Induction of Multiple Drug Transporters by Efavirenz

Efavirenz, an important component of human immunodeficiency virus 1 (HIV-1) therapy, causes substantial drug interactions as an inducer of cytochromes and the transporter ABCB1. So far its effect on the expression of other transporters is unknown. We therefore investigated the effect of long-term exposure of cells to efavirenz on expression of a large number of important drug transporters and on cell proliferation as a surrogate of intracellular availability. LS180 cells were used as a surrogate for the major site of drug interactions and Jurkat cells were used as a surrogate for the main target cells of HIV therapy. Cells were treated with efavirenz over 4 weeks and mRNA expression of drug transporters was repeatedly quantified. After 4 weeks, efavirenz significantly up-regulated the mRNA of ABCB1, ABCG2, ABCC2, ABCC3, ABCC5, and SLCO3A1 in LS180 cells and ABCG2, ABCC1, ABCC4, ABCC5, and SLCO2B1 in Jurkat cells. However these changes in transporter expression did not influence cell proliferation indicating that intracellular efavirenz concentrations were likely not altered. Efavirenz induces mRNA expression of several drug transporters critically modulating the kinetics of other drugs. While these expressional changes will most likely not influence the efficiency of efavirenz itself, they might change the effect of other co-administered drugs.     

The pharmacokinetics,pharmacodynamics, and clinical role of fixed dose combination of tenofovir disoproxil fumarate,lamivudine and reduced dose efavirenz (TLE-400) in treating HIV-1 infection

Introduction: Co-formulated fixed dose combination (FDC) of antiretroviral drugs tenofovir disoproxil fumarate, lamivudine, and reduced dose efavirenz [TDF 300 mg/3TC 300mg/EFV400 mg (TLE-400)] is a single daily tablet recently approved for the treatment of HIV-1 infection.

Areas covered: An overview of the pharmacokinetics, pharmacodynamics and role of TLE-400 in the treatment of HIV-1 infection based on the publications from Medline and Pubmed as of February, 2018.

Expert opinion: Although TLE-400 has not been formally evaluated in a clinical trial as a new formulation, previous studies have evaluated its components individually and in different doses as other FDCs have shown favorable efficacy and safety results to support continuing its approval and indication in the management of HIV-1 infection. Due to the lower dose of EFV, TLE-400 has a lower rate of toxicity and higher tolerability compared to its predecessor, the TLE-600, which contained a higher 600 mg dose of EFV. Given its low cost and ease of administration, TLE-400 is a promising alternative first line FDC in the management of HIV-1.     

Artemether-lumefantrine co-administration with antiretrovirals: population pharmacokinetics and dosing implications

AIM

Drug–drug interactions between antimalarial and antiretroviral drugs may influence antimalarial treatment outcomes. The aim of this study was to investigate the potential drug–drug interactions between the antimalarial drugs, lumefantrine, artemether and their respective metabolites desbutyl-lumefantrine and dihydroartemisinin, and the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir.

METHOD

Data from two clinical studies, investigating the influence of the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir on the pharmacokinetics of the antimalarial drugs lumefantrine, artemether and their respective metabolites, in HIV infected patients were pooled and analyzed using a non-linear mixed effects modelling approach.

RESULTS

Efavirenz and nevirapine significantly decreased the terminal exposure to lumefantrine (decrease of 69.9% and 25.2%, respectively) while lopinavir/ritonavir substantially increased the exposure (increase of 439%). All antiretroviral drugs decreased the total exposure to dihydroartemisinin (decrease of 71.7%, 41.3% and 59.7% for efavirenz, nevirapine and ritonavir/lopinavir, respectively). Simulations suggest that a substantially increased artemether-lumefantrine dose is required to achieve equivalent exposures when co-administered with efavirenz (250% increase) and nevirapine (75% increase). When co-administered with lopinavir/ritonavir it is unclear if the increased lumefantrine exposure compensates adequately for the reduced dihydroartemisinin exposure and thus whether dose adjustment is required.

CONCLUSION

There are substantial drug interactions between artemether-lumefantrine and efavirenz, nevirapine and ritonavir/lopinavir. Given the readily saturable absorption of lumefantrine, the dose adjustments predicted to be necessary will need to be evaluated prospectively in malaria-HIV co-infected patients.     

Standard-dose efavirenz vs. standard-dose nevirapine in antiretroviral regimens among HIV-1 and tuberculosis co-infected patients who received rifampicin

Background

There is limited comparative data between efavirenz (EFV) 600 mg/day and nevirapine (NVP) 400 mg/day‐based antiretroviral therapy (ART) among HIV‐1 patients with tuberculosis (TB) and receiving rifampicin.

Methods

A retrospective cohort study was conducted in all ART‐naïve patients who were receiving rifampicin between January 2002 and December 2005.

Results

Of 188 patients, 77 and 111 patients were initiated on EFV‐based ART (EFV group) and NVP‐based ART (NVP group), respectively. Overall, median [interquartile range (IQR)] CD4 count was 36 (15–77) cells/μL and median (IQR) viral load was 5.6 (5.2–5.9) HIV‐1 RNA log copies/mL. At 48 weeks, 77.9% (60/77) in the EFV group and 67.6% (75/111) in the NVP group achieved HIV‐1 RNA <50 copies/mL (P=0.140, odds ratio =0.590, 95% confidence interval=0.302–1.153). At 24 and 48 weeks, respective median CD4 counts were 174 and 254 cells/μL in the EFV group and 156 and 218 cells/μL in the NVP group (P>0.05). By binary logistic regression, treatment group was not associated with HIV‐1 RNA <50 copies/mL (P>0.05). No patient in the EFV group and eight (7.2%) patients in the NVP group discontinued ART because of adverse reactions (P=0.084).

Conclusions

For HIV–TB co‐infected patients who receive rifampicin, efficacy of 600 mg EFV‐based and 400 mg NVP‐based ART may be similar, although adverse events tend to be higher in NVP‐based ART.     

Histomorphological changes in the pancreas and kidney and histopathological changes in the liver in male Wistar rats on antiretroviral therapy and melatonin treatment

Combination antiretroviral therapy (cART) has shown to cause inflammation, cellular injury and oxidative stress, whereas melatonin has been successful in reducing these effects. The aim of the study was to determine potential morphometric changes caused by cART in combination with melatonin supplementation in human immunodeficiency virus (HIV)-free rats.Tissue samples (N?=?40) of the pancreas, liver and kidney from a control (C/ART-/M-), cART group (C/ART?+?), melatonin (C/M?+?) and experimental group (ART+/M?+?) were collected and stained with haematoxylin and eosin (H&E) and evaluated for histopathology. The pancreata were labelled with anti-insulin and anti-glucagon to determine α- and β-cell regions. Kidneys were stained with periodic acid Schiff (PAS) to measure the area, perimeter, diameter and radius of renal corpuscles, glomeruli and proximal convoluted tubules (PCTs). Blood tests were conducted to determine hepatotoxicity.No significant changes in histopathology were seen. Melatonin stimulated pancreatic islet abundance, as the number of islets per mm² was significantly higher in the C/M+ than in the C/ART-/M- and ART+/M+. Parameters of the renal corpuscle, glomeruli, renal space and PCTs were significantly lower in the C/ART+ compared to the other groups, thus cART may have caused tubular dysfunction or cellular damage. A significant increase in serum haemoglobin was observed in the C/ART+ compared to the C/ART-, which showed cART increases serum haemoglobin in the absence of immune deficiency. Serum lipids were significantly decreased in the C/M+ compared to the C/ART-, possibly due to the effect of melatonin on the decrease of lipolysis, decreasing effect on cholesterol absorption and stimulation of lipoprotein lipase (LPL) activity.In conclusion, we have demonstrated that melatonin stimulated α-cell production, increased the number of pancreatic islets and caused a decrease in total lipids, whereas cART increased serum haemoglobin and decreased various parameters of the nephron in an HIV-free rat model, suggestive of tubular dysfunction.     

含多替拉韦与含依非韦伦方案抗逆转录治疗对人类免疫缺陷病毒感 染母婴影响的荟萃分析

目的:分析含多替拉韦方案对比含依非韦伦方案抗逆转录治疗对人类免疫缺陷病毒(HIV)感染母婴影响情况。 方法:检 索建库至 2023 年 6 月在 PubMed、EMBase、the Cochrane Library、Medline、中国知网、万方、维普、中国生物医学文献数据库公开发 表的中英文研究,采用纽卡斯尔-渥太华量表(NOS)评分方法,纳入符合条件的文献,提取相关数据资料,利用 RevMan 5. 4 软件 进行荟萃分析。 结果:最终共纳入文献 6 篇,其中多替拉韦组 2 769 例患者,依非韦伦组 6 006 例患者。 两组孕产妇抗逆转录治 疗后病毒应答率比较差异有统计学意义(RR= 1. 25,95%CI 1. 06~1. 46,Z = 2. 73,P<0. 05)。 胎儿及新生儿情况分析中,两组新 生儿出生体质量比较差异有统计学意义(MD= 0. 14,95% CI 0. 05~0. 22,Z = 3. 03,P<0. 05),而在胎儿及新生儿严重不良事件胎 儿宫内死亡(OR= 1. 08,95%CI 0. 78~1. 49,Z = 0. 47,P>0. 05)、早产(RR = 0. 95,95% CI 0. 85 ~ 1. 07,Z = 0. 82,P>0. 05)、新生儿 死亡(OR= 0. 71,95% CI 0. 25~2. 00,Z = 0. 65,P>0. 05)比较差异无统计学意义。 结论:孕期使用含多替拉韦抗逆转录治疗方案 的病毒应答率高于含依非韦伦治疗组,同时依非韦伦治疗组新生儿体质量低于含多替拉韦组。