The Use of Efavirenz As a Part of Late Rescue Antiretroviral Treatment
The Use of Efavirenz As a Part of Late Rescue Antiretroviral Treatment
复制标题
使用依非韦伦作为晚期救援抗逆转录病毒治疗的一部分
作者：
R. Manfredi;E. Rizzo;L. Calza;F. Chiodo
摘要：目的：由于越来越需要抗逆转录病毒救援策略，我们评估了患者对包括依非韦伦加一种新型蛋白酶抑制剂（PI）在内的晚期救助治疗的反应，无论是否有至少一种新型核苷类似物。方法：41例连续患者，既往治疗失败4次或以上，单独接受核苷类似物治疗≥18个月，以pi为基础的HAART治疗≥15个月，进行12至24个月的前瞻性随访。排除3-8周后因副作用中断治疗的6例患者。在其余35名可评估的参与者中，含有依非韦伦的救援方案包括23例奈非那韦，7例因地那韦，2例利托那韦，其余3例利托那韦加硬凝胶沙奎那韦。35例患者中有17例同时引入一种或多种新型核苷类似物。初始平均病毒血症为4.8±0.9 log10 HIV RNA拷贝/mL，而平均基线CD4+淋巴细胞计数约为100个细胞/μL。改良处理时进行基因分型耐药试验。结果：病毒学反应是有限的和短暂的。平均病毒血症在第3个月显著下降（-0.7 log10），但在第6个月后没有维持；只有4例患者在前6个月达到病毒抑制。在整个研究过程中，观察到CD4+细胞计数更明显和持续的益处（与基线相比，p < 007）。12个月后仍可评估的31例患者未出现相关的实验室参数修改。在接受依非韦伦辅助治疗时接受≥1种新型核苷类似物的患者亚组在随访第9个月前的病毒学结果明显更有利，包括所有达到病毒抑制的病例。抗病毒耐药模式显示蛋白酶基因频繁突变，并与非核苷类逆转录酶抑制剂（NNRTIs， 41例中有19例发现）交叉耐药，尽管我们的患者以前没有接触过这些化合物。结论：基于依非韦伦外加一种新型PI的晚期补救性治疗，对于同时使用核苷类似物和PI且同时病毒血症升高的患者，预计不会取得完整和持续的病毒学成功，这可能是由于随着时间的推移获得了广泛的耐药性。我们的病毒学失败率甚至比之前包括NNRTIs在内的抢救治疗研究中观察到的还要高。先前长期使用分离核苷类似物和HAART治疗，使用高灵敏度技术监测病毒血症，以及相当长的观察期可能起了作用。然而，CD4+反应被证明比病毒学反应更明显和持续，并且同时引入≥1核苷类似物显著增加，特别是在挽救治疗的前9个月。
Abstract Purpose: Because rescue antiretroviral strategies are increasingly needed, patients’ response to a late salvage treatment including efavirenz plus a novel protease inhibitor (PI), with or without at least one novel nucleoside analogue, was assessed. Method: 41 consecutive patients, who underwent four or more prior therapeutic failures and received nucleoside analogues alone for ≥ 18 months and a PI-based HAART for ≥ 15 months, had a 12- to 24-month prospective follow-up. 6 patients who interrupted treatment after 3-8 weeks because of side effects were excluded. In the remaining 35 evaluable participants, the efavirenz-containing rescue regimen included nelfinavir in 23 cases, indinavir in 7, ritonavir in 2, and ritonavir plus hard gel saquinavir in the remaining 3 cases. 17 of 35 patients concurrently introduced one or more novel nucleoside analogues. Initial mean viremia was 4.8 ± 0.9 log10 HIV RNA copies/mL, while mean baseline CD4+ lymphocyte count was around 100 cells/μL. Genotyping resistance testing was obtained at the time of treatment modification. Results: The virologic response was both limited and transient. A significant drop of mean viremia was reached at the third month (-0.7 log10), but it was not maintained beyond the sixth month; only 4 patients reached viral suppression during the first 6 months. A more evident and sustained benefit on CD4+ cell count was observed throughout the study (p < .007, compared with baseline). The 31 patients who remained evaluable beyond 12 months did not show relevant modifications of laboratory parameters. The patient subgroup that received ≥ 1 novel nucleoside analogue at the time of efavirenz adjunct had a significantly more favorable virologic outcome until the ninth month of follow-up and included all cases who reached viral suppression. Antiviral resistance pattern showed frequent mutations of the protease gene, and a cross-resistance with nonnucleoside reverse transcriptase inhibitors (NNRTIs; found in 19 cases of 41), although our patients were not previously exposed to these compounds. Conclusion: A late salvage therapy based on efavirenz plus a novel PI is not expected to achieve a complete and sustained virologic success in patients highly experienced with both nucleoside analogues and PIs and with a concurrent elevated viremia, probably due to extensive resistances acquired through time. Our rate of virologic failure proved even greater than that observed in previous studies of salvage therapy including NNRTIs. Prior long-term treatment with isolated nucleoside analogues and HAART, the use of highly sensitive techniques for monitoring of viremia, and a quite prolonged observation period may have played a role. However, the CD4+ response proved to be more evident and sustained than the virologic one, and the concurrent introduction of ≥ 1 nucleoside analogue added significantly, especially during the first 9 months of salvage therapy.