| Objectives:The level of T cell activation is a better predictor of CD4+T cell depletion in highly active anti-retroviral therapy(HAART)-treated patients than viral load.Artesunate is an artemisinin derivative that has an immunomodulatory effect.This study preliminarily investigated whether artesunate tablet reduces T cell activation and improves immune reconstitution among patients with suboptimal immune recovery despite receiving long-term effective HAART.Methods:This was a randomized,prospective,parallel,open-label trial consisting of 45 participants who was being under HAART for more than one year and having a plasma HIV load of less than 50 copies/mL for greater than 18 months and had CD4+T cell counts of less than 300 cells/ul or an increase of less than 20%from baseline.The patients were randomized 2:1 into the artesunate group or the control group and received artesunate tablets(orally,50 mg two times daily)combined with HAART or HAART alone,respectively.During the 48-week trial,T cell subsets,activation markers,proliferation and apoptosis markers were detected by flow cytometry at each follow-up point,changes in viral load before and after the intervention were detected,and drug safety was assessed.Results:1.A total of 45 subjects were enrolled.In the artesunate group,31 cases were included,and 2 cases were excluded.14 cases were included in the control group.In the artesunate group,there were 26 males(89.7%)with a mean age of 39.6±7.7,25 cases(86.2%)receiving NNRTI,and the median absolute count of CD4+T cells was 229.0(167.5-253.5)cells/ul.In the control group,there were 11 males(78.6%)with an average age of 38.2±10.2.10 cases(71.4%)were treated with NNRTI,and the median absolute count of CD4+T cells was 203.0(148.5-245.5)cells/ul.The two groups were comparable on baseline in terms of sex,age,antiviral drugs,and CD4+T cell count(P>0.05).2.The major subsets of T lymphocytes and helper T lymphocytes subsets:The median increase in the number of CD4+CD45RA+T cells in the artesunate group was higher than that in the control group at week 12,24,36 and 48,and there was statistically significant difference between the groups at the week 12(P<0.05).The increase of CD4+T cell number in the artesunate group at 48 was significantly lower than that in the control group(P<0.05).The average increase of CD8+T and CD3+T cells at week 24 and week 48 was lower than that of the control group,but the difference was not statistically significant(P>0.05).At week 48,the absolute CD3+T lymphocyte count in the control group was significantly higher than that in the artesunate group(P<0.05).There were no significant differences in the number of CD4+T,CD8+T,CD4+CD45RA+T,CD4+CD45RO+T cells and the ratio of Th/Ts between the two groups at each observation point(P>0.05).3.The effective rate of immune reconstitution:There was no significant difference in the efficacy of immune reconstitution between the two groups within one-year treatment(P>0.05).4.The detection of T cell function:①The reduction of CD4+CD25+(%)in the artesunate group at week 24 was significantly higher than that in the control group(P<0.05),and CD4+CD25+(%)was significantly lower at week 24 compared to baseline(P<0.05),and then increased at week 48(week 48 vs.baseline:P>0.05).In the control group,there was no significant difference in CD4+CD25+(%)at week 24 and week 48 compared to baseline(P>0.05).There was no significant difference among the groups at each follow-up point(P>0.05).②There was no statistical difference in CD4+CD28+(%)between the two groups at each follow-up point(P>0.05).③In the artesunate group,CD4+CD38+(%)and CD8+CD38+(%)were significantly higher than those in the control group at week 48(P<0.05).5.The proliferation and apoptosis of T cells:①CD4+Ki67+/CD4+(%)in the artesunate group was significantly higher than that in the control group at week 48(P<0.05).There was no significant difference in CD8+Ki67+/CD8+(%)between the two groups(P>0.05).②The reduction of early apoptotic cells/CD4+(%),early apoptotic cells/CD8+(%)and early apoptotic cells/CD3+(%)in the artesunate group at week 24 and 48 were significantly higher than those in control group(P<0.05).In addition,early apoptotic cells/CD8+(%)at week 24 and 48 was significantly lower than that of the control group(P<0.05),and early apoptotic cells/T(%)at week 48 was significantly lower than that of the control group(P<0.05).Early apoptotic cells/CD4+(%)in the artesunate group were significantly lower than baseline at 24 and 48 weeks(P<0.05).Early apoptotic cells/CD3+(%)at week 24 was significantly lower than that at baseline(P<0.05),and then increased at week 48 with no significant difference(P>0.05).In the control group,the median of the three early apoptotic indexes all showed an upward trend,and the early apoptotic cell/CD8+(%)and early apoptotic cell/CD3+(%)were both significantly higher than baseline at week 48(P<0.05).6.Compliance and viral load:Overall,the subjects in both groups had good medication compliance with well controlled viral load during the trial,and their plasma HIV-1 RNA was lower than 50copies/ml.7.Safety analysis:Two subjects withdrew from the trial because of the aggravation of fatigue and insomnia after taking artesunate tablets,respectively.One subject was diagnosed with moderate anemia,which was probably caused by artesunate.At week 48,the absolute lymphocyte count in the artesunate group was significantly lower than that in the control group(P<0.05).Conclusions:Among HAART-treated patients with incomplete immune responses,one-year administration of artesunate tablets at a dose of 50mg two times daily did increase the number of CD4+CD45RA+T cells,and effectively reduce the level of early T cell apoptosis.However,the effect of improving CD4+T cell recovery and reducing the activation of T cell subsets was probably minimal.Long-term(more than six months)use of artesunate tablets may even increase the levels of T cell activation markers.Most of the subjects tolerated the treatment well.The results initially suggest that long-term use of artesunate tablet may produce few substantial immunological benefits in patients on HAART with incomplete immune responses.Due to the relatively small number of cases included in this trial,a larger sample size is needed to reach a more accurate conclusion. |
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