Introduction Oral HIV Pre‐Exposure Prophylaxis (PrEP) with tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC) is highly effective. Transgender women (TGW) have increased HIV risk, but have been underrepresented in trials. For TGW on oestrogens for gender‐affirming hormone treatment (GAHT), TDF/FTC‐oestrogen interactions may negatively affect HIV prevention or gender‐affirming goals. Our aim was to evaluate any pharmacokinetic drug‐drug interaction between GAHT and TDF/FTC. Methods We performed a pharmacokinetic study, in an urban outpatient setting in 2016 to 2018, of the effects of GAHT on TFV, FTC and the active forms TFV diphosphate (TFV‐DP) and FTC triphosphate (FTC‐TP) in eight TGW and eight cisgender men (CGM). At screening, participants were HIV negative. TGW were to maintain their GAHT regimens and have plasma oestradiol concentrations >100 pg/mL. Under direct observation, participants took oral TDF/FTC daily for seven days. At the last dose, blood was collected pre‐dose, one, two, four, six, eight and twenty‐four hours, and colon biopsies were collected at 24 hours to measure drug concentration. TGW versus CGM concentration comparisons used non‐parametric tests. Blood and colon tissue were also obtained to assess kinase expression. Results Plasma TFV and FTC C24 (trough) concentrations in TGW were lower by 32% (p = 0.010) and 32% (p = 0.038) respectively, when compared to CGM. Plasma TFV and FTC 24‐hr area under the concentration‐time curve in TGW trended toward and was significantly lower by 27% (p = 0.065) and 24% (p = 0.028) respectively. Peak plasma TFV and FTC concentrations, as well as all other pharmacokinetic measures, were not statistically significant when comparing TGW to CGM. Oestradiol concentrations were not different comparing before and after TDF/FTC dosing. Plasma oestrogen concentration, renal function (estimated creatinine clearance and glomerular filtration rate), and TFV and FTC plasma concentrations (trough and area under the concentration‐time curve) were all correlated. Conclusions GAHT modestly reduces both TFV and FTC plasma concentrations. In TGW taking GAHT, it is unknown if this reduction will impact the HIV protective efficacy of a daily PrEP regimen. However, the combination of an on demand (2 + 1 + 1) PrEP regimen and GAHT may result in concentrations too low for reliable prevention of HIV infection.
LRP1 (LDL receptor-related protein-1) is a ubiquitous receptor with both cell signaling and ligand endocytosis properties. In the liver, LRP1 serves as a chylomicron remnant receptor and also participates in the transport of extracellular cathepsin D to the lysosome for prosaposin activation. The current study showed that in comparison with wild type mice, hepatocytespecific LRP1 knock-out (hLrp1 ؊/؊ ) mice were more susceptible to fasting-induced lipid accumulation in the liver. Primary hepatocytes isolated from hLrp1 ؊/؊ mice also accumulated more intracellular lipids and experienced higher levels of endoplasmic reticulum (ER) stress after palmitate treatment compared with similarly treated hLrp1 ؉/؉ hepatocytes. Palmitatetreated hLrp1 ؊/؊ hepatocytes displayed similar LC3-II levels, but the levels of p62 were elevated in comparison with palmitate-treated hLrp1 ؉/؉ hepatocytes, suggesting that the elevated lipid accumulation in LRP1-defective hepatocytes was not due to defects in autophagosome formation but was due to impairment of lipophagic lipid hydrolysis in the lysosome. Additional studies showed increased palmitate-induced oxidative stress, mitochondrial and lysosomal permeability, and cell death in hLrp1 ؊/؊ hepatocytes. Importantly, the elevated cell death and ER stress observed in hLrp1 ؊/؊ hepatocytes were abrogated by E64D treatment, whereas inhibiting ER stress diminished cell death but not lysosomal permeabilization. Taken together, these results documented that LRP1 deficiency in hepatocytes promotes lipid accumulation and lipotoxicity through lysosomalmitochondrial permeabilization and ER stress that ultimately result in cell death. Hence, LRP1 dysfunction may be a major risk factor in fatty liver disease progression.
Reduced low-density lipoprotein receptor-related protein-1 (LRP1) expression in the liver is associated with poor prognosis of liver cirrhosis and hepatocellular carcinoma. Previous studies have shown that hepatic LRP1 deficiency exacerbates palmitate-induced steatosis and toxicity and also promotes high-fat diet-induced hepatic insulin resistance and hepatic steatosis The current study examined the impact of liver-specific LRP1 deficiency on disease progression to steatohepatitis. mice with normal LRP1 expression and mice with hepatocyte-specific LRP1 inactivation were fed a high-fat, high-cholesterol (HFHC) diet for 16 weeks. Plasma lipid levels and body weights were similar between both groups. However, the mice displayed significant increases in liver steatosis, inflammation, and fibrosis compared with the mice. Hepatocyte cell size, liver weight, and cell death, as measured by serum alanine aminotransferase levels, were also significantly increased in mice. The accelerated liver pathology observed in HFHC-fed mice was associated with reduced expression of cholesterol excretion and bile acid synthesis genes, leading to elevated immune cell infiltration and inflammation. Additional studies revealed that cholesterol loading induced significantly higher expression of genes responsible for hepatic stellate cell activation and fibrosis in hepatocytes than in hepatocytes. These results indicate that hepatic LRP1 deficiency accelerates liver disease progression by increasing hepatocyte death, thereby causing inflammation and increasing sensitivity to cholesterol-induced pro-fibrotic gene expression to promote steatohepatitis. Thus, LRP1 may be a genetic variable that dictates individual susceptibility to the effects of dietary cholesterol on liver diseases.
Emtricitabine (FTC), tenofovir (TFV), efavirenz (EFV), and rilpivirine (RPV) are currently used as components of HIV combination therapy. Although these drugs are widely used in antiretroviral therapy, several organ toxicities related to TFV and EFV have been observed clinically. TFV is associated with nephrotoxicity, whereas EFV-related hepatotoxicity and neurotoxicity have been reported. While the precise molecular mechanisms related to the above-mentioned clinically observed toxicities have yet to be elucidated, understanding the local tissue distribution profiles of these drugs could yield insights into their safety profiles. To date, the distributions of these drugs in tissue following in vivo exposure are poorly understood. Therefore, in this study, we employed a matrix-assisted laser desorption/ionization mass spectrometry imaging method to generate spatial distribution profiles of FTC, TFV, EFV, and RPV in mouse tissues following in vivo dosing of following drug regimens: TFV–FTC–EFV and TFV–FTC–RPV. For this study, liver, brain, kidney, spleen, and heart tissues were obtained from mice ( n = 3) following separate oral administration of the above-mentioned drug regimens. Interestingly, EFV was detected in liver, brain, and heart following TFV–FTC–EFV treatment. Additionally, hydroxylated EFV, which encompasses the cytochrome P450-dependent monooxygenated metabolites of EFV, was detected in liver, brain, spleen, and heart tissue sections. Notably, the tissue distribution profiles of RPV and hydroxylated RPV following in vivo dosing of TFV–FTC–RPV were different from EFV/hydroxylated EFV despite RPV belonging to the same drug class as EFV. In conclusion, the observed spatial distribution profiles of the study drugs are in agreement with their safety profiles in humans.
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