RU2595832C9 - Method of achieving prolonged clinical remission of chronic hpv infection, manifesting pointed condyloma of anogenital region - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, specifically to virology, and can be used for achieving prolonged clinical remission of chronic HPV infection, manifesting condyloma of anogenital region. Method includes triple vaccination of patients against 6, 11, 16 and 18 HPV types with "Gardasil" preparation for 0-2-6 months. Simultaneously applying 5 % Aldara cream on condyloma 3 times a week before bedtime, with subsequent washing in morning with soap until disappearance of visible anogenital warts, but not more than 16 weeks. Aldara 5 % cream is applied on day of first dose of "Gardasil" vaccine.

EFFECT: invention provides clinical recovery of pointed condylomas and prevents repeated infection with condyloma types of HPV.

1 cl

Description

Genital condylomas of the anogenital region are an infection transmitted mainly through sexual contact and caused by human papillomavirus (HPV) viruses of low oncogenic risk, namely HPV types 6 and 11. Anogenital warts are formations of a doughy consistency, having a lobed structure, in shape resembling a "cock's comb" or "cauliflower" and located on a narrow base. Genital warts are prone to self-healing, but their recurrent course due to the persistence of the virus is more often noted. The prevalence of HPV infection in the population reaches 80%.

Genital warts in extremely rare cases are able to malignant. The greater damage caused by the appearance of genital warts is associated with a significant decrease in the quality of life of patients due to the development of depression, the occurrence of psychological and sexual problems [Howell-Jones R., de Silva Ν., Akpan M., Oakeshott P., Carder C. et al . Prevalence of human papillomavirus (HPV) infections in sexually active adolescents and young women in England, prior to widespread HPV immunization. Vaccine 2012; 30: 3867-3875].

Many approaches to the treatment of this problem have been developed (cryodestruction with liquid nitrogen, surgical removal, laser therapy, electrocoagulation, the use of podophyllotoxin, interferons, imichimod, and other immune preparations). However, none of them is ideal. Currently, there is no cure for HPV infection. Modern therapy for genital warts is inherently symptomatic and aims to remove or reduce the symptoms of the disease. It does not eliminate HPV infection and does not prevent further transmission of the virus. HPV persists in epithelial cells. According to current data, after any treatment, the risk of relapse is about 30%. All this determines the relevance of developing new effective methods of treating chronic HPV infection, manifested by genital warts of the anogenital region, aimed at achieving long-term remission with the possible elimination of the virus.

The most promising in terms of solving this problem are the immunologic preparation imichimod (Aldara cream) and the 4-valent vaccine Gardasil, aimed at creating immunity to HPV types 6, 11, 16 and 18.

"Aldara" 5% cream for external use (MEDA, Sweden) as an active substance per 100 mg of the drug contains 5 mg imihimod, as well as the following excipients: isostearic acid - 25.0 mg, cetyl alcohol - 2.2 mg, stearyl alcohol - 3.1 mg, soft white paraffin - 3.0 mg, polysorbate-60 - 3.4 mg, sorbitan stearate - 0.6 mg, benzyl alcohol - 2.0 mg, methyl parahydroxybenzoate - 0.2 mg, propyl parahydroxybenzoate - 0.02 mg, glycerol - 2.0 mg, xanthan gum - 0.5 mg, purified water - 52.98 mg [Instructions for medical use of the drug "Aldara"].

Imichimod does not have a direct antiviral effect. Its effect is due to the activation, by stimulation of TLR-7 receptors, of factors of both non-specific protection and a specific immune response, the induction of the synthesis of interferon alpha and other cytokines, attracting immunocompetent cells with cytotoxic activity to the site of application, which determine the antiviral effect and the destruction of virus-infected cells. This is an important point that distinguishes this drug from other therapeutic approaches. The use of this drug leads not only to the apparent disappearance of genital warts, but also to the destruction of virus-infected cells, which is not observed when using other known therapeutic approaches [Hengge U.R. et al. Topical immunomodulators - progress towards treating inflammation, infection, and cancer. Lancet Infect Dis 2001; 1: 189-198; Gibson S. et al. Cellular requirements of cytokine production in response to the immunomodulators imiquimod and S-27609. J Interferon Cytokine Res 1995; 15: 537-545; Burns R.P. et al. The imidazoquinolines, imiquimod and R-848, induce functional, but not phenotypic, maturation of human epidermal Langerhans ′ cells. Clin Immunol 2000; 94: 13-23; Suzuki H. et al. Imiquimod, a topical immune response modifier induces migration of Langerhans cells. J Invest Dermatol 2000; 114: 135-141; Hemmi H. et al. Small antiviral compounds activate immune cells via the TLR7 MyD88-dependent pathway. Nat Immunol 2002; 3: 196-200].

When using an imichimod, clinical remission can occur due to the elimination of the virus, however, after monotherapy with an imichimod, recurrence of genital warts of the anogenital region is observed. This is due to incomplete destruction of virus-infected cells, for example, in patients with immunodeficiency states (absolute deficiency of cells with cytotoxic activity or their functional failure), low compliance with the use of imichimod, and re-infection of HPV types 6 and 11. According to the literature, the effectiveness of therapy with imichimod ranges from 35 to 68%, the relapse rate is from 6 to 26% during the year [Gomberg MA, Soloviev A.M. The treatment of warts and genital warts is simple and effective. Medical advice. 2011; 5-6: 60-65].

According to a brief description of the drug, the cream is applied in a thin layer on the previously cleansed surface of the condyloma and gently rubbed into the skin until completely absorbed. It is applied only externally. The cream should be applied only to the affected area, avoiding contact with internal surfaces. Aldara cream is applied 3 times a week before bedtime and is left on the skin for 6-10 hours, during which time you should not take a shower or bath. After this period, the cream must be washed off with soap and water. Treatment is continued until the disappearance of visible anogenital warts, but no more than 16 weeks.

The Gardasil vaccine is intended for the prevention of diseases caused by HPV types 6, 11, 16 and 18, and contains L1 proteins of the human papillomavirus of these types. The following components are contained as auxiliary substances: amorphous aluminum hydroxyphosphate sulfate - 225 μg, sodium chloride - 9.56 mg, L-histidine - 780 μg, polysorbate 80-50 μg, sodium borate - 35 μg, water for injection.

Destructive methods of treating genital warts of the anogenital region are known: electrosurgical methods, cryotherapy, laser therapy, surgical excision, laser photothermolysis. Relapse frequency does not depend on the choice of the method of destructive treatment. The advantage of these methods is that when they are used, condylomas are destroyed quickly, often simultaneously. The disadvantages of these methods: the pain of the procedure, relapse of genital warts, the need for special rooms, expensive equipment, trained personnel who have certificates for this type of medical activity [Gomberg MA, Soloviev A.M. The treatment of warts and genital warts is simple and effective. Medical advice. 2011; 5-6: 60-65].

There is a method of treating genital warts of the anogenital region with the Solcoderm preparation by application using capillary tubes followed by mechanical action with a plastic spatula for deeper penetration of the solution. The effectiveness of the method is 80.1%, the recurrence rate is 6-10% during the year. The advantages of this method are the outpatient nature of the treatment, the use of expensive equipment and pain relief, the absence of scars at the end of treatment, and the acceptable cost of therapy are not required. The disadvantages of this method: relapse of genital warts, the need for a drug by a doctor [Kuznetsova Yu.N. Treatment of genital warts of the anogenital region with Solcoderm. Ural Medical Journal. 2005; 3: 2-3].

Also known is a method of treating genital warts of the anogenital region with podophyllotoxin (Condilin, Vartek) by applying 2 times a day for 3 days, followed by a 4-day break (treatment duration not more than 5 weeks). The effectiveness of the method is 87% in men and 77% in women, the relapse rate is 6-100% during the year. The advantages of this method are the outpatient nature of the treatment, the possibility of independent use of the drug by the patient. The disadvantages of this method: relapse of genital warts, the high cost of the drug, the long duration of treatment in combination with not very high efficiency [Apolikhina IA, Salekh Yu.V. Modern possibilities in the treatment of genital warts. Obstetrics and gynecology. 2011; 5: 134-136].

A known method of treating genital warts of the anogenital region with isoprinosine, which is prescribed 3 g / day (2 tablets 3 times a day) as an adjunct to local therapy or surgery for 14-28 days or 5 days a week, sequentially for 1-2 weeks per month for 3 months. The effectiveness of combination therapy with isoprinosine is 41-87.5%, the relapse rate is 7-28% [Neymark B.A., Kondratyeva Yu.S., Zologina B.C., Torbik D.V. The effectiveness of the combined treatment of human papillomavirus infection. Urology. 2015; 2: 39-42].

The problem solved by the invention is to achieve long-term clinical remission of chronic HPV infection, manifested by genital warts of the anogenital region, through the use of Aldar 5% cream and Gardasil vaccination. The specified technical result is achieved by the fact that in the method of achieving long-term clinical remission of chronic HPV infection, manifested by genital warts of the anogenital region, in patients the application of 5% cream to Aldara warts 3 times a week before bedtime, followed by washing in the morning with soap and water to the disappearance of visible anogenital warts, but no more than 16 weeks, with the simultaneous three-time administration of the Gardasil vaccine according to the scheme of 0-2-6 months. This intervention provides a clinical cure (disappearance of genital warts) with the possible elimination of the virus and prevents re-infection with condylomagenic types of HPV, which is accompanied by prolonged remission.

The way to achieve long-term clinical remission of chronic HPV infection, manifested by genital warts of the anogenital region, is as follows. Patients with genital warts of the anogenital region are vaccinated with the Gardasil preparation three times according to the schedule of 0-2-6 months by intramuscular injection of it into the deltoid muscle of the shoulder. Simultaneously with the start of vaccination, they start applying 5% cream to Aldara condylomas 3 times a week before bedtime, followed by rinsing with soap and water in the morning until visible anogenital warts disappear, but no more than 16 weeks.

Analysis of the effectiveness of the proposed method for achieving long-term clinical remission of chronic HPV infection, manifested by genital warts of the anogenital region, was carried out according to the results of 18 patients with this pathology. 18 subjects with 1 to 5 genital warts localized in the anogenital region were vaccinated with the Gardasil vaccine according to the schedule of 0-2-6 months with the simultaneous use of Aldara 5% cream 3 times a week before bedtime, followed by rinsing in the morning with water with soap until the disappearance of visible anogenital warts, but not more than 16 weeks. The average age of the patients was 26.4 ± 4.1 years, 11 men and 7 women.

The number of genital warts of the anogenital region was determined in all subjects; only those patients whose number did not exceed 5 were included in the study. Three participants in the study had concomitant HIV infection. All HIV-infected patients were on virologically effective antiretroviral therapy and had an undetectable viral load, and the number of CD4 + cells in all HIV-infected subjects exceeded 350 in 1 ml of blood.

The initial number of genital warts of the anogenital region was distributed as follows: 1 genital warts - 2 patients, 2 genital warts - 4 patients, 3 genital warts - 3 patients, 4 genital warts - 2 patients, 5 genital warts - 7 patients. All subjects completed the study. After completion of the established course of therapy (three times Gardasil vaccination according to the scheme 0-2-6 months + use of Aldara 5% cream 3 times a week for no more than 16 weeks), complete disappearance of genital warts was observed in 17 out of 18 people (94.4 %), including patients with HIV infection. In 1 patient without HIV infection, the number of condylomas decreased from the initial 5 to 1 at the end of the observation after 1 year. Within 1 year, no relapses of genital warts of the anogenital region were detected.

Thus, Gardasil vaccination according to the scheme of 0-2-6 months with the simultaneous use of Aldara 5% cream 3 times a week for no more than 16 weeks leads to long-term clinical remission of chronic HPV infection, manifested by genital warts of the anogenital region. Perhaps we are talking about the elimination of HPV from surrounding tissues using Aldar 5% cream and the formation of immunity against HPV 6, 11, 16, 18 types using the Gardasil vaccine, which prevents re-infection. Significant local or general reactions using this method to achieve long-term clinical remission of chronic HPV infection, manifested by genital warts of the anogenital region, were not noted. The method is safe, available for modern medical institutions.

At the filing date, the applicants did not find a way to achieve long-term clinical remission of chronic HPV infection, manifested by genital warts of the anogenital region, with the claimed combination of features, as a result of which it is concluded that the claimed technical solution meets the criteria of the invention of “novelty”.

The use to achieve long-term clinical remission of chronic HPV infection, manifested by genital warts of the anogenital region, three times vaccination with the drug "Gardasil" with the simultaneous use of "Aldara" 5% cream 3 times a week for no more than 16 weeks is also not known, which indicates the criterion "Inventive step".

The inventive method can be carried out in any specialized medical institution, therefore, it meets the criterion of "industrial applicability".

Literary sources

1. Howell-Jones R., de Silva N., Akpan M., Oakeshott P., Carder C. et al. Prevalence of human papillomavirus (HPV) infections in sexually active adolescents and young women in England, prior to widespread HPV immunization. Vaccine 2012; 30: 3867-3875.

2. Instructions for the medical use of the drug “Aldara”.

3. Hengge U.R. et al. Topical immunomodulators - progress towards treating inflammation, infection, and cancer. Lancet Infect Dis 2001; 1: 189-198.

4. Gibson S. et al. Cellular requirements of cytokine production in response to the immunomodulators imiquimod and S - 27609. J Interferon Cytokine Res 1995; 15: 537-545.

5. Burns R.P. et al. The imidazoquinolines, imiquimod and R - 848, induce functional, but not phenotypic, maturation of human epidermal Langerhans ′ cells. Clin Immunol 2000; 94: 13-23.

6. Suzuki H. et al. Imiquimod, a topical immune response modifier induces migration of Langerhans cells. J Invest Dermatol 2000; 114: 135-141.

7. Hemmi H. et al. Small antiviral compounds activate immune cells via the TLR7 MyD88-dependent pathway. Nat Immunol 2002; 3: 196-200.

8. Gomberg M.A., Soloviev A.M. The treatment of warts and genital warts is simple and effective. Medical advice. 2011; 5-6: 60-65.

9. Kuznetsova Yu.N. Treatment of genital warts of the anogenital region with Solcoderm. Ural Medical Journal. 2005; 3: 2-3.

10. Apolikhina I.A., Salekh Yu.V. Modern possibilities in the treatment of genital warts. Obstetrics and gynecology. 2011; 5: 134-136.

11. Neymark B.A., Kondratyev Yu.S., Zologina B.C., Torbik D.V. The effectiveness of the combined treatment of human papillomavirus infection. Urology. 2015; 2: 39-42.

Claims (1)

A method for achieving long-term clinical remission of chronic HPV infection, manifested in genital genital warts, including triple vaccination of patients against 6, 11, 16 and 18 types of HPV with Gardasil drug according to the 0-2-6 month regimen with simultaneous use of Aldara condylomas 5% cream 3 times a week before bedtime, followed by rinsing in the morning with soap and water until the visible anogenital warts disappear, but no more than 16 weeks. Aldara 5% cream begins to be used on the day of the first dose of Gardasil vaccine.