Hepatitis B virus(HBV) infection is a global health problem. It is estimated there are more than 2 billion individuals exposed to the virus and 250 million are chronically infected. Hepatitis B is the cause of more th...Hepatitis B virus(HBV) infection is a global health problem. It is estimated there are more than 2 billion individuals exposed to the virus and 250 million are chronically infected. Hepatitis B is the cause of more than 600000 annual deaths due to cirrhosis and hepatocellular carcinoma. An effective vaccine exists and preventative initiatives center around universal vaccination especially in those at highest risk. Effective vaccination algorithms have led to a significant decline in the development of new infections and its devastating consequences. The vaccine is administered intramuscularly in three doses, with 95% showing long lasting serologic immunity. An additional fourth dose or a repeated higher dose three course regimen is given to those that fail to show immunity. Despite these additional regimens, some remain vulnerable to hepatitis B and are deemed nonresponders. Individuals with chronic disease states such as kidney disease, liver disease, diabetes mellitus, as well as those with a genetic predisposition, and those on immunomodulation therapy, have the highest likelihood of non-response. Various strategies have been developed to elicit an immune response in these individuals. These include increased vaccination dose, intradermal administration, alternative adjuvants, alternative routes of administration, co-administration with other vaccines, and other novel therapies. These alternative strategies can show improved response and lasting immunity. In summary, HBV vaccination is a major advance of modern medicine and all individuals at risk should be sought and vaccinated with subsequent adequate titers demonstrated.展开更多
Objective With the same times of injection to compare low-dose intradermal regimen with routine-dose intramuscular inoculation in revaccination of non-responders to hepatitis B vaccine. Methods 40 healthy non-responde...Objective With the same times of injection to compare low-dose intradermal regimen with routine-dose intramuscular inoculation in revaccination of non-responders to hepatitis B vaccine. Methods 40 healthy non-responder children collected by screening were administrated a three-dose revaccination randomly by intramuscular or intradermal route (10vs 2g per dose), and regularly tested for serologic markers up to five years. By the end of follow-up, a booster dose (5μg) was given to those who had lost anti-HBs of ≥10mIU/mL (seroprotection) and anamnestic response was estimated thereafter. Results All 17 intramuscular and 22 of 23 intradermal children effected seroprotection after revaccination. Intradermal children lost seroprotection over time significantly rapider compared with intramuscular children (Log Rank test, P= 0.029). In year 5, 50% of intramuscular but only 18.2% of intradermal children still maintained seroprotection (P=0.075). 12-14 days after the booster dose, all the eight intramuscular children developed an anamnestic response with anti-HBs titer increasing greater, but two of the 18 intradermal children failed to mount seroprotective level. Conclusion Three-routine-dose intramuscular revaccination was significantly effective than low-dose intradermal one with the same times of injection, especially in long-term immunity. We recommend routine-dose intramuscular protocol in revaccination of non-responders.展开更多
Incomplete immune reconstitution remains a global challenge for human immunodeficiency virus(HIV)treatment in the present era of potent antiretroviral therapy(ART),especially for those individuals referred to as immun...Incomplete immune reconstitution remains a global challenge for human immunodeficiency virus(HIV)treatment in the present era of potent antiretroviral therapy(ART),especially for those individuals referred to as immunological non-responders(INRs),who exhibit dramatically low CD4^(+)T-cell counts despite the use of effective antiretroviral therapy,with long-term inhibition of viral replication.In this review,we provide a critical overview of the concept of ART-treated HIV-positive immunological non-response,and also explain the known mechanisms which could potentially account for the emergence of immunological non-response in some HIV-infected individuals treated with appropriate and effective ART.We found that immune cell exhaustion,combined with chronic inflammation and the HIV-associated dysbiosis syndrome,may represent strategic aspects of the immune response that may be fundamental to incomplete immune recovery.Interestingly,we noted from the literature that metformin exhibits properties and characteristics that may potentially be useful to specifically target immune cell exhaustion,chronic inflammation,and HIV-associated gut dysbiosis syndrome,mechanisms which are now recognized for their critically important complicity in HIV disease-related incomplete immune recovery.In light of evidence discussed in this review,it can be seen that metformin may be of particularly favorable use if utilized as adjunctive treatment in INRs to potentially enhance immune reconstitution.The approach described herein may represent a promising area of therapeutic intervention,aiding in significantly reducing the risk of HIV disease progression and mortality in a particularly vulnerable subgroup of HIV-positive individuals.展开更多
为探索神经反馈训练在提升射击表现方面的应用效果和训练过程中的无应答者特性,开展一项用于提升射击表现的神经反馈训练(neurofeedback training for sport performance,SP-NFT)实验研究,招募20名受试者,进行2周4次的“巅峰”范式SP-N...为探索神经反馈训练在提升射击表现方面的应用效果和训练过程中的无应答者特性,开展一项用于提升射击表现的神经反馈训练(neurofeedback training for sport performance,SP-NFT)实验研究,招募20名受试者,进行2周4次的“巅峰”范式SP-NFT,采集受试者前、后测隐显目标射击表现和相关脑电(electroencephalograph,EEG)数据,检验SP-NFT对射击表现的提升效果、静息态EEG特征、SP-NFT期间正常组和无应答组EEG特性变化情况。结果表明:受试者后测射击成绩显著高于前测(P<0.01),静息态theta频带功率显著降低(P<0.01);相对正常受试者,无应答者在SP-NFT期间的努力程度更高,theta频段功率和SMR功率的变化程度更低,SP-NFT能够有效提升受试者射击表现,进一步揭示了无应答者的相关生理机制。研究成果为用于提升射击表现的SP-NFT技术进一步发展提供理论支撑和实验证据。展开更多
Background Cardiac resynchronization therapy （CRT） is a major breakthrough in therapy for advanced heart failure patients; however, a number of key clinical research questions remain, perhaps most importantly the is...Background Cardiac resynchronization therapy （CRT） is a major breakthrough in therapy for advanced heart failure patients; however, a number of key clinical research questions remain, perhaps most importantly the issue of why apparently suitable patients do not respond to CRT. Methods Seven patients, six males and one female, aged （56.43±6.13） years, all diagnosed with dilated cardiomyopathy, were included in this study. They were all non-responders to CRT who underwent routine optimization postoperatively, and received optimal drug therapy. On the basis of biventricular pacing, titrating various atrioventricular （AV） intervals were performed to get the true fusional QRS complexes composed of biventricular pacing and AV intrinsic conduction. Then, the effects of AV intrinsic conduction during CRT were evaluated. Results On the setting of AV intrinsic conduction during CRT, the true fusional QRS complexes were the narrowest, and all patients showed alleviation of symptoms, improvement of exercise tolerance, life quality and hemodynamic parameters during more than 6 months of follow-up. Conclusions Titrating AV intervals to get the true fusional QRS complexes composed of biventricular pacing and AV intrinsic conduction will be beneficial for non-responders to CRT. Maintaining AV intrinsic conduction during CRT may decrease the rates of non-resoonders to CRT.展开更多
Background:Natural killer(NK)cells play a critical role in suppressing human immunodeficiency virus-1(HIV-1)infection,but knowledge on whether and how NK cells affect immune reconstitution in HIV-1-infected individual...Background:Natural killer(NK)cells play a critical role in suppressing human immunodeficiency virus-1(HIV-1)infection,but knowledge on whether and how NK cells affect immune reconstitution in HIV-1-infected individuals who receive antiretroviral therapy(ART)is limited.Methods:We performed a case-control study with 35 healthy individuals and 66 HIV-1-infected patients including 32 immunological non-responders(INRs)with poor CD4+T-cell recovery(<500 cells/μL after 4 years of ART)and 34 immunological responders(IRs)with improved CD4+T-cell recovery(>500 cells/μL after 4 years of ART).NK cell phenotype,receptor repertoire,and early activation in INRs and IRs were investigated by flow cytometry.Results:A significantly higher proportion of CD56dimCD16dim/-NK cells was observed in INRs than IRs before ART and after 4 years of ART.The number of CD56dimCD16dim/-NK cells was inversely correlated with CD4+T-cell counts in INRs before ART(r=-0.344,P=0.050).The more CD69-expressing NK cells there were,the lower the CD4+T-cell counts andΔCD4,and these correlations were observed in INRs after ART(r=-0.416,P=0.019;r=-0.509,P=0.003,respectively).Additionally,CD69-expressing CD56dimCD16dim/-NK cells were more abundant in INRs than those in IRs(P=0.018)after ART,both of which had an inverse association trend towards significance with CD4+T-cell counts.The expression of the activating receptors NKG2C,NKG2D,and NKp46 on CD56dimCD16dim/-NK cell subsets were higher in IRs than that in INRs after 4 years of ART(all P<0.01).Strong inverse correlations were observed between CD69 expression and NKG2C,NKG2A-NKG2C+,NKG2D,and NKp46 expression on CD56dimCD16dim/-NK cells in INRs after ART(NKG2C:r=-0.491,P=0.004;NKG2A-NKG2C+:r=-0.434,P=0.013;NKG2D:r=-0.405,P=0.021;NKp46:r=-0.457,P=0.008,respectively).Conclusions:INRs had a larger number of CD56dimCD16dim/-NK cells characterized by higher activation levels than did IRs after ART.The increase in the CD56dimCD16dim/-NK cell subset may play an adverse role in immune reconstitution.Further functional studies of CD56dimCD16dim/-NK cells in INRs are urgently needed to inform targeted interventions to optimize immune recovery.展开更多
Background:Allogeneic natural killer(NK)cell immunotherapy is recognized as a promising anti-tumor strategy,but whether it plays a role in poor CD4 recovery among human immunodeficiency virus type 1(HIV-1)infected pat...Background:Allogeneic natural killer(NK)cell immunotherapy is recognized as a promising anti-tumor strategy,but whether it plays a role in poor CD4 recovery among human immunodeficiency virus type 1(HIV-1)infected patients is unknown.This study aimed to investigate the safety and effectiveness of allogeneic NK cells immunotherapy on HIV-1 immunological non-responders(INRs)receiving antiretroviral therapy(ART).Methods:From February to April 2018,a prospective,randomized,controlled,open-label clinical trial,which enrolled 20 HIV-1 INRs following specific inclusion criteria,was conducted at Nankai University Second People’s Hospital.Participants were randomly allocated(simple randomization 1:1)to either the combined treatment(NK+ART)group(n=10)or the control(ART)group(n=10).The allogenic highly activated NK cells from killer cell immunoglobulin-like receptor(KIR)/human leukocyte antigen(HLA)-Cw mismatched healthy donor were prepared(108 cells in each injection)and intravenously infused to each recruited patient of NK+ART group in three courses.Key immune parameters(CD4 count,CD8 count,CD4/CD8 ratio),laboratory tests(count of blood cells,biochemistry panel)and symptoms at baseline and at month 1,3,6,9,12,and 24 were measured/collected to analyze the safety and efficacy of the therapy.Comparisons were between the seven time-points of both groups using repeated measurement analysis of variance(ANOVA)test.Generalized estimating equations(GEE)model was performed to evaluate the overall effect of the NK+ART group vs.the ART group.Results:From baseline to 24 months,we noted a mean CD4 count augmentation(139 to 243 cells/μL)in the NK+ART group and(144 to 176 cells/μL)in the ART group(difference,67;95%CI,10 to 124;P=0.024).Our estimations revealed that NK+ART group could improve CD4 level(β=54.59,P=0.006)and CD8 level(β=322.47,P=0.010)on average among the six measurements compared with the ART group.Only two(2/10,20%)participants in the NK+ART group developed a transient mild fever after the first course.Conclusions:This preliminary study informs that HIV-1 INRs,allogenic NK cells immunotherapy is safe and could significantly improve CD4 recovery but not CD4/CD8 ratio.The practical effects,however,need long-term follow-up observations.Further study on the potential underlying mechanism is warranted.Registration info:www.chictr.org.cn/showproj.aspx?proj=34912(No.ChiCTR1900020634).展开更多
OBJECTIVE:To evaluate the effects of the Wenshen Jianpi recipe(温肾健脾方,WJR)on immune reconstruction and natural killer(NK)cells in immunological non-responders(INRs)of people living with human immunodeficiency viru...OBJECTIVE:To evaluate the effects of the Wenshen Jianpi recipe(温肾健脾方,WJR)on immune reconstruction and natural killer(NK)cells in immunological non-responders(INRs)of people living with human immunodeficiency virus(HIV)(PLWH)and propose new therapeutic strategies for HIV.METHODS:Based on Traditional Chinese Medicine treatment principle“invigorating Qi and warming Yang in the spleen and kidneys”,WJR combined with antiretroviral therapy(ART)therapy was performed in a randomized,double-blind,placebo-controlled study of 60 patients with non-responders.The randomized process was executed by the Clinical Evaluation Center of China Academy of Chinese Medical Sciences.Sixty patients who met the inclusion criteria obtained random numbers(that is the drug number)was randomly divided into a treatment group and a placebo control group according to a 1∶1 ratio.CD4+T cell counts and natural killer(NK)cells counts were evaluated at baseline and 12-week,24-week follow-ups.RESULTS:Four participants received random numbers and did not enter the group due to the patient’s own reasons.A total of 56 patients were enrolled,including 28 in the treatment group and 28 in the control group.CD4+T cell counts in the treatment group were significantly increased at week 24(P=0.01<0.05),which were significantly higher than those in the control group(P=0.01<0.05).Although no significant differences were observed between two groups,the CD56bri CD16-NK cell counts in the treatment group were significantly increased after duration.and CD56dim CD16+NK cell counts in the treatment group were significantly higher than those in the control group after 24 weeks of treatment(P=0.025<0.05).As compared with the control group,the treatment group had significantly lower CD56neg CD16+NK cell counts after 24 weeks of treatment(P=0.023<0.05).CONCLUSIONS:WJR promotes the immune reconstruction of INRs and redistribution of NK cell subsets,notably decreasing CD56neg CD16+NK cell counts in INRs.However,the redistribution of NK cell subsets is not beneficial for immune reconstruction in INRs.Further large-scale RCTs are required to evaluate the effect of WJR on immune recovery in INRs and decipher the underlying mechanism.展开更多
Acute and chronic hepatitis C virus (HCV) infection remains a serious health problem worldwide, however, there has been advancement in the treatment of HCV infection due to standard treatment using pegylated interfero...Acute and chronic hepatitis C virus (HCV) infection remains a serious health problem worldwide, however, there has been advancement in the treatment of HCV infection due to standard treatment using pegylated interferon and ribavirin. The literature indicates that therapy for HCV is becoming more individualized. In addition to considering genotype and viral RNA levels before treatment, achievement of an early virologic response (EVR) and a rapid virologic response (RVR) is now possible during therapy. Moreover, problem patients, such as non-responders, relapsers, HIV or HBV co- infected patients, patients with liver cirrhosis, and pre- or post-liver transplantation patients are an increasing fraction of the patients requiring treatment. This article reviews the literature regarding standard treatments and problem patients with acute and chronic HCV infection. It also includes discussion on contraindications and side effects of treatment with interferon and ribavirin, as well as new drug development.展开更多
文摘Hepatitis B virus(HBV) infection is a global health problem. It is estimated there are more than 2 billion individuals exposed to the virus and 250 million are chronically infected. Hepatitis B is the cause of more than 600000 annual deaths due to cirrhosis and hepatocellular carcinoma. An effective vaccine exists and preventative initiatives center around universal vaccination especially in those at highest risk. Effective vaccination algorithms have led to a significant decline in the development of new infections and its devastating consequences. The vaccine is administered intramuscularly in three doses, with 95% showing long lasting serologic immunity. An additional fourth dose or a repeated higher dose three course regimen is given to those that fail to show immunity. Despite these additional regimens, some remain vulnerable to hepatitis B and are deemed nonresponders. Individuals with chronic disease states such as kidney disease, liver disease, diabetes mellitus, as well as those with a genetic predisposition, and those on immunomodulation therapy, have the highest likelihood of non-response. Various strategies have been developed to elicit an immune response in these individuals. These include increased vaccination dose, intradermal administration, alternative adjuvants, alternative routes of administration, co-administration with other vaccines, and other novel therapies. These alternative strategies can show improved response and lasting immunity. In summary, HBV vaccination is a major advance of modern medicine and all individuals at risk should be sought and vaccinated with subsequent adequate titers demonstrated.
文摘Objective With the same times of injection to compare low-dose intradermal regimen with routine-dose intramuscular inoculation in revaccination of non-responders to hepatitis B vaccine. Methods 40 healthy non-responder children collected by screening were administrated a three-dose revaccination randomly by intramuscular or intradermal route (10vs 2g per dose), and regularly tested for serologic markers up to five years. By the end of follow-up, a booster dose (5μg) was given to those who had lost anti-HBs of ≥10mIU/mL (seroprotection) and anamnestic response was estimated thereafter. Results All 17 intramuscular and 22 of 23 intradermal children effected seroprotection after revaccination. Intradermal children lost seroprotection over time significantly rapider compared with intramuscular children (Log Rank test, P= 0.029). In year 5, 50% of intramuscular but only 18.2% of intradermal children still maintained seroprotection (P=0.075). 12-14 days after the booster dose, all the eight intramuscular children developed an anamnestic response with anti-HBs titer increasing greater, but two of the 18 intradermal children failed to mount seroprotective level. Conclusion Three-routine-dose intramuscular revaccination was significantly effective than low-dose intradermal one with the same times of injection, especially in long-term immunity. We recommend routine-dose intramuscular protocol in revaccination of non-responders.
基金Chongqing Talent Cultivation Program(No.cstc2021ycjh-bgzxm0275)Key Project of the Chongqing Science&Technology Bureau(No.cstc2020jscx-cylhX0001)
文摘Incomplete immune reconstitution remains a global challenge for human immunodeficiency virus(HIV)treatment in the present era of potent antiretroviral therapy(ART),especially for those individuals referred to as immunological non-responders(INRs),who exhibit dramatically low CD4^(+)T-cell counts despite the use of effective antiretroviral therapy,with long-term inhibition of viral replication.In this review,we provide a critical overview of the concept of ART-treated HIV-positive immunological non-response,and also explain the known mechanisms which could potentially account for the emergence of immunological non-response in some HIV-infected individuals treated with appropriate and effective ART.We found that immune cell exhaustion,combined with chronic inflammation and the HIV-associated dysbiosis syndrome,may represent strategic aspects of the immune response that may be fundamental to incomplete immune recovery.Interestingly,we noted from the literature that metformin exhibits properties and characteristics that may potentially be useful to specifically target immune cell exhaustion,chronic inflammation,and HIV-associated gut dysbiosis syndrome,mechanisms which are now recognized for their critically important complicity in HIV disease-related incomplete immune recovery.In light of evidence discussed in this review,it can be seen that metformin may be of particularly favorable use if utilized as adjunctive treatment in INRs to potentially enhance immune reconstitution.The approach described herein may represent a promising area of therapeutic intervention,aiding in significantly reducing the risk of HIV disease progression and mortality in a particularly vulnerable subgroup of HIV-positive individuals.
文摘为探索神经反馈训练在提升射击表现方面的应用效果和训练过程中的无应答者特性,开展一项用于提升射击表现的神经反馈训练(neurofeedback training for sport performance,SP-NFT)实验研究,招募20名受试者,进行2周4次的“巅峰”范式SP-NFT,采集受试者前、后测隐显目标射击表现和相关脑电(electroencephalograph,EEG)数据,检验SP-NFT对射击表现的提升效果、静息态EEG特征、SP-NFT期间正常组和无应答组EEG特性变化情况。结果表明:受试者后测射击成绩显著高于前测(P<0.01),静息态theta频带功率显著降低(P<0.01);相对正常受试者,无应答者在SP-NFT期间的努力程度更高,theta频段功率和SMR功率的变化程度更低,SP-NFT能够有效提升受试者射击表现,进一步揭示了无应答者的相关生理机制。研究成果为用于提升射击表现的SP-NFT技术进一步发展提供理论支撑和实验证据。
文摘Background Cardiac resynchronization therapy （CRT） is a major breakthrough in therapy for advanced heart failure patients; however, a number of key clinical research questions remain, perhaps most importantly the issue of why apparently suitable patients do not respond to CRT. Methods Seven patients, six males and one female, aged （56.43±6.13） years, all diagnosed with dilated cardiomyopathy, were included in this study. They were all non-responders to CRT who underwent routine optimization postoperatively, and received optimal drug therapy. On the basis of biventricular pacing, titrating various atrioventricular （AV） intervals were performed to get the true fusional QRS complexes composed of biventricular pacing and AV intrinsic conduction. Then, the effects of AV intrinsic conduction during CRT were evaluated. Results On the setting of AV intrinsic conduction during CRT, the true fusional QRS complexes were the narrowest, and all patients showed alleviation of symptoms, improvement of exercise tolerance, life quality and hemodynamic parameters during more than 6 months of follow-up. Conclusions Titrating AV intervals to get the true fusional QRS complexes composed of biventricular pacing and AV intrinsic conduction will be beneficial for non-responders to CRT. Maintaining AV intrinsic conduction during CRT may decrease the rates of non-resoonders to CRT.
基金National Natural Science Foundation of China(Nos.81772165,81974303,81571973,and 82072271)the NSFC-NIH Biomedical collaborative research program(No.81761128001)+3 种基金the National 13th Five-Year Grand Program on Key Infectious Disease Control(Nos.2017ZX10202102-005-003 and 2017ZX10202101-004-001)the Beijing Municipal of Science and Technology Major Project(No.D161100000416003)the Beijing Key Laboratory for HIV/AIDS Research(No.BZ0089)the Key Project of Tianjin Second People’s Hospital(No.YS0001)。
文摘Background:Natural killer(NK)cells play a critical role in suppressing human immunodeficiency virus-1(HIV-1)infection,but knowledge on whether and how NK cells affect immune reconstitution in HIV-1-infected individuals who receive antiretroviral therapy(ART)is limited.Methods:We performed a case-control study with 35 healthy individuals and 66 HIV-1-infected patients including 32 immunological non-responders(INRs)with poor CD4+T-cell recovery(<500 cells/μL after 4 years of ART)and 34 immunological responders(IRs)with improved CD4+T-cell recovery(>500 cells/μL after 4 years of ART).NK cell phenotype,receptor repertoire,and early activation in INRs and IRs were investigated by flow cytometry.Results:A significantly higher proportion of CD56dimCD16dim/-NK cells was observed in INRs than IRs before ART and after 4 years of ART.The number of CD56dimCD16dim/-NK cells was inversely correlated with CD4+T-cell counts in INRs before ART(r=-0.344,P=0.050).The more CD69-expressing NK cells there were,the lower the CD4+T-cell counts andΔCD4,and these correlations were observed in INRs after ART(r=-0.416,P=0.019;r=-0.509,P=0.003,respectively).Additionally,CD69-expressing CD56dimCD16dim/-NK cells were more abundant in INRs than those in IRs(P=0.018)after ART,both of which had an inverse association trend towards significance with CD4+T-cell counts.The expression of the activating receptors NKG2C,NKG2D,and NKp46 on CD56dimCD16dim/-NK cell subsets were higher in IRs than that in INRs after 4 years of ART(all P<0.01).Strong inverse correlations were observed between CD69 expression and NKG2C,NKG2A-NKG2C+,NKG2D,and NKp46 expression on CD56dimCD16dim/-NK cells in INRs after ART(NKG2C:r=-0.491,P=0.004;NKG2A-NKG2C+:r=-0.434,P=0.013;NKG2D:r=-0.405,P=0.021;NKp46:r=-0.457,P=0.008,respectively).Conclusions:INRs had a larger number of CD56dimCD16dim/-NK cells characterized by higher activation levels than did IRs after ART.The increase in the CD56dimCD16dim/-NK cell subset may play an adverse role in immune reconstitution.Further functional studies of CD56dimCD16dim/-NK cells in INRs are urgently needed to inform targeted interventions to optimize immune recovery.
基金This study was funded by the Key Project of Tianjin Second People’s Hospital(No.YS0001)the National Natural Science Foundation of China(No.82002136)the 13th Five-year National Major Project for HIV/AIDS and Hepatitis B Control and Prevention,and the Chinese Ministry of Science and Technology(Nos.2017ZX10202102005004,2018ZX10302104-002)。
文摘Background:Allogeneic natural killer(NK)cell immunotherapy is recognized as a promising anti-tumor strategy,but whether it plays a role in poor CD4 recovery among human immunodeficiency virus type 1(HIV-1)infected patients is unknown.This study aimed to investigate the safety and effectiveness of allogeneic NK cells immunotherapy on HIV-1 immunological non-responders(INRs)receiving antiretroviral therapy(ART).Methods:From February to April 2018,a prospective,randomized,controlled,open-label clinical trial,which enrolled 20 HIV-1 INRs following specific inclusion criteria,was conducted at Nankai University Second People’s Hospital.Participants were randomly allocated(simple randomization 1:1)to either the combined treatment(NK+ART)group(n=10)or the control(ART)group(n=10).The allogenic highly activated NK cells from killer cell immunoglobulin-like receptor(KIR)/human leukocyte antigen(HLA)-Cw mismatched healthy donor were prepared(108 cells in each injection)and intravenously infused to each recruited patient of NK+ART group in three courses.Key immune parameters(CD4 count,CD8 count,CD4/CD8 ratio),laboratory tests(count of blood cells,biochemistry panel)and symptoms at baseline and at month 1,3,6,9,12,and 24 were measured/collected to analyze the safety and efficacy of the therapy.Comparisons were between the seven time-points of both groups using repeated measurement analysis of variance(ANOVA)test.Generalized estimating equations(GEE)model was performed to evaluate the overall effect of the NK+ART group vs.the ART group.Results:From baseline to 24 months,we noted a mean CD4 count augmentation(139 to 243 cells/μL)in the NK+ART group and(144 to 176 cells/μL)in the ART group(difference,67;95%CI,10 to 124;P=0.024).Our estimations revealed that NK+ART group could improve CD4 level(β=54.59,P=0.006)and CD8 level(β=322.47,P=0.010)on average among the six measurements compared with the ART group.Only two(2/10,20%)participants in the NK+ART group developed a transient mild fever after the first course.Conclusions:This preliminary study informs that HIV-1 INRs,allogenic NK cells immunotherapy is safe and could significantly improve CD4 recovery but not CD4/CD8 ratio.The practical effects,however,need long-term follow-up observations.Further study on the potential underlying mechanism is warranted.Registration info:www.chictr.org.cn/showproj.aspx?proj=34912(No.ChiCTR1900020634).
基金Supported by National Science and Technology Major Project of China During the 13th Five-year Plan Period:New Adjuvant Strategies of Traditional Chinese Medicine on Immune Reconstruction for Longterm ART-treated People Living with HIV(2017ZX10205501)Effects of Traditional Chinese Medicine on Intestinal Bacterial Community Structure of AIDS Patients(2017ZX10205501-001-010)National Natural Science Foundation of China:Immune Mechanism of Immunological Non-responders of HIV/AIDS Treated with Traditional Chinese Medicine from Immune Activation and Toll like Receptor Signal Pathway(No.81503571)。
文摘OBJECTIVE:To evaluate the effects of the Wenshen Jianpi recipe(温肾健脾方,WJR)on immune reconstruction and natural killer(NK)cells in immunological non-responders(INRs)of people living with human immunodeficiency virus(HIV)(PLWH)and propose new therapeutic strategies for HIV.METHODS:Based on Traditional Chinese Medicine treatment principle“invigorating Qi and warming Yang in the spleen and kidneys”,WJR combined with antiretroviral therapy(ART)therapy was performed in a randomized,double-blind,placebo-controlled study of 60 patients with non-responders.The randomized process was executed by the Clinical Evaluation Center of China Academy of Chinese Medical Sciences.Sixty patients who met the inclusion criteria obtained random numbers(that is the drug number)was randomly divided into a treatment group and a placebo control group according to a 1∶1 ratio.CD4+T cell counts and natural killer(NK)cells counts were evaluated at baseline and 12-week,24-week follow-ups.RESULTS:Four participants received random numbers and did not enter the group due to the patient’s own reasons.A total of 56 patients were enrolled,including 28 in the treatment group and 28 in the control group.CD4+T cell counts in the treatment group were significantly increased at week 24(P=0.01<0.05),which were significantly higher than those in the control group(P=0.01<0.05).Although no significant differences were observed between two groups,the CD56bri CD16-NK cell counts in the treatment group were significantly increased after duration.and CD56dim CD16+NK cell counts in the treatment group were significantly higher than those in the control group after 24 weeks of treatment(P=0.025<0.05).As compared with the control group,the treatment group had significantly lower CD56neg CD16+NK cell counts after 24 weeks of treatment(P=0.023<0.05).CONCLUSIONS:WJR promotes the immune reconstruction of INRs and redistribution of NK cell subsets,notably decreasing CD56neg CD16+NK cell counts in INRs.However,the redistribution of NK cell subsets is not beneficial for immune reconstruction in INRs.Further large-scale RCTs are required to evaluate the effect of WJR on immune recovery in INRs and decipher the underlying mechanism.
文摘Acute and chronic hepatitis C virus (HCV) infection remains a serious health problem worldwide, however, there has been advancement in the treatment of HCV infection due to standard treatment using pegylated interferon and ribavirin. The literature indicates that therapy for HCV is becoming more individualized. In addition to considering genotype and viral RNA levels before treatment, achievement of an early virologic response (EVR) and a rapid virologic response (RVR) is now possible during therapy. Moreover, problem patients, such as non-responders, relapsers, HIV or HBV co- infected patients, patients with liver cirrhosis, and pre- or post-liver transplantation patients are an increasing fraction of the patients requiring treatment. This article reviews the literature regarding standard treatments and problem patients with acute and chronic HCV infection. It also includes discussion on contraindications and side effects of treatment with interferon and ribavirin, as well as new drug development.
