| The situation of Human immunodeficiency virus(HIV)infection/Acquired immunodeficiency syndrome(AIDS)is still severe.Although the immune function of most patients is reconstituted by antiretroviral therapy(ART),the virus is still not completely cleared.Due to the rich intestinal lymphoid tissue,the co-receptor required for HIV to enter cells,C-C chemokine receptor 5(CCR5),is highly expressed in the intestinal tract,making the intestinal tract a priority target for HIV and a major site of replication.The intestinal barrier of HIV patients has been damaged for a long time,and the permeability is increased.The translocation of intestinal microorganisms and metabolites into the circulatory system promotes abnormal immune activation,which leads to a significant increase in the risk of AIDS complications such as cancer.Therefore,impaired intestinal barrier function and microbial translocation have become one of the major issues facing HIV patients in the ART era.In addition,microbial dysbiosis(including bacteria,fungi,viruses,archaea,etc.)is closely related to HIV disease progression and clinical outcomes of patients.Among them,bacterial flora and fungal flora account for the vast majority of intestinal flora,the two interact and are closely related to maintain the ecological balance of the intestinal tract.As an important component of the body’s flora ecosystem,fungi have a significant impact on the intestinal barrier function.Fungal infection is the most common opportunistic infection in HIV patients,and antifungal drugs are widely used in clinical practice as first-line treatment.However,whether these drugs(especially oral antifungal drugs)affect the intestinal barrier function and microbial translocation in HIV patients by affecting the fungal flora is still unclear,which hinders the development and optimization of antifungal treatment regimens.In view of this,this study takes HIV patients with stable condition,no major interfering factors and oral terbinafine treatment of onychomycosis as the research object.Adopts a single-arm longitudinal cohort study design,and collects 20 patients’plasma,stool samples and clinical data before and after medication and drug withdrawal(i.e.Baseline,1-2 weeks after treatment,12 weeks after treatment,12 weeks after drug withdrawal,four follow-up points),to study the effect of oral terbinafine treatment on intestinal barrier function(intestinal damage,microbial translocation,inflammatory factors and intestinal flora)and its correlation with clinical outcome,provide a scientific basis for the rational application of antifungal drugs in clinical practice.The research content and results are reported as follows:1.Effect of oral terbinafine on intestinal barrier in patients with HIV complicated with onychomycosisWe collected plasma and stool samples from 20 HIV patients with chronic fungal infection at four follow-up points.Enzyme-linked immunosorbent assay(ELISA)was used to measure the concentrations of Intestinal fatty acid binding protein(I-FABP)and regenerating islet derived protein 3 alpha(REG3α)in plasma samples to analyze the degree of intestinal injury.The results showed that the concentration of intestinal injury marker I-FABP increased significantly during the course of taking the drug(P=0.021,0.044),and returned to the level before taking the drug after stopping the drug,suggesting that terbinafine may have a certain damage effect on the intestinal barrier.There was no statistical difference in REG3αamong the four follow-up points.Determination of lipopolysaccharides(LPS)and(1,3)-β-D-glucan(BDG)concentration by ELISA and limulus amebocyte lysate(LAL)assay to analyze intestinal microbial translocation,the results showed that microbial translocation markers LPS and BDG had no statistical difference among the four follow-up points.ELISA was used to measure the concentrations of interleukin(IL)-6,IL-10,soluble CD14(s CD14),and tumor necrosis factor alpha(TNF-α)in plasma samples to analyze the levels of inflammatory factors in the body.Found that the inflammatory factor IL-6 decreased after taking the drug for 1 week(P=0.048),and then returned to normal.And the concentrations of IL-10,s CD14 and TNF-αhad no statistical difference at the four follow-up points.q PCR was used to measure the relative changes in the total amount of bacterial and fungal DNA in feces.It was found that there was no significant change in the total amount of bacterial DNA in feces before and after oral administration of terbinafine.The total amount of fungal DNA was decreased gradually during the medication period,and there was a statistical difference between the two groups at the first week and the12th week of medication(P=0.022).16S r DNA and ITS1(Internal transcribed spacer1)high-throughput sequencing were used to analyze the diversity and community composition of intestinal bacteria and fungi in stool sample.The results showed that there was no significant difference in the Alpha diversity and Beta diversity.And the analysis of species composition showed that:At the 12th week of taking the drug,the abundance of beneficial bacteria Eubacterium hallii,Lachnospira,and Akkemmansia increased,while the abundance of harmful bacteria Campylobacter and Succinivibrio decreased in bacterial flora,and the abundance of Candida in fungal flora decreased.Spearman correlation analysis was used to analyze the correlation between intestinal flora and intestinal injury markers,microbial translocation markers,and inflammatory factor levels.Found that multiple genera in the intestinal bacterial and fungal flora were positively or negative correlated with these markers.2.The effect of oral terbinafine on the clinical outcome of HIV patients with onychomycosisWe statistically analyzed the clinical efficacy data of the subjects,and analyzed the impact of oral terbinafine on HIV disease status.The results showed that the HIV viral load didn’t change before and after taking the drug,and it was always below the lower limit of detection(<50copy/ml).The number of CD4~+T cells increased(P=0.065),the number of CD8~+T cells decreased,and the ratio of CD4~+/CD8~+increased significantly(P=0.003).Analysis of the treatment of onychomycosis by oral administration of terbinafine showed that after taking the drug,the number of onychomycosis infections in the subjects was significantly reduced,the area of infection was significantly reduced,the thickness of the nail bed was significantly thinner,and onychomycosis was effectively treated.The safety data of the subjects showed that there was no significant change in the liver and kidney functions of the subjects before and after oral administration of terbinafine,and no serious adverse events occurred.Based on the above,this study can draw the following main conclusions:(1)Oral antifungal drug terbinafine had little effect on the intestinal barrier of patients with HIV infection complicated with onychomycosis,but the fungal flora composition,bacterial flora composition,intestinal barrier damage index,and inflammation index were significantly affected during the medication process.Significant changes of different degrees occurred,suggesting that oral administration of terbinafine is a potential influencing factor of intestinal barrier function.(2)The results of the study suggest that after oral administration of terbinafine,the level of CD4~+T cells in patients increases,but this effect and its specific mechanism need to be further verified and explored. |
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