MATTEELLI, ALBERTO MD*; BELTRAME, ANNA MD*; GRAIFEMBERGHI, SEVERO MD†; FORLEO, MARIA ANTONIETTA MD*; GULLETTA, MAURIZIO MD*; CIRAVOLO, GIUSEPPE MD‡; TEDOLDI, SIMONA MD*; CASALINI, CATIA MD* AND; CAROSI, GIAMPIERO PhD*
From the Clinics of *Infectious and Tropical Diseases, †Dermatology, and ‡Obstetrics and Gynaecology, University of Brescia, Brescia, Italy
This study was approved by the Institutional Review Board of the Spedali Civili, Brescia, and written informed consent was obtained from each patient. The study drug was provided complimentarily by Pharmacia Upjohn.
Reprint requests: Alberto Matteelli, MD, Clinic of Infectious and Tropical Diseases, Piazza Spedali Civili, 1, 25125 Brescia, Italy. E-mail: firstname.lastname@example.org
Received for publication August 10, 2000, revised November 7, 2000, and accepted November 16, 2000.
HUMAN PAPILLOMAVIRUS (HPV), the most common viral sexually transmitted disease (STD) in the world, is the etiologic agent that causes anogenital warts. 1 The prevalence of anogenital warts is increased in patients infected with HIV-1, and poor host immune control results in extensive lesions, reduced treatment response, and higher relapse rate. 2,3
Current treatment options are unsatisfactory in both HIV-infected and uninfected subjects because of high relapse rates. Such options include cryotherapy, surgical excision, electrocautery, laser therapy, and antimitotic agents (podophyllin, podophyllotoxin, trichloroacetic acid). All these methods are unrewarding mainly because they remove warty tissue but often fail to eradicate subclinical disease and latent virus. 4
A new compound of the nucleoside phosphonates class, cidofovir, the cytosine analog (S)-1-[3-hydroxy-2-(phosphonyl-methoxypropyl)] cytosine (HPMPC, Vistide), offers antiviral and antiproliferative activity against a broad range of DNA viruses including herpesviruses, adenoviruses, and poxviruses. 5 A topical gel preparation of cidofovir provided significant benefits in the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. 6 Cidofovir shows in vitro and in vivo activity against HPV. 7,8 It currently is available for intravenous administration only, to treat cytomegalovirus retinitis in patients with AIDS. The effective use of topical cidofovir for the treatment of anogenital warts in HIV-infected patients has been suggested in a limited number of cases. 9–12
A randomized, placebo-controlled, single-blind pilot study on the efficacy and tolerability of topical 1% cidofovir cream for the treatment of external anogenital warts in HIV-infected patients was conducted.
Men and women 18 years of age or older with a laboratory-confirmed diagnosis of HIV infection and a clinical diagnosis of external anogenital warts established by physical examination were screened for participation in this study. Most were patients who had relapsed after surgery. Eligible patients were those able to give signed, informed consent, and to use condoms during the treatment and follow-up period. They had to be free of signs and symptoms associated with other HIV-related opportunistic infections and neoplasms at the time of enrollment. Patients were ineligible for the study if they had impaired renal function, were pregnant, or had received chemical or surgical therapy for their anogenital warts in the previous 2 months.
Study Design and Treatment
A randomized, placebo-controlled, single-blind pilot study design was used. Eligible patients were randomized in a 1:1 ratio to 1% cidofovir cream or placebo (vehicle control) applied once daily on all external warts at bedtime 5 days a week for 2 weeks, followed by 2 weeks of observation. Open-label cidofovir cream was given at the end of the follow-up period to all the patients allocated to the placebo group. This design generated three groups for the analysis: patients randomized to 1% cidofovir cream (group A), patients randomized to placebo during the first 4 weeks of the study (group B), and patients of the placebo group receiving 1% cidofovir cream after the first 4 weeks of the study (group C). Cidofovir was formulated in an aqueous cream containing Vaseline, paraffin, cetastearilic alcohol, sodium monobasic phosphate, and cetomacrol (Essex base cream).
A clinical examination was performed at baseline and on days 7, 14 (end of treatment), and 28 (end of follow-up period). At each visit, the patients were monitored for safety by assessment of local skin reactions, other adverse events, and vital signs. Laboratory tests, performed at baseline and day 28, comprised full blood count, liver and renal function examinations, CD4 T-lymphocyte counts, and HIV viral load in the serum.
Efficacy was assessed on day 28. Wart clearance was assessed by comparison of baseline and posttreatment photographic documentation of the lesions by three independent clinicians blinded to the type of treatment. Treatment outcome was categorized as follows: no modification or worsening of the total wart area between baseline and end of the follow-up period, a reduction less than 25%, a 25% to 50% reduction, and a 50% reduction or more. No attempt was made to measure the total wart area or to enumerate the total number of warts because most patients had very extensive lesions.
Statistical analysis was performed with the Epi Info (Centers for Disease Control and Prevention). Categorical data were analyzed using the χ2 test with Mantel-Haenszel stratified analysis.
In this study, 12 patients (6 men and 6 women) were enrolled and evaluated for efficacy and tolerability. The mean age of patients was 32.8 years (range, 25–39 years). Eight patients were in HIV class A, three in class B, and one in class C. The median baseline CD4 cell count was 142/mm3 (range, 24–974/mm3), and the mean baseline HIV-RNA was 17,225 copies/ml (range, undetectable–129,000 copies/ml). The warts were located in the perianal (n = 8), vulvar (n = 5), perineum (n = 4), and penile (n = 3) areas. Some patients had warts in more than one location. Nine patients (75%) had been treated previously for anogenital warts. Patients in the 1% cidofovir cream group (n = 6) and the vehicle cream treatment group (n = 6) had similar demographic variables and disease-related characteristics at baseline (Table 1).
In the intent-to-treat analysis of efficacy, 18 treatment rounds were evaluated: 12 with cidofovir (groups A and C) and 6 with placebo (group B). A total wart area reduction of more than 50% was achieved significantly more frequently by cidofovir (groups A and C together: 7/12, 58%) than by placebo (group B: 0/6) (P = 0.02) (Table 2). The seven patients who achieved a total wart area reduction of more than 50% were equally distributed in groups A (n = 3) and C (n = 4). Male patients had a significantly higher probability (6/6) of clearance after cidofovir treatment (groups A and C) than female patients (1/6) (P = 0.003). The clearance rate also was greater for penile (3/3) than for vulvar warts (0/5) (P = 0.01). The effectiveness of treatment was independent of HIV disease stage, CD4 counts, HIV-RNA burden, and type of antiretroviral treatment.
Local reactions (signs or symptoms) were reported by 10 of the 12 patients treated with cidofovir, as compared with 0 of the 6 patients in the placebo group (P < 0.001) (Table 2). The most commonly reported symptom was local itching (7/12), and the most frequently observed local reaction was moderate to severe erosion of the mucosa (5/12). Cidofovir treatment was discontinued after the first week of therapy by 4 of the 12 patients (33%) because of severe mucosal erosions. Three of these patients had a total wart area reduction of more than 50% at the end of the follow-up period. In one female patient, mucosal erosion was complicated by vulvar folliculitis and urinary tract infection.
No signs of systemic adverse events were observed in patients treated with cidofovir cream. Hematochemical parameters, including renal function, remained stable throughout the treatment period.
The efficacy of cidofovir for the treatment of anogenital warts in the HIV-infected patient had been reported previously. 9–12 The results of this randomized, placebo-controlled, pilot study demonstrate that 1% cidofovir cream is more effective that vehicle cream in clearing anogenital warts initially in this population. The results from the cidofovir-treated group, which show a partial (>50% decrease) response rate of 58%, are consistent with those of Douglas et al. 10 A lower efficacy of the cream was observed on vulvar than on anal warts, a finding also reported by others. 9 In previously published studies, the topical preparations of cidofovir used for treatment were prepared in gel vehicles. The cream preparation used in this study is absorbed readily by the mucosal surface, but less effectively by intact skin than gel preparations. Because mucosal involvement usually was larger in anal warts than in vulvar warts, a difference in drug absorption may explain the effect of wart location on efficacy. The same mechanism likely justifies the observed effect of gender on clearance rate.
Remarkably, cidofovir was effective in a very short course of 10 days of treatment over a 2-week period. The short period required to achieve effective wart clearance is important because it is likely to ensure increased patient adherence and reduced costs. Topically applied imiquimod, a novel immune-response modifier, has been reported to reduce the wart area in HIV infected subjects, but the drug needs to be applied for at least 16 weeks. 13
Local reactions to 1% cidofovir cream were common. Local toxicity occurred almost invariably at the mucosal level, whereas the skin remained unaffected. Mucosal erosion was observed in almost half of the patients, as reported also in other studies. 11 In one third of all cidofovir-treated patients, mucosal erosions were severe enough to warrant therapy discontinuation. However, erosions healed completely in approximately 7 days in all patients, and no scarring occurred. Erosions could lead potentially to an increased risk of HIV transmission by increasing the HIV load in genital secretions in a manner similar to that demonstrated for ulceration of the cervix after surgical treatment of cervical intraepithelial lesions. 14 While awaiting more information on this possible downside of topical cidofovir treatment, potential patients should be counseled extensively not to engage in unprotected sexual relations during and shortly after treatment.
The pharmacokinetic properties of topical cidofovir preparations in humans are unknown. However, no systemic adverse reactions were observed, and such reactions after topical or intralesional administration of cidofovir have not been reported so far. 7 These observations are consistent with the hypothesis that absorption of cidofovir from the skin and mucosae is very limited. It seems that erosions of the mucosae do not significantly increase absorption of the drug.
Current treatment regimens for anogenital warts usually do not eradicate HPV from the epithelia. Relapses in the immunocompromised host are particularly common, showing the importance of the immune system in controlling this disease. 15 Cidofovir acts as an antiviral and antiproliferative agent that may aim at viral eradication by exposing a larger number of infected cells in the epithelia surrounding the wart than excisional methods. Because HPV does not use a virally encoded polymerase to replicate its genome, cidofovir’s mechanism of action probably consists of a cytotoxic rather than a cytostatic effect because it specifically inhibits human DNA synthesis and the apoptotic response, which are restricted to infected cells. 8 The occurrence of extensive erosions in a high proportion of treated patients seems to support this hypothesis.
At this writing, no satisfactory therapy exists for anogenital warts. Cidofovir, a new antiviral drug active against HPV, holds great promise The current randomized, controlled pilot study has demonstrated that a 2-week regimen with cidofovir cream 1% is effective in clearing anogenital warts initially in HIV-infected subjects. This study did not aim at measuring the recurrence rate of warts after discontinuation of treatment, although this was recognized as a critical issue in the treatment of anogenital warts, especially in immunocompromised patients. It is well known that the difficulties in eradicating HPV infection from the epithelia and the persistent immunosuppression in the HIV-infected subject are responsible for a high relapse rate in this population. There is concern that the short regimen used in this study, although effective in the initial clearance, may not lead to virus eradication, thus failing to prevent relapses. Larger studies and a longer follow-up period are required to establish the recurrence rate after treatment discontinuation, and to define the appropriate vehicle, dose, and frequency of topical treatment with cidofovir.
1. Gerbase AC, Rowley JT, Mertens TE. Global epidemiology of sexually transmitted diseases. Lancet 1998; 351 (suppl 3): 2–4.
2. Lowy DR, Kirnbauer R, Sciller JT. Genital human papillomavirus infection. Proc Natl Acad Sci USA 1994; 91: 2436–2440.
3. Fennema JS, van Ameidjden EJ, Coutinho RA, et al. HIV, sexually transmitted diseases, and gynecologic disorders in women: increased risk for genital herpes and warts among HIV-infected prostitutes in Amsterdam. AIDS 1995; 9: 1071–1078.
4. Beutner KR, Reitano MV, Richwald GA, Wiley DJ, the AMA Expert Panel on External Genital Warts. External genital warts: report of the American Medical Association consensus conference. Clin Infect Dis 1998; 27: 796–806.
5. De Clercq E. Therapeutic potential of cidofovir (HPMPC, Vistide) for the treatment of DNA virus (e.g., herpes-, papova-, pox- and adenovirus) infection. Verh K Acad Geneeskd Belg 1996; 58: 19–49.
6. Lalezari J, Schaker T, Feinberg J, et al. A randomised, double-blind, controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. J Infect Dis 1997; 176: 892–898.
7. Zabawski EJ Jr, Cockerell CJ. Topical and intralesional cidofovir: a review of pharmacology and therapeutic affects. J Am Acad Dematol 1998; 39: 741–745.
8. Johnson JA, Gangemi JD. Selective inhibition of human papillomavirus-induced cell proliferation by (S)-1-[3-hydroxy-2-(phosphonomethoxy)-propyl]cytosine. Antimicrob Agents Chemother 1999; 43: 1198–1205.
9. Snoeck R, Van Ranst M, Andrei G, et al. Treatment of anogenital papillomavirus infections with an acyclic nucleoside phosphonate analogue. N Engl J Med 1995; 333: 943–944.
10. Douglas J, Corey L, Tyring S, et al. A phase I/II study of cidofovir topical gel for refractory condyloma acuminatum in patients with HIV infection. In: Programme and Abstracts of the 4th Conference on Retroviruses and Opportunistic Infections, Washington, DC, 1997, poster 334.
11. Orlando G, Fasolo MM, Beretta R, et al. Intralesional or topical cidofovir (HPMPC, vistide) for the treatment of recurrent genital warts in HIV-1 infected patients. AIDS 1999; 13: 1978–1980.
12. Hengge UR, Tietze G. Successful treatment of recalcitrant condyloma with topical cidofovir. Sex Transm Inf 2000; 76: 143.
13. Gilson RJC, Shupack JL, Friedman-Kien AE, et al. A randomised, controlled, safety study using imiquimod for the topical treatment of anogenital warts in HIV infected patients. AIDS 1999; 13: 2397–2404.
14. Lawn SD, Subbarao S, Wright TC, et al. Correlation between human immunodeficiency virus type 1 RNA levels in the female genital tract and immune activation associated with ulceration of the cervix. J Infect Dis 2000; 181: 1950–1956.
15. Vernon SD, Holmes KK, Reeves WC. Human papillomavirus infection and associated disease in persons infected with human immunodeficiency virus. Clin Infect Dis 1995; 21 (suppl 1): S121–S124.