Evaluation Of Clinical Efficacy And Immune Effect Of Nocardia Rubra Cell Wall Skeleton For External Use In The Treatment Of Persistent Cervical HPV Infection

Objective:To investigate the clinical efficacy and immune effect of Nocardia rubra Cell Wall Skeleton for External Use(Nr-CWS)in the treatment of persistent cervical infection with high-risk human papilloma virus(HPV),and to provide basis for its further clinical promotion.Methods:A total of 110 patients with persistent cervical HPV infection with high risk were selected from the department of gynaecology of Qingdao Women’s and Children’s Hospital from January 2018 to January 2020.According to the patients’wishes,80 patients were randomly divided into study group and control group by stratified group.In the study group,50patients were treated with 120ug/time of Nr-CWS,applied to the cervix once every other day,10 times as a course of treatment(1 month in total).The control group(n=30)was treated with recombinant human interferonα2b vaginal effervescent tablet(Jinshuxi)combined with Baofukang suppository.Baofukang suppository was treated with vaginal medicine once a time and Jinshuxi vaginal medicine once a time,once every other day,10times a month.The two drugs were alternately used for 3 months.According to the patients’wishes,30 patients who refused treatment were included in the follow-up group.Regular follow-up was conducted only according to the requirements without any treatment.General data of patients in the three groups,such as age at the time of treatment,course of HPV infection,pregnancy and delivery,etc.,were collected.Gynecological fluid based thin-layer cell test(TCT),non-amplification qualitative test of human papillomavirus m RNA(HPVE6E7 m RNA)and colpopharyngeal pathology results were collected before and after treatment.The level of immune cells in peripheral blood,the level of various immune factors in vaginal lavage fluid and the occurrence of adverse reactions before and after treatment were compared.Results:1.There were no significantly difference among three groups in age,pregnancy times,parity times,HPV type,and HPV infection course at the time of admission(P>0.05).2.Comparison of intra-group results between the three groups:2.1 Study group:47 patients completed the treatment and follow-up(the remaining 3patients did not complete the treatment as required and were excluded from this study).According to the efficacy evaluation indexes,32 cases were cured and 15 cases were not cured,with a negative HPV conversion rate of 68.09%.The ratio of CD4~+T and CD4~+/CD8~+in peripheral blood lymphocyte subsets were increased(9.13±2.39)and(0.29±0.11),which were statistically different with those before treatment(P<0.05).There was no statistical difference in the ratio of CD8~+T before and after treatment(P>0.05).The concentrations of Interleukin-2(IL-2),Interferon-γ(Interferon,IFN-γ),and Tumour neciosis factor-α(Tumour neciosis factor-α,TNF-α)in vaginal lavage fluid were increased(9.31±3.77 ng/l),(7.66±3.48 ng/l),(6.05±2.73 ng/l),and the concentration of IL-4 was reduced(4.73±2.41ng/l),all of above were significantly difference between those before treatment(P<0.05);There was no statistical difference between IL-6 and IL-10 before and after treatment(P>0.05).2.2 Control group:28 patients completed the treatment and follow-up(the remaining 1 patient was lost to follow-up,and the other 1 patient was added to other treatments by himself,all of which were excluded from this study).According to the efficacy evaluation indexes,12 patients were cured and 16 patients were not cured,with a negative conversion rate of 42.86%.The ratio of CD4~+T and CD4~+/CD8~+in peripheral blood lymphocyte subsets were increased(5.17±2.23)and(0.19±0.11),which were significantly different with those before treatment(P<0.05).There was no statistical difference in the ratio of CD8~+T before and after treatment(P>0.05).The concentrations of IL-2,IFN-γ,and TNF-α in vaginal lavage fluid were increased(4.68±3.91ng/l),(4.03±2.17 ng/l),(3.12±2.61 ng/l),and the concentration of IL-4 was reduced(2.60±1.74 ng/l),and all of above are significantly different from those before treatment(P<0.05);There was no statistical difference between IL-6 and IL-10 before and after treatment(P>0.05).2.3 Follow-up group:30 patients completed the follow-up,according to the efficacy evaluation indexes,5 cases turned negative,25 cases did not turn negative,natural conversion rate was 16.67%.The ratio of CD4~+T,CD8~+T and CD4~+/CD8~+in the peripheral blood lymphocyte subsets were not significantly different before and after follow-up(P>0.05);The concentrations of IL-2,IL-4,IL-6,IL-10,IFN-γ and TNF-α in vaginal lavage fluid were not significantly different before and after follow-up(P>0.05).3.Comparison of the results between the three groups after treatment and follow-up:3.1 Comparison of changes of various immune cells in peripheral blood:The ratio of CD4~+T and CD4~+/CD8~+in the study group were significantly higher than that in the control group,and both the study and the control group were significantly higher than that in the follow-up group,with statistical differences(P<0.05).There was no statistical difference in the ratio of CD8~+T among those three groups(P>0.05).3.2 Comparison of the concentration changes of various immune factors in vaginal lavage fluid:The increase in concentrations of IL-2,IFN-γ,TNF-α and the decrease in IL-4 in the study group were greater than those in the control group,and both the study and the control group were greater than those in the follow-up group,with statistical differences(P<0.05).There was no statistical difference in the concentrations of IL-6 and IL-10 among those three groups(P>0.05).3.3 Comparison of therapeutic efficacy of HPV:The negative conversion rate of HPV in the study group was higher than that in the control group.The negative conversion rate of HPV both in the study and the control group were higher than the natural conversion rate of the follow-up group,with statistical differences(P<0.05).4.The effect of age on the treatment of HPV:There was no statistical difference in negative conversion rate of HPV among different age groups(P>0.05).In all age groups,the negative conversion rate of HPV in the study group was higher than the natural conversion rate in the follow-up group,with statistical differences(P<0.05).There were no statistical difference between the study group and the control group,the control group and the follow-up group(P>0.05).5.Comparison of different HPV types:In each group,the negative conversion rate of HPV16/18/45 was lower than that of other high-risk types,with statistical differences(P<0.05);For HPV16/18/45 and other high-risk HPV infections,the negative conversion rate of HPV in the study group was higher than the natural conversion rate in the follow-up group,with statistical difference(P<0.05).There were no statistical difference between the study group and the control group,the control group and the follow-up group(P>0.05).6.There were no obvious adverse reactions during the period of treatment and follow-up.Conclusion:1.Both Nr-CWS and recombinant human interferonα2b vaginal effervescent tablet combined with Baofukang can increase the proportion of CD4~+T and the ratio of CD4~+/CD8~+in peripheral blood,increase the local levels of IL-2,IFN-γ and TNF-α,decrease the level of IL-4,and improve the local and systemic immune function of the cervix.It promotes negative HPV infection,but Nr-CWS is more effective.2.Topical application of Nr-CWS can improve the HPV negative conversion rate of high-risk HPV persistent infection in all ages.3.The HPV conversion rate of persistent HPV16/18/45 patients was lower than that of persistent HPV infection of other high-risk HPV types.