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Abstract

This study aims to determine the effect of paiteling by placing a vaginal stump on the outcome of persistent high-risk human papillomavirus (HR-HPV) infection after hysterectomy for cervical intraepithelial neoplasia (CIN). From January 2013 to December 2015, 125 patients were enrolled in the study. These patients were divided into groups, according to patient’s preference. There were 55 patients in the paiteling group, while there were 70 patients in the control group. At the end of the third and ninth month, Thinprep cytology test (TCT) and human papillomavirus (HPV) typing were reviewed to determine the changes in HR-HPV and its complications. The negative conversion rates of these two groups were observed. Patients in the control group were observed and followed up without treatment. At the third month after treatment, HPV negative rates were 83.64% and 34.29% in the paiteling group and control group, respectively (χ² = 30.444, P < 0.01). In the ninth month, the rate of HPV negative conversion was 90.91% in the paiteling group and 48.57% in the control group (χ² = 25.047, P < 0.01). The difference between the two groups was statistically significant, and patients in both groups had no obvious adverse reactions. Paiteling irrigation at the vaginal stump can accelerate the positive-to-negative conversion of HR-HPV infection after panhysterectomy.

Keywords

HR-HPV hysterectomy outcome paiteling

Introduction

Human papillomavirus (HPV) is an annular, unencapsulated, double-stranded DNA virus. HPV infection of the reproductive tract can be classified into two types: benign low-risk type and malignant high-risk type. The persistent infection of high-risk human papillomavirus (HR-HPV) is the prerequisite and main carcinogenic factor of cervical cancer.¹ There is no unified treatment option for the persistent infection of HR-HPV. Furthermore, its preventive vaccine has a certain efficacy and safety² and may make cervical cancer an avoidable preventable cancer. However, malignant tumors caused by HPV remain very common, accounting for one-third of infection-related cancers.³ Furthermore, the 2017 cancer statistics in the United States revealed 12,820 new cases of cervical cancer and 4210 deaths, and 6010 new cases of vulvar cancer and 1150 deaths.⁴ As the detection rate of cervical intraepithelial neoplasia (CIN) increases year by year, the number of patients undergoing panhysterectomy due to CIN also increases. After hysterectomy, patients need long-term follow-ups, especially in the first 2 years after the operation.⁵ Vaginal stump cytology and HPV detection are recommended after panhysterectomy. However, a “second” or “continuous” infection of HR-HPV after surgery aggravates the burden of many patients. Patients want to get rid of HPV infection as soon as possible. The treatments for HR-HPV infection after an operation mainly include expectant management and drug therapy.⁶ However, these treatments do not have satisfactory effects, allowing HPV infection to become a serious problem that plagues doctors and patients.⁷ As a new field of antivirus, traditional Chinese medicine (TCM) for antivirus has aroused great concern. In this study, the pure TCM-prepared paiteling was applied in HR-HPV-infected patients after panhysterectomy to explore its curative effect in the treatment of HR-HPV infection.

Materials and methods

General information

Patients who were admitted to the First Hospital of Shanxi Medical University between January 2013 and December 2015 were enrolled into the study. These patients met the following criteria: (1) the cervical colposcopic biopsy result was a high-grade squamous intraepithelial lesion (HSIL); (2) the pathological margin of the tissue specimen was positive after the first loop electrical excision procedure (LEEP); (3) patients had no reproduction requirement and received panhysterectomy and had no residual cervix after the operation; (4) patients who have persistent HP-HPV infection after hysterectomy were detected to have HR-HPV infection two consecutive times after 6-month interval. So, patients were detected to have HR-HPV infection at 3 months after the operation and had no natural positive-to-negative conversion at 9 months after the operation; (5) patients’ results of the liquid-based thin layer cytology (TLC) were benign (no intraepithelial lesions or malignant cells are seen) and patients confirmed by colposcopy and biopsy without vaginal intraepithelial neoplasia (VAIN). Patients with the following conditions were excluded: (1) patients who were lost to follow-up or did not receive the prescribed regular follow-up, (2) patients who had invasive cervical cancer confirmed by pathology and received further treatment, (3) patients who did not receive treatment or did not receive standard treatment for various reasons, (4) patients who had previously suffered from other malignant tumors, and (5) patients with VAIN have been confirmed before panhysterectomy. According to the criteria, 125 patients were enrolled into the study. According to the economic condition and preference of the patients, these patients were divided into two groups: control group (n = 70), and paiteling group (n = 55). The age of patients in the control group ranged within 28–52 years old, with an average of 45.6 years old, while the age of patients in the paiteling group ranged within 29–56 years old, with an average of 47.3 years old. Differences in age between the two groups were not statistically significant (P > 0.05). Hence, these two groups were comparable. Before the medication, all patients were informed in detail the condition, the need for treatment, and the alternative method of medication. All patients provided an informed consent. This study was conducted in accordance with the Declaration of Helsinki and approved by Ethics Committee of our hospital.

Research methods

Therapeutic methods

Patients in the paiteling group were medicated by specially trained personnel, and the medication situations were recorded. The frequency of paiteling use was once a day for a continuous period of 4 days, followed by 3 days of suspension. A total of three courses of treatment were given. Thinprep cytology test (TCT) and HPV typing were carried out at the third and ninth month after the end of drug use to determine the alteration of the HR-HPV infection and its complications. Patients in the control group were only observed and did not receive any treatment.

Detection methods

HPV typing

The HPV sampler was used to collect the exfoliated cells of the vaginal stump. According to Hybribio company’s detection method, polymerase chain reaction (PCR), and membrane hybridization, 21 HPV subtypes were performed. If any of the high-risk types (including multiple infections) was positive, the patient was defined as a high-risk HPV infection patient.

Colposcopy and biopsy

A thorough examination was taken from the vaginal orifice to the top, especially the top of the vagina. Suspicious lesions on vaginal wall should be followed by biopsy; if necessary, do acetic acid test and iodine test first.

Judgment methods

Typing detection of HPV: (1) positive-to-negative conversion: the results of all high-risk HPV subtypes were negative; (2) invalid outcome: the high-risk HPV subtype continued to exist, or the lesion was upgraded.

Classification of VAIN: (1) VAIN I: it affects one-third of the epithelial layer; (2) VAIN II: it affects two-thirds of the epithelial layer; and (3) VAIN III: it affects more than two-thirds of the epithelial layer and even the entire epithelium.

Statistical analysis

Data were statistically analyzed using statistical software SPSS 19.0. The positive-to-negative conversion rate was evaluated using χ² test. P < 0.05 was considered statistically significant.

Results

Comparison of the positive-to-negative conversion rate of HR-HPV between the two groups

The positive-to-negative conversion rate at 3 months after drug withdrawal

At 3 months after the discontinuation of paiteling treatment, 46 patients in the paiteling group had a positive-to-negative conversion, accounting for 83.64% (46/55), while 24 patients in the control group had a positive-to-negative conversion, accounting for 34.29% (24/70), and the difference between these two groups was statistically significant (χ² = 30.444, P < 0.01). In one patient in the control group, TCT revealed atypical squamous and glandular cells of undetermined significance (ASCUS) and HPV 18 (+), while colposcopy and biopsy revealed vaginal intraepithelial neoplasia I (VAIN I). In the paiteling group, one patient presented with HPV16 and HPV52 (+). At 3 months after drug withdrawal, a recheck revealed HPV52 (+). This patient chose to receive expectant management. At 9 months after drug withdrawal, the recheck revealed HPV52 (+).

Positive-to-negative conversion rate at 9 months after drug withdrawal

At 9 months after the discontinuation of paiteling treatment, 50 patients in the paiteling group had a positive-to-negative conversion, accounting for 90.91% (50/55), while 34 patients in the control group had a positive-to-negative conversion, accounting for 48.57%(34/70), and the difference between these two groups was statistically significant (χ² = 25.047, P < 0.01). In one patient in the control group, TCT revealed HSIL and HPV 16 (+), while colposcopy and biopsy revealed VAIN II. Hence, the patient underwent CO₂ laser and electrocision. In the paiteling group, two patients presented with HPV18 and HPV53 (+). At 3 months after drug withdrawal, the recheck continued to reveal HPV18 and HPV53 (+). These patients received another course of paiteling treatment. At 3 months after drug withdrawal, the recheck revealed HPV53 (+). In the recheck at 9 months after drug withdrawal, one patient presented with HR-HPV (–), and the other patient continued to present with positive HPV53 (Table 1).

Table 1.

The comparison of positive-to-negative conversion rate of HPV between the two groups.

	Group	Total cases (n)	Positive-to-negative conversion cases (n)	Non-positive-to-negative conversion cases	Positive-to-negative conversion rate (%)
3 months after drug withdrawal	Paiteling group	55	46	9	83.64
	Control group	70	24	46	34.29
	χ² value	χ² = 30.444 (P < 0.01)
9 months after drug withdrawal	Paiteling group	55	50	5	90.91
	Control group	70	34	36	48.57
	χ² value	χ² = 25.047 (P < 0.01)

HPV: human papillomavirus.

Adverse reactions

During the paiteling treatment, all patients presented with good tolerance, and no adverse reaction occurred.

Discussion

Persistent positive HR-HPV results after treatment for cervical cancer and precancerous lesions increased the risk of recurrence and death.⁸ It was also revealed that VAIN is associated with HR-HPV infection.⁹ Follow-ups for HPV infection and effective antiviral therapy after surgery are necessary.

Paiteling is the first pure TCM preparation for the topical treatment of high-risk HPV infection developed by the Chinese Academy of Sciences. The main ingredients include Folium isatidis, Radix Sophorae flavescentis, Fructus cnidii, Hedyotis diffusa, Brucea javanica, and so on. Pharmacological efficacy studies have revealed that paiteling can selectively destroy the cell membrane and mitochondria membrane system, inhibit the proliferation of tumor cells by cytotoxicity, enhance the destruction of tumor cells, and scavenge and inhibit parasitic HPV in cells while destroying cells. Among these herbs, F. isatidis, Radix S. flavescentis, and F. cnidii contain a large amount of tannins and alcohols and have potent antibacterial and antiviral effects.¹⁰

This study revealed that for persistent HR-HPV infection in the vaginal stump, after paiteling treatment, the HPV positive-to-negative conversion rate at 3 and 9 months was 83.64% and 90.91%, respectively. This suggests that paiteling can effectively eliminate HR-HPV infection. The HPV16 and HPV18 genotypes are the reliable prognostic factors for CIN after panhysterectomy.¹¹ In the patients with HPV16 or/and HPV18 infection in this study, the positive-to-negative conversion rate in the paiteling group reached 100%.

In summary, paiteling irrigation at the vaginal stump can accelerate the positive-to-negative conversion of HR-HPV infection after panhysterectomy. Furthermore, the drug is simple to use and inexpensive and has no obvious toxic and side effects (such as vulvar and vagina burning, itching, severe pain, and drug fever). Therefore, it has broad application prospects. However, the sample size of this study was small, and its conclusions need to be verified through studies with expanded sample sizes.

Footnotes

Acknowledgements

Y.Z. and Q.-M.W. contributed equally to this work.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Ye Zhao

References

Gizzo

Ancona

Patrelli

et al . (2013) Fertility preservation in young women with cervical cancer: An oncologic dilemma or a new conception of fertility sparing surgery. Cancer Investigation 31(3): 189.

Sipp

Frazer

Rasko

JEJ

(2018) No vacillation on HPV vaccination. Cell 172(6): 1163–1167.

Trimble

(2014) HPV Infection-associated cancers: Next-generation technology for diagnosis and treatment. Cancer Immunology Research 2(10): 937–942.

Siegel

Miller

Jemal

(2017) Cancer statistics, 2017. CA: A Cancer Journal for Clinicians 67(6): 7–30.

Khan

Massad

Kinney

et al . (2016) A common clinical dilemma: Management of abnormal vaginal cytology and human papillomavirus test results. Journal of Lower Genital Tract Disease 20(2): 119–125.

Pachman

Barton

Clayton

et al . (2012) Randomized clinical trial of imiquimod: An adjunct to treating cervical dysplasia. American Journal of Obstetrics and Gynecology 206(1): 42.e1–42.e7.

Elfgren

Elfstrom

Naucler

et al . (2017) Management of women with human papillomavirus persistence: Long-term follow-up of a randomized clinical trial. American Journal of Obstetrics and Gynecology 216(3): 264.e1–264.e7.

Song

Kong

Zhang

et al . (2017) Relationship between high-risk human papillomavirus negative prognosis and prognosis after treatment of cervical cancer. Chinese Journal of Practical Gynecology and Obstetrics 33: 975–978.

Rhodes

Chenevert

Munsell

(2014) Vaginal intraepithelial neoplasia (VaIN 2/3): Comparing clinical outcomes of treatment with intravaginal estrogen. Journal of Lower Genital Tract Disease 18(2): 115–121.

10.

Chen

Zhao

Liao

(2011) Clinical efficacy of paiteling in treatment of cervical intraepithelial neoplasia grade 1 and 2. Chinese Journal of Practical Gynecology and Obstetrics 27: 703–705.

11.

Kang

Kim

(2016) A human papillomavirus (HPV)-16 or HPV-18 genotype is a reliable predictor of residual disease in a subsequent hysterectomy following a loop electrosurgical excision procedure for cervical intraepithelial neoplasia 3. Journal of Gynecologic Oncology 27: e2.

Effect of paiteling on the alteration of persistent HR-HPV infection after panhysterectomy