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Clinical: Original Papers

A randomized, controlled, safety study using imiquimod for the topical treatment of anogenital warts in HIV-infected patients

Gilson, Richard J.C.a; Shupack, Jerome L.b; Friedman-Kien, Alvin E.b; Conant, Marcus A.c; Weber, Jonathon N.d; Nayagam, Andrew T.e; Swann, Robert V.f; Pietig, Diane C.g; Smith, Michael H.g; Owens, Mary L.g the Imiquimod Study Group

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Abstract

Introduction

Genital human papillomavirus (HPV) infection is one of the most common sexually transmitted viral diseases[1]. The prevalence of external anogenital warts, the most frequent clinical manifestation of HPV infection, is increased in patients infected with HIV[2]. Poor host immune control in these patients often results in extensive and prominent lesions and contributes to the poor treatment response. The prevalence of HPV lesions in patients with AIDS has been reported to increase with progressive immunosuppression; whether this is related solely to impaired immune function or involves a direct interaction between the viruses is unclear[3].

Numerous treatment modalities are available to treat external anogenital warts including cryotherapy, surgical excision, electrocautery, laser therapy, podophyllin, podophyllotoxin, and trichloroacetic acid. Many of these therapies cannot be self-administered, require multiple clinic visits, local anesthesia, and may cause bleeding and pain, all of which contribute to both patient and physician dissatisfaction[4,5]. Until recently, interferon (IFN) alpha has been the only immune-based therapy; however, its use has been limited by side effects, cost, and routes of delivery. The primary goal of most of these treatments, other than with IFN-agr;, has been physical removal or cytodestruction of the clinically apparent wart tissue. Often, however, subclinical and/or latent HPV infection remains within the epidermis. Therefore, it is not surprising that there is a high rate of recurrence of anogenital warts following such interventions, particularly in immunosuppressed patients[4].

Studies have shown that untreated or placebo-treated anogenital warts can spontaneously regress[5,6]. While the mechanism of regression has not been fully elucidated, there does appear to be a direct relationship between spontaneous clearance of warts and activation of cell-mediated immunity (CMI)[7,8]. An enhanced CMI response has been associated with IFN-agr; treatment in several animal models, as well as in patients with anogenital warts[9-11].

Recently, imiquimod 5% cream (Aldara, 3M Pharmaceuticals, St Paul, Minnesota, USA) became available in several countries as a patient-applied therapy for the treatment of external anogenital warts. A novel immune response modifier, imiquimod has indirect antiviral and antitumor activity mediated through induction of IFN-agr;, tumor necrosis factor alpha (TNF-agr;) and other cytokines produced by cells primarily of the monocyte/macrophage lineage[12]. In clinical studies involving immunocompetent patients, imiquimod was shown to be safe and significantly more effective than vehicle (placebo) in clearing anogenital warts[13,14]. In addition, imiquimod-treated warts that cleared tended to remain clear during post-treatment follow-up of up to 12 weeks[14]. Treatment of external anogenital warts with imiquimod has been associated with significant increases in messenger RNA (mRNA) for IFN-agr;, IFN-γ, and 2′,5′ oligoadenylate synthetase, as well as significant decreases in viral copies of HPV DNA (genotypes 6 and 11) and in mRNA for HPV L1 in imiquimod-treated skin[15]. Immunologic activity was consistent with stimulation of a T helper type 1 (Th1) CMI response and not consistent with stimulation of a T helper type 2 (Th2) humoral response.

This report describes a randomized, double-blind, vehicle-controlled, multicenter, multinational study designed to assess the safety of imiquimod 5% cream when applied topically to external anogenital warts in HIV-infected patients; assessment of efficacy was a secondary objective.

Methods

Patient population

Males and females 18 years of age or older with a clinical diagnosis of external anogenital warts and a laboratory-confirmed diagnosis of HIV were screened for participation in this study. Eligible patients were required to have a minimum of two warts with a wart area totaling at least 10 mm2, a CD4 T lymphocyte count of ≥ 100 3 106 cells/l, hemoglobin ≥ 10 g/dl, granulocytes ≥ 1.5 3 109 cells/l, platelet count ≥ 75 3 109 cells/l, total bilirubin ≤ 26 μmol/l, aspartate aminotransferase (AST) and alanine transaminase (ALT) less than three times the upper limit of normal, creatinine ≤ 130 μmol/l, and a minimum Karnofsky score of 70. Patients with AIDS were eligible provided they were clinically stable for the 4 weeks prior to enrollment.

Patients were ineligible for the study if they had previously been treated with imiquimod; had a sexual or household partner who was currently being treated with imiquimod; were pregnant, lactating or less than 3 months postpartum or postabortion; or had class 2 or greater vaginal, vulvar, or cervical intraepithelial neoplasia. The presence of psoriasis, other dermatologic disease at the wart site, or more than six outbreaks per year of herpes genitalis precluded study participation. Patients were also ineligible if they had received IFN, IFN inducers, cytotoxic or investigational drugs, immunomodulators, topical acyclovir (aciclovir); or if they had received chemical or surgical wart therapy within 4 weeks of study initiation. Oral acyclovir and approved antiretroviral agents were permitted.

All patients provided written informed consent and the study was approved by the research ethics committee of each center.

Study design

Eligible patients were randomized to imiquimod 5% cream or vehicle cream at a 2 : 1 ratio, stratified for gender. Study medication was self-applied for 8 ± 2 h three times per week, (prior to normal sleeping hours, every other day followed by 2 consecutive days without treatment) for a maximum of 16 weeks.

Patients returned to the clinic every 2 weeks for 16 weeks or until their baseline warts (warts present at study entry that were treated with study medication) cleared, whichever occurred first. New warts that developed during treatment were eligible for treatment but were analyzed separately. Patients who experienced greater than 80% but less than 100% clearance of their baseline warts at the end of the 16-week treatment period were permitted to continue blinded treatment for an additional 8 weeks (extended treatment).

At clinic visits, patients were monitored for safety by assessment of local skin reactions and other adverse events, vital signs, laboratory tests (including CD4 T lymphocyte counts), and, where indicated, serum pregnancy tests. Wart clearance was assessed visually, by two-dimensional measurement of the wart area, and by photographic documentation.

Statistical methods

The primary objective of the study was to obtain data on the safety of topical imiquimod in HIV-infected patients. In consultation with the US Food and Drug Administration (FDA), the study was designed to enroll a minimum of 60 patients to be treated with imiquimod for at least 8 weeks; enrollment of at least 90 patients (2 : 1 randomization) was planned, to allow for dropouts. Wilcoxon rank sum tests were used to compare the treatment groups for changes in laboratory parameters, vital signs, and local skin reactions. A Fisher exact test compared the incidence of adverse events grouped by preferred terms between treatment groups. However, the study was not powered to show statistically significant differences in defined safety or efficacy parameters between treatment groups nor to demonstrate equivalence.

An independent safety review board comprised three physicians experienced in the treatment of HIV-positive/AIDS patients and otherwise not involved in the study who reviewed individual patient data in a blinded manner to assess the relationship of adverse events to study drug, underlying HIV disease, or associated treatments. All patients randomized were included in the safety analysis.

In the efficacy analyses, two populations were analyzed: intent-to-treat (ITT), defined as all patients who were randomized, and per-protocol (PP), defined as all patients who were randomized except those who withdrew from the study prior to completing 8 weeks of treatment for personal reasons, non-compliance, intercurrent illness, other (such as pregnancy), or were lost to follow-up. Patients discontinuing because of possible, probable, or definite drug-related adverse reactions were included in the PP analysis with their last observation carried forward. The proportion of patients achieving total wart clearance was compared between treatment groups using a Fisher exact test. A Wilcoxon rank sum test compared the percentage change in baseline wart area at the end of treatment between imiquimod-treated and vehicle-treated patients. A Spearman rank correlation test was used to assess the relationship between wart reduction and baseline CD4 T lymphocyte counts. No adjustments for multiple testing were done and all tests were assessed at a 0.05% significance level.

Results

The study enrolled 100 patients (97 males and three females) (Table 1) among eight sites in the United Kingdom and five sites in the United States. At entry, imiquimod-treated and vehicle-treated patients had similar median CD4 T lymphocyte counts, mean Karnofsky scores, and percentage in a particular AIDS classification group. Eight imiquimod-treated and three vehicle-treated patients were in HIV disease class C[16]. There was a statistically significant difference between treatment groups in terms of age and weight, but the differences were not considered clinically meaningful. The median duration since initial onset of warts (imiquimod 31.6 months, vehicle 30.6 months), median duration of the current episode of warts (imiquimod 12.0 months, vehicle 12.3 months), and the baseline median wart area (imquimod 48 mm2, vehicle 60.5 mm2) were also similar between the groups (Table 1). For those patients previously treated, the three most common previous wart therapies reported were podophyllin (imiquimod 62%, vehicle 46%), cryotherapy (imiquimod 54%, vehicle 54%), and electrocautery (imiquimod 28%, vehicle 14%). There were no statistical differences between the treatment groups for any of these variables.

Table 1
Table 1:
Patient characteristics.

Safety

For patients assigned to imiquimod, the median amount of 5% cream applied during the 16-week treatment period was 2476 mg (123.8 mg imiquimod), while for patients assigned to vehicle, the median amount of cream applied was 2450 mg. During the 16-week treatment period 46 patients (26 imiquimod, 20 vehicle) discontinued from the study, and during the 8-week extended treatment period one patient (imiquimod) discontinued (Table 2). Only two patients, one patient from each treatment group, discontinued from the study for reasons related to documented adverse events; both patients discontinued because of reactions at the application site. More patients discontinued from the vehicle group for ‚lack of therapeutic effect‚ and ‚lost to follow-up‚, although the difference was not statistically significant; some of those lost to follow-up may also reflect a lack of therapeutic effect. No patient was discontinued from the study for laboratory abnormalities.

Table 2
Table 2:
Reasons for discontinuation from study.

Local skin reactions

As certain types of local skin reaction are expected as a result of the pharmacologic action of imiquimod, these were recorded and analyzed separately from other adverse events. In the analysis of local skin reactions, only 92 patients had analyzable data; eight patients were lost to follow-up immediately after the initiation visit.

Erythema, erosion, and ulceration at the wart site and at remote sites (non-treated areas near the wart site where study cream may have come in contact with the skin) were the most frequently reported local skin reactions reported by the investigators; these were generally mild in intensity. Overall, specific local skin reactions at either the wart site (any reaction: imiquimod 45.1% and vehicle 36.7%) or at the remote sites (any reaction: imiquimod 16.1% and vehicle 10.0%) were seen more frequently in the imiquimod group than in the vehicle group (Table 3). However a statistical difference was not detected between treatment groups for local skin reactions, in contrast to prior studies[13,14].

Table 3
Table 3:
Frequency of most common investigator-reported local skin reactions by maximum reported severity.

Other adverse events

All 100 randomized patients were included in the analysis of other adverse events and concomitant medications because patients could report adverse events and medications at the initiation visit.

At least one adverse event was reported by 45 (69.2%) of the 65 imiquimod-treated patients and 23 (65.7%) of the 35 vehicle-treated patients. Thirty-four (52%) of the imiquimod-treated patients reported at least one moderate or severe adverse event compared with 23 (66%) of the vehicle-treated patients. The three most frequently reported adverse events were application site reactions (imiquimod 15.4% and vehicle 20%), diarrhea (imiquimod 18.5%, vehicle 5.7%), and herpes simplex infection (imiquimod 12.3%, vehicle 8.6%). The three most common application site reactions reported were pruritus, pain, and soreness at the wart site. Statistically significant differences in adverse events or in application site reactions between treatment groups were not detected.

A total of five patients experienced severe adverse events possibly or probably attributed to study drug. Of two patients assigned to vehicle, one experienced severe pain and one experienced severe pruritus at the wart site. Of three patients assigned to imiquimod, one experienced severe pain at wart site, one experienced severe pruritus and burning at the wart site and one required circumcision. The patient requiring circumcision experienced swelling and soreness of the prepuce and glans penis at the wart site, prompting discontinuation of study drug at week 20 during the extended treatment period. By 3 weeks after the end of the study, these reactions had resolved, but at 6 weeks stricturing of the foreskin was observed. Foreskin stricturing has been reported as a consequence of warts at this location[17].

Concomitant medications

Similar proportions of patients in both treatment groups received HIV/AIDS-related medications pre-study and during the study. Concomitant medications taken by more than 10% of patients during the study were trimethoprim/sulfamethoxazole (imiquimod 43%, vehicle 29%), fluconazole (imiquimod 19%, vehicle 9%), acyclovir (imiquimod 37%, vehicle 57%), zidovudine (imiquimod 22%, vehicle 29%), lamivudine (imiquimod 9%, vehicle 11%), metronidazole (imiquimod 11%, vehicle 3%) and erythromycin (imiquimod 11%, vehicle 6%).

Lamivudine, saquinavir, ritonavir, and indinavir were approved during the conduct of this study and were subsequently permitted as pre-study or concomitant medications. Nine patients (four in the imiquimod arm and five in the vehicle arm) initiated or added new antiretroviral agents during the study. The median wart area for these few patients actually increased by 13% (range: 28% decrease to 76% increase) at end of treatment compared with a median reduction of 14% (range: 100% decrease to 200% increase) for patients who did not initiate a new antiretroviral regimen during the study. Only three patients initiated protease inhibitor-containing regimens during the study.

Laboratory values, vital signs and physical examination

There were no clinically meaningful changes from baseline for hematologic and serum chemistry parameters between treatment groups over the course of the study. There were no clinically meaningful changes from baseline between treatment groups for blood pressure, pulse, respiration rate, and temperature. Physical examination data showed no clinically meaningful changes from baseline between treatment groups.

HIV disease progression

Progression of HIV disease was defined as the development of a confirmable new category B or C symptom and/or disease[16], or by having two consecutive CD4 T lymphocyte counts of < 200 3 106 cells/l during the study if a patient entered the study with a count of ≥ 200 3 106 cells/l. Possible events were reviewed by an independent review safety board in a blinded manner. No exacerbation of any patient‚s HIV/AIDS disease was attributed to treatment with imiquimod.

There were no clinically significant changes from baseline for median CD4 T lymphocyte counts between treatment groups over the course of the study. Progression of HIV disease occurred in three patients by clinical criteria and in three patients by CD4 criteria (five total; one patient was both a clinical and a CD4 progression). Clinical progressions included two new diagnoses of oral candidiasis (both entering the study as A2) and one esophageal candidiasis (entered the study as B2). CD4 cell progressions included one patient entering with a CD4 count of 210 decreasing to a minimum of 120 3 106 cells/l, one entering at 215 decreasing to a minimum of 159 3 106 cells/l (this patient also had a new diagnosis of oral candidiasis as listed above), and one entering at 214 decreasing to a minimum of 164 3 106 cells/l (this patient finished the study at 208 3 106 cells/l without institution of any antiretroviral therapy). All five patients received imiquimod 5% cream; however, with the 2 : 1 randomization, the frequency of progression was not significantly different from vehicle (P = 0.159, Fisher exact test).

Efficacy

Although the focus of this study was safety, the efficacy of imiquimod was also evaluated. Statistical analyses compared treatment groups with respect to the number of patients who cleared their baseline warts and the reduction in wart area over time during the treatment period.

Wart clearance

In the ITT analysis, seven (11%) of 65 imiquimod-treated patients and two (6%) of 35 vehicle-treated patients (P = 0.488) achieved total (100%) clearance of their baseline warts. In the PP analysis, seven (13%) of 53 patients in the imiquimod group and two (8%) of 25 patients in the vehicle group (P = 0.710) achieved total clearance. However, significantly more of the patients in the imiquimod group than in the vehicle group experienced a greater than 50% reduction in total wart area in both the ITT [imiquimod 25 of 65 (38%), vehicle five of 35 (14%); P = 0.013] and the PP analysis [imiquimod 25 of 53 (47%), vehicle five of 25 (20%); P = 0.026].

The percentage reduction in wart area over time was significantly (P < 0.05) better for imiquimod than for vehicle from week 6 through week 16. The median wart area, as a proportion of baseline, is plotted over time by treatment group in Fig. 1. There was no correlation between wart reduction at the end of treatment and baseline CD4 T lymphocyte counts for imiquimod patients (r = 0.15; P = 0.238, Spearman rank correlation test). Median wart reductions for imiquimod and vehicle patients with CD4 T lymphocyte counts of ≥ 500 3 106 cells/l were 79% (n = 7) and 0% (n = 5), respectively; 200-499 3 106 cells/l were 11% (n = 34) and 0% (n = 18) respectively; and < 200 3 106 cells/l were 41% (n = 24) and 0% (n = 12), respectively. Initiation of new antiretroviral therapy during the study was not associated with further reduction of wart area.

Fig. 1.
Fig. 1.:
Median wart area as a proportion of baseline (bars depict 1st and 3rd quartiles).

Only three imiquimod-treated patients and one vehicle-treated patient at the end of the 16-week treatment period entered the 8-week extended treatment period. Only one patient subsequently cleared his warts during this extended treatment period. No additional analysis was performed for these patients.

New warts

New warts (warts not present at the initiation visit) developed during the treatment period in 12 of 62 (19%) patients in the imiquimod group and seven of 30 (23%) patients in the vehicle treated group (P = 0.784). Although not statistically significant, three of 12 (25%) patients in the imiquimod group cleared their new warts compared with none of the seven (0%) patients in the vehicle group.

Discussion

HPV infection and anogenital warts can be difficult to treat even in immunocompetent patients, as currently available therapies remove warty tissue but often fail to eradicate subclinical disease and latent virus, resulting in a high rate of wart recurrence. HIV-infected individuals have an increased incidence of anogenital warts. As many as 40% of HIV-infected homosexual males may develop genital warts, and there is an increased incidence of genital warts in HIV-infected females[18,19]. Anogenital warts can be more difficult to treat in HIV-infected patients, who have more extensive lesions and experience more frequent recurrences[20].

This study was conducted primarily to assess the safety of imiquimod cream applied topically to anogenital warts in HIV-infected patients. Local skin reactions, erythema in particular, are an expected consequence of the pharmacologic action of the drug. In studies conducted in immunocompetent patients with anogenital warts, statistically significant differences in local skin reactions were observed between imiquimod and vehicle-treated patients[13,14]. Overall, the incidence of local skin reactions in this study was lower than anticipated and was not statistically different between treatment groups, possibly as a result of an HIV-induced decrease in immune responsiveness, as well as the limited sample size of the study.

Topical imiquimod applied three times per week appeared to be less effective in achieving total clearance than observed in previous studies in immunocompetent HIV-negative patients[13,14]. The lower total clearance rate may reflect the impaired CMI response in this HIV-infected population with moderately advanced disease (median CD4 T lymphocyte count 270 3 106 cells/l). In addition, reduced dendritic cell activity and circulating IFN inhibitors have been described in HIV-infected patients, both of which may contribute to the reduced efficacy[21,22]. Over one third of imiquimod-treated patients in this study, however, achieved ≥ 50% reduction in wart area. This effect may be a result of direct antiviral and antiproliferative effects of IFN-agr; and possibly other locally induced cytokines. Imiquimod therapy after debulking wart tissue has been utilized and may be of some benefit in selected patients (M. Conant, personal communication). Although recurrence of treated anogenital warts was not evaluated in this study, the rate of sustained wart clearance may be reduced because of the impairment of CMI in many of these patients.

Initiation of a new antiretroviral regimen did not appear to be responsible for the observed wart regression. Highly active antiretroviral therapy (HAART) with HIV protease inhibitor-containing combination regimens has been reported to be associated with profound immunologic improvement and a reduction in the development of new opportunistic infection, as well as resolution of certain HIV-associated lesions such as Kaposi‚s sarcoma[23,24]. While it is possible that immune reconstitution in the setting of HAART might result in spontaneous regression of anogenital warts or an improvement in the response to imiquimod 5% cream, conclusions cannot be drawn from this study as the study was conducted prior to the wide availability of HIV protease inhibitors and only three patients initiated a new antiretroviral regimen containing an HIV protease inhibitor during the study.

Imiquimod has been shown to induce TNF-agr; production from human monocytes and macrophages in vitro, and TNF-agr; has been reported to activate HIV in vitro[12,25]. In animals, however, systemic induction of cytokines from topically applied imiquimod is generally minimal[26]. In a limited dose-escalation study of oral imiquimod administered as single and then as weekly doses of up to 500 mg in patients with early HIV infection and CD4 T lymphocyte counts >300 x 106 cell/l, no clinically meaningful effects on CD4 T lymphocyte counts, serum HIV p24 antigen levels, or HIV serum RNA levels were observed[27]. Based on these results, it is unlikely that the minimal systemic drug exposure from topically applied imiquimod 5% cream would have systemic consequences in HIV-infected patients.

Topically applied imiquimod 5% cream was not associated with an unacceptable incidence of local or systemic adverse reactions when used for the treatment of external anogenital warts in HIV-infected patients, although these observations are limited by sample size and by drop-outs, which were mostly unrelated to study drug. Although total clearance may not be achieved, imiquimod 5% cream may have clinical utility in reducing the overall wart burden in this traditionally refractory patient population.

Acknowledgements

We thank the following physicians for serving on the Independent Safety Review Board: David Cooper, Sydney, Australia; Charles Lacey, London; and Kenneth Trofatter, Cleveland, Ohio, USA. We also thank Ruth Clark, Candis Kapsner, and Katherine Tygum for assisting in monitoring the study; Barbara Boswell for compiling the database; and Kathleen Laska and Tze Chiang Meng for editorial assistance.

References

1. Becker TM, Stone KM, Alexander ER. Genital human papillomavirus infection. A growing concern.Obstet Gynecol Clin North Am 1987, 14:389-396.
2. Lowy DR, Kirnbauer R, Schiller JT. Genital human papillomavirus infection.Proc Natl Acad Sci USA 1994, 91:2436-2440.
3. McLachlin CM. Pathology of human papillomavirus in the female genital tract.Curr Opin Obstet Gynecol 1995, 7:24-29.
4. Kraus SJ, Stone KM. Management of genital infection caused by human papillomanvirus.Rev Infect Dis 1990, 12(Suppl. 6):S620-S632.
5. Stone KM. Human papillomavirus infection and genital warts: Update on epidemiology and treatment.Clin Infect Dis 1995, 20:S91-S97.
6. Oriel JD. Natural history of genital warts.Br J Vener Dis 1971, 47:1-13.
7. Coleman N, Birley HDL, Renton AM, et al.Immunological events in regressing genital warts.Am J Clin Pathol 1994, 102:768-774.
8. Bishop PE, McMillan A, Fletcher S. An immunohistological study of spontaneous regression of condylomata acuminata.Genitourin Med 1990, 66:79-81.
9. Nakajima H, Nakao A, Watanabe Y, et al.IFN-agr; inhibits antigen-induced eosinophil and CD4+ T cell recruitment into tissue.J Immunol 1994, 153:1264-770.
10. Arany I, Tyring SK. Status of local cellular immunity in interferon-responsive and nonresponsive human papillomavirus-associated lesions.Sex Transm Dis 1996, 23:475-480.
11. Arany I, Trying SK. Activation of local cell-mediated immunity in interferon-responsive patients with human papillomavirus-associated lesions.J Interferon Cytokine Res 1996, 16:453-460.
12. Gibson SJ, Imberston LM, Wagner TL, et al.Cellular requirements for cytokine production in response to the immunomodulators imiquimod and S-27609.JInterferon Cytokine Res 1995, 15:537-545.
13. Beutner K, Tyring S, Trofatter K et al.Imiquimod, a patient applied immune-response modifier for treatment of external genital warts. Antimicrob Agents Chemother 1998, 42:789-794.
14. Edwards L, Ferenczy A, Eron L, et al.Self-administered topical 5% imiquimod cream for external anogenital warts.Arch Dermatol 1998, 134:25-30.
15. Tyring SK, Arany I, Stanley MA, et al.A randomized, controlled, molecular study of condylomata acuminata clearance during treatment with imiquimod.J Infect Dis 1998, 178:551-555.
16. US Department of Health and Human Services; Center for Disease Control. 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults.MMWR 1992, 41(RR-17):1-19.
17. Wikstrom A, von Krogh G, Hedblad, MA, et al.Papillomavirus-associated balanoposthitis.Genitourin Med 1994, 70:175-181.
18. McMillan A, Bishop PE. Clinical course of anogenital warts in men infected with human immunodeficiency virus.Genitourin Med 1989, 65:225-228.
19. Fennema JS, van Ameijden EJ, Coutinho RA, et al.HIV, sexually transmitted diseases and gynaecologic disorder in women: increased risk for genital herpes and warts among HIV-infected prostitutes in Amsterdam.AIDS 1995, 9:1071-1078.
20. Judson FN. Interactions between human papillomavirus and human immunodeficiency virus infections.IARC Sci Publ 1992, 119:199-207.
21. Knight SC, Macatonia SE. Effect of HIV on antigen presentation by dendritic cells and macrophages.Res Virol 1991, 142:123-78.
22. Ambrus JL, Poiesz BJ, Lillie MA, et al.Interferon and interferon inhibitor levels in patients infected with varicella-zoster virus, acquired immunodeficiency syndrome, acquired immunodeficiency-related complex, or Kaposi‚s sarcoma, and in normal individuals.Am J Med 1989, 87:405-407.
23. Hammer SM, Squires KE, Hughes MD, et al.A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Eng J Med 1997, 337:725-733.
24. Aboulafia DM. Regression of acquired immunodeficiency syndrome-related pulmonary Kaposi‚s sarcoma after highly active antiretroviral therapy.Mayo Clin Proc 1998, 73:439-443.
25. Okamato T, Matsuyama T, Mori S, et al.Augmentation of human immunodeficiency virus type 1 gene expression by tumor necrosis factor-agr;.AIDS Res Hum Retroviruses 1989, 5:131-138.
26. Imbertson LM, Beaurline JM, Couture AM, et al.Cytokine induction in hairless mouse and rat skin after topical application of immune response modifiers imiquimod and S-28463.J Invest Dermatol 1998, 110:734-739.
27. Goldstein D, Hertzog P, Tomkinson E, et al.Administration of imiquimod, an interferon inducer, in asymptomatic HIV infected persons to determine safety and biological response modification.J Infect Dis 1998, 178:858-861.

Appendix

Members of the Imiquimod Study Group: Brian Berman, Miami, Florida, USA; Libby Edwards, Charlotte, North Carolina, USA; Beng T. Goh, Phillip E. Hay, Robert N Thin, and Thomas J. McManus, London; Donald M. Poretz, Annandale, Virginia, USA; Gordon R. Scott, Edinburgh, Scotland.

Keywords:

condylomata acuminata; anogenital warts; HIV; human papillomavirus; HPV; imiquimod; immune response modifier; immunomodulator

© 1999 Lippincott Williams & Wilkins, Inc.