| BackgroundSince National free antiretroviral treatmentprogram (NFATP) had been implemented in China in 2003, after ten years of efforts, the national coverage of antiretroviral therapy (ART) was over 70%,and the increase in life expectancy and the decrease in mortality were obvious. However, as the prolonging of ART, part of infected person will appear drug resistance, which may lead to virologic failure and also treatment failure. Since the increasing people who received ART, drug resistance is increasingly severe.Highly active antiretroviral therapy (HAART) can decrease the morbidity and mortality only with strict adherence. Poor adherence to antiretroviral treatment lead to unsatisfactory drug concentrations, and this will result in treatment failure. Therefore, assessing patients’adherence to drug is of great importance in predicting virologic outcomes, as well as knowing the progression of disease. Traditional assessment methods, such as questionnaires, measurement of drug levels, have different limitations including reporting bias and the small window of exposure. Comparing to these assessment methods, hair drug levels provide a longer window of exposure as well as an impersonal result, which make more sense in predicting virologic outcomes. Also, considering 3TC have been the most widely used NRTIs in China, assessing the 3TC concentrations in hair can provide medication compliance of most patients in China.Objective1、To understand the characteristic of HIV drug-resistant mutations.2、To understand the prevalence of virologic failure and drug resistance among patients in five highlighted province;and also exploring factors influenced virologic failure and drug resistant to raise feasible measurements in decreasing the rate of virologic failure and drug resistant.3、Establishing methods to evaluate medication adherence through testing 3TC concentrations in hair.; Exploring if hair 3TC concentrations can predict virologic failure and drug resistance, and also comparing the capacity of hair 3TC concentrations with self-reported adherence in predicting virologic responsesResultsThe first sectionThis virus genome has insertions and multiple drug-resistant mutations to both nucleosidereverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), as well asa complex intersubtype recombinant structure with 11 breakpoints. Phylogenetic analysis of the near full-lengthgenome (NFLG) shows that this URF is comprised of gene regions originating from three circulating viralstrains:CRF01_AE, subtype B, and subtype C. The parental CRF01_AE regions of the recombinant cluster witha previously described cluster 4 sublineage of CRF01_AE. The B regions of the recombinant cluster within theB (United States-European origin) subtype and the three subtype C regions cluster with a strain detected inChina in 1998. The second sectionAccording to the inclusion criteria,2779 patients were enrolled in our study in 2013 and in 2014 2509 patients were followed. For patients in 2013,60.3% were male, and 70.9% were Han nationality; 53.6% have a lower education than junior high school; 57.4% were farmers. "The most patients were infected by former plasma donors. The rate of virologic failure in 2013 was 14.4% in 2013. The result of multivariate logistic regression with virologic failure as dependent variable demonstrated that patients who aged≤40; patients who were junior high school or less; not farmers; self-reported missed doses in the past month; self-reported stop doses in the past month; starting treatment after 2008; CD4 counts≥200cells/mm3 before ART; CD4 counts<200cells/mm3 when surveys; using second-line treatment when surveys were associated with virologic failure. There were 2335 patients without drug resistance followed. At the last of 2014,59 patients emerged drug resistance, and the incidence of drug resistance was 2.3/100 person year. Multivariate survival analysis demonstrated that self-reported missed doses in the past month (AHR=2.6;95%CI:1.3-5.4;p<0.01); ratio of on-time drug intake in the past month<90% (AHR=2.2;95%CI:1.0-4.8;p=0.04);baseline CD4 counts in 2013 (comparing to 0-199cells/mm3,200-349cells/mm3, AHR=0.6;95%CI:0.3-1.2;p=0.17;^350cells/mm3, AHR=0.3; 95%CI:0.1-0.5;p<0.01); baseline viral load in 2013<1000copies/ml (AHR=0.4;95%CI: 0.2-0.7;p<0.01).The third sectionA total of 287 patients who received ART≥12 month were enrolled in this survey. The average age was 44.9±10.2 years,52.6% were male,76.0% were married,19.5% had a high school or higher education level, and farmers accounted for 68.3%. The two major reported transmission routes were former plasma donation and sexual intercourse, which accounted for 70.7% and 25.8%, respectively. The median duration of ART treatment was 87.4±39.2 months. Among these 287 patients,79 (27.5%) had experienced virologic failure and 40 (13.9%) had drug resistant mutations.The Wilcoxon signed rank test was used to compare the medians of hair 3TC concentrations among patients who experienced virologic suppression, virologic failure without HIVDR, and virologic failure with HIVDR, and the difference among these groups were statistically significant.The multivariate logistic regression modelwas used to examine the association of different indictors with the dichotomous outcome of virologic suppression. The adjusted odds ratio of the 3TC concentration in hair was 11.5 (comparing to 3TC concentration< 260ng/g,95% CI 5.7,23.2, p<0.001). Missing doses in the past month and the ratio of on-time drug intake in the past month were not included in the final model.Through receiver operating characteristic curve (ROC) among patients without HIVDR, the optimal cut-off was approached at 260ng/g, with 76.9% sensitivity,89.9% specificity,58.8% positive predictive value, and 95.4% negative predictive value. When using the threshold of hair 3TC concentration at 260ng/g, the hair 3TC concentration was a much stronger indicator than variables of self-reported adherence in predicting virologic failure. Using stratified subgroups we examined whether demographic and treatment factors would influence the threshold of hair 3TC in predicting virologic failure. Sensitivity, specificity, positive predictive value, and negative predictive values were not significantly affected by most stratified factors, except for CD4+ cell counts, initial ART treatment, and current ART treatment.According to the receiver operating characteristic curve (ROC) among 79 HIV patients with a viral load>1000 copies/ml, the optimal operating point on the ROC curve was 180ng/g with the area under the ROC curve of 0.72. This threshold corresponds to a sensitivity of 70.0%, a specificity of 74.4%, a positive predictive value of 73.7%, and a negative predictive value of 70.7%. Although hair 3TC concentrations had a lower sensitivity than self-reported adherence in predicting HIVDR, its specificity was an obvious advantage and the You-den Index was also higher, which means a better reliability. Through the stratified analysis to explore factors which may influence the association between hair 3TC concentrations and the emergence of drug resistance, we found that 3TC in the initial treatment regimensinfluenced the specificity in predicting HIVDR (87.5%vs.57.3%,p=0.03).ConclusionThe detection and characterization of this complex drug-resistant URF indicate an ongoinggeneration of recombinant strains among MSM, and will help to provide insight into our understanding of thedynamics and complexity of the HIV-1 epidemic in China. And through the analysis of the factors associated with virologic failure, lower education experience and treating with second-line regimens increased the risk. For people who had less cognition to HIV/AIDS, strating treatment earlier lead to higher risk to virologic failure. What’s more, the incidence of drug resistance in China was high. The viral load and CD4 counts at baseline influence the incidence of drug resistance. Less optimal medication adherence leads to unsatisfactory outcomes. According to several assessments, we conclude the hair 3TC concentration was a stronger indicator than self-reported adherence in predicting virologic failure and drug resistance in HIV patients receiving free ART.Our study provide scientific evidence to expand ART in China more efficiently and decrease HIV-1 drug resistant and also establish a new method to evaluate medication compliance. |
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