Solas Caroline, Lafeuillade Alain, Halfon Philippe, Chadapaud Stéphane, Hittinger Gilles, Lacarelle Bruno
Laboratory of Pharmacokinetics, University Hospital, Marseilles, France.
Antimicrob Agents Chemother. 2003 Jan;47(1):238-43. doi: 10.1128/AAC.47.1.238-243.2003.
The variable penetration of antiretroviral drugs into sanctuary sites may contribute to the differential evolution of human immunodeficiency virus (HIV) and the emergence of drug resistance. We evaluated the penetration of indinavir, nelfinavir, and lopinavir-ritonavir (lopinavir/r) in the central nervous system, genital tract, and lymphoid tissue and assessed the correlation with residual viral replication. Plasma, cerebrospinal fluid (CSF), semen, and lymph node biopsy samples were collected from 41 HIV-infected patients on stable highly active antiretroviral therapy regimens to determine drug concentrations and HIV RNA levels. When HIV RNA was detectable, sequencing of the reverse transcriptase and protease genes was performed. Ratios of the concentration in semen/concentration in plasma were 1.9 for indinavir, 0.08 for nelfinavir, and 0.07 for lopinavir. Only indinavir was detectable in CSF, with a concentration in CSF/concentration in plasma ratio of 0.17. Differential penetration into lymphoid tissue was observed, with concentration in lymph node tissue/concentration in plasma ratios of 2.07, 0.58, and 0.21 for indinavir, nelfinavir, and lopinavir, respectively. HIV RNA levels were <50 copies/ml in all CSF samples of patients in whom HIV RNA was not detectable in plasma. HIV RNA was detectable in the semen of three patients (two patients receiving nelfinavir and one patient receiving lopinavir/r), and its detection was associated with multiple resistance mutations, while the viral load in plasma was undetectable. HIV RNA was detectable in all lymph node tissue samples. Differential drug penetration was observed among the three protease inhibitors in the sanctuary sites, but there was no correlation between drug levels and HIV RNA levels, suggesting that multiple factors are involved in the persistence of viral reservoirs. Further studies are required to clarify the role and clinical relevance of drug penetration in sanctuaries in terms of long-term efficacy and drug resistance.
抗逆转录病毒药物进入免疫豁免部位的渗透率存在差异，这可能导致人类免疫缺陷病毒（HIV）的不同进化及耐药性的出现。我们评估了茚地那韦、奈非那韦和洛匹那韦-利托那韦（洛匹那韦/利托那韦）在中枢神经系统、生殖道和淋巴组织中的渗透率，并评估了其与残余病毒复制的相关性。从41例接受稳定高效抗逆转录病毒治疗方案的HIV感染患者中收集血浆、脑脊液（CSF）、精液和淋巴结活检样本，以测定药物浓度和HIV RNA水平。当可检测到HIV RNA时，对逆转录酶和蛋白酶基因进行测序。茚地那韦的精液浓度/血浆浓度之比为1.9，奈非那韦为0.08，洛匹那韦为0.07。仅在脑脊液中可检测到茚地那韦，脑脊液浓度/血浆浓度之比为0.17。观察到三种药物在淋巴组织中的渗透率存在差异，茚地那韦、奈非那韦和洛匹那韦的淋巴结组织浓度/血浆浓度之比分别为2.07、0.58和0.21。在血浆中未检测到HIV RNA 的患者的所有脑脊液样本中，HIV RNA水平均<50拷贝/ml。在三名患者的精液中检测到了HIV RNA（两名接受奈非那韦治疗的患者和一名接受洛匹那韦/利托那韦治疗的患者），其检测结果与多个耐药突变相关，而血浆中的病毒载量未检测到。在所有淋巴结组织样本中均检测到了HIV RNA。在免疫豁免部位观察到三种蛋白酶抑制剂的药物渗透率存在差异，但药物水平与HIV RNA水平之间无相关性，这表明病毒储存库的持续存在涉及多种因素。需要进一步研究以阐明药物渗透在免疫豁免部位对长期疗效和耐药性的作用及临床相关性。
