Tudor-Williams G, St Clair M H, McKinney R E, Maha M, Walter E, Santacroce S, Mintz M, O'Donnell K, Rudoll T, Vavro C L
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina.
Lancet. 1992 Jan 4;339(8784):15-9. doi: 10.1016/0140-6736(92)90140-x.
In adults with the acquired immunodeficiency syndrome, long-term monotherapy with zidovudine selects for human immunodeficiency virus type 1 (HIV-1) strains with substantially reduced in-vitro susceptibility to the drug. We have assessed the relation between in-vitro resistance to zidovudine and clinical outcome in children, in whom disease progression is more rapid than in adults. We studied 23 children with symptoms of HIV-1 disease during extended monotherapy with zidovudine. An in-vitro assay was used to determine the concentration of zidovudine required to inhibit by 50% the replication of viral isolates (IC50) obtained after 9 to 39 months of treatment. Viral stocks of high enough titre to yield reproducible results were obtained from 19 of the children. During the following 6 months of therapy, 9 children were stable, 7 deteriorated, and 3 died. There was a highly significant relation between decreased zidovudine susceptibility and poor clinical outcome (p less than 0.001) but no relation between IC50 and age at start of therapy or length of time on treatment. Age-adjusted CD4 lymphocyte counts were lower at the start of treatment (p = 0.02) and at the time of sampling (p = 0.01) in children whose viral isolates had an increased zidovudine IC50. Initial serum p24 antigen levels were not predictive of subsequent emergence of resistant virus, but at the time of sampling for viral sensitivity higher p24 antigen levels were associated with raised IC50 (p = 0.004). The findings suggest that most children who become unresponsive to monotherapy with zidovudine, as judged by clinical criteria, will have changes in in-vitro sensitivity to the drug. In these children, an alternative antiretroviral therapy should be considered.
在获得性免疫缺陷综合征成人患者中，长期使用齐多夫定单一疗法会筛选出对该药物体外敏感性大幅降低的1型人类免疫缺陷病毒（HIV-1）毒株。我们评估了儿童体外对齐多夫定的耐药性与临床结局之间的关系，儿童的疾病进展比成人更快。我们研究了23名在接受齐多夫定长期单一疗法期间出现HIV-1疾病症状的儿童。采用体外试验来确定抑制治疗9至39个月后获得的病毒分离株复制50%所需的齐多夫定浓度（IC50）。从19名儿童中获得了滴度足够高以产生可重复结果的病毒储备液。在接下来的6个月治疗期间，9名儿童病情稳定，7名儿童病情恶化，3名儿童死亡。齐多夫定敏感性降低与不良临床结局之间存在高度显著的关系（p<0.001），但IC50与治疗开始时的年龄或治疗时间长短无关。病毒分离株的齐多夫定IC50升高的儿童在治疗开始时（p=0.02）和采样时（p=0.01）经年龄调整的CD4淋巴细胞计数较低。初始血清p24抗原水平不能预测耐药病毒的后续出现，但在进行病毒敏感性采样时，较高的p24抗原水平与IC50升高相关（p=0.004）。这些发现表明，根据临床标准判断，大多数对齐多夫定单一疗法无反应的儿童，其对该药物的体外敏感性会发生变化。对于这些儿童，应考虑采用替代抗逆转录病毒疗法。
