We conducted a systematic review and meta-analysis according to the latest Preferred Reporting Items for Systematic Reviews and Meta Analyses(PRISMA)(Page et al.,2021)and registered it in PROSPERO(No.CRD42023393340).

We conducted a comprehensive search of PubMed, MEDLINE,Cochrane Library, Web of Science,China Biology Medicine(CBM),SinoMed,China National Knowledge Infrastructure(CNKI),VIP database,and Wanfang database,using the synonym of "Condyloma acuminatum" and "Paiteling",and restricting the search to articles written in English and Chinese up until December 1,2022.We also double-checked the list of included studies to identify any additional eligible trials that were not found through the initial search.

The eligible studies for inclusion in this review met the following criteria:

1) Participants: Individuals diagnosed with CA based on typical clinical manifestations and history.For atypical and exceptional skin lesions,ancillary examination(acetowhite test,dermatoscopy,vaginal speculum examination,anoscopy)and laboratory examination (histopathologic biopsy, nucleic acid amplification test)could be used to support the diagnosis.There were no restrictions on stage,age, race,sex,complications,or previous treatment.

2) Interventions: PTL administered alone or combined with physical therapies.The usual clinical application method of PTL is to dilute the potion with normal saline at a ratio of 1:50 as a topical agent for compressing and cleaning of warts(once a day for a seven-day course).

3) Control group:Based onl physical therapy with CO2 laser therapy, aminoketovaleric acid (ALA) photody namic therapy, microwave therapy, high-frequency electrocautery,high-frequency electroion therapy,and cryotherapy.There are no restrictions on which way is chosen regardless of whether recombinant human interferon alpha-2b is added.Therefore,the comparison is set asfollows:(1)single therapy group:PTL versus physical therapies,(2)combination therapy group:PTL plus physical therapies versus physicaltherapies.

4) Outcomes: The primary outcome was clinical effectiveness,and the secondary outcomes were recurrence rate, the negative conversion rate of HPV and immune cell levels. The incidence of adverse events was chosen as the safety indicator.

5) Studies were designed as RCTs.

Studies that met any of the following criteria were considered ineligible for inclusion:

1) Reviews, case reports, animal studies and other non-RCT studies.

2) Studies that lack consistency with this review in research content and intervention methods.

3) Conference papers,inaccessible data and papers with a sample size of less than 10.

4) Repeated papers count as one.

Endnote 9 and manual review were used to remove any duplicates.Two authors(G.Jin and YH.Liu) carried out the data extraction independently,using a common standardized form.In the event of missing or unclear data,we contacted the authors to obtain clarification. If we did not receive a response, we would either measure the data or exclude it based on our best judgment. In case of disagreement,a third author(ZJ.Zhao)would be consulted for a joint decision. The following information was extracted from the literature:first author,publication date,age,sex,sample size,treatment course,intervention ways,and outcomes.

To assess the quality of these trials,we utilized the risk of bias tool recommended in the Cochrane Handbook.Two reviewers independently conducted the assessment,covering seven areas: random sequence generation,allocation concealment,blinding of participants and personnel,blinding of outcome assessment,incomplete outcome data,selective reporting,and other sources of bias.Any disagreements were resolved through discussion until a consensus was reached.

We conducted a comprehensive data analysis using Revman 5.4 and Stata 15.0.Continuous outcomes were expressed as mean difference(MD)with 95% confidence intervals (CI) between the experimental and control groups, and dichotomous data were presented as risk ratios(RR)with 95% CI. We evaluated heterogeneity using the I² statistic, with low heterogeneity considered as I²<50% and high heterogeneity as I²>50%.If heterogeneity was low,we applied a fixed-effects model for the meta-analysis,and if not,a random-effects model was utilized.To explore the source of heterogeneity and assess the robustness of the results,we performed subgroup and sensitivity analyses. Subgroup analyses were pre-specified based on the type of interventions (PTL versus physical therapies, PTL plus physical therapies versus physical therapies) and post-hoc subgroups were based on the type of physical therapy and the gender of subjects. Publication biases were assessed by conducting funnel plots, egger’s test,and begg’s test (P value represents the significance of bias,P<0.05 indicates significant publication bias,otherwise, no significant bias).If the funnel plot was symmetrical,it indicated the absence of publication biases, while any asymmetry was analyzed using the trim and fill method to assess the impact of publication biases. If the change in CI before and after applying the trim and fill method is less than 1, this indicates that publication bias has little impact and the results are relatively robust.

396 eligible studies were identified in our literature search,including 132 from the Wanfang database,114 from CNKI,73 from SinoMed,64 from VIP,5 from MEDLINE,4 from Web of Science,3 from PubMed,1 from Cochrane Library and 0 through manual search of other resources.After excluding 257 duplicates, we performed further selection and deleted 91 based on title and abstract screening.17 studies were then excluded for intervention methods inconsistent with the requirements of this review, non-randomized controlled trials, or inability to obtain the full text. Finally, 31 were included and assessed in the pooled analysis.The process of the literature search is shown in Fig.1.

A total of 31 RCTs with 2868 participants(1426 in the experimental group and 1442 in the control group)were included.The maximum sample size in the experimental group was 96, in the control group was 156, and the minimum sample size was 27 in both groups. All included trials were conducted in China and published between the years 2008 and 2022. The overview of their characteristics is shown in Table 1.

Of all, 17 trials compared PTL alone with physical therapies, and 13 compared PTL plus physical therapies with physical therapies. The types of physical therapies in the studies can be divided into 12 studies using CO₂ laser therapy(Tang and Jin, 2011; Wang et al.,2012;Zhou,2013;Cui,2018;Cai et al.,2013;Chen and Chen,2014;Huang,2009;Zhang,2014,2017b;Li, 2016;Guo, 2013; Ma et al., 2022),6 using ALA photodynamic therapy(Liu,2014;Li,2018;2017a; Lu,2017;C.C Xu et al.,2020;Bi et al.,2013),6 using microwave therapy(Yao and Zhang,2013;Zhang et al.,2017;Ma et al.,2021;Wang et al.,2020a;Zhu and Li,2010;Cheng,2018),4 using high-frequency electrocautery(Zhu,2008;Zheng et al.,2018;Wang et al.,2020b;Zhu and Xin,2014),2 using high-frequency electroionization(Wu et al.,2020;Bi,2012),and 1 using cryotherapy (Wang et al.,2021b).As for the gender of the subjects,it can be further divided into 6 with male subjects(Chen and Chen,2014;Guo,2013;Li, 2018;Lu,2017;Wu et al.,2020;Zheng et al.,2018),7 with female subjects (Huang,2009;Tang and Jin,2011;Wang et al.,2021a;Wang et al.,2012;Yao and Zhang,2013;Zhu and Li, 2010;Zhang,2014),and the other 18 with both male and female subjects. The basic characteristics of physical therapy and gender are shown in Fig.2.

The Cochrane collaboration criteria were used to assess the quality of the included studies. For randomization, 5 studies explained the methods they use, which were assessed as low risk, including 3 using the random number table method(Cui,2018;Wu et al.,2020;Xu et al.,2020),2 using the simple random sampling method(Zhang,2017b;Chen and Chen,2014).None of the included studies described the concealed allocation scheme, which was rated as unclear risk. Since the blinding method was not reported by any of the studies due to the difference in intervention methods of the experimental group and the control group, making it unlikely to conduct double-blinded experiments, all studies were assessed as high risk.The outcome of evaluating the efficacy of CA was considered relatively objective, so all trials were considered low risk. As for the missing outcome data,1 study only reported the clinical efficacy rate(Li,2018),and another only reported the recurrence rate, so it was assessed as unclear risk(Zhu,2008).None of the 31 included studies mentioned non-selective reporting of research results,and there was not enough information to determine whether there was high or low bias,so it was assessed as an unclear risk (Fig.3).

30 trials reported the clinical effectiveness, with the exception of‘Zhu,2008’.17 focused on PTL administered alone and 13 investigated combined use of PTL and other therapies.The results showed strong heterogeneity among the trials(P<0.00001,I²=81%),as well as high heterogeneity between the two subgroups(P=0.14,I²=54%).Therefore, a random effects model was chosen for analysis.The meta-analysis showed that PTL significantly improved the clinical effectiveness comparing with the physical therapies, whether in single therapy groups(RR=1.39,95% CI[1.24, 1.56];P<0.00001)or in combination therapy groups(RR=1.60,95% CI[1.38,1.86];P<0.00001).Furthermore,we found that the combination therapy group had better efficacy with a statistically significant difference(Fig.4).To further understand the reasons of the high heterogeneity, we further performed two subgroup analyses according to the types of physical therapies and the gender of the subjects.

(1) Subgroup analysis according to different physical therapies

The results indicate that the heterogeneity of the ALA photodynamic therapy(P=0.16, I²=37%),high-frequency electroion therapy(P=0.35, I²=0%)and microwave therapy(P = 0.41,I²=1%) groups was significantly reduced,compared to the CO₂ laser therapy(P<0.0001,I²=72%)and high-frequency electrocautery therapy (P<0.00001,I²=94%).However,since only one study was included in the cryotherapy group,the heterogeneity analysis was not performed for this type of treatment.Overall,the random effect model was used for consolidation.These findings suggest that different physical therapies in the control group may have a significant impact on the results of the meta-analysis.At the same time, since the experimental groups were intervened with PTL or PTL plus physical therapies, the control groups received various physical treatments, the subgroup analyses also indirectly compared the efficacy of the physical therapies. As shown in Table 2., the effectiveness of ALA photodynamic therapy was comparable to that of PTL(RR =1.20,95% CI [1.09,1.32];P=0.0002),while high frequency electroion therapy(RR=2.08,95% CI[1.51,2.86];P<0.00001),CO₂ laser therapy(RR=1.67,95% CI[1.41,1.97];P<0.00001)and microwave therapy(RR=1.34,95% CI[1.21,1.48];P< 0.00001)were less effective than PTL,and the difference was statistically significant.

(2) Subgroup analysis based on the gender of subjects

As for the gender subgroup analysis,the result indicates that the heterogeneity of female patients was reduced(P=0.45, I²=0%),while there was no significant change between the male subgroups(P<0.00001,I²=88%)and those containing both male and female patients(P<0.00001,I²=81%).Additionally,the meta-analysis revealed that compared with conventional physical therapy,PTL had a higher effectiveness in women(RR=1.35,95% CI[1.24,1.47];P<0.00001)and men(RR=1.40,95% CI[1.04,1.89];P=0.03),but the heterogeneity islower in women. (Table 2.).

(1) Recurrence rate at 3-month follow-up

11 studies reported the recurrence rate at 3-month follow-up(Chen and Chen,2014;Guo,2013;Lu,2017;Ma et al.,2021,2022;Bi et al.,2013;Wang et al.,2012;Wu et al.,2020;Zhang,2014;Zheng et al.,2018; Zhou,2013),including 5 using PTL along and 6 using PLT in combination with other therapies.For a low heterogeneity,the fixed-effects model was used.In the PTL groups,the 3-month recurrence rate was 4.25%(11/259),and that of the control group was 18.9%(48/254). The comparison between the two groups was statistically significant(RR=0.23,95% CI[0.13,0.43];P<0.00001).In the combination groups,the 3-month recurrence rate of PTL was 7.66%(21/274)and that of the control group was 26.20%(71/271).The comparison between the two groups was statistically significant(RR=0.29,95% CI[0.19,0.46];P < 0.00001).The results of the meta- analysis showed that PTL could significantly reduce the recurrence rate of CA patients at 3-month follow-up(RR=0.27,95% CI[0.19,0.39];P<0.00001),and the effect of the PTL groups was similar to that of the combination groups.(Fig.5).

(2) Recurrence rate at 6-month follow-up

14 studies reported the recurrence rate at 6-month follow-up(Cai et al.,2013;Ma et al.,2021;Tang and Jin,2011;Wang et al.,2021a;Bi,2012; Li,2016;Xu et al.,2020;Yao and Zhang,2013;Wang et al.,2020a;Liu, 2014;Zhang,2017a;Zhu and Xin,2014;Zhang et al.,2017;Zhang,2017b),including 7 using PTL alone and 7 using PTL plus other therapies.The heterogeneity test showed that there was no significant heterogeneity among the studies(P=0.27,I² = 21%),so the fixed effect model was used.Subgroup analysis showed that in the PTL groups,the recurrence rate at 6-month follow-up was 7.01%(23/328)in the experimental group and 20.41(79/387) in the control group,and the comparison between the two groups was statistically significant (RR=0.32,95% CI[0.21, 0.48];P < 0.00001).As for the combination groups,the recurrence rate at 6-month follow-up was 10.12%(33/326) in the experimental group and 35.67%(107/300) in the control group,and the comparison of between the two groups was statistically significant (RR=0.29,95% CI[0.20, 0.41];P < 0.00001)(Fig. 6).In general, the follow-up rates reported in the literature varied widely.Our analysis reveals that the recurrence rate was higher at 6 months than at 3 months. China‘s clinical diagnosis and treatment guidelines for CA state that patients infected with HIV or other immunocompromised patients may still have a high risk of recurrence even after successful treatment and removal of warts. These patients should be advised to monitor any changes in the affected areas and see the doctor regularly for extended follow-ups. Scientists generally agree that if no more new warts are found after 6-9 months of treatment, the risk of recurrence decreases. Therefore, after 3 months of treatment, the follow-up interval may be appropriately extended to 6-9 months after the last treatment, depending on individual conditions.

2 studies reported the negative conversion rate of HPV after 1 and 4months of treatment (Zhang,2017a;Zhang et al.,2017).The heterogeneity test showed that there was no significant heterogeneity between them,so the fixed effect model was used.Compared with the control group,after 1 month of treatment,the negative conversion rate of HPVin the experimental group was equivalent to that in the control group,with no significant difference(RR=1.37,95% CI[0.98,1.92];P= 0.07)(Fig.7A).However,after 4 months of treatment,the negative conversionrate of HPV in the experimental group was 1.15 times higher than that inthe control group(RR=1.15,95% CI[1.02,1.3];P=0.02),with astatistically significant difference (Fig.7B).Therefore,we speculatedthat prolonging the use of PTL according to the patient‘s conditions has aprotective effect on improving the negative conversion rate of HPV andtreatment efficacy.

2 studies reported improvement in T-cell subsets CD4⁺,CD8⁺ and CD4⁺/CD8⁺ ratio(Ma et al.,2021,2022).The heterogeneity test showed that there was significant heterogeneity between them for CD4⁺ and CD8⁺ cells(Fig.8A and 8B).Therefore,a random effects model was used for analysis.For the CD4⁺/CD8⁺ ratio,there was no significant heterogeneity(P=0.69,I²=0%),so the fixed effects model was used (Fig.8C).The metaanalysis showed that PTL could significantly increase the CD4⁺ cell levels(MD=7.56,95% CI[3.76,11.36];P<0.0001)and regulate the CD4⁺/CD8⁺ ratio(MD=0.49,95% CI[0.39,0.59];P<0.00001). However,CD8⁺ cells did not appear to improve.Due to the apparent heterogeneity between CD4⁺ and CD8⁺ indices,we further reviewed the literature to investigate the heterogeneity between the two studies.We found that one study had a treatment duration of 3 months and another had 9 months,suggesting that the inconsistent duration may be the main cause of the high heterogeneity.

A total of 20 studies reported the occurrence of adverse effects (Lu,2017;Zhang,2017a;Chen and Chen,2014;Cui,2018;Guo,2013;Huang,2009;Li, 2016;Zhang,2014;Zhang,2017b;Wang et al.,2020b;Bi, 2012;Cheng,2018;Zhang et al.,2017;Zhu and Li,2010;Bi et al.,2013;Zhou, 2013;Ma et al.,2022;Wang et al.,2012;Wang et al.,2021a;Zhu and Xin,2014).The adverse events of PTL mainly involved local mucosal erythema,pain,mild erosion of the skin and mucosa, pruritus,etc.(Table 3.),which were tolerable by the patients.In addition,the symptoms disappeared spontaneously after 3–5 days of drug withdrawal,without any serious side effects.

To determine whether any individual study can influence the overall pooled results, sensitivity analysis was performed by sequentially omitting one study at a time. The result showed that the 95% CI was consistent and overlapped extensively, indicating that the meta-analysis results were largely stable(Fig.9).Publication biases were examined for both clinical effectiveness and recurrence rate. The funnel plot of clinical effectiveness was asymmetrical(Fig.10A) and the begg’s and egger’s tests showed a significant publication bias(P<0.05),which might be due to the lowquality of the included studies,small sample sizes,small negative results.When there are publication biases,the trim and fill method was applied to further analyze,and the results showed that publication biases had a minimal effect and the results were mostly stable.Before applying the trim and fill method,Q=95.638 (P=0),the combined result for clinical effectiveness was log RR=0.37(95% CI[0.29,0.45]).After six iterations using the linear method,we obtained the following results,the number of missing trials was estimated to be 12,the heterogeneity was Q=152.82(P=0) and the combined result was log RR=0.25(95% CI[0.16,0.33])(Fig.10B).The funnel plot was drawn based on the recurrence rate at 3-month and 6-month,which showed basic symmetry(Fig.10C and D).Begg’s bias test (P_3-month=0.640>0.05, P_6-month = 0.58>0.05) and egger’s bias test (P3_-month=0.513>0.05, P6_-month=0.27>0.05)also indicated that there was no significant publication bias.

In this review,we assessed the efficacy of PTL in patients with CA and included 31 RCTs with 2868 participants.The results demonstrated that PTL was highly influential effective in alleviating CA symptoms,reducing recurrence rates,improving the negative conversion rate of HPV,and regulating immune functions.Although we conducted a prespecified subgroup analysis to examine the effectiveness of PTL,we still found high heterogeneity among the trials.We further performed two subgroup analyses and discovered that the heterogeneity persisted.Through the literature review, we found that the different physical therapies differed somewhat in treatment principles,instrumentation and operating methods in the control group, and we speculated that it might be the other source of heterogeneity.Especially,the highfrequency electrocautery subgroup showed the highest heterogeneity(P<0.0000,I₂=94%).We propose two possible reasons for this:one is the limited number of trials included, and the other is that the treatment was different in terms of gender and location of warts between the two trials.

Furthermore, the gender subgroup analysis revealed that the heterogeneity within the female group was eliminated(P=0.45,I²=0%),whereas there was no significant change in the male group (P<0.00001,I²=88%)and in the group consisting of both male and female patients(P<0.00001,I²=81%).A careful reading of the literature revealed that of these 30 studies,6 studies of male patients reported warts located in a wider range of areas,including the glans,coronal sulcus,frenulum,penis,urethral orifice,perianal area and scrotum,while 7 studies of female patients reported a more concentrated distri- bution of warts,mainly in the labia,perianal area,the vaginal wall and cervix.It turned out that the varying locations of warts between men and women were another source of heterogeneity.Based on these findings,we conjectured that the type of physical therapies,gender,and wart location might be the primary sources of the heterogeneity in clinical effectiveness,which explains the discrepancies in efficacy between various treatment options.Therefore,in clinical diagnosis and treatment,patients should receive personalized treatment,according to their conditions and wart locations to choose the most appropriate option(Wu et al.,2022).

In this analysis,we found that PTL exhibited a significantly greater reduction in the follow-up recurrence rate and improvement of the negative conversion rate of HPV, which was consistent with a metaanalysis published by Liu Lianhui on the efficacy of PTL in treating high-risk HPV infection(Liu et al.,2022).It is well-known that HPV infection is the leading cause of cervical cancer,which ranks fourth among all female malignant tumors worldwide(Ikenoyama et al.,2022;Yousefi et al.,2016).Some studies have suggested that PTL contains indigo,brassin and glycoside compounds known to have broad-spectrum antibacterial and antiviral properties,which can change the microenvironment for HPV and increase human epidermal cell metabolism(Purzycka-Bohdan et al.,2022).In addition,our previous studies have shown that PTL could induce apoptosis of cervical cancer cells and reduce the incidence of cervical cancer by inhibiting the E6/E7-Pi3k/Akt signaling pathway and may have significant benefits for women’s health (Liu et al., 2023).T lymphocytes are the primary effector cells responsible for cellular immunity (Dai et al., 2023).Clinical studies have shown that the expression of CD4⁺ T lymphocytes decreases in CA patients,resulting in a limited immune response to HPV infection and inhibited cellular immune function(H.Xu et al.,2020;Gu et al.,2022).In this study,we found that PTL was able to increase the amount of CD4⁺ cells and the CD4⁺/CD8⁺ ratio,which has a significant effect on the regulation of immune cell function.

The literature indicates that adverse reactions associated with theuse of PTL in treating CA include genital redness, swelling,pain,pru- ritus,etc.Most of these reactions were related to the increased sensitivity of the genital tract caused by the disruption in the hormone levels and could resolve spontaneously after drug withdrawal. Studies suggest that the low side effects of PTL may be attributable to the supercritical carbon dioxide extraction technology,which removes toxic and ineffective components in the herbs while retaining high concentration of the active compounds.The macromolecules in the drug can pass through the epidermal cell space and reach the basal layer,but do not enter the dermis or damage it and subcutaneous tissue.Therefore,PTL is a good choice for patients planning to become pregnant as it can effectively avoid cervical structural damage caused by physical therapies(Berrada et al.,2021).

We acknowledge that this study has some limitations.For instance, the analysis of the negative conversion rate of HPV and immune cells may have low reliability since only two studies were included.However,they are still chosen for inclusion because of their high research quality(Mohammed et al.,2023;S.R.Yousefi et al.,2021;Mehdizadeh et al.,2023).In addition,the dosages,frequencies,and treatment courses vary slightly in some studies,and since PTL is a TCM reagent,all included studies were conducted in China only(Wang et al.,2022).Finally,although subgroup analyses were performed,the results showed that the heterogeneity between groups was generally high,and some of the causes remained unexplained.

This systematic review and meta-analysis has confirmed a significant role for PTL in relieving CA symptoms,reducing recurrence rates,improving the negative conversion rate of HPV,regulating immune cell function,and providing better safety profiles and benefits for women’s health.The subgroup analysis suggests that the type of physical therapies,gender and wart location might be the primary sources of heterogeneity in clinical efficacy.However,due to methodological limitations and heterogeneity,these results should be interpreted with caution.Therefore,further rigorous RCTs are recommended to strengthen this clinical evidence.

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