Mallolas J, Blanco J L, Sarasa M, Giner V, Martínez E, García-Viejo M A, Arnaiz J A, Cruceta A, Soy D, Tuset M, Soriano A, Codina C, Pumarola T, Carné X, Gatell J M
Infectious Diseases, Clinical Pharmacology, Pharmacy, and Microbiology Services, Institut D'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Fundació Clínic, Barcelona, Spain.
J Acquir Immune Defic Syndr. 2000 Nov 1;25(3):229-35. doi: 10.1097/00126334-200011010-00004.
Strategies for treatment of HIV need to be considered in terms of combining potency, safety, and convenience of dosage. However, regimens including once-daily protease inhibitors are not yet available. We have performed a pilot study to determine an indinavir/ritonavir (IND/RTV) regimen for once-daily dosing, by monitoring plasma levels.
Antiretroviral-naive HIV-infected adults were eligible. Therapy was zidovudine/lamivudine 1 pill twice daily plus IND/RIT (liquid formulation) 800/100 mg twice daily with food. At 4-week intervals, plasma levels were measured and dosage of IND/RIT switched to 1000/100 mg daily and then 800/200 mg daily. If 12-hour minimum concentrations (Cmin12h) of IND were too low (<0.1 microg/ml) with IND/RIT 1000/100 mg once daily in the first half of the patients, it was planned to switch directly to 800/200 mg once daily in the other half.
In all, 27 patients were recruited. Mean baseline CD4+ lymphocyte count was 107 x 106/L (range, 4-623 x 106/L). Eleven patients (40%) discontinued the study medication within the first 4 weeks due to clinical progression (n = 3) or grade 1-2 RTV related side effects (n = 8). Nine patients (group A) switched from 800/100 mg twice daily to 1000/100 mg once daily and then to 800/200 mg once daily. Seven patients (group B) switched directly to 800/200 mg once daily. At week 32, viral load was <5 copies/ml in 15 of 16 patients (94%). RTV levels were always <2.1 microg/ml. The mean and 95% confidence interval for IND Cmin and Cmax in microg/ml was: using IND/RTV 800/100 mg twice daily (n = 16) 1.4 (0.5-2.3) and 6.7 (4.4-9.1), respectively; using IND/RTV 1000/100 mg once daily (n = 9) 0.18 (0-0.41) and 8.6 (3.3-14), respectively; and using 800/200 mg once daily (n = 16) 0.38 (0-0.9), and 7.5 (0.8-14.8). For all 16 patients who received IND/RTV 800/100 mg twice daily, the Cmin value for IND was >/=0.1 microg/ml. Conversely, IND Cmin was <0.1 microg/ml in 4 of 9 receiving 1000/100 mg once daily but in only 1 of 16 receiving 800/200 mg once daily.
Once-daily regimen of IND/RIT is feasible and deserves further evaluation in larger randomized trials. Liquid formulation of RIT was not well tolerated by our antiretroviral-naive patients despite lower than suggested doses.
治疗HIV的策略需要从疗效、安全性和给药便利性方面进行考量。然而，每日一次给药的蛋白酶抑制剂治疗方案尚未问世。我们开展了一项初步研究，通过监测血浆水平来确定茚地那韦/利托那韦（IND/RTV）每日一次给药的方案。
未接受过抗逆转录病毒治疗的HIV感染成年患者符合条件。治疗方案为齐多夫定/拉米夫定每日2次，每次1片，加IND/RIT（液体制剂）每日2次，每次800/100mg，与食物同服。每隔4周测量血浆水平，并将IND/RIT的剂量改为每日1000/100mg，然后改为每日800/200mg。如果在前半部分患者中，每日一次服用IND/RIT 1000/100mg时茚地那韦的12小时最低浓度（Cmin12h）过低（<0.1μg/ml），则计划在后半部分患者中直接改为每日一次服用800/200mg。
共招募了27名患者。基线时CD4+淋巴细胞计数的平均值为107×10⁶/L（范围为4 - 623×10⁶/L）。11名患者（40%）在最初4周内由于临床进展（n = 3）或1 - 2级与利托那韦相关的副作用（n = 8）而停用研究药物。9名患者（A组）从每日2次800/100mg改为每日1次1000/100mg，然后改为每日1次800/200mg。7名患者（B组）直接改为每日1次800/200mg。在第32周时，16名患者中有15名（94%）的病毒载量<5拷贝/ml。利托那韦水平始终<2.1μg/ml。茚地那韦Cmin和Cmax的平均值及95%置信区间（μg/ml）为：每日2次服用IND/RTV 800/100mg（n = 16）时分别为1.4（0.5 - 2.3）和6.7（4.4 - 9.1）；每日1次服用IND/RTV 1000/100mg（n = 9）时分别为0.18（0 - 0.41）和8.6（3.3 - 14）；每日1次服用800/200mg（n = 16）时分别为0.38（0 - 0.9）和7.5（0.8 - 14.8）。对于所有每日2次服用IND/RTV 800/100mg的16名患者，茚地那韦的Cmin值≥0.1μg/ml。相反，每日1次服用1000/100mg的9名患者中有4名茚地那韦Cmin<0.1μg/ml，而每日1次服用800/200mg的16名患者中只有1名如此。
IND/RIT每日一次给药方案是可行的，值得在更大规模的随机试验中进一步评估。尽管利托那韦的剂量低于建议剂量，但我们未接受过抗逆转录病毒治疗的患者对其液体制剂的耐受性不佳。
