Efficacy in Treatment of Cervical Hrhpv Infection by Combination of Beta Interferon , and Herbal Therapy in Woman with Different Cervical Lesions

Cervical dysplasia, a premalignant lesion that can progress to cervical cancer, is caused primarily by a sexually transmitted infection with an oncogenic strain of the human papillomavirus (HPV). Th e HPV infections are treated through destroying the clinical lesions: laser, cryotherapy, podophylline... Th e hope is that by causing local tissue infl ammation that the body will be stimulated to mount an antibody response and thereby prevent recurrence. In contrast to other prevention approaches, vaccines can reduce susceptibility in uninfected partners by stimulating the immune system. Aloa vera has also been reported to retard tumour growth and stimulate the immune response to viruses. A list of possible actions of propolis includes: antibacterial, antifungal, antiviral, antioxidant, anticarcinogenic, antithrombotic and immunomodulatory. Research on the possible role of some B vitamins in preventing cancer began in the last few decades, but however this complex have an infl uence on immune status. Th e aim of our study is to try to treat the HPV infection as confi rmed cause of neoplastic transformation with some herbal therapy and interferon and to try defi ne the guidelines in the management of the HPV positive patients. Goal of this paper is to search for evidence of effi cacy of any treatment for HPV infection of the cervix mostly in woman with no concomitant CIN. Fifty fi ve woman aff ected by HPV genital infection were enrolled in the study from September  to April . Patients were classifi ed according to the results of the HPV testing prior and after the therapy. Patients were randomized into two groups: the fi rst group was HPV positive woman treated with other than recommanded therapy (n=), (control group); the second group was pharmacologically treated with intravaginal administration of an interferon and aloa vera – propolis in


Introduction
Cervical dysplasia, a premalignant lesion that can progress to cervical cancer, is caused primarily by a sexually transmitted infection with an oncogenic strain of the human papillomavirus (HPV) (, , ).Women less than  years old display a high rate of HPV positivity with normal cytologic fi ndings.HPV is most usually detected in women, but it has been shown that up to  of the male partners of women diagnosed with HPV test positive for the virus.Th e HPV infections are treated through destroying the clinical lesions: laser, cryotherapy, podophylline... (, ).Th e hope is that by causing local tissue infl ammation that the body will be stimulated to mount an antibody response and thereby prevent recurrence.In contrast to other prevention approaches, vaccines can reduce susceptibility in uninfected partners by stimulating the immune system.The vaccine protects against some of the cancer-causing strains of HPV, but not all.In  B.C. Egyptians recorded use of the herbal plant in treating burns, infections and parasites.Aloe, native to Africa, is also known as "lily of the desert", the "plant of immortality", and the "medicine plant".Th e name was derived from the Arabic alloeh meaning "bitter" because of the bitter liquid found in the leaves.Aloe vera has also been reported to retard tumor growth and stimulate the immune response to viruses ().Propolis, also known as bee glue and bee propolis, is a brownish resinous substance collected by bees.It is said that propolis is the most natural antibiotic that man has ever discovered.Th e remarkable thing about this statement is the fact that this discovery took place some  years ago.A list of possible actions of propolis includes: antibacterial, antifungal, antiviral (including anti HIV- activity), antioxidant, anticarcinogenic, antithrombotic and immunomodulatory.Research on the possible role of some B vitamins in preventing cancer began in the last few decades, but however this complex has an infl uence on immune status.B vitamins are essential nutrients for growth, development, and a variety of other bodily functions.Th ey play a major role in the activities of enzymes (proteins) that regulate chemical reactions in the body.Th is is especially important in turning food into energy and other needed substances.B vitamins are found in a variety of plant and animal food sources.Because of the public health importance of cervical cancer and its precursor lesion, this report focuses on the possible treatment of genital HPV infection and its sequelae in both sexual partners with mostly natural, herbal therapy.Th e aim of our study is to try to treat the HPV infection as confi rmed cause of neoplastic transformation with some herbal therapy and interferon and to try defi ning the guidelines in the management of the HPV positive patients.Goal of this paper is to search for evidence of effi cacy of any treatment for HPV infection of the cervix mostly in woman with no concomitant CIN.

STUDY DESIGN
Fifty-fi ve women aff ected by HPV genital infection were enrolled in the study from September  to April .Patients were classifi ed according to the results of the HPV testing prior and after the therapy.Patients were randomized into two groups: the fi rst group was HPV positive women treated with other than recommended therapy (n=), (control group); the second group was pharmacologically treated with intravaginal administration of an interferon and aloe vera -propolis in recommended scheme (n=) with treatment of the possible fungal or bacterial genital infection prior to the specifi c therapy.Th e almost same therapy was recommended to the male partner.Patients from the second group used B complex during the therapy.Patients were retested for the HPV presence after three or six month from therapy depends of the presence bacterial or fungal genital coinfection.Th e study was conducted under University Clinical Center Tuzla and proved by Ethical committee.

Results
Overall,  HPV positive women with diff erent cytology results were enrolled in the study:  women in the examined group (II group), and  women in the control group (I group).Cytology evaluation of the smears was presented in the Table .
Recommended therapy: .Treat the possible infection of vaginal fl ora (bacterial, fungal, mixed) .Interferon vagitorie or cream (xvag in the evening, two months for women;  tube to spread for man)..Aloe vera/propolis vag (x vag in the evening, three months for women,  tube of gel to spread for man).

Scheme:
First treat the possible infection of vaginal flora than start with specifi c therapy; x vag in the evening followed by x vag aloe vera/propolis, repeat during next two months).

ACTIVE INGREDIENTS OF ALOE VERA/PROPOLIS VAGITORIE AND BASIC MECHANISM OF ACTION
Vagitories: Propolis, Aloe vera, Echinacea (xgr) Extract of propolis (), filtered juice of aloe (Aloe barbadensis) with certifi ed organic quality, Extract of over ground part of Echinacea (Echinacea purpurea); extract of marigold fl ower, (Calendula offi cinalis).Th e additional ingredients: white wax (Cera alba); Witespol H-hydrogenised herbal glicerids (Adeps solidus), propylene glycol, alfa tokoferol.Th e pharmacy contains the extract of propolis () with more than  identified ingredients, mostly biologically active.Propolis as natural antibiotic, works actively against different bacteria, fungi, and viruses and with enhanced action in combination with antracinons from aloe, and ingredients from Echinacea and marigold.Anti-inflammatory action is result of eff ectivity of few diff erent active ingredients with point on CAPE (cafeic acid of phenitil ester) from propolis, which also has an antitumor eff ect.

BIOLOGIC CHARACTERISTICS OF THE HERBS AND VITAMIN B
Aloe vera: Aloe is derived from the A. vera plant, a green, succulent, cactus-like plant belonging to the lily family.Th e substance, A. vera, is derived from thin-walled mucilaginous cells of the inner central zone of the leaf.Th is gel is thought to have emollient and moisturizing eff ects and therapeutic properties.A. vera is a complex plant that contains many biologically active substances.Davis, Parker, Samson et al., () () reported that one tablespoon of A. vera contains over  diff erent chemicals that have biological activity.Th erefore it has proved diffi cult to isolate a single active ingredient, and it has been suggested that there is a synergistic relationship between the constituents.Mannose--phosphate is a major structural constituent of A. vera.Research conducted by Davis, Di Donato, Hartman et al, suggested that mannose--phosphate is an active ingredient in A. vera which demonstrates wound healing and anti-infl ammatory activity in a dose response fashion.Current theory suggests that mannose--phosphate needs to be protein linked to yield its therapeutic activity.Th e authors speculate that the binding of fi broblast receptors with mannose-phosphate is capable of activating fi broblast proliferation.Propolis: Th e use of Propolis in popular medicine goes back all the way to ancient times.Egyptians, Greeks and Romans reported the use of Propolis for its general healing qualities and for the cure of some lesions of the skin.Propolis has a long history of use in folk medicine and was even used as an offi cial drug in London in the s.Th ey are also critically required for the metabolism of both, fats and proteins, as well as the health and maintenance of the body's nervous system ().
Interferon: Belong to the group of the regulatory glicoproteins of low molecular mass.Besides the antiviral and antiproliferative eff ects, they have also eff ect in the treatment of malignant disease, and act protectively against the radiation.Interferon beta posses' only one protein molecule the product of fi broblast as well as the epithelial cells resistant to the low pH as well as alfa is antiviral and antiproliferative eff ect.Application of exogenous IFN has the signifi cant eff ect in initiative phase's virus infection by stoppage of viral replication.
EFFECTS OF THE THERAPY Th ree months after applied therapy HPV infection was still present in more than  of the patients in the fi rst group.In the second group treated according to the recommended therapy scheme HPV infection disappeared in , of the patients after three months and in  of patients after six months (Figure ).After adjustment for the therapy, there was a signifi cant trend of increasing success to cure the HRHPV infection with recommended therapy scheme (χ  =,; P< ,).Compared with other applied therapy for HRHPV infection, the success of the recommended therapy scheme was signifi cantly higher OR= , ( CI: ,-,).In the fi rst group (control group, n=) vaginal fl ora analyses showed persistent mixed bacterial/fungal infection in  of women during the therapy, while in the second (examined group, n=) group treatment of the possible infection and infl ammation was a precondition to start the specifi c recommended HRHPV therapy., () of the women from the second group was still HPV positive after three months of applied therapy. women out of  had persistent mixed vaginal infection, while in  patients; the male partner was not adequately treated.In this group of patients the whole recommended therapy procedure was repeated, with point on the treatment of vaginal infection and male partner.Th erapeutic options used in the patients of the first (control) group with HRHPV infection included laser, cryotherapy, podophylline but without treatment of the male partner and without prior treatment of possible vaginal infection.

Discussion
Genital infection with human papillomavirus (HPV) is very common in sexually active man and woman and can sometimes have serious health consequences.Th e virus can infect the genital skin and the linings of the vagina, cervix, rectum, and urethra.Although the majority of infections cause no symptoms, they are self-limited, and go away on their own without clinical consequenc- es, genital HPV is of public health concern because persistent infection with certain high-risk types can cause cervical cancer in women ().Th e results conducted in Bosnia and Herzegovina by E. Iljazović and co-workers, as well as the results of numerous studies conducted world-wide point to the central role of the HPV in the pathogenesis of cervical lesions with an etiologically important co-action with other mutually independent factors, primarily factors related to sexual habits/behavior ().All those facts underline the necessity for active treatment of HPV infection.Th e HPV specifi c vaccine has been designed solely for the prevention of cancer.Cervical Cancer is the second most frequent cancer in women worldwide,  of the cases occur in developing countries where screening programs for early detection do not exist.Prevention of cervical cancer can be achieved by prophylactic vaccination preventing disease or therapeutic vaccination (immune therapy) curing disease.Over the two and a half years of follow-up after vaccination, quadrivalent human papillomavirus (HPV) (types , , , and ) recombinant vaccine, reduced the combined incidence of persistent infection from HPV , , , or  and related genital disease including new cervical pre-cancers and genital warts by  percent compared with placebo among women who were naïve to the relevant HPV types at baseline (p<,) ().Th e results of our study showed that low risk cervical lesion are very often associated with HRHPV (, in the examined group and , in the control group).According to the data of the National Cancer Institute HRHPV is present in  of patients with ASCUS/LGSIL, and in , of women with ASCUS/LGSIL in Bosnia and Herzegovina ().The combination of smears with detection of high-risk HPV types increases the triage sensitivity especially at patients with mild changes, and therapeutic procedure is more simple ().Th e incorporation of HPV testing into primary screening will result in informing millions of women with normal cytology that they are at increased risk of cervical cancer.Medical treatment of cervical lesion is usually painful, invasive, and generally traumatic.Th e most common methods are cauterization (burning off ) and cryosurgery (freez-ing off ).Th ere are also topical medications (podophyllin, bichloroacetic acid, and trichloroacetic acid), which are applied weekly until the lesion goes away (, ).In any case it has been shown that treatment or not the recurrence level is the same.Th ere are no enough references in the literature about possible diff erent approach to the treatment of HRHPV and cervical lesion ().Unfortunately, eff ective therapy is currently not available.Therapeutic options are limited, expensive and often ineff ective ().Immunotherapy seems to be one of the more promising options.Persistent mixed bacterial/fungal infection was verifi ed in  of women in the fi rst, control group during the therapy and in only , of women in the second, examined group.Th ree months after applied therapy HPV infection was still present in more than  of the patients in the fi rst group.In the second group treated according to the recommended therapy scheme HPV infection disappeared in , of the patients.We concluded that coexistence of other diff erent infection compromise the local and systemic immune status of the patients.Treatment of the possible mixed vaginal infection should be the fi rst step in the therapeutic approach to HRHPV infection.Since treatment options are limited and typically not very satisfactory, the development of safe and eff ective antiviral drugs for HPV could have substantial clinical impact.Interferon combined with propolis, aloe vera and B Complex vitamins with their basic antibacterial, antifungal, antiviral, antioxidant, anticarcinogenic, antithrombotic and immunomodulatory action can cure HPV infection and prevent recurrence of disease.A substantial medical need exists for the development of antiviral medicines for the treatment of diseases associated with infection by human papillomaviruses (HPVs) ().Our results suggest that HRHPV infection associated with diff erent cervical lesion could be cured with: a) treatment of the possible fungal or bacterial genital infection, b) treatment of the both sexual partners should be the rule, c) local application of aloe vera and propolis could improve local immune status and help to HPV go away, d) B complex vitamins may have an influence on systemic immune status.

Conclusion
Papillomaviruses have proved to be the most complex group of human pathogenic viruses.Specifi c types, most notably human papillomavirus (HPV) types , , and a few others, have been shown to cause the majority of cervical cancers and their high-grade precursor lesions ().Our results suggest that the combination of interferon and herbal therapy with B complex is eff ective, atraumatic and simple non-surgical treatment of HPV infection.Clinical trials are being conducted to test the preventive and therapeutic effi cacy of HPV vaccines and in the meantime a diff erent therapeutic option should be considered in order to prevent development of possible high-grade cervical lesion.
ERMINA ILJAZOVIĆ ET AL.: EFFICACY IN TREATMENT OF CERVICAL HRHPV INFECTION BY COMBINATION OF BETA INTERFERON, AND HERBAL THERAPY IN WOMAN WITH DIFFERENT CERVICAL LESIONS Th e composition of propolis is variable, depending on the locale and variety of trees and other plant species used for the collection.For example, unique constituents have been identifi ed in propolis collected in Cuba and Brazil.Th e main chemical classes found in propolis are fl avonoids, phenolics and terpenes.Th e fl avonoids include quercetin, apegenin, galangin, kaempferol, luteolin, pinocembrin, pinostrobin and pinobanksin.
cal ways.Th ey are formed from bacteria, yeast's, fungi, or moulds.Th ey are responsible for providing energy to the body during the conversion of glucose, from carbohydrates.
ERMINA ILJAZOVIĆ ET AL.: EFFICACY IN TREATMENT OF CERVICAL HRHPV INFECTION BY COMBINATION OF BETA INTERFERON, AND HERBAL THERAPY IN WOMAN WITH DIFFERENT CERVICAL LESIONS