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Management of human papilloma virus vulvo-perineal infection with systemic β-interferon and thymostimulin in HIV-positive patients
Int J Gynecol Obstet, 1994, 44: 255-258 International Federation of Gynecology and Obstetrics
255
Management of human papilloma virus vulvo-perineal infection with systemic fl-interferon and thymostimulin in HIV-positive patients A. Frega, F. di Renzi, P. Stentella 11 Clinic of Obstetrics
and Gynecology,
(Received September 14th, 1993) (Revised and accepted November
and A. Pachì
University of Rome “La Sapienza”,
Rome (Italy)
30th, 1993)
Abstract
Introduction
OBJECTIVES: To evaluate the effect of a combined therapy based on B-interferon and thymostimulin in HIV-seropositive women with fì’orid vulvoperineal condylomatosis. HI V-seropositive Nineteen METHODS: women affected by HPV florid vulvo-perineal infection were studied. Their ages ranged from 19 to 32 years (mean = 26); al1 were smokers; 11 (57.89%) were intravenous drug users with a mean period of drug addiction of 5 years. NO patient was on AZT therapy. Al1 patients underwent a combined medical therapy based on /3-interferon administration with doses of 3 000 000 IU i.m. daily for 7 days and subsequently on alternate days for 2 weeks associated with the administration of 70 mg i.m. of thymostimulin per day on alternate days for 30 days. RESULTS: Seven (36.84%) patients showed complete recovery at the end of followup; 5 (26.31 %J) patients showed partial recovery and 7 (36.84(X) did not respond to therapy. CONCLUSION: A pro-host immunotherapy seems to be indicated in patients affected by immunodeficiency syndrome.
The immune system plays a fundamental role in the defense against and control of viral infections; in fact, several studies on the evaluation of lymphocyte subpopulations have demonstrated that female patients affected by genital condylomatosis, namely recurrent, or CIN + VCE present a remarkable cell-mediated immune defìciency [ 11. For HIV-seropositive women, i.e. when immunodelïciency is a peculiar characteristic of the disease, the incidence of viral and opportunistic pathogens infections is higher than in the genera1 population; furthermore, in these patients HPV genital infections often present florid clinical features and extensively involve the lower genital tract [2]. On this basis, it is obvious that the physical destructive therapy alone does not permit a total remission of the disease since the immune system changes linked to the specific features of the disease may determine a partial recovery or recurrences more frequently than in the population as a whole [3-61. Therefore, together with the destructive therapy, a medical treatment to reduce the extent of lesions and prevent recurrence, as wel1 as to avoid possible neoplastic degeneration, can be necessary.
Keywords: fl-Interferon; Thymus Human papilloma virus; HIV 0020-7292194/%07.00 0 1994 International Federation Printed and Published in Ireland
extracts;
Article of Gynecology
and Obstetrics
256
Frega et al.
Currently, the ever-increasing variety of chemically well-defined biological substances and of pharmacological preparations with relative specificity for the various immune system effector cells allows a more specific clinical management. To this aim, it has been demonstrated that thymostmulin enhances the production of interferon [7]. The purpose of the present study was to evaluate the effectiveness of a combined medical therapy based on P-interferon and thymostimulin in 19 HIV-seropositive women affected by florid vulvo-perineal condylomatosis.
Pregnant women and those already subjected to other physically destructive therapies were ruled out of the study. Al1 patients underwent a combined medical therapy based on &IFN (Frone, Serono, Italy) administration with doses of 3 000 000 (IU) i.m. daily for 7 days and subsequently on alternate days for 2 weeks along with the administration of 70 mg i.m. of thymostimulin (TPl, Serono, Italy) per day on alternate days for 30 days. The follow up required controls 1, 3, and 6 months from the end of therapy. NO patient was lost during the follow up. Results
Materials and methods
At the 11 Clinic of Obstetrics and Gynecology of the University of Rome “La Sapienza”, from June 1990 through June 1991, 19 HIV-seropositive women with florid vulvoperineal condylomatosis were studied. Ages ranged from 19 to 32 years (mean = 26). Nine (47.36%) of the 19 patients were nulliparous and the remaining ones had had 1-3 deliveries; al1 were smokers with a daily average of 18 cigarettes; 17 years was the mean age of the tïrst sexual intercourse and the mean number of partners was 4. At enrolment, 11 (57.89%) patients were stil1 intravenous drug users; the longest period of drug addiction was 9 years, the shortest 2 years, mean 5 years. At the time of the study no patient was on AZT therapy. Al1 patients underwent the following examinations: Pap smear, colposcopy and directed biopsy of condylomatous lesions. Present male partners of the patients, in case of relationships not shorter than 1 year, underwent peniscopic examination and directed biopsy of the suspected lesions. Ten (76.92%) partners out of a total of 13 had been intravenous drug users; the mean period of addiction was 4 years, with a minimum of 2 and a maximum of 7 years. Five (38.46%) partners were HIV-seropositive; the mean number of their female partners was 6, minimum = 3, maximum = 12. Int J Gynecol Obstet 44
In 7 (36.84%) patients we observed a complete recovery (CR) from the condylomatous lesions at the end of follow up; in 5 (26.31%) patients we recorded a partial regression (PR) of lesion size of about 50%; 7 (36.84%) patients did not show any clincal reaction to treatment (NR) (Table 1). The patients that did not react to therapy or who reacted only partially, subsequently underwent laser vaporization of the lesions associated with excision in some cases. In this study, cytological, colposcopic and histologie fmdings from the 19 patients before and after treatment did not reveal cervical dysplastic lesions; however, viral cytopathic effects were found in 16 patients. As for the 13 male partners, we detected 8 (61.53%) cases of flat condylomata (macular or papular) and 5 (38.46%) cases of a florid form involving extensively the glans and shaft.
Table 1. Results of treatment in 19 HIV sero-positive with florid vulva-perineal condylomatosis.
Complete recovery Partial recovery NO recovery
N
WJ)
7 5 7
36.84 26.3 I 36.84
patients
B-IFN and thymostimulin for HPV lesions in HIV-positive women
Al1 male partners underwent laser treatment with a follow up of three controls, 1, 3, and 6 months from the end of treatment. Discussion In recent years immunopharmacology has dynamically developed with regard to the study of pharmacological regulation of the immune system and also to the therapy of immunitary diseases. HIV-induced alterations of cell-mediated immunity exposes the subject to infective pathologies with various clinical manifestations [8]. The immune system is a highly specialized regulatory system that, together with the nervous and endocrine systems, help to maintain body homeostasis. It picks up complex chemical signals (antigens) and under particular conditions it triggers the adequate corrective effector mechanism. The immune system regulatory activity is involved in the functional maturation of lymphocytic subclones of the stem cells, the release of functionally active cells from the ‘reserves’, the recruitment, differentiation, and transport to the bloodstream of T cel1 precursors from the ‘virgin’ lymphocytes of the reserve, and in the regulation of the functional activity of the mature cells [9]. With the advent of the AIDS epidemie, thymic extracts were taken into consideration for the immuno-preventive treatment and/or the immunotherapy of HIV-seropositive subjects and of ARC and AIDS patients [ 101. Both the thymus and thymic hormones seem to play a fundamental role in the regulation of the immune system; furthermore, clinical studies have proved their capacity in enhancing the production of mitogen IFN in the peripheral blood lymphocytes and of IL-2, as wel1 as the expression of the 0KT4 antigen in T cell. The peculiar feature of thymostimulin is the induction of an increment of the functional activity of NK cells [ 111. With regard to the therapeutical aspect,
251
therefore, thymic hormones seem to permit physiological pharmacological properties, with no side effect, such as to increase and sustain the action of the natura1 control defences against infective diseases. The ascertained effectiveness of thymic hormones in the defense system against infective pathogens in immunocompromised animals and the prolongation of lifetime of immunodepressed animals paved the way for further clinical studies on this matter; therefore, for patients with recurrent infections, i.e. with a certain leve1 of immunodelïciency, treatment should consist of administration of immunorestoring agents, such as thymic hormones, or of other immunoenhancing substances, so as to change the natura1 course of the disease, through the reduction of the incidence of recurrences. As for HPV pathologies in HIV-serothe physical positive women, although destructive therapy is stil1 the treatment of choice, we believed that the combined administration of fl-IFN and thymostimulin could be a valid support in the management of these patients, with special regard for the reduction of lesion size, persistente, and recurrences. This therapeutical association is justilïed by its possible synergistic effect: in fact, thymostimulin acts more specifically on cellmediated immunity (increase in the NK activity) and enhances the production of endogenous IFN, whereas fl-IFN influences viral replication by breaking the various stages of the replicative cycle thanks to its immunomodulatory, antiviral, and antiproliferative properties [ 121. The results of our study seem to be encouraging since about 63% of our patients showed a total or at least a partial remission of the lesions; besides, up to date, we have recorded no recurrences. Pro-host immunotherapy, based on the use of purifïed natura1 biological substances (thymic hormones, IFN, etc.) combined with the synergistic and additive action of conventional therapies, administered in proper doses and in the most appropriate way, bring about Article
258
Frega et al.
a major change in the treatment of human pathologies linked to or based on the immune deficit, thus obtaining new and more rational biological frontiers [ 131.
8
References 9 Avgerinou G, Georgala S, Taerdorids A, Vareltzdis A, Stradigos J: Reduction of cel]-mediated immunity in patients with genital warts of long duration. Genitourin Med 62: 396, 1986. Maiman M, Fruchter RG, Serur E, Remy JC, Feuer G, Boyce J: Human immunodeficiency virus infection and cervical neoplasia. Gynecol Oncol 38; 377, 1990. Caubel P, Folques H, Blondon J, Lefranc JP: Lésions cervico-vaginales et vulvaire a papillomavirus: épidémiologie chez les femmes séropositive pour le VIH. Etude preliminaire sur une série continue. Presse Méd 18: 1239, 1989. Kent C, Samuel M, Winkelstein W: The role of anal/ genital warts in HIV infection. Letter to the Editor. J Am Med Assoc 258: 3385, 1987. Kiviat N, Rompalo A, Bowden R, Galloway D, Holmes KK, Corey L, Roberts PL, Stamn W: Anal Human Papillomavirus infection among Human Immunodeficiency Virus-positive and-seronegative men. J Infect Dis 162: 358, 1990. Beek DE, Jaso RG, Zajac RA: Surgical management of anal condylomata in the HIV-positive patient. Dis Colon Rectum 33: 180, 1990. Shoham J, Eshel 1, Aboud M, Salzberg S: Thymic hormonal activity on human peripheral lymphocytes in vitro.
IIII J Gynecol Ohsret 44
10
11
12 13
11. Enhancement of the production of immune interferon by acitvated cells. J Immunol 125: 54, 1980. Barbaro G, Murri G, Profenna LM, De Rosa F: Role of Thymostimulin in the treatment of acute Cryptosporidium enteritis with erythromicin in patients with acquired immunodeficiency syndrome. Curr Ther Res 48: 974, 1990. Fagiolo U, Amadori A, Borghesan F, Zamarchi R, Veronese ML, De Silvestro G, Passarella E, Crepaldi G: Immune disfunction in the elderly: effect of thymic hormone administration on several in vivo and in vitro immune function parameters. Aging 2: 347, 1990. Palmisano L, Chisesi T, Galli M, Gritti FM, Ielasig, Lazzarin A, Mezzaroma 1, Moroni M, et al: Thymostimulin treatment in AIDS-related complex. Clin Immunol Immunopathol 47: 253, 1988. Setti M, Pende A, Vergassola C, Marsano L, Pierri 1, Scudeletti M, Indiveri F: Immune and endocrine effects of a thymic extract in healthy subjects. Int J Immunother 3: 175, 1990. Michaelis B, Levy J: HIV replication can be blocked by recombinant human Interferon-beta. AIDS 3: 27, 1989. Skotnicki AB: Thymic hormones and Lymphokines. Drugs Today 25: 337, 1989.
Address for reprints:
A. Frega c/o 11 Clinic of Obtsetrics and Gynecology University of Rome “La Sapienza” Rome Italy
255
Management of human papilloma virus vulvo-perineal infection with systemic fl-interferon and thymostimulin in HIV-positive patients A. Frega, F. di Renzi, P. Stentella 11 Clinic of Obstetrics
and Gynecology,
(Received September 14th, 1993) (Revised and accepted November
and A. Pachì
University of Rome “La Sapienza”,
Rome (Italy)
30th, 1993)
Abstract
Introduction
OBJECTIVES: To evaluate the effect of a combined therapy based on B-interferon and thymostimulin in HIV-seropositive women with fì’orid vulvoperineal condylomatosis. HI V-seropositive Nineteen METHODS: women affected by HPV florid vulvo-perineal infection were studied. Their ages ranged from 19 to 32 years (mean = 26); al1 were smokers; 11 (57.89%) were intravenous drug users with a mean period of drug addiction of 5 years. NO patient was on AZT therapy. Al1 patients underwent a combined medical therapy based on /3-interferon administration with doses of 3 000 000 IU i.m. daily for 7 days and subsequently on alternate days for 2 weeks associated with the administration of 70 mg i.m. of thymostimulin per day on alternate days for 30 days. RESULTS: Seven (36.84%) patients showed complete recovery at the end of followup; 5 (26.31 %J) patients showed partial recovery and 7 (36.84(X) did not respond to therapy. CONCLUSION: A pro-host immunotherapy seems to be indicated in patients affected by immunodeficiency syndrome.
The immune system plays a fundamental role in the defense against and control of viral infections; in fact, several studies on the evaluation of lymphocyte subpopulations have demonstrated that female patients affected by genital condylomatosis, namely recurrent, or CIN + VCE present a remarkable cell-mediated immune defìciency [ 11. For HIV-seropositive women, i.e. when immunodelïciency is a peculiar characteristic of the disease, the incidence of viral and opportunistic pathogens infections is higher than in the genera1 population; furthermore, in these patients HPV genital infections often present florid clinical features and extensively involve the lower genital tract [2]. On this basis, it is obvious that the physical destructive therapy alone does not permit a total remission of the disease since the immune system changes linked to the specific features of the disease may determine a partial recovery or recurrences more frequently than in the population as a whole [3-61. Therefore, together with the destructive therapy, a medical treatment to reduce the extent of lesions and prevent recurrence, as wel1 as to avoid possible neoplastic degeneration, can be necessary.
Keywords: fl-Interferon; Thymus Human papilloma virus; HIV 0020-7292194/%07.00 0 1994 International Federation Printed and Published in Ireland
extracts;
Article of Gynecology
and Obstetrics
256
Frega et al.
Currently, the ever-increasing variety of chemically well-defined biological substances and of pharmacological preparations with relative specificity for the various immune system effector cells allows a more specific clinical management. To this aim, it has been demonstrated that thymostmulin enhances the production of interferon [7]. The purpose of the present study was to evaluate the effectiveness of a combined medical therapy based on P-interferon and thymostimulin in 19 HIV-seropositive women affected by florid vulvo-perineal condylomatosis.
Pregnant women and those already subjected to other physically destructive therapies were ruled out of the study. Al1 patients underwent a combined medical therapy based on &IFN (Frone, Serono, Italy) administration with doses of 3 000 000 (IU) i.m. daily for 7 days and subsequently on alternate days for 2 weeks along with the administration of 70 mg i.m. of thymostimulin (TPl, Serono, Italy) per day on alternate days for 30 days. The follow up required controls 1, 3, and 6 months from the end of therapy. NO patient was lost during the follow up. Results
Materials and methods
At the 11 Clinic of Obstetrics and Gynecology of the University of Rome “La Sapienza”, from June 1990 through June 1991, 19 HIV-seropositive women with florid vulvoperineal condylomatosis were studied. Ages ranged from 19 to 32 years (mean = 26). Nine (47.36%) of the 19 patients were nulliparous and the remaining ones had had 1-3 deliveries; al1 were smokers with a daily average of 18 cigarettes; 17 years was the mean age of the tïrst sexual intercourse and the mean number of partners was 4. At enrolment, 11 (57.89%) patients were stil1 intravenous drug users; the longest period of drug addiction was 9 years, the shortest 2 years, mean 5 years. At the time of the study no patient was on AZT therapy. Al1 patients underwent the following examinations: Pap smear, colposcopy and directed biopsy of condylomatous lesions. Present male partners of the patients, in case of relationships not shorter than 1 year, underwent peniscopic examination and directed biopsy of the suspected lesions. Ten (76.92%) partners out of a total of 13 had been intravenous drug users; the mean period of addiction was 4 years, with a minimum of 2 and a maximum of 7 years. Five (38.46%) partners were HIV-seropositive; the mean number of their female partners was 6, minimum = 3, maximum = 12. Int J Gynecol Obstet 44
In 7 (36.84%) patients we observed a complete recovery (CR) from the condylomatous lesions at the end of follow up; in 5 (26.31%) patients we recorded a partial regression (PR) of lesion size of about 50%; 7 (36.84%) patients did not show any clincal reaction to treatment (NR) (Table 1). The patients that did not react to therapy or who reacted only partially, subsequently underwent laser vaporization of the lesions associated with excision in some cases. In this study, cytological, colposcopic and histologie fmdings from the 19 patients before and after treatment did not reveal cervical dysplastic lesions; however, viral cytopathic effects were found in 16 patients. As for the 13 male partners, we detected 8 (61.53%) cases of flat condylomata (macular or papular) and 5 (38.46%) cases of a florid form involving extensively the glans and shaft.
Table 1. Results of treatment in 19 HIV sero-positive with florid vulva-perineal condylomatosis.
Complete recovery Partial recovery NO recovery
N
WJ)
7 5 7
36.84 26.3 I 36.84
patients
B-IFN and thymostimulin for HPV lesions in HIV-positive women
Al1 male partners underwent laser treatment with a follow up of three controls, 1, 3, and 6 months from the end of treatment. Discussion In recent years immunopharmacology has dynamically developed with regard to the study of pharmacological regulation of the immune system and also to the therapy of immunitary diseases. HIV-induced alterations of cell-mediated immunity exposes the subject to infective pathologies with various clinical manifestations [8]. The immune system is a highly specialized regulatory system that, together with the nervous and endocrine systems, help to maintain body homeostasis. It picks up complex chemical signals (antigens) and under particular conditions it triggers the adequate corrective effector mechanism. The immune system regulatory activity is involved in the functional maturation of lymphocytic subclones of the stem cells, the release of functionally active cells from the ‘reserves’, the recruitment, differentiation, and transport to the bloodstream of T cel1 precursors from the ‘virgin’ lymphocytes of the reserve, and in the regulation of the functional activity of the mature cells [9]. With the advent of the AIDS epidemie, thymic extracts were taken into consideration for the immuno-preventive treatment and/or the immunotherapy of HIV-seropositive subjects and of ARC and AIDS patients [ 101. Both the thymus and thymic hormones seem to play a fundamental role in the regulation of the immune system; furthermore, clinical studies have proved their capacity in enhancing the production of mitogen IFN in the peripheral blood lymphocytes and of IL-2, as wel1 as the expression of the 0KT4 antigen in T cell. The peculiar feature of thymostimulin is the induction of an increment of the functional activity of NK cells [ 111. With regard to the therapeutical aspect,
251
therefore, thymic hormones seem to permit physiological pharmacological properties, with no side effect, such as to increase and sustain the action of the natura1 control defences against infective diseases. The ascertained effectiveness of thymic hormones in the defense system against infective pathogens in immunocompromised animals and the prolongation of lifetime of immunodepressed animals paved the way for further clinical studies on this matter; therefore, for patients with recurrent infections, i.e. with a certain leve1 of immunodelïciency, treatment should consist of administration of immunorestoring agents, such as thymic hormones, or of other immunoenhancing substances, so as to change the natura1 course of the disease, through the reduction of the incidence of recurrences. As for HPV pathologies in HIV-serothe physical positive women, although destructive therapy is stil1 the treatment of choice, we believed that the combined administration of fl-IFN and thymostimulin could be a valid support in the management of these patients, with special regard for the reduction of lesion size, persistente, and recurrences. This therapeutical association is justilïed by its possible synergistic effect: in fact, thymostimulin acts more specifically on cellmediated immunity (increase in the NK activity) and enhances the production of endogenous IFN, whereas fl-IFN influences viral replication by breaking the various stages of the replicative cycle thanks to its immunomodulatory, antiviral, and antiproliferative properties [ 121. The results of our study seem to be encouraging since about 63% of our patients showed a total or at least a partial remission of the lesions; besides, up to date, we have recorded no recurrences. Pro-host immunotherapy, based on the use of purifïed natura1 biological substances (thymic hormones, IFN, etc.) combined with the synergistic and additive action of conventional therapies, administered in proper doses and in the most appropriate way, bring about Article
258
Frega et al.
a major change in the treatment of human pathologies linked to or based on the immune deficit, thus obtaining new and more rational biological frontiers [ 131.
8
References 9 Avgerinou G, Georgala S, Taerdorids A, Vareltzdis A, Stradigos J: Reduction of cel]-mediated immunity in patients with genital warts of long duration. Genitourin Med 62: 396, 1986. Maiman M, Fruchter RG, Serur E, Remy JC, Feuer G, Boyce J: Human immunodeficiency virus infection and cervical neoplasia. Gynecol Oncol 38; 377, 1990. Caubel P, Folques H, Blondon J, Lefranc JP: Lésions cervico-vaginales et vulvaire a papillomavirus: épidémiologie chez les femmes séropositive pour le VIH. Etude preliminaire sur une série continue. Presse Méd 18: 1239, 1989. Kent C, Samuel M, Winkelstein W: The role of anal/ genital warts in HIV infection. Letter to the Editor. J Am Med Assoc 258: 3385, 1987. Kiviat N, Rompalo A, Bowden R, Galloway D, Holmes KK, Corey L, Roberts PL, Stamn W: Anal Human Papillomavirus infection among Human Immunodeficiency Virus-positive and-seronegative men. J Infect Dis 162: 358, 1990. Beek DE, Jaso RG, Zajac RA: Surgical management of anal condylomata in the HIV-positive patient. Dis Colon Rectum 33: 180, 1990. Shoham J, Eshel 1, Aboud M, Salzberg S: Thymic hormonal activity on human peripheral lymphocytes in vitro.
IIII J Gynecol Ohsret 44
10
11
12 13
11. Enhancement of the production of immune interferon by acitvated cells. J Immunol 125: 54, 1980. Barbaro G, Murri G, Profenna LM, De Rosa F: Role of Thymostimulin in the treatment of acute Cryptosporidium enteritis with erythromicin in patients with acquired immunodeficiency syndrome. Curr Ther Res 48: 974, 1990. Fagiolo U, Amadori A, Borghesan F, Zamarchi R, Veronese ML, De Silvestro G, Passarella E, Crepaldi G: Immune disfunction in the elderly: effect of thymic hormone administration on several in vivo and in vitro immune function parameters. Aging 2: 347, 1990. Palmisano L, Chisesi T, Galli M, Gritti FM, Ielasig, Lazzarin A, Mezzaroma 1, Moroni M, et al: Thymostimulin treatment in AIDS-related complex. Clin Immunol Immunopathol 47: 253, 1988. Setti M, Pende A, Vergassola C, Marsano L, Pierri 1, Scudeletti M, Indiveri F: Immune and endocrine effects of a thymic extract in healthy subjects. Int J Immunother 3: 175, 1990. Michaelis B, Levy J: HIV replication can be blocked by recombinant human Interferon-beta. AIDS 3: 27, 1989. Skotnicki AB: Thymic hormones and Lymphokines. Drugs Today 25: 337, 1989.
Address for reprints:
A. Frega c/o 11 Clinic of Obtsetrics and Gynecology University of Rome “La Sapienza” Rome Italy