1. Introduction

It is well known that 15–20% of all human neoplasms have a viral cause, that is, they are developed due to so‐called oncogenic viruses. The experts of the International Agency for Research on Cancer (IARC) consider the following viruses as human oncogenic viruses:

RNA viruses: Hepatitis B and C viruses (HBV/HCV) causing hepatocellular carcinoma;

Human T‐cell leukemia virus (HTLV‐1) which is the etiological agent of adult T‐cell leukemia, as well as of tropical spastic paraparesis and several other non‐oncologic diseases;

Human immunodeficiency virus (HIV) which contains no transforming genes yet provides the requisite conditions (immunodeficiency) for the development of cancer. 2. DNA viruses: Epstein‐Barr virus (EBV) participating in the development of a whole host of malignant tumors, such as Burkitt lymphoma, nasopharyngeal carcinoma, and Hodgkin’s lymphoma;

Human herpesvirus type 8 (HHV‐8) playing an important role in the occurrence of Kaposi’s sarcoma, primary effusion lymphoma, Castleman disease, and some other pathological conditions;

Human papillomaviruses (HPV) which are an etiological agent of cervical cancer and several other anogenital tumors.

Considering the severity of and unfavorable prognosis in these diseases, as well as their proven viral etiology, the development of prophylactic methods for such viral infections is becoming a topical issue. Currently, vaccines against hepatitis B virus and HPV are already available.

The problem of HPV infection is one of the most topical health issues in the modern world. According to the World Health Organization (WHO), about half a million new cases of cervical cancer are reported annually worldwide, and 240 thousand women are dying from this disease.

In Russia, symptoms of papillomavirus infection are found in 15.0–34.4% of women aged 19 years or older, and among women attending the gynecology clinic for suspected sexually transmitted diseases, the fraction of HPV‐infected subjects is reaching 44.9%. The risk for acquiring HPV infection begins from the moment of a sexual debut and continues throughout an individual’s life [1].

HPVs are the oncogenic viruses, that is, they can induce tumors, from harmless to fatal forms. The oncogenic effect is due to their ability to impair differentiation and induce proliferation of the skin and mucosal epitheliocytes which manifest in the form of papillomas (warts) of different types and various localization, as well as epithelial dysplasias which can be transformed into invasive (cancerous) tumors.

Skin warts more often occur in children and usually persist for several years causing only cosmetic inconveniences. The genital (or anogenital) warts are a much more serious condition. They are called condyloma accuminata and form a warty growth that in its typical form resembles the cauliflower. Genital warts more often occur on the outer genitals, although they may affect vagina, cervix, or penis. This is one of the most common sexually transmitted infections [2].

Papillomavirus infection affects both women and men; however, owing to hormonal differences, the likelihood of tumor development in men is much lower than in women. Nonetheless, men can be the HPV carriers for a long time and able to transmit the virus to women.

Papillomaviruses are small (55–60 nm in diameter) non‐coated viruses. They are represented by cubical capsids containing two proteins—L1 and L2. The L1 is the major capsid protein comprising more than 80% of capsid material to form the blocks (capsomers) from which the capsid is built.

The anti‐L1 antibodies possess the virus‐neutralizing activity which underscores the significance of L1 in the initiation of infection. L2 is a minor protein that is not a part of the capsid structure but is involved in capsid stabilization and its coupling with viral genome [3].

Anogenital warts are manifestations of mostly sexually transmitted HPV infection caused by low‐oncogenic risk HPV types, such as HPV types 6 and 11. The HPV infections tend to self‐resolve on their own but more often they are characterized by recurrent course due to virus persistence. Among the general population, the overall prevalence of HPV infection reaches 80%.

On exceptionally rare occasions, anogenital warts can become cancerous. Anogenital warts may negatively impact patients’ quality of life owing to the development of depression and occurrence of psychological and sexual problems [4].

There are numerous approaches for the treatment of anogenital warts (liquid nitrogen cryotherapy, surgical removal, laser therapy, electrocoagulation, use of podophyllotoxin, interferons, imiquimod, and other immune preparations). However, none of the above proved to be ideal. Current therapy for anogenital warts is essentially symptomatic and is aimed at reducing the intensity of symptoms. According to numerous data, the risk of wart recurrence following any type of treatment reaches 30% [4].

One of the new frontiers for solving this problem is the use of an immune preparation imiquimod in combination with HPV quadrivalent recombinant vaccine aiming at eliciting immunity to HPV types 6, 11, 16, and 18. The likely mechanism of combined action of imiquimod and HPV quadrivalent recombinant vaccine is as follows: imiquimod plays an important role in HPV elimination from the infected tissue, while the vaccination using quadrivalent recombinant vaccine promotes specific immune response to prevent re‐infection. However, this hypothesis needs to be elaborated and confirmed in further studies using laboratory investigations capable of detecting HPV.

Currently, the following HPV vaccine dosing schedules are being used:

A classic three‐dose vaccination schedule: 0–2–6 months (i/m in deltoid muscle of arm). An alternative two‐dose vaccination schedule: two doses 6 months apart. Three‐dose extended schedule: three doses of which the first two are administered within 6 months followed by a booster (third) dose given 5 years later.

Along with the bivalent (Cervarix®) and quadrivalent (Gardasil®) HPV vaccines, currently a 9‐valent HPV vaccine (Gardasil‐9) has been registered worldwide, which evokes immune response against the following HPV types: 6, 11, 16, 18, 31, 33, 45, 52, and 58. To date, Gardasil‐9 is not registered in Russian Federation [5].

The aim of this study is to evaluate the effectiveness of combined use of 5% imiquimod crème and human HPV quadrivalent recombinant vaccine to achieve a durable clinical remission of chronic HPV infection manifesting in anogenital warts.