Efficacy of imiquimod on external anogenital warts in HIV-infected patients previously treated by highly active antiretroviral therapy.

Abstract

The incidence of human papillomavirus (HPV)- induced anogenital lesions in HIV-infected patients is higher than in the general population [1–3], with few long-lasting responses and frequent relapses after common destructive therapies (podophyllin or podophyllotoxin, cryotherapy, carbon dioxide laser, or surgical excision). Poor immune control in these patients is believed to contribute to the poor treatment response and rapid relapse [4]. Highly active antiretroviral therapy (HAART) reduces the incidence of most opportunistic infections by decreasing the plasma HIV viral load, increasing CD4 cell counts and inducing partial immune restoration [5]. The outcome of HPV infection seems to be less improved than other opportunistic infections in HIV-infected patients treated with HAART [6]. Imiquimod 5% cream has recently been approved for the treatment of external anogenital warts in immunocompetent patients, in whom it induces complete responses in 40–70% of patients. In HIV-infected patients not treated by HAART, imiquimod seemed to induce complete responses in only 11% of patients (versus 6% on placebo) and over 50% partial responses in 38% of patients [4]. We have evaluated the efficacy and tolerance of imiquimod 5% cream applied topically for at least 3 months to treat recalcitrant anogenital warts in four HIV-infected patients with good control of HIV infection previously achieved by HAART. Observations Four male HIV-infected patients (aged 38 ± 7 years) were admitted for long-standing anogenital warts (three patients) and penile intra-epithelial neoplasia caused by HPV 33 (one patient). They had all been on HAART for 18.1 ± 12.5 months, with very low or undetectable viral loads and median CD4 cell numbers increasing from 133 ± 136 × 109/l before HAART to 668 ± 350 × 109/l at the beginning of imiquimod treatment (see Table 1). In all patients the warts were numerous, heavily infiltrated (tumour-like in one patient) and were located on the penile skin (two patients), perianal and anal skin (one patient), or involving the whole anogenital area (one patient).Table 1: Patient characteristics. The warts had been present for 45 ± 52 months and persisted or rapidly recurred despite multiple local treatments (carbon dioxide laser, topical podophyllotoxin, keratolitics, cryosurgery, and surgical excision). The last destructive treatments were performed 1.5 month before imiquimod treatment, and were followed by a rapid recurrence in all patients. Imiquimod 5% cream was applied topically by patients themselves for 6–12 h a day, three times a week for 2.9 ± 1.8 months. Bi-dimensional measurements of each lesion (when possible) or of the whole affected area were performed before treatment and bimonthly thereafter. Imiquimod was well tolerated in one patient. Local irritation was mild in one patient, moderate in one patient, who interrupted imiquimod for 15 days, and very important in one patient, who definitely stopped treatment after 15 days. At the end of treatment, one complete response, two partial responses (80–95% clearing of lesions) and one treatment failure as a result of intolerance were observed. The median time to response was 2.5 months. During a follow-up period of 9 ± 5 months, the patient with the complete response stayed completely cleared of lesions; one of the two patients with a partial response had his lesions completely cleared, and the patient with the partial response who had interrupted his treatment for 15 days because of local irritation had his lesions first cleared and they then recurred. Re-treatment with imiquimod for another 12 weeks induced a complete response in this patient, with no recurrence after two additional years of follow-up. Discussion After common destructive therapies, rapid relapses of anogenital warts are frequent in HIV-infected patients [7]. In the only published randomized vehicle-controllelled trial, the responses of anogenital warts to imiquimod in HIV-infected patients not treated by HAART were low [4]. Neither time to recurrence after imiquimod treatment nor the impact of HAART on wart clearance could be evaluated in the trial. Very few studies assessed the clinical evolution of HPV infection on HAART alone, suggesting at least a moderate improvement of the HPV-induced condition [6,8]. In our patients the response to HAART was long-lasting, with rapid and important increases in blood CD4 cell counts. However, no substantial improvement of warts had been obtained after different destructive therapies before imiquimod treatment. Therefore we believe that the immune restoration obtained by HAART might result in the better efficacy of imiquimod on external anogenital warts in HIV-infected patients. We propose that topical imiquimod be associated with HAART only when good control of HIV infection has already been achieved. Of course, this new strategy should be evaluated by a properly designed vehicle-controlled double-blind study in order to assess the efficacy and the safety of imiquimod in this situation. Philippe Saiag Isabelle Bourgault-Villada Mira Pavlovic Caroline Roudier-Pujol