Raloxifene hydrochloride is an adjuvant antiviral treatment of postmenopausal women with chronic hepatitis C: A randomized trial

Background & Aims

Early menopause in women with chronic hepatitis C virus (HCV) infection is associated with a low likelihood of a sustained virological response (SVR) in conjunction with their antiviral treatment. This is potentially related to their reduced estrogen secretion. The study was done to determine whether selective estrogen receptor modulator administration might improve the efficacy of the current standard of care (SOC) treatment, pegylated interferon (PegIFN) α2a plus ribavirin (RBV), for postmenopausal women.

Methods

One hundred and twenty-three postmenopausal women with genotype 1b chronic hepatitis C were randomly assigned to one of two treatment groups: raloxifene hydrochloride (RLX) (60 mg/day) plus SOC (PegIFNα2a 180 μg/week and RBV 600–1000 mg/day) (n = 62) or SOC only (n = 61). Genotyping was performed of the polymorphism in the interleukin-28B (IL28B) gene region (rs8099917) of DNA collected from each patient.

Results

One RLX-treated patient discontinued RLX because of a systemic rash following 2 weeks of treatment. Twenty-four weeks after treatment, the SVR rate was significantly higher for RLX plus SOC patients (61.3%) than for SOC only patients (34.4%) (p = 0.0051). Further, the SVR rate was significantly higher for RLX plus SOC patients with IL28B TT (72.5%) than for SOC only patients with IL28B TT (39.2%) (p = 0.0014), but no such relationship was observed in patients carrying the minor IL28B allele.

Conclusions

RLX improved the efficacy of SOC in the treatment of postmenopausal women with chronic hepatitis C. RLX shows promise as an adjuvant to the standard antiviral treatment of such patients.

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.