Analysis of the mechanism of action of REBACIN®
Owing to the complexity of persistent hrHPV infection, the development of anti-hrHPV drugs and therapeutic vaccines is still in progress despite many attempts. The results of three different modes of clinical evaluation in clearing persistent hrHPV infection were highly consistent: the negative conversion rate of REBACIN®intervention was 62–70%, whereas the self-negative conversion rate of the control was 13–20.0%. All clinical studies confirmed that REBACIN® is a safe and effective non-invasive clinical intervention for the clearance of persistent hrHPV infection. Recently, Murakami et al. performed a comparative analysis investigating the specific requirements for HPV16 and HPV11 genome replication in ”infected” basal-like keratinocytes. They observed that the HPV16 genome, but not HPV11, is maintained in keratinocytes during tissue culture; however, in the presence of HPV16 E6 and/or E7, HPV11 genomes also replicated in cultured tissue cells.25 This finding indicates that hrHPV E6/E7 oncogenes play a pivotal role in enabling maintenance of hrHPV genome replication in host cells. If the hrHPV E6/E7 oncogene is suppressed, the viral genome cannot continue to replicate and the virus is thereby eliminated. Thus, this finding provides further evidence that REBACIN®eliminates persistent high-risk HPV infection via targeting and inhibiting the expression of hrHPV E6/E7 oncogenes.
A pioneer clinical study in regression of hrHPV associated HSIL
It is well known that hrHPV infection and integration of the hrHPV genome into the host chromosome are key early events in tumor progression of cervical lesions. The viral oncoproteins hrHPV E6 and E7 are responsible for initial changes in epithelial cells. Progression from hrHPV infection of epithelial cells to invasive carcinoma is a prolonged process, taking at least 15–20 years for transition from precancerous lesions to invasive carcinoma. During this period epigenetic changes in oncogenes and tumor suppressor genes occur. After HPV infects the host’s basal squamous cells, it evades the host’s immune system and continues to replicate in the basal epithelial cells. Cervical intraepithelial neoplasia grade 1 (CIN 1) is the stage at which the virus continues to infect cervical cells. CIN 1 lesions may progress to CIN 2/3 within 2–3 years of infection.26Therefore, the regression of cervical lesions can be promoted by inhibiting the expression of hrHPV E6/E7 oncoproteins, restoring the activity of p53 and pRb tumor suppressors, restoring cellular innate immunity, and recovering the repair function of cellular DNA. Based on the previous finding that REBACIN® can effectively target and inhibit the expression of viral E6/E7 oncogenes, several clinical exploratory and pioneering studies have been conducted on the regression of high-grade cervical intraepithelial neoplasia with REBACIN® treatment.
REBACIN®-mediated regression of HSIL
In a recent clinical observation of regression of HSIL (CIN2), 88.89% (16/18) of patients with HSIL (CIN2) and persistent hrHPV infection regressed after one to three courses of REBACIN®treatment, and exhibited clearance of hrHPV infection (Table S1).14
Although variable rates of spontaneous regression have been reported in patients with CIN2/3,27-29 it is difficult to verify because of differences in patient enrollment and duration of clinical observation. In the current study, 88.89% (16/18) of patients with HSIL (CIN2) displayed not only regression but also clearance of hrHPV infection, indicating that REBACIN® intervention is indeed a potential non-invasive therapy for HSIL (CIN2) regression. However, owing to the limitation of participants in this observation, more data from prospective studies are required to accurately evaluate the effect of REBACIN® on HSIL regression.
Combinative effect of REBACIN ® with LEEP
In a previous investigation of patients with HSIL (CIN 2/3) and hrHPV infection who underwent loop electrosurgical excision procedure (LEEP) following REBACIN® treatment, 51 of 53 patients were negative for both CIN and hrHPV infection during the 24-month follow-up assessment. This 96.23% (51/53) disease-free rate was significantly higher than that of 73.47% (36/49) in the LEEP control group. Two patients in the REBACIN® treatment group showed persistent HPV positivity and re-developed CIN during follow-ups, resulting in a disease recurrence rate of 3.77% in the REBACIN® group, while the recurrence rate in the control group was 26.53% (Table S2).30 This study illustrated that REBACIN® treatment in combination with LEEP can effectively enhance the cure rate of high-grade cervical intraepithelial neoplasia and significantly reduce relapse compared to treatment with LEEP only.