCV treatment is working. People with chronic hepatitis C often have increased levels of two liver enzymes called ALT and AST. Women tend to have lower ALT levels than men. However, this does not necessarily means that their liver disease is less severe. According to Terrault, ALT is “not a perfect reflection” of liver damage, and screening tests based on ALT levels alone may miss some women with liver disease.
HCV Treatment in Women
Not everyone with hepatitis C needs treatment. Doctors determine whether treatment is appropriate based on various factors including HCV genotype, viral load, liver enzyme levels, and extent of liver damage. Since women tend to have less severe liver damage that develops more slowly, they may be less likely than men to need treatment. However, treatment recommendations should not be based solely on ALT levels, which are typically lower in women.
Today, the current standard treatment for chronic hepatitis C is a combination of two medications, interferon and ribavirin. Interferon is a manufactured version of a natural substance produced by the body's immune system. Ribavirin (brand name Rebetol) is an antiretroviral drug that kills certain types of viruses. Combination treatment with interferon plus ribavirin was approved by the Food and Drug Administration (FDA) in 1998. Studies have shown that the combination works better than treatment with interferon alone (monotherapy). But interferon monotherapy does appear to work well for some people with mild hepatitis who have minimal liver damage. Recent studies have shown that a new type of interferon -- called pegylated interferon -- works better with ribavirin than standard interferon. Pegylated interferon lasts longer in the body and does not have to be injected as often. This August, the FDA approved the combination of pegylated interferon plus ribavirin for the treatment of chronic hepatitis C. The standard treatment regimen for HCV is the same for women and men.
Since HCV treatment works best in people with milder liver damage, women tend to benefit more from therapy than men. According to Terrault, this is true “across the board” for different types of HCV therapy, although the gender difference is “less striking” with pegylated interferon compared to standard interferon. A couple of studies have found that interferon therapy worked better in pre-menopausal women than in men of the same age or postmenopausal women, suggesting again that estrogen may play some role in protecting women’s livers. Some research indicates that treatment does not work as well in African-Americans as it does in whites; more study is needed to determine how these race and gender effects interact in black women.
The drugs used to treat HCV cause side effects in some people. The most common side effects of interferon include headache, nausea, fatigue, loss of appetite, muscle and joint pain, and mental depression or anxiety. The most serious side effects of ribavirin are low levels of certain types of blood cells (anemia, neutropenia, and thrombocytopenia). In the population as a whole, women have higher rates of depression than men, and so may be more likely to experience this side effect; interferon is typically not recommended for people who are already experiencing major depression or other psychiatric illnesses. Interferon may worsen autoimmune conditions; the relationship between interferon and autoimmune conditions in women with HCV is an area for further study. Also, because women lose blood each month through menstruation, they are more likely than men to develop anemia (a low red blood cell count). Women taking ribavirin should have their blood cell levels monitored regularly.
Because women tend to weigh less than men, treatment dosage has been a concern. Standard interferon therapy is based on a fixed dose, and lighter-weight women may receive more of the drug than is necessary to control their HCV. Higher doses are associated with more severe side effects. Pegylated interferon, however, is dosed based on weight. People who weigh less received a lower dose, thus reducing the possibility of “overtreatment.”
HCV and Pregnancy
Many women with HCV are concerned about the risk of transmitting the virus to their babies during pregnancy or birth. Studies consistently show that the rate of perinatal or vertical transmission is low, about 5% or 1 in 20. Vertical transmission is most likely to happen when the mother has a high HCV viral load; several studies have shown that no transmission occurred when women had undetectable viral loads. Studies also show that women who are co-infected with both HCV and HIV have a higher risk (15-35%) of transmitting HCV to their infants. One British study has suggested that the risk of vertical HCV transmission may be reduced through Cesarean delivery; however, according to the Society of Obstetricians and Gynecologists of Canada, “routine Cesarean section is not recommended as a specific measure to reduce the risk of vertical transmission of HCV.”
Although HCV has been detected in breast milk in some studies, there is no indication that breastfeeding transmits the virus. Most experts do not discourage HCV-positive women from breastfeeding. But women may wish to exercise caution if their nipples are cracked or bleeding. HCV is not transmitted from mothers to children through normal household contact.
According to Terrault, who treats many women with HCV, being pregnant does not adversely affect the progression of hepatitis C. Likewise, women with HCV do not have a higher rate of pregnancy or birth complications compared to uninfected women. However, women with severe, advanced liver disease may experience difficulties during pregnancy.
Universal prenatal screening of women for HCV is not currently recommended. Babies of HCV-positive women should be tested for HCV after 12-18 months. According to the Centers for Disease Control and Prevention, most infants infected with HCV at birth have no symptoms and do well during childhood. Studies suggest that infants are more likely than adults to completely clear the virus from their bodies. HCV treatment has not been well studied in infants and children.
Ribavirin is known to cause miscarriages and birth defects, so pregnant women should not take this drug. In addition, both women of childbearing potential and men taking ribavirin should use two reliable forms of birth control during treatment and for six months after treatment ends. Most doctors also recommend that interferon should not be taken during pregnancy, because its effects on the human fetus is not well known.
Hormones and HCV
Because hormones are processed by the liver, traditionally some doctors have recommended that women with HCV should not take hormone replacement therapy (HRT) or hormonal contraceptives such as the pill. But according to Terrault, hormone doses used to be much higher than they are now, and this belief is outdated. She says that HRT should not be withheld from women with HCV if it is indicated for their overall health. Likewise, the risks of hormonal contraceptives, Terrault says, are “very low.” Some early studies suggested that women who used combined estrogen plus progesterone contraceptive pills were at higher risk for liver cancer, but a more recent study of women using newer, lower-dose pills did not find an association. Nevertheless, some doctors still recommend progesterone-based rather than estrogen-based birth control pills for women with HCV.
After menopause, when their bodies produce less estrogen, many women develop osteoporosis, or brittle bones. It is known that thinning of the bones occurs in people with liver damage. Treatment with ribavirin has also been associated with bone loss. Therefore, taking estrogen to prevent bone loss may be beneficial to women with HCV. Moderate exercise can also help maintain healthy bones, and is recommended for women with HCV unless they are feeling very ill. Avoid high dose supplements of vitamin D, which can harm the liver.
Terrault emphasizes that the effect of menopause on women with HCV should be better studied. Some women with hepatitis C and other chronic diseases have reported early menopause, and at least one study has found that liver cirrhosis is associated with reduced fertility. Terrault notes that some of her patients find it difficult to tell whether symptoms such as fatigue and depression are due to menopause or HCV. How menopause affects HCV progression and treatment is not well known, and more research is clearly needed.
Take Care of Yourself
Living with a chronic disease can be stressful. Rates of HCV are high in women who use drugs, economically disadvantaged women, and women in prison. Many women with hepatitis C face issues such as lack of access to quality health care, lack of health insurance, stigma, and discrimination.
There are several measures you can take to improve the health of your liver and your overall quality of life. Good nutrition is important for people with hepatitis C. A healthy diet is low in fat, salt, and sugar, and high in carbohydrates and fiber. Processed foods often have chemical additives, so eat less canned or frozen foods, and more fresh fruits and vegetables. Avoid high dose vitamin and mineral supplements. Some doctors recommend that people with hepatitis should drink less coffee, eat less chocolate, and avoid raw or undercooked shellfish. Avoid alcohol, which can be very harmful to the liver. The NIH recommends that people with HCV drink no more than one alcoholic beverage per day. Certain illegal or recreational drugs, prescription drugs, over-the-counter (non-prescription) medications, and herbal remedies can also damage the liver. Tell your doctor about all drugs and herbs you are taking. Because other types of viral hepatitis can be much worse in people who already have hepatitis C, anyone with HCV should ask their doctor about getting the hepatitis A and B vaccines (there is no vaccine for hepatitis C). See your doctor regularly and get checkups to monitor your liver health.
Many women with hepatitis C experience chronic fatigue and depression. Try to plan activities in advance and make realistic schedules. Pace your activities, and don’t forget to take time out for relaxation or naps. Try to maintain a realistic picture of your health. Learn to say ‘no’ to those who have unrealistic expectations of your energy level, and don’t be afraid to ask family and friends for the help you need. Meditation can be a useful tool to help reduce stress. Many people find that peer support groups with other HCV-positive people can help them cope with their disease and overcome feelings of isolation. Support groups can provide a safe space to share information and discuss the emotional issues surrounding chronic hepatitis C.
Women often put the care of their families above their own needs and neglect their own health. If you have chronic hepatitis C, don’t forget to take care of yourself!
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Women Experience Higher Rates of Adverse Events During Hepatitis C Virus Therapy in HIV Infection