García F, Romeu J, Grau I, Sambeat M A, Dalmau D, Knobel H, Gomez-Sirvent J L, Arrizabalaga J, Cruceta A, Clotet B G, Podzamczer D, Pumarola T, Gallart T, O'Brien W A, Miró J M, Gatell J M
Institut d'Investigacions Biomèdiques August Pi I Sunyer, Faculty of Medicine, University of Barcelona, Spain.
AIDS. 1999 Dec 3;13(17):2377-88. doi: 10.1097/00002030-199912030-00009.
Most current guidelines state that antiretroviral therapy should be considered for HIV-infected patients with plasma HIV RNA > 5000-10000 copies/ml and CD4 cells > 500 x 10(6) cells/l. However, there is increasing concern about whether this is the optimal point to begin treatment or whether it is better to delay the initiation to more advanced stages.
To study the immunological and virological benefits of starting antiretroviral therapy at these early stages.
A total of 161 HIV-infected asymptomatic patients with CD4 cell count > 500 x 10(6) cells/l and viral load > 10000 copies/ml were randomly assigned to one of five treatment groups: no treatment, twice daily zidovudine and thrice daily zalcitabine (ZDV-ddC), twice daily zidovudine and didanosine (ZDV-ddI), twice daily stavudine and didanosine (D4T-ddI), or a twice daily three-drug regimen with stavudine and lamivudine and ritonavir. The endpoints were progression to < 350 x 10(6) cells/l CD4 cells, to < 500 x 10(6) cells/l with either two Centers for Disease Control class B symptoms or an increase of viral load > 0.5 log10 copies/ml above baseline, or to AIDS or death. In various substudies, the lymphoid tissue and cerebrospinal fluid viral load, development of genotypic resistance, proliferative responses to mitogens and cytomegalovirus, and HIV-1 specific antigens and other immunophenotypic markers were also analysed.
Progression rates to study endpoints within 1 year were greater in the control group (31%) than in all groups receiving antiretroviral therapy pooled together (5%; estimated hazard ratio 7.41; 95% confidence interval 5.72-74.55; P < 0.001). The peak mean viral load decrease was greater in the three-drug group when compared with any of the three groups with a two-drug regimen (2.32, 1.65, 1.72 and 1.84, respectively; P < or = 0.001). At 1 year, viral load remained below 20 copies/ml in 30 out of 33 patients in the three-drug group (91%) and in only eight out of 94 patients (9%) in two-drug groups (P = 0.001). The peak mean increase in CD4 cells was also greater in the three-drug group than in the double treatment arms (259 versus 85, 144 and 145 x 10(6) cells/l, respectively; P = 0.001). By comparison, 36% of patients in the three-drug group regimen had to change the therapy as a result of adverse events. Substudies were performed in 60 patients recruited at two sites. Tonsillar tissue HIV RNA was measured in seven patients (two in the two-drug groups and five in the three-drug group) in whom plasma HIV RNA was < 20 copies/ml at 1 year. It was 15151 and 133333 copies/mg tissue in the two patients from the two-drug group, < 40 copies/mg tissue in four patients in the three-drug group, and 485 copies/mg in one patient in the three-drug group. At 1 year there was a mean increase of 4.21+/-2.94% in CD8+CD38+ cells in the control group and a decrease of 9.48+/-3.36% in the two-drug groups (P = 0.01), and 19.87+/-3.64 in the three-drug group (P = 0.001 and P = 0.05, for comparisons with control group and two-drug groups, respectively). Although proliferative responses to cytomegalovirus antigens were significantly greater in those receiving antiretroviral therapy, response to HIV-1 p24 antigen was not detected in any patient in either treatment group.
This study supports the recommendation to start antiretroviral therapy with a three-drug combination during very early stages of HIV-1 disease, at least if viral load is above a cut-off point (10000 copies/ml in our study). The risk of progression was sevenfold higher in non-treated patients at 8 months of follow-up. Some immune system parameters improved toward normal values after 1 year of antiretroviral therapy, but the proliferative response of CD4 T lymphocytes against the p24 HIV-1 antigen was not recovered. Therapeutic approaches with more potent, better-tolerated and more convenient regimens will increasingly favour early intervention with antiretroviral t
目前大多数指南指出，对于血浆HIV RNA>5000 - 10000拷贝/毫升且CD4细胞>500×10⁶细胞/升的HIV感染患者，应考虑进行抗逆转录病毒治疗。然而，人们越来越关注这是否是开始治疗的最佳时机，还是延迟到更晚期阶段更好。
研究在这些早期阶段开始抗逆转录病毒治疗的免疫学和病毒学益处。
总共161例CD4细胞计数>500×10⁶细胞/升且病毒载量>10000拷贝/毫升的HIV感染无症状患者被随机分配到五个治疗组之一：不治疗、齐多夫定每日两次和扎西他滨每日三次（ZDV-ddC）、齐多夫定每日两次和去羟肌苷（ZDV-ddI）、司他夫定每日两次和去羟肌苷（D4T-ddI），或司他夫定、拉米夫定和利托那韦每日两次的三联疗法。终点指标为进展至CD4细胞<350×10⁶细胞/升、出现两种美国疾病控制中心B类症状或病毒载量比基线增加>0.5 log₁₀拷贝/毫升时进展至CD4细胞<500×10⁶细胞/升，或进展至艾滋病或死亡。在各种亚研究中，还分析了淋巴组织和脑脊液病毒载量、基因型耐药性的发展、对有丝分裂原和巨细胞病毒的增殖反应、HIV-1特异性抗原和其他免疫表型标志物。
对照组在1年内进展至研究终点的比例（31%）高于所有接受抗逆转录病毒治疗组合并后的比例（5%；估计风险比7.41；95%置信区间5.72 - 74.55；P<0.001）。与任何一种双药治疗组相比，三联疗法组的病毒载量平均下降峰值更大（分别为2.32、1.65、1.72和1.84；P≤0.001）。1年后，三联疗法组33例患者中有30例（91%）病毒载量仍低于20拷贝/毫升，而双药治疗组94例患者中只有8例（9%）（P = 0.001）。三联疗法组CD4细胞的平均增加峰值也高于双药治疗组（分别为259对85、144和145×10⁶细胞/升；P = 0.001）。相比之下，三联疗法组36%的患者因不良事件不得不更换治疗方案。在两个地点招募的60例患者中进行了亚研究。在1年时血浆HIV RNA<20拷贝/毫升的7例患者（双药治疗组2例，三联疗法组5例）中测量了扁桃体组织HIV RNA。双药治疗组的2例患者组织中为15151和133333拷贝/毫克，三联疗法组4例患者组织中<40拷贝/毫克，三联疗法组1例患者组织中为485拷贝/毫克。1年后，对照组CD8⁺CD38⁺细胞平均增加4.21±2.94%，双药治疗组减少9.48±3.36%（P = 0.01），三联疗法组减少19.87±3.64%（与对照组和双药治疗组比较，P分别为0.001和0.05）。尽管接受抗逆转录病毒治疗的患者对巨细胞病毒抗原的增殖反应明显更大，但两个治疗组的任何患者均未检测到对HIV-1 p24抗原的反应。
本研究支持在HIV-1疾病的极早期阶段开始使用三联药物组合进行抗逆转录病毒治疗的建议，至少如果病毒载量高于某个临界点（本研究中为10000拷贝/毫升）。在随访8个月时，未治疗患者进展的风险高出7倍。抗逆转录病毒治疗1年后，一些免疫系统参数朝着正常值改善，但CD4 T淋巴细胞对HIV-1 p24抗原的增殖反应未恢复。采用更有效、耐受性更好且更方便的治疗方案将越来越有利于早期进行抗逆转录病毒治疗干预。
