Spontaneous Fluctuations in Liver Biochemistries in Patients with Compensated NASH Cirrhosis: Implications for Drug Hepatotoxicity Monitoring.

INTRODUCTION: Patients with cirrhosis may have spontaneous fluctuations in liver enzymes, which may confound detection of drug-induced liver injury (DILI), but these fluctuations have not been described. OBJECTIVE: We sought to quantify spontaneous liver enzyme abnormalities in patients with cirrhosis due to nonalcoholic steatohepatitis (NASH) enrolled in clinical trials. METHODS: We examined the laboratory values of patients with compensated cirrhosis randomized to placebo in two clinical trials for NASH. Patients in one study were followed every 13 weeks up to week 57; patients in the other study were followed every 4 weeks up to week 120. RESULTS: In total, 53 and 85 patients were randomized to placebo in the trials. Baseline alanine aminotransferase (ALT) was greater than the laboratory upper limit of normal (ULN) in 53% and 49% of participants, aspartate aminotransferase (AST) was > ULN in 49% and 59%, alkaline phosphatase was > ULN in 36% and 27%, and bilirubin was >ULN in 13% and 19%. During follow-up, ALT increased to 2× baseline in 8% and 15%, AST increased to 2× baseline in 6% and 21%, and bilirubin increased to 2× baseline in 9% and 18%. Alkaline phosphatase did not increase to 2× baseline for any patient. The maximum ALT was 3× ULN in 9% and 12%. ALT increased to 3× baseline in three patients and to 5× ULN in two patients. No patients had elevations consistent with Hy's law. The maximum ALT for patients with abnormal baseline values was higher [median 48 U/L (range 34-299) and 56 U/L (47-85)] than for those with normal baseline values [median 26.5 U/L (range 18-33) and 29 U/L (25.5-30.5)] in both studies, respectively, with p < 0.001. CONCLUSION: Spontaneous liver enzyme abnormalities are common in patients with NASH cirrhosis in clinical trials, and these abnormalities rarely met criteria for DILI suspicion. Further work to better define these abnormalities and continued vigilance to detect DILI in this population is needed.

Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension.

BACKGROUND & AIMS: Increased levels of galectin 3 have been associated with nonalcoholic steatohepatitis (NASH) and contribute to toxin-induced liver fibrosis in mice. GR-MD-02 (belapectin) is an inhibitor of galectin 3 that reduces liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies. We performed a phase 2b, randomized trial of the safety and efficacy of GR-MD-02 in patients with NASH, cirrhosis, and portal hypertension. METHODS: Patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mm Hg) from 36 centers were randomly assigned, in a double-blind manner, to groups that received biweekly infusions of belapectin 2 mg/kg (n = 54), 8 mg/kg (n = 54), or placebo (n = 54) for 52 weeks. The primary endpoint was change in HVPG (Δ HVPG) at the end of the 52-week period compared with baseline. Secondary endpoints included changes in liver histology and development of liver-related outcomes. RESULTS: We found no significant difference in ΔHVPG between the 2 mg/kg belapectin group and placebo group (-0.28 mm HG vs 0.10 mm HG, P = 1.0) or between the 8 mg/kg belapectin and placebo group (-0.25 mm HG vs 0.10 mm HG, P = 1.0). Belapectin had no significant effect on fibrosis or nonalcoholic fatty liver disease activity score, and liver-related outcomes did not differ significantly among groups. In an analysis of a subgroup of patients without esophageal varices at baseline (n = 81), 2 mg/kg belapectin was associated with a reduction in HVPG at 52 weeks compared with baseline (P = .02) and reduced development of new varices (P = .03). Belapectin (2 mg/kg) was well tolerated and produced no safety signals. CONCLUSIONS: In a phase 2b study of 162 patients with NASH, cirrhosis, and portal hypertension, 1 year of biweekly infusion of belapectin was safe but not associated with significant reduction in HVPG or fibrosis compared with placebo. However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce HVPG and development of varices. ClinicalTrials.gov number: NCT02462967.

Safety and efficacy of low-dose esterified estrogens and methyltestosterone, alone or combined, for the treatment of hot flashes in menopausal women: a randomized, double-blind, placebo-controlled study.

This study evaluated safety and efficacy of esterified estrogens and methyltestosterone administered alone or in combination for the treatment of hot flashes in menopausal women. The 0.30-mg esterified estrogens and 0.30-mg methyltestosterone combination was the lowest effective dose, and our results are consistent with the known safety profile of estrogen and androgen combination products.

Validation of a Women's Sexual Interest Diagnostic Interview--Short Form (WSID-SF) and a Daily Log of Sexual Activities (DLSA) in postmenopausal women with hypoactive sexual desire disorder.

INTRODUCTION: Currently, there is no clear standard assessment tool for the diagnosis and daily monitoring of hypoactive sexual desire disorder (HSDD) in postmenopausal women. AIM: The aim of the study was to validate (i) the Women's Sexual Interest Diagnostic Interview-Short Form (WSID-SF) which is a structured tool to identify HSDD; and (ii) the Daily Log of Sexual Activities (DLSA) which is a diary to monitor daily HSDD status in postmenopausal women. Both assessments were collected as self-reports by an interactive voice response system (IVRS). METHODS: At the initial study visit, 629 postmenopausal women, age 39-66, were evaluated for HSDD by the WSID-SF. In addition, in a subgroup of 175 subjects at five study sites, HSDD was assessed by physicians who were blinded to the WSID-SF diagnosis. During the 58-day study period, patients completed the DLSA daily through self-reported IVRS. All women also completed the Female Sexual Function Index (FSFI), Menopause Sexual Interest Questionnaire (MSIQ), Female Sexual Distress Scale (FSDS), Dyadic Adjustment Scale (DAS), and Kellner Symptom Questionnaire (KSQ) at both the initial study visit and at the end of the study. The WSID-SF-based identifications were compared with clinical diagnoses made based on physicians' clinical experience. Construct validity of the WSID-SF and DLSA were assessed based on comparisons with questionnaire results. Internal consistency and test-retest reliability of the DLSA were also evaluated. MAIN OUTCOME MEASURES: Main outcome measures include the agreement between WSID-SF diagnosis and clinician diagnosis, convergent and divergent validity of the WSID-SF and DLSA, and reliability of the DLSA. Results. Enrolled subjects were classified into HSDD (N = 468) and non-HSDD (N = 161) groups by WSID-SF. When compared with physician's diagnosis, WSID-SF-based diagnosis had a specificity of 89% and a sensitivity of 70% (kappa = 0.46, P < 0.001). WSID-SF showed significant correlation with each domain of the FSFI, MSIQ, and FSDS (all P < 0.001). As anticipated, WSID-SF had low or nonsignificant correlations with all domains of the DAS and the KSQ. Four different algorithms were piloted to calculate DLSA scores. Data on the detailed analysis conducted to evaluate the four scoring strategies is on file (not presented in this article). Ultimately, the weekly DLSA total score calculated by algorithm #4 was selected to validate the DLSA. In the test-retest reliability evaluation, the intraclass correlation coefficient was 0.80 for women with HSDD and 0.84 for women without HSDD (P < 0.001 for all analysis). In the known-group validity comparison, the weekly DLSA total score was significantly different (P < 0.001) among the HSDD and the no HSDD groups, with an effect size of 0.89-0.92 based on Cohen's d. The DLSA also showed convergent validity with moderate to high correlations with each domain of the FSFI, MSIQ, and FSDS (P < 0.001 for all correlations). As anticipated, the DLSA had weak correlations with the DAS and KSQ demonstrating divergent validity. CONCLUSIONS: The WSID-SF had good specificity and sensitivity (i.e., discriminative validity) in identifying HSDD in postmenopausal women. In addition, the DLSA is a reliable and valid patient-reported outcomes tool that can be utilized to assess effectiveness of treatments in postmenopausal women with HSDD. Further, the WSID-SF and DLSA both demonstrated good convergent and divergent validity.

Development and evaluation of the Women's Sexual Interest Diagnostic Interview (WSID): a structured interview to diagnose hypoactive sexual desire disorder (HSDD) in standardized patients.

INTRODUCTION: Female sexual dysfunction (FSD) is a common disorder in postmenopausal women. Currently, there is no clear "gold standard" for the diagnosis of FSD. AIM: The aim of this study was to evaluate the interrater reliability of the Women's Sexual Interest Diagnostic Interview (WSID), a new structured clinical interview designed to diagnose hypoactive sexual desire disorder (HSDD). The reliability of additional interview questions focused on the diagnosis of other types of FSD was also evaluated. MAIN OUTCOME MEASURES: The main outcome measure was the level of agreement in the diagnosis of FSD among clinical experts, between clinical experts and study coordinators, and between clinical experts and patients' self-reported interactive voice response system (IVRS) version of the WSID. METHODS: Two versions of WSID were developed based on current diagnostic criteria: a clinician-administered version using a structured interview guide, and a patient self-report version using an IVRS. Three sexual medicine experts developed 20 clinical scenarios portraying cases and noncases of HSDD and other FSD diagnostic subtypes. Ten actresses with experience in standardized patient interviewing rehearsed these scenarios and performed the scripted patient roles in a standardized clinical interview with clinical experts (not the author of the script) and study coordinators, on a one-on-one basis, using the WSID interview format. In addition, all actresses completed the IVRS version of the WSID. Interviews were videotaped and viewed by the expert panel. In each instance, the diagnosis that the interview was scripted to portray was considered as the "gold standard." Kappa (kappa) coefficients were utilized to assess the level of agreement among experts, between study coordinators and the "gold standard", and between the IVRS version of the WSID and the "gold standard". RESULTS: All experts agreed with the gold standard diagnosis provided by the author of the script (kappa=1.0). Similarly, there was perfect agreement among the experts on the presence of depressive symptomatology (kappa=1.0). On the related diagnoses of arousal disorder, orgasmic disorder, and sexual pain disorder, kappas of 0.894, 0.966, and 0.946 were observed (P<0.0001 for all comparisons). When study coordinator's WSID diagnoses were compared with the "gold standard," kappa for HSDD was 0.851; sensitivity was 0.864, and specificity and positive predictive value (PPV) were 1.00 (P<0.001 for all comparisons). When diagnoses obtained via IVRS interviews were compared with the "gold standard", kappa for HSDD was 0.802, sensitivity was 0.818, and specificity and PPV were 1.00 (P<0.001 for all comparisons). CONCLUSION: Agreement as estimated by kappa coefficients was consistently high in both clinician-administered and patient self-reported IVRS versions in the diagnosis of HSDD.