| BackgroundAIDS is a major infectious disease threatening human life and health.The policy of expanding antiretroviral therapy(ART)has been positively implemented in China to reduce death and prevent new infections.HIV have mutated into different genotypes.At present,the main epidemic strains are CRF01＿AE,CRF07＿BC and CRF08＿BC in China.Studies have shown that there are differences in disease progression among different genotypes of HIV.However,there are few studies regarding death as the outcome of disease progression,either on virus inhibition after receiving ART for 12 months.The basic reproductive number(R0)refers to the average number of the secondary transmission of infected people in a certain population during the whole infectious period.It is an epidemiological index to measure the disease transmission.Based on the Bayesian genetic evolution theory,combined with the principle of propagation dynamics,R0 can be calculated directly using gene sequence.There are few reports about the difference of Ro between HIV genotypes.Clinical trials and observational studies have shown that ART can reduce the secondary transmission of HIV between single positive couples.However,except the clinical population trials of HIV prevention trials network(HPTN)071 found that extensive testing and a variety of preventive measures combined with ART reduced the secondary transmission of HIV,there were few observational studies to evaluate the secondary transmission of HIV at community.In recent years,HIV molecular transmission network representing transmission in community,provides a feasible way to assess secondary transmission risk and its influencing factors.Guangxi Zhuang Autonomous Region(Guangxi)is located in Southwest China.In recent years,it ranked top three in the number of new reports in China.Qinzhou is one of the most serious epidemic areas in Guangxi.To provide scientific data for reducing the death and secondary transmission of HIV,this study carried out a survey on disease progression and secondary transmission risk of different HIV genotypes.ObjectivesPart one:to analyze the first CD4 count and mortality of newly reported HIV patients with different genotypes before ART,and the mortality,loss and 12-month VL inhibition(VL<50copies/mL)after ART in Qinzhou,Guangxi from 2014 to 2020.Part two:to analyze the secondary transmission R0 of different HIV genotypes and molecular transmission clusters among newly reported HIV patients in Qinzhou from 2014 to 2020.Part three:to analyze the secondary transmission risk reduced by ART and the related factors of newly reported HIV patients in Qinzhou from 2014 to 2020.MethodsThe first part was a prospective cohort study.Subjects were newly reported HIV infected people in Qinzhou,Guangxi from January 2014 to June 2020.The social,follow-up and ART data were collected from the 2014-2020 AIDS comprehensive prevention and control information system of Qinzhou,Guangxi,including age,gender,education level,nationality,occupation,route of transmission,diagnosis date,ART number,ART start date,CD4 date,CD4,viral load(VL)date,VL,diagnosed date,follow-up status and time.The CD4 of HIV people who had not received ART and tested for the first time was regarded as first CD4.The remaining blood samples of western blot(WB)were collected for nucleic acid extraction,nested PCR amplification,first generation sequencing and combination.The fasttree phylogenetic tree was constructed by approximate maximum likelihood method,and the genotypes were identified according to the clustering results with reference strains.The study started in January 2014 and ended in June 2020.The outcome of the cohort before treatment was death.Follow-up was conducted every 3 months after the newly reported.The outcome of the cohort after treatment was death or withdrawal from corhot.Patients were followed up half month,1 month,2 months,3 months,and then every 3 months after ART,The cohort was divided into groups according to the subtypes of CRFOI＿AE(Cluster 1,Cluster 2 and other Clusters),CRF07 BC,CRF08 BC and other subtypes.The indexes of disease progression were first CD4 and death before treatment,and death,loss and VL inhibition rate after treatment.Wilcoxon rank sum test was used to compare the difference of first CD4 in different subtypes of HIV;Cox model was used to compare the differences of death and loss among different subtypes;Logistic regression model was used to compare the difference of VL inhibition of different subtypes after 12 months of treatment.The adjusted variables included age,gender,marital status,nationality,education level,occupation,route of transmission,first CD4,the interval between newly report date and first CD4,CD4 before treatment,and the reported year.The difference was statistically significant if P<0.05.SAS 9.4 software was used for statistical analysis.The second part was a cross-sectional study.The subjects and social demographic data were the same as part one.The laboratory data included HIV genotypes,pol sequences,blood collection date,molecular transmission cluster(sequence cluster greater than 10 in molecular transmission network)and newly infections from 2018 to 2020(restricted antigen affinity laboratory detection method).R0 and 95%BCI of the HIV subtypes and molecular network transmission clusters were calculated by birth death(BD)model.BD model calculates Ro directly,based on Bayesian genetic evolution theory,combined with the classical propagation dynamics theory,using the gene sequence evolution theory.Markov Chain Monte Carlo(MCMC)algorithm were used to construct the maximum clade credibility(MCC)tree of the sequence evolution.The differentiation nodes of the evolution tree were used to represent the secondary transmission,and the secondary transmission rate was then calculated.The evolution theory of sequence was regarded as the likelihood function,and the distribution of effective propagation time and sampling proportion were updated as priors.Spearman correlation test was used to analyze the correlation between Ro and CGR.Spearman correlation test was used to analyze the correlation between Ro and the number of new infections in molecular transmission clusters.The difference was statistically significant if P<0.05.SAS 9.4 software was used for statistical analysis.The third part was HIV molecular transmission network and longitudinal investigation.Subjects and social demographic data were the same as part one.Laboratory data included genotype,molecular transmission network and recent infections from 2018 to 2020.In molecular network,the threshold of gene distance was determined according to the number of clusters.The basic molecular transmission network was constructed by the newly HIV patients reported from 2014 to 2016,2017,2018 and 2019,respectively.At the beginning of each observation,HIV patients were divided into three groups according to the status of ART:untreated group,treatment group and withdrawal group.According to the VL of the latest date,the treated group was further divided into group with VL<50 copies/mL,VL 50-999 copies/mL,VL≥1000 copies/mL and VL loss.Withdrawal from treatment included stopping ART and loss of follow-up.The secondary transmission of HIV was represented by the connection in molecular transmission network.The new connection of different groups of basic HIV patients with newly reported HIV patients were observed in 2017,2018,2019 and 2020,respectively.Ordinal logistic regression model was used to analyze the influencing factors of the connection between different basic groups and newly reported HIV patients every year;A longitudinal study was conducted to analyze the influencing factors of the connection between different basic groups and newly reported HIV patients in each year by using generalized estimating equation(GEE)model;Adjusted odds ratio(AOR)was used to measure secondary transmission risk;The adjusted variables included age,gender,nationality,education level,marriage,occupation,route of transmission,reported year,subtype,first CD4.The difference was statistically significant if P<0.05.SAS 9.4 software was used for statistical analysis.ResultsPart one:From 2014 to 2020,6335 HIV infected patients were newly reported in Qinzhou,Guangxi.A total of 4270 were included in this study.CRF01＿AE,CRFO1＿AE Cluster 1,CRF01＿AE Cluster 2,CRF07＿BC,CRF08＿BC and other subtypes were 2350(55.0%),474(11.1%),1687(39.5%),395(9.3%),1275(29.9%)and 250(5.9%),respectively.The first CD4 of CRF01＿AE,CRF01＿AE Cluster 1,CRF01＿AE Cluster 2,CRF07＿BC,CRF08＿BC BC and other subtypes were 119,141,118,264,209 and 209(/mL),respectively.The first CD4 of CRFOI AE was lower than that of CRF07＿BC,CRF08 BC and other genotypes,respectively(all P<0.05).The total mortality rate was 24.9/100 person years in none-ART cohort.Among them,the mortality rates of CRF01＿AE、CRF01＿AE Cluster 1,CRF01＿AE Cluster 2,CRF07＿BC,CRF08＿BC and other subtypes were 35.5,34.6,39.4,16.5,15.5 and 14.4(/100 person years),respectively.The results of Cox model showed that the mortality of CRF01＿AE was higher than that of CRF07＿BC(AHR=0.53,95%CI:0.38-0.75),CRF08＿BC(AHR=0.62,95%CI:0.50-0.75)and other subtypes(AHR=0.57,95%CI:0.37-0.89),respectively.The total mortality rate was 2.7/100 person years in ART cohort,and the total loss rate was 3.8/100 person years.Among them,the mortality rates of CRFO1＿AE,CRF01＿AE Cluster 1,CRF01＿AE Cluster 2,CRF07＿BC,CRF08＿BC and other subtypes were 2.9,2.9,3.0,1.5,2.9 years and 2.2(/100 person years),respectively,and the loss rates were 3.3,3.0,3.2,3.7,4.8 and 3.7(/100 person years),respectively.Multivariate Cox model showed that there was no significant difference in mortality among the major HIV subtypes.The loss rate of CRF08 BC was higher than that of CRF01＿AE(AHR=1.31,95%CI:1.01.71).After 12 months of treatment,2066 patients had VL detection,1785 patients had VL<50copies/mL,and the virus inhibition rate was 86.4%.Among them,the virus inhibition rates of CRF01＿AE,CRF01＿AE Cluster 1,CRF01＿AE Cluster 2,CRF07＿BC,CRF08＿BC and other subtypes were 84.1%,83.9%,84.0%,90.7%,90.0%and 87.4%,respectively.The results of multivariate logistic regression model showed that the inhibition rate of CRFOI AE infection was lower than that of CRF07＿BC(AOR=1.77,95%CI:1.02-3.08)and CRF08＿BC(AOR=1.80,95%CI:1.27-2.56),respectively.Part two:From 2014 to 2020,the Ro of CRF01＿AE,CRF01＿AE Cluster 1,CRF01＿AE Cluster 2,CRF07＿BC and CRF08＿BC were 1.48,1.48,1.48,1.65 and 1.63,respectively.Each Ro of CRF07 BC and CRF08 BC was higher than that of CRF01＿AE and its clusters(all P<0.05).From 2018 to 2020,Ro was positively correlated with CGR(P<0.05)and the number of new infections of the major molecular transmission clusters.Part three:The number of clusters was large when the threshold of gene distance was 0.50%.As the year of 2016,2017,2018 and 2019,the basic number of HIV patients in Qinzhou was 2176,2771,3378 and 4069,respectively.The connection rates of treated groups with newly reported HIV patients in years of 2017,2018,2019 and 2020 were 17.2%,17.7%,15.7%and 9.1%,respectively,and the untreated groups were 13.5%,14.2%,12.1%and 7.1%,respectively,and the withdrawal groups were 14.5%,10.7%,12.2%and 6.8%respectively.From 2017 to 2020,four surveys were conducted using ordinal logistic regression model.Compared with the untreated group,the connection rates of basic HIV patients in treatment groups with newly reported HIV patients were lower(all P<0.05),and there was no significant difference between the withdrawal group and untreated group in connection rates with newly reported HIV patients.The total number of repeated observation subjects was 12394.Compared with untreated group,treatment group had less connection with the newly reported HIV patients(AOR=0.68,95%CI:0.56-0.83),and treatment reduced the secondary transmission rate by 32%;There was no significant difference in connection rate between the withdrawal group and the untreated group with the newly reported HIV patients.Subgroup analysis showed that:compared with the untreated group,the HIV patients group with VL<50 copies/mL had less connection with the newly reported HIV patients(AOR=0.64,95%CI:0.51-0.79),and the secondary transmission rate was reduced by 36%in the treated group with VL<50 copies/mL;Compared with the untreated group,the HIV infected group with VL<50 copies/mL have less connection with the newly reported HIV patients(AOR=0.293 95%CI:0.22-0.38)after treatment for 3 years or more(excluding invalid connection),and the secondary transmission rate was reduced by 71%after treatment for 3 years or more and VL<50 copies/mL;There was no significant difference in the connection rate between treatment group and untreated group with the newly reported HIV patients.HIV patients of aged 30-49(AOR=1.56,95%C1:1.05-2.31),50-69(AOR=4.36,95%CI:2.97-6.40)and≥70(AOR=6.18,95%CI:4.02-9.49),men(AOR=1.70,95%CI:1.37-2.11),Zhuang and other minorities(AOR=1.41,95%CI:1.08-1.84),retirees(AOR=1.64,95%CI:1.01-2.66),heterosexual transmission(AOR=l.87,95%CI:1.26-2.76),CRF07＿BC(AOR=1.69,95%CI:1.25-2.28),CRF08＿BC(AOR=1.61,95%CI:1.32-1.95)and other subtypes(AOR=3.42,95%CI:2.38-4.92),first CD4 of 200-349 cells/mL(AOR=1.55,95%CI:1.22-1.95),≥350 cells/mL(AOR=1.55,95%CI:1.23-1.97)and VL loss(AOR=1.27,95%CI:1.00-1.61)were all risk factors of HIV seconday transmssion.There was no significant difference between different education levels,marital status,recently infection in the secondary transmission risk.Conclusions1.Before ART,CRF01＿AE patients had lower first CD4 and higher mortality compared with CRF07 BC,CRF08 BC and other subtypes.After ART,there was no difference in mortality among CRFOI＿AE,CRF07＿BC,CRP08 BC and other subtypes,and the loss rate of CRF08＿BC was higher than that of CRF01＿AE,and CRF01＿AE had lower virus inhibition rate than CRF07 BC and CRF08 BC after ART for 12 months.2.2014-2020,The Ro of CRF07 BC and CRF08 BC were higher than that of CRF01＿AE.CRF07 BC and CRP08＿BC had high risk of transmission.There was no significant difference in Ro among CRF01＿AE cluster 1 and CRFOI AE cluster 2.R0 was positively correlated with CGR and the number of new infections in molecular transmission clusters.3.Compared with untreatment,ART had reduced 32%secondary transmission rate of HIV,and ART with VL<50 copies/mL had reduced 36%secondary transmission rate,and ART with VL<50 copies/mL treated for more than 3 years had reduced 71%secondary transmission rate.High age group,male,Zhuang and other ethnic minorities,retirees,heterosexual transmission,non CRF01＿AE and high first CD4 group were related factors of secondary transmission. |
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