A randomized trial of immunotherapy

for persistent genital warts

Human Vaccines & Immunotherapeutics 8:5, 623–629; May 2012

• Genital warts are caused by infection with human papillomavirus type 6 (HPV6) or less commonly the closely related HPV 11.

• While benign, these lesions commonly persist, with less than half of immunocompetent patients resolving infection within six months.

• Despite use of destructive therapies including electrocautery, cryotherapy, or application of podophyllotoxin or trichloroacetic acid, disease recurrence is common.

• However, generation of specific immunity to papillomavirus proteins appears important for clearance, as immunosuppressed individuals with impaired cell mediated immunity clear genital warts more slowly, and more commonly have recurrence after treatment.

• Therefore a randomized placebo controlled trial was undertaken to establish whether VLP immunotherapy could educe the recurrence of genital warts following locally destructive therapy

Method • Eligible subjects were those 18 y or over presenting with visible

external genital wart disease of at least three months duration and treated with destructive therapy on at least one prior occasion that in the opinion of the treating physician could be removed by a single treatment course with a destructive therapy.

• Subjects were eligible if they were not immunosuppressed, had no other anogenital disease requiring treatment, and consented to both further destructive treatment and experimental immunotherapy.

• Patients were recruited and treated at two sexual health clinic in

Brisbane, Australia and at two hospital in Wenzhou, China. Demographics of recruitrd patients are shown in Table 1.

• Randomization and masking. Consecutive patients attending the participating clinics for treatment of genital warts were offered participation if they fulfilled the wart related entry criteria, and were then screened for disqualifying conditions including abnormal hematology or biochemistry, a recent vaccination or evidence of immunosuppression.

• Immunotherapy was allocated to eligible patients sequentially by randomization number using consecutively numbered vials of stated dose, within which placebo vials were included in a predefined sequence generated by random number table, to which the data monitors, patients and investigators remained blinded until database lock.

• Procedures. The immunotherapy consisted of 1, 5 or 25 µg of HPV6b VLPs suspended in 1 ml of 0.9% NaCl without adjuvant or preservative.

• Wart destructive therapy was administered according to the current standard wart treatment at each trial site, with all visible disease treated.

• At the same visit the first dose of coded vaccine or placebo was administered by intramuscular injection.

• Four weeks later a second dose of vaccine or placebo was administered.

• After four more weeks disease status was assessed

• Warts were assessed at each visit by magnification assisted visual inspection and recurrence assessed with reference to photographs and chart drawings

Statistical analysis. • The predefined efficacy outcome measures specified in the

protocol were disease status, classified as complete responder (CR) if there was no visible disease, a partial responder (PR) if total wart area was , >50% of the original pre-treatment area, and non-responder (NR) if the area was >50% of the original area, and the percentage reduction of wart disease area from baseline.

• VLP immunotherapy at the two higher doses (5 µg and 25 µg) was associated with less disease recurrence two months after treatment for patients recruited to the Australian trial site, as assessed by number of responding subjects ,and by percentage reduction in disease from pre-treatment. No significant effect of any dose of VLP immunotherapy was observed at the Chinese site.

• The extent of presenting disease was significantly less at the Chinese site.

• Disease duration prior to treatment was significantly shorter for Chinese than for Australian subjects.

• Primary destructive therapy at the Chinese site was exclusively cautery, whereas other options were also used at the Australian site.

• Different treatment choices gave different probabilities of disease recurrence. Choice of treatment was associated with duration of disease, but not with initial lesion area.

• Poorest outcome without VLP immunotherapy was seen for patients treated with cryotherapy and in this group there was a significant association between dose of VLP immunotherapy and better disease outcome

• Recipients of 5 µg or more of VLP immunotherapy and treated with other than trichloroacetic acid (TCA) or cautery, had significantly shorter duration of disease when compared with similarly treated patients receiving lower VLP immunotherapy doses.

• This study demonstrates that administration of two doses of 5 µg or more of a VLP immunotherapy based on the L1 capsid protein of HPV6 was associated with a significantly reduced rate of recurrence of genital warts after conventional destructive therapy, and reduced burden of wart disease.

• Analysis of the results suggested that the benefit of VLP immunotherapy was not uniformly observed, but rather was restricted to patients treated with cryotherapy or podophyllotoxin, which on their own were relatively ineffective.

• The current study failed to observe an association of recurrence with subject age or gender, or with the extent of disease at presentation, as has been observed in previous studies.

• Analysis of the results suggested that the benefit of VLP immunotherapy was greater in those with shorter disease duration.

• In conclusion, immunotherapy warrants further trial as part of the management of recurrent genital warts being treated with destructive therapy, as a possible strategy to reduce the failure rate of primary destructive therapy

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