Nonavalent human papillomavirus vaccination as alternative treatment for genital warts

Genital warts caused by the human papillomavirus (HPV) are the most common sexually transmitted disease and have a negative impact on quality of life. Of the more than 200 different types of HPV, low‐risk types 6 and 11 are mainly responsible for the development of condyloma acuminata. Despite a large arsenal of local therapies such as numerous topical agents, CO₂ laser ablation, and surgical removal, genital warts tend to be recalcitrant. HPV vaccination is mainly used as a preventive strategy to prevent genital warts, cervical cancer, and other anogenital cancers. However, in a few cases, HPV vaccination has been shown to be a good treatment alternative for patients with recalcitrant skin warts. Here we report five cases of recalcitrant genital warts that responded well to treatment with the nonavalent HPV vaccine. HPV vaccines could be beneficial as a noninvasive treatment alternative for recalcitrant genital warts.     

Topical Polyphenon E in the treatment of external genital and perianal warts: a randomized controlled trial

Background Benign external genital and perianal warts (condylomata acuminata) are disfiguring, displeasing skin tumours caused by human papillomavirus that may vitally burden affected patients and their partners. Current treatment options are still unsatisfactory due to low efficacy, high recurrence rates or an unfavourable side‐effect profile. Although most recently prophylactic vaccines have been recommended for adolescent women, appropriate treatment modalities for anogenital warts are still needed. Green tea catechins exert antiviral, antioxidative, antiproliferative and immunostimulatory activity. Polyphenon^® E (MediGene AG, Munich, Germany), a proprietary extract of green tea leaves, was therefore investigated for the topical treatment of this frequent viral disease. Objectives To investigate Polyphenon^® E 15% and 10% ointment for efficacy and safety in the treatment of anogenital warts in immunocompetent men and women. Methods Five hundred and three patients were randomized to receive either Polyphenon^® E 15% or 10% ointment or matching vehicle. The topical treatment was self‐applied by the patients three times daily to all warts. Assessment of response and of adverse events was performed biweekly until complete clearance of all (baseline and new) anogenital warts or for up to 16 weeks. Recurrence was evaluated during a 12‐week treatment‐free follow‐up period for patients with complete clearance. Results About 53% of patients treated with Polyphenon^® E 15% ointment showed complete clearance of all baseline and new anogenital warts, 51% for Polyphenon^® E 10% ointment, and 37% for vehicle (P = 0·01 and P = 0·03, respectively; two‐sided Fisher’s exact test; intent‐to‐treat population, last observation carried forward analysis). Women responded better than men, with about 60% of women and 45% of men in both active groups achieving complete clearance of all warts. Time to complete clearance was comparable for both strengths of Polyphenon^® E ointment. About 78% of all patients treated with either Polyphenon^® E 15% or 10% ointment showed wart clearance rates of 50% or better. Less than 6% and 4% of patients in the Polyphenon^® E 15% and 10% ointment groups experienced wart recurrence during follow‐up. Polyphenon^® E ointments demonstrated a good safety profile with the majority of all adverse events being local application site reactions assessed as mild or moderate. Local reactions declined during continued treatment. Conclusions The results indicate that Polyphenon^® E ointment is an efficacious and safe patient‐applied topical treatment for external genital and perianal warts. Its use in intra‐anal, intravaginal and cervical condylomas and other intraepithelial lesions warrants further clinical investigation.     

Efficacy,safety and tolerability of green tea catechins in the treatment of external anogenital warts: a systematic review and meta‐analysis

Background External anogenital warts (EGWs) are non‐malignant skin tumours caused by human papillomavirus. They are one of the fastest growing sexually transmitted diseases. Current treatments are unsatisfactory. Green tea sinecatechin Polyphenon E ointment is a botanical extract from green tea leaves exhibiting anti‐oxidant, anti‐viral and anti‐tumour properties. Objective The aim of this study was to integrate valid information and provide basis for rational decision making regarding efficacy and safety of green tea extracts in the treatment of EGWs. Methods A systematic search in electronic databases was conducted using specific key terms. Main search was performed independently by two reviewers. The accumulated relevant literature was subsequently systematically reviewed and a meta‐analysis was conducted. Results Three randomized, double‐blind, placebo‐controlled studies evaluating efficacy and safety of Polyphenon E 15% and 10% in the treatment of warts were included in the systematic review and meta‐analysis. A total of 660 men and 587 women were enrolled. Regarding primary outcome, both Polyphenon E 15% and 10% demonstrated significantly higher likelihood of complete clearance of baseline and baseline and new warts compared with controls. No significant heterogeneity was detected. Recurrence rates were very low. Commonest local skin sign was erythema and local skin symptom was itching. Conclusions Efficacy of Polyphenon 15% and 10%, at least for the primary endpoint, is clearly indicated. Polyphenon E treatment exhibits very low recurrence rates and appears to have a rather favourable safety and tolerability profile. Recommendations for future studies should include evaluation of the efficacy of green tea catechins in the treatment of internal anogenital warts and direct comparison with its principal comparator, imiquimod.     

棒状光源盐酸5-氨基酮戊酸光动力治疗肛管内尖锐湿疣

目的:评价棒状光源盐酸5-氨基酮戊酸光动力疗法治疗肛管内尖锐湿疣的临床疗效。方法:棒状光源盐酸5-氨基酮戊酸治疗肛管内尖锐湿疣男性患者46例,每周1次,共4次。结果:35例(76.1%)患者疣体完全清除,无感染、溃疡、瘢痕、痔疮病例。随访12周复发5例,复发率为14.3%。疼痛程度可视模拟评分(VAS)为(6.96±1.41)分。结论:棒状光源盐酸5-氨基酮戊酸治疗肛管内尖锐湿疣疗效好,中度疼痛,复发率低,不良反应少。     

Topical treatment for plantar warts: A systematic review

There are a wide variety of treatments for plantar warts, but none has been shown to be effective in all patients. We aimed to perform a systematic review of the efficacy of different topical treatments on plantar warts. Systematic electronic searches (Pubmed, Cochrane Library, Embase, and Web of Science) were conducted in April 2020. Meta‐analyses, systematic reviews, and retrospective or prospective clinical trials of the effects of topical and nonsurgical treatments of plantar warts were included. Two authors performed the study selection and data extraction. Any discrepancies between the two reviewers were discussed with a third reviewer. Forty‐four studies were included. The average cure rates of the most frequent treatments were variable across the studies: cryotherapy (45.61%), salicylic acid (13.6%), cantharidin‐podophyllin‐salicylic acid formulation (97.82%), laser (79.36%), topical antivirals (72.45%), intralesional bleomycin (83.37%), and intralesional immunotherapy (68.14%). Twenty‐two studies (50%) had a level of evidence 1b and grade of recommendation A, five studies (11.4%) had a level of evidence 2b and grade of recommendation B, two studies (4.5%) had a level of evidence 3b and grade of recommendation B, and 15 studies (34,1%) with a level of evidence 4 and grade of recommendation C. First‐choice treatments for common warts, such as cryotherapy and salicylic acid, have low‐cure rates for plantar warts. Other treatments, such as CPA formulation, immunotherapy, and intralesional bleomycin, which have compassionate use, have higher cure rates. This review should stimulate future high‐quality research to evaluate these specialized treatments.     

Increased risk of dementia in patients with genital warts: A nationwide cohort study in Taiwan

Genital warts are a common sexually transmitted disease caused by human papillomavirus (HPV) infections. The prevalence of dementia is 4–8% in those aged 65 years or older in Taiwanese community studies, with a high social and economic burden for patients, family caregivers, the community and society. Previous studies have shown that viral infections such as herpes simplex and herpes zoster were associated with dementia. This study aimed to investigate the association between dementia and HPV infections. A population-based cohort study using data from Taiwan’s National Health Insurance Research Database was conducted. Fine and Grays’s survival analysis was employed to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the association between genital warts and dementia. From all of the potential participants aged 50 years or more, a total of 16 116 patients were enrolled, including 4029 genital warts-infected patients, with 12 087 sex-, age- and indexed date-matched controls (1:3). The cumulative incidences of dementia were 10.72 per 10³ person-years and 6.43 per 10³ person-years in the genital warts and control group, respectively. There were 475 dementia cases from the genital warts cohort during the follow-up period of 15 years. The adjusted HR for dementia was 1.485 (95% CI, 1.321–1.668; P < 0.001) for genital warts patients after adjusting for all of the covariates. Our study indicates that genital warts infection may increase the risk of dementia.     

Prognostic factors for the response to treatment in males with genital warts

Background  Factors predicting an unfavourable course of genital warts to treatment have not been determined.
Materials and methods  Behavioural and baseline disease characteristics were recorded from 246 males with anogenital warts. Urethral swabs were obtained and examined using the Hybrid Capture 2 Microplate assay. Patients were treated for their anogenital warts with cryotherapy, imiquimod cream 5% or podophyllotoxin. They were followed up every 3 months for 1 year.
Results  Patients with a negative or low-risk initial test tended to respond earlier to treatment than those with a high/intermediate-risk human papillomavirus (HPV) or with a dual infection ( P  = 0.028). The response rate was unrelated ( P  > 0.05) to the duration, number and anatomical location of the lesions and to the patient's age and sexual orientation, and only marginally to the initial extent of the lesion ( P  = 0.046). However, the type of treatment predicted a favourable response (P ≤ 0.001), with patients who received both imiquimod and crotherapy responding worse. Considering all factors simultaneously in logistic regression, only the type of treatment and extent of the disease were found to influence the response rate.
Conclusion  The type of treatment and extent of the disease were the only factors found critical for patients' response.     

Closing the feedback loop: an audit of the use of imiquimod for the treatment of genital warts

A retrospective case-note audit of 74 patients with 81 treatment episodes of anogenital warts with imiquimod from April 1999 until July 2000 was performed. The majority of patients had failed to clear their warts with other treatments, had recurrences after other treatments, or had other medical problems complicating their genital wart treatment. The overall clinically confirmed complete clearance rate was 33%. This is lower than other published data, but may be so because it includes patients with immunosuppression and difficult-to-treat warts. The complete clearance rate in immunocompetent patients was 37%. In addition, in this audit of clinical practice 17% of the patients did not return for full response to be assessed. The complete clearance rate in those who were able to tolerate treatment and who returned for follow-up was 45%. Based on the results of the audit we have extended the indications for the use of imiquimod in the clinic treatment guidelines. Patients are now offered imiquimod if six or more episodes of other treatments fail to give a good response. Earlier treatment with imiquimod is also offered to those patients with recurrent anogenital warts, and it is recommended as a first-line therapy for patients with multiple keratinized warts.     

Polyphenon E®: a new treatment for external anogenital warts

Background External genital warts (EGWs, condylomata acuminata) are a common, highly contagious disease caused by human papillomavirus (HPV), predominantly HPV 6 and HPV 11. Green tea catechins have been identified for their immunostimulatory, antiproliferative and antitumour properties. Two phase III trials evaluated treatment of EGWs with ointment containing a mixture of green tea catechins (Polyphenon E^®, U.S. adopted name: sinecatechins). Objectives To obtain additional data on the efficacy and safety of Polyphenon E^® ointment in the treatment of EGWs from two randomized, double‐blind, vehicle‐controlled trials. Methods Men and women aged ≥ 18 years (n = 1005), with two to 30 EGWs (12–600 mm² total area) applied vehicle (G_Veh; n = 207), Polyphenon E^® ointment 10% (G_10%; n = 401) or Polyphenon E^® ointment 15% (G_15%; n = 397) three times daily until complete clearance of all EGWs (baseline + new EGWs) or for a maximum of 16 weeks. Results A total of 1004 patients were evaluable for safety and 986 for efficacy; 838 completed treatment after 16 weeks. Complete clearance of all EGWs was obtained in 53·6% (G_10%) and 54·9% (G_15%) of patients with Polyphenon E^® vs. vehicle (35·4%) (P < 0·001). Statistically significant differences in clearance rates appeared after 6 weeks of active treatment. Odds ratios vs. G_Veh for G_10% [2·10; 95% confidence interval (CI) 1·49–2·98] and G_15% (2·22; 95% CI 1·57–3·14) indicated about a twofold higher chance of complete clearance under active treatment. Time to complete clearance was shorter with active treatment (hazard ratios 1·57 and 1·87, respectively, for G_10% and G_15% vs. G_Veh groups; P < 0·001). Recurrence rates during follow‐up were low and similar across groups: 5·8%, 6·8% and 6·5% (G_Veh, G_10% and G_15% groups, respectively). Adverse events were evenly distributed across groups (～ 30% of patients). Severe local signs were more frequent but moderate in the active treatment groups (1·5%, 9·2% and 13·5% for G_Veh, G_10% and G_15% groups, respectively). Conclusions Polyphenon E^® ointment is effective and well tolerated in the treatment of EGWs.     

High prevalence of genital HPV infection among long‐term monogamous partners of women with cervical dysplasia or genital warts—Another reason for HPV vaccination of boys

We conducted a cross‐sectional study on the occurrence of a specific type of genital human papillomavirus (HPV) among long‐term monogamous male partners of women with cervical dysplasia and genital warts. The purpose of the study was to improve knowledge with regards to the management of these couples. The presence of genital HPV‐DNA was detected by PCR with broad spectrum primers followed by hybridization. 82 males met the study criteria, 41 in each group. Genital HPV‐DNA prevalence was 67.5% in the genital warts group and 72.2% in the cervical dysplasia group. The prevalence of high risk HPVs was higher in the cervical dysplasia group, while low risk HPVs were more prevalent in the genital warts group (p < .05). The prevalence of HPV in males was independent of the duration of the relationship (73.5% for 6–24 months and 66.7% for longer relationships). In conclusion, our results suggest that the prevalence of the genital HPV infection in both groups of male partners is comparable and very high, but the spectrum of HPV types varies significantly. The presence of the genital HPV infection in male sexual partners seems to be independent of the duration of the relationship. Applying the HPV vaccination to boys may prevent this phenomenon.     

Possible role of interleukin 21 and interleukin 33 in patients with genital warts

Genital warts (GWs) are most prevalent sexually transmitted infections, presenting especially among the sexually active young population of both sexes. Efficient cell‐mediated immunity is needed for regression of GWs. To clarify the reactivity of cellular immunity among patients with GWs by means of measurements of their levels of serum interleukin (IL)‐21 and IL‐33, hence, to identify the possible role of IL‐21 and IL‐33 in GWs, this study aimed to evaluate serum levels of IL‐21 and IL‐33 among patients with GWs in comparison with the results of the controls. Levels of serum IL‐21 and IL‐33 were assayed utilizing commercially enzyme‐linked immune‐sorbent assay kits in 45 patients with GWs and 45 healthy control subjects. Levels of serum IL‐21 and IL‐33 were significantly decreased among patients with GWs in comparison with the controls (p < .0001). There was a highly significant positive correlation between IL‐21 and IL‐33 (r = .73, p < .0001). Low levels of serum IL‐21 and IL‐33 could have a contributive role in development, persistence, severity, and recurrence of GWs which rely basically on the defectiveness of cell‐mediated immunity. This could receive new light on nonconventional strategies for the prospective medical therapies of GWs by means of regulation of IL‐21 and IL‐33.     

Management of Female Genital Warts with an Analog of Imiquimod 2% in Cream: A Randomized,Double-Blind,Placebo-Controlled Study

The purpose of this randomized, double-blind, placebo-controlled study was to determine the clinical efficacy and tolerability of an analog of imiquimod (2%) in cream to cure genital warts in women. Sixty preselected women, ranging between 18 and 45 years of age (mean 24.3) and having 411 lesions (mean 6.8) with clinical, histopathological and polymerase chain reaction (PCR) confirmed diagnosis of human papilloma virus (HPV) infection were randomized to two parallel groups. Each patient received a precoded 40-g tube and instructions on how to apply the trial medication to their lesions at home two times daily for five consecutive days per week. The active treatment period was six weeks. Patients were evaluated on a weekly basis. A clinically and PCR established total clearance of target warts was recorded as a cure. By the end of the treatment, 43.3% of patients and 42.8% of warts were cured. Code disclosure revealed that imiquimod cream had cured 83.3% of the treated patients and 84.3% of the treated warts, while the placebo healed one subject and four warts (p<0.0001). Eight patients (13.3%) in the imiquimod group experienced mild to moderate, non-objective, drug-induced symptoms with no dropouts. Among the 26 cured patients, five had a relapse after 11 months. In conclusion, the data presented demonstrate that 2% imiquimod in cream with mild to moderate subjective side effects is significantly more effective than placebo in eliminating genital warts in women.     

盐酸丁卡因胶浆联合CO_2激光治疗尖锐湿疣的临床疗效观察及安全性分析

目的:观察盐酸丁卡因胶浆联合CO_2激光治疗尖锐湿疣的疗效及安全性,为尖锐湿疣的治疗探索一条新途径,以期为尖锐湿疣患者的治疗提供帮助。方法:随机选取2014年10月至2015年10月,我院符合纳入标准的尖锐湿疵患者60例,其中男性24例、女性36例,分为治疗组和对照组,每组各30例。两组患者男性均12例、女性均18例,对照组采用CO_2激光治疗,而治疗组采用盐酸丁卡因胶浆联合CO_2激光治疗。治疗后第7d、第15d、1个月、2个月和3个月对两组患者观察,比较其痊愈率、复发率以及不良反应情况。结果:治疗结束时,治疗组的痊愈率为93.3%,对照组为66.7%,治疗组明显高于对照组,两组差异有统计学意义(P<0.05);治疗组复发率为6.6%,明显低于对照组的20%,差异无统计学意义(P>0.05);观察组不良反应发生率为9.8%,对照组为4.9%,差异无统计学意义(P>0.05)。结论:盐酸丁卡因胶浆联合CO_2激光治疗尖锐湿疣疗效显著且安全性好,提高了痊愈率,可以作为治疗尖锐湿疣的好方案之一。     

Self-administered topical 5% imiquimod for the treatment of common warts and molluscum contagiosum

BACKGROUND: Despite numerous therapeutic options the treatment of common warts and molluscum contagiosum remains unsatisfactory for both patients and physicians. Imiquimod, a novel topical immune response modifier, has been successfully used for the treatment of external anogenital warts. OBJECTIVES: We aimed to evaluate the safety, tolerance and efficacy of imiquimod for the treatment of common cutaneous warts and mollusca that were resistant to previous therapeutic interventions. METHODS: Imiquimod 5% cream was self-applied by the patients to the warts or mollusca once daily for 5 days per week and left in place overnight. Assessment for response and the occurrence of side-effects was performed every 4 weeks until clinical cure or up to a maximum of 16 weeks. RESULTS: Twenty-eight of 50 (56%) patients with warts achieved a total clearance (n = 15; 30%) or a > 50% reduction in wart size (n = 13; 26%) after a mean treatment period of 9.2 weeks. Twelve of 15 (80%) patients with mollusca achieved a total clearance (n = 8; 53%) or a > 50% reduction in molluscum size (n = 4; 27%). There was no difference in response with regard to gender, human immunodeficiency virus serostatus or atopic predisposition. CONCLUSIONS: Patient-applied 5% imiquimod cream holds promise as an effective treatment of common warts and mollusca in a difficult-to-treat patient population.     

Imiquimod 5% cream for external genital or perianal warts in human immunodeficiency virus-positive patients treated with highly active antiretroviral therapy: an open-label, noncomparative study

Background  Human immunodeficiency virus (HIV)+ patients have an increased risk of anogenital warts. High-risk (HR) human papillomaviruses (HPVs), especially types 16 and 18, are major risk factors for precancerous and cancerous lesions of the anogenital tract, while low-risk (LR) HPVs are associated with benign lesions. Cure of genital warts with ablative techniques, surgical excision, podophyllotoxin or trichloroacetic acid is frequently difficult. Treatment with imiquimod cream showed a total clearance of external genital or perianal warts in about 50% of immunocompetent subjects. However, total clearance was reduced in HIV+ subjects not treated with highly active antiretroviral therapy (HAART).
Objectives  To assess clinically and by monitoring HPV content the efficacy of 5% topical imiquimod to treat anogenital warts in HIV+ subjects with at least partially restored immune functions.
Methods  Fifty HIV+ patients successfully treated with HAART (total CD4+ cells ≥ 200 cells mm⁻³ and plasma HIV RNA load < 10⁴ copies mL⁻¹) with anogenital warts were included. Imiquimod 5% cream was applied on external genital or perianal warts three times weekly for up to 16 weeks. Warts were tested at entry and after treatment for human LR- and HR-HPV DNA.
Results  Total wart clearance was observed in 16 of 50 (32%) patients at week 16. At enrolment, HPV DNA was present in more than 90% of lesions with a majority of lesions co-infected by HR- and LR-HPV. At study end, the HPV load decreased or became undetectable in 40% of cases studied.
Conclusions  Imiquimod 5% cream did not show safety concerns and is suitable for use in HIV+ subjects with anogenital warts and successful HAART treatment.     

Time‐lapse imaging points towards a non‐toxic,mainly immune‐driven mode of action of ingenol mebutate in the treatment of anogenital warts

Recently, it has been reported that ingenol mebutate (IM) is an effective treatment option for anogenital warts (AGW), inducing fast wart necrosis within 24 hours in vivo. With regard to its mode of action, IM is thought to act both as an inducer of direct cytotoxic effects and immunologic mechanisms. To distinguish whether the wart necrosis is mainly caused by cytotoxic effects, or whether immune mechanisms are leading, we used time‐lapse imaging to analyse IM‐treated warts ex vivo over 24 hours. Ex vivo IM‐treated warts, which have been detached from the immune system, did not show destructive necrosis, pointing towards a primarily immune‐driven mode of action of IM in the treatment of AGW.     

Complete remission of recalcitrant genital warts with a combination approach of surgical debulking and oral isotretinoin in a patient with systemic lupus erythematosus

Genital warts in immunocompromised patients can be extensive and recalcitrant to treatment. We report a case of recalcitrant genital warts in a female patient with systemic lupus erythematosus (SLE), who achieved complete remission with a combination approach of surgical debulking and oral isotretinoin at an initial dose of 20 mg/day with a gradual taper of dose over 8 months. She had previously been treated with a combination of topical imiquimod cream and regular fortnightly liquid nitrogen. Although there was partial response, there was no complete clearance. Her condition worsened after topical imiquimod cream was stopped because of her pregnancy. She underwent a combination approach of surgical debulking and oral isotretinoin after her delivery and achieved full clearance for more than 2 years duration. Oral isotretinoin, especially in the treatment of recalcitrant genital warts, is a valuable and feasible option when other more conventional treatment methods have failed or are not possible. It can be used alone or in combination with other local or physical treatment methods.