Research ArticleRaloxifene hydrochloride is an adjuvant antiviral treatment of postmenopausal women with chronic hepatitis C: A randomized trial☆
Introduction
Chronic hepatitis C virus (HCV) infection is the predominant cause of chronic liver disease. Over time, it has become apparent that men more often develop progressive liver disease than women do, with an associated, disproportionate number of men being afflicted with liver cancers [1]. However, the spontaneous clearance of HCV infection is more likely in women than in men [1]. These observations indicate sex-related differences in HCV infection status and its liver pathophysiology.
Dramatic improvements in antiviral response have been observed since the use of standard of care (SOC) treatment for chronic hepatitis C, consisting of a combination of pegylated interferon α (PegIFNα) and ribavirin (RBV), was adopted, leading to improved patient outcomes [2], [3], [4], [5]. There are several predictors associated with the sustained virological response (SVR), including younger age, not being obese, absence of liver fibrosis, HCV non-genotype 1, and low levels of HCV RNA [2], [3], [4], [5]. Women, particularly those who are premenopausal, respond better than men [2], [5]. The response of Japanese older women is poor, with mutations in the HCV core region or iron metabolism being suggested as reasons for the comparatively poor efficacy [6], [7], [8], [9]. These observations led to the suggestion that the low antiviral response rates of older women might be related to declining estrogen secretion [9].
Raloxifene hydrochloride (RLX) is an oral selective estrogen receptor modulator (SERM) that has estrogenic actions on bone and anti-estrogenic actions on the uterus and breast. RLX is prescribed for postmenopausal women to prevent the progression of osteoporosis, and manifests its pharmacological activity by binding to intra-nuclear estrogen receptors and altering gene transcription [10]. Thus, SERM agents exhibit estrogen agonist and antagonist actions to produce tissue-selective estrogen-like effects. In the liver, these agents have been suggested to function as estrogen agonists that directly protect hepatocytes and control liver fibrosis [11].
To the best of our knowledge, no previous study had shown a difference in SVR between postmenopausal women and age-matched men. Recently, an Italian clinical study has reported similar SVR rates for both postmenopausal women and men [12]. These rates are significantly lower than those observed in women of childbearing age. Early menopause has been reported to be the most predictive factor for failure to achieve an SVR, and this again links SVR to estrogen secretion. In this study, we tested the hypothesis that RLX can improve the efficacy of SOC treatment for postmenopausal women with chronic hepatitis C.
Section snippets
Patients and study design
This study was a prospective, open-label, randomized, controlled trial to investigate the SVR rate achieved when RLX administration was combined with the SOC treatment, relative to that observed with the SOC treatment alone for postmenopausal women infected with HCV genotype 1. The study design was approved by the independent ethical committee of each hospital and was carried out in accordance with the 1975 Declaration of Helsinki, as updated in 2008. Each patient gave written, informed consent
Patient characteristics at baseline
Sixty-two of the 123 patients were assigned to the RLX plus SOC group and 61 to the SOC only group (Table 1). The overall mean length of time since menopause was 10.2 ± 4.2 years (range: 2–22 years). The two groups showed no significant differences in age, time since menopause, body mass index, previous IFN use, previous RBV use, pretreatment levels of HCV RNA and alanine aminotransferase (ALT), glucose tolerance, blood lipid profiles, serum ferritin levels, or IL28B genotype distribution between
Discussion
When non-pegylated IFNα monotherapy is used to treat Japanese patients with chronic hepatitis C, women aged <40 years show higher SVR than do similarly aged men. At ages >40 years, SVR rates are lower for women than for men. The fact that non-pegylated IFNα is more effective for younger women than for older women is suggestive of a potential link to reduced estrogen secretion [9]. The present study demonstrated that the addition of RLX to SOC for postmenopausal women with chronic hepatitis C
Financial support
This study was supported in part by a Grant-in-Aid for Comprehensive Research from the Ministry of Education, Culture, Sports Science and Technology of Japan.
Author contributions
N. Furusyo: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; statistical analysis. E. Ogawa: acquisition of data; critical revision of the manuscript for important intellectual content; statistical analysis. M. Sudoh: analysis of the anti-HCV replicon activity study; critical revision of the manuscript for important intellectual content. M. Murata: acquisition of data; critical revision of the manuscript for important intellectual
Conflict of interest
M.S. is an employee of the Chugai Pharmaceutical Co., Ltd., Tokyo, Japan. The remaining authors declare that there are no conflicts of interest relevant to this manuscript.
Acknowledgments
The authors thank Drs. Hachiro Ohnishi, Kunimitsu Eiraku, Koji Takayama, Fujiko Mitsumoto, and Kazuya Ura from our department for assistance with data collection. The authors also thank Mr. Yoshitaka Etoh for his excellent lab work on IL28B SNPs in this study. The authors thank Mrs. Hiroshi Koyama, Junji Usa, and Masahiko Kondo for assisting in this study. The authors also thank Dr. Isamu Kusanagi for technical assistance.
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These data were reported at the 47th Annual Meeting of the European Association for the Study of the Liver in Barcelona (Spain) from April 18–22, 2012 (Abstract No. 1112, ePoster).