洛匹那韦/利托那韦联合干扰素治疗新型冠状病毒肺炎的疗效

目的　探讨洛匹那韦/利托那韦联合干扰素治疗新型冠状病毒肺炎（新冠肺炎）的有效性及安全性。方法　选取2020年1月3日—4月7日于我中心住院治疗的62例新冠肺炎确诊患者作为研究对象,并将其分为治疗组（43例）和对照组（19例）,其中对照组采用常规对症支持治疗,治疗组在对照组常规治疗基础上使用洛匹那韦/利托那韦抗病毒治疗;同时,根据患者临床分型对上述患者实施非重症组与重症组亚组分析。比较对照组和治疗组核酸转阴时间、住院时间、退热时间、症状缓解时间及药物不良反应发生情况。结果　在非重症组患者中,治疗组与对照组在退热时间、症状缓解时间、核酸转阴时间及住院时间方面的差异均无统计学意义（P均＞0.05）;而在重症组患者中,治疗组核酸转阴时间显著长于对照组[（23.62±2.12 ）d vs.（9.25±0.95）d],差异有统计学意义（P＜0.05）。在药物不良反应方面,治疗组腹泻发生率为46.5%,显著高于对照组,差异有统计学意义（P＜0.05）,但均为轻到中等程度腹泻,经对症治疗后腹泻症状消失。结论　洛匹那韦/利托那韦联合干扰素治疗新冠肺炎非重症患者效果不明显,治疗重症患者,核酸转阴时间更长,虽临床应用总体安全性较好,但存在腹泻等不良反应,不推荐使用。     

A Clinical Study of the Combination of 100 mg Ritonavir plus 800 mg Indinavir as Salvage Therapy: Influence of Increased Plasma Drug Levels in the Rate of Response

Abstract

Purpose: The purpose of our study was to evaluate the efficacy of indinavir (IDV) in a twice daily dosing regimen with coadministration of 100 mg ritonavir (RTV) and to explore the influence of plasma drug levels in the rate of virologic response. Method: We performed a prospective study of 59 patients who switched to a salvage regimen with two nucleoside analogs plus the combination of 100 mg RTV plus 800 mg IDV twice daily. Pharmacokinetics of IDV and RTV were assessed in 11 patients. Results: Previous antiretroviral exposure was 44 months, and 78% and 39% of patients had previously failed regimens with either IDV or RTV. Median CD4 count was 248 × 10⁶/L and HIV load was 3.9 log₁₀ copies/mL. The median number of mutations in the protease gene was 9 (3–14), predominantly at residues 82 (53%), 90 (42%), and 46 (32%). After 24 weeks, 61% of patients had a viral load decrease greater than 1 log₁₀, and 38% had a viral load below 50 copies/mL. Nephrolitiasis, hematuria, or flank pain was observed in 13 patients (22%), leading to withdrawal in six cases (10%). IDV trough levels were well above the IC₉₅ (median 1.75 mg/L, interquartile range 1.07-2.57), but RTV trough levels were below the IC₉₅ in 88% of patients. There was a close correlation between higher peak levels of IDV, virological response, and renal toxicity. Conclusion: RTV/IDV 100/800 mg in a twice daily dosing regimen is associated with a significant virological response in patients with antiretroviral treatment failure. The correlation between plasma drug levels, toxicity, and response suggests the usefulness of individualized drug monitoring.     

Inhaled corticosteroid use in HIV‐positive individuals taking protease inhibitors: a review of pharmacokinetics,case reports and clinical management

As a consequence of inhibition of the hepatic cytochrome P450 3A4 isozyme, treatment with HIV protease inhibitors can result in significant drug?drug interactions. One noteworthy interaction is between protease inhibitors and inhaled or intranasal corticosteroids. This interaction can result in adrenal insufficiency and iatrogenic Cushing's syndrome (with symptoms such as rapid weight gain, obesity, facial hirsutism and swelling), as well as hypertension, osteoporosis and decreased CD4 cell count. In this paper, we review and unite pharmacokinetic data, case reports and current research regarding this drug?drug interaction in order to suggest options for the clinical management of HIV‐positive patients requiring treatment with protease inhibitors and inhaled or intranasal corticosteroids.     

Does lopinavir/ritonavir alter the primary gingival epithelium?

Evaluation of: Israr M, Mitchell D, Alam S, Dinello D, Kishel JJ, Meyers C. The HIV protease inhibitor lopinavir/ritonavir (Kaletra) alters the growth, differentiation and proliferation of primary gingival epithelium. HIV Med. DOI: 10.1111/j.1468-1293.2010.00863.x (2010) (Epub ahead of print).

In clinical practice, a significant proportion of HIV-infected patients receive lopinavir/ritonavir (LPV/r) as a component of highly active antiretroviral therapy (HAART). The study by Israr et al. was designed to evaluate the effects of the HIV protease inhibitor LPV/r on gingival epithelium growth and differentiation. The authors isolated gingival keratinocytes from human gingival tissue from patients undergoing dental surgery. Raft cultures of gingival keratinocytes were established and treated with a range of LPV/r concentrations. LPV/r inhibited the growth of gingival epithelium when the drug was present throughout the growth period of the tissue. When LPV/r was added on day 8 of tissue growth, it compromised tissue integrity and altered the proliferation and differentiation of gingival keratinocytes. The expression pattern of cytokeratin-5, -14, -10 and -6, proliferating cell nuclear antigen and cyclin A were altered in treated rafts. These findings suggest that LPV/r compromised tissue integrity and deregulated the cell cycle/proliferation and differentiation pathways, resulting in abnormal epithelial repair and proliferation. However, these findings do not correlate with those observed in clinical practice. In clinical trials, the adverse effects in the oral cavity have been uncommon in patients receiving HAART containing standard doses of LPV/r. This disparity may be due to a few limitations in the study design. The investigators assumed that the blood levels of LPV/r would be the same as in the saliva, and thus chose the peak concentration of LPV/r in blood serum as the baseline concentration in the study. However, the correlation between LPV/r levels in blood serum and in oral tissues has not been widely studied. Lopinavir and ritonavir are highly (98–99%) bound to serum proteins. Thus, the concentrations of these drugs in saliva would be expected to be 50–100-times lower than total plasma concentrations, rather than equivalent, as the authors assumed. Thus, the concentrations assessed in this in vitro study are very likely to be much higher than the actual concentrations of LPV/r encountered in the saliva of patients.     

Steady-State Amprenavir,Tenofovir, and Emtricitabine Pharmacokinetics Before and After Reducing Ritonavir Boosting of a Fosamprenavir/Tenofovir/Emtricitabine Regimen from 200 mg to 100 mg Once Daily (TELEX II)

Abstract

Purpose: Evaluate how reducing ritonavir (RTV) boosting from 200 mg to 100 mg once daily (QD) affects steady-state pharmacokinetics of components of a fosamprenavir (FPV)-based regimen. Methods: Prospective, open-label, pharmacokinetic study in 12 HIV-infected patients stabilized on FPV/RTV 1400 mg/200 mg + tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) 300 mg/200 mg QD (TELEX II). Pharmacokinetics were assessed by noncompartmental analysis at baseline and 4 weeks after RTV reduction to 100 mg QD. Results: Baseline median minimum plasma concentration (C_min) and area under the plasma concentration-time curve over 24 hours post dose (AUC_24h) were as follows: APV: 1,708 ng/mL, 84,260 h ? ng/mL; tenofovir: 53 ng/mL, 2,420 h ? ng/mL; FTC: 58 ng/mL, 9,190 h ? ng/mL; RTV: 80 ng/mL, 10,230 h ? ng/mL. Four weeks after reducing RTV, changes in C_min and AUC_24h were: APV: +26%, +0.6%; tenofovir: +77%, +30%; FTC: +188%, +13%; RTV –64%, –79%. Component plasma concentration ranges were consistent with historical values. Median APV C_min was 14.7-fold above the protein-binding-adjusted 50% inhibitory concentration of wild-type HIV. Four weeks after RTV reduction, HIV-1 RNA levels remained <50 copies/mL in all patients, median CD4+ count increased from 465 to 495 cells/mm³, and favorable lipid changes and no adverse events were observed. Conclusion: Reducing RTV boosting from 200 to 100 mg QD of FPV/TDF/FTC QD conferred no detrimental effect on APV, tenofovir, FTC, or RTV pharmacokinetics and maintained virologic suppression.     

Treatment Durability,Effectiveness, and Safety with Atazanavir/Ritonavir-Based HAART Regimen in Treatment-Naïve HIV-lnfected Patients

Abstract

Purpose: To describe the durability of treatment, virological and immunologi-cal response, and safety of an atazanavir/ritonavir (ATV/RTV)-based highly active antiretroviral therapy (HAART) regimen in treatment-naïve HIV-infected patients. Methods: This was a multicentre retrospective study. Medical charts of antiret-roviral-na’i’ve HIV-infected adults who initiated ATV/RTV (300/100 mg) from January 2004 to December 2007 in 10 Canadian clinics were reviewed. Data were collected from time of ATV/RTV treatment initiation until discontinuation of ATV. Durability of treatment and time to virological response were estimated with Kaplan-Meier functions. Change in viral load, CD4 cell counts, and lipid parameters were assessed with linear regression analyses. Results: 176 patients were enrolled, 153 (86.9%) were male, and the majority (52.3%) were 40 to 54 years old. Duration of observation ranged from 1.6 to 56 months. The mean (S£) durability of treatment was 33.5 (0.7) months. There were 37 (21.0%) patients who discontinued ATV/ RTV, among whom 18 (10.2%) discontinued due to toxicity, suboptimal virological response, loss to follow-up, or death. The mean (S£) time to HIV viral load of <50 and <400 copies/mL was 6.6 (0.4) and 4.3 (0.3) months, respectively. At 96 weeks of treatment, least squares mean (LSM) estimated change in log₁₀(HIV copies/mL) was -2.94 (P < .001) and +245 cells/mL (P < .001) for CD4 cell count. A significant LSM increase in HDL-C of 0.24 mmol/L (P = .007 for trend over time) was also observed; total cholesterol, triglycerides, and LDL-C increased over time but their change did not reach statistical significance. The most frequently reported adverse event was increased bilirubin (16.5%). Conclusions: ATV/RTV-based first-line HAART regimen demonstrated durability and effectiveness and was well tolerated in treatment-naïve HIV-infected patients.     

基于FDA不良事件数据库对洛匹那韦/利托那韦安全信号的检测与分析

目的挖掘和评价新型冠状病毒肺炎(COVID-19)治疗方案中建议试用的抗病毒药"洛匹那韦/利托那韦"上市后的安全信号,为临床合理用药提供参考。方法检索美国FDA不良事件报告系统(FDA adverse event reporting system,FAERS)数据库2004年1月1日-2019年12月31日收录以"洛匹那韦/利托那韦"为首要怀疑对象的不良事件(Adverse drug events,ADEs)报告,采用报告比值比法和贝叶斯可信区间递进神经网络法检测该ADE信号,重点评估胃肠、肝肾、神经以及代谢等系统所涉及的安全信号。结果纳入分析的11170959份ADEs报告中,以洛匹那韦/利托那韦为首要怀疑药物的ADEs报告共10120份,发现该药不良反应信号累及多个系统,具有临床参考意义的高风险信号包括急性胰腺炎(ROR=4.32,IC-2SD=1.65)、细胞溶解性肝炎(ROR=20.90,IC-2SD=3.66)、高甘油三酯血症(ROR=27.80,IC-2SD=4.07)、脑室扩张(ROR=58.04,IC-2SD=4.26)、获得性脂肪营养不良(ROR=165.80,IC-2SD=6.10)等;另有高风险且说明书中未收录的安全信号包括呼吸急促(ROR=5.27,IC-2SD=1.79)、获得性范可尼综合征(ROR=122.34,IC-2SD=5.48)和线粒体毒性(ROR=225.12,IC-2SD=5.61),药物-不良事件组合的时间扫描图谱显示这3种安全信号与该药关联性较强。结论基于FAERS不良事件信号检测显示,COVID-19疫情中使用洛匹那韦/利托那韦除密切关注该药的急性胰腺炎、肝功能不全、高甘油三酯血症、脑室扩张、获得性脂肪营养不良等不良事件外,也应注意可能的呼吸急促、获得性范可尼综合征、线粒体毒性等风险。     

洛匹那韦/利托那韦在新型冠状病毒肺炎特殊人群治疗中的合理使用及药学监护

2019年底以来新型冠状病毒感染肺炎在全球的暴发,国家卫生健康委员会发布的《新型冠状病毒肺炎诊方案（试行）第七版》中推荐了一些治疗新型冠状病毒肺炎的药物。其中洛匹那韦/利托那韦在特殊人群中的使用需要引起关注。本文将该药在儿童、妊娠期、哺乳期、肝肾功能不全及老年患者使用中应该关注的合理使用内容以及药学监护点进行阐述,为进一步提高该药在临床的安全、合理使用提供依据。     

基于液相色谱法的洛匹那韦/利托那韦血药浓度分析研究进展

洛匹那韦/利托那韦是《新型冠状病毒感染的肺炎诊疗方案》的推荐药物。洛匹那韦/利托那韦作为特殊情况下治疗COVID-19的药物,其相关的有效性和安全性数据尚未确立,有必要开展治疗药物监测（TDM）,以确保在获得良好疗效的同时避免或减轻毒副反应,并为药物毒副作用的诊断和处理提供有价值的实验室依据,将临床用药从经验模式提高到比较科学的水平。本文综述了近年来洛匹那韦/利托那韦基于液相色谱法的血药浓度测定方法研究进展,包括高效液相色谱法、液相色谱-质谱联用法、超高效液相色谱法等,以及相应的样品前处理方法,为本次COVID-19治疗药物的TDM工作提供参考。