The effect of medical grade honey (L-Mesitran) for cervical intraepithelial neoplasia-II

Cervical cancer is caused by the high-risk human papillomavirus (hr-HPV). 80%
of sexually active women get infected by hr-HPV during their lifetime, 10%
persists and 0.6% develops cervical cancer. This development proceeds gradually
through precursor lesions (CIN I, II and III). The standard treatment for CIN
II/III is a large loop excision of the cervix(LLETZ). In young women with a
(future) desire to have children, a LLETZ can lead to an increased risk of
premature birth and fertility disorders. An alternative is an immunomodulatory
cream (Imiquimod), unfortunately, 45% of patients do not respond to the
treatment, in addition, there is a 10% dropout due to side effects.

With CIN II, the chance of spontaneous regression is +/- 55%, so the advice for
young women is to wait and see. However, the other half persists or progresses
to CIN III and the often lengthy follow-up can lead to anxiety and worry.
Patients with CIN II benefit from non-invasive treatments with minimal side
effects. It is known that both the immune system and the vaginal microbiota
play an important role in the clearance of HPV. Medical grade honey has the
potential to act on these defense mechanisms of the body to help clear hr-HPV
and CIN II. Firstly, medical grade honey positively influences the vaginal
microbiome through its favorable acidity, the release of hydrogen peroxide,
reducing pathogenic bacteria, and the promotion of Lactobacilli. Secondly,
medical grade honey has immunomodulatory and anti-inflammatory activity.
Moreover in vitro studies and pre-liminary human cohort studies show a direct
antiviral activity. This suggests that honey may be able to modulate the
microenvironment to clear the hr-HPV and precursor lesions.
This is the first study using honey to treat CIN. The potential impact is fewer
additional treatments 1and a quicker resolution of HPV, necessitating less
aftercare thereby reducing stress and costs. Moreover, due to a decrease in
invasive treatments (less LLETZ), we expect a long-term effect on the care
burden due to a decrease pregnancy related complications such as preterm
rupture of membrane and preterm births

The primary aim of this study is to investigate the effect of honey on the
clearance of the hr-HPV virus in patients with CIN II.
Secondary, the effect of honey on the normalization of CIN lesions, the role of
the vaginal microbiome, the local immune system and the intravaginal
inflammatory status is investigated.

In this pilot study, we will include 60 patients with newly diagnosed CIN II.
Patients will be counseled according to standard guidelines between a LLETZ,
imiquimod or expectant management. Patients choosing for expectant management
will be asked to participate in the study for the intervention cohort with
medical grade honey. Expectant managment patients who choose not to participate
in the intervention cohort are ask for the control cohort of the study
(observational cohort with regular standard care). Follow-up assessment takes
place in accordance with the national guideline (first check-up is after 6
months). In addition, swabs for vaginal microbiota analysis will be taken at 0
and 6 months. Immunohistochemical stainings for the local immune infiltrate
will be performed on biopsies taken during regular colposcopy at t=0. At the
start of treatment, 6,12 and 24 months two questionaires regardings
side-effects and quality of life will be sent to the patient.
This exploratory study assesses the potential effect of honey, the optimal
dosage and provides insight into its mechanisms of action.

Medical grade honey formulation (MGH) (L-Mesitran®) for CIN II
Daily application of 5 grams (with applicator) for 3 months. Then weekly
applications (5 grams with applicator) for 3 months.

Only one extra visit is needed for participation in the study (explanation of
L-Mesitran treatment and delivery of L-Mesitran) . In order to investigate the
effect of MGH on microbiological and vaginal gene expression levels at the
start of the study and 6 months, vaginal swabs will be collected at these time
points. To minimize the burden on the patients, patients will be asked to take
a vaginal swab themselves using a self-test at the start of the study or the
researcher will perform them if requested during the starting visit, the swabs
and PAP smear after 6 months can be collected during the regular visit. The
swabs will be sent by pre-paid mail to the MUMC were they will be stored for
analysis. In addition, patients will be asked to fill in 2 questionnaires at
inclusion, and 6, 12 and 24 months after the start of L-Mesitran. The
questionnaires will be sent digitally. To check for adherence and side-effects
we ask the participants to fill in a weekly journal.
The investigational product L-Mesitran® is registered for the treatment of
wounds and has CE certification and FDA approval. No contraindications are
known to date. It is advised not to use the product on patients who are
sensitive to the product or any of its components or patients with an allergy
to honey, which is very rare and only very few cases have been reported. Based
on previous studies investigating the activity of honey for the beneficial
effect on vaginitis, we do not expect any health problems, side effects, or
discomfort as a result of MGH.
No additional risks are foreseen for participation in the study.