Salomon H, Montaner J S, Belmonte A, Wainberg M A
McGill University AIDS Centre, Jewish General Hospital, Montreal, Quebec, Canada.
Antivir Ther. 1998;3(3):177-82.
To study the extent to which phenotypic resistance to stavudine occurs under therapy, we studied 18 pairs of human immunodeficiency virus type 1 (HIV-1) isolates from patients both prior to and following 24-48 weeks of treatment with stavudine monotherapy or stavudine in combination with either didanosine or lamivudine. We also used a nested polymerase chain reaction (PCR) assay to probe for the presence of specific mutations associated in culture with stavudine resistance. The results showed that resistance to stavudine (approximately 3-10 fold) was observed in nine of ten cases of monotherapy, in three of four cases of therapy involving both stavudine and didanosine, and in two of four cases involving stavudine and lamivudine. Viruses from the four patients receiving stavudine plus didanosine became resistant to didanosine in only one instance while the use of lamivudine plus stavudine yielded resistance to lamivudine each time. Whereas changes in the reverse transcriptase (RT) genes of resistant isolates were frequently observed, two mutations, previously identified with stavudine resistance in tissue culture (i.e., V75T and I50T), could not be identified in the clinical samples by either direct sequencing of the RT gene or by PCR amplification. Thus, resistance to stavudine can occur, albeit at low levels, in the context of prolonged therapy with this drug but is not associated with specific mutations in HIV RT at either codons 75 or 50 in clinical samples.
为研究司他夫定治疗过程中表型耐药的发生程度，我们对18对人类免疫缺陷病毒1型（HIV-1）分离株进行了研究，这些分离株分别来自接受司他夫定单药治疗或司他夫定与去羟肌苷或拉米夫定联合治疗24 - 48周的患者治疗前和治疗后的样本。我们还使用巢式聚合酶链反应（PCR）检测法来探查与司他夫定耐药相关的特定突变的存在情况。结果显示，在接受单药治疗的10例患者中有9例出现了对司他夫定的耐药（约3 - 10倍），在接受司他夫定与去羟肌苷联合治疗的4例患者中有3例出现耐药，在接受司他夫定与拉米夫定联合治疗的4例患者中有2例出现耐药。接受司他夫定加去羟肌苷治疗的4例患者中，只有1例患者的病毒对去羟肌苷产生了耐药，而每次使用拉米夫定加司他夫定都会导致对拉米夫定产生耐药。虽然耐药分离株的逆转录酶（RT）基因经常出现变化，但通过对RT基因直接测序或PCR扩增，在临床样本中均未发现先前在组织培养中确定的与司他夫定耐药相关的两个突变（即V75T和I50T）。因此，在使用该药物进行长期治疗的情况下，可能会出现对司他夫定的耐药，尽管耐药水平较低，但在临床样本中，HIV RT的75或50密码子处的耐药与特定突变无关。
