福建省HIV-毒株耐药基因变异分析

目的了解福建省I型艾滋病病毒（HIV-1）的耐药基因变异情况。方法选取2005-2012年福建省抗病毒治疗1年以上、病毒载量高于1000拷贝／mL的HIV感染者／艾滋病病人标本,进行基因型耐药性检测。同时收集前期研究中的耐药性检测数据进行对比分析。结果共检测73例病毒学治疗失败病人标本,其中60例（82.19％）成功扩增序列,结合125份未接受抗病毒治疗者的样本,共获得185份样本进行耐药分析。未治疗组和治疗组对蛋白酶抑制剂（PI）的耐药发生率均较低,分别为1.60％（2／125）和8.33％（5／60）;未治疗组对反转录酶抑制剂（RTI）的耐药发生率为4.80％（6／125）;治疗组对RTI耐药发生率较高,为61.67％（37／60）,尤其是对NVP、EFV、3TC和FTC。最常见的耐药突变有M184V、D67N、K70R、K219Q、T215F、G190A、Y181C和K103N。结论福建省HIV-1感染者的总体原发性耐药突变率较低,病毒学治疗失败病人对PI耐药发生率仍处于低水平,但对RTI耐药发生率较高。     

HIV-1的耐药基因突变

人免疫缺陷病毒(HIV)耐药,是影响艾滋病抗病毒治疗效果的主要因素。随着抗病毒治疗的发展及新型靶点抗病毒药物的临床应用,已确定了200多个各种类型HIV耐药相关的基因突变,它们对于耐药及病毒的生物学特性产生不同程度的影响。该文对HIV的耐药基因突变,及其对耐药的作用和对复制适应性的影响进行了综述,并分析了今后耐药性研究应关注的重点。     

北京地区未经抗病毒治疗的HIV感染者HIV-1毒株耐药基因变异研究北大核心

目的观察北京地区未经抗病毒治疗的艾滋病病毒（HIV）感染者HIV-1毒株耐药基因的变异情况,用于指导临床用药。方法以2014年4-7月北京地区601例未经抗反转录病毒治疗的HIV感染者/艾滋病（AIDS）病人（简称HIV/AIDS病人）为对象。采集病人的静脉血,提取血浆病毒核糖核酸（RNA）,用反转录/巢式聚合酶链式反应扩增病毒pol基因,并进行序列测定和亚型分析。在Stanford University HIV耐药数据库查询,分析是否存在基因型耐药以及耐药种类。结果 601例未经抗反转录病毒治疗的HIV/AIDS病人中,扩增成功的458例,其中男性434例（94.8%）,女性24例（5.2%）;平均年龄33岁（17~77岁）。主要感染亚型依次为CRF01_AE（211例,46.1%）、CRF07_BC（126例,27.5%）、B亚型（106例,23.1%）和C亚型（15例,3.3%）。在扩增成功的病人中,7.4%（34/458）的病人存在原发耐药基因变异,其中7例病人对核苷类反转录酶抑制剂（NRTIs）耐药,16例病人对非核苷类反转录酶抑制剂（NNRTIs）耐药,8例对蛋白酶抑制剂（PIs）耐药,3例病人同时对NRTIs和NNRTIs耐药。结论北京地区未经治疗的HIV/AIDS病人中,有部分病人存在原发耐药基因变异,极少数病人同时存在对两种主要治疗药物耐药,因此治疗前需要根据耐药检测结果制定用药方案,有助于提高治疗有效率,避免治疗失败。     

福建省MSM人群中HIV-1感染者原发性耐药基因突变研究

目的研究我省男男性行为者(MSM)中未经抗病毒治疗的人类免疫缺陷病毒(HIV)感染者的原发性基因耐药性突变发生情况,为该人群的抗病毒治疗药物选择提供依据。方法采集福建省尚未接受抗病毒治疗的MSM HIV-1感染者的外周静脉抗凝全血,分离血浆,提取血浆中HIV RNA,用RT-PCR方法扩增HIV pol区蛋白酶基因全序列与部分逆转录酶序列。所得扩增片段进行序列测定后,数据运用Contig Express拼接编辑校正后上传至斯坦福大学HIV耐药数据库进行比对,同时运用Bio-Edit和Mega等软件进行系统发生分析。结果获得50份HIV-1分离株完整的PR和RT基因序列,其中60%(30/50)为01_AE重组亚型,18%(9/50)为B亚型,20%(10/50)为07_BC重组亚型,1例08_BC重组亚型。耐药分析显示,1例发生PI(蛋白酶抑制剂)药物的主要耐药突变M46I,造成对NFV中度耐药。10例样本出现NNRTIs和NRTIS的耐药相关突变,仅1例解释为对NNRTIs的潜在低水平耐药,由V179E引起。结论福建省MSM HIV-1感染者的原发性耐药突变发生率低,有利于今后该人群抗病毒治疗工作的开展,但需加强监控该人群耐药毒株的传播。     

福建省未经抗病毒治疗的HIV-1毒株耐药基因变异研究

目的研究福建省未经抗逆转录病毒治疗的艾滋病病毒感染者伎滋病患者（HIV／AIDS患者）HIV的逆转录酶和蛋白酶耐药基因变异情况，为福建省开展HIV-1抗病毒治疗提供本底资料。方法采集福建省未经抗病毒治疗的HIV／AIDS病例的抗凝全血，分离血浆，用逆转录聚合酶链反应（RT—PCR）扩增HIV—lpol区序列并直接进行序列测定，提交Web站点http：／／hivdb．stanford．edu进行耐药突变分析。结果选取74份流行病学资料及序列资料完整的样本进入耐药基因分析，结果显示，蛋白酶基因的次要耐药突变广泛存在，以M36I、L63P、193L等多态性突变类型为主，未发现与蛋白酶抑制剂耐药相关的突变。逆转录酶区的耐药突变分布较为分散，发生率为20．27％（15．74）。依据耐药性解释，发现3例样本（4．05％）表现为对部分逆转录酶抑制剂的潜在或低度耐药。结论福建省未用药的HIV感染者中，耐药相关突变尚处于低流行状态，在开展抗病毒治疗后应当定期进行耐药性检测以期获得较好的效果。     

2019-2020年地坛医院HIV-1感染者治疗前耐药及影响因素

目的 分析北京市地坛医院HIV-1感染者治疗前耐药(PDR)流行情况及影响因素.方法 收集2019年1月至2020年12月首都医科大学附属北京地坛医院就诊的未经ART的HIV-1感染者人口学特征、实验室检查结果及血浆标本,通过巢式反转录聚合酶链反应扩增HIV-1 pol基因,将测序结果与美国斯坦福大学HIV耐药数据库比...     

HIV-1耐药突变的研究进展

至2015年止,全球约有1 700万HIV/AIDS病例得到抗逆转录病毒治疗,使HIV-1死亡率和发病率迅速下降。随着抗逆转录病毒治疗向所有感染HIV者全面推进,HIV耐药突变问题对长期治疗也构成了威胁,并对全球2030年消除艾滋病这一重要公共卫生战略产生了负面影响。本综述试图从不同的经济和地理环境出发,从个体和群体水平上阐述了常用的抗逆转录病毒药物的遗传屏障、交互耐药程度、耐药突变的流行病学和耐药管理;同时本文汇总了高、中低两类国家的可传播性耐药(TDR)和获得性耐药(ADR)的流行方式,分析了两类具有重要的公共卫生意义HIV耐药突变问题,即治疗前耐药和暴露前预防性服药的耐药。此外,鉴于有效地对不同类国家的HIV病例的治疗和管理,分别分析了基因型耐药性检测和治疗实践方面的关联,这些内容对我国的艾滋病防治也具有一定的参考作用。     

福建省HIV-1流行毒株基因分型与流行特征分析

目的了解HIV-I流行株在福建省感染人群中的基因亚型分布及流行特征。方法随机抽取福建省2003-2005年发现的70例HIV感染者血样，提取前病毒DNA进行体外扩增，获得核心蛋白（gag）、包膜蛋白（env）及pol区基因的核酸片段，并对各基因区核苷酸序列进行测定和序列分析。结果选取46份流行病学资料以及不同基因区域序列资料完整的样本进入亚型分析，结果显示目标人群中存在B、C2种亚型以及CRF07-BC、CRF08-BC、CRF01-AE3种流行重组型，以及国内未见报道的B／F重组毒株、A1／D重组毒株等，其中以CRF01-AE重组毒株为主，占69．56％。基因亚型的流行特征分析显示，本省感染的HIV患者中以CRF01-AE重组型占多数，可能的新型重组型全部分布于境外感染者中；在性接触传播的感染者（71．74％）中呈现多种亚型分布的特征；随着时间变化福建省HIV感染者的亚型分布发生变化。结论福建省HIV-I亚型分布众多，各亚型在不同感染地分布不平衡，性乱人群中的亚型分布较为复杂，从总的亚型流行特征来看，HIV-1在我省有流行加快的趋势。     

广州市外籍HIV-1抗体阳性者的基因型耐药分析

目的了解广州市外籍人类免疫缺陷病毒Ⅰ型（HIV-1）抗体阳性者中,耐药毒株的流行情况。方法应用巢式聚合酶链反应（PCR）方法,从广州市2008-2010年新确证的外籍HIV-1抗体阳性样本中,扩增蛋白酶（PR）和反转录酶（RT）基因序列,并与斯坦福耐药数据库比对,辨别耐药突变位点,分析耐药性。结果共获得90例外籍HIV-1抗体阳性者的PR和RT序列,耐药率为23.33%（21/90）,其中对蛋白酶抑制剂（PIs）耐药率为15.56%（14/90）,且集中表现为对NFV/r耐药,对核苷类反转录酶抑制剂（NRTIs）耐药率为6.67%（6/90）,对非核苷类反转录酶抑制剂（NNRTIs）耐药率为5.56%（5/90）;发现1例对除DRV/r外的所有其他PIs耐药,4例对所有NNRTIs耐药,2例对所有NRTIs耐药;发生频率较高的突变是L10I/V和K20I。结论广州市外籍HIV-1抗体阳性病例中存在耐药株的流行,尤其是耐多药毒株的存在,增加了广州市耐药毒株传播的风险。     

HIV-1针对整合酶抑制剂耐药研究进展

在HIV抗病毒治疗过程中,耐药问题仍然是影响治疗效果的重要因素。整合酶抑制剂具有较高的遗传耐药屏障、较长半衰期,更加受到人们关注。但随着整合酶抑制剂的不断推广使用,各地也相继出现耐药报道。相关研究表明不同亚型毒株的耐药突变位点存在差异,这对整合酶抑制剂的治疗效果提出了挑战。因此整合酶抑制剂的耐药研究成了抗病毒治疗的一个不能回避的问题。本文将从整合酶抑制剂的种类及应用、国内外整合酶抑制剂的耐药流行情况、不同亚型的耐药突变位点差异所导致的药物敏感性差异及目前整合酶抑制剂面临的挑战及展望进行综述。     

An algorithm-based genotypic resistance score is associated with clinical outcome in HIV-1-infected adults on antiretroviral therapy

OBJECTIVES: The aim of this study was to evaluate the association between genotypic drug resistance and the occurrence of HIV-related diseases and death in HIV-1-infected adults on antiretroviral therapy. METHODS: We performed an observational study on patients from an out-patient clinic in a university hospital. Genotypic drug resistance analysis after virological treatment failure was performed in 141 patients receiving two or more antiretroviral drugs. All patients had follow up of at least 6 months after the resistance test. An algorithm was developed to estimate the level of genotypic drug resistance and to assign an actual resistance score (ARS) for the drugs prescribed to each patient. The patient population was divided into quartiles according to patients' ARS values. Our endpoint was the risk of developing an HIV-related disease [Centers for Disease Control and Prevention (CDC) category B or C] during the period starting 6 months prior to and ending 6 months after the genotypic resistance test, or death during the 6 months following the resistance test. RESULTS: There was a significant association between the level of resistance to the drugs prescribed (ARS) and our clinical endpoint: the odds ratio for an endpoint (with 95% confidence interval) was 3.20 (1.28-7.99), adjusted for CD4 cell count and HIV RNA, in patients in the highest ARS quartile compared with patients in the other three quartiles. CONCLUSIONS: Our study indicates that patients with high-level genotypic drug resistance are at increased risk of developing an HIV-related disease. This association could not be explained by differences in CD4 cell count or HIV RNA levels.     

福建省艾滋病患者抗病毒疗效和耐药性检测分析

目的了解我省艾滋病患者的抗病毒疗效与基因耐药性突变发生情况,为抗病毒治疗提供依据。方法采集我省25例接受抗病毒治疗的艾滋病患者外周静脉抗凝全血进行CD4+T淋巴细胞计数,分离血浆进行HIV病毒载量检测,并提取血浆标本中HIVRNA,用RT-PCR方法扩增HIVpol区蛋白酶基因全序列与部分逆转录酶序列。所得扩增片段进行序列测定后,数据运用ContigExpress编辑校正后上传至斯坦福大学HIV耐药数据库进行比对,同时运用Bio-Edit、Clustal和Mega等软件进行系统发生分析。结果本研究中的17例(68%)患者的病毒载量在1000cp/ml以下,其中40%(10例)降至检测限之下。RT-PCR获得10例患者的扩增片段。对其序列亚型测试结果表明:7例属于HIV-1AE亚型,2例HIV-1B亚型,1例为HIV-1D亚型;耐药性分析表明:10份序列对PI(蛋白酶抑制剂)药物均表现为敏感,8份序列对NRTI(核苷类逆转录酶抑制剂)及NNRTI(非核苷类逆转录酶抑制剂)表现出至少对3种药物高度耐药,最常见的突变位点为G190A、K103N和M184V,造成对NVP、3TC的高度耐药。结论目前我省艾滋病患者的抗病毒治疗取得预期效果。随着治疗时间延长,患者免疫功能也逐渐恢复,但耐药性突变发生种类和数量有所增加,出现对现有各类一线药物不同程度的耐药。为保证可持续性治疗策略的施行,需加强对抗病毒治疗患者的依从性教育,同时加强耐药性监测,及时评估治疗失败者耐药性情况,必要时提供二线药品,减少我省HIV病毒耐药株的产生与传播,保障抗病毒治疗的有效进行。     

河北省治疗前人群HIV-1耐药毒株分子传播网络研究

目的 了解河北省抗病毒治疗前人群HIV-1耐药毒株流行与分子传播网络情况。方法 用in-house的方法扩增HIV-1 pol区基因序列,并利用TN93模型计算pol序列基因距离,构建HIV-1分子网络图。结果 研究发现17名HIV-1感染者出现耐药突变,耐药突变率为6.16%(17/276),其中,NNRTI类耐药率为4.35%(12/276),PI类耐药率为1.09%(3/276), NRTI类耐药率为0.36%(1/276),NNRTI类和PI类双重耐药率为0.36%(1/276);多因素Logistic回归分析显示年龄和亚型是HIV-1产生耐药的影响因素,虽然HIV-1耐药突变在CRF07_BC(2.44%)亚型中的分布明显低于CRF01_AE(8.03%)和B(3.70%)亚型,然而CRF07_BC序列构建的分子传播网络最多,传播速度最快。结论 河北省治疗前HIV-1耐药突变处于较高水平, 应制定措施实时监测未治疗人群中HIV-1耐药毒株流行情况。     

Prevalence and Spectrum of HIV-1 Resistance Mutations in the Siberian Federal District

The Siberian Federal District is among the most affected regions with a high prevalence of HIV-infection and is characterized by high HIV-infection incidence rate and high mortality among the HIV-infected population. HIV drug resistance poses a major threat to public health and is associated with increased mortality, HIV incidence, and cost of epidemic control programs. A total of 1281 samples from HIV-infected patients were sequenced and analyzed with the DEONA and HIVdb Program to assess the prevalence of drug resistance mutations in patients in the Siberian Federal District in 2016–2018. The federal surveillance data obtained from 0.5% of HIV-infected patients during the long-term follow-up care in 2021 were also used. The incidence rate of HIV infection in the Siberian Federal District has declined since 2016: from 135.8 per 100 thousand population to 81.1 per 100 thousand population in 2021. Mutations associated with resistance to NRTI and NNRTI were found in 10.3% of the samples in 2016–2018 and in 28.4% of the samples in 2020. The rising prevalence of drug resistance in HIV-infected patients indicates that it is increasingly important to continuously monitor and improve the approaches to the use of effective treatment regimens.     

深圳地区男男同性恋人群中HIV-1感染者耐药基因变异研究

目的调查分析深圳地区未接受抗病毒治疗的男男同性恋人群中,人免疫缺陷病毒（HIV）感染者的耐药突变流行情况,以进一步指导抗病毒药物的选择。方法收集2007—2008年,从未接受抗病毒治疗的男男同性恋人群中HIV—1感染者的血浆,采用逆转录聚合酶链反应（RT—PCR）和套式聚合酶链反应（Nested—PCR）方法,扩增蛋白酶（PR）1基因区和反转录酶（RT）基因区,并对扩增片断进行序列测定和分析,并用Mega等软件构建进化树及亚型分析。结果共获得94份HIV-1分离株的完整的PR和RT基因序列,发生耐药突变位点的35份（37．2％）样本序列检出42个耐药性突变位点,其中1份样本产生了核苷类抑制剂（NRTI）、非核苷类抑制剂（NNRTI）耐药性突变,以及蛋白酶抑制剂（PI）主要耐药突变和P1次要耐药突变;5份样本产生了NRTI耐药性突变,20份样本产生了NNRTI耐药性突变,9份样本产生了P1次要耐药突变。非核苷类耐药性突变、核苷类耐药性突变和P1次要耐药突变位点分别以V179E、V118I和A71V为主,分别占65．0％（13／20）、66．7％（4／6）和55．6％（5／9）。结论深圳地区男男同性恋人群中的、未经抗病毒治疗的HIV1感染者中,存在原发性耐药相关基因突变位点变异,耐药基因变异处于较低水平的流行状态。     

Large age shifts in HIV-1 incidence patterns in KwaZulu-Natal,South Africa

Recent declines in adult HIV-1 incidence have followed the large-scale expansion of antiretroviral therapy and primary HIV prevention across high-burden communities of sub-Saharan Africa. Mathematical modeling suggests that HIV risk will decline disproportionately in younger adult age-groups as interventions scale, concentrating new HIV infections in those >age 25 over time. Yet, no empirical data exist to support these projections. We conducted a population-based cohort study over a 16-y period (2004 to 2019), spanning the early scale-up of antiretroviral therapy and voluntary medical male circumcision, to estimate changes in the age distribution of HIV incidence in a hyperepidemic region of KwaZulu-Natal, South Africa, where adult HIV incidence has recently declined. Median age of HIV seroconversion increased by 5.5 y in men and 3.0 y in women, and the age of peak HIV incidence increased by 5.0 y in men and 2.0 y in women. Incidence declined disproportionately among young men (64% in men 15 to 19, 68% in men 20 to 24, and 46% in men 25 to 29) and young women (44% in women 15 to 19, 24% in women 20 to 24) comparing periods pre- versus post-universal test and treat. Incidence was stable (<20% change) in women aged 30 to 39 and men aged 30 to 34. Age shifts in incidence occurred after 2012 and were observed earlier in men than in women. These results provide direct epidemiological evidence of the changing demographics of HIV risk in sub-Saharan Africa in the era of large-scale treatment and prevention. More attention is needed to address lagging incidence decline among older individuals.

Despite remarkable progress in the expansion and scale-up of HIV treatment and prevention, 1.7 million new HIV infections and 770,000 deaths from AIDS-related illnesses occur every year globally (1). Almost half of new HIV infections and 40% of AIDS-related deaths are in East and southern Africa. South Africa, with an adult HIV prevalence of 20%, has the largest HIV epidemic in the world, with 7.7 million people currently living with HIV (1).Recent declines in adult HIV-1 incidence across high-burden communities of sub-Saharan Africa (SSA) are testament to the success of large-scale combination HIV prevention, including the expansion of antiretroviral therapy (ART) under universal test and treat (UTT) and the scale-up of voluntary medical male circumcision (VMMC) (2–5). When implemented at scale, large increases in viral load suppression from ART expansion are associated with substantial declines in population-level HIV incidence (2, 3, 5). The results from four large cluster randomized trials of UTT effectiveness demonstrated the feasibility of achieving high population ART coverage and viral load suppression through community mobilization (6–9). Yet, the results also showed the challenge of reducing population-level incidence with treatment alone (10–12).At the same time that HIV incidence has fallen, the burden of HIV infection (HIV prevalence) has more than doubled in those >age 25 (13–17), a result of extended life expectancy among people living with HIV (PLHIV) on suppressive ART (18, 19). Mathematical models suggest that new HIV infections will become increasingly concentrated in older adults over time, a result of prioritized HIV prevention in youth (20), increasing HIV prevalence in older adults, and delayed age at infection with declining risk (12), yet no empirical evidence exists to support these projections.Young age is one of the strongest predictors of HIV risk in SSA, a result of a sexual network structure that places younger individuals at greater risk of infection from older individuals (21–23), heterogeneous behavior and biology that increases exposure to and acquisition of HIV in younger women (24–28), and lower treatment coverage in younger PLHIV (29, 30). Disparities in HIV risk have supported efforts to target HIV prevention to younger individuals, especially to women <age 25 (23). As the epidemic ages, however, older cohorts of HIV-negative individuals now face a greater probability of exposure to sexual partners living with HIV than they did a decade ago (31), albeit with a reduced viral load because of ART scale-up (13–17, 32, 33). The expansion of treatment and primary prevention, by lowering the overall force of infection (transmission rate), may also increase the average time to infection, a dynamic observed in other infectious diseases (34–37). The fewer individuals who become infected earlier in life means those individuals stay in the population at risk for longer, thereby shifting the relative share of infections to older individuals. Age-structured sexual contact patterns specific to sexually transmitted infections can further magnify age shifts in risk, as individuals tend to mix preferentially with partners of a similar age-group (21). Older cohorts may thus account for a growing proportion of HIV incidence as the overall transmission rate declines in the era of large-scale treatment and prevention.Despite enormous progress in efforts to scale-up treatment and prevention, HIV incidence remains well above epidemic control thresholds in high-burden communities (2–5, 38). More will be needed to identify subgroups with elevated risk to guide regional targets for HIV prevention over the next decade. The remarkable demographic and geographic heterogeneity characteristic of HIV epidemics across high-burden regions (39, 40) has ushered in an era of prioritizing the highest risk groups and geographies to achieve maximum population-level effect (41, 42). Understanding how the demographic landscape of HIV risk has shifted with the scale-up of combination HIV prevention is needed to realign prevention targets with current and future distributions of risk.Here, we measure nonlinear age- and sex-specific trends in HIV-1 incidence between 2004 and 2019 from one of the world’s largest ongoing population-based cohorts in rural KwaZulu-Natal, South Africa, a region with among the highest HIV incidence rates in the world. Following recent work showing significant declines in adult HIV incidence in the region (2), we use statistical approaches that can flexibly reveal a wide range of HIV incidence patters to test the hypothesis that incidence has declined differentially by age and gender over a period spanning the expansion and scale-up of ART and VMMC. We provide plausible epidemiological explanations for the observed changes in the age distribution of risk. Our results have major implications for expanding demographic targets for HIV prevention in the era of UTT.     

18例抗病毒治疗失败儿童艾滋病患者耐药基因突变规律研究

目的对儿童艾滋病抗病毒治疗失败病例的耐药基因突变规律及特点进行研究。方法分析18例接受过高效抗逆转录病毒治疗并已经出现病毒学及免疫学失败儿童艾滋病患者的横断面临床及实验室资料,对其耐药突变结果进行分析。结果患者年龄11.6±2.4岁,治疗的时间为36±12个月,其中15例患者曾经接受过成人抗病毒药物治疗,患者的 CD4~ T 淋巴细胞为34±30个/μl(3～96个/μl),病毒载量为5.23±0.57 log10 copies/ml(4.27～6.53 log10 copies/ml)。耐药发生率为100%。对非核苷类逆转录酶抑制剂(NNRTIs)耐药突变结果分析显示:所有患者均对奈韦拉平(NVP)产生高度耐药,对依非韦伦(EFV)高度耐药的有16例。对核苷类逆转录酶抑制剂(NRTIs)耐药突变结果分析显示:对拉米夫定(LAM)高度耐药的有14例,对去羟肌苷(ddI)高度耐药的有11例,对齐多夫定(AZT)高度耐药的有14例,对司他夫定(d4T)高度耐药的有16例。重要突变位点包括 Y181C(9例)、K103N(7例)、G190A(8例)、TAMs(17例)、M184V(10例)、K65R(5例)、Q151M(2例)。结论该组治疗失败儿童患者对正在使用的 NRTIs 及 NNRTIs 均已产生高度耐药,须考虑更换新的抗病毒治疗方案。