Hepatitis C ; Hormones: A Potential Explanation for Differences in Response Rates to Therapy

Hormones: A Potential Explanation for Differences in Response Rates to Therapy for Chronic Hepatitis C Infection

Kimberly A. Forde
Affiliations
Reprint 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 Outline
References
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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.29

When 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, 39

In 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.

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