102例HIV-1感染者病毒株反转录酶基因多态性及耐药性变异研究

目的:目前中国未接受或已接受反转录酶抑制剂(RTI)治疗的HIV感染者的HIV反转录酶基因类型的数据较少。本研究探讨了HIV-1反转录酶的基因多态性,及在RTI选择性压力下出现的已知和未知变异位点。方法:分析研究21例未接受治疗及81例接受RTI治疗的HIV感染者的RT基因。大部分感染者(>80%)应用司他夫定(d4T) 地达诺新(ddI) 奈韦拉平(NVP)或d4T 拉米夫定(3TC) 依菲韦仑(EFV)三联HAART治疗方案。结果:在未接受治疗的患者中,发现了4个高度多态性位点(122、200、207和211)。在接受RTI治疗的患者中,发现了2种耐药相关变异(RAMs):①接受ddI d4T NVP治疗方案的患者中发现,K65R(9.8%)、L74V(7.4%)、M184V(7.4%)、Q151M(5%)和胸腺嘧啶类似物变异(TAMs)(9.3%),包括T215Y(5.5%);②接受d4T 3TC EFV治疗方案的患者中发现,T215Y(23%)、M184V(20%)和TAMs(15.4%)。在所有病例中,非核苷反转录酶抑制剂(NNRTI)RAM的出现率很高(41.9%),而在142、221、224和228位点发现了4种可疑的新RAMs。结论:目前中国非核苷类反转录酶抑制剂(NNRTI)耐药相关变异十分普遍,本研究描述了RTI选择性变异的基因模式,提出了新的一些变异与RTI治疗的相关性。     

Dideoxynucleoside resistance emerges with prolonged zidovudine monotherapy. The RV43 Study Group.

Human immunodeficiency virus type 1 (HIV-1) isolates resistant to zidovudine (ZDV) have previously been demonstrated to exhibit in vitro cross-resistance to other similar dideoxynucleoside agents which contain a 3'-azido group. However, cross-resistance to didanosine (ddI) or dideoxycytidine (ddC) has been less well documented. ZDV, ddI, and ddC susceptibility data have been collected from clinical HIV-1 isolates obtained by five clinical centers and their respective retrovirology laboratories. All subjects were treated only with ZDV. Clinical HIV-1 isolates were isolated, amplified, and assayed for drug susceptibility in standardized cultures of phytohemagglutinin-stimulated donor peripheral blood mononuclear cells obtained from healthy seronegative donors. All five cohorts showed a correlation between decreased in vitro susceptibility to ZDV and decreased susceptibility to ddI and ddC. For each 10-fold decrease in ZDV susceptibility, an average corresponding decrease of 2.2-fold in ddI susceptibility was observed (129 isolates studied; P < 0.001, Fisher's test of combined significance). Similarly, susceptibility to ddC decreased 2.0-fold for each 10-fold decrease in ZDV susceptibility (82 isolates studied; P < 0.001, Fisher's test of combined significance). These data indicate that a correlation exists between HIV-1 susceptibilities to ZDV and ddI or ddC for clinical HIV-1 isolates.     

A pilot case-control study of zidovudine compared with zidovudine plus didanosine in patients with advanced HIV-1 disease and no previous experience with antiretrovirals

Although zidovudine (ZDV) is effective in HIV-1-infected patients, the duration of its efficacy may be short when treatment is started in advanced HIV disease. This pilot prospective case-control study was designed to evaluate the combination of ZDV plus didanosine [ddI] compared with ZDV monotherapy as an initial therapeutic strategy. 'Control' patients (ZDV monotherapy) were matched with 'case' patients (ZDV plus ddI combination therapy) according to the presence or absence of AIDS-defining criteria at entry and CD4 cell count. The case patient group consisted of 35 consecutive HIV-1-infected individuals with < or = 300 CD4 cells/mm3, no previous experience of antiretroviral therapy and who accepted treatment with a combination of ZDV plus ddI. The control patient group consisted of 35 consecutive patients with similar characteristics, but who preferred to start treatment with ZDV alone. Control patients received 250 mg ZDV bid and case patients received ZDV at the same dose plus ddI (200 mg bid). Primary study endpoints were virological (serum HIV-1 RNA) and immunological (CD4 cell count) responses. Viral phenotype (syncytium-inducing (SI) or non-syncytium-inducing (NSI)), development of mutations at codons 215, 41 and 74 and clinical progression (new AIDS-defining event or death) were also assessed. Virological and CD4 cell count responses were significantly greater and more sustained in the group treated with ZDV plus ddI than in the control group, with peak responses of -1.2 +/- 0.7 log10 versus -0.3 +/- 0.4 log10 at 1 month (P = 0.0003) and 61 +/- 52 cells/mm3 versus 19 +/- 25 cells/mm3 at 2 months (P = 0.001), respectively. In both groups the percentage of patients developing a mutation at codon 215 was around 80 per cent at 12 months. A mutation at codon 74 was detected in 30 per cent of case patients at 12 months. Five case patients (14 per cent) versus 12 control patients (34 per cent) showed signs of clinical progression (P = 0.09). In a multivariate model, clinical progression was significantly associated with a baseline