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    Efficacy and safety of Mianyi granules (免疫Ⅱ顆粒) for reversal of immune nonresponse following antiretroviral therapy of human immunodeficiency virus-1:a randomized,double-blind,multi-center,placebo-controlled trial

    2022-07-20 15:54:06LIUYingZOUWenXIANQingfeiDENGXinZHANGFuchunWANGLiLIYonghongLUNWenhuiWANGJian
    關鍵詞:顆粒

    LIU Ying,ZOU Wen,XIAN Qingfei,DENG Xin,ZHANG Fuchun,WANG Li,LI Yonghong,LUN Wenhui,WANG Jian

    LIU Ying,ZOU Wen,XIAN Qingfei,WANG Jian,Traditional Chinese Medicine Center for Acquired Immune Deficiency Syndrome Prevention and Treatment,China Academy of Chinese Medical Sciences,Beijing 100700,China

    DENG Xin,Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine,Nanning 530011,China

    ZHANG Fuchun,Infectious Disease Department of Guangzhou Eighth People’s Hospital,Guangzhou 510060,China

    WANG Li,Internal Medicine Department of Traditional Chinese Medicine,Yunnan Provincial Academy of Traditional Chinese Medicine,Kunming 650031,China

    LI Yonghong,Department of Hepatology,Shenyang Sixth People’s Hospital,Shenyang 110006,China

    LUN Wenhui,Department of Dermatology,Beijing Ditan Hospital,Beijing 100015,China

    Abstract OBJECTIVE:To investigate whether Mianyi granules (免疫Ⅱ顆粒) are effective and safe in reversing immune nonresponse following antiretroviral therapy (ART) in individuals with human immunodeficiency virus (HIV)infection.METHODS:Randomized,double-blind,multi-center,placebo-controlled trial (factorial design) of daily oral Mianyi granules versus placebo for 72 weeks.A total of 361 HIV-positive individuals receiving ART at five Class III Grade I hospitals in China between September 2013 and January 2016 completed the study.The primary endpoints were frequencies of CD3+,CD4+,CD8+,and CD45RA+cells at seven timepoints over the 72 weeks.Secondary endpoints included viral loads,clinical symptoms,and quality of life at 72 weeks.RESULTS:A total of 400 participants were enrolled in the study and randomized,of whom 361 completed the study:189 individuals (140 men and 49 women) in the Mianyi granule group and 172 individuals (135 men and 37 women) in the placebo group.In the intent-to-treat population,CD4+T cell counts increased from (193 ± 71)cells/mm3 at baseline to (288 ± 131) cells/mm3 posttreatment in the Mianyi granule group and from (200 ± 75)cells/mm3 at baseline to (264 ± 124) cells/mm3 posttreatment in the placebo group.Patients treated with Mianyi granule had higher increases in CD4+T cell counts than those treated with placebo (P=0.045).Reversal of immune nonresponse was defined as a CD4+T cell increase of more than 100 cells/mm3.After treatment for 72 weeks,Mianyi granule was effective in reversing immune nonresponse in a higher proportion of individuals (20.2%) compared with placebo (9.7%).CD45RA+cell counts increased from (34 ± 32) cell/mm3 at baseline to (51 ± 61) cells/mm3 post-treatment in the Mianyi granule group and from (37 ± 33) cells/mm3 at baseline to (48 ± 37) cells/mm3 post-treatment in the placebo group.Mianyi granules were more effective than placebo in increasing CD45RA+cell counts.CONCLUSIONS:In ART-treated HIV-positive adults with immune nonresponse,treatment with Mianyi granules for 72 weeks was safe and significantly increased CD4+and CD45RA+cell counts,thereby promoting immune reconstitution.

    Keywords:HIV-1;immunity;antiretroviral therapy;treatment outcome;safety;Mianyi granules

    In patients with human immunodeficiency virus (HIV)infection and acquired immunodeficiency syndrome(AIDS),antiretroviral therapy (ART) typically results in diminished viral replication,increased CD4+T cell counts,reversal of most immunological disturbances,and reduced risks of morbidity and mortality.1Although ART causes a rapid reduction in HIV RNA viral loads and restoration of CD4+T-cell numbers in most patients,up to 40% of patients receiving HAART experience incomplete immune recovery despite sustained viral suppression.2-4Alternative approaches to promote immune reconstitution are urgently necessary.

    Traditional Chinese medicine (TCM) plays a unique role in regulating the human immune system.Promoting immune reconstitution using TCM is a major focus in HIV research.TCM can improve CD4+T cell counts,naive CD4+T cell counts,memory CD4+T cell counts,and CD45RA and/or CD45RO cell counts while simultaneously decreasing T-cell immune activation.5-9A prior study showed that Mianyi granules (免疫Ⅱ顆粒)were effective in increasing CD4+T cell counts in patients with HIV undergoing HAART.10 This trial was designed to evaluate the therapeutic effects of Mianyi granules on CD4+T cells in HIV-positive patients with incomplete immune reconstitution following ART.

    2.METHODS

    2.1.Ethics

    The study protocol was approved by the China Academy of Traditional Chinese Medicine (2013 No.001) and was registered in the Chinese Clinical Trial Registry(Registration No.ChiCTR-TRC-13003716).The study was conducted in accordance with the ethical principles laid out in the Declaration of Helsinki,the International Conference on Harmonization Tripartite Guideline on Good Clinical Practice,and local institutional guidelines.11Written informed consent was obtained from all participants.The purpose,procedures,and potential risks and benefits of the study were explained to prospective participants.

    2.2.Study design and participants

    This randomized,double-blind,placebo-controlled clinical trial consisted of a pretreatment phase (screening and a run-in visit) followed by randomization of participants into two groups.Participants in both groups underwent a 72-week treatment protocol.A cohort of 361 HIV-infected adults with incomplete immune recovery following HAART were recruited between September 2013 and January 2016 in collaboration with five Class III Grade I hospitals in China (Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine,Guangzhou Eighth People's Hospital,Yunnan Provincial Academy of Traditional Chinese Medicine,Shenyang Sixth People's Hospital,and Beijing Ditan Hospital).

    2.3.Randomization and masking

    This was a randomized,double-blind,multi-center,placebo-controlled trial conducted by the Center for AIDS Prevention and Treatment with Traditional Chinese Medicine,China Academy of Traditional Chinese Medicine.Randomization was controlled by an independent clinical research coordinator (CRC).Patients were randomly allocated at a 1∶1 ratio to the Mianyi granule group or placebo group.First,patient basic information was transmitted to an independent statistician;at this stage the randomization number was left blank.The statistician then allocated a randomization number based on the allocation sequence.The number was generated in advance using a random number creation program.The CRC then informed the investigators of the specific identification number.Investigators did not contact the CRC or statistician,and the CRC was separated from all researchers.The statistician was not allowed to contact the other researchers.

    2.4.Inclusion criteria

    Diagnosis of HIV was made using the Diagnostic Criteria for AIDS and HIV infection from the Ministry of Public Health of China (WS293-2008).All participants were confirmed to be HIV-antibody-positive by Western blotting.12Participants were between the ages of 18 and 70 years.For patients who had received HAART for more than 12 months and less than 24 months,CD4 counts had to be < 200 cells/mm3,while for those who had received HAART for more than 24 months,CD4 counts had to be < 350 cells/mm3.Additionally,viral loads had to be below the limit of detection and CD4 cell counts had to be ≥ 50 cells/mm3at baseline.

    2.5.Exclusion criteria

    Participants with serious and uncontrolled opportunistic infections as well as patients who participated in other clinical drug trials or received immunomodulatory therapy within 1 month of study entry were excluded.Patients with malignant tumors,severe hepatic or renal dysfunction,and autoimmune diseases were excluded.Pregnant or lactating women and women trying to conceive were excluded.Additionally,patients with intellectual deficiencies or psychotic disorders who could not provide valid informed consent and/or were deemed unlikely to comply with the study protocol were excluded.

    2.6.Procedures

    The randomization flow chart is shown in Figure 1.Study physicians and nurses screened individuals and conducted a run-in pre-randomization phase to obtain written informed consent,confirm eligibility,and identify potentially non-adherent individuals.Demographic characteristics were collected and participants were counseled regarding Mianyi granule adherence.

    Eligible participants were then randomly assigned to one of the study groups using the next sequential number in a randomization list generated by the Academy of Chinese Medical Sciences Data Center.

    In both groups,participants were treated with ART regimens prior to participation in the study.

    In the Mianyi granule group,participants took Mianyi granules orally twice a day,1 to 2 h after breakfast and dinner.A minimum 1-hour interval was recom-mended between taking Mianyi granules and ART.Mianyi granules were provided by Jiangyin Tianjiang Pharmaceutical Co.,Ltd.(Jiangyin,China).The batch numbers of Mianyi granules were 1311327 (first batch)and 1409358 (second batch).Mianyi granules were packaged in 5.5-g bags.

    In the placebo group,participants took placebo orally twice a day,1 to 2 h after breakfast and dinner.A minimum 1-hour interval was recommended between taking placebo and ART.The placebo was the same as Mianyi granules in appearance and taste and was provided by Jiangyin Tianjiang Pharmaceutical Co.,Ltd.(Jiangyin,China).

    All granules were indistinguishable in shape,size,and color.Bags containing granules were prelabeled by the pharmacist for the entire study period with identification numbers according to the assignment list using doubleblind masking.During monthly visits,the remaining granules from the previous month were counted to assess adherence.

    2.7.Outcomes

    The primary endpoints were CD3/CD8/CD45/CD4 cell counts at 72 weeks.Secondary endpoints included viral load,clinical symptoms,and quality of life measured using the World Health Organization (WHO) Quality of Life Scale at 72 weeks.These parameters were assessed by each study sub-center.

    2.8.Safety evaluation

    Safety indices included laboratory parameters (red blood cell count,white blood cell,aspartate transaminase,alanine aminotransferase,blood urea nitrogen,and serum creatinine),electrocardiography,and a general physical examination at 72 weeks.These parameters were assessed by each research center.

    2.9.Statistical analysis

    Statistical analyses were performed using SAS 9.1 statistical software (SAS Institute,Cary,NC,USA).All statistical tests were two-sided.Data were presented as mean ± standard deviation ().Differences between groups were assessed usingT-tests or nonparametric tests.Differences within groups before and after intervention were assessed using pairedt-tests.Differences in symptom frequency were assessed usingt-tests and differences in rank order were assessed using the Cochran-Mantel-Haenszel test.Values ofP <0.05 were considered statistically significant.

    2.10.Data and safety monitoring

    The Data Safety Monitoring Board reviewed the unblended safety and efficacy data before the initiation of the study,annually,at the study midpoint,and at the end of the study.The early stopping boundaries were based on nominal values ofP <0.001 for efficacy endpoints andP <0.05 for safety endpoints.11All adverse events (AEs) were characterized using the AE form rating scale as follows:1,remote;2,possible;3,probable;and 4,definite.13

    3.RESULTS

    Of 1156 patients with HIV infection screened,396 were randomized and 361 completed the study (Figure 1).The demographic characteristics of the Mianyi granule group were as follows (mean ± standard deviation):age (44 ±11) years,height (166 ± 8) cm,and weight (59 ± 8) kg.The demographic characteristics of the placebo group were as follows:age (44 ± 11) years,height (167 ± 7) cm,and weight (60 ± 9) kg.There were no statistically significant baseline differences between the two groups in immune indices,symptoms and signs,body temperature,heart rate,respiration rate,or blood pressure(P >0.05).Baseline demographic characteristics were similar in the two groups.

    Figure 1 Study flow diagram

    Frequencies of CD4 cells increased in both groups after treatment for 72 weeks,but this increase was significantly more pronounced in the Mianyi granule group (193 ± 71) cells/mm3at baselinevs(288 ± 131)cells/mm3post-treatment) compared with the placebo group (200 ± 75) cells/mm3at baselinevs(264 ± 124)cells/mm3post-treatment) (P=0.045).Differences in CD4 cell increases from baseline between study arms were observed at other time points post-treatment as well(Table 2).

    Effective treatment was first defined as CD4 cell count increases of more than 50 cells/mm3.CD4 cell counts increased by more than 50 cells/mm3compared with baseline in both groups at various time points.In the Mianyi granule arm,the number of patients with changes in CD4 cell counts of more than 50 cells/mm3gradually increased over time,while in the placebo arm this was not the case.After treatment for 72 weeks,administration of Mianyi granule was effective in 47.5% of participants while placebo was effective in only 31.3% of participants(Table 3).

    Next,we applied a more stringent definition of effective treatment (increase in CD4 cell count of more than 100 cells/mm3).CD4 cell counts increased by more than 100 cells/mm3compared with baseline in both groups at various time points.In the Mianyi granule arm,the number of patients with changes with CD4 cell counts of more than 100 cells/mm3gradually increased over time,particularly after treatment for 48,60,and 72 weeks.In the control arm,no such trends were observed.After treatment for 72 weeks,administration of Mianyi granule was effective in 20.2% of participants while administration of placebo was effective in only 9.7% of participants (Table 4).

    Table 1 Enrolment and completion cases at each study center (n)

    Table 2 Comparison of CD4 cell counts (cells/mm3) at baseline and post-treatment in patients receiving Mianyi granule or placebo ()

    Table 2 Comparison of CD4 cell counts (cells/mm3) at baseline and post-treatment in patients receiving Mianyi granule or placebo ()

    Notes:treatment group:the Mianyi granules+HAART,the Mianyi granules take 5.5-g twice a day for 72 weeks;control group:the placebo +HAART,the placebo take 5.5-g twice a day for 72 weeks.P:treatment group compared with control group.

    The CD4/CD8 ratio showed no significant differences between the two groups.However,in the Mianyi granule group there was a suggestion of a rapid increase in the CD4/CD8 ratio starting from 36 weeks post-treatment(Table 5).CD45RA cell counts were increased in both groups after treatment for 72 weeks.CD45RA counts increased to a greater degree in patients receiving Mianyi granule(33.87 ± 32.15 cells/mm3at baseline and 52.82 ±61.53 cells/mm3post-treatment) compared with placebo (36.75 ± 32.94 cells/mm3at baseline and 48.27± 36.91 cells/mm3post-treatment) (P=0.035).At other time points,increases from baseline in CD45RA cell counts were observed in the Mianyi granule group but not in the placebo group (Table 6).

    Table 3 Participants whose CD4 cells increased or decreased by more than 50 cells/mm3 (n)

    Table 4 Participants whose CD4 cells increased or decreased by more than 100 cells/mm3 (n)

    Table 5 Comparison of CD4/CD8 ratios at baseline and post-treatment in patients receiving Mianyi granule or placebo ()

    Table 5 Comparison of CD4/CD8 ratios at baseline and post-treatment in patients receiving Mianyi granule or placebo ()

    Notes:treatment group:the Mianyi granules+ART,the Mianyi granules take 5.5-g twice a day for 72 weeks;control group:the placebo +ART,the placebo take 5.5-g twice a day for 72 weeks.P:treatment group compared with control group.

    A survival curve was generated to display CD4 cell count restoration,which was defined as an increase of 30%compared with baseline (Figure 2).In the figure,the xaxis shows time and the y-axis shows the percentage of patients in whom treatment was ineffective (increase in CD4 cell counts of less than 30%).At baseline,the survival curves for the two groups coincided,and remained basically the same at 20 weeks post-treatment.Over time,the distance between the two groups gradually widened,showing that treatment with Mianyi granules was ineffective in far fewer participants compared with placebo.

    Figure 2 Survival analysis of CD4 cell count restoration (30%increase) in patients treated with Mianyi granules or placebo

    TCR-γ-f2 receptor gene fragment diversity (mean D value of PCR product dispersion) was compared in the two groups.In the Mianyi granule group,the mean D value for TCR-γ-f2 receptor gene fragment diversity was significantly lower post-treatment compared with baseline (pairedttest,P <0.05).In the placebo group,the mean D value for TCR-γ-f2 receptor gene fragment was significantly lower compared with baseline (paired t test,P <0.05).Post-treatment changes in TCR-γ-f2 receptor gene fragment diversity were similar in both groups(ttest,P=0.145) (Table 7).Thus,TCR-γ-f2 receptor gene fragment diversity post-Mianyi granule treatment was significantly lower than before treatment.Diversity was greatly improved,indicating that the function of mucosal immune γδ-T cells in patients receiving Mianyi granules was improved and restored.

    There were no statistically significant differences in the frequencies of symptoms between the two groups (Table 7).

    There were no statistically significant differences in theWHO Quality of Life Scale results between the two groups (Table 8).

    Table 6 Comparison of CD45RA (cells/mm3) at baseline and post-treatment in patients receiving Mianyi granule or placebo ()

    Table 6 Comparison of CD45RA (cells/mm3) at baseline and post-treatment in patients receiving Mianyi granule or placebo ()

    Notes:treatment group:the Mianyi granules+ART,the Mianyi granules take 5.5-g twice a day for 72 weeks;control group:the placebo +ART,the placebo take 5.5-g twice a day for 72 weeks. P:treatment group compared with control group.

    Safety evaluation

    During the 72 weeks of treatment,a total of 18 AEs were reported.The frequency of AEs in the Mianyi granule group was 4.76% compared with 6.40% in the placebo group (Table 9).

    Table 7 Comparison of symptom frequency at baseline and post-treatment in patients receiving Mianyi granule or placebo ()

    Table 7 Comparison of symptom frequency at baseline and post-treatment in patients receiving Mianyi granule or placebo ()

    Notes:treatment group:the Mianyi granules+ART,the Mianyi granules take 5.5-g twice a day for 72 weeks;control group:the placebo +ART,the placebo take 5.5-g twice a day for 72 weeks.P:treatment group compared with control group.

    Table 8 Comparison of WHO Quality of Life Scale results in patients receiving Mianyi granules or placebo ()

    Table 8 Comparison of WHO Quality of Life Scale results in patients receiving Mianyi granules or placebo ()

    Notes:treatment group:the Mianyi granules+ART,the Mianyi granules take 5.5-g twice a day for 72 weeks;control group:the placebo +ART,the placebo take 5.5-g twice a day for 72 weeks.P:treatment group compared with control group.

    Table 9 Adverse events in patients receiving Mianyi granules or placebo (n)

    4.DISCUSSION

    This study showed that Mianyi granules can stabilize CD4 counts and reconstitute immune function in patients with HIV/AIDS who previously received ART and experienced poor immune recovery.Mianyi granules are a component of TCM.The prescription uses Huangqi(Radix Astragali Mongolici) and Dangshen (Radix Salviae Miltiorrhizae) as the monarch medicine;Lingzhi(Ganoderma Lucidum) and Gouqizi (Fructus Lycii) as the minister medicine;and Yinyanghuo (Herba Epimedii Brevicornus),Bajitian (Radix Morindae Officinalis),and Ezhu (Rhizoma Curcumae Phaeocaulis) as the adjuvant medicine.TCM depends on strict compatibility between medicines to improve the immune function of the body by invigorating theQiin the middle-jiao,tonifying the kidneys,and nourishing bone marrow.Together,the overall effect is strengthening of human immune function.Numerous studies have shown that these components have a regulatory effect on imm-unity.14

    Based on TCM theory,the effectiveness of Mianyi granules occurs by reinforcingQi,nourishingYin,and supporting healthy energy.Some clinical observations support the notion that TCM can play an important role in immune reconstitution.15

    A cohort study of 2235 patients positive for HIV in Switzerland16who received HAART found that CD4 cell counts recovered to 500 cells/mm3in just 39% of patients.Because of the presence of viral reservoirs,HIV virions can escape from immune responses or drugs.Thus,it is difficult for HAART to suppress or clear HIV completely.It is also difficult to completely restore normal immune function following long-term HAART.For optimal prognosis of patients with HIV/AIDS receiving HAART,immune function must be fully restored.17

    Immune reconstitution is an important aspect of the management of patients with HIV/AIDS.HAART can effectively control HIV replication,permitting immune reconstitution and reducing abnormal immune activation.18CD4+T cells,which play important roles in regulating humoral and cellular immune function,are decreased in patients with HIV/AIDS through direct HIV cytotoxicity and indirect apoptosis induction mechanisms.19Restoration of immune function in patients with HIV/AIDS can stabilize the patient’s condition and improve the efficacy of existing treatments,thus improving survival and prognosis.20The combined treatment strategy of integrated TCM and Western Medicine promotes long-term reconstitution of the immune system and thus,is beneficial and has potential use for improving INR in PLWH.21Over the last 30 years,the use of TCM to treat HIV/AIDS has made significant strides and TMC now plays a key role in the battle against HIV/AIDS in China.More and more clinicians and patients are convinced of the efficacy and safety of TCM for treatment of HIV/AIDS in conjunction with HAART.22

    In conclusion,Mianyi granules could increase CD4+and CD45RA+cell counts in immune reconstitution,it is safe and effective for ART-treated HIV-positive adults with immune nonresponse.

    5.ACKNOWLEDGEMENTS

    We thank Liwen Bianji (Edanz) (www.liwenbianji.cn/)for editing the English text of a draft of this manuscript.

    6.REFERENCES

    1.Julie CG,Hans JH,Jan G,et al.Incomplete immune recovery in HIV infection:mechanisms,relevance for clinical care,and possible solutions.Clin Dev Immunol 2012;2012:670957.

    2.Kelley CF,Kitchen CM,Hunt PW,et al.Incomplete peripheral CD4+cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment.Clin Infect Dis 2009;48:787-94.

    3.Nakanjako D,Kiragga A,Ibrahim F,et al.Sub-optimal CD4 reconstitution despite viral suppression in an urban cohort on antiretroviral therapy (ART) in sub-Saharan Africa:frequency and clinical significance.AIDS Res Ther 2008;5:23.

    4.Negredo E,Massanella M,Puig J et al.Nadir CD4 T cell count as predictor and high CD4 T cell intrinsic apoptosis as final mechanism of poor CD4 T cell recovery in virologically suppressed HIVinfected patients:clinical implications.Clin Infect Dis 2010;50:1300-8.

    5.Wu XF,Wang J,Li Y.Intervention of Immune 1 combined HAART on immune function in patients with HIV/AIDS reconstruction.Zhong Guo Zhong Yao Za Zhi 2013;38:2453-7.

    6.Wang J,Li Y,Tang YL,et al.Effect of immune No.2 on the immune reconstitution in patients with HIV/AIDS after highly active antiretroviral treatment:a randomized double blind placebo controlled clinical trial.Zhong Guo Jie He Yi Xue Za Zhi 2013;19:340-6.

    7.Li T,Xie J,Li Y,et al.Tripterygium wilfordii Hook F extract in cART-treated HIV patients with poor immune response:a pilot study to assess its immunomodulatory effects and safety.HIV Clin Trials 2015;16:49-56.

    8.Shao BP.Clinical research report on the efficacy and safety of Tangcao Tablets in the treatment of HIV/AIDS.Compilation of Papers of the 6th Annual Academic Conference of the AIDS Prevention and Treatment Branch of the Chinese Society of Traditional Chinese Medicine;2008 Dec;Anhui,China.2008;11:179-90.

    9.Wu H,Zhao M,Li XW,et al.Clinical observation of the efficacy and safety of Aifukang capsule in patients with HIV infections and AIDS.Zhong Guo Ai Zi Bing Xing Bing 2012;18:434-7.

    10.Wang J,Lin HSH,Li Y,et al.Effect of Mianyi No.2 formula on the symptoms and signs of HIV/AIDS Patients with insufficient immune reconstitution.Zhong Yi Za Zhi 2012;53:923-6.

    11.Hughes MD,Pocock SJ.Interim monitoring of clinical trials.In:Finkelstein DM,Schoenfeld DA,eds.AIDS Clinical Trials.Hoboken.NJ:Wiley&Sons,1995:177-96.

    12.The ministry of health standard professional committee of infectious diseases,China (2012) the diagnostic criteria of AIDS and HIV infected,Beijing,China.Zhong Guo Ai Zi Bing Xing Bing 2012;18:354-6.

    13.Department of Health and Human Services (2003) Safety reporting requirements for human drug and biological products;Proposed rule.Food and Drug;Administration Federal Register 68.

    14.Chen H,Liu X,Su YX,et al.Notch signaling pathway mediates the immunomodulatory mechanism of Yangfei Huoxue decoction alleviating bleomycin-induced pulmonary fibrosis in rats.J Tradit Chin Med 2020;40:204-11.

    15.Wang J,Lin HS,Liu MY,Li Y.lmmune reconstitution of acquired immune deficiency syndrome.Chin J Integr Med 2010;16:557-564.

    16.Kaufmann GR,Perrin L,Pantaleo G,et al.CD4+T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years:the Swiss HIV cohort study.Arch Intern Med 2003;163:2187-95.

    17.Wang J,Huang SJ.Clinical research on the combination of TCM and Western Medicine on AIDS.Beijing:People's Medical Publishing House,2007:75-6.

    18.Sun J,Wu NP,Feng TT,et al.Effect of long term highly active antiretroviral therapy on abnormal immune activation and immune reconstruction in HIV-1 infected individuals.Zhejiang Da Xue Xue Bao (Yi Xue Ban) 2010;39:618-22.

    19.Herbeuval JP,Boasso A,Grivel JC,et al.TNF-related apoptosisinducing ligand (TRAIL) in HIV-1-infected patients and its in vitro production by antigen-presenting cells.Blood 2005;105:2458-64.

    20.Goicoechea M,Smith DM,Liu L,et al.Determinants of CD4+T cell recovery during suppressive antiretroviral therapy:association of immune activation,T cell maturation markers,and cellular HIV-1 DNA.J Infect Dis 2006;194:29-37.

    21.Tao Z,Huang Xj,Liu Y,et al.Efficacy of integrated Traditional Chinese Medicine and anti-retroviral therapy on immunological nonresponse in patients with human immunodeficiency virus/acquired immunodeficiency syndrome:a Meta-analysis of randomized controlled trials.J Tradit Chin Med 2021;41:669-76.

    22.Liu ZB,Wang X,Liu HJ.Treatment of acquired immunodeficiency syndrome with Chinese medicine in China:opportunity,advancement and challenges.Chin J Integr Med 2013;19:563-7.

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