Combining Real-world Data With Systematic Evaluation To Explore The Efficacy And Safety Of Traditional Chinese Medicine In The Treatment Of AID

1.BackgroundHuman immunodeficiency virus(HIV)threatens human immune system,leading to immune deficiency.HIV/acquired immunodeficiency syndrome(AIDS)is one of the critical public health problems in China.Patients with HIV/AIDS usually choose to use traditional Chinese medicine because of the limited therapeutic effects,high cost,or adverse reactions of antiviral drugs.Randomized controlled trials are the gold standard for assessing treatment efficacy,but they are challenging to achieve long-term follow-ups.Since 2004,our state has invested a large amount of money in providing free Chinese medicine treatment to patients,forming observational data for a longer follow-up period.This study combined evidence of randomized controlled trials and real-world research to explore the efficacy and safety of traditional Chinese medicine in the treatment of HIV/AIDS patients.2.PurposesWe analyzed the longitudinal data using the Propensity Score Matching and Generalized Estimated Equation to explore the efficacy and safety of traditional Chinese medicine for patients with HIV/AIDS.We comprehensively searched the evidence of randomized controlled trials of traditional Chinese medicine for HIV asymptomatic patients,systematically evaluated and meta-analyzed them.3.MethodsStudy OneThe longitudinal data was composed of two sets of data,namely the Chinese medicine combined highly active anti-retroviral therapy group(integrated Chinese and Western medicine group)and the highly active anti-retroviral therapy group(western medicine group).The research object of the integrated Chinese and Western medicine group came from the Guangxi pilot database of the national pilot project of Chinese medicine treatment of AIDS.The research object of the western medicine group came from the case data of antiviral treatment sites in Ruikang Hospital affiliated to Guangxi University of Traditional Chinese Medicine.In this study,we used a logistic regression analysis to explore the covariates for propensity score matching.We used propensity score matching(1:1 matching based on the principle of nearest neighbour matching and caliper matching),to balance the baseline and eliminate confounding factors.The generalized estimation equation model(matrix was in the AR(1)type,the connection function was Gamma family and log link function)was for longitudinal data analysis.Study TwoThe researchers searched CNKI,Wanfang Data,Chongqing VIP,SinoMed,PubMed,Cochrane Library,EMBASE and,Web of Science to collect the relevant literature on the treatment of HIV asymptomatic patients with traditional Chinese medicine.After re-checking the retrieved literature and eliminating duplicate researches,two researchers independently conducted literature screening,data extraction,methodological evaluation,and quality evaluation of the evidence.The discrepancies were resolved through consensus and,if necessary,arbitrated by another researcher.We used Excel for data extraction.We used the Cochrane risk of bias tool to evaluate the methodological quality of randomized controlled trials.We used the GRADE tool and GRADEpro GDT software to assess the evidence quality of the primary outcome.We pooled the data using RevMan 5.3.4.ResultsStudy OneAfter data processing,455 people entered the data analysis in the integrated Chinese and Western medicine group among the total data set,and 174 people entered the data analysis in the western medicine group.In this study,the total data set was divided into two subgroups(CD4+baseline>200,CD4+baseline≤200)according to the CD4+baseline level for analysis.Combining logistic regression results with the important baseline characteristics of patients and clinically important indicators,we selected gender,age,CD4+baseline,and CD4+/CD8+baseline as covariates for propensity score matching.After matching the propensity scores,the total data set matched 166 pairs,the CD4+baseline>200 subgroup matched 98 pairs,and the CD4+baseline≤200 subgroup matched 55 pairs.We used the generalized estimation equation model performing longitudinal data analysis.The analysis results showed that:in the full data set,the CD4+T lymphocytes(OR=1.119,95%CI[1.018,1.230])and CD4+/CD8+value(OR=1.168,95%CI[1.045,1.305])of the Western medicine group were higher than that of the integrated Chinese and western medicine group.In the CD4+baseline>200 subgroup,the CD4+T lymphocytes(OR=1.326,95%CI[1.214,1.449])and CD4+/CD8+value(OR=1.429,95%CI[1.278,1.598])of the Western medicine group were higher than the integrated Chinese and Western medicine group.In the CD4+baseline≤200 subgroup,the CD4+T lymphocytes(OR=0.825,95%CI[0.694,0.980])and CD4+/CD8+value(OR=0.826,95%CI[0.684,0.997]of the integrated Chinese and Western medicine group were higher than that of the Western medicine group.The safety indicators showed that there was no statistically significant difference between the integrated Chinese and Western medicine group and the Western medicine group in the three data sets.Study TwoA total of 10295 indexes were retrieved in this study.After the screening,14 RCTs were finally included,with a total of 1379 patients.The comparison of ten studies was Chinese herbal medicines versus placebo.Comparison of the two studies was Chinese herbal medicines versus no intervention.Comparison of two studies was Chinese herbal medicines combined with highly active antiretroviral therapy versus highly active anti-retroviral therapy.Chinese herbal medicines included in this study included Fuzheng Detox Tablets,Aikang Capsules,Ailing Granules,Fuzheng Kangdu Pills,Shenling Fuzheng Capsules,Qingdu Capsules,Immune No.1 Decoction,Sanren Decoction,Shenling Baizhu Powder,Kangai Baosheng Pills,Compound Sanhuang Capsules,and medication based on syndrome differentiation.The courses of treatment ranged from 3 months to 18 months.Meta-analysis results show:(1)Evidence summary of comparison one(Chinese herbal medicines versus placebo):①Low or very low certainty evidence showed that Aikang capsules might increase CD4+T lymphocytes compared with placebo in HIV-infected patients after 3 months(MD=80.53,95%CI[11.41,149.65];P=0.02).②Very low certainty evidence showed that Ailing granules might increase CD4+T lymphocytes compared with placebo in HIV-infected patients after 12 months(MD=99.34,95%CI[12.84,185.84];P=0.02).Low certainty evidence showed that Ailing Granules interfered with HIV-infected patients for 3 months(MD=226.20,95%CI[35.06,417.34];P=0.02),6 months(MD=228.63,95%CI[42.18,415.08];P=0.02),9 months(MD=226.90,95%CI[50.41,403.39];P=0.01),12 months(MD=290.57,95%CI[101.19,479.95];P=0.003)compared with placebo may increase CD3+T lymphocytes with a significant difference between the two groups.Low certainty evidence suggested that Ailing granules may increase the KPS score compared with placebo after 12 months in HIV-infected patients(MD=5.50,95%CI[2.01,8.99];P=0.002).③Moderate certainty evidence showed that Immune No.1 Decoction likely resulted in an increase of CD4+T lymphocytes compared with placebo after 6 months in HIV-infected patients(MD=124.08,95%CI[38.02,210.14];P=0.005).④Moderate certainty evidence showed that compound Sanhuang capsules likely increased CD4+T lymphocyte levels compared with placebo after 9 months in HIV-infected patients(MD=129.73,95%CI[64.52,194.94];P<0.001).Moderate certainty evidence showed that compound Sanhuang capsules probably reduced viral load compared with placebo after 9 months of intervention in HIV-infected patients(MD=-1.31,95%CI[-1.84,-0.90];P<0.001).⑤Very low certainty evidence suggested that Shenling Fuzheng capsules may increase the level of CD4+T lymphocytes compared with placebo after 12 months in HIV-infected patients(MD=50.74,95%CI[6.34,95.14];P=0.03).Low certainty evidence showed that Shenling Fuzheng capsules compared with placebo may improve the KPS score after 12 months for HIV-infected patients(MD=7.83,95%CI[4.02,11.64];P<0.001).⑥Moderate certainty evidence showed that syndrome differentiation treatment increased CD4+T lymphocytes compared with placebo after 18 months in HIV-infected patients(MD=57.68,95%CI[16.33,99.03];P=0.006).Low certainty evidence showed that syndrome differentiation treatment compared with placebo may improve the quality of life after 18 months for HIV-infected patients but it was very uncertain(MD=0.25,95%CI[0.01,0.49];P=0.04).⑦Very low certainty evidence showed that Shenling Fuzheng Capsules/Qingdu Capsules compared with placebo may improve the quality of life after 18 months for HIV-infected patients but it was very uncertain(MD=0.97,95%CI[0.59,1.35];P<0.001).(2)Evidence summary of comparison two(Chinese herbal medicines versus no intervention):Low certainty evidence showed that Kangai Baosheng pills might increase CD4+T lymphocytes after 9 months for HIV-infected patients(MD=163.62,95%CI[105.60,221.64];P<0.001).Very low or low certainty evidence showed that Kangai Baosheng pills interfered with HIV-infected patients for 3 months(MD=88.13,95%CI[31.28,144.98];P=0.002),6 months(MD=99.93,95%CI[43.15,156.71];P<0.001),12 months(MD=192.60,95%CI[129.87,255.33];P<0.001)might increase CD4+T lymphocytes but it was very uncertain.Very low certainty evidence showed that Kangai Baosheng pills might reduce viral load after 6 months in HIV-infected patients(MD=-0.33,95%CI[-0.63,-0.03];P=0.03).Low or moderate certainty evidence showed that Kangai Baosheng pills interfered with HIV-infected patients for 3 months(MD=2.74,95%CI[0.83,4.65];P=0.005),6 months(MD=3.54,95%CI[1.75,5.33];P<0.001),9 months(MD=3.58,95%CI[1.75,5.41];P<0.001),12 months(MD=4.78,95%CI[2.90,6.66];P<0.001)may improve quality of life.(3)Evidence summary of comparison three(Chinese herbal medicines combined with highly active anti-retroviral therapy versus highly active anti-retroviral therapy):①Very low certainty evidence showed that Fuzheng Kangdu pills combined with highly active anti-retroviral therapy may increase CD3+T lymphocytes after 12 months in HIV-infected patients(MD=506.32,95%CI[228.65,783.99];P<0.001).②Very low or low certainty evidence showed that Sanren decoction combined with highly active anti-retroviral therapy may increase CD4+T lymphocytes after 6 months in HIV-infected patients(MD=31.68,95%CI[12.31,51.05];P=0.001)and quality of life(MD=6.47,95%CI[1.69,11.25];P=0.008).The safety evaluation results showed that none of the patients had severe adverse reactions,and no patients died.5.ConclusionsStudy OneThe results of the study show that after three years of treatment,the difference between Chinese medicine combined with antiviral therapy and the use of antiviral therapy alone in improving the immune function of HIV infection and AIDS patients has no clinical significance.The results of the two subgroups are in opposite directions,and chance does not explain the apparent subgroup effect.In order to increase the credibility,it is necessary to repeat the study.The rate of data lost to follow-up is relatively high.Although appropriate analytical models adopted for processing,the high rate of loss to follow-up will have an impact on the accuracy of the results.Study TwoModerate quality evidence showed that the Immune No.1 Decoction increased the HIV-infected patients CD4+lymphocyte levels after 6 months.Moderate quality evidence showed that the syndrome differentiation treatment increased the HIV-infected patients CD4+lymphocyte levels after 18 months.Moderate quality evidence showed that the Compound Sanhuang Capsule increased the HIV-infected patients CD4+lymphocyte levels and reduced the viral load after 9 months.Limited evidence showed that Chinese herbal medicine might improve immune function and quality of life.Insufficient evidence showed that Chinese herbal medicine might reduce viral load and the incidence of AIDS.Due to the limited evidence,it’s hard to make confident conclusions about specific Chinese medicine intervention.If we want to draw a definite conclusion,a well-designed large sample clinical trial was warranted.