Efficacy of a Coriolus versicolor–Based Vaginal Gel in Women With Human Papillomavirus–Dependent Cervical Lesions: The PALOMA Study

DISCUSSION

Approximately 30% of Spanish women younger than 30 years are HPV carriers.25 The likelihood of HPV infection decreases over time, from 47% between the ages of 15 and 19 years to 12% in women older than 45 years.26 The HPV is a fundamental factor for the development of cervical cancer.27 The World Health Organization has recently established the elimination of cervical cancer as a priority medium-term objective.28 This trial aimed to explore whether treatment with Papilocare provides better results than the conventional watchful waiting strategy in improving low-grade cervical lesions, which are the first step in the natural history of cervical cancer.29 Clearance of LSILs after a conservative approach is of approximately 59% within 2 years of the diagnosis. Nevertheless, the likelihood of progression of these lesions to a high-grade squamous intraepithelial lesion within 5 years is 12.7%.30 In addition, treatments for cervical cancer severely compromise the reproductive health of women. In a systematic review of Cochrane, Kyrgiou et al.31 demonstrated a higher baseline risk for prematurity in women with cervical intraepithelial neoplasia, which increased with excisional and ablative treatments. Therefore, the scenario is conflicting, as choosing an excisional or ablative approach for the treatment of LSILs can result in negative reproductive outcomes, but avoiding treatment and just monitoring the disease results in its progression to high-grade lesions in 12 of 100 women. The current recommendation in Spain also includes monitoring the disease.32,33 However, based on the results of this present study, a novel strategy involving Papilocare has become available. The results of this treatment in the repair of low-grade lesions have demonstrated to significantly exceed those obtained with the watchful waiting approach (8 in 10 women achieved a normalization in their lesions).

Spontaneous clearance of the HR HPV occurs in approximately 29% and 41% of cases at 6 and 18 months, respectively.34 The HPV clearance rates seen in our study were higher, i.e., more than twice (63%) the established value at 6 months. This finding has important clinical implications considering the fact that the only guidelines that a physician can provide to their female patients to clear HPV is to maintain their vaginal health or, in the case or active smokers, to quit smoking. This absence of solutions may increase stress levels in many women. Indeed, the results of our study revealed a differential trend with respect to perceived stress, with increased reported levels in the control group and reduced ones in the treatment group. Thus, based on the results of our study, we believe that Papilocare should be included among the advices for the treatment of HPV considering its ability to double the clearance rate of HR HPV.

The results of our study have been replicated in several independent, observational, noncontrolled studies performed in Spanish public university hospitals.35–37 The 6-month effectiveness of Papilocare was evaluated and confirmed in all of the studies (between 53% and 72.5% of cases achieved a negative cytology and/or HPV clearance/reduced viral load). An update of the study by Riera et al.,38 which included a watchful waiting control group, revealed a significantly higher percentage of responders in the group treated with Papilocare compared with the controls (80.0% vs 51.4%). Recent interim results from the observational, multicenter, prospective, single-cohort PAPILOBS study (#NTC04199260) revealed a notable effect of Papilocare at 6 months in repairing HPV-dependent low-grade cervical lesions and clearing HPV (66% and 63% of patients, respectively) under real-life conditions.39 Data obtained in the present study in relation to the HPV clearance, especially in HR HPV patients, are consistent with real-world data obtained in other studies.40 Moreover, in this trial, the degree of cervical re-epithelization was significantly higher with Papilocare compared with the control group. This beneficial effect on re-epithelization was also observed by Palacios et al.15 in a pilot study performed with 21 asymptomatic non–HPV-infected women, in which women treated Papilocare achieved improved cervical re-epithelization (from 3.1 to 4.4 according to the same cervical epithelization scoring system used in the present study). Similarly, Gálvez et al.16 reported a significant 20% improvement in cervical re-epithelialization in HPV-positive lesion-free women treated with Papilocare (3.8 vs 4.5) compared with baseline.

In addition, treatment with Papilocare is safe, as most AEs reported in this study were mild or moderate in severity. Moreover, most of the participants were satisfied with the treatment, and therapeutic adherence exceeded 90%. Nevertheless, our study has certain limitations: (1) the lack of information about cofactors for the progression of cervical HPV infection to cancer, such as smoking41 (lacking in the present study), or adjusting all analyses by covariables in patients, which could have avoided potential interferences in the results, and (2) it should be noted that we used a cytology plus concordant colposcopic observations to evaluate the normalization of lesions. Biopsies were not performed in the study because all women presented low-grade cytological alterations with normal colposcopy or grade 1 changes, decision in agreement with guidelines recommendations,32,42 and also because biopsy can modify the natural history of the lesion. Thus, the present article does not provide evidence on the treatment and prevention of dysplasia; (3) colposcopic concordance and epithelization assessments were also performed in an unblinded manner; thus, subjectivity associated with these outcomes could have resulted in an assessment bias; (4) the “partial clearance” was included as part of the overall HPV clearance secondary end point (see method section) according to the concept that 1 HPV-related lesion is very frequently caused by just 1 viral subtype, despite the presence of multiple HPV types.43 With regression of the lesion as well as clearance of one of the oncogenic HPV subtypes, it is likely that the causative virus has been eliminated. Nevertheless, the risk of future lesions and dysplasia remains if the residual HPV subtype is a HR HPV, (5) Given the exploratory nature of the study and the concomitant determination of the sample size, the number of patients was insufficient for identifying statistical differences in certain secondary variables for which tendencies were observed. (6) Moreover, for our initial exploration, we aimed to analyze all women, not only those with HR HPV, and to obtain results that could be extrapolated for the general population. Additional subanalyses that already were planned in the protocol will determine the efficacy and safety of Papilocare on HR HPV patients. Further ongoing clinical trials have already included only HR HPV patients (the PAPILOCAN clinical trial #NCT04210336 and the PALOMA II clinical trial #NTC04199078). Besides these limitations, comparisons made with the conventional approach applied in standard clinical practice are very useful and provide evidence that new interventions for the management of HPV are required.

CONCLUSIONS

Treatment with Papilocare has demonstrated a better clinical benefit than the conventional watchful waiting approach in clinical practice for HPV-positive patients, especially for those with HR HPV. Papilocare has shown significant efficacy in the treatment of low-grade cervical lesions associated with HPV and a positive trend in increasing HPV clearance after a 6-month period. Moreover, it shows good safety and tolerability and confers additional benefits, such as a significant improvement in cervical re-epithelization, a positive trend in perceived stress reduction, and high therapeutic adherence.

ACKNOWLEDGMENTS

Footnotes

REFERENCES