| ObjectivesHuman Immunodeficiency Virus(HIV)infection continues to be a serious public health problems in China and around the world.With the application of antiretroviral therapy(ART)drugs,the life expectancy of people living with HIV or AIDS improved a lot,and acquired immune deficiency syndrome(AIDS)gradually become a chronic non-communicable disease.The good immune status of people living with HIV is conducive to controlling AIDS related diseases and deaths.At present,most of the studies have analysed the impact of baseline CD4 cells count,CD8 cells count and CD4/CD8 ratio on prognosis in people living with HIV or AIDS.However,people living with HIV or AIDS need to take ART for life,which is a long-term process.The impact of immune index changing trajectories for patients on prognosis would be clinical significance for clinical intervention,the disease process control and the mortality decrease.Moreover,there were different each individual clinical background,ART regimen,drug resistance and compliance,there were population heterogeneity in changing trajectories of CD4 cells count,CD8 cells count and CD4/CD8 ratio.Our study intends to identify the heterogeneity of CD4 cells count,CD8 cells count and CD4/CD8 ratio development trajectories in people living with HIV during long ART period by Latent Growth Mixture Model(LGMM).Furthermore,we explore the risk of death in different immune index changing trejactories,and then identify the population in high-risk of death.Providing a target prevention and treatment meaures,and a basic refference on long-term mornitoring of immune index for sub-classes in people living with HIV.Also to provided a theroticcal basis for improving the effect of ART,improving the quality of life and immune founction during ART period.MethodsA retrospective cohort study was conducted from the largest infectious disease hospital in Guangzhou.Collecting baseline and follow-up data of people living with HIV,who started ART firstly,aged more than 15 years during 2004 to 2019.The information of cohort included baseline demographic characteristics(gender,age,ect.),epidemiological and clinical characteristics(infection pathways,clinical stage of WHO,etc.),antiviral treatment regimen,laboratory indicators(such as hemoglobin,blood sugar,HBV and HCV infection indicators,etc.).The CD4 cells count,CD8 cells count,CD4/CD8 ratio was monitored in baseline and every follow-up.LGMM with 1 to 4 latent classes was applied for three imuninity index in people living with HIV.The optimal model was determined according to the following criteria: smallest infromation criteria value of AIC,BIC,a BIC,and higher entropy value,smaller VLRT P value.To obtaining different development trajectories of CD4 cells count,CD8 cells count,CD4/CD8 ratio.The influencing factors for immune index groups were used by chi square test,rank sum test and multivariate logistic regression model.Log-rank test were used to compare the difference of mortality,and Cox proportional hazard models were fitted to investigate the association between the trajectory group and mortality.ResultsA total of 14293 people living with HIV or AIDS,who started ART firstly,aged≥15 years,baseline and follow-up more than 3 times during 2004-2019 years in the largest infectious disease hospital in Guangzhou,were included in the study.55615.41 person-years were follwed-up,229 patients of whom were dead,and the motality density was 0.40/100 person-years.The started ART mean age was 36.64±11.97 years old,male dominated80.95%.The baseline median and quartile range of CD4 cells count,CD8 cells count,CD4/CD8 ratio were 208.0(70.0-316.0)cells per μL,788.0(521.0-1116.0)cells per μL,0.225(0.107-0.358)cells per μL respectively.With the increase of ART period of people living with HIV,the CD4 cell count and CD4/CD8 ratio were gradually increasing,the CD8 cell count was gradually increasing during three months and than starts decreasing.The LGMM results show that there were two potential classes of CD4 cell count development trajectories,53.4% included in baseline low-level then stable growth grouplow(Class-1)and 46.6% included in baseline high-level then rapid growth group(Class-2).During the whole ART period in CD4 cell count two trajectories,the baseline CD4 cell count was no more than 200 cells per μL in the class-1.After ART the CD4 cell count increase from 135 cells perμL to 227 cells per μL,the other group increase from 292 cells per μL to 425 cells per μL in three months,and overall level of the class-2 aways higher than class-1.Three distinct trajectories groups were identified of CD8 cell count:baseline high-level the rapid decrease group(12.2%,Class-1),baseline low-level then stable group(58.0%,Class-2),baseline high-level then slow decrease group(29.8%,Class-3).After starting ART of people living with HIV,the trajectories increase rapidly in the class-1 and class-3 in three months,and then decrease rapidly and slowly respectively,the trajectory had the lowest start level and cotinious keep in low level after three months in the class-2.Three distinct trajectories groups were identified of CD4/CD8 ratio:baseline low-level then slow growth group(57.4%,Class-1),baseline high-level then rapid growth group(8.3%,Class-2),baseline middle-level then rapid growth group(34.3%,Class-3).Moreover,the trajectoris of CD4/CD8 ratio were also different,after starting ART of people living with HIV in three months,the growth trend was the lowest from 0.07 to 0.13 in class-1,the highest from0.49 to 0.84 in the class-2.The CD4/CD8 ratio was still lower than 0.4 in whole follw-up period in the class-1,more than 0.8 after ART four years and no more than 1.0 in whole follw-up period in the class-3,more than 1.0 after one year and keep whole follw-up period in the class-2.The multivariate Logistic results showed that gender,age,time interval from dignosis to start ART,infection regimen,now use of cotrimoxazole,opportunistic infections,types of clinical symptoms,initial ART protocol and so on,baseline laboratory indicators such as CD4 cell count groups,anemia,serum creatinine,total bilirubin,hepatitis B and hepatitis C infection would affect the grouping of immunity indexes.The survival probability of people living with HIV was statistically significant(all P value no more than 0.001)in different changing trajectories of three immunity index.Death density was 0.52 and 0.26 per 100 person-years in CD4 cell count two trajectories,and 0.27,0.56,0.20 per 100 person-years in CD8 cell count three trajectories,and 0.53,0.13,0.25 per 100 person-years in CD4/CD8 ratio three trajectories,recpectively.Compared with the class-1,the death risk was 0.509 fold in the class-2 of CD4 cell count trajectory(HR=0.509,95%CI:0.381-0.680,P<0.001).Compared with the class-1,the death risk increase 0.864 fold in the class-2 of CD8 cell count trajectory(HR=1.864,95%CI:1.001-3.737,P=0.039).The hazard raio and 95% CI were0.220(0.054-0.879)and 0.360(0.213-0.608)in the class-2 and class-3 compare with the class-1,respectively.Conclusion1.There were group heterogeneity in free ART cohort of people living with HIV.Baseline CD4 cells count of people living with HIV recover to more than500 cells per μL rapidly,and keep this level during ART period.After starting ART,the patients with a high-level CD8 cells count in baseline would increased in three months then decreased slowly.If patients’ baseline CD4/CD8 ratio was more than 0.4,CD4/CD8 ratio would recover to normalization after ART(more than 1.0)rapidly and maintain it during ART period.It showed that with a good immune status of people living with HIV immediate start ART,who would maintain at good immune function.Timely starting ART after diagnosis,before infected with opportunistic infection and appeared clinical symptoms,and formulating a target ART regimen or intervention measures based on baseline blood and kidney dysfunction would be good at the recovery of immune function.2.With higher baseline CD4 cell count level,CD8 cell count level,CD4/CD8 ratio level of people living with HIV when starting ART,their immune function would recover to normarlazation or higher level,also with a lower mortality.Individualized intervention measures and treatment plans can be formulated according to individual baseline status and long-term changes of immune indexes,and guidance for clinical intervention can be provided.Longterm monitoring of immune indexes is of great clinical significance for the control of disease progression. |
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