Systematic Review On Efficacy And Safety Of Heat-clearing And Detoxification Therapy In TCM For People Living With HIV And Clinical Trial On Immunological Non-responders By Artesunate

IntroductionAntiretroviral therapy(ART)is widely recommended intervention for people living with HIV(PLWH),which could greatly reduce virus load,promote immune reconstruction,improve clinical symptoms,and delay disease progression.ART has made great progress and achievements in treatment of PLWH in the past decades,however,it is limited by lifelong medication,HIV reservoir,adverse reaction,drug resistance,and non-AIDS-defining illnesses.Partly long-term ART-treated PLWH could not obtain ideal immune reconstruction after virological success,who are defined as immunological non-responders(INRs).Compared to immunological responders,INRs are characterized by more non-AIDS-defining illness,faster disease progress,and higher mortality.Among past 30 years,traditional Chinese medicine(TCM)made meaningful exploration on the prevention and treatment for HIV/AIDS,there were numerous achievements on pathogeny,pathogenesis,intervention,guidelines,and efficacy evaluation from the perspective of TCM.At present,immune reconstruction is the urgent problems for PLWH,the mechanism of immune activation and chronic inflammation has attracted more and more attention.Based on previous evidences in epidemiological investigation and clinical trials,this study pay attention on the clinical efficacy and safety of heat-clearing and detoxification therapy for PLWH,providing more choices for treatment and improving the clinical efficacy of existing treatment methods.Part 1 Multi-dimensional visualization analysis on the prevention and treatment of HIV/AIDS with TCMObjective:To explore the trends and frontiers in field of TCM on HIV/AIDS among the past 10 years through the principles and applications of analyzing a citation space.Methods:We conducted electronic search and handsearching to obtain related reports collected by China national knowledge infrastructure,Wanfang database,Chinese medical journal database,and China biology medicine disc from January 01,2011 to December 31,2020.We carried out multi-dimensional visualization analysis on the prevention and treatment of HIV/AIDS with TCM,visualizing clusters of year of publication,research topics,journals,authors,institutions,keywords by using CiteSpace and VOSviewer software.Results:A total of 628 reports were included in our study,88(14.01%)of them were published in 2011,after that,the number of published reports showed an overall downward trend.In the field of the prevention and treatment of HIV/AIDS with TCM,the journal with the largest number of related reports was China Journal of Traditional Chinese Medicine and Pharmacy,up to 172 first authors were from Henan province,Prof.XU Liran from the First Affiliated Hospital of Henan University of TCM was the author with the largest number of reports,the research topics mainly focus on immune reconstruction(31.53%),TCM syndrome(8.63),etiology and pathogenesis(7.03%),syndrome differentiation(6.43%),and AIDS-defining skin lesions(6.43%).11 clusters are formed in keywords analyzation,which are "#2 TCM syndrome","#3 syndrome differentiation","#5 etiology and pathogenesis","#6 clinical efficacy","#7 non-pharmacological therapy","#8 co-infection","#9 lung infection","#10 oral ulcer","#13 diarrhea","#14 immunological non-responders",and "#18 fever".Conclusion:In the past 10 years,the field of TCM on HIV/AIDS has entered a relatively mature stage,representing a relatively stable networks of teams and collaboration.However,there are some limitations on studies of AIDS-defining illness and non-AIDS-defining illness,which are needed to be improved in our further study.Part 2 Strategies in TCM on immune reconstruction for PLWHTo systematically and comprehensively summarize and explore the achievements on immune reconstruction in the treatment of integrated traditional and Western medicine(ITWM)on HIV/AIDS,so as to provide clinical plan with evidences.PLWH would benefit from ITWM,which is manifested in improving clinical efficacy,promoting immune reconstruction,reducing adverse reaction or drug resistance,and preventing the occurrence of opportunistic infection.Principles of supplementing and strengthening Qi,invigorating spleen and infiltrating dampness,warming spleen and kidney,circulating blood and dispelling stasis,and heat-clearing and detoxification are proved to promote immune reconstruction for PLWH in TCM.Further study on start time,mechanism,guidelines,and efficacy evaluation on HIV/AIDS might be inevitable for ITWM.Part 3 Clinical efficacy and safety of heat-clearing and detoxification therapy in TCM for PLWH:a systematic reviewObjective:To evaluate the clinical efficacy and safety of heat-clearing and detoxification therapy in TCM on immune reconstruction for PLWH,so as to provide evidence-based strategies for the treatment of HIV/AIDS.Methods:We conducted electronic search and handsearching to obtain relevant reports collected by China national knowledge infrastructure,Wanfang database,Chinese medical journal database,China biology medicine disc,PubMed database,Cochrane Library,and EMBase database from the establishment of the database to January 01,2022.We identified reports by detailed and strict inclusion criteria,then carried out research screening,data extraction,quality assessment,and statistical analysis by Review Manager 5.3 and Stata 14.0.Results:15 randomized controlled trials were included in our study,and most of reports(86.67%)were identified as high quality.The results of Meta-analysis showed that heat-clearing and detoxification therapy in TCM has certain advantages in increasing the level of CD4+T cell counts(SMD=0.73,95%CI=[0.29,1.16]),enhancing clinical efficacy of immune reconstruction(RR2.15,95%CI=[1.21,3.82]),inhibiting HIV viral load(MD=-0.32,95%CI=[-0.60,-0.03]),and improving clinical syndromes(SMD=-1.41,95%CI=[-1.93,-0.89]).According further subgroup analysis,the intervention mode of single heat-clearing and detoxification therapy in TCM did not significantly improve CD4+T cell counts(SMD=0.23,95%CI=[-0.81,1.28]);Compared with single ART treatment,heat-clearing and detoxification therapy combined with ART treatment strategies would be instrumental in CD4+T cell counts(SMD=0.98,95%CI=[0.48,1.49]).In terms of safety evaluation,11 reports(73.33%)mentioned results of indicator monitoring and adverse events,of which 7 reports showed no abnormalities,and other 4 reports showed no significant differences between groups in safety evaluation.Conclusion:The intervention of heat-clearing and detoxification therapy in TCM benefit PLWH in promoting immune reconstruction,inhibiting HIV viral load and improving clinical symptoms,with well drug tolerance.ITWM could effectively improve level of CD4+T cell counts by heat-clearing and detoxification therapy,further studies are suggested to carry out in suit crowds,entry point,and courses.Part 4 Clinical trial for artesunate on immune reconstruction in INRsObjective:To explore the clinical efficacy and safety of artesunate on INRs from the perspective of immune activation,and in order to establish optimal treatment strategies of ITWM for INRs.Methods:A multicenter,non-randomized concurrent control trial was carried out in eight clinical medical centers in China.Participants who met inclusion criteria were divided into three groups,the control group maintained to be treated with ART,the low-dose artesunate group was treated with ART+artesunate tablets(50mg qd),and the high-dose artesunate group was treated with ART+artesunate(50mg bid),with 48 weeks follow-up period.CD4+,CD8+,CD45RA+,CD45RO+,CD4+CD38+,CD8+CD38+,CD4+CD25+,CD4+Ki67+/CD4+,CD8+Ki67+/CD8+,early apoptotic cell counts/CD4+,and early apoptotic cell counts/CD8+ were monitored at baseline,24 weeks and 48 weeks,HIV RNA was tested at baseline and 48 weeks,and safety indicators were monitored at baseline,12 weeks,24 weeks,36 weeks,and 48 weeks.Results:A total of 197 participants completed the follow-up period,75 participants were in low-dose artesunate group,66 participants were in high-dose artesunate group,and 56 participants included in control group.Comparison among groups,after 24 weeks of treatment duration,compared with control group and low-dose artesunate group,CD4+T and CD45RA+T cell counts in high-dose artesunate group are significantly increased(Padj<0.05);level of CD4+CD38+T cell counts in high-dose artesunate group is significantly decreased when compared with control group(Padj<0.05);there are significantly differences on CD8+CD38+T cell counts between high-dose artesunate group and low-dose artesunate group(Padj<0.05);compared with control group and high-dose artesunate group,level of early apoptotic cell counts/CD4+in low-dose artesunate group is significantly decreased(Padj<0.05).At 48 weeks of treatment duration,compared with control group and low-dose artesunate group,CD4+T and CD45RA+T cell counts in high-dose artesunate group are significantly increased(Padj<0.05);there are significantly differences on CD8+CD38+T cell counts between high-dose artesunate group and low-dose artesunate group(Padj<0.05).No significant differences are observed on CD8+T,CD45RO+T,CD4+/CD8+ratio,clinical efficacy of immune reconstruction,CD4+CD25+T,CD4+Ki67+/CD4+,CD8+Ki67+/CD8+,and early apoptotic cell counts/CD8+during follow-up among three groups.Compared with baseline,after 24 weeks of treatment duration,CD4+T and CD45RA+T cell counts are significantly increased as well as CD4+CD25+T,CD4+CD38+T,CD8+CD38+T,CD4+Ki67+/CD4+,early apoptotic cell counts/CD4+are decreased in high-dose artesunate group(P<0.05);level of CD4+Ki67+/CD4+,CD8+Ki67+/CD8+,and early apoptotic cell counts/CD4+are significantly decreased in low-dose artesunate group(P<0.05);after 48 weeks of treatment duration,CD4+T and CD45RA+T cell counts are significantly increased as well as early apoptotic cell counts/CD4+are decreased in high-dose artesunate group(P<0.05),level of CD4+T and CD8+CD38+T are significantly increased as well as early apoptotic cell counts/CD4+ are decreased in low-dose artesunate group(P<0.05).Compared with baseline,level of CD4+Ki67+/CD4+and CD8+Ki67+/CD8+are significantly decreased in three groups(P<0.05).No significant differences were observed in HIV RNA among three groups during our follow-up period(P>0.05).In terms of safety evaluation,there were no significant differences in blood routine and renal function among three groups(P>0.05).Compared with control group and high-dose artesunate group,urine routine in low-dose artesunate group show a lower abnormal rate(Padj<0.05)at 12 weeks.There are significant differences on liver function between low-dose artesunate group and high-dose artesunate group at 24 weeks(Padj<0.05).Conclusion:The intervention of artesunate could significantly improve the level of CD4+T cell counts for INRs,combined with the phenomenon of na?ve T cells,we speculate that artesunate is conductive to immune reconstruction through promoting the thymus function.Considering limitations in our study,the potential mechanism of artesunate on immune reconstruction in INRs could be further explored by high-quality randomized controlled trials.