Comparative effectiveness of 8 versus 12 weeks of Ombitasvir/Paritaprevir/ritonavir and Dasabuvir in treatment-naïve patients infected with HCV genotype 1b with non-advanced hepatic fibrosis

PurposeSince 2017 treatment-naïve patients infected with genotype 1b of hepatitis C virus and minimal or moderate fibrosis can be treated with Ombitasvir/Paritaprevir/ritonavir + Dasabuvir (OPrD) for 8 weeks according to updated Summary of Product Characteristics. The aim of our study was to assess the comparative efficacy of 8 and 12-weeks therapy with OPrD in large cohort of patients eligible for 8 weeks regimen treated in real-world setting.Materials and methodsWe analysed data of 3067 HCV genotype 1b infected patients treated with OPrD between 2015 and 2017. Final analysis included patients with none, minimal or moderate fibrosis (F0–F2).ResultsA total of 771 patients were enrolled in the study, including 197 (26%) treated for 8-weeks and 574 patients fulfilling criteria for 8-weeks but assigned to 12-weeks regimen. Majority of patients had no or minimal fibrosis (F0–F1). Longer treatment duration was more often administered in patients with moderate fibrosis, comorbidities, concomitant medications. SVR was achieved in 186 (94%) patients treated for 8 weeks and 558 (97%) for 12 weeks (p = 0.07). After exclusion of lost to follow-up patients, sustained virological response (SVR) rate reached 95% and 99%, respectively (p = 0.01). We were not able to identify factors associated with non-response.ConclusionsThis real-word experience study confirmed similar, high effectiveness of 8 and 12-weeks regimens of OPrD in genotype 1b HCV infected patients with non-advanced fibrosis. Despite of reduced SVR rate after 8-weeks regimen, there is no need to extend therapy to 12-weeks in vast majority of such patients and no need to add ribavirin.     

Population pharmacokinetics and dosing regimen optimisation of lopinavir in Chinese adults infected with HIV

Lopinavir (LPV) is a protease inhibitor (PI) for the treatment of human immunodeficiency virus (HIV) infections. Current studies on LPV are mainly focused on Caucasians, and none have investigated the population pharmacokinetics (PPK) of LPV in Chinese population. The present study aimed to develop a PPK model for oral LPV in Chinese adults who are HIV‐infected. A total of 460 LPV concentrations from 174 Chinese patients who received LPV/ritonavir (LPV/r) 400/100 mg orally every 12 hours (q12h) were analysed using the non‐linear mixed‐effects modelling approach. Simulations of the LPV concentration profile were performed with different dosing regimens. A one‐compartment model with first‐order absorption and elimination process described the data. The estimated apparent clearance (CL/F) and volume of distribution (V/F) (% relative standard error [RSE]) for oral LPV were 5.9 L/h (3%) and 117 L (8%), respectively. Body‐weight was identified as a covariate on CL/F. In patients who weighed between 45 and 115 kg and received the standard 400/100 mg q12h regimen, the probability of achieving target trough concentration (C_trough) of 1 mg/L was >98% for PI‐naïve patients and the probability of achieving target C_trough of 4 mg/L was <80% for PI‐pretreated patients. This is the first population pharmacokinetic study to characterise the PK of LPV in Chinese patients with HIV infection. There were no obvious ethnic differences in the PK of LPV between the Chinese population and Caucasian population. The simulations demonstrated that the standard dosing regimen of 400/100 mg q12h (LPV/r tablets) appears to be sufficient for PI‐naïve patients but suboptimal for PI‐pretreated patients. Therefore, the regimen of 800/200 mg q12h was recommended for PI‐pretreated patients. Further investigation of dosage recommendation could be helpful in optimising LPV therapy for HIV infections.     

川东北地区洛匹那韦/利托那韦治疗新型冠状病毒肺炎不良反应分析

目的探讨川东北地区使用洛匹那韦/利托那韦治疗新型冠状病毒肺炎(简称新冠肺炎)所致药品不良反应(ADR)的规律及特点,为临床安全、有效用药提供参考。方法收集川东北地区确诊新冠肺炎患者的病历资料,采用回顾性分析法对洛匹那韦/利托那韦所致ADR的临床表现、处理措施及预后进行分析。结果截至2020年2月22日,南充、广安、巴中3个地区累计收治确诊患者92例,其中84例使用了洛匹那韦/利托那韦治疗,各地区患者ADR发生率分别为52.94%,58.62%,66.67%,无明显差异(P>0.05);ADR临床表现主要为腹泻、恶心、皮疹等,其中腹泻、恶心的发生率与治疗获得性免疫缺陷病毒(HIV)感染的发生率差异显著(P<0.05)。结论川东北地区应用洛匹那韦/利托那韦治疗新冠肺炎的ADR发生率均较高,其中腹泻、恶心的发生率及总ADR发生率在不同疾病间的差异显著。洛匹那韦/利托那韦用于治疗新冠肺炎的安全性和有效性有待进一步确认,临床用药需谨慎。     

Acquired macroglossia due to lopinavir/ritonavir treatment

A HIV-positive patient, 3 months after the treatment initiation with lopinavir-/ritonavir (LPV/r) acquired macroglossia. The tongue biopsy revealed mature adipose tissue accumulated into submucosa. The drug was discontinued and the patient showed a significant improvement. This case is the first case in the medical literature of acquired macroglossia because of LPV/r, a drug causing changes in body fat composition.     

Adrenal suppression and Cushing's syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature

Objective

The purpose of this article is to provide a systematic overview of the literature on adrenal suppression and Cushing's syndrome secondary to an interaction between inhaled/intranasal fluticasone and ritonavir. The clinical presentation, diagnosis and management will be discussed.

Methods

A literature search using Medline and EMBASE and a search of abstracts of the three previous years of major HIV‐related conferences were carried out.

Results

There were 25 cases (15 adult and 10 paediatric) of significant adrenal suppression secondary to an interaction between ritonavir and inhaled fluticasone, and three cases involving ritonavir and intranasal fluticasone. Cases with other steroids were not reported; however, there were cases of adrenal suppression with itraconazole [also a potent cytochrome p (CYP) 3A4 inhibitor] and inhaled budesonide. Clinicians need to differentiate between antiretroviral‐induced lipodystrophy syndrome and iatrogenic Cushing's syndrome secondary to glucocorticoid use. Long‐term fluticasone and ritonavir should be avoided. If ritonavir is required, another inhaled steroid such as low‐dose budesonide or beclomethasone can be used cautiously. Upon discontinuation of inhaled corticosteroids, close monitoring for symptoms of adrenal insufficiency is warranted. The need for steroid replacement therapy at physiological doses should be assessed.

Conclusions

The combination of ritonavir and fluticasone should be avoided. Budesonide, beclomethasone, triamcinolone and flunisolide appear to be safer options.     

儿童奈玛特韦/利托那韦片临床使用情况及药物相互作用分析

目的 分析儿童奈玛特韦/利托那韦片的使用及治疗过程中药物相互作用情况,为临床合理用药提供参考。方法 收集2022年12月23日—2023年2月8日浙江大学医学院附属儿童医院所有使用奈玛特韦/利托那韦片的住院患儿病例资料,分析该药的使用情况,并对相关的联用药物进行分类,通过micromedex药物相互作用数据库分析该药的临床潜在相互作用药物情况并进行严重性分级。结果 共收集使用奈玛特韦/利托那韦片病例48例,中位年龄6.71岁,年龄范围87 d~17.75岁。使用科室集中在血液科、ICU、感染科、综合内科,合并基础疾病主要为肿瘤,用药后中位退热时间3 d。用药期间联用药物较多,共收集奈玛特韦/利托那韦片潜在相互作用药物15种,需关注与抗真菌药的潜在药物相互作用。结论 儿童使用奈玛特韦/利托那韦片较多的科室为血液科,合并基础疾病主要为肿瘤,用药期间联用潜在相互作用的药物时应当注意监测疗效和药物不良反应。     

HIV/AIDS患者二线抗病毒治疗后发生免疫重建不良及影响因素研究

背景 以洛匹那韦/利托那韦（LPV/r）为基础的HIV/AIDS二线抗病毒治疗方案在我国已实施10余年,但有关HIV/AIDS患者接受二线抗病毒治疗后免疫重建不良（INR）的研究较少。 目的 了解HIV/AIDS患者更换二线抗病毒治疗方案进行治疗后INR的发生率,探究发生INR的影响因素。 方法 以艾滋病综合防治数据信息系统和中医药治疗艾滋病数据库为数据来源,选取2009年1月至2015年12月更换为二线抗病毒治疗方案且CD4+ T淋巴细胞计数<200个/μl的HIV/AIDS患者3 016例,收集患者的一般资料及二线抗病毒治疗后3年内的随访资料,根据随访数据计算HIV/AIDS患者INR发生率,采用多因素Logistic回归分析探究INR的影响因素。 结果 HIV/AIDS患者二线抗病毒治疗后满1、2、3年INR发生率分别为42.34%（774/1 828）、32.31%（608/1 882）和24.11%（421/1 746）。多因素Logistic回归分析结果显示,性别〔女：OR=0.60,95%CI（0.49,0.73）〕、基线CD4+ T淋巴细胞计数〔<50个/μl：OR=3.42,95%CI（2.51,4.69）;50~100个/μl：OR=3.26,95%CI（2.50,4.27）;101~150个/μl：OR=1.51,95%CI（1.19,1.92）〕是HIV/AIDS患者二线抗病毒治疗后第1年发生INR的影响因素（P<0.05）;性别〔女：OR=0.70,95%CI（0.57,0.86）〕、年龄〔40~50岁：OR=1.37,95%CI（1.05,1.80）;>50岁：OR=1.81,95%CI（1.36,2.42）〕、感染途径〔血液：OR=1.40,95%CI（1.06,1.85）〕、HIV阳性时间〔3~6年：OR=1.48,95%CI（1.02,2.13）〕、HAART治疗时间〔3~5年：OR=0.66,95%CI（0.48,0.90）;>5年：OR=0.71,95%CI（0.53,0.95）〕、基线CD4+ T淋巴细胞计数〔<50个/μl：OR=2.54,95%CI（1.84,3.49）;50~100个/μl：OR=2.49,95%CI（1.90,3.27）;101~150个/μl：OR=1.59,95%CI（1.23,2.05）〕是HIV/AIDS患者二线抗病毒治疗后第2年发生INR的影响因素（P<0.05）;年龄〔>50岁：OR=1.8,95%CI（1.31,2.49）〕、感染途径〔血液：OR=1.45,95%CI（1.07,2.00）〕、基线CD4+ T淋巴细胞计数〔<50个/μl：OR=2.07,95%CI（1.52,2.82）;50~100个/μl：OR=2.14,95%CI（1.57,2.92）;101~150个/μl：OR=1.49,95%CI（1.12,1.98）〕是HIV/AIDS患者二线抗病毒治疗后第3年发生INR的影响因素（P<0.05）。 结论 HIV/AIDS患者二线抗病毒治疗后满1、2、3年INR发生率分别为42.34%、32.31%和24.11%。性别、年龄、基线CD4+ T淋巴细胞计数、经血液传播途径感染HIV是INR发生的影响因素,实际工作中要特别关注男性、年龄>50岁及基线CD4+ T淋巴细胞计数≤150个/μl的HIV/AIDS患者的免疫力状况。     

Ritonavir-boosted protease inhibitor based therapy: a new strategy in chronic hepatitis C therapy

Chronic hepatitis C virus (HCV) infection is a worldwide health issue. All oral therapies are quickly replacing peg-interferon-based treatment regimens. Developing effective, well tolerated, treatments accessible for difficult to treat populations remains an unmet need. Ritonavir, an HIV-1 protease inhibitor, has pharmacokinetic properties that enhance the activity of concomitantly administered direct acting antivirals against HCV. Ritonavir inhibits Cytochrome P450 isozyme 3A4, diminishing first pass effect and hepatic metabolism, changing the pharmacokinetic parameters of Cytochrome P450 isozyme 3A4 substrates. When combined with the HCV protease inhibitor paritaprevir, ritonavir increases mean area under the curve, allowing once daily dosing. While Phase II and III clinical trials with ritonavir-boosted paritaprevir, ombitasvir, and dasabuvir demonstrated high efficacy in those with HCV infection, drug–drug interactions warrant cautious use of ritonavir in specific patient populations. Consideration of the patients’ full medication list is imperative due to the ubiquitous nature of the Cytochrome P450 isozyme 3A4 system.