Immunotherapy of gynaecological high-risk human papilloma virus infection with human leukocyte ultrafiltrate.

OBJECTIVE
In this preliminary presentation the outcome of women following systemic treatment of cervical human papilloma virus (HPV) with a leukocyte ultrafiltrate is reported.


METHODS
Cervical brush specimens of 819 women with low-grade CIN-1 were evaluated for HPV infection. HPV-positive patients were treated either by cone biopsy because of suspicious colposcopy or by antibiotics for symptoms of bacterial cervicitis. The remaining women were considered as asymptomatic carriers of HPV and underwent systemic therapy by a human leukocyte ultrafiltrate in a dosage of 5 IE, 6 times in the first 2 weeks, and additionally as a single dose at weeks 4, 6, 8 and 10.


RESULTS
The leukocyte ultrafiltrate was administered to 97 HPV-positive women. In follow-up 88.7% were HPV negative at week 6; the remaining 11 women were tested negative after completion of a second course of therapy.


CONCLUSIONS
These preliminary data on the successful treatment of HPV infection by a leukocyte ultrafiltrate are very promising but have to be supported by additional research.

KEY WORDS cervical HPV infection; immunomodulating therapy; antiviral therapy of HPV in our population is estimated to be as high as 10% in women in the reproductive age, but significantly higher in symptomatic patients. In the past decade convincing data on the relationship of human papilloma virus (HPV) infection to cervical neoplasia have been published.
About 30 of more than 100 serotypes appear to be relevant in this respect. HPV detection seems to be associated with at least a 10 times greater risk of cervical neoplasia. 1,z Lorincz et al. 3 defined the following categories for the associated risk of common anogenital types: Topical podophyllin and surgery have been used for years in the routine treatment of condylomata acuminata and HPV infection, respectively, but podophyllotoxin, interferon, and imiquimod are alternatives under serious consideration. Von Krogh and Hellberg 8 reported a complete and per manent cure with 0.5% podophyllotoxin cream in 77% of their study group (34 out of 44 patients). Stellato 9 achieved a complete response of 33% (8 of 24 women) in their study group and a partial regression one year after treatment of 58% (14 of 24 women) with recombinant 2b interferon administered by intra-/perilesional injection. Edwards et al. 1 reported a 72% success rate in women with condylomata acuminata following treatment With 5% imiquimod cream, however, most reports about these latter regimen lack data concerning cervical HPV infection.
Considering the high prevalence of HPV infection, its infectious and oncogenic potential, as well as the poor treatment results, a great deal of interest is directed towards the evaluation of alternative therapies. In this preliminary investigation the outcome of women following systemic treatment of cervical HPV with a leukocyte ultrafiltrate is reported.

MATERIALS AND METHODS
Cervical brush specimen of 819 women with lowgrade CIN-1 were evaluated by means of in situhybridization (Biohit, Helsinki, Finland) and polymerase chain reaction (PCR) (  All women were evaluated by PCR for HPV at week 6 and if still positive at week 10. In women testing positive at week 10, a second course of therapy was administered (10 doses of 5 IE 2 weeks apart). Complete long-term follow-up was not possible for technical reasons.

RESULTS
A total of 33.3% of all women investigated (273/ 819) were found to be HPV positive. A total of 921 different strains of HPV were found, at least two in each of the patients ( Table 1).
In follow-up 86 of the 97 patients who received leukocyte ultrafiltrate (88.7%) were HPV negative at week 6; the remaining 11 women tested negative after completion of therapy at week 30. All women were asymptomatic following treatment. Adverse reactions possibly due to the leukocyte preparation were not observed.

DISCUSSION
Convincing data in the literature support the hypothesis that cervical lesions referred to as CIN comprise two distinct and histologically separable entities: low-grade CIN-1 with HPV types 16, 18, or 33, in less than 30% of cases, and high-grade CIN-2 and CIN-3 associated with these types in almost 90% of cases. The high oncogenic risk types 16, 18, or 33 were detected in 29% of 100 cases with CIN-1 and in 88% of 176 cases with CIN-2 or CIN-3.11 To put the reported findings into practice it appears efficient, at present, to re-evaluate patients with oncogenic HPV types in association with lowgrade cytology, as well as women with high-grade cytology or suspicious colposcopy at frequent intervals.
The management of women with low-grade or borderline cytology is still unsettled. An efficient therapy for HPV infection would be promising, since it is likely that it would be able to reduce the risk of subsequent carcinoma. However, other contributing risk factors such as smoking, drugs, promiscuity, immunosuppression or incompetence, and chronic diseases also have to be taken into account.
In our study we used a leukocyte ultrafiltrate that is supposed to induce an immunological response by means of ribonucleopeptides of still unknown structure. The mechanism is thought to be enhanced by immunological stimulation of proliferation and maturation of T-lymphocytes as well as by stimulation of lymphokines, lz The same mode of action has been applied successfully in treatment of chronic infections in general medicine.
These preliminary data on the successful treatment of HPV infection by a leukocyte ultrafiltrate have to be supported by additional research focusing on two topics: (1) What is the mode of action of this immunomodulating (ribonucleopeptide) substance and (2)  However, in the current stage of research, the use of the leukocyte ultrafiltrate investigated has to be limited to proven low-grade CIN-1 in order not to postpone adequate therapy of possible carcinoma.