Anal Canal Condyloma Acuminatum Treated with Anti-HPV Biological Dressing: Clinical Analysis of 64 Cases.

Background: Anal canal condyloma acuminatum (CA) is a refractory disease with a high recurrence rate caused by human papillomavirus (HPV). Multiple clinical trials demonstrate that anti-HPV biological dressing is safe and effective in treating HPV infection, which has been used in treating high-risk HPV-positive and cervical intraepithelial neoplasia I (CIN I) patients. Yet, there is still a lack of clinical data for the treatment of anal canal CA. Aims and
Objectives: To evaluate the clinical efficacy and application value of anti-HPV biological dressing in anal canal CA. Materials and
Methods: Taken currently recommended treatment 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) as a positive control, 128 patients were included with 64 in each group, and a prospective, randomized, positive controlled, non-inferiority clinical trial was conducted. After removing visible skin lesions with conventional microwave, the treatment group was given anti-HPV biological dressing, while the control group received the conventional ALA-PDT treatment. Patients were followed up on the 1st, 12th and 24th weeks after the treatment. The cure rate, recurrence rate, HPV-negative conversion rate, and adverse events were recorded.
Results: In the 1st, 12th and 24th weeks after treatment, the cure rate, recurrence rate and HPV-negative conversion rate of the treatment group and the control group showed no statistically significant difference. In the treatment group, 56 patients developed transient mild itching and all were relieved spontaneously, while in the control group, most of the patients experienced obvious pain and some patients needed symptomatic treatment. No severe systemic adverse events were observed.
Conclusion: Compared with ALA-PDT, topical application of anti-HPV biological dressing has comparable promising outcomes in the treatment of anal canal CA, with fewer side effects and simpler operation making it suitable for clinical applications. Copyright:

Introduction

Condyloma acuminatum is the most common sexually transmitted disease (STD) caused by human papillomavirus (HPV) infection, which is highly infectious and prone to relapse. Anal canal CA is refractory and closely related to rectal tumours.[1] With special physiological structure and environment, such as folded mucosa, higher temperature and moderate humidity, the anal canal is susceptible to HPV infection and reproduction. Traditional treatments such as electrocoagulation, laser treatment, freezing and topical drugs can remove visible warts. However, complete elimination of viruses in areas of subclinical or latent infection cannot be achieved, further causing a high local recurrence rate. ALA-PDT is an effective and safe therapy to treat recurrent and refractory CA, that has been clinically recommended as the first-line treatment for intracavitary CA.[23] However, during the PDT treatment, patients suffer from the obvious pain, besides high cost. Anti-HPV biological dressing is a newly marketed topical drug for HPV infection. The effective antiviral agent is bovine β-lactoglobulin modified with 3-hydroxyphthalic anhydride (JB protein). It has been used in the treatment of high-risk HPV-positive and (or combined) CIN I patients in gynaecology, yet there is still a lack of clinical data for the treatment of anal canal CA.[45] To assess the clinical efficacy and application value of anti-HPV biological dressing in anal canal CA treatment, we conducted a prospective randomized controlled non-inferiority trial that enrolled 128 patients.

Materials and Methods

Sample size estimation

The sample size was assessed by the non-inferiority test. A preliminary test estimated that the cure rate of anti-HPV biological dressing combined with microwave is 70%. Reported data[6] show that the cure rate of ALA-PDT combined with microwave is 83.7%. The volume ratio is 1:1 (k = 1), α = 0.05, β = 0.1, Δ = -0.1, P1 = 72.8%, P2 = 83.7%, while the calculation formula for sample size is as follows: N2 = (Z1-α+Z1-β)2[P2 (1- P2) + P1 (1-P1)/k]/[(P1-P2)- Δ]2, N1 = kN2 (N1: the sample size of the treatment group; N2: the sample size of the control group; P1: the cure rate of the treatment group; P2: the cure rate of the control group). An additional 20% sample size was added to reduce the impact of loss to follow-up, thereby N1 = N2 ≈ 64.

Diagnostic criteria

According to the CA diagnostic criteria in Chinese Clinical Dermatology (second edition) edited by Bian Zhao, patients were diagnosed with clinical manifestations, with or without epidemiological history.

Inclusion criteria

(1) 18-65 years old; (2) anal canal CA confirmed by diagnostic criteria; (3) no topical treatments within 2 weeks; and (4) no systemic treatments within 4 weeks.

Exclusion criteria

(1) CA in other areas except for the anal canal; (2) skin photosensitivity or porphyria; (3) allergic to the test drug or drugs with similar chemical structures; (4) other diseases that may affect the evaluation of curative effect; (5) scar constitution, severe immune deficiency, severe visceral system diseases, pregnant or lactation; or (6) previous history of drug abuse.

Methods

Research protocol

A clinical randomized controlled trial was conducted. The trial was registered at the Chinese Clinical Trial Registry (ChiCTR-IOR-17012361). Random sequences were automatically generated by the computer, and the allocation plan was put in an opaque sealed envelope by A. The envelope was kept by B. Qualified patients were enrolled by C. D assigned patients into two groups based on random draw lots. Microwave therapy was performed by E. F carried out the photodynamic therapy. The pain of patients during treatment, the usage and the dosage of analgesic drugs were carefully recorded. G distributed the anti-HPV biological dressing, recycled the packaging and took notes about the quantity. H was responsible for observation and follow-up. I performed a statistical analysis of the collected data.

Blind-breaking

This trial was only blind to researchers. When severe adverse reactions or other special circumstances occur, treatment can be terminated.

Treatment

After the microwave contacted warts and the tissue coagulated, the treatment group was topically treated with anti-HPV biological dressing (Shanxi Jinbo Bio-Pharmaceutical Co., Ltd.; trade name Jinbo) three times a day for 4 weeks with one fingertip unit at a time and 10 tubes for 4 weeks, while the control group received ALA-PDT treatment once a week for 4 weeks. When patients suffer from obvious pain that cannot be relieved spontaneously, they are allowed to take the oral analgesic pregabalin capsule.

Observation and follow-up

Before treatment, the number and size of warts were recorded. Patients were reviewed once a week during treatment, and new skin lesions were recorded. After the last treatment, patients are followed up on the 1st, 12th and 24th weekend to evaluate the efficacy. Blood routine, urine routine, liver function, renal function and HPV genotyping and adverse events were all checked and recorded. Adverse events were evaluated based on severity and analysed by causal analysis as definitely related, probably related, possibly related, unlikely to be related and definitely not related. The incidence of adverse events = (number of adverse events/total number of cases) × 100%.

Efficacy and safety evaluation

(1) Cure rate = (number of patients without relapse after treatment/number of patients received treatment) ×100%; (2) relapse rate = (number of patients who relapse after cure/number of patients cured after treatment) × 100%; (3) HPV-negative conversion rate = (number of HPV-negative patients after treatment/number of HPV-positive patients before treatment) × 100%. Note: Cure means that original warts disappeared completely after treatment, and no new warts were seen during follow-up. Relapse refers to the fact that original warts disappeared after treatment, but new warts appeared during follow-up with a positive result in the acetowhite test.

Statistical analyses

Data analyses were performed in SPSS19.0 statistical software, using Pearson's Chi-square test.

Results

Participants

One hundred and thirty-six patients were randomly assigned into two groups. Three patients in the control group quitted for personal reasons, and 133 patients completed the treatment. Five patients were lost to follow-up, with four patients in the treatment group and one patient in the control group. Except for patients who withdrew and lost to follow-up, the number of final effective cases in the trial was 128, with 64 in each group. There was no statistical difference between the two groups in gender, age, course of disease, number of warts and wart size (P > 0.05).

Treatment results

The cure rate, recurrence rate and HPV-negative conversion rate of the treatment group and the control group in the 1st, 12th and 24th week after treatment are shown in Table 1 (P > 0.05), and the anal canal warts before and in the 24th week after treatment with anti-HPV protein dressing are shown in Figure 1. The first week after treatment, the cure rate, recurrence rate and HPV-negative conversion rate of the treatment group were 82.81%, 17.19% and 56.25%, respectively, while 87.50%, 12.50% and 60.94% in the control group, indicating no statistically significant difference between these two groups (P > 0.05). In the 12th week after treatment, the cure rate, recurrence rate and HPV-negative conversion rate were 76.56%, 23.44% and 60.94% in the treatment group and 82.81%, 17.19% and 64.06% in the control group, with no statistically significant difference between these two groups (P > 0.05). 3. In the 24th week after treatment, the cure rate, recurrence rate and HPV-negative conversion rate were 71.88%, 28.12% and 65.63% in the treatment group and 75.00%, 25.00% and 68.75% in the control group. There was also no statistically significant difference between these two groups (P > 0.05).

Table 1

Cure rate, recurrence rate and HPV-negative conversion rate after treatment

	1st week after treatment			12th week after treatment			24th week after treatment
	Cure	Recurrence	HPV(-)	Cure	Recurrence	HPV(-)	Cure	Recurrence	HPV(-)
Treatment group	53	11	36	49	15	39	46	18	42
Control group	56	8	39	53	11	41	48	16	44
χ2 value	0.556	0.556	0.290	0.772	0.772	0.133	0.160	0.160	0.142
P value	0.456	0.456	0.590	0.380	0.380	0.715	0.689	0.689	0.707

Figure 1

Anal canal warts images of two patients before and after treatment with anti-HPV protein dressing (treatment group). Patient 1: Wart images of a 26-year-old male before (a) and after (b) treatment. Patient 2: Wart images of a 44-year-old female before (c) and after (d) treatment

Adverse reactions

Fifty-six patients (87.50%) in the treatment group developed transient mild itching within 15 min after topical medication, which was definitely related to the treatment, and they all relieved spontaneously. In contrast, 61 patients (95.31%) in the control group had pain, which was definitely related to ALA-PDT. Among them, 24 patients (37.50%) suffered from moderate to severe pain and took oral analgesic pregabalin capsules to relieve symptoms. Thirty-three patients (51.56%) in the control group had mild redness, swelling, blisters, itching and other side effects, which were definitely related to treatment and all relieved after symptomatic treatment. No serious systemic adverse events were observed in these two groups.

Conclusion

Anal canal CA has increasingly become the focus of clinicians in dermatology and venereal diseases due to its high recurrence rate and closely related to tumours.[17] Clinical data show that anal canal CA accounts for about 14% of CA patients, more than half of the men with anal canal warts are men who have sex with men (MSM), and about 20% of HIV-positive MSM anal canal CA patients have anal canal warts combined with high-grade squamous intraepithelial neoplasia.[89] With high curative effect and low recurrence rate, ALA-PDT is currently recommended treatment for anal canal CA; however, PDT-related pain is still a major challenge.[210] Anti-HPV biological dressing, a newly marketed topical drug, has a strong inhibitory activity on HPV infection. JB protein is the main effective antiviral agent, which blocks HPV infection through physical mechanisms. The negatively charged surface of the JB protein binds to the positively charged areas on the surface of the HPV major capsid protein L1 and minor capsid protein L2, blocking the binding of HPV to negatively charged receptors on the surface of basal cells. Thus, HPV infection is prevented by inhibiting the viral entry process and inactivates HPV by changing the conformation of capsid proteins.[11] Moreover, the anti-HPV biological dressing also contains carbomer and green tea extracts. As a stable, non-irritating and non-allergenic medical polymer material, carbomer can isolate and prevent wound infection, thus promoting wound healing. The green tea extract polyphenols possess antiviral activity through immune regulation and have been approved by the USFDA for the treatment of CA.[1213] In addition, clinical data show that anti-HPV biological dressing is effective and safe in treating high-risk HPV-positive female patients or HPV-positive CIN I patients. No adverse events were observed after vaginal administration for 3 months, while the vaginal microenvironmental indicators such as vaginal pH and secretion white blood cell count also have been improved.[41415]

Similar to the cervix, the dentate line of the anal canal is the migration area of human squamous and columnar epithelium, with large numbers of immature squamous epithelial cells. Therefore, it is one of the largest reservoirs for human HPV. Given the good performance of anti-HPV biological dressing in treating gynaecology, especially cervical HPV infection, here we conducted a prospective, randomized, positive controlled, non-inferiority trial for the first time to investigate the clinical efficacy in treating anal canal CA using ALA-PDT as the positive control. The results showed that in the 1st week, 12th week, and 24th week after treatment, the cure rate and recurrence rate of anal canal CA treated with anti-HPV biological dressing are not inferior to ALA-PDT. Considering the less side effects, anti-HPV biological dressing is even better than ALA-PDT. Except for transient itching, anti-HPV biological protein dressing displays a good safety profile. Furthermore, anti-HPV biological dressing is easier to operate, with lower cost, and does not need special medical equipment, making it suitable for widely used in treating anal canal CA.

Conflict of interest

The authors declare no conflict of interest.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.