Invest Clin 66(2): 131 - 146, 2025 https://doi.org/10.54817/IC.v66n2a01

Corresponding author: Cen Ma. Department of Obstetrics and Gynecology Laboratory, The First Affiliated Hospi-

tal of Soochow University, 188 Shizi Street, Soochow 215006, Jiangsu, China. E-mail: ydm1368@163.com

Correlation between human papillomavirus

infection and vaginal microecological

environment, and the effect of

Lactobacillus vaginal capsules combined

with recombinant human interferon α-2b

gel on human papillomavirus infection.

Yanling Sun, Li Li, Wenxin Xu and Cen Ma

Department of Obstetrics and Gynecology Laboratory, The First Affiliated Hospital

of Soochow University, Soochow 215006, Jiangsu, China.

Keywords: human papillomavirus infection; vaginal microecology; bacterial vaginosis;

Lactobacillus vaginal capsule; recombinant human interferon α-2b gel.

Abstract. This study mainly analyzed the correlation between human pap-

illomavirus infection (HPV) and vaginal microecological environment and ex-

plored the effect of Lactobacillus vaginal capsule combined with recombinant

human interferon α-2b gel on HPV infection. Five hundred patients who un-

derwent a gynecological examination in our hospital from June 2021 to June

2023 were selected and divided into HPV-positive and HPV-negative groups.

Relative to the HPV-negative group, the HPV-positive group presented a higher

abnormal rate of Lactobacillus, catalase, cleanliness, neuraminidase and pro-

line aminopeptidase (p<0.05) and a higher positive rate of bacterial vaginosis

(BV) (p<0.05). Multivariate logistic regression analysis showed that catalase,

proline aminopeptidase and BV were risk factors for HPV infection (p<0.05). In

addition, 180 HPV-positive patients were randomly divided into a control group

(CG) and an observation group (OG). The CG was given recombinant human

interferon α-2b gel, and the OG was treated with recombinant human inter-

feron α-2b gel plus a Lactobacillus vaginal capsule. Relative to the CG, the OG

presented a higher total effective rate (p<0.05), lower inflammation (p<0.01),

better immune function (p<0.01), and a higher proportion of grade II-III vagi-

nal flora density and grade II-III vaginal flora diversity (p<0.001). Collectively,

HPV is significantly correlated with the vaginal microecological environment,

and catalase, proline aminopeptidase and BV were closely related to HPV infec-

tion. In addition, Lactobacillus vaginal capsule plus recombinant human inter-

feron α-2b gel has practical clinical efficacy, which can reduce inflammation,

promote immune function, improve vaginal microecological environment, and

is safe in the treatment of patients with HPV infection.

132 Sun et al.

Investigación Clínica 66(2): 2025

Correlación entre la infección por el virus del papiloma humano

y el entorno microecológico vaginal, y el efecto de cápsulas

vaginales de Lactobacillus combinada con gel de interferón

α-2b humano recombinante sobre la infección por el virus

del papiloma humano.

Invest Clin 2025; 66 (2): 131 – 146

Palabras clave: infección por virus del papiloma humano; microecología vaginal;

vaginosis bacteriana; cápsula vaginal de Lactobacillus; gel recombinante

humano de interferón α-2b.

Resumen. Este estudio analizó principalmente la correlación entre la in-

fección por el virus del papiloma humano (VPH) y el entorno microecológico

vaginal, y exploró el efecto de cápsulas vaginales de Lactobacillus combinadas

con gel de interferón humano recombinante α-2b sobre la infección por VPH. Se

seleccionaron 500 pacientes que se sometieron a examen ginecológico en nues-

tro hospital de junio de 2021 a junio de 2023 y se las dividió en un grupo positivo

para VPH y un grupo negativo para VPH. En relación con el grupo VPH negativo,

el grupo VPH positivo presentó mayor tasa anormal de Lactobacillus, catalasa,

neuraminidasa, prolina aminopeptidasa y limpieza (p<0,05) y mayor tasa positi-

va de vaginosis bacteriana (BV) (p<0,05). El análisis multivariado de regresión

logística mostró que la catalasa, la prolina aminopeptidasa y la BV fueron facto-

res de riesgo para la infección por VPH (p<0,05). Además, 180 pacientes VPH

positivos se dividieron aleatoriamente en un grupo control (GC) y un grupo de

observación (OG). Al CG se le administró gel recombinante humano de interfe-

rón − -2b, y al OG se le administró gel recombinante humano de interferón − -2b

más cápsulas vaginales de Lactobacillus. En relación con el GC, el OG presentó

mayor tasa efectiva total (p<0,05), menor inflamación (p<0,01), mejor función

inmune (p<0,01) y mayor proporción de densidad de flora vaginal de grado II-III

y diversidad de flora vaginal de grado II-III (p< 0,001). Colectivamente, el VPH se

correlaciona significativamente con el entorno microecológico vaginal, y la cata-

lasa, la prolina aminopeptidasa y el BV se relación estrechamente con la infección

por VPH. Además, las cápsulas vaginales de Lactobacillus más el gel de interferón

α-2b recombinante humano tienen eficacia clínica efectiva, lo que puede reducir

la inflamación, promover la función inmune, mejorar el entorno microecológico

vaginal, y es seguro en el tratamiento de pacientes con infección por VPH.

Received: 29-12-2024 Accepted: 12-04-2025

INTRODUCTION

Cervical cancer is a serious threat to

the majority of women’s health. In develop-

ing countries, its incidence is second only

to breast cancer, ranking second in female

malignant tumors, and is the most common

female reproductive system tumor 1. Ac-

cording to the cancer report released by the

International Agency for Research on Can-

cer under the World Health Organization,

in 2020, about 604,000 women around the

Papilloma virus infection and microecological environment 133

Vol. 66(2): 131 - 146, 2025

infection, such as recombinant human in-

terferon α-2b gel, which can inhibit the

replication of the virus and increase the im-

mune regulation of lymphocytes to specific

cytotoxicity after medication, thus playing

a particular therapeutic effect 11. However,

with the single use of antiviral drugs, the

drug interacts with the vaginal environment

and affects the overall effect. Lactobacillus

vaginal capsules is a kind of microecologi-

cal preparation whose main ingredient is liv-

ing intestinal streptococcus; it is a common

drug to treat bacterial disorder vaginosis

and can play a role in the decomposition of

lactic acid produced by sugar and regulate

the pH of the vagina 12.

In our study, we intended to explore the

correlation between HPV infection and the

vaginal microecological environment and

the effect of Lactobacillus vaginal capsules

combined with recombinant human inter-

feron α-2b gel on HPV infection.

PATIENTS AND METHODS

Patients

Five hundred patients who underwent

gynecological examination in the gynecolog-

ical outpatient department of our hospital

from June 2021 to June 2023 were selected

as the study participants. Inclusion crite-

ria: (1) Non-pregnant and lactation period;

(2) Regular menstrual cycle; (3) No vaginal

bleeding; (4) No serious diseases of other

systems; (5) No history of vaginal douch-

ing treatment and other vaginal operations

within three days; (6) No sexual intercourse

within three days; (7) No drugs taken within

one month, no abnormalities in cervical cy-

tology within one year. Exclusion criteria:

(1) Patients had other systemic diseases; (2)

Patients had no sexual history. The hospital

Medical Ethics Committee approved this

study, and all patients signed an informed

consent. According to the HPV test results,

180 cases were divided into the HPV-positive

group and 320 cases were the HPV-negative

group. The HPV-positive group was 22-65

world were diagnosed with cervical cancer,

and about 342,000 women died from the dis-

ease, among which the number of cervical

cancer cases in China was about 110,000,

and the number of deaths was 60,000 2. Eti-

ological studies have found that persistent

infection by human papillomavirus (HPV) is

a significant factor in cervical cancer 3. HPV

is a kind of virus which can be classified into

low-risk human papillomavirus (LR-HPV)

and high-risk human papillomavirus (HR-

HPV) according to the strength of the patho-

genicity or carcinogenic risk of HPV 4. HPV is

highly host-specific and easily infects human

epidermal and mucous squamous epithe-

lium, mainly through sexual transmission5.

HPV infection is the leading cause of most

cervical cancer, anal and oropharyngeal in-

vasive cancers and preinvasive lesions, and

is also the cause of genital warts (condylo-

ma acuminatum) and recurrent respiratory

papillomatosis 6. Therefore, the prevention

of HPV infection and intervention in the dis-

ease process after HPV infection are the key

to reducing the incidence and mortality of

cervical cancer.

There is evidence that maintaining the

balance of vaginal microecology plays an im-

portant role in preventing female reproduc-

tive system infection, and when the vaginal

microecology is destroyed, it may lead to cer-

vical lesions 7. Under normal circumstances,

the vaginal microecology is in a state of dy-

namic balance. When the loss of this dynamic

balance, the immune system of the vaginal

mucosa, is damaged, and foreign microorgan-

isms are more likely to invade the reproduc-

tive tract and cause inflammation 8. Studies

have shown that changes in the vaginal mi-

croenvironment, such as vaginal douching,

bacterial vaginosis (BV), as well as sexually

transmitted infections, are thought to be co-

factors in the persistence of HPV infection 9.

Studies have also found that reconstructing

vaginal microecological homeostasis can re-

duce the risk of HPV infection 10.

Antiviral drugs are commonly used in

clinical treatment for patients with HPV

134 Sun et al.

Investigación Clínica 66(2): 2025

years, with a median age of (37.36±3.75)

years. The HPV-negative group was 23-68

years, with a median age of (37.28±3.67)

years. The two groups exhibited no signifi-

cant difference in age (p>0.05). In addition,

180 HPV-positive patients were randomly di-

vided into a control group (CG) and an obser-

vation group (OG); each group had 90 cases.

The control group was 22-68 years old, with

a median age of (38.36±3.78) years. The

observation group was aged 23-65, with a

median age of (37.45±3.69) years. The two

groups exhibited no significant difference in

age (p>0.05).

HPV detection

All 500 enrolled patients underwent

HPV testing during the gynecological ex-

amination phase of the study, including the

180 patients later identified as HPV-positive.

HPV detection was carried out using the

second-generation Hybrid Capture 2 (HC2)

DNA assay (Qiagen Digene, USA), a gold-

standard, FDA-approved diagnostic method

for detecting high-risk and low-risk human

papillomavirus DNA in cervical samples. This

method employs RNA probes complemen-

tary to 13 high-risk (e.g., HPV16, 18, 31,

33) and five low-risk HPV genotypes. Sample

collection involved using a cervical sampler

brush (Digene), which was rotated clockwise

three times at the cervical ostium to obtain

epithelial cells. The brush was then placed

into the HPV DNA collection medium and

stored at 4°C. Samples were processed ac-

cording to the manufacturer’s protocol. In

the HC2 system, RNA:DNA hybrids formed

during hybridization were captured and de-

tected via chemiluminescence, and results

were interpreted quantitatively based on a

Relative Light Unit (RLU) ratio ≥1.0, with

values above this threshold considered HPV-

positive. This method was used consistently

across all participants to ensure homogene-

ity of diagnostic criteria, including initial di-

agnosis in the 180 HPV-positive patients and

post-treatment evaluation of viral clearance.

All HPV-positive patients (n=180) were sub-

jected to this post-treatment re-evaluation

4–6 weeks after completion of therapy to

minimize false negatives due to transient

viral suppression. This re-evaluation enabled

an accurate assessment of HPV viral persis-

tence or clearance.

HPV Detection Pre- and Post-Treatment

Vaginal microecological examination

The patient was instructed to take the

bladder lithotomy position, and the dispos-

able vaginal speculum was slowly inserted

into the vagina along the lateral posterior

wall of the vagina. As the speculum went

deeper, the speculum was turned straight

and slowly opened to expose the vaginal wall,

fornix, and cervix fully. The vaginal mucus

and cells were gently scraped from the upper

1/3 side of the vagina’s wall with a dispos-

able sterile cotton swab and then placed in a

disposable sterile test tube for sealing. The

samples were immediately sent to our hospi-

tal’s laboratory.

Diagnostic criteria of vaginal

microecology

The results were determined by the

vaginitis five-test kit (Autobio, Zhengzhou,

China). Light yellow or no color of catalase

was positive (+), indicating the presence of

a small amount of Lactobacillus; light red

was weakly positive (±), indicating the pres-

ence of moderate Lactobacillus, and red or

purple-red was negative (-); indicating the

presence of a large number of Lactobacil-

lus. Leucocyte esterase displayed blue for

positive (+, ++, +++), light blue for weak

positive (±), and no color or light color for

negative (-).

Neuraminidase displayed red, purple,

blue, brown or black for positive (+), light

red for weak positive (±), and no color or

orange for negative (-). Proline aminopepti-

dase showed positive (+) in yellow, weakly

positive (±) in light yellow, and negative (-)

in no color or light color. Acetylglucosamini-

dase showed yellow as positive (+), light

yellow as weakly positive (±), and no color

Papilloma virus infection and microecological environment 135

Vol. 66(2): 131 - 146, 2025

or light color as negative (-). Proline ami-

nopeptidase showed positive, and acetylglu-

cosaminidase showed negative, indicating

positive BV. Proline aminopeptidase showed

positive with a pH ≥4.8, indicating positive

trichomonas vaginitis (TV), and proline ami-

nopeptidase showed positive with a PH ≤4.5,

indicating positive vulvovaginal candidiasis

(VVC). The PH color from yellow-cyan-green-

blue indicated a change from 3.8 to 5.4, and

the PH value was obtained against the colo-

rimetric card. Vaginal PH of 3.8 to 4.5 was

normal. Cleanliness I and II were normal.

A large or medium amount of Lactobacillus

was normal. The negative and weak posi-

tive of catalase and leucocyte esterase were

normal. Negative neuraminidase, proline

aminopeptidase, and acetylglucosaminidase

were normal. Negative BV, candida, tricho-

monas was normal. If there was any abnor-

mality, the vaginal microecology was in an

unbalanced state.

Treatment methods

The control group was given recom-

binant human interferon α-2b gel (Zhaoke

Pharmaceutical (Hefei) Co., LTD.; specifica-

tion: 100,000 IU/g, 5 g/ branch). After the

menstrual period was clear, the vulva was

cleaned every night, and 1 g of gel was ap-

plied to the vaginal dome using a disposable

thruster. Seven to ten times was used in a

menstrual cycle as a course of treatment, for

a total of three courses of treatment.

The observation group was treated with

recombinant human interferon α-2b gel com-

bined with Lactobacillus vaginal capsules.

The treatment method of recombinant hu-

man interferon α-2b gel was the same as that

of the control group. A Lactobacillus vaginal

capsule (Xi’an Zhenghao Bio-pharmaceuti-

cal Co., LTD., specification: 0.25 g: 6 million

live lactic acid bacteria) was added in the

recombinant human interferon α-2b gel ad-

ministration daily, transvaginal medication,

two capsules/time, one time/day, with the

same treatment course as the control group.

During the treatment period, both groups

suspended sexual activity and prohibited

from vaginal irrigation.

Observation indicators

1. Clinical efficacy: a. Obvious effect: Af-

ter treatment, the characteristics of va-

ginal secretions returned to normal, all

symptoms disappeared, HPV was nega-

tive; b. Effective: After treatment, the

characteristics and symptoms of the

vaginal secretions were significantly

improved, and HPV was negative; c. In-

effective: After treatment, HPV was still

positive, and symptoms and vaginal se-

cretion traits did not improve or even

worsen. Total effective rate = (Obvious

effect + Effective) Number of cases/To-

tal cases ×100%.

2. Inflammation: 3 mL fasting venous

blood samples were taken from the pa-

tient and centrifuged for 10 min at a ro-

tational speed of 3000 r/min and a ra-

dius of 15 cm. After that, an automatic

biochemical analyzer measured the le-

vels of tumor necrosis factor-α (TNF-α)

and interleukin-6 (IL-6).

3. Immune function: Fasting venous

blood was collected and centrifuged in

parallel according to (2). The levels of

CD4+ and CD8+ were measured by flow

cytometry, and the ratio of CD4+/CD8+

was calculated.

4. Vaginal microecology: A sterile cotton

swab was used to collect secretions on

1/3 of the vaginal wall and detect them

under a microscope. The density of va-

ginal flora was divided into grade I (ave-

rage bacterial count of field ≤9), grade

II (average bacterial count of field 10-

99), grade III (average bacterial count

of field ≥100), and grade IV (bacteria

gathered into clusters or densely cove-

red mucosal epithelial cells). Among

them, grade II and III were considered

as normal concentrations of vaginal flo-

ra. Vaginal flora diversity was divided

into grade I (identify 1 ~ 3 kinds of

bacteria), grade II (identify 4 ~ 6 kinds

136 Sun et al.

Investigación Clínica 66(2): 2025

of bacteria), grade III (identify 7 ~ 9

kinds of bacteria), grade IV (identify

≥10 kinds of bacteria), of which grade

II and grade III were considered as nor-

mal vaginal flora diversity.

5. The occurrence of adverse reactions,

including a burning sensation of the

vulva, pruritus and gastrointestinal dis-

comfort in the two groups were recor-

ded.

Statistical analysis

The data were analyzed using SPSS 22.0

statistical software. Measurement data were

expressed as (±s), and the t-test was ad-

opted for comparison. Statistical data were

expressed as n (%), and the χ2 test was used

for comparison. A logistic regression model

was used to analyze the influencing factors.

The difference was statistically significant at

p<0.05.

RESULTS

Comparison of vaginal microecology

between two groups

As Table 1 reveals, relative to the HPV-

negative group, the HPV-positive group pre-

sented a higher abnormal rate of Lactoba-

cillus, catalase, cleanliness, neuraminidase

and proline aminopeptidase (p<0.05). How-

ever, no difference was exhibited in the ab-

normal rates of pH value, leukocyte esterase

and acetylglucosaminidase between the two

groups (p>0.05).

Comparison of positive rates of Bacterial

vaginosis, Trichomonas vaginitis and

Vulvovaginal candidiasis between the two

groups

As Table 2 indicates, relative to the HPV-

negative group, the HPV-positive group pre-

sented a higher positive rate of BV (p<0.05).

However, no differences were exhibited in

the positive rates of TV and VVC between the

two groups (p>0.05).

Correlation between HPV infection

and vaginal microecology

According to the results of univariate

analysis between the two groups, Lactoba-

cillus, catalase, cleanliness, neuraminidase,

proline aminopeptidase and BV were taken

as covariables, and HPV infection as depen-

dent variables, and a multivariate logistic

regression analysis was performed. The mul-

tivariate logistic regression analysis results

showed that catalase, proline aminopepti-

dase and BV were closely related to HPV in-

fection (p<0.05), and were risk factors for

HPV infection, as shown in Table 3.

Clinical efficacy between two groups

Relative to the CG, the OG presented a

higher total effective rate (p<0.05, Table 4).

Inflammation between the two groups

Before therapy, there were no differ-

ences in levels of inflammatory markers be-

tween the two groups (p>0.05). After ther-

apy, TNF-α and IL-6 levels were declined in

the two groups (p<0.01). Importantly, rela-

tive to the CG, the OG presented lower lev-

els of the above inflammatory markers after

therapy (p<0.01, Fig. 1).

Immune function between two groups

Prior to therapy, there were no differ-

ences in levels of immune function indexes

between the two groups (p>0.05). After

therapy, CD4+ and CD4+/CD8+ levels were

elevated, while CD8+ levels declined in the

two groups (p<0.01). Importantly, relative

to the CG, the OG presented better improve-

ments in the above immune function indexes

after therapy (p<0.01, Fig. 2).

Vaginal microecology between two groups

The proportion of grade II-III vaginal

flora density and grade II-III vaginal flora

diversity in group 2 were higher than those

before treatment (p<0.001 and p=0.002).

Importantly, relative to the CG, the OG pre-

sented a higher proportion of grade II-III

Papilloma virus infection and microecological environment 137

Vol. 66(2): 131 - 146, 2025

vaginal flora density and grade II-III vaginal

flora diversity (p<0.001, Tables 5 and 6).

Occurrence of adverse reactions between

two groups

As Table 7 shows, no difference was

seen in adverse reactions between the two

groups (p>0.05).

HPV clearance between two groups

Following the three-month treatment

period, HPV testing was repeated. The clear-

ance rate of HPV in the observation group

(OG) (interferon α-2b + Lactobacillus) was

significantly higher compared to the control

group (CG) (interferon α-2b alone) (Table 8).

Specifically, HPV clearance was observed in:

• OG: 68 of 90 cases (75.56%)

• CG: 51 of 90 cases (56.67%)

• χ² = 7.156, P = 0.0076

This finding strongly suggests that the

addition of Lactobacillus vaginal capsules

Table 1. Comparison of vaginal microecology between two groups.

Index HPV-negative group

(n=320)

HPV-positive group

(n=180) χ²p

Lactobacillus 8.638 0.003

Normal 131 (40.94)* 50 (27.78)

Abnormal 189 (59.06) 130 (72.22)

Catalase 8.316 0.004

Normal 134 (41.88) 52 (28.89)

Abnormal 186 (58.12) 128 (71.11)

pH 0.278 0.598

≤4.5 304 (95.00) 169 (93.89)

>4.5 16 (5.00) 11 (6.11)

Cleanliness 5.532 0.019

Normal 163 (50.94) 72 (40.00)

Abnormal 157 (49.06) 108 (60.00)

Leukocyte esterase 1.468 0.226

Normal 80 (25.00) 54 (30.00)

Abnormal 240 (75.00) 126 (70.00)

Neuraminidase 12.90 <0.001

Normal 272 (85.00) 129 (71.67)

Abnormal 48 (15.00) 51 (28.33)

Proline aminopeptidase 40.47 <0.001

Normal 265 (98.75) 147 (81.67)

Abnormal 4 (1.25) 33 (18.33)

Acetylglucosaminidase 0.015 0.904

Normal 268 (83.75) 150 (83.33)

Abnormal 52 (16.25) 30 (16.67)

*Data is express as n (%)

138 Sun et al.

Investigación Clínica 66(2): 2025

Table 2. Comparison of positive rate of Bacterial vaginosis, Trichomonas vaginitis

y Vulvovaginal candidiasis between the two groups.

Index HPV-negative group

(n=320)

HPV-positive

group (n=180) χ²p

Bacterial vaginosis 5.023 0.025

Positive 30 (9.38)* 29 (16.11)

Negative 290 (90.62) 151 (83.89)

Trichomonas vaginitis 0.183 0.669

Positive 15 (4.69) 10 (5.56)

Negative 305 (95.31) 170 (94.44)

Vulvovaginal candidiasis 0.020 0.142

Positive 29 (9.06) 17 (9.44)

Negative 291 (90.94) 163 (90.56)

*Data is expressed as n (%)

Table 3. Correlation between HPV infection and vaginal microecology.

Influencing factors β SE Wald OR 95% CI p

Catalase 1.0 0.1 66.5 2.8 2.2-3.6 <0.05

Proline aminopeptidase 1.7 0.4 15.0 5.6 2.3-13.5 <0.05

Bacterial vaginosis 1.1 0.5 4.5 3.1 1.1-8.9 <0.05

Table 4. Clinical efficacy between the two groups.

Groups Cases

(n)

Obvious Effect

n (%)

Effective

n (%)

Ineffective

n (%)

Total Effective

Rate n (%) χ² p

Control Group 90 38 (42.23%)* 32 (35.55%) 20 (22.22%) 70 (77.78%) 10.22 0.001

Observation Group 90 57 (63.33%) 28 (31.11%) 5 (5.56%) 85 (94.44%)

Fig. 1. Comparison of inflammation between the two groups. **p<0.01.

Papilloma virus infection and microecological environment 139

Vol. 66(2): 131 - 146, 2025

Table 5. Vaginal flora density (grade II-III).

Groups Cases

Vaginal flora density

χ² pBefore treatment After treatment

Cases % Cases %

Control group 90 36 40.00 61 67.78 13.97 <0.001

Observation group 90 34 37.78 81 90.00 53.19 <0.001

χ² 0.093 13.34

p 0.759 <0.001

Table 6. Vaginal flora diversity (grade II-III).

Groups Cases

Vaginal flora density

χ² pBefore treatment After treatment

Cases % Cases %

Control group 90 39 43.33 60 66.67 9.899 0.002

Observation group 90 41 45.56 83 92.23 45.73 <0.001

χ² 0.090 18.00

p 0.764 <0.001

Table 7. Occurrence of adverse reactions between two groups.

Groups Cases Burning sensation

of vulva

Pruritus Gastrointestinal

discomfort

Total incidence

rate

Control group 90 2 (2.22)* 0 (0.00) 2 (2.22) 4 (4.44)

Observation group 90 2 (2.22) 1 (1.11) 2 (2.22) 5 (5.55)

χ² 0.117

p 0.732

*Data is express as n (%).

Fig. 2. Immune function between the two groups. **p<0.01.

140 Sun et al.

Investigación Clínica 66(2): 2025

improves the antiviral effect of interferon

α-2b and contributes to a more favorable

microecological environment for viral clear-

ance.

DISCUSSION

About 10% to 30% of adults are infected

with HPV, and sexually active people are even

higher, reaching 50% to 80%, and the most

susceptible age is 20 to 29 years old 13. Af-

ter HPV infection, some patients continue

to be infected with high-risk HPV, cervical

intraepithelial tumour-like lesions, after 10

to 15 years, the development of early cervi-

cal cancer, and then advanced cervical can-

cer 14. HR-HPV is the leading cause of cervical

cancer, with 99% of cervical cancer HPV posi-

tive, of which HPV16 and HPV18 accounted

for about 70%. HPV infection is necessary

to cause cervical cancer, but the number of

copies of HPV-DNA is not directly related to

disease progression, and only persistent high-

risk HPV infection increases the risk of cer-

vical cancer 15. At present, HPV monitoring

is the primary screening method for cervical

cancer, the tracking method of cervical le-

sions after treatment and the indicator of the

risk of cervical intraepithelial neoplasia 16.

The vaginal microecosystem is a rela-

tively complex system among the four major

human ecosystems, which plays an impor-

tant role in preventing microbial invasion 17.

In our study, the results showed that com-

pared to the HPV-negative group, the HPV-

positive group presented a higher abnormal

rate of Lactobacillus, catalase, cleanliness,

neuraminidase, and proline aminopeptidase,

consistent with previous reports 18,19. The

typical vaginal microecological environment

of women is Lactobacillus as the dominant

bacteria 20. Lactobacillus can maintain a sta-

ble pH value (pH ≤4.5) in the vagina by pro-

ducing lactic acid, lactobacillin, H2O2, and

bioactive substances so that the vaginal flora

can maintain a balanced state, and through

its adsorption on the vaginal mucosa, the for-

mation of a biological barrier against patho-

genic microorganisms 21. Hydrogen peroxide

can inhibit or kill bacteria, and the function

of catalase is to promote the decomposition

of hydrogen peroxide, and reduce the effect

of hydrogen peroxide on killing pathogens,

resulting in the survival and proliferation

of pathogens in the vagina, increasing HPV

susceptibility 22. Reproductive system infec-

tions can also lead to changes in cleanliness,

abnormal levels of neuraminidase and pro-

line aminopeptidase, aggravate vaginal mi-

croecological environment disorders, form a

vicious cycle, and increase the risk of HPV

infection 23. In addition, HPV infection may

also cause oxidative stress, damage the an-

tioxidant oxidase system in the patient, re-

duce the level of antioxidants, and damage

cellular DNA. In the process of cellular DNA

replication, HPV DNA can be transferred to

the DNA of host cells, aggravating the degree

of mucosal damage, further aggravating the

abnormality of the vaginal microecological

environment, and forming a vicious cycle 24.

Therefore, the vaginal flora is the first line of

defense against pathogenic microorganisms.

Our study also revealed that relative to

the HPV-negative group, the HPV-positive

group presented a higher positive rate of BV.

The reason is as follows: (1) The decrease

or disappearance of vaginal Lactobacillus in

BV patients provides opportunities for the

growth and reproduction of other bacteria

Table 8. Comparison of HPV clearance between the two groups after treatment.

Group Total Cases

(n)

HPV Negative

(Cleared)

HPV Positive

(Persistent)

Clearance Rate

(%) χ² p

Control Group 90 51 39 56.67%

Observation Group 90 68 22 75.56% 7.156 0.0076

Papilloma virus infection and microecological environment 141

Vol. 66(2): 131 - 146, 2025

such as Gardner-bacteria and anaerobic bac-

teria, causing the imbalance of vaginal mi-

croecological environment, the reduction of

the protective function of Lactobacillus on

the vagina, and the decreased ability of vagi-

nal virus clearance, thus susceptible to HPV

infection 25; (2) BV can affect the expression

of vaginal local immune factors, thereby de-

stroying the immune response and making

it more susceptible to HPV infection 26; (3)

BV can cause the destruction of cytoskele-

ton protein of vaginal mucosal epithelium,

accelerate the damage of vaginal mucosal

epithelial cells, and increase susceptibility

to HPV27; (4) The sialoglycoidase produced

by BV leads to the degradation of vaginal

mucosal epithelial protective factors, which

enables bacteria to adhere and form bio-

films, further leading to the difficulty of

HPV removal and the formation of persistent

infection 28. For these reasons, BV not only

increases the susceptibility to HPV but also

delays the body’s clearance of HPV.

Antiviral therapy is the preferred treat-

ment for HPV infection, with commonly

used drugs such as recombinant human in-

terferon α-2b gel, an important glycoprotein

produced by white blood cells that play a

key role in fighting viral infection and has

antibacterial activity against a variety of

pathogens 29. Interferon α-2b can inhibit cell

proliferation, inhibit angiogenesis, and have

cytotoxic effects on tumor cells in various

ways 30. On the one hand, it can bind to spe-

cific receptors on the cell surface, thereby

inhibiting the growth of virus-infected cells

and prolonging the cell cycle of malignant

cells 31. On the other hand, biosynthase plays

an important role in promoting cell prolif-

eration in viral cells, and the inhibition of

interferon α-2b can play a good role in in-

hibiting viral replication 32. In treating HPV

infection, transvaginal medication can di-

rectly act on cervical epithelial cells and has

a specific effect. However, the vagina has a

complex microenvironment, which can pro-

duce metabolites that compete with drug re-

ceptors under the action of the microbiome,

resulting in limited effects of single drugs 33.

In this study, the observation group was

given Lactobacillus vaginal capsules based

on interferon α-2b, and the results manifest-

ed that relative to the CG, the OG present-

ed a higher total effective rate. The reason

may be that Lactobacillus vaginal capsule is

a kind of microbial preparation, with living

intestinal streptococcus as the main compo-

nent 34, which can increase the production

of acidic substances through the decomposi-

tion of internal glycogen, thus reducing the

pH value of the vaginal environment, effec-

tively promoting the proliferation of Lacto-

bacillus in the host body, adjusting the mi-

croecological environment, strengthening

the self-purification function of the mucosal

immune system, and thus enabling the mu-

cosal immune system to rebuild more effec-

tively 35. In addition, Lactobacillus vaginal

capsules play a particular role in regulating

the immune system, stimulating the release

of antibodies in the body and inhibiting the

reproduction of bacteria 36. By rebuilding a

good vaginal environment and establishing

a protective barrier, the effect of interferon

α-2b can be reduced, and the clinical efficacy

can be improved.

IL-6 and TNF-α are inflammatory factors

that correlate specifically with HPV infec-

tion37. When the body is infected with HPV,

the levels of IL-6 and TNF-α as pro-inflamma-

tory factors will increase abnormally 38. There-

fore, the body’s inflammation can be judged

by observing the changes of IL-6 and TNF-α

levels in the body. The results of our study

manifested that relative to the CG, the OG

presented lower levels of the above inflamma-

tory markers after therapy, suggesting that

Lactobacillus vaginal capsules combined with

recombinant human interferon α-2b gel could

suppress inflammation of the body. Similarly,

Dobrohotova et al. suggested that the addi-

tional use of Lactobacillus vaginal capsules

in the complex therapy of lower urinary tract

infections reduced inflammation 39.

142 Sun et al.

Investigación Clínica 66(2): 2025

Under normal circumstances, the body’s

own immune system can resist the invasion

of pathogenic microorganisms, but the im-

mune system has obstacles; the resistance to

viruses will decline, easy to cause viral infec-

tions, such as HPV infection 40. The immune

function of the body mainly depends on T

lymphocytes. CD4+ can coordinate B cells,

promote their differentiation and produce

antibodies; CD8+ are viral T lymphocytes.

When the body’s CD4+, CD8+, and CD4+/

CD8+ decline, the body’s immune function

is disturbed and vulnerable to HPV invasion

41. Our study demonstrated that relative to

the CG, the OG presented better improve-

ments of CD4+, CD8+ and CD4+/CD8+ levels

after therapy, suggesting that Lactobacillus

vaginal capsule combined with recombinant

human interferon α-2b gel could enhance

the immune function of the body, which was

following a study proposed by Ang et al. 42.

In addition, our study pointed out that

relative to the CG, the OG presented a higher

proportion of grade II-III vaginal flora densi-

ty and grade II-III vaginal flora diversity. The

reason is that recombinant human interfer-

on α-2b can regulate immune responses by

activating intracellular signalling pathways

43. The drug acts on immune cells, such as

macrophages and dendritic cells, thereby en-

hancing their phagocytosis 44. Recombinant

human interferon α-2b induces a series of

cell signalling events by binding to specific

receptors, ultimately activating and enhanc-

ing immune cells 45. Besides, HPV infection

is directly related to the dysregulation of

the vaginal microenvironment and the lack

of Lactobacillus, which leads to a vicious

cycle of the disease 46. After the application

of recombinant human interferon α-2b, the

proliferation of antiviral protein in the body

was promoted, and the antiviral ability was

improved 47. At the same time, the lactobacil-

lus vaginal capsule is vaginally administered,

which takes live lactic acid bacteria as the

main component and has a certain antibac-

terial effect, and inhibits the reproduction

of harmful bacteria by producing organic ac-

ids and other antibacterial substances 48. In

addition, Lactobacillus vaginal capsules con-

tain a large number of active lactic acid bac-

teria cells. After vaginal medication, it can

increase the number of beneficial bacteria,

inhibit the excessive reproduction of harm-

ful bacteria, promote the balance of vaginal

flora and maintain a healthy microecological

environment 49.

Moreover, the results of this study

showed that there was no statistical differ-

ence in the total incidence of adverse re-

actions between the two groups, which re-

flected that the adverse reactions produced

by Lactobacillus vaginal capsule combined

with recombinant human interferon α-2b gel

were within the acceptable range and the

safety was reasonable.

In conclusion, our study indicates that

HPV is significantly correlated with vaginal

microecological environment, and catalase,

proline aminopeptidase and BV were closely

related to HPV infection. In addition, the

Lactobacillus vaginal capsule combined with

recombinant human interferon α-2b gel has

practical clinical efficacy, which can reduce

inflammation, promote immune function,

improve vaginal microecological environ-

ment, and is safe in the treatment of pa-

tients with HPV infection.

ACKNOWLEDGMENTS

None.

Funding

There was no funding for the study.

Conflict of interest

There is no conflict of interest with this

manuscript.

Numbers ORCID of authors

• Yanling Sun (YS):

0009-0003-1834-8742

• Li Li (LL):

0009-0007-9455-7027

Papilloma virus infection and microecological environment 143

Vol. 66(2): 131 - 146, 2025

• Wenxin Xu (WX):

0009-0009-8991-6560

• Cen Ma (CM):

0009-0003-1178-199X

Participation of the authors

YS and LL: conceived and designed the

study, as well as collected and analysed the

data. WX and CM: drafted and reviewed the

manuscript, and finally approved the manu-

script.

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