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Combined surgery and cidofovir is an effective treatment for genital warts in HIV-infected patients

Orlando, Giovanna; Fasolo, Maria Michela; Beretta, Rosangela; Merli, Stefania; Cargnel, Antonietta

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From the II Department Infectious Diseases, STD Service, L Sacco Hospital, Milan, Italy.

Requests for reprints to: G. Orlando, II Divisione Malattie Infettive, Osp L Sacco, Via GB Grassi 74, 20157 Milano, Italy.

Received: 13 July 2001;

revised: 21 September 2001; accepted: 26 September 2001.

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Abstract

Objective: To evaluate the efficacy of surgical-cidofovir (SCT), surgical (ST) and cidofovir (CT) treatment of genital warts in HIV-infected patients.

Design: Open randomized prospective pilot study.

Setting: Outpatients attending the sexually transmitted disease service of the II Dept of Infectious Diseases, L Sacco Hospital, Milan-Italy.

Patients: Consenting HIV-positive patients with anal–genital warts recruited from January 2000 to March 2001.

Interventions: Three treatment arms: surgical excision by electrocautery, topical 1% cidofovir-gel (5 days per week, maximum 6 weeks) and electrocautery–cidofovir treatment with 1% cidofovir-gel applied within 1 month of surgical treatment (5 days per week for 2 weeks).

Main outcome measures: Rate of wart clearance and time and rate of relapses within a 6-month follow-up period.

Results: Complete response was achieved in 93.1% of 29 patients treated by ST, 76.2% of 26 treated by CT and in 100% of 19 patients treated by SCT (P = 0.0033). The relapse rate in 49 patients followed-up was 73.68% in ST, 35.29% in CT and 27.27% in SCT patients (P = 0.018). Median time to relapses in ST patients was 66 days (Kaplan–Meyer, P = 0.0012). Human papillomavirus DNA was cleared in 52.63% of 19 patients evaluated. The rate of clearance of high risk and low risk genotypes was 0% and 57.14% 25% and 50% 100% and 71.42% in ST, CT and SCT patients, respectively.

Conclusions: A combination of surgical and medical treatment was most effective in clearing lesions completely and in reducing the relapse rate. Human papillomavirus DNA clearance can be attributed to the antiviral effect of cidofovir and could explain the low relapse rate observed. Larger studies are required to determine the most appropriate medical treatment for viral eradication after surgery.

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Introduction

The very high prevalence of genital warts in HIV-positive patients can be related to at least three factors: HIV and human papillomavirus (HPV) epidemiological synergism, the lack of appropriate immune mechanisms able to clear subclinically infected cells thus resulting in very low rates of spontaneous clearance, and the lack of effective treatment [1–4].

Sun et al. [1] reported that 20% of HIV-positive women maintained HPV during a 3–12-month period, compared with 3% of HIV-uninfected women. HIV seropositivity and lower CD4 cell counts were the strongest risk factors for HPV DNA persistence [1–2].

Recently, a wide-spectrum antiviral drug (cidofovir) that is active against HPV has been used successfully for the topical treatment of genital warts in HIV-positive patients [5–11] but its use is limited by a high rate of adverse local events and the long-term treatment required to achieve complete wart clearance. The surgical approach to treatment is poorly effective in the long-term: there is a high recurrence rate due to the persistence of HPV-infected cells that remain uncleared by the host immune system [1,4,12–14]. We attempted a combined surgical–medical approach to the treatment of genital warts in HIV-positive patients, and evaluated its short- and long-term effectiveness.

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Patients and methods

An open-randomized prospective pilot study design was used. HIV-positive patients with genital warts who were referred to the sexually transmitted disease service (II Department of Infectious Diseases, L. Sacco Hospital, Milan, Italy) from January 2000 to March 2001 were enrolled and assigned randomly to one of three treatment arms: surgical treatment (ST) by electrocautery, 1% cidofovir gel (CT) self-applied for 1–2 h 5 days per week (for a maximum of 6 weeks) and combined surgical–cidofovir treatment (SCT) consisting of electrocautery followed within 1 month by 1% cidofovir gel self-applied for 1–2 h for 5 days per week for 2 weeks. Cidofovir gel (1%) was obtained by adding 2 ml (150 mg) of vistide to beeler base cream (15 cetylalcohol, 1 g white wax, 10 g propylenglicole, 2 g sodium laurylsulfate, 72 g water). All subjects gave written informed consent for participation in the study. The use of cidofovir for the treatment of genital warts in HIV infected subjects received Ethical Committee's authorization.

Patients were followed-up weekly during treatment and then monthly for 6 months and were counselled to prevent transmission of both HPV and HIV by practising protected sexual intercourse. The sum of the lesions’ sizes (mm), number and anatomic localization gave the lesion score. Complete response, partial response and treatment failures were defined as end-of-treatment score = 0, < 50% and > 50% of the baseline respectively. The Digene test (Digene specimen collection kit, Hybrid Capture System HPV DNA Assay, Digene, Gaithersburg, Maryland, USA) for typing HPV in high-risk (HR) of neoplastic evolution and low-risk (LR) genotypes was performed at baseline and after the end of treatments in a subset of patients (to limit the cost of analysis).

Rate and time of relapses during a 6-month period were defined as the reappearance of lesions in the same anatomic area after a complete response. Baseline evaluation of HIV infection (Centers for Disease Control and Prevention stage, viral load, CD4 cell counts) and antiretroviral treatments were recorded.

Clinical end-points were the response to treatment, and the time and number of relapses within 6 months. Short- (at the end of any treatment arm) and long-term (at the end of the 6-month follow-up period) clinical efficacy was compared across treatment groups by the chi-squared test and Fisher's exact test; the time of recurrences was determined by Kaplan–Meier estimates.

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Results

A total of 74 patients were enrolled (53 males and 21 females) and randomly assigned to ST (29 patients), CT (26 patients) and SCT (19 patients) groups. Warts lesions were located in the perianal area (15 patients), the vulval area (15 patients), on the perineum (three patients) and on the penis (42 patients). Thirty patients were classified as HIV stage III according to CDC criteria, 19 as stage IVC2 and 25 as stage IVC1 or IVD. The mean age was 33.4 years (range, 24–41 years). Mean baseline CD4 cell counts were 264.9 × 106/l (range, 25 × 106–839 × 106/l) and HIV RNA was detectable in 47 patients (mean viral load, 34.576 copies/ml). Fifty patients were on antiretroviral treatment. The mean lesion score was 76.57 (range, 5–292). HR HPV genotypes were found in 25 out of 52 patients (48.07%), and LR HPV genotypes were found in 31 out of 52 (59.61%); in 12 patients hybrid capture test was negative for both HR and LR HPV genotypes and in 16 a co-infection with HR and LR HPV genotypes was observed. There were no differences among treatment arms in terms of age, baseline CD4 cell counts, lesion score and prevalence of HR, LR or HR/LR HPV genotypes.

In the intent-to-treat analysis of short-term efficacy complete response was achieved more frequently in surgically treated patients (both ST or SCT): 93.1% ST, and 100% SCT versus 76.2% CT (P = 0.033); in two ST patients complete response was not achieved because of non-compliance. Mild local erosions were observed after 1% cidofovir application in 42.3% of CT and 31.57% of SCT; in three cases drug was definitively stopped. Among 66 patients who achieved complete response, 47 completed the 6 months follow-up. Recurrence rate was 73.68% (14/19) in the ST group, 35.29% (6/17) in the CT group and 27.27% (3/11) in the SCT group (P = 0.018). The relative-risk of recurrences in the ST group was 2.29 (95% confidence interval, 1.256–4.184). Recurrence rate was independent from baseline CD4 cell count (P = 0.35), antiretroviral treatments (P = 0.75) and presence of HR HPV genotypes (P = 0.056).

Times of recurrences are significantly different in the Kaplan–Meier evaluation by treatment group (P = 0.0012) (Fig. 1); in ST patients the median time to recurrence was 66 days.

Fig. 1
Fig. 1
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In 19 patients HPV DNA was investigated at the end of treatment (five in the ST group, seven in the CT group and seven in the SCT group). In 10 (52.63%) patients HPV DNA was no longer detectable. Clearance rate was independent of baseline CD4 cell count (t, 0.66). HR HPV genotypes were cleared in five out of 12 (41.66%) patients and LR genotypes in 10 out of 14 (71.42%). The rate of HR HPV genotype clearance was 0% 57.14% 25% and that of LR HPV genotype clearance was 50% 100% and 71.42% in the ST, CT and SCT groups, respectively (Fig. 2).

Fig. 2
Fig. 2
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Discussion

Currently available surgical treatments for genital warts (cryotherapy, laser vaporization, excision or electrocautery) are rapidly effective [15] but relapses are very common (52.38% in HIV-positive patients versus 8.33% in HIV-negative patients among 743 patients over a 6-month period; unpublished observations). The effectiveness of topical cidofovir treatment for anogenital warts in HIV-infected patients had been reported previously [8,9–11] and the results of our open randomized trial shows that the combination of a surgical approach and medical treatment is the most effective in the short- and the long-term, rapidly achieving complete local clearing of the lesions and significantly reducing recurrence rate after treatment. Cidofovir, a nucleoside analogue of deoxycytidine monophosphate and suitable for the treatment of cytomegalovirus retinitis in AIDS patients, showed its effectiveness in HPV infections by the inhibition of DNA synthesis and induction of DNA fragmentation in HPV-infected cells [16,17]. In addition to its antiviral effect cidofovir acts also as an anti-proliferative agent thus explaining the reduction in epithelialization and the excoriations frequently observed during treatment. These were slightly more frequent in CT than in SCT patients (42.3% of CT and 31.57% of SCT) in our experience. As spontaneous viral clearance is rarely observed in immunocompromised patients, the rate of HPV DNA clearance observed can be attributed to the antiviral effect of the drug and this is more prominent in the CT group, probably as the result of the longer course needed. The prolonged treatment could in part explain the lower, even if not statistically significant, relapse rate observed in this group than in SCT patients. Data on HPV DNA clearance rate after treatment are limited and no definitive hypothesis can be argued but the high association between HPV DNA clearance and long-term cure is noteworthy. In summary, a combined surgical–medical approach resulted in the best outcome both in the short- and the long-term and could represent a rational treatment of genital warts in immunocompromised patients. Larger studies are required to define the most appropriate medical treatment period after surgery, and this will probably be longer than that used to achieve viral eradication.

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References

1. Sun XW, Kuhn L, Ellerbrock TV. et al. Human papillomavirus infection in women infected with the human immunodeficiency virus. N Engl J Med 1997, 337: 1343–1349.

2. Jay N, Moscicki A-B. Human papillomavirus infections in women with HIV disease: prevalence, risk, and management. AIDS Reader 2000, 10: 659–668.

3. Delmas MC, Larsen C, van Benthem B. et al. Cervical squamous intraepithelial lesions in HIV-infected women: prevalence, incidence and regression. AIDS 2000, 14: 1775–1784.

4. Wasserheit JN. Epidemiological synergy: interrelationships between HIV infection and other sexually transmitted diseases. Sex Transm Dis 1992, 19: 61–77.

5. Hengge UR, Tietze G. Successful treatment of recalcitrant condyloma with topical cidofovir. Sex Transm Infect 2000, 76: 143.143.

6. Schurmann D, Bergmann F, Temmesfeld-Wollbruck Bgrobusch MP, Suttorp N. Topical cidofovir is effective in treating extensive penile condylomata acuminata. AIDS 2000, 14: 1075–1076.

7. Snoeck R, Noel JC, Muller C, De Clercq E, Bossens M. Cidofovir, a new approach for the treatment of cervix intraepithelial neoplasia grade III (CIN III). J Med Virol 2000, 60: 205–209.

8. 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.

9. Douglas J, Corey T, Tyring S, et al. A phase I/II study of cidofovir topical gel for refractory condyloma acuminatum in patients with HIV infection. Presented at Fourth Conference on Retroviruses and Opportunistic Infections. Washington DC, January 1997 [poster #334].

10. Snoeck R, Bossens M, Parent D, et al. A double-blind, placebo-controlled study of cidofovir gel for human papillomavirus (HPV)-associated genital warts. 11 th International Conference on Antiviral Research. San Diego, April 1998. [abstract #27].

11. Mattelli A, Beltrame A, Graifemberghi S. et al. Efficacy and tolerability of topical 1% Cidofovir cream for the treatment of external anogenital warts in HIV-infected persons. Sex Transm Dis 2001, 28: 343–346.

12. Minkoff H, Feldman J, DeHovitz J. et al. A longitudinal study of human papillomavirus carriage in human immunodeficiency virus-infected and human immunodeficiency virus-uninfected women. Am J Obstet Gynecol 1998, 178: 982–986.

13. Hankins C, Coutlee F, Lapointe N, et al. Persistence of human papilloma virus (HPV) infection in HIV positive and HIV negative women. XII International Conference on AIDS. Geneva, June 1998 [abstract 22303].

14. Andieh L, Munoz A, Vlahov D, et al. Cervical neoplasia and the persistence of HPV infection in HIV + women. Sixth Conference on Retroviruses and Opportunistic Infections. Chicago, January–February 1999 [abstract 463].

15. Edward J, Zabawski,Jr. A review of topical and intralesional cidofovir. Dermatol Online J 2000, 6:3.

16. Andrei G, Snoeck R, Piette J, Delvenne P, De Clercq E. Antiproliferative effects of acyclic nucleoside phosphonates on human papillomavirus (HPV)-harbouring cell lines compared with HPV-negative cell lines. Oncol Res 1998, 10: 523–531.

17. De Clercq E, Andrei G, Balzarini J. et al. Antitumor potential of acyclic nucleoside phosphonates. Nucleosides Nucleotides 1999, 18: 759–771.

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Keywords:

Papillomavirus; treatment; HIV; cidofovir; sexually transmitted disease

© 2002 Lippincott Williams & Wilkins, Inc.

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