我国部分地区HIV/AIDS初治患者的原发耐药与亚型流行状况及特殊患者的疗效与耐药研究
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摘要
高效抗逆转录病毒疗法(Highly active antiretroviral therapy, HAART)被认为是现今治疗HIV/AIDS
最行之有效的方法。但HIV-1病毒的耐药突变是艾滋病抗病毒治疗的主要障碍,无论是未治疗患者体内HIV-1原发耐药突变还是已接受治疗患者体内的HIV-1继发性耐药突变,都会导致治疗失败,加重患者的病情和艾滋病传播概率；而特殊亚型的HIV-1毒株也会加快疾病的进展。因此,分析HIV-1病毒的原发耐药突变状况和亚型分布的动态变化有助于及时了解HIV病毒的流行病学特征,指导临床的针对性治疗；此外,由于国内用于艾滋病救治的药物还非常欠缺而且分布不均衡,目前国内对合并HBV等其他病毒感染以及一线治疗失败的特殊艾滋病患者群体的耐药和疗效缺乏总体分析和评价,将不利于这些患者的长期可持续性治疗。因此,本论文就上述几部分内容开展了相应的研究。
第一部分未治疗患者的HIV-1病毒原发性耐药及亚型/噬性研究
第一节：HIV-1病毒的原发性耐药与亚型分析目的：分析我国部分地区近20年来在HIV/AIDS患者中的HIV-1的原发性耐药发生情况,及在这种长时间跨度中流行病毒株亚型的变化情况。
方法：以1990-2012年间收治的全国20多个地区的914例未接受抗病毒治疗的成年艾滋病患者为研究对象,通过In-house的RT-PCR加测序的方法检测pol基因的耐药突变,并通过斯坦福大学HIV耐药数据库(http://hivdb.stanford.edu)获得耐药突变位点及耐药分析结果。采用REGA HIV BLAST确定病毒的基因亚型。利用计算生物学比较pol基因中非同义突变/同义突变基因(Ka/Ks)比例,确定不同选择压力之下pol基因耐药突变随时间的动态变化规律。
结果：(1)本研究原发耐药检测成功率为82.5%(754/914),其中70.9%的患者是经性途径传播的。20年来平均原发耐药率为4.64%(35/754)左右,其中针对一种药物原发耐药率为3.97%(30/754),针对两种药物的是0.66%(5/754)其中90年代初期最低,后缓慢增加到2004年前后快速增高,近5年则达到较高水平,原发耐药率为8.67%的,显著高于其他三个时间段：<1995年的1.61%(p=0.01),1996-1999年间的2.0%(p=0.004)和2000-2004年间的4.58%(p=0.013)。(2)针对RT基因的原发耐药比例为68.57%,针对Pro区的占42.86%。其中NRTI发生原发耐药15例次(1.99%),NNRTI有13例次(1.72%),针对PI有12例次(1.59%)。原发耐药率在三中药物间没有统计学差异(p=0.759)。NNRTIs原发耐药中有10例为高度耐药(10113,76.9%),而NRTIs耐药病例中只有1例为高度耐药(1/15,6.7%),对Pls耐药的病例中有3例为高度耐药(3/12,25.0%)。最常见的NRTI突变位点在TAMs中是K70NR(11.11%)和L210WM(8.33%),非TAMs区是V75IML (13.89%)和V118I(13.89%),多重耐药位点中T69Ins的比例也达到13.89%。针对NNRTI中最常见的突变时K103N(13.89%)%,还有VI79AE(11.11%):和Y181C(11.11%)。针对PI类药物常见的位点有M46I(11.11%), N88D (8.33%)、N83K (8.33%)和A71T(8.33%)。35例原发耐药患者中有34.1%(11/35)来自北京。(3) Ka/Ks比值显示在02-06年及07-10年间,HIV-1pol基因受到较强的正向选择压力,突变率显著上升。Ka/Ks比值较高区域主要分布在pol基因中蛋白酶基因Pro(36-99aa)、逆转录基因RT-1(162-333aa)和RT-thumb (337-406aa)区段,与国内使用的药物相符合。累计Ka/Ks比值动态反映了pol基因突变频率可能在受到国内整体治疗策略和实施方案的影响下的动态变化规律。(4)在754例患者中,主要亚型分布是AE亚型227例(30.13%)、B/B’亚型205例(27.18%)、BC亚型187例(24.82%)为主,三者占总体亚型的82.13%。在95年前感染的患者60%是B亚型,但到了2010年减低到13%左右(p<0.05)；AE亚型在90年代初期不到1%,目前已经上升到47.3%(p<0.01)。但07/08BC的总体变化稳定在20.8-25.9%之间。(5)共754例患者的亚型分布有地区性的差异,其中各地区中B亚型主要分布在河南(76.4%),还有北京(26.8%)、陕西(35.0%)、上海(21.9%)。AE亚型主要分布在北京(占32.6%)、上海(占37.0%)、广东(占42.1%)、福建(40.4%)、陕西(占40.0%)等地区。07/08_BC亚型主要分布在云南(占58.0%),还有广东(占23.8%)、北京(占24.7%)、福建(占21.7%)等地区。(6)在754例研究对象中,性途径感染520例(占69.0%),其中异性性接触感染314例(占41.7%),同性性接触感染206例(占27.3%)；血液途径传播152例(占20.2%)。CRF01_AE亚型占全部性途径感染的38.8%%,占同性性传播途径感染者的42.7%,占异性性传播途径感染者的36.3%。(7)B亚型、CRF_01AE和07BC/08BC的原发耐药率分别是8.78%(18/205)、5.29%(12/227)和1.07(2/178),三者间有显著差异(p=0.017)。
结论：本研究首次对我国部分地区近20年来的原发耐药情况进行了研究,发现平均原发耐药率为4.64%。从最早的1.61%逐步增高到现在的8.67%,20年间原发耐药率提高了近5倍,且多是针对RT区的耐药突变。计算生物学的Ka/Ks比值动态反映了pol基因突变频率随在药物种类以及国内宏观治疗策略和实施方案影响下的动态变化规律。在非静脉吸毒的初治患者人群中早年以B亚型为主,近期以AE亚型为主,相应的传播途径也由血液途径转为性途径为主。性途径传播的主要亚型是AE亚型,并且亚型分布也随着感染途径的不同呈现地区性差异。
第二节：AE亚型病毒及噬性与疾病快速进展的相关性研究
目的：研究HIV-1的亚型CRF01_AE作为一个可能的危险因素,其分子流行病学的特点与经性途径感染患者出现疾病快速进展的相关性。
方法：本研究收集了来自12个分中心的201例未治疗的患者,采集抗凝血浆进行了HIV-1病毒噬性的分析。噬性的判断是通过v3环的序列测定得到的。共有包括这201例患者在内的235例未治疗的性感染的患者参与研究,并回顾性的评估了可能血清学转阳的时间(EDS)。从EDS到进入艾滋病发病期的平均时间用Kaplan-Meier曲线进行分析。风险比值HR用Cox模型分析完成。
结果：在研究患者人群中CRF01_AE亚型占优势(46.0%),特别是在男同性恋者(MSM)组中。进一步分析显示,×4嗜性的比例在CRF01_AE亚型中的比例(45.5%)要显著高于在其他亚型中的比例(CRF07/08_BC,4.3%, B,6.1%, P<0.001)。与非AE亚型的患者相比较,感染了CRF01_AE亚型与患者从EDS快速进展到艾滋病期(4.8年Vs6.4年,P=0.018)密切相关。在多变量模型的分析中,感染CRF01_AE病毒的校正风险比值(AHR)为1.42(95%CI,0.99-2.03, P=0.057),且和病毒载量因素无关。AE亚型的存在也与快速进展到艾滋病严重免疫缺陷的晚期密切相关(AHR,1.81,95%CI为1.03-3.18,P=0.038)。
结论：CRFO1_AE亚型在我国性途径传播的HIV感染中占主要优势,感染了AE亚型的病毒与快速进展到艾滋病期以及出现严重的免疫缺陷密切相关。在CRFO1_AE亚型中出现×4噬性的病毒株比例明显高于其他亚型中×4噬性出现的比例。进一步深入研究这些危险因素对今后针对这一类患者的临床治疗方案的制定有显著的意义。
第二部分特殊艾滋病患者的疗效评价与耐药分析
第一节：HIV-HBV共感染患者的疗效评价与耐药分析目的：研究合并HBV共感染的HIV患者,使用含3TC单药HAART方案与含有3TC+TDF双药HAART方案的针对HIV和HBV病毒的抑制效果,以及共感染患者体内的HBV和HIV在治疗过程中耐药的发生情况。
方法：从913例初治的成年艾滋病患者中挑选出HBsAg阳性至少6个月时间的HIV-HBV共感染者共55例。给予3TC+TDF+EFV/NVP或3TC+AZT/d4T+EFV/NVP两种方案治疗96周,分别在基线、12周、48周和96周检测这些患者的HIV-RNA和HBV-DNA的载量。对这些点采集的血浆标本,用Luminex液相芯片技术同时检测共感染者血浆中HIV-1病毒和HBV病毒针对3TC的耐药突变情况。同时用普通sanger测序方法进行比对。用单因素方差分析的重复测量检验(Kruskal-Wallis nonparametric test)来比较CD4计数、HIV-1RNA和HBV DNA在基线和各随访点的统计学差异。
结果：接受HAART治疗96周后,共感染患者的CD4细胞的计数在治疗前的基线时为149个/uI,96周治疗后上升到281个/ul。HIV-1RNA载量和HBV-DNA载量均下降到了检测下限(<20拷贝/ML和<201U/ML)。HIV-1RNA在治疗12W时已经显著降低,进一步按照是否含有TDF的方案来分组发现,含有3TC+TDF方案的组中HIV VL下降的速度略低于3TC组。而HBV-DNA的载量在治疗过程中也呈现显著降低,但完全控制的比例较低。有趣的是HBV的载量在3TC+TDF组中被抑制的更快,到治疗48周时,几乎达到100%完全抑制。在10例患者中没有1例出现HBV-DNA反弹,而在3TC单药组有26.7%(12/45)出现了HBV-DNA反弹。HBV针对3TC的rt180和rt204的耐药突变分别为60%和80%左右。在3TC方案组中有1例患者(2.2%,1/45)发生了HIV针对M184V和K103N的耐药突变。
结论：本研究首次报道了我国HIV合并HBV感染患者抗病毒治疗2年的疗效和耐药分析。含有3TC或3TC+TDF的HAART方案均能控制HIV和HBV病毒的复制,但仅使用3TC单药治疗HBV的效果比3TC+TDF的效果差,并且长期治疗后易引起HBV针对3TC的耐药突变。
第二节二线治疗患者的疗效评价与耐药分析
目的：通过建立多中心、前瞻性的队列,开展我国一线治疗失败的耐药患者在使用TDF/3TC/LPVr的二线方案治疗两年时间的疗效和安全性研究。方法：本研究入选条件为一线方案治疗失败的成年患者,病毒载量要求>400拷贝/ml。共有符合条件的患者84人被纳入,进行国家二线方案TDF/3TC/LPVr治疗为期两年。每3个月随访一次,采集基线和每个随访点的CD4+T细胞计数和病毒载量。对每例患者在基线和病毒反弹时采用RT-PCR的方法检测基因型耐药。对病毒学无应答或病毒反弹的患者用HPLC+UV的方法检测了血浆中LPV的药物浓度。对基线和治疗2年时的患者的血肌酐、eGFR和CrCI进行了检测。
结果：在基线,84例接受二线方案治疗的患者中分别有47.6%、19.0%和17.9%的患者发生了针对3TC、TDF或者是3TC+TDF的耐药。最常见的耐药是TAMs、 M184V、K103NS以及Y181CI。治疗2年后,CD4细胞计数中位数从基线的191增加到341个/mm3(P<0.001),病毒载量从4.391g下降到低于检测下线(1.60lg)(P<0.001)。共有66.7%的患者在治疗2年后病毒载量低于40cp/ml的检测下线,但同时有11例患者发生了病毒反弹,这其中有72.7%(8/11)的患者血浆LPV的浓度远低于有效药物浓度的下线。治疗2年期间在26.6%的患者中共发生68例次的药物相关不良事件,其中胃肠功能紊乱、肝毒性以及皮疹最为常见。94.1%的不良事件为Ⅰ级或Ⅱ级。检测结果显示血肌酐、eGFR和CrCI等指标在治疗前后有显著性差异(p<0.01)。
结论：在为期2年的治疗时间里,对于一线治疗失败的耐药患者,采用二线TDF/3TC/LPVr的方案能有效控制病毒复制；对于那些原本就有针对3TC和TDF耐药的患者,在仅有LPV单药发挥作用的情况下仍能很好的抑制病毒复制。治疗失败的患者中有因为服药依从性差导致的病毒反弹,反映了血药浓度检测能有效地帮助监控患者的服药依从性,有利于合理分析和评估药物方案的临床疗效。
It is well known that highly active antiretroviral therapy (HAART) is the most effective therapeutics for HIV/AIDS patients. However, Drug resistance of HIV-1is the main obstacle for it. Of not only the primary drug resistance in treat-free patients but also the secondary drug resistance in treat-experience patients, HIV-1mutation to drugs can induce the failure of antiviral therapy and accelerate the transmission to new population finally. Moreover, special viral subtype may play an important role in improving AIDS fast progression. Hereby, it will be very helpful to understand the epidemical of HIV primary drug resistance and to conduct the adjustment of treat strategy in AIDS patients via analyzing on prevalence of HIV-1primary drug resistance and subtype and viral tropism. Besides, due to unbalance healthy resource and relative shortage of antiviral medicine along with complicated situation, most special patients such as co-infected by HBV or first-line failure patients have not received comfortable evaluation and seasonable therapy yet.
PART I. Prevalence of primary drug resistance and subtype with viral tropism of treatment-naive AIDS patients
Section I. Prevalence of genotypic primary drug resistance of HIV-1and viral subtype in China
Objective:To investigate the genotypic primary drug resistance and distribution of HIV-1subtype along with viral tropism in drug-naive AIDS patients in some parts of China.
Methods:Total914adult drug-naive AIDS patients were collected from twenty areas of China from1991to2010. The entire protease gene and255codons of the reverse transcriptase of HIV-1were amplified and sequenced. Furthermore, genotypic drug resistance and their subtype were analyzed with Stanford database and software. Based on the bio-math system model, Ka/Ks ration was calculated with different virus pol sequences and identified the pol gene mutation patterns under different selection pressures.
Results:(1) A total of82.5%(754/914) pol gene sequences were amplified successfully. In which were70.9%cases transmitted by sexual. The average prevalence of primary drug resistance was4.64%(35/754) during1990-2010including3.97%(30/35) and0.66%(5/754) mutation for one and two family, respectively. The primary resistance incidence of last five years was8.67%, significant higher than other prior time period:1.61%within<1995(p=0.01),2.0%within1996-1999(p=0.004) and4.58%within2000-2004(p=0.013).(2) The proportion of primary drug resistance genes for RT was68.57%, while42.86%for Pro gene.There were no significant difference of primary mutation among NRTI(1.99%), NNRTI(1.72%)and PI(1.59%), p=0.759. High level resistance were observed in NNRTIs (10/13,76.9%) rather than in NRTIs (1/15,6.7%) and PIs (3/12,25.0%)。The most common NRTI mutations in TAMs was K70NR (11.11%) and L210WM (8.33%). Non-TAMs area was V75IML (13.89%) and V118I (13.89%), the proportion of multi-drug resistance was T69Ins13.89%. Most common NNRTI mutation were K103N (13.89%), V179AE (11.11%) and Y181C (11.11%). M46I (11.11%) in PI was common mutation, followed by N88D (8.33%), N83K (8.33%) and A71T (8.33%). There were34.1%(11/35) cases of primary drug resistance patients from Beijing.(3) Ka/Ks ratio displayed that during2002-06years and2007-10years, HIV-1pol gene received the strong positive selection pressure with a significant increase in the mutation rate. Ka/Ks ratio higher areas were mainly distributed in the pol gene of the protease gene (36-99aa), the RT gene RT-1(162-333aa) and RT-thumb (337-406aa) matching up national therapy time-window. Cumulative Ka/Ks ratio reflects the dynamic frequency of pol gene mutation may reflect national the changing treatment strategy and implementation of the program.(4) In the754cases of patients, the main subtypes were AE subtype227cases (30.13%), B/B'subtype205cases (27.18%) and BC subtypes187cases (24.82%). Prior to1995AIDS patients were infected by subtype B about60%, but by2010was reduced to about13%(p<0.05); whereas AE subtype in the early1990s, less than1%, has now risen to47.3%(p<0.01). But the prevalence of07/08BC was stabile20.8-25.9%within two decades.(5) Of754patients with subtype distribution were regional differences, subtype B/B'mainly in Henan (76.4%), Beijing (26.8%), Shaanxi (35.0%) and Shanghai (21.9%). AE subtype mainly in Beijing (32.6%), Shanghai (37.0%), Guangdong (42.1%), Fujian (40.4%) and Shaanxi (40.0%).07/08_BC subtypes were mainly distributed in Yunnan (58.0%), and Guangdong (23.8%), Beijing (24.7%) and Fujian (21.7%).(6) In the transmitted pathway study of754cases,520cases with sexual transmission infection (69.0%), of which314cases of heterosexual contact (41.7%),206cases of homosexual sexual contact (27.3%); only152patients (20.2%) infection by blood. About38.8%percent were CRF01_AE subtype in full sexual infected patients (42.7%from homosexual and36.3%from heterosexual transmission of infected persons). The incidence of8.78%(18/205) primary mutation in B subtype was significant higher than5.29%(12/227) and1.07%(2/178) in CRF_01AE and in07BC/08BC, respectively (p=0.017).
Conclusion:It is the first report of primary drug resistance during the past20years in parts of China. We found that the average rate was4.64%of primary drug resistance. It was from the earliest1.61%gradually increased to the current8.67%, about increased five-fold within two decades mainly mutated resistance to RT area. Computational Biology Ka/Ks ratio reflects the dynamic pol gene mutation frequency in the types of medicines as well as treatment strategies and implementation impact from the programs by the government. Except IDU individuals, treated-free patients of B subtype in the early years were given main proportion to ones of AE subtype recently consisting with the change of transmission from blood to sexually route. The common subtype by sexual transmission was AE subtype with different prevalence area distributions.
Section Ⅱ. HIV-1AE subtype is associated with X4tropism and fast HIV progression in patients infected through sexual transmission
Objective:To research the relationship between molecular epidemiology of the HIV-1CRF01_AE subtype as a possible risk factor and fast HIV-1progression in drug-naive patients.
Methods:We analyzed HIV-1tropism by utilizing samples from201treatment-naive patients in our multicenter cohort (12research centers in different provinces of China). Tropism was determined by V3loop sequencing. Data from235treatment-naive patients infected sexually (including aforementioned201patients) in this cohort with the estimated date of seroconversion (EDS) were retrospectively evaluated. Median time from EDS to AIDS was analyzed by Kaplan-Meier curves. Hazard ratios were determined by Cox proportional model.
Results:CRF01_AE subtype was predominant (46.0%), especially in the men having sex with men (MSM) group. Further analysis revealed that the proportion of X4tropism was higher in the CRF01_AE subtype (45.5%) than in others (C/CRF07_BC/CRF08_BC,4.3%; B,6.1%; p<0.001). CRF01_AE subtype was associated with faster progression from EDS to AIDS (4.8vs.6.4years, p=0.018) compared with non-CRF01_AE subtypes. In a multivariate model, the adjusted hazard ratio (aHR) of CRF01_AE was1.42(95%CI,0.99-2.03, p=0.057), independent of HIV-1viral load; it was also associated with fast progression to advanced immunodeficiency (aHR,1.81,95%CI,1.03-3.18, p=0.038).
Conclusion:CRF01AE, a predominant HIV-1subtype in Chinese HIV-1sexually infected patients, tends to be associated with fast progression to AIDS and advanced immunodeficiency, which might be ascribed to high proportion of X4tropism. Further investigation of these risk factors may have significant implications to clinical practice and policy-making.
PART Ⅱ. Evaluation of Therapeutic Efficacy and Secondary Drug Resistance of Special AIDS patients in some parts of China
Section Ⅰ. Evaluation of efficacy and emergence of drug resistance in HIV-HBV co-infected patients in China:2-year multi-central pilot study
Objective:To study the efficacy of suppression of HIV and HBV viral load with HAART including3TC-or3TC+TDF regimens and the occurrence of secondary drug resistance in HIV-HBV co-infected patients during2years treatment in China.
Methods:Total55AIDS patients with HBsAg positive for at least six months were selected from913enrolled subjects.3TC+TDF+EFV/NVP or3TC+AZT/d4T+EFV/NVP were for patients within96weeks. HIV-RNA and HBV-DNA viral load were detected at baseline,12weeks,48weeks and96weeks from plasma. All samples were detected HIV and HBV drug resistance against3TC using Luminex fluorescent beads and common Sanger sequencing. Using One-way ANOVA repeated measures test (Kruskal-Wallis nonparametric test) to compare CD4cell counts, HIV RNA and HBV DNA before and during3TC treatment at baseline and at each follow-up point.
Results:After96weeks on HAART, CD4count at baseline with149/ul was up to281/ul at96weeks. Both HIV-1RNA and HBV-DNA loads were lower to the detection limit (<20copies/ml and <20IU/ml). HIV-1RNA was significantly reduced in the treatment of12W. According to different groups, the rate of HIV VL decline in3TC+TDFgroup was slightly lower than in only3TC group which can play more powerful efficacy to control HBV-DNA load almost100%suppression at48weeks. No case appeared rebound of HBV-DNA in3TC+TDF group, while in3TC group,26.7%(12/45) appeared rebound of HBV-DNA. HBV resistance mutations rt204rt180against3TC was about60%and80%, respectively. Only one patient (2.2%) in the group3TC was found resistance mutations for HIV at Ml84V and K103N.
Conclusion:This study is the first report of efficacy on HIV-HBV co-infected patients and drug resistance analysis during two years HAART.3TC or3TC+TDF-containing HAART regimen was able to control HIV and HBV viral replication. But it was a little bit weak effective anti HBV using only3TC-group. Moreover,3TC monotherapy to HBV can lead to its resistance mutations after long-term treatment.
Section Ⅱ. Efficacy and drug resistance of TDF/3TC/LPVr in treated failure of HIV-infected Chinese adults:a2-year prospective multicenter pilot cohort study
Objective:To evaluate the efficacy of the second-line highly active antiretroviral therapy regimen TDF/3TC/LPVr in AIDS patients with resistance to first-line anti-retroviral drugs in China.
Methods:84eligible AIDS patients were studied prospectively for2years. CD4count and HIV-1VL were measured at baseline and each subsequent visit. Genotype drug resistance testing was performed at baseline and on VL rebound in house. The plasma lopinavir concentration was determined by a validated HPLC coupled to UV detection. Additional, routine clinical laboratory including serum creatinine, eGFR and CRcl were detected.
Results:At baseline,47.6%,19.0%and17.9%patients had high-or middle-level resistance to3TC or TDF or dual resistance, respectively. The common resistant mutation were TAMs、M184V、K103NS and Y181CI. After2years of therapy, the median CD4count increased from191to341cells/mm3(P<0.001), and the median VL decreased from4.39to<1.60log10(cps/mL)(P<0.001) in ITT assay.66.7%patients had a VL<40cps/mL while VL failure or rebound occurred in11patients.In72.7%(8/11) patients the absence of valid drug levels indicated poor adherence.68drug-related adverse events were reported in26.6%of patients. Gastrointestinal disorders, hepatotoxicity and rash were common.94.1%adverse events (64/68) were grade Ⅰ or Ⅱ. The levels of serum creatinine, eGFR and CrCl showed significant difference (P=0.000) compared to baseline at48and96weeks.
Conclusions:This study indicates that TDF/3TC/LPVr (even LPVr monotherapy) can suppress HIV replication and improve renal function for2years in first-line drug resistance patients in China. Measuring drug plasma concentration can help to monitor adherence and to evaluate clinical efficacy.
最行之有效的方法。但HIV-1病毒的耐药突变是艾滋病抗病毒治疗的主要障碍,无论是未治疗患者体内HIV-1原发耐药突变还是已接受治疗患者体内的HIV-1继发性耐药突变,都会导致治疗失败,加重患者的病情和艾滋病传播概率；而特殊亚型的HIV-1毒株也会加快疾病的进展。因此,分析HIV-1病毒的原发耐药突变状况和亚型分布的动态变化有助于及时了解HIV病毒的流行病学特征,指导临床的针对性治疗；此外,由于国内用于艾滋病救治的药物还非常欠缺而且分布不均衡,目前国内对合并HBV等其他病毒感染以及一线治疗失败的特殊艾滋病患者群体的耐药和疗效缺乏总体分析和评价,将不利于这些患者的长期可持续性治疗。因此,本论文就上述几部分内容开展了相应的研究。
第一部分未治疗患者的HIV-1病毒原发性耐药及亚型/噬性研究
第一节：HIV-1病毒的原发性耐药与亚型分析目的：分析我国部分地区近20年来在HIV/AIDS患者中的HIV-1的原发性耐药发生情况,及在这种长时间跨度中流行病毒株亚型的变化情况。
方法：以1990-2012年间收治的全国20多个地区的914例未接受抗病毒治疗的成年艾滋病患者为研究对象,通过In-house的RT-PCR加测序的方法检测pol基因的耐药突变,并通过斯坦福大学HIV耐药数据库(http://hivdb.stanford.edu)获得耐药突变位点及耐药分析结果。采用REGA HIV BLAST确定病毒的基因亚型。利用计算生物学比较pol基因中非同义突变/同义突变基因(Ka/Ks)比例,确定不同选择压力之下pol基因耐药突变随时间的动态变化规律。
结果：(1)本研究原发耐药检测成功率为82.5%(754/914),其中70.9%的患者是经性途径传播的。20年来平均原发耐药率为4.64%(35/754)左右,其中针对一种药物原发耐药率为3.97%(30/754),针对两种药物的是0.66%(5/754)其中90年代初期最低,后缓慢增加到2004年前后快速增高,近5年则达到较高水平,原发耐药率为8.67%的,显著高于其他三个时间段：<1995年的1.61%(p=0.01),1996-1999年间的2.0%(p=0.004)和2000-2004年间的4.58%(p=0.013)。(2)针对RT基因的原发耐药比例为68.57%,针对Pro区的占42.86%。其中NRTI发生原发耐药15例次(1.99%),NNRTI有13例次(1.72%),针对PI有12例次(1.59%)。原发耐药率在三中药物间没有统计学差异(p=0.759)。NNRTIs原发耐药中有10例为高度耐药(10113,76.9%),而NRTIs耐药病例中只有1例为高度耐药(1/15,6.7%),对Pls耐药的病例中有3例为高度耐药(3/12,25.0%)。最常见的NRTI突变位点在TAMs中是K70NR(11.11%)和L210WM(8.33%),非TAMs区是V75IML (13.89%)和V118I(13.89%),多重耐药位点中T69Ins的比例也达到13.89%。针对NNRTI中最常见的突变时K103N(13.89%)%,还有VI79AE(11.11%):和Y181C(11.11%)。针对PI类药物常见的位点有M46I(11.11%), N88D (8.33%)、N83K (8.33%)和A71T(8.33%)。35例原发耐药患者中有34.1%(11/35)来自北京。(3) Ka/Ks比值显示在02-06年及07-10年间,HIV-1pol基因受到较强的正向选择压力,突变率显著上升。Ka/Ks比值较高区域主要分布在pol基因中蛋白酶基因Pro(36-99aa)、逆转录基因RT-1(162-333aa)和RT-thumb (337-406aa)区段,与国内使用的药物相符合。累计Ka/Ks比值动态反映了pol基因突变频率可能在受到国内整体治疗策略和实施方案的影响下的动态变化规律。(4)在754例患者中,主要亚型分布是AE亚型227例(30.13%)、B/B’亚型205例(27.18%)、BC亚型187例(24.82%)为主,三者占总体亚型的82.13%。在95年前感染的患者60%是B亚型,但到了2010年减低到13%左右(p<0.05)；AE亚型在90年代初期不到1%,目前已经上升到47.3%(p<0.01)。但07/08BC的总体变化稳定在20.8-25.9%之间。(5)共754例患者的亚型分布有地区性的差异,其中各地区中B亚型主要分布在河南(76.4%),还有北京(26.8%)、陕西(35.0%)、上海(21.9%)。AE亚型主要分布在北京(占32.6%)、上海(占37.0%)、广东(占42.1%)、福建(40.4%)、陕西(占40.0%)等地区。07/08_BC亚型主要分布在云南(占58.0%),还有广东(占23.8%)、北京(占24.7%)、福建(占21.7%)等地区。(6)在754例研究对象中,性途径感染520例(占69.0%),其中异性性接触感染314例(占41.7%),同性性接触感染206例(占27.3%)；血液途径传播152例(占20.2%)。CRF01_AE亚型占全部性途径感染的38.8%%,占同性性传播途径感染者的42.7%,占异性性传播途径感染者的36.3%。(7)B亚型、CRF_01AE和07BC/08BC的原发耐药率分别是8.78%(18/205)、5.29%(12/227)和1.07(2/178),三者间有显著差异(p=0.017)。
结论：本研究首次对我国部分地区近20年来的原发耐药情况进行了研究,发现平均原发耐药率为4.64%。从最早的1.61%逐步增高到现在的8.67%,20年间原发耐药率提高了近5倍,且多是针对RT区的耐药突变。计算生物学的Ka/Ks比值动态反映了pol基因突变频率随在药物种类以及国内宏观治疗策略和实施方案影响下的动态变化规律。在非静脉吸毒的初治患者人群中早年以B亚型为主,近期以AE亚型为主,相应的传播途径也由血液途径转为性途径为主。性途径传播的主要亚型是AE亚型,并且亚型分布也随着感染途径的不同呈现地区性差异。
第二节：AE亚型病毒及噬性与疾病快速进展的相关性研究
目的：研究HIV-1的亚型CRF01_AE作为一个可能的危险因素,其分子流行病学的特点与经性途径感染患者出现疾病快速进展的相关性。
方法：本研究收集了来自12个分中心的201例未治疗的患者,采集抗凝血浆进行了HIV-1病毒噬性的分析。噬性的判断是通过v3环的序列测定得到的。共有包括这201例患者在内的235例未治疗的性感染的患者参与研究,并回顾性的评估了可能血清学转阳的时间(EDS)。从EDS到进入艾滋病发病期的平均时间用Kaplan-Meier曲线进行分析。风险比值HR用Cox模型分析完成。
结果：在研究患者人群中CRF01_AE亚型占优势(46.0%),特别是在男同性恋者(MSM)组中。进一步分析显示,×4嗜性的比例在CRF01_AE亚型中的比例(45.5%)要显著高于在其他亚型中的比例(CRF07/08_BC,4.3%, B,6.1%, P<0.001)。与非AE亚型的患者相比较,感染了CRF01_AE亚型与患者从EDS快速进展到艾滋病期(4.8年Vs6.4年,P=0.018)密切相关。在多变量模型的分析中,感染CRF01_AE病毒的校正风险比值(AHR)为1.42(95%CI,0.99-2.03, P=0.057),且和病毒载量因素无关。AE亚型的存在也与快速进展到艾滋病严重免疫缺陷的晚期密切相关(AHR,1.81,95%CI为1.03-3.18,P=0.038)。
结论：CRFO1_AE亚型在我国性途径传播的HIV感染中占主要优势,感染了AE亚型的病毒与快速进展到艾滋病期以及出现严重的免疫缺陷密切相关。在CRFO1_AE亚型中出现×4噬性的病毒株比例明显高于其他亚型中×4噬性出现的比例。进一步深入研究这些危险因素对今后针对这一类患者的临床治疗方案的制定有显著的意义。
第二部分特殊艾滋病患者的疗效评价与耐药分析
第一节：HIV-HBV共感染患者的疗效评价与耐药分析目的：研究合并HBV共感染的HIV患者,使用含3TC单药HAART方案与含有3TC+TDF双药HAART方案的针对HIV和HBV病毒的抑制效果,以及共感染患者体内的HBV和HIV在治疗过程中耐药的发生情况。
方法：从913例初治的成年艾滋病患者中挑选出HBsAg阳性至少6个月时间的HIV-HBV共感染者共55例。给予3TC+TDF+EFV/NVP或3TC+AZT/d4T+EFV/NVP两种方案治疗96周,分别在基线、12周、48周和96周检测这些患者的HIV-RNA和HBV-DNA的载量。对这些点采集的血浆标本,用Luminex液相芯片技术同时检测共感染者血浆中HIV-1病毒和HBV病毒针对3TC的耐药突变情况。同时用普通sanger测序方法进行比对。用单因素方差分析的重复测量检验(Kruskal-Wallis nonparametric test)来比较CD4计数、HIV-1RNA和HBV DNA在基线和各随访点的统计学差异。
结果：接受HAART治疗96周后,共感染患者的CD4细胞的计数在治疗前的基线时为149个/uI,96周治疗后上升到281个/ul。HIV-1RNA载量和HBV-DNA载量均下降到了检测下限(<20拷贝/ML和<201U/ML)。HIV-1RNA在治疗12W时已经显著降低,进一步按照是否含有TDF的方案来分组发现,含有3TC+TDF方案的组中HIV VL下降的速度略低于3TC组。而HBV-DNA的载量在治疗过程中也呈现显著降低,但完全控制的比例较低。有趣的是HBV的载量在3TC+TDF组中被抑制的更快,到治疗48周时,几乎达到100%完全抑制。在10例患者中没有1例出现HBV-DNA反弹,而在3TC单药组有26.7%(12/45)出现了HBV-DNA反弹。HBV针对3TC的rt180和rt204的耐药突变分别为60%和80%左右。在3TC方案组中有1例患者(2.2%,1/45)发生了HIV针对M184V和K103N的耐药突变。
结论：本研究首次报道了我国HIV合并HBV感染患者抗病毒治疗2年的疗效和耐药分析。含有3TC或3TC+TDF的HAART方案均能控制HIV和HBV病毒的复制,但仅使用3TC单药治疗HBV的效果比3TC+TDF的效果差,并且长期治疗后易引起HBV针对3TC的耐药突变。
第二节二线治疗患者的疗效评价与耐药分析
目的：通过建立多中心、前瞻性的队列,开展我国一线治疗失败的耐药患者在使用TDF/3TC/LPVr的二线方案治疗两年时间的疗效和安全性研究。方法：本研究入选条件为一线方案治疗失败的成年患者,病毒载量要求>400拷贝/ml。共有符合条件的患者84人被纳入,进行国家二线方案TDF/3TC/LPVr治疗为期两年。每3个月随访一次,采集基线和每个随访点的CD4+T细胞计数和病毒载量。对每例患者在基线和病毒反弹时采用RT-PCR的方法检测基因型耐药。对病毒学无应答或病毒反弹的患者用HPLC+UV的方法检测了血浆中LPV的药物浓度。对基线和治疗2年时的患者的血肌酐、eGFR和CrCI进行了检测。
结果：在基线,84例接受二线方案治疗的患者中分别有47.6%、19.0%和17.9%的患者发生了针对3TC、TDF或者是3TC+TDF的耐药。最常见的耐药是TAMs、 M184V、K103NS以及Y181CI。治疗2年后,CD4细胞计数中位数从基线的191增加到341个/mm3(P<0.001),病毒载量从4.391g下降到低于检测下线(1.60lg)(P<0.001)。共有66.7%的患者在治疗2年后病毒载量低于40cp/ml的检测下线,但同时有11例患者发生了病毒反弹,这其中有72.7%(8/11)的患者血浆LPV的浓度远低于有效药物浓度的下线。治疗2年期间在26.6%的患者中共发生68例次的药物相关不良事件,其中胃肠功能紊乱、肝毒性以及皮疹最为常见。94.1%的不良事件为Ⅰ级或Ⅱ级。检测结果显示血肌酐、eGFR和CrCI等指标在治疗前后有显著性差异(p<0.01)。
结论：在为期2年的治疗时间里,对于一线治疗失败的耐药患者,采用二线TDF/3TC/LPVr的方案能有效控制病毒复制；对于那些原本就有针对3TC和TDF耐药的患者,在仅有LPV单药发挥作用的情况下仍能很好的抑制病毒复制。治疗失败的患者中有因为服药依从性差导致的病毒反弹,反映了血药浓度检测能有效地帮助监控患者的服药依从性,有利于合理分析和评估药物方案的临床疗效。
It is well known that highly active antiretroviral therapy (HAART) is the most effective therapeutics for HIV/AIDS patients. However, Drug resistance of HIV-1is the main obstacle for it. Of not only the primary drug resistance in treat-free patients but also the secondary drug resistance in treat-experience patients, HIV-1mutation to drugs can induce the failure of antiviral therapy and accelerate the transmission to new population finally. Moreover, special viral subtype may play an important role in improving AIDS fast progression. Hereby, it will be very helpful to understand the epidemical of HIV primary drug resistance and to conduct the adjustment of treat strategy in AIDS patients via analyzing on prevalence of HIV-1primary drug resistance and subtype and viral tropism. Besides, due to unbalance healthy resource and relative shortage of antiviral medicine along with complicated situation, most special patients such as co-infected by HBV or first-line failure patients have not received comfortable evaluation and seasonable therapy yet.
PART I. Prevalence of primary drug resistance and subtype with viral tropism of treatment-naive AIDS patients
Section I. Prevalence of genotypic primary drug resistance of HIV-1and viral subtype in China
Objective:To investigate the genotypic primary drug resistance and distribution of HIV-1subtype along with viral tropism in drug-naive AIDS patients in some parts of China.
Methods:Total914adult drug-naive AIDS patients were collected from twenty areas of China from1991to2010. The entire protease gene and255codons of the reverse transcriptase of HIV-1were amplified and sequenced. Furthermore, genotypic drug resistance and their subtype were analyzed with Stanford database and software. Based on the bio-math system model, Ka/Ks ration was calculated with different virus pol sequences and identified the pol gene mutation patterns under different selection pressures.
Results:(1) A total of82.5%(754/914) pol gene sequences were amplified successfully. In which were70.9%cases transmitted by sexual. The average prevalence of primary drug resistance was4.64%(35/754) during1990-2010including3.97%(30/35) and0.66%(5/754) mutation for one and two family, respectively. The primary resistance incidence of last five years was8.67%, significant higher than other prior time period:1.61%within<1995(p=0.01),2.0%within1996-1999(p=0.004) and4.58%within2000-2004(p=0.013).(2) The proportion of primary drug resistance genes for RT was68.57%, while42.86%for Pro gene.There were no significant difference of primary mutation among NRTI(1.99%), NNRTI(1.72%)and PI(1.59%), p=0.759. High level resistance were observed in NNRTIs (10/13,76.9%) rather than in NRTIs (1/15,6.7%) and PIs (3/12,25.0%)。The most common NRTI mutations in TAMs was K70NR (11.11%) and L210WM (8.33%). Non-TAMs area was V75IML (13.89%) and V118I (13.89%), the proportion of multi-drug resistance was T69Ins13.89%. Most common NNRTI mutation were K103N (13.89%), V179AE (11.11%) and Y181C (11.11%). M46I (11.11%) in PI was common mutation, followed by N88D (8.33%), N83K (8.33%) and A71T (8.33%). There were34.1%(11/35) cases of primary drug resistance patients from Beijing.(3) Ka/Ks ratio displayed that during2002-06years and2007-10years, HIV-1pol gene received the strong positive selection pressure with a significant increase in the mutation rate. Ka/Ks ratio higher areas were mainly distributed in the pol gene of the protease gene (36-99aa), the RT gene RT-1(162-333aa) and RT-thumb (337-406aa) matching up national therapy time-window. Cumulative Ka/Ks ratio reflects the dynamic frequency of pol gene mutation may reflect national the changing treatment strategy and implementation of the program.(4) In the754cases of patients, the main subtypes were AE subtype227cases (30.13%), B/B'subtype205cases (27.18%) and BC subtypes187cases (24.82%). Prior to1995AIDS patients were infected by subtype B about60%, but by2010was reduced to about13%(p<0.05); whereas AE subtype in the early1990s, less than1%, has now risen to47.3%(p<0.01). But the prevalence of07/08BC was stabile20.8-25.9%within two decades.(5) Of754patients with subtype distribution were regional differences, subtype B/B'mainly in Henan (76.4%), Beijing (26.8%), Shaanxi (35.0%) and Shanghai (21.9%). AE subtype mainly in Beijing (32.6%), Shanghai (37.0%), Guangdong (42.1%), Fujian (40.4%) and Shaanxi (40.0%).07/08_BC subtypes were mainly distributed in Yunnan (58.0%), and Guangdong (23.8%), Beijing (24.7%) and Fujian (21.7%).(6) In the transmitted pathway study of754cases,520cases with sexual transmission infection (69.0%), of which314cases of heterosexual contact (41.7%),206cases of homosexual sexual contact (27.3%); only152patients (20.2%) infection by blood. About38.8%percent were CRF01_AE subtype in full sexual infected patients (42.7%from homosexual and36.3%from heterosexual transmission of infected persons). The incidence of8.78%(18/205) primary mutation in B subtype was significant higher than5.29%(12/227) and1.07%(2/178) in CRF_01AE and in07BC/08BC, respectively (p=0.017).
Conclusion:It is the first report of primary drug resistance during the past20years in parts of China. We found that the average rate was4.64%of primary drug resistance. It was from the earliest1.61%gradually increased to the current8.67%, about increased five-fold within two decades mainly mutated resistance to RT area. Computational Biology Ka/Ks ratio reflects the dynamic pol gene mutation frequency in the types of medicines as well as treatment strategies and implementation impact from the programs by the government. Except IDU individuals, treated-free patients of B subtype in the early years were given main proportion to ones of AE subtype recently consisting with the change of transmission from blood to sexually route. The common subtype by sexual transmission was AE subtype with different prevalence area distributions.
Section Ⅱ. HIV-1AE subtype is associated with X4tropism and fast HIV progression in patients infected through sexual transmission
Objective:To research the relationship between molecular epidemiology of the HIV-1CRF01_AE subtype as a possible risk factor and fast HIV-1progression in drug-naive patients.
Methods:We analyzed HIV-1tropism by utilizing samples from201treatment-naive patients in our multicenter cohort (12research centers in different provinces of China). Tropism was determined by V3loop sequencing. Data from235treatment-naive patients infected sexually (including aforementioned201patients) in this cohort with the estimated date of seroconversion (EDS) were retrospectively evaluated. Median time from EDS to AIDS was analyzed by Kaplan-Meier curves. Hazard ratios were determined by Cox proportional model.
Results:CRF01_AE subtype was predominant (46.0%), especially in the men having sex with men (MSM) group. Further analysis revealed that the proportion of X4tropism was higher in the CRF01_AE subtype (45.5%) than in others (C/CRF07_BC/CRF08_BC,4.3%; B,6.1%; p<0.001). CRF01_AE subtype was associated with faster progression from EDS to AIDS (4.8vs.6.4years, p=0.018) compared with non-CRF01_AE subtypes. In a multivariate model, the adjusted hazard ratio (aHR) of CRF01_AE was1.42(95%CI,0.99-2.03, p=0.057), independent of HIV-1viral load; it was also associated with fast progression to advanced immunodeficiency (aHR,1.81,95%CI,1.03-3.18, p=0.038).
Conclusion:CRF01AE, a predominant HIV-1subtype in Chinese HIV-1sexually infected patients, tends to be associated with fast progression to AIDS and advanced immunodeficiency, which might be ascribed to high proportion of X4tropism. Further investigation of these risk factors may have significant implications to clinical practice and policy-making.
PART Ⅱ. Evaluation of Therapeutic Efficacy and Secondary Drug Resistance of Special AIDS patients in some parts of China
Section Ⅰ. Evaluation of efficacy and emergence of drug resistance in HIV-HBV co-infected patients in China:2-year multi-central pilot study
Objective:To study the efficacy of suppression of HIV and HBV viral load with HAART including3TC-or3TC+TDF regimens and the occurrence of secondary drug resistance in HIV-HBV co-infected patients during2years treatment in China.
Methods:Total55AIDS patients with HBsAg positive for at least six months were selected from913enrolled subjects.3TC+TDF+EFV/NVP or3TC+AZT/d4T+EFV/NVP were for patients within96weeks. HIV-RNA and HBV-DNA viral load were detected at baseline,12weeks,48weeks and96weeks from plasma. All samples were detected HIV and HBV drug resistance against3TC using Luminex fluorescent beads and common Sanger sequencing. Using One-way ANOVA repeated measures test (Kruskal-Wallis nonparametric test) to compare CD4cell counts, HIV RNA and HBV DNA before and during3TC treatment at baseline and at each follow-up point.
Results:After96weeks on HAART, CD4count at baseline with149/ul was up to281/ul at96weeks. Both HIV-1RNA and HBV-DNA loads were lower to the detection limit (<20copies/ml and <20IU/ml). HIV-1RNA was significantly reduced in the treatment of12W. According to different groups, the rate of HIV VL decline in3TC+TDFgroup was slightly lower than in only3TC group which can play more powerful efficacy to control HBV-DNA load almost100%suppression at48weeks. No case appeared rebound of HBV-DNA in3TC+TDF group, while in3TC group,26.7%(12/45) appeared rebound of HBV-DNA. HBV resistance mutations rt204rt180against3TC was about60%and80%, respectively. Only one patient (2.2%) in the group3TC was found resistance mutations for HIV at Ml84V and K103N.
Conclusion:This study is the first report of efficacy on HIV-HBV co-infected patients and drug resistance analysis during two years HAART.3TC or3TC+TDF-containing HAART regimen was able to control HIV and HBV viral replication. But it was a little bit weak effective anti HBV using only3TC-group. Moreover,3TC monotherapy to HBV can lead to its resistance mutations after long-term treatment.
Section Ⅱ. Efficacy and drug resistance of TDF/3TC/LPVr in treated failure of HIV-infected Chinese adults:a2-year prospective multicenter pilot cohort study
Objective:To evaluate the efficacy of the second-line highly active antiretroviral therapy regimen TDF/3TC/LPVr in AIDS patients with resistance to first-line anti-retroviral drugs in China.
Methods:84eligible AIDS patients were studied prospectively for2years. CD4count and HIV-1VL were measured at baseline and each subsequent visit. Genotype drug resistance testing was performed at baseline and on VL rebound in house. The plasma lopinavir concentration was determined by a validated HPLC coupled to UV detection. Additional, routine clinical laboratory including serum creatinine, eGFR and CRcl were detected.
Results:At baseline,47.6%,19.0%and17.9%patients had high-or middle-level resistance to3TC or TDF or dual resistance, respectively. The common resistant mutation were TAMs、M184V、K103NS and Y181CI. After2years of therapy, the median CD4count increased from191to341cells/mm3(P<0.001), and the median VL decreased from4.39to<1.60log10(cps/mL)(P<0.001) in ITT assay.66.7%patients had a VL<40cps/mL while VL failure or rebound occurred in11patients.In72.7%(8/11) patients the absence of valid drug levels indicated poor adherence.68drug-related adverse events were reported in26.6%of patients. Gastrointestinal disorders, hepatotoxicity and rash were common.94.1%adverse events (64/68) were grade Ⅰ or Ⅱ. The levels of serum creatinine, eGFR and CrCl showed significant difference (P=0.000) compared to baseline at48and96weeks.
Conclusions:This study indicates that TDF/3TC/LPVr (even LPVr monotherapy) can suppress HIV replication and improve renal function for2years in first-line drug resistance patients in China. Measuring drug plasma concentration can help to monitor adherence and to evaluate clinical efficacy.
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