Human Papillomaviruses are double-stranded DNA viruses characterised by their lack of a lipid
envelope. To date, more than 100 different types of HPV have been identified. They can be
divided into cutaneous or mucosal depending on the tissues they usually infect 1. In
parallel, HPVs can be classified as low-risk (HR-HPV) or high-risk (HR-HPV) viruses,
depending on the risk of developing cancer due to their persistence of infection 2. Fifteen
HPV types are considered high-risk (16, 18, 31, 33, 35, 35, 39, 45, 51, 52, 56, 58, 59, 68,
73 and 82) while three other types are classified as probable high-risk (26, 53 and 66).
HPV infection occurs through direct contact with the skin or mucous membranes of an infected
person, who may or may not have visible lesions. In the case of genital infection, vaginal or
anal intercourse is the main route of transmission. HPV is very common, and it is estimated
that, in the United States, approximately 80% of women will have acquired an infection by the
age of 50.
Most HPV infections do not cause symptoms or disease and disappear 12-24 months after
infection. The small proportion of these infections that persist result in precancerous
lesions that may progress to cancer. HPV infection is associated with virtually 100% of
cervical cancer cases and with a high rate of anogenital and oropharyngeal cancers.
According to the World Health Organisation, the approach to cervical cancer prevention
consists of primary prevention through HPV vaccination to prevent HPV infection, and
secondary prevention through screening programmes to achieve early detection of HPV
infection. Screening programmes differ from country to country, but are mainly based on
determination of the presence of the virus by viral DNA testing and determination of
intraepithelial lesions by cytology (Pap smear). A positive HPV DNA test implies the presence
of the virus in the sample, while positive cytology implies an alteration or lesion in the
tissue.
The morphology of squamous intraepithelial lesions caused by HPV in the lower anogenital
tract is identical in all locations and in both sexes. The LAST Terminology classifies
HPV-associated histological squamous intraepithelial lesions into two grades, low-grade
lesions (LSIL) and high-grade lesions (HSIL). The term LSIL also includes cervical
intraepithelial neoplasia grade 1 (CIN1) of the Richart classification, adopted by WHO in
2004.
LSIL/CIN1 lesions are the histological manifestation of a self-limiting HPV infection that
most often resolves spontaneously. Close follow-up of patients with LSIL lesions minimises
the risk of developing cervical cancer by observing whether the lesions resolve or,
conversely, detecting early if they progress to HSIL. CIN2 and CIN3 lesions are included in
the term HSIL. HSIL/CIN2 lesions can still revert to L-SIL or progress to neoplasia. In
contrast, HSIL/CIN3 lesions are considered true intraepithelial neoplasms with a high
potential for progression and are the necessary precursor lesion to cervical cancer and
should be treated by destructive or excisional methods.
Another relatively common cytological alteration is atypical squamous cells of undetermined
significance (ASCUS). An ASCUS cytology result may be due to HPV infection or other causes,
so when detected, HPV-DNA testing is recommended. ASCUS is usually associated with SIL
lesions, mainly LSIL, although HSIL cannot be ruled out.
On the other hand, colposcopy is an essential examination in the secondary prevention of
cervical cancer (CCU) as it is the only procedure that allows the identification of
intraepithelial cervical lesions, their location, extension and characteristics, and directs
the biopsy to obtain diagnostic confirmation.
As previously advanced, secondary prevention is useful for early diagnosis of HPV infections,
allowing treatment of high-grade lesions (HSIL) before they progress to cervical cancer. At
the same time, it allows close follow-up of patients with low-grade lesions (LSIL). However,
there is currently no specific treatment for LSILs, so it is limited to "wait and see" or
observation without treatment.
Adequate nutritional status of patients with HPV infections is essential for optimal immune
system function. Therefore, maintaining an adequate diet, smoking cessation and regular
exercise are recommended as part of observational management strategies for patients with HPV
infections. In some cases, supplementation of relevant macro- and micronutrients may help to
stimulate the immune system and accelerate HPV clearance and lesion resolution. Indeed,
dietary deficiencies of nutrients such as folates, vitamin C, vitamin B12, zinc and others
have been linked to increased persistence of HPV infections and progression of HPV-related
lesions. Moreover, other bio-functional ingredients with immunomodulatory, antiviral or
antiproliferative activity could be useful both orally and topically.
Glizigen® vaginal gel and Glizigen® oral solution contain glycyrrhizinic acid as a common
ingredient. Glycyrrhizinic acid or glycyrrhizin is a natural triterpenoid from liquorice root
(Glycyrrhiza glabra) whose topical and systemic use has been evaluated in a multitude of
studies that have demonstrated its safety and efficacy against different viral processeS.
Among its most studied properties are its antiviral, anticarcinogenic and immunomodulatory
action, and it has also been shown to have re-epithelialising, antibacterial,
anti-inflammatory and antioxidant properties.
The mechanisms of antiviral action described for glycyrrhizinic acid against different
viruses include: direct inactivation of the virus, reduction of virus fusion with the cell
membrane, inhibition of viral replication, modulation of the immune response and stimulation
of apoptosis:
In addition, glycyrrhizinic acid has demonstrated antiproliferative action against different
types of cell lines or animal models of cervical, skin, colon or ovarian cancer.
Specifically, it has been shown to be able to induce apoptosis and arrest the cell cycle in
the G0/G1 phase in cervical cancer cells. Furthermore, it has a synergistic effect with
cisplatin and 5-fluorouracil (5-FU) when combined with them. However, unlike cisplatin and
5-FU, glycyrrhizinic acid has no cytotoxic action against non-cancerous cells. Therefore, all
these properties described for glycyrrhizinic acid make it a perfect candidate to prevent the
proliferation of HPV-associated precancerous lesions.
Topical and systemic use of glycyrrhizinic acid activated by a catalytic process (Glizigen®)
has been evaluated in women with HPV infections of the cervix, vagina or vulva, as well as in
women and men with anogenital condylomas. The use of these formulations with activated
glycyrrhizinic acid has shown good efficacy in favouring HPV negativisation and resolution of
low-grade lesions (LSIL). It has also demonstrated a good safety profile and significantly
superior efficacy to placebo and slightly superior efficacy to podophyllotoxin in the
treatment of anogenital condylomata.
Rationale for the study HR-HPV infection carries a risk of developing cervical cancer,
especially when precancerous lesions have already developed. The current screening system
allows us to identify these patients; however, there is still no clear therapeutic option to
treat patients before they develop high-grade lesions, where the most common management is
surgical treatment.
Previous studies with Glizigen® provide evidence of its potential benefit in patients with
cervical HPV infections, but there are a number of limitations that need to be addressed.
Among them, the main limitation is that they are open-label, uncontrolled studies. It is true
that Glizigen® has been used in comparative studies against placebo or podophyllotoxin in
patients with anogenital condylomas . On the other hand, these studies in patients with HPV
in the cervix included patients with both high- and low-risk HPV infection, who may or may
not have histological lesions.
Therefore, this study would be justified by the following points:
There is a need to investigate new therapeutic options, as there is no approved
treatment for CIN1 lesions caused by HPV. It is therefore of interest to evaluate the
efficacy of Glizigen® in the group of patients with HR-HPV LSIL/CIN1.
It is of interest to evaluate the efficacy of the topical and systemic combination of
Glizigen® with the new topical formulation.
There is a need to provide higher quality evidence on the efficacy of Glizigen® than is
currently available.