Modern approaches to the treatment of human papillomavirus infection of the urogenital tract

In recent years, in Russia, as in many countries of the world, the incidence of human papillomavirus infection has been increasing. The problem of its diagnosis and treatment attracts the attention of doctors of various specialties: dermatologists, gynecologists, urologists, oncologists, pathomorphologists, immunologists, virologists. This is explained by the high contagiousness and tendency to increase the frequency of this disease, as well as the ability of some varieties of human papillomavirus (HPV) to initiate malignant processes. The latter mostly concerns the genital manifestations of human papillomavirus infection.

Human papillomavirus (HPV) is epitheliotropic and is found in the skin, oral mucosa, conjunctiva, esophagus, bronchi, and rectum.

There is information in the literature that the introduction of HPV infection occurs at the level of immature epithelial cells of the skin and mucous membranes (basal layer). The result of this invasion is cell proliferation, but without the production of viral particles, since proliferating epithelial cells are not able to support the life cycle of viruses. Complete replication of HPV occurs only in highly specialized cells of stratified squamous epithelium: granular, spinous cells of the skin, superficial epithelial cells of the cervical mucosa. Currently, about 100 types of papillomaviruses have been described. Their tissue and species specificity should be noted. Different types of HPV are associated with different types of lesions. It has been established that certain types of HPV are associated with the urogenital area. There are varieties:

low cancer risk;
average cancer risk;
high cancer risk.

Viral genome structure

Papilloma viruses belong to the papovavirus family (Papovaviridae), which infect cattle, birds, and humans and can infect basal cells of the skin and squamous epithelium. Papillomaviruses are one of the most heterogeneous groups of viruses, the differentiation criterion of which is the degree of genetic relatedness of the viruses according to molecular hybridization: it ranges from 10 to 85%. The diameter of viral particles is 55 nm. The virus does not have an outer shell. The virus capsid consists of 72 capsomeres. A detailed analysis of the HPV DNA molecule became possible after the development of a technique for DNA cleavage using endonucleases and analysis of these fragments using gel electrophoresis.

When studying preparations stained by Papanicolaou, a specific set of signs was identified that characterizes the nucleus and cytoplasm of epithelial cells (koilocytic cell atypia), caused by the cytopathic effect of papilloma viruses.

A specific cell for this infection is the koilocyte, which is an oxyphilt-stained epithelial cell with clear boundaries and a clearly defined perinuclear clearing zone and numerous vacuoles in the cytoplasm.

The term “koilocytic dysplasia” was introduced by HS Stegner in 1981. It is assumed that these changes are a consequence of the reproduction of a virus that causes disruption of cell metabolism, leading to their partial necrosis with the formation of balloon-like cells.

Cytological examination of lesions caused by HPV infection showed that the cellular material contains mostly anucleate, or orthokeratotic, cells. About 20% of scales contain nuclei - the so-called. "parakeratotic cells".

It should be remembered that morphology alone is not enough to identify HPV. In this regard, it is advisable to use the polymerase chain reaction (PCR) method and in situ hybridization. Increasingly, there are reports in the literature about the determination of HPV infection in urine using PCR as an alternative method for testing samples from the cervix. Along with this, nested PCR in one tube and type-specific nucleotide hybridization are used.

The PCR method is used for low-symptomatic or asymptomatic forms of the disease caused by HPV infection.

Using immunochemical methods, it is possible to detect HPV antigens in the tissues of genital warts in 71.4% of cases, by hybridization in 96.5%, and by PCR in 10% of cases.

The effectiveness of DNA hybridization does not exceed the effectiveness of histological examination, but it allows identifying patients with a high degree of this infection.

HPV infection clinic

The clinical manifestations of genital HPV infection are highly variable. Currently, they are divided into genital condylomas, papillary varieties of condylomas (with pronounced exophytic growth), as well as flat and inverted (intraepithelial) with endophytic growth. The last option, also known as “subclinical HPV infection,” is the most difficult in diagnostic terms, since there are no clear microscopic changes in the epithelium. In this case, special screening techniques are required to determine clear boundaries of the lesion.

A peculiar variant of genital warts is bowenoid papulosis and giant Buschke-Levenshtein condyloma. Condylomas acuminata (AC) are fibroepithelial formations on the surface of the skin and mucous membranes, with a thin stalk or a wide base in the form of a single nodule or multiple epithelial outgrowths, resembling cockscombs or cauliflower in appearance. Diagnosis of large condylomas does not cause difficulties. Genital condylomas are localized mainly in places of maceration: labia minora, vagina, cervix, urethral orifice, anal area, skin. In men, OCs are located in the foreskin, on the glans penis, in the perinatal area, and less commonly in the endurethral region. The incubation period ranges from one to 12 months (average 3-6 months).

Studies of recent decades indicate that 85% of patients with typical OC of the vulva and perineum have additional foci of HPV infection in the vagina or cervix, and almost every fourth of them has diseases associated with HPV infection - cervical intraepithelial neoplasia (CVN) of various types. degree of severity. One of the clinical types of diseases caused by HPV infection are bowenoid papules associated with HPV 16, sometimes pigmented on the skin and mucous membranes of both sexes, more often resembling common warts or seborrheic keratosis. In contrast to Bowen's disease, Bowenoid papules are benign and regress spontaneously, although they can occasionally become malignant. The course is asymptomatic.

Some authors include Lewandowski-Lutz epidermodysplasia verruciformis in this group of diseases. This disease is based on local and genetic disorders associated with chronic HPV infection.

JM Handley and WJ Dinsmore (1994), based on literature data, as well as their own studies, proposed a classification of clinical forms of HPV infection and associated diseases (Table 1).

In the vast majority of cases, manifest forms of HPV infection are combined with other sexually transmitted diseases. According to Bernard K. and Mugi K. (1996), manifest forms of HPV infection usually arise as a result of a number of factors:

social;
infectious, associated with associations of sexually transmitted diseases (STDs);
associated with changes in immune status.

The most significant is the influence of urogenital tract infections associated with HPV lesions: urogenital chlamydia, mycoplasmosis, cytomegalovirus and herpetic infections, dysbiotic conditions. The result of their influence on the course of HPV infection is the chronicization of the process, the formation of persistent, usually nonspecific inflammatory changes in the genitourinary area and significant difficulties in carrying out therapeutic measures.

The significance of the presence of concomitant infection for the treatment of condylomatosis is explained by the following circumstances.

The presence of STDs associated with HPV infection prolongs the treatment period for the latter by an average of three times.
In most cases, relapses are associated with the above reason.
Epithelization of cervical erosions after destruction of condylomas can be achieved only if there is a preliminary scan for concomitant STDs and bacterial vaginosis.

The possibility of a relationship between cervical neoplasia and sexually transmitted diseases has been discussed for many years. In the group of women suffering from invasive cervical cancer (CC), a higher frequency of detection of nonspecific microflora, including Trichomonas and Gardnerella infections, was noted. Examples of such effects have been discussed in relation to Treponema pallidum, Neisseria gonorrhoeae, Chlamydia trachomatis, herpes simplex virus type 2, cytomegalovirus, and human papillomavirus. Epidemiological studies have convincingly shown that genital HPV infection is an undeniable risk factor for the occurrence of precancerous changes and cervical cancer.

Principles of treatment of HPV infection

Considering the fact that specific antiviral drugs and vaccines that act on HPV are not yet available, it is generally accepted that complete elimination of the virus from the body cannot be achieved. The goal of therapy is to eliminate clinical and subclinical forms of HPV infection.

Today, practitioners have many methods for removing anogenital warts in their arsenal. Their effectiveness varies from 30 to 90%, but none of the methods is a panacea, since the relapse rate is quite high with any method of treatment. Treatment must be strictly individual: it is necessary to select the most optimal solution in each specific case, sometimes taking into account the wishes of the patient himself. The problem of relapse does not depend on the choice of therapy. Recurrences of anogenital warts are most often associated not with reinfection from a sexual partner, but with reactivation of the infection. There are three ways that events can develop in the absence of treatment:

warts may resolve on their own;
remain unchanged;
progress.

At the same time, one must always take into account the possibility of persistence of the virus in the absence of any clinical manifestations.

When choosing the most optimal method in each specific case, you must be guided by four main characteristics:

effectiveness for this pathology;
relapse rate after treatment;
tolerability (minimal side effects);
ease of performing procedures.

In addition to removing anogenital warts, it is necessary to solve the following important problems:

1. Identify and treat other sexually transmitted diseases (STDs) in patients with anogenital warts (and their sexual partners).

2. Screen all women with anogenital warts for cervical intraepithelial neoplasia (CVN) using cytology and colposcopy.

3. Maintain further monitoring of CVN lesions in the early stages for timely detection of their progression or development of microinvasive carcinoma.

4. Conduct active treatment of anogenital warts, neoplasia in the early stages, occurring with a detailed clinical picture, neoplasia in the later stages and squamous cell carcinoma.

5. Provide patients with recommendations on the use of condoms and limiting casual sexual contact to prevent infection (and reinfection) with HPV infection and other STDs.

In fact, treatment of anogenital HPV lesions is aimed either at destroying papillomatous lesions by one method or another, or at stimulating an antiviral immune response; a combination of these approaches is possible.

Destructive methods

Physical destructive methods

Surgical excision. Currently used infrequently, it is mainly used in the treatment of malignant neoplasms when wide excision is necessary. This method may require hospitalization due to the fact that quite severe bleeding may occur during excision, and a long postoperative period will require special therapy.

Electrosurgical methods. These include electrocoagulation, electroacoustics, fulgation, electrosurgical excision (electroexcision) using an electric knife. Not so long ago, plasma began to be used in medicine. Our scientists have developed an original plasma coagulator (plasmaskin) EKH-1, which has no foreign analogues. Temperature measurements in plasma showed that it can reach 2000-2500°C. Such high temperature values, in turn, provide the ability to work in a non-contact mode, the operation time is significantly reduced and thereby the necrosis zone is reduced. In addition, with this effect in most cases the pain threshold is not exceeded. This temperature regime ensures almost complete combustion of tumors.

Advantages of this method:

availability;
cheapness;
fairly high efficiency;
possibility of use in outpatient settings;
the risk of bleeding is reduced.

Flaws:

need for pain relief
When using this method, infectious HPV DNA is released along with the resulting smoke, so it is necessary to create adequate working conditions - vacuum extraction of smoke, the use of protective masks.

Laser excision. A fairly effective and safe method is excision of warts using a laser. Neodymium and CO lasers are used in practice. When using a CO laser, surrounding tissues are less damaged, and a neodymium laser provides a better hemostatic effect. In addition to the laser physically removing lesions, studies have shown that laser radiation has a toxic effect on HPV. The procedures require well-trained personnel. When using lasers, anesthesia is necessary - often local or local anesthesia is sufficient, which allows the procedures to be performed on an outpatient basis. Laser excision and surgical methods are approximately equally effective. Laser therapy can be successfully used to treat common condylomas that are resistant to other treatments. It allows you to stop recurrence in approximately 40% of patients. Studies have shown that such an ineffective result is due to the fact that the CO laser is ineffective when it comes to eliminating the genome from lesions that are resistant to treatment (according to the PCR method, a molecular biological cure occurs in 26% of patients).

The use of a CO laser is the method of choice in the treatment of CVI. Laser conization of the cervix is used. Relapses occur in 2% of patients. A mild method of laser therapy is vaporization, which does not cause virtually any complications. Laser vaporization has been successfully used in the treatment of low-grade CVN. Relapses are observed in 4% of patients.

Laser therapy has been successfully used to treat genital warts in pregnant women. There are reports of treatment in pregnant women at 28–35 weeks of pregnancy. In most patients, healing occurred after the first session. There were no complications during childbirth or in newborns.

Side effects include ulceration, bleeding, secondary infection, and scarring. As with electrosurgical methods, HPV DNA is released through smoke, which also requires precautions.

Laser therapy is not widely used due to the high cost of equipment and the need to train experienced personnel.

Cryotherapy. A fairly effective and safe method that involves the use of liquid nitrogen, nitrogen oxide and carbon dioxide as a refrigerant. In this case, rapid freezing of both intra- and extracellular fluid occurs, leading to lysis and death of cells upon thawing. Cryotherapy does not usually require pain relief, although local anesthetics can be used if necessary. Cryotherapy can be used to treat small warts of various locations. If the warts are multiple, then removal should be carried out in several stages. This method is characterized by the following side effects: the development of local redness, swelling, followed by the formation of blisters and their ulceration. To reduce damage to surrounding tissues, before the procedure, the surface of the warts is treated with KY-gel, which, when frozen, makes it possible to carefully lift and separate the lesion from the underlying epithelium.

The method can be used in gynecological practice.

We think the combined use of cryodestruction and plasma coagulation is extremely promising, allowing us to avoid the disadvantages inherent in the above methods separately.

Chemical destructive methods. This group of products includes solutions of acids, alkalis, and salts. Among them we can mention Feresol, hydrogen peroxide, solutions of quinacrine and hingamine, preparations of mercury and arsenic, bismuth, preparations based on salicylic and lactic acids, acetic and nitric acids, thuja and celandine juices. All these drugs are easily available, but have low, poorly predictable effectiveness, and produce numerous side effects.

Isoprinosine should be used in combination with locally destructive methods of treatment.

The effectiveness of combination treatment for PV, according to the literature, ranges from 38 to 96%.

Combined treatment methods. To treat the manifestations of HPV infection, various methods are proposed, based on the use of immune drugs in combination with laser, electrosurgical and cryodestructive effects.

The combined use of the above methods can reduce the number of relapses and thereby increase the effectiveness of treatment.

Good results have been obtained using a combined method of treating condylomas, including destruction of lesions using cryodestruction (exposure temperature from –160 to –180°C, exposure 40–120 s, twice) in combination with immune stimulation. To stimulate local immunity, the affected area was treated with an emulsion containing interferon (IF), and to stimulate the immune system of the whole body, the drug Kemantan was prescribed at a dose of 0.2 g three times a day orally for 10 days.

A combination of various destructive methods is possible. If there are manifestations of HPV infection on the skin and mucous membranes, cryospraying is first performed for 10–30 s, which makes it possible to clearly identify the boundaries of the lesion due to the characteristic papillary surface of the lesions, which turns white. Then the affected area is exposed to plasma (using the plasmaskin device).

A number of researchers recognize the best method of treating anogenital warts as surgical removal of all visible lesions followed by local administration of IF. In some cases, it is advisable to use general and local IF before surgical excision of extensive condylomas.

There is no therapeutic effect from the use of IF if the disease lasts more than one year, as well as with immunodeficiency.

Currently, there are not many remedies that can be used after using destructive methods. In particular, the drug impran has now appeared for local use in the area of lesions after destructive effects.

Specific antiviral therapy

Currently, there are no drugs that have a specific effect on HPV. Known drugs that suppress the replication of the herpes simplex virus (acyclovir, ganciclovir) turned out to be ineffective in the treatment of anogenital HPV infection.

Theoretically, vaccination is an ideal method for the treatment and prevention of anogenital warts.

There are reports of the effective use of IF inductors. Of interest is the local use of a low molecular weight derivative of imiquidaquinolamine, imiquimod, which is an inducer of cytokines and, in particular, L-IF. It is used in the form of a 5% cream three times a week or daily at night until the rash completely disappears (but not more than 4 months). Complete disappearance of condylomas is observed in 13–56% of cases. With daily use, local side effects more often developed: redness, swelling, erosion. The cream is especially indicated for the treatment of subclinical HPV infection. It is possible to use virazole.

The effect of using IF monotherapy has not been sufficiently studied and is not very high; in addition, it is necessary to take into account the high cost of such treatment. In this regard, this method is not widely used in practice.

Isoprinosine. In recent years, the new immunomodulator isoprinosine, which is a complex of inosine and the salt of N,N-dimethylamine-2-propanol and P-acetaminobenzoic acid, has attracted the close attention of immunologists. The drug can be used in the form of tablets or a solution for parenteral injection. The active substance in this complex appears to be inosine, and the amino alcohol salt stimulates its penetration through the membrane of lymphocytes and other cells.

Isoprinosine has a powerful and broad immunomodulatory effect. Numerous data and extensive literature indicate that in vitro the drug significantly enhances the proliferation of T lymphocytes induced by mitogens or specific antigens, as well as the differentiation of pre-T lymphocytes into more mature T lymphocytes, accompanied by the appearance of corresponding antigens on their surface. PI also stimulates mitogen-induced B cell proliferation. The stimulating effect of isoprinoline on the activity of natural killer cells (NK cells) in healthy people and the functional ability of cytotoxic T lymphocytes has been proven. The drug improves the CD4+/CD8+ ratio; increases the production of IL-2 by T lymphocytes; promotes the maturation and proliferation of T cells; activates the synthesis of IL-1 by macrophages. PI has an antiviral effect and prevents the use of ribosomal RNA for virus replication. It should be noted that when isoprinoline was used with other immunocorrectors, it significantly enhanced the antiviral effect of the latter.

Various treatment regimens using isoprinoline have been adopted depending on the size of condylomas, their location and the degree of malignancy.

Scheme 1: treatment of small, multiple genital warts with a low degree of malignancy.

The drug is taken in 2 tablets. three times a day for 14–28 days.

Scheme 2: treatment of multiple condylomas with individual large condylomas or flat condyloma of the cervix.

Among the chemicals used in our country and abroad that have a destructive effect are TCA and nitric acid, as well as a combined acid preparation - solcoderm.

TCA and nitric acid. TCA is used in 80-90% concentration and causes the formation of local coagulative necrosis. A solution of nitric acid has a similar effect. Due to their cheapness and availability, both methods are quite widespread to this day. Acids are effective for the treatment of condylomas of the vulva, preputial sac, coronary sulcus, glans penis, especially in cases where the use of PF and PFG is contraindicated. Cauterization is carried out once a week for 5-6 weeks. The effectiveness of using TCA and nitric acid is approximately 70-80%. In some cases, a local reaction may develop in the form of weeping and ulceration.

Solcoderm. Solcoderm is an aqueous solution, the active component of which is the interaction products of organic acids (acetic, oxalic and lactic) and metal ions with nitric acid.

acid. The solution contains nitrites in an amount of 0.02 mg/ml.

Listed below are the properties and mechanism of action of Solcoderm, which distinguish it from other drugs in this group used as part of destructive methods:

when applied topically, solcoderm causes immediate intravital fixation of the tissue to which it is applied;
the effect of the drug is strictly limited to the place of application;
a sign of an immediate effect is a change in the color of the treated area;
devitalized tissue dries out and darkens (mummification effect);
The “mummified” scab is rejected on its own;
The healing process is short and complications (secondary infection or scarring) are rare.

General characteristics of treatment with Solcoderm:

the drug has a precisely limited local effect on the pathologically altered tissue to which it is applied, while the surrounding tissue is not damaged;
the method is suitable for the treatment of various skin tumors;
the treatment is painless;
rapid healing, no complications;
treatment is carried out on an outpatient basis and does not require special equipment;
absence of any restrictions for the patient.

Indications for the use of Solcoderm: simple warts, plantar warts, anogenital warts (genital warts), seborrheic keratoses, actinokeratoses, basal cell epitheliomas (basaliomas).

Solcoderm is very easy to use and quite effective for the treatment of condylomas of any location. In most cases, a single application is sufficient.

Cytotoxic drugs

Podophyllin (PF). Pophylline is a resin obtained from the plants P.pelatum and P.emodi, which grow in North America and the Himalayas. To treat warts of the anogenital area, a 10-25% solution of PF in ethanol or benzoin tincture is used. It binds to the microtubule apparatus of the cell and inhibits mitosis, and also inhibits the transport of nucleic acids, resulting in inhibition of DNA synthesis and cell division.

The use of PF is a simple, affordable, fairly safe treatment method that can be used in an outpatient setting, as well as by patients independently. The drug is applied once or twice a week for a maximum of 5 weeks in an amount of no more than 0.5 ml per procedure. The patient must ensure that water does not enter the treated area for 4-6 hours after the procedure. PF is not recommended for use on vaginal, cervical and intraepithelial warts. According to some authors, the recurrence rate varies from 0 to 67%.

Approximately 10-15% of patients develop local adverse reactions in the form of weeping contact dermatitis. Particularly severe complications in the form of multiple ulcerations occur when used incorrectly. As a result of long-term or improper use of PF, patients may experience various adverse reactions, such as nausea, vomiting, abdominal pain, diarrhea, symptoms of damage to the kidneys, myocardium, liver, central nervous system and bone marrow.

The use of PF is contraindicated during pregnancy, since cases of teratogenic effects on the fetus and intrauterine fetal death have been reported.

Many researchers consider PF to be an insufficiently studied and crudely purified plant extract, and therefore recommend using only highly purified podophyllotoxins, and independent use of the drug by patients themselves is undesirable due to the above-mentioned complications.

Podophyllotoxin (PFT) (condylin). PFT is the most therapeutically active fraction of PF. Available in the form of solutions of 0.25, 0.3 and 0.5%, as well as in the form of cream 0.15, 0.3 and 0.5%.

It is usually prescribed twice a day for three days a week in a row for 4-5 weeks.

Although PFT is better purified than PF, a high incidence of side effects has been reported with the use of PFT, especially its 0.5% solution. The following side effects are most often observed as a result of the use of PFT: local inflammatory reactions (erythema, burning, soreness, itching, weeping and erosion in the area of application). Although systemic side effects have not been reported in the literature, it is recommended to limit the use of PFT to a dose of 0.2 ml per treatment.

The disadvantages of PFT are its high cost and long duration of treatment.

5-fluorouracil (5-FU). 5-fluorouracil (5-FU) is a pyrimidine antagonist and has the ability to disrupt the synthesis of both cellular and viral DNA. For the treatment of warts of the anogenital area, it is prescribed in the form of a 5% cream. When treating intravaginal warts, the drug is prescribed once at night for a week or once a week for 10 weeks. The degree of effectiveness of the drug, according to various researchers, is 85-90%. When using 5-FU, weeping erosions on the vaginal mucosa may occur, up to the development of severe weeping contact dermatitis. When treating warts of the terminal part of the urethra, the cream is administered immediately after urination at night for 3-8 days. Complete cure of intraurethral warts is observed in 90-95% of men. However, during treatment there are many side effects: stenosis and stricture of the urethra, dysuria, ulceration. The drug is contraindicated during pregnancy.

Immunological methods

Interferon. Since the human papillomavirus persists in epithelial cells and the use of destructive methods does not guarantee against relapses, the use of IF is promising in this regard, both as monotherapy and in combination with other treatment methods.

IFs are endogenous cytokines with antiviral, antiproliferative and immunomodulatory properties. There are three main classes of IF: leukocyte (L-IF), fibroblast (F-IF) and T-lymphocyte (T-IF). IF can be used locally, intralesional and systemically (subcutaneous, IM or IV). It has been established that when using IF in patients, the amount of viral DNA in the lesions decreases (according to PCR data), which correlates with clinical improvement or disappearance of the lesion.

There is data regarding the use of domestic IF, human leukocyte interferon (HLI), for the treatment of condylomas. It was used intralesional (under papilloma) at a dose of 100,000-500,000 IU, for a course of 3-6 procedures in combination with the application of interferon ointment with an activity of 40 IU to the lesions. PLI can be prescribed systemically and in the treatment of widespread lesions in combination with destructive methods.

L-IF can be considered the most effective drug for various methods, schedules and doses of administration. With systemic use of L-IF, complete disappearance of warts was observed in 11–100% of patients. The effectiveness of using F-IF was 45–82%. The effectiveness of T-IF, shown in different studies, is much lower than that of L-IF and F-IF, and varies from 7 to 57%.

It should be remembered that the unsystematic use of various treatment methods leads to a high percentage of relapses, however, the development of certain algorithms that take into account the gender of patients, the location and number of rashes can significantly reduce the number of relapses.

Table 1. Anogenital HPV infection and HPV-associated diseases

HPV infection

Detailed clinical forms (visible to the naked eye or invisible, but determined in the presence of appropriate symptoms):

warts (genital condylomas, flat condylomas, vulgar warts)
symptomatic intraepithelial neoplasia in the early stages - koilocytosis, dyskeratosis in the absence of dysplasia (flat condylomas)

Subclinical forms (not visible to the naked eye and asymptomatic, detected only by colposcopy and/or cytological or histological examination

asymptomatic intraepithelial neoplasia (IN) in the early stages - koilocytosis, dyskeratosis in the absence of dysplasia (flat warts)

Latent forms (no morphological or histological changes when HPV DNA is detected)

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Table 2. Diseases associated with HPV

Clinical and subclinical forms:

VN in the early stages - mild dysplasia, /+-/ koilocytosis, dyskeratosis (VN stage 1)
VN in late stages - severe dysplasia, /+-/ koilocytosis, dyskeratosis (VN stage 2)
Late stage LN - severe dysplasia or carcinoma in situ /+-/ koilocytosis, dyskeratosis (stage 3 LN, or CIS)

Microinvasive squamous cell carcinoma:

clinically visible or invisible, but in the presence of appropriate symptoms
subclinical, not visible to the naked eye and asymptomatic, revealed only by cytological and histological examination
latent - absence of morphological and histological changes when detecting DNA HPV infection by molecular hybridization
intraepithelial neoplasia

Table 3. Classification of treatment methods for anogenital warts

Destructive methods

physical
electrosurgical methods
cryotherapy
laser therapy
chemical
trichloroacetic acid (TCA)
solcoderm

Cytotoxic methods

podophyllin (PF)
podophyllotoxin (PFT)
5-fluorouracil

Immunological methods

interferons
isoprinosine

Combined methods

combined use of various methods

Every day a person comes into contact with a huge number of microorganisms and viruses, which can cause changes in the functions of body systems, leading to diseases of varying severity and duration, as well as the adverse consequences of these diseases.

The main stages of the interaction of viruses with the host cell are adsorption (interaction of specific receptors of the virus and the host cell), fusion of the supercapsid with the cell membrane, release of nucleic acids of the nucleocapsid and activation of viral nucleic acid, synthesis of nucleic acids and viral proteins, assembly of virions and release of new viral particles from cells into the intercellular space, blood or lymph [1, 2].

The most common infections include infection caused by herpes simplex viruses (HSV), the main features of which, according to modern concepts, are the global nosoareal of prevalence, many routes and modes of transmission of viruses, extremely high infection rates throughout the world, correlation of seropositivity with socio-economic conditions, the existence of viruses in associations with co-infections, high natural susceptibility of people and a number of other factors. In the Russian Federation and CIS countries, about 22 million cases of relapses of herpesvirus infection are registered annually [3].

The group of viruses that cause herpes infection includes cytomegaloviruses (CMV). The relevance of studying diseases caused by these viruses is due to the adverse consequences that can occur in the event of infection in the neonatal period or in the first year of a child’s life, or in the case of a primary disease of the mother during pregnancy [4]. According to statistics, in the first year of life, antibodies to cytomegalovirus infection (CMVI) are detected in 20% of children. In children attending kindergartens, the prevalence of infection is 25–80%; in the adult population, antibodies to CMV are found in 85–90% of the population [5].

The source of infection can be a virus carrier, a patient with an acute form (in the case of primary infection) or a patient during an exacerbation of the infection. Routes of transmission of infection: airborne, sexual, contact, oral, parenteral, enteral and vertical, while transmission of viruses can occur through all biological fluids and body secretions (saliva, urine, etc.). When penetrating into the body of immunocompetent individuals, after primary infection, the virus can remain in the body for life; in this case, the infection is asymptomatic (virus carriage), since the virus is protected by lymphocytes from the action of specific antibodies and interferon [6].

In modern medical literature, the latent course of infection caused by CMV is referred to as CMV infection, and the clinically pronounced course with organ damage is referred to as CMV disease. The development of CMV disease is characterized by leukocyte infiltration of various organs, which indirectly indicates the participation of interleukin-8, macrophage inflammatory protein-1α (MIP-1α) and other chemokines and adhesion molecules in this pathological process [7].

A clinically pronounced disease can develop during primary infection, during activation of a latent infection against the background of a decrease in the body’s resistance, which can be observed in children, pregnant women, and adults with reduced immunity.

The clinical picture of CMV infection is nonspecific and largely depends on the route of infection and the state of the immune system. The most typical symptoms of CMV disease are fever above 38 °C, leukopenia, thrombocytopenia, and increased activity of liver enzymes [8]. With CMV disease, damage to the gastrointestinal tract, flu-like symptoms, and inflammatory processes in the nasopharynx and oropharynx can develop. The most severe form of the disease, CMV pneumonia, is characterized by the development of severe respiratory failure, often with resistance to antibiotics.

Virus carriage, manifested by persistent detection of class G antibodies to CMV, is observed in 90-95% of the adult population (HCMV positivity), while the virus carrier is not dangerous to others, however, with a decrease in immunity, carriage can become active, which causes the appearance of class M antibodies or a multiple increase in the level of class G antibodies. The generalized form can occur in individuals with severe immunodeficiency and is manifested by inflammation of the parotid and submandibular salivary glands, liver tissue, adrenal glands, spleen, joints and other organs. Manifestations of the localized form in women may be cervicitis, endometritis, salpingoophoritis, inflammation of the salivary glands, cervical lymph nodes; in men there may be asymptomatic carriage or sluggish urethritis.

In pregnant women, antibodies to cytomegaloviruses are detected in 50–85% of cases, and in 1–12% of pregnant women, primary infection can be observed, which poses a danger to the fetus [5].

Primary CMV infection and reactivation of the chronic process can cause complications such as non-developing pregnancy or miscarriage, placental insufficiency, fetal growth restriction syndrome, polyhydramnios, premature placental abruption and others. It should be noted that with primary infection, the risk of transmission of the virus to the fetus is higher than with exacerbation of chronic infection, and the consequences for the fetus depend on the gestational age at which the primary infection or reactivation of the infection occurred [9]. If the primary infection of a woman occurs in the first half of pregnancy, then 8-10% of children born to these mothers may experience clinical manifestations in the form of hepatosplenomegaly, hepatitis, thrombocytopenia, petechial rash, microcephaly, retinitis, hyperbilirubinemia, malnutrition, retention syndrome fetal growth, pneumonia and other manifestations [10, 11].

Infection in the second half of pregnancy can lead to chronic congenital CMV infection, and in severe cases to dysfunction of the central nervous system, liver, visual and hearing impairment. Intranatal and early postnatal infection, which occurs when feeding newborns by seropositive mothers, usually occurs without clinical manifestations and is more common than transplacental infection.

Difficulties in diagnosing CMV infection are associated with the lack of seasonal cyclicality of incidence, characteristic clinical manifestations of the disease, and the frequent prevalence of latent forms of the infectious process.

Another widespread viral infection, human papillomavirus (PVI), is the leading cause of cervical cancer, condylomas, and squamous cell neoplasia of various locations. The global prevalence of human papillomavirus (HPV) infection among women aged 15–74 years with negative cytological smears varies by region and ranges from 5 to 40%. The infection is most widespread among sexually active adolescents and young women; 85% of women become infected with the virus during their lifetime [12].

More than 200 types of papillomavirus are described in the literature, which are strict epitheliotropes that infect the epithelium of the skin and mucous membranes of the genitals and other organs (larynx, oral cavity, eyes, etc.) [13].

HPV is divided into two groups: low-risk and high-risk HPV. Highly oncogenic HPV types are associated primarily with squamous intraepithelial lesions of the anogenital area (cervix - CIN, vulva - VIN, vagina - VaIN, anus - AIN). HPV is the cause of cervical cancer in 91-99.7%, cancer of the vulva (69%), vagina (75%), penis (63%), prostate, ovary - in 10-30%, cancer of the larynx and oral cavity - in 10-30% of cases [10].

The ability for HPV to persist indefinitely in the patient’s body is due to the peculiarities of the life strategy of these viruses, based on blocking the mechanisms of innate and adaptive antiviral immunity [11]. The mechanism of cancer development is associated with the integration of the viral genome into the chromosomes of host cells and its long-term persistence [13].

Antiviral defense of the host organism is a very complex and multicomponent mechanism. A distinctive property of viruses in general, CMV and HPV in particular, is that they cannot reproduce independently, but are able to effectively reproduce in sensitive cells of the macroorganism, where they implement their genetic program to create offspring [14-16]. During the initial interaction with viruses, infectious agents are resisted by the body's nonspecific defense mechanisms, which include the skin epithelium and mucous membranes. After the virus penetrates into the cell, the main role in providing local immunity is played by interferons, other cytokines produced by infected cells, as well as lymphocytes and macrophages, which ensure phagocytosis and destruction of viruses. Antibodies formed during viral infections act directly on viruses or on cells infected by them [17].

Almost all viruses induce the production of interferons; their formation is one of the body’s earliest protective reactions to the introduction of viruses; interferons are able to suppress the intracellular stages of viral reproduction in infected cells, provide immunity to viruses to surrounding healthy cells and prevent the dissemination of viruses in the body. Therefore, the use of immunotropic drugs, interferon and its inducers is becoming a necessary part of the generally accepted pathogenetic treatment of various infectious diseases [18].

The main method for diagnosing CMV is serological with the detection of specific antibodies to virus antigens. To identify the characteristics of the course of infection, it is recommended to determine the avidity of immunoglobulins of classes M and G and antibodies to the viral protein. Molecular biological methods (DNA hybridization, ligand chain reaction, polymerase chain reaction) in the diagnosis of CMV, PVI and other infections make it possible to identify early stages, latent and persistent infection, and quantitative parameters of pathogens. The cytological method is used for express diagnosis of CMV infection on the surface of the chorion and fetal membranes.

Treatment

. There are no etiotropic drugs for the treatment of patients with viral (cytomegalovirus, herpesvirus, human papillomavirus, etc.) infections. When treating patients with severe, generalized forms of CMV, it is possible to use drugs that have an antiviral effect (acyclovir, ganciclovir, valacyclovir, famciclovir, foscarnet, etc.), which directly or indirectly inhibit viral DNA polymerase, reduce viral production in patients with clinical symptoms, characteristic of herpes virus infections. However, these agents are very toxic, and strict monitoring, especially with long-term use, of the drug levels in the blood is required. As a rule, these drugs are prescribed to patients after transplantation or with a pronounced decrease in immunity [19, 20].

The toxicity of the drugs greatly limits their use. The drugs are contraindicated for pregnant women, nursing mothers and newborns, and are also not recommended for women planning pregnancy.

For patients with active infection in the preconception period, in order to prevent and treat intrauterine infection, as well as treat generalized forms, it is possible to carry out prophylactic treatment, which makes it possible to ensure in the vast majority of cases the onset of pregnancy and its favorable course. For this purpose, during the preconception period, the use of herbal antiviral drugs, recombinant interferon α-2, normal human immunoglobulin, etc. is indicated [21, 22].

Currently, a drug of plant origin is very promising, the main active component of which is a purified extract of shoots of the plant Solanum tuberosum

, which has an antiviral effect. Based on this extract, the drug Panavir was created, which is a polysaccharide belonging to the class of hexose glycosides. Panavir is capable of increasing the body's nonspecific resistance to infections and interferon induction, leading to stabilization of tissue and humoral immunity, which is extremely important for women planning pregnancy.

Panavir release forms: solution for intravenous injection, rectal and vaginal suppositories, gel for external use and gel spray Panavir-Intim and Panavir-Inlight. Panavir has shown its effectiveness in the treatment of patients with papillomavirus [23], cytomegalovirus and herpes infections [24-26], viral hapatitis C [27], tick-borne encephalitis [28] and a number of other diseases.

Treatment of patients with exophytic condylomas, surgical treatment for condylomatous rashes (cryodestruction, radio wave surgery, drug coagulation, laser vaporization), especially carried out in preparation for pregnancy, can be combined with local treatment with Panavir. At the same time, treatment of condylomas with Panavir gel, vaginal irrigation with a spray or the use of vaginal (rectal) suppositories contribute to faster healing of skin scars and a reduction in the frequency of relapses, which is important for women planning pregnancy. Exophytic forms of human papillomavirus infection can occur against the background of herpetic eruptions or in women carriers of HSV during chlamydial or other infections. Before prescribing treatment, it is recommended to conduct a preliminary examination of women, and if infections are detected, to carry out etiotropic therapy with subsequent restoration of the vaginal microbiocenosis, which improves treatment results. According to G.G. Antashyan [23], with complex treatment of patients with exophytic forms of PVI, there is a significant decrease in the frequency of destructive procedures, as well as an increase in inter-relapse intervals.

The use of Panavir in the treatment of patients with herpetic lesions of the skin and mucous membranes, as well as virus carriage, is justified. When treating patients with recurrent genital herpes, a significant immunocorrective and anti-inflammatory effect of the drug was revealed, as well as an increase in the duration of periods of remission, which indicates the effectiveness of Panavir [29-31]. Carrying out treatment during pregnancy planning will reduce the risk of exacerbation of infection during the gestational period.

Studies have shown good tolerability of the drug. Clinical trials have shown the absence of mutagenic, teratogenic, carcinogenic, allergenic and embryotoxic effects of the drug in the presence of weak cytotoxic and antiproliferative effects [32]. Prescription of Panavir is possible during the preconception period, in the second and third trimesters of pregnancy in the case of a primary infection or reactivation of the infectious process.

For the treatment of patients with diseases caused by viruses, parenteral forms of Panavir may be recommended, with the therapeutic dose of the drug being 200 mcg of the active substance. The frequency of intravenous administration and duration of treatment depend on the causative agent of the disease. In case of preparation for pregnancy, treatment of cytomegalovirus and papillomavirus infections, Panavir solution is used three times during the 1st week with an interval of 48 hours and twice during the 2nd week with an interval of 72 hours intravenously in a slow stream. It is also possible to use Panavir in the form of rectal suppositories daily at night for 10 days, with a possible repeat of the course of treatment after 1 month.

Intravaginal administration of suppositories is possible in the treatment of patients with PVI-associated cervical pathology or HSV infection, while the recommended duration of treatment is also 10 days. For the treatment of patients with exophytic condillomas, it is recommended to apply a thin layer of Panavir gel to the affected areas of the skin and/or mucous membranes 5 times a day. The duration of treatment is 4-5 days; if necessary, the course of treatment can be extended to 10 days.

MM. Damirov et al. [33] showed the high effectiveness of complex treatment of patients with low-grade squamous intraepithelial lesions of the cervix against the background of persistent HPV infection with a 0.004% Panavir solution according to the scheme: 5 ml of solution intravenously slowly in a course of 5 injections with an interval of 48 hours between the first and second injections followed by an interval of 72 hours with simultaneous local use of the drug Panavir-Intim in the form of a gel intravaginally 2 times a day for 10 days with an exposure of 10-15 minutes after administration of the drug.

In 2012, an open randomized comparative multicenter controlled clinical trial was conducted to study the safety, tolerability and therapeutic efficacy of Panavir solution for intravenous administration 0.04 mg/ml in complex therapy of pregnant women with chronic cytomegalovirus infection in the acute stage in the II and III trimesters of pregnancy [34 ].

The purpose of the study was to assess the safety, tolerability and effectiveness of Panavir for intravenous administration as part of complex therapy for cytomegalovirus infection in pregnant women in the 2nd and 3rd trimester. It was found that therapy for CMV infection with Panavir contributed to the eradication of viruses, while CMV was not detected by serological method in women receiving treatment, and the viral infection did not have an adverse effect on the course of pregnancy, fetal development and the health of newborns.

A generalization of the results of the studies allows us to conclude that further study of the therapeutic properties of the drug Panavir in relation to viral infections is promising; they have convincingly proven that the antiviral drug Panavir is an effective remedy in the treatment of patients with CMV, HPV, HSV, tick-borne encephalitis, and can be used during the preconception period women at high risk of activation of these infections during pregnancy. The drug is indicated in the case of preparation for pregnancy in women with a burdened medical history, with persistent human papillomavirus infection, chronic, recent acute or exacerbation of other viral infections, as well as women who have been diagnosed with impaired interferon status.

The search for natural pharmacological agents and analysis of the mechanisms of their action is a very relevant aspect in the creation of a new generation of antiviral drugs for the treatment of human infections.