| Objective The aim of this study was to comprehensively analyze immune restoration in HIV-1-infected patients with antiretroviral therapy(ART)in China based on national multicenter real-world data,and to explore a new system to evaluate the immune recovery of patients more accurately and comprehensively in the era of “treat all”.Meanwhile,we aim to analyze the long-term outcomes and related risk factors of HIV-1-infected patients after ART initiation,which would provide theoretical basis for intervening the adverse outcomes of those patients.In addition to severely immunosuppressed patients(CD4+ T cell count < 50/μl)who rarely realize immune reconstitution,epidemic analysis of this population was required for further targeted intervention.On the basis of promoting immune recovery of patients with severe immunosuppression by allogeneic adoptive immunotherapy(Adoptive allogeneic immunotherapy,AAIT),a clinical trial conducted by our team,the possible mechanism of immunological therapy was explored preliminarily,it would provide a new direction for future HIV related immunotherapy research.Methods1.Based on the National Free Antiretroviral Therapy Program(NFATP)database,a retrospective cohort study was conducted among 91805 HIV-1/AIDS adult who started ART from January 1,2005 to June 30,2018.The incidence and risk factors of immune recovery at different levels,mortality and non-HIV defined disease(NAD)were analyzed.We defined NAD outcomes of interest as cardiovascular disease(CVD),end-stage liver disease(ESLD),advanced renal disease(ARD),and non-AIDS-defining cancers(NADCs).The cumulative incidence was calculated by Kaplan-meier method,and multivariate analysis was performed by Cox proportional hazard regression model,and the contribution of different risk factors on outcomes was quantified by population attributable fraction(PAF).2.We extracted all data of treatment-na?ve HIV-1-infected patients with severe immunosuppression during 2005-2018 from NFATP database.Distribution in spatial,temporal and population were analyzed.Kaplan-meier method was used to calculate the mortality of patients within 6 months and 12 months after ART initiation.To analyze the geographical distribution,divided the 31 provinces,municipalities,and administrative regions of mainland China into six different regions: the North,the Northeast,the East,the Northwest,the Southwest and the South-central.In terms of analyzing the time distribution,we calculated the trend of the proportion of all severely immunosuppressed patients to the total treatment-na?ve population in each year from 2005 to 2018,and calculated the trend of regional distribution of patients in the four periods(2005-2007,2008-2013,2014-2015 and2016-2018).In population characteristics analysis,the main variables were age,sex and transmission.And we analyzed the trends of distribution of those variables in each of the areas mentioned.Use Linear by Linear Association Linear correlation to compare the differences in trends over time in the proportion of different regions3.Severely immunosuppressed patients receiving AAIT combined with ART and only ART were matched in groups with baseline age,CD4+ T cell counts,and associated opportunistic infection.The dynamic changes of immune status were compared between the two groups at baseline,4 weeks after treatment and 24 weeks after treatment.The levels of activation,exhaustion and immunosenescence of T cells and the dynamic changes of T cell subsets were analyzed by Flow cytometry.Meanwhile,the dynamic changes of plasma inflammatory factors were detected by flow cytometry.In addition,peripheral blood lymphocyte of AAIT patients were analyzed by single-cell transcriptome sequencing to explore the mechanism of improving immune recovery after AAIT treatment.Results1.ART was started in HIV-1 patients with baseline CD4 counts <50,50–199,200–349,350–499,and ≥500 cells/μl,and results showed an increase in the median CD4 counts to 445(12-year),467(12-year),581(11-year),644(7-year),and 768 cells/μl(5-year),as well as the CD4/CD8 ratio to 0.59(12-year),0.65(12-year),0.79(11-year),0.82(7-year),0.9(5-year),respectively.Meanwhile,the median CD8 count was relatively high(median range 732–845cells/μl),regardless of the baseline CD4 counts,even after the longest follow-up period.Furthermore,the probabilities of death in patients achieving a combination of CD4 counts≥500 cells/μl and CD4/CD8 ratio ≥0.8 were significantly lower than those in patients achieving either CD4 counts ≥500 cells/μl(2.77% vs 3.50%,P = 0.02)or CD4/CD8 ≥0.8(2.77% vs 4.28%,P < 0.001)after 12 years of ART.2.Overall,8,301 participants(median age at study entry,31 years)contributed 33,146person-years of follow-up(PYFU)in NAD cohort.Incidence of CVD(362/100,000 PYFU)was the highest among outcomes.Totally,34.14% of CVD was attributable to smoking,7.98% to hypertension,and 6.44% to diabetes.For ESLD,24.57% and 25.04% of it could be avoided if chronic hepatitis B and C virus infection,respectively,did not present.The leading PAFs for ARD were declined estimated glomerular filtration rate(e GFR)(39.68%)and low CD4 count(39.61%),followed by diabetes(10.19%).PAFs of hypertension,diabetes,and smoking for CVD,and declined e GFR and diabetes for ARD increased with age.3.Totally,105785 treatment-na?ve severely immunosuppressed patients aged more than15-year-old were included between 2005-2018.Their mean age was 40.87 ± 12.60 years and79% were male.Among all treatment-na?ve patients,the proportion of severely immunosuppressed patients plateaued to around 11–12% from 2015 onward.The proportion of patients among all severely immunosuppressed patients in the South-central remained the highest,despite consistently decreasing(from 64.68% to 39.16%,c2=2712.873,P < 0.0001),while various increasing trends presented in the other five regions.Among patients in the South-central and Southwest,the proportion of patients aged 45–59 years increased from21.64% and 20.50% in 2005 to 34.02% and 33.77% in 2018,respectively,becoming one of the dominant burden groups in 2018;while,the proportion of 15–29 year-old in the North(11.96% to 27.24%)and Northeast(0% to 27.24%)increased significantly during 2005-2018.The proportion of male-to-male contact increased and became the dominant in the North(from 4.35% in 2005 to 57.8% in 2018)and Northeast(from 7.14% in 2005 to 59.94% in2018,c2=-9.2432,P < 0.0001)in 2018.Heterosexual contact remained the dominant transmission route in the other four regions.4.Through group matching of baseline information,this study included 5 patients in the AAIT group and 5 patients in the control group,there was no significantly statistic difference in baseline age,CD4+ T cell counts,and associated opportunistic infection between those two groups.The proportion of CD4+HLA-DR+ T cells,CD4+CD38+T cells and CD8+CD38+HLA-DR+ T cells in AAIT group decreased,while the proportion of those subsets in control group increased first and then decreased.The percentage of CD4+ PD-1+ T cells decreased in AAIT group,but slightly increased in control group,and the percentage of CD8+PD-1+ T cells decreased significantly in AAIT group(P = 0.022),compared with the control group,the na?ve CD4+ T cell subsets in the AAIT group increased and were higher than those in the control group(P = 0.028)at 24 weeks.the proportion of CD57+CD8+ T cells in AAIT group were lower than control group after treatment.The levels of IL-6(P = 0.015),s CD163(P = 0.041)and IP-10(P = 0.041)in AAIT group were significantly decreased.Conclusions Our findings provided evidence of dynamic changes during host immune restoration in HIV-1patients with long-term ART.Our data suggest that CD4/CD8 ratio should be integrated together with CD4 counts for the holistic evaluation of immune restoration.Compared with the binary indicator-based immune restoration assessment,using CD4 counts(≥500 cells/μl)as the only immune evaluation parameter might lead to an overestimation of successful immune restoration and neglection of the risk of death in the era of “treat all”.The contribution of traditional risk factors for these NAD far outweighed the HIV-related risk factors.Individual-level interventions and population-level policy-making is needed to focus on these factors to prevent NAD in long-term management of HIV infection.The persistent burden of treatment-na?ve HIV-1-infected patients with severe immunosuppression remains challenges.Our results provide evidence for policy-makers to allocate resources and establish targeting strategies to identify early infection of patients.AAIT reduce the level of immune activation,exhaustion and immunosenescence among T cells,as well as reduce the level of inflammatory activation in patients,these findings provide a new direction for future research. |
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