Severe flare of genital warts after intralesional nonvalent HPV vaccine and development of multiple nodules at the sites of injection

Introduction

Genital warts are benign lesions, which present most commonly as skin colored or brownish papules or raised plaques often with a cauliflower appearance on the skin of the anogenital area. In most of the cases they are asymptomatic but occasionally may cause irritation or bleeding and most of all they can be emotionally distressing, and often require prolonged, time consuming and uncomfortable treatment. No effective treatment exists for the elimination of persistant genital warts and recurrences are common.

Different regimes have been suggested to prevent relapses including sinecatechins 15% ointment and imiquimod 5% cream after destructive treatment, claiming to treat subclinical warts, which are likely to have remained in or around the wound. ¹ The potential role of the HPV vaccine as a therapy or secondary prevention for anogenital warts has not yet been determined. A strategy of priming or boosting anti-HPV 6/11 responses with HPV vaccine could influence the persistence of HPV 6/11 infection and therefore the rate of disease recurrence. ² Based on this rational we tried the nonvalent HPV vaccine intralesionally in order to prevent relapses in two patients with recurrent disease.

Case 1

A 52 year old man had been suffering from genital warts for 15 years and had been submitted to various treatments, including cryotherapy, CO₂ laser, podophyllotoxin cream and solution, sinecathechins 15% cream and imiquimod 5% cream, which all resulted in relapses. He also used for 1 month imiquimod 5% cream three times/week, as a preventive treatment, which did not help. His disease improved over time with less lesions and recurrences but was still troublesome. The patient was circumsized and healthy and was HIV negative. We tried the nonvalent HPV vaccine intralesionally to prevent relapses and the nonvalent HPV vaccine (Gardasil 9, 0.5 ml) was injected on multiple sites on the prepuce and the shaft of the penis. After a week the patient developed multiple swollen, movable, non tender nodules (Figure 1(a)) on the sites of injection resulting in major discomfort and after 2 weeks he had a severe flare of his disease with more than 20 small lesions affecting the prepuce and the shaft of the penis. He was treated with CO2 laser. The nodules gradually improved after 1 month by 70% but did not disappear.OPEN IN VIEWER

Case 2

A 23 year-old healthy, non immunocompromized and HIV negative man, with 8 months history of an isolated, asymptomatic and indurated whitish plaque on the coronal sulcus of the penis, confirmed as genital wart histologically, did not respond to imiquimod 5% three times/week for 2 months and treatment with CO2 laser resulted in multiple relapses. The patient was treated once more with CO2 laser and the nonvalent HPV vaccine (Gardasil 9, 0.5 ml) was injected intralesionally to prevent relapses. One month after the combination treatment the lesion relapsed again but smaller. However, the patient developed four fleshy movable non-tender nodules on the sites of nonvalent HPV vaccine injection (Figure 2). He remains on follow up.OPEN IN VIEWER

Discussion

The treatment of anogenital warts including topical podophyllin, imiquimod, podophyllotoxin, sinecatechins, trichloroacetic acid, surgical excision, electrosurgery, cryosurgery, laser surgery, and intralesional immunotherapy, remains unsatisfactory, given that all are characterized by a high percentage of recurrences. On the other hand, there is no doubt that the implementation of HPV vaccines has produced a wide benefit for public health decreasing the incidences of HPV infections, AGWs, and HPV-related precancer cervical lesions. The effective prophylactic use of HPV vaccine has encouraged its use as a therapeutic method for recalcitrant warts, without an established mechanism of action. It has been postulated that the vaccine IgG neutralizing antibodies, much stronger than those induced by natural infection, are directed against HPV L1 capsid, thus reducing the manifestations of HPV infection. ³ Two studies have assessed the efficacy of quadrivalent and nonvalent HPV vaccines as a treatment for genital warts under the three-dose intramuscular scheme, reporting complete response in 40% and 60% respectively with no recurrence.^4,5 On the other hand in two randomized controlled trials intramuscular HPV quadrivalent vaccine was not found to offer any benefit in preventing relapses.^6,7 HPV vaccine has also been tried intralesionally, the bivalent HPV vaccine 0.2 mL at 2 weeks intervals for a maximum of five sessions, ³ and the quadrivalent HPV vaccine 0.1 mL, three injections given at three weekly intervals, ⁸ offering partial or complete remission in 63% and 83,3% of patients respectively. Based on those observations we tried the vaccine intralesionally on the patients’ genital area of frequent relapses. Unfortunately, the first patient did not achieve a remission but instead he had a severe flare of his disease necessitating a destructive treatment like laser CO2. Both patients had a major discomfort from the multiple nodules they developed at the sites of injection.

No major adverse events, topical or systemic, are reported from studies using the HPV vaccine intralesionally and above all no patient has experienced a severe flare immediately after topical vaccination. To our opinion intralesional use of HPV vaccine should be abandoned.