| BackgroundDespite the ability of antiretroviral therapy(ART)to suppress the viral load below the limit of detection among HIV-infected patients,ART cannot eradicate the infection.If the ART is discontinued,plasma viral load rapidly rebounds to high levels,which confirmed the existence of the viral reservoir.Currently,the mechanism for the persistence of HIV reservoir among viral suppressed patients is not clear.Some researcher suggesting that HIV replication exists in the reservoir even if the patient with suppressed viral load.Other researchers indicated that there is no virus replication,and HIV maintains its stability through cell proliferation.Since China began to implement free treatment for AIDS patients in 2003,the incidence and mortality of AIDS have been effectively controlled.However,with the extension of treatment time,there will be first-line antiretroviral treatment failure,drug resistance and other conditions requiring switched to second-line regimens.And there were less study on the treatment outcomes of patients switched to second-line regimens for 36 months.Objective1.To understand if there were evolution of HIV among patients received long-term antiretroviral treatment.2.To study the treatment outcomes and HIV drug resistance of patients switching to second-line regimens after long-term first-line antiretroviral therapy.Methods1.Six patients with long-term antiretroviral treatment were included in our study,RNA and DNA of five time points before and after antiretroviral treatment of these patients were extracted.We used the method of SGA to obtain a single gene sequence,and then analyze its evolution relationship,divergence and drug resistance.2.304 patients switched to second-line regimens from Jun.2008 to Jun.2015 were enrolled from an observational cohort.In addition,patients continuing first-line ART and had a viral load<1000 copies/ml were included as control group.And we study the treatment outcomes,drug resistance and factors caused VF after switched to second-line regimens.Results1.There were six patients included in our study,and viral suppression group has 4 patients,and another two were virologic failure group;And these research with four female and two male patients,the average age of 6 patients was 43.8 years old.The average sequence number of each sample time point obtained by SGA amplification method is 24.0,and finally 15.5 sequences were included in analyzing.The total of 675 sequences and reference strains included in this study were analyzed by ML(Maximum-likehood method)evolutionary tree,and the tree indicates there was no pollution between the samples and the laboratory strains.After analyzed the ML phylogenetic tree between 6 patients,we found:(1)the sequence of each treatment time point in the viral load suppressed group was randomly distributed,and there was no cluster phenomenon along with treatment time;(2)consistent sequences was developed from the viral load suppressed group,but no correlation with time was found.Through calculating divergence between various time points of two groups of patients,we found that:(1)divergence of HIV DNA sequence before treatment,6 months,12 months and 10 years of ART were similar or a slight trend of decrease;(2)the divergence between the RNA and DNA of each treatment time was increased with the extension of treatment time between the two samples of the viral suppressed failure group,and there is no difference between RNA and DNA.According to the slope of the fitting line,the rate of evolution of the viral suppressed failure group is 2.0～2.8×10-3 each year.Among viral load suppressed group,there were no drug resistance mutations sites of NRTI,NNRTI and PI before and after ART.Before ART,there were no drug resistance mutations among patients with failure antiviral treatment.However,drug resistance mutations were detected after 4 time points of antiretroviral treatment.2.There were 304 patients switching to second-line regimens and 46 patients remaining on first-line therapy enrolled in our study.Of the 350 patients,the median age was 47.2 years old,and the majority were female(61.1%).In 304 patients switching to second-line therapy,the proportions of VL>1000 copies/ml were decreased dramatically from 59.2%to 18.5%in the first year of switch,the trend was prolonged during the second and third year of switch,with 14.1%and 13.2%of VF,respectively(trend test,p<0.001);And among these patients switching to second-line regimens,a significant raise in CD4 cell count was found while on second-line therapy,from 262(IQR 139-410)cells/μL at baseline,to 343(IQR 226-503)cells/μL,394(IQR 248-555)cells/μL,and 380(IQR 230-554)cells/μL after 12,24 and 36 months of switch(p=0.01),respectively;Among these patients,individuals with drug resistance at regimen switch had a better virological responses as compared with those without DR.Among 180 patients with VL>1000 copies/ml before switching to second-line regimens,the rates of drug resistance at 12,24 and 36 months of switching to second-line regimens were 79.4%,18.8%,12.6%and 7.5%(trend test,p<0.001).Among 143 patients with VF and drug resistance before switching to second-line regimens,the rates of NNRTI-and NRTI-related drug resistance mutations were from 100%and 84.6%at baseline,to 8.3%and 6.7%at 36 months,respectively.No PI-related resistance was found.Having self-reported missing doses after switching to second-line regimens were independently associated with VF at 36 months of switching.Conclusions:1.There were no virus evolution has been detected among patients with long-term antiretroviral rherapy and suppressed viral load.2.Patients with the failure of first-line regimens had a significant decrease in VF rate throughout 36 months of second-line switch.3.Adherence is the major risk factor of treatment failure after switching to second-line regimens. |
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