Quality of life in women with chronic recurrent vulvovaginal candidosis: A sub-analysis of the prospective multicentre phase IIb/III Prof-001 study

Background: Chronic recurrent vulvovaginal candidosis (RVVC), defined as three or more episodes of vulvovaginal candidosis per year, significantly impairs quality of life (QoL) and sexual health. Objectives: The primary objective of this study was to assess health-related QoL in women with RVVC using validated questionnaires before and after treatment. The secondary objective was to analyse the effect of RVVC on women's sexual health. Patients/Methods: This was a sub-analysis of a randomised, controlled, double-blinded study titled ‘A phase IIb/III, parallel-arm, randomized, active-controlled, double-blind, double-dummy, multicenter, non-inferiority study in patients with recurrent vulvo-vaginal candidosis to compare the clinical efficacy, safety and tolerability of topically administered ProF-001 (Candiplus®) to oral fluconazole , which was conducted at 35 study sites in Austria, Poland and Slovakia. QoL was assessed using the European Quality of Life (EQ) five-dimension five-level scale (EQ- 5D-5L) and visual analogue scale (EQ-VAS) questionnaires, followed by specific questions regarding sexuality


exact relationship between vulvodynia and previous infections with
Candida has not been fully examined, but it seems that more than 70% of women with vulvodynia have a history of RVVC. 8,9,15,18 In 2019, Fukazawa et al. showed the negative impact of RVVC on different aspects of health-related QoL using a validated questionnaire. 19,20 In their study, women with RVVC showed significantly lower QoL, especially regarding satisfaction with general health, well-being, self-perception of their own physical and mental health and satisfaction with social interactions, when compared to a healthy control group. 17 Zhu et al. evaluated 102 women with RVVC and reported significantly lowered scores in the categories of performance, pain, general health, emotional health and mental health among women with RVVC. 21 Aballéa et al. assessed the QoL and health status of women with RVVC in a multinational setting using an online survey, and compared it to other diseases. 22 The authors found significantly impaired QoL scores in affected women, even when they previously received treatment. The average index score was worse in women with RVVC than in the other groups, such as patients with migraine. Women with RVVC showed similar QoL impairment as those with bronchial asthma or chronic obstructive pulmonary disease. This impairment is also known to result in significantly lower productivity at work and daily life. 22 This was confirmed in studies that reported high rates of burnout and stress among women with RVVC. 23,24 Despite the availability of long-term treatment, recurrence of vulvovaginal candidosis remains a common problem. As previously described, a significant impairment in QoL has been described in women with RVVC. In contrast to the existing literature, the present study aimed to assess the effect of RVVC treatment on the QoL of affected women with individual health perception assessments over a 6-month period. Moreover, as part of a prospective, larger multicentre study, we evaluated whether maintenance treatment had an effect on the individual sexual health of affected women with RVVC. unblinding was conducted for this sub-analysis. Due to the multiple assessments of the relevant variables, data collection followed a longitudinal approach. Women were evaluated during four study visits over a 6-months maintenance period, and women who completed visits one and four were considered eligible for the sub-analysis.

| Data collection and questionnaires
Data were collected using electronic case report forms, questionnaires and diaries. Sociodemographic data were also assessed with the language of the questionnaires adapted to the individual study centre. Questionnaires were assessed at the time of study enrolment (visit one), as well as after 6 months (visit four), which was mandatory for women in this sub-analysis. Study visits two and three of the umbrella study were not relevant for the sub-analysis, as the women did not receive any questionnaires during these visits. The results of this later phase of the study will be presented along with the final outcomes of the study in soon-to-be-published papers.
We used the European quality of life visual analogue scale (EQ-VAS) to evaluate women's subjective perception of their general health, rating their health perception from 0 to 100 points, with higher scores indicating a better health status than lower scores. The more specific European quality of life five-dimension five-level scale (EQ-5D-5L) was used to evaluate mobility, body hygiene, everyday routine, pain and fear/depression, where women were able to rate each of the categories from one to five, with lower scores representing fewer difficulties. Finally, we assessed individual sexual activity in the previous 4 weeks using the question 'Have you been sexually active during the last 4 weeks?' with possible dichotomous answers of yes/no, followed by a question on the frequency of associated problems using six statements with a score ranging from zero to four, where a score of zero indicated no associated problems and four indicated that there was always a problem. These parameters were evaluated at the time of inclusion and after 6 months of therapy with either ProF-001 or fluconazole. Since no unblinding was conducted for this specific analysis, the focus was not on differences in interventional efficacy, but rather on the general effect of RVVC treatment on the affected women's QoL and sexual health.

| Statistical analysis
The significance interval was determined at p < .05, using Bonferroni correction to eradicate the uncontrolled increase of the alpha error in multiple analyses. The adjusted significance level was determined at .05/k (k = number of tests performed), using the effect size classification according to Cohen to determine the clinical relevance of our findings. The standardised effect value r was defined as r ≥ 0.10, small; r ≥ 0.30, medium; and r ≥ 0.50, considerable. We used the Wilcoxon method to calculate the change in QoL, measured using the EQ-VAS and EQ-5D-5L. Differences in ordinal data were examined using the Kruskal-Wallis test, and paired independent group comparisons were analysed using the Mann-Whitney U-test.
Spearman and chi-squared tests were used for correlation analysis.
Finally, we used a multiple logistic regression model to determine the probability of outcomes depending on the predictors, where odds ratios (OR) were determined as a relative risk estimation. The statistical program IBM SPSS® 22.0 for MacOsX was used for descriptive and inferential statistical analyses.

| Patient collective
Out of a total of 432 women who were enrolled in the larger umbrella trial, 360 (83.3%) women had completed the 6-month maintenance period of treatment at the study centres and were therefore included in this sub-analysis. Of these, 76 (21.1%) were Austrian, 199 (55.3%) were Polish and 85 (23.6%) were of Slovakian origin.
Sociodemographic data of the enrolled women are shown in Table 1.
The average duration of RVVC symptoms in these women was 39.5 ± 4.9 months across all three study regions. Of the 360 women, 72 (20%) experienced at least one episode of RVVC relapse during the study period, ranging from one to four episodes per patient ( Table 2). We could not determine a significant difference in the distribution of relapse occurrence between countries. The frequency of relapse and duration of RVVC were positively correlated (r = 0.07; p = .099). Accordingly, a trend towards a higher number of relapse episodes can be assumed with longer RVVC duration. Neither age nor BMI were found to be significant predictors of an increased relapse rate, with an OR of 1.014 (confidence interval [CI] 95%, 0.989-1.039) and 0.994 (CI 95%, 0.929-1.064), respectively.

| Quality of life
Evaluation of QoL using EQ-VAS and EQ-5D-5L scores showed a significant correlation between the scores at study visits one and four (p < .001). During the 6-month maintenance treatment, women experienced significant QoL improvement according to these questionnaires, as shown in Figure 1 and Table 3. Specifically, we found an TA B L E 1 Sociodemographic data according to the study region (values are mean and standard deviation). respectively. In contrast, 20 (9.5%) and 24 (11.3%) women showed a decline in QoL and subjective health perception, respectively, after maintenance treatment. The remaining patients' scores showed no significant changes during the observational period ( Figure 2).

| Sexual health
Regarding sexual health, we found that 147 (73.5%) women reported sexual activity at both study visits, 18 (9%) reported no sexual activ- However, when asked about the impairment caused by F I G U R E 1 Relationship between the EQ-VAS and EQ-5D-5L score and at study visit one in the 360 women with RVVC of our study.

TA B L E 3 EQ-VAS and EQ-5D
-5L score at study visits one and four in the 360 women with RVVC of our study.
the disease in this aspect, an improvement after the 6-month period was observed in 70 (37.6%) of the women who were interviewed.
The results of the questionnaire are summarised in Table 4 However, thorough evaluation of the effects on different aspects of sexuality using detailed and validated questionnaires are still missing. Therefore, we performed this sub-analysis of a prospective study to evaluate the effect of RVVC on women's sexual lives and partnerships. By using this large dataset, which was designed to test different treatment options in women with RVVC, we could measure the effect of different treatment options on QoL and sexual health.
In our study, the median duration of RVVC complaints was The questionnaire used in our study was the EQ-5D-5L questionnaire, which assesses mobility, body hygiene, everyday routine, episodes was found to be significantly lower than in the average population, even with therapy. The average index score was comparable to other diseases such as chronic obstructive pulmonary disease and asthma, and worse than in patients with migraine. 22 Our data support these findings for women who affected RVVC.
The significant improvement in QoL and subjective perception of their health, as measured by the EQ-VAS score, served as an optimistic insight into the disease. When comparing EQ-5D-5L and EQ-VAS scores, we also found a significant correlation between these scores.
Approximately 65-75% of women reported improvement during the study period according to both scores, which demonstrates the benefit of each treatment in these patients, even though we found considerably high relapse rates during maintenance treatment. Previous studies have examined the impact of RVVC on women's sexual health. 8,9,20 This severe negative impact, which has been described in the literature, is supported by the findings of our study.
In addition to the existing literature, we focused on specific aspects of sexuality, such as pain, fear, avoidance, frustration and problems in partnership. Our data confirmed the fact that there is a significant impairment of different aspects of women's sexual health. However, this improved after the 6-months period of maintenance treatment. The treatment agent seems to be less important than treating the patient per se to relieve symptoms. In particular, we observed an improvement in symptoms during sexual intercourse, which was associated with a reduced relapse rate. To date, the negative impact of RVVC on sexual health has been confirmed in the literature; however, no specific data on the effect of treatment have been described. 8,9,20 We are aware of the strengths and limitations of this study. One of the strengths is that we used standardised questionnaires with a large number of women to evaluate QoL and sexual health. However, in qualitative studies such as ours, both selection and reporting biases are inherent. We were unable to unblind the treatment regimens that women received, which is subject to the final analysis of the larger umbrella trial that we will present in the near future.
In conclusion, recurrent vulvovaginal candidosis affects numerous women worldwide and can lead to significant impairment of QoL and impaired sexual health. Relapses may occur in some cases under maintenance therapy, but different treatments offer improvement.

ACK N O WLE D G E M ENTS
None.

CO N FLI C TS O F I NTER E S T S TATEM ENT
This study was sponsored by Profem GmbH as part of a randomised,