Pharmacogenetics of tenofovir drug transporters in the context of HBV: Is there an impact?

BACKGROUND: Current treatments for chronic hepatitis B management include orally administered nucleos(t)ide analogues, such as tenofovir (TDF), which is an acyclic adenine nucleotide analogue used both in HBV and human immune deficiency virus (HIV). The course of HBV infection is mainly dependent on viral factors, such as HBV genotypes, immunological features and host genetic variables, but a few data are available in the context of HBV, in particular for polymorphisms of genes encoding proteins involved in drug metabolism and elimination. Consequently, the aim of this study was to evaluate the potential impact of genetic variants on TDF plasma and urine concentrations in patients with HBV, considering the role of HBV genotypes. METHODS: A retrospective cohort study at the Infectious Disease Unit of Amedeo di Savoia Hospital, Torino, Italy, was performed. Pharmacokinetic analyses were performed through liquidi chromatography, whereas pharmacogenetic analyses through real-time PCR. FINDINGS: Sixty - eight patients were analyzed: ABCC4 4976 C>T genetic variant showed an impact on urine TDF drug concentrations (p = 0.014). In addition, SLC22A6 453 AA was retained in the final regression multivariate model considering factors predicting plasma concentrations, while ABCC4 4976 TC/CC was the only predictor of urine concentrations in the univariate model. INTERPRETATION: In conclusion, this is the first study showing a potential impact of genetic variants on TDF plasma and urine concentrations in the HBV context, but further studies in different and larger cohorts of patients are required.

Sensorimotor integration is affected by acute whole-body vibration: a coherence study.

Introduction: Several whole-body vibration (WBV) effects on performance have been related to potential changes in the neural drive, motor unit firing rate, and sensorimotor integration. In the present paper, motor unit coherence analysis was performed to detect the source of neural modulation based on the frequency domain. Methods: Thirteen men [25 ± 2.1 years; Body Mass Index (BMI) = 23.9 ± 1.3 kg m2; maximal voluntary force (MVF): 324.36 ± 41.26 N] performed sustained contractions of the Tibialis Anterior (TA) at 10%MVF before and after acute WBV. The vibrating stimulus was applied barefoot through a platform to target the TA. High-Density surface Electromyography (HDsEMG) was used to record the myoelectrical activity of TA to evaluate coherence from motor unit cumulative spike-trains (CSTs). Results: Mean coherence showed a significant decrease in the alpha and low-beta bandwidths (alpha: from 0.143 ± 0.129 to 0.132 ± 0.129, p = 0.035; low-beta: from 0.117 ± 0.039 to 0.086 ± 0.03, p = 0.0001), whereas no significant changes were found in the other ones (p > 0.05). The discharge rate (DR) and the Force Covariance (CovF%) were not significantly affected by acute WBV exposure (p > 0.05). Discussion: According to the significant effects found in alpha and low-beta bandwidths, which reflect sensorimotor integration parameters, accompanied by no differences in the DR and CovF%, the present results underlined that possible neural mechanisms at the base of the previously reported performance enhancements following acute WBV are likely based on sensorimotor integration rather than direct neural drive modulation.

The acute effects of whole-body vibration on motor unit recruitment and discharge properties.

Introduction: several studies have reported improved neuromuscular parameters in response to whole-body vibration (WBV). This is likely achieved by modulation of the central nervous system (CNS). Reduced recruitment threshold (RT), which is the % of Maximal Voluntary Force (%MVF) at which a given Motor Unit (MU) is recruited, may be responsible for the force/power improvements observed in several studies. Methods: 14 men (25 ± 2.3 years; BMI = 23.3 ± 1.5 kg m2 MVF: 319.82 ± 45.74 N) performed trapezoidal isometric contractions of the tibialis anterior (TA) at 35-50-70 %MVF before and after three conditions: WBV, STAND (standing posture), and CNT (no intervention). The vibration was applied through a platform for targeting the TA. High-density surface electromyography (HDsEMG) recordings and analysis were used to detect changes in the RT and Discharge Rate (DR) of the MUs. Results: Mean motor unit recruitment threshold (MURT) reached 32.04 ± 3.28 %MVF before and 31.2 ± 3.72 %MVF after WBV, with no significant differences between conditions (p > 0.05). Additionally, no significant changes were found in the mean motor unit discharge rate (before WBV: 21.11 ± 2.94 pps; after WBV: 21.19 ± 2.17 pps). Discussion: The present study showed no significant changes in motor unit properties at the base of neuromuscular changes documented in previous studies. Further investigations are needed to understand motor unit responses to different vibration protocols and the chronic effect of vibration exposure on motor control strategies.

Enhanced Photoluminescence of Curcuma longa Extracts via Chitosan-Mediated Energy Transfer for Textile Authentication Applications.

Dyes for security markings play a pivotal role in safeguarding the integrity of products across various fields, such as textiles, pharmaceuticals, food, and manufacturing among others. However, most commercial dyes used as security markings are costly and may contain toxic and harmful substances that pose a risk to human health. Curcumin, a natural phenolic compound found in turmeric, possesses distinct photoluminescent properties alongside its vibrant yellow color, making it a potential candidate material for authentication applications. This study demonstrates a cost-effective and eco-friendly approach to develop enhanced photoluminescent emissions from curcumin dyes for textile authentication. Curcumin was extracted from C. longa using sonication-assisted-solvent extraction method. The extract was dip-coated and dyed into the textile substrates. Chitosan was introduced as a post-mordanting agent to stabilize the curcumin and as a co-sensitizer. Co-sensitization of curcumin with chitosan triggers energy transfer to enhance its luminescent intensity. The UV-visible absorption peak at 424 nm is associated with the characteristic absorption of curcumin. The photoluminescence measurements showed a broad emission peaking at 545 nm with significant enhancement attributed to the energy transfer induced by chitosan, thus showing great potential as a naturally derived photoluminescent dye for authentication applications.

Prevalence and Clinical Significance of Persistent Viral Shedding in Hospitalized Adult Patients with SARS-CoV-2 Infection: A Prospective Observational Study.

BACKGROUND: The goal of this study was to investigate the prevalence and factors associated with persistent viral shedding (PVS) in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: This was a prospective observational study including all consecutive adults hospitalized with SARS-CoV-2 infection. When the first nasopharyngeal swab was positive for SARS-CoV-2 RNA (day 0), additional samples were obtained on days + 3, + 5, + 7 and then once every 7 days until virus detection was negative. PVS was defined as the duration of shedding of at least 21 days after diagnosis. The primary endpoint of this study was the prevalence of PVS. RESULTS: Data were obtained regarding 121 consecutive hospitalized patients with SARS-CoV-2 infection (median age 66 years, male sex 65.3%). Overall, the prevalence of PVS was 38% (46/121 patients). According to univariate analysis, factors associated with PVS were immunosuppression (6.7% vs 21.7%, p = 0.02), increased interleukin-6 (IL-6) levels (≥ 35 ng/ml) at the time of diagnosis (43.4% vs 67.3%, p = 0.02), time from onset of symptoms to diagnosis (median days 7.0 vs 3.5, p = 0.001), intensive care unit admission (22.7% vs 43.5%, p = 0.02), and need for invasive mechanical ventilation (20.0% vs 41.3%, p = 0.01). The multivariate analysis indicated that immunosuppression, increased IL-6 levels at the time of diagnosis, time from onset of symptoms to diagnosis, and need for mechanical ventilation were independent factors associated with PVS. CONCLUSIONS: PVS was detected in up to 38% of hospitalized patients with SARS-CoV-2 infection and was strongly associated with immunosuppression, increased IL-6 levels, and the need for mechanical ventilation.

Multi-Site Cation Control of Ultra-Broadband Near-Infrared Phosphors for Application in Light-Emitting Diodes.

Near-infrared (NIR) phosphors are fascinating materials that have numerous applications in diverse fields. In this study, a series of La3Ga5GeO14:Cr3+ phosphors, which was incorporated with Sn4+, Ba2+, and Sc3+, was successfully synthesized using solid-state reaction to explore every cationic site comprehensively. The crystal structures were well resolved by combining synchrotron X-ray diffraction and neutron powder diffraction through joint Rietveld refinements. The trapping of free electrons induced by charge unbalances and lattice vacancies changes the magnetic properties, which was well explained by a Dyson curve in electron paramagnetic resonance. Temperature and pressure-dependent photoluminescence spectra reveal various luminescent properties between strong and weak fields in different dopant centers. The phosphor-converted NIR light-emitting diode (pc-NIR LED) package demonstrates a superior broadband emission that covers the near-infrared (NIR) region of 650-1050 nm. This study can provide researchers with new insight into the control mechanism of multiple-cation-site phosphors and reveal a potential phosphor candidate for practical NIR LED application.

Data on compounding lopinavir and ritonavir suspension for non-cooperative COVID-19 patients.

The COVID-19 outbreak is now one of the most critical crises to manage for most of national healthcare systems in the world. The situation is complicated by the absence of vaccines and authorized pharmacological treatments, except for remdesivir. In this context, many medicaments, including different Ebola and HIV antivirals, are used off-label in the hospital wards as life-treating medicines for COVID-19 patients. Authorized medicaments manipulation is sometimes necessary because they are not always formulated to be administered to non-cooperative patients or they are in shortage. It is this the case of the fixed combination of lopinavir/ritonavir, which was extensively used in the first phase of the outbreak inducing a shortage of the oral solution available in the EU market. This work provides data on size distribution, osmolarity other than drug chemical stability of a lopinavir/ritonavir extemporaneous preparation made by using the solid dosage form (i.e., tablet) available on the market as drug source. The reported data indicate that such preparation is suitable to be delivered through a nasogastric tube, and enough stable for two weeks from the preparation at room temperature.

Clinical characteristics, management and in-hospital mortality of patients with coronavirus disease 2019 in Genoa, Italy.

OBJECTIVES: To describe clinical characteristics, management and outcome of individuals with coronavirus disease 2019 (COVID-19); and to evaluate risk factors for all-cause in-hospital mortality. METHODS: This retrospective study from a University tertiary care hospital in northern Italy, included hospitalized adult patients with a diagnosis of COVID-19 between 25 February 2020 and 25 March 2020. RESULTS: Overall, 317 individuals were enrolled. Their median age was 71 years and 67.2% were male (213/317). The most common underlying diseases were hypertension (149/317; 47.0%), cardiovascular disease (63/317; 19.9%) and diabetes (49/317; 15.5%). Common symptoms at the time of COVID-19 diagnosis included fever (285/317; 89.9%), shortness of breath (167/317; 52.7%) and dry cough (156/317; 49.2%). An 'atypical' presentation including at least one among mental confusion, diarrhoea or nausea and vomiting was observed in 53/317 patients (16.7%). Hypokalaemia occurred in 25.8% (78/302) and 18.5% (56/303) had acute kidney injury. During hospitalization, 111/317 patients (35.0%) received non-invasive respiratory support, 65/317 (20.5%) were admitted to the intensive care unit (ICU) and 60/317 (18.5%) required invasive mechanical ventilation. All-cause in-hospital mortality, assessed in 275 patients, was 43.6% (120/275). On multivariable analysis, age (per-year increase OR 1.07; 95% CI 1.04-1.10; p < 0.001), cardiovascular disease (OR 2.58; 95% CI 1.07-6.25; p 0.03), and C-reactive protein levels (per-point increase OR 1.009; 95% CI 1.004-1.014; p 0.001) were independent risk factors for all-cause in-hospital mortality. CONCLUSIONS: COVID-19 mainly affected elderly patients with predisposing conditions and caused severe illness, frequently requiring non-invasive respiratory support or ICU admission. Despite supportive care, COVID-19 remains associated with a substantial risk of all-cause in-hospital mortality.

Data on the stability of darunavir/cobicistat suspension after tablet manipulation.

The COVID-19 outbreak is now one of the most critical crises to manage for most of the national healthcare systems in the world. In the absence of authorised pharmacological treatments, many antiretrovirals, including darunavir/cobicistat fixed combination, are used off-label in the hospital wards as life-treating medicines for COVID-19 patients. Unfortunately, for most of them, the drug products available on the market are not designed to be administered by a nasogastric tube to inpatients of intensive care units. Therefore, their manipulation, even if it can strongly affect the product quality, is necessary for the preparation of suspension to meet patients' need. In this situation, it is urgent to provide data and guidance to support hospital pharmacists and clinicians in their activity. The data in this article indicate that darunavir/cobicistat suspensions compounded by pharmacists using as active ingredient a commercially available tablet can be stable at least for one week.

Antiretroviral concentrations in the presence and absence of valproic acid.

OBJECTIVES: An unexpected drug-drug interaction has been recently reported between dolutegravir, an HIV integrase inhibitor, and valproic acid. Despite there being several potential underlying mechanisms, plasma protein displacement has been suggested. The aim of this study was to assess plasma concentrations of several antiretrovirals when administered with or without valproic acid. METHODS: We performed a therapeutic drug monitoring registry analysis and identified patients concomitantly taking antiretrovirals and valproic acid and without clinical affecting conditions or interacting drugs. RESULTS: One hundred and thirty-four patients were identified. Median (IQR) age and BMI were 49.7 years (45-56) and 23.4 kg/m2 (20.8-26.3) and 78 were male (58.2%). Despite small groups, we observed no major effect on antiretroviral exposure, even when considering highly protein-bound compounds (such as etravirine), with the exception of dolutegravir trough concentrations [median (IQR) = 132 ng/mL (62-227) in individuals on valproic acid versus 760 ng/mL (333-1407) in those not receiving valproic acid]. CONCLUSIONS: Valproic acid does not have a major effect on antiretrovirals other than dolutegravir. The mechanism of this unexpected drug-drug interaction may be the combination of protein displacement, reduced absorption and CYP3A4 induction.

Serum Trimethylamine-N-oxide Concentrations in People Living with HIV and the Effect of Probiotic Supplementation.

BACKGROUND: The incidence of cardiovascular disorders in people living with HIV (PLWH) is higher than that in non-infected individuals. Traditional and specific risk factors have been described but the role of the gut microbiota-dependent choline metabolite, trimethylamine-N-oxide (TMAO) is still unclear. METHODS: A cross-sectional analysis and a longitudinal analysis (with high-dose probiotic supplementation) were performed to measure serum TMAO concentrations through UHPLC-MS/MS. Stable outpatients living with HIV on highly active antiretroviral treatment with no major cardiovascular disease were enrolled. Non-parametric tests (bivariate and paired tests) and a multivariate linear regression analysis were used. RESULTS: A total of 175 participants were enrolled in the study. Median serum TMAO concentrations were 165 (103-273) ng/mL. An association with age, serum creatinine, number of antiretrovirals, multimorbidity and polypharmacy was observed; at linear logistic regression analysis, multimorbidity was the only independent predictor of TMAO concentrations. Carotid intima media thickness (IMT) was 0.85 (0.71-1.21) mm, with a trend towards higher TMAO concentrations observed in patients with IMT >0.9 mm (P=0.087). In the 25 participants who received probiotic supplementation, TMAO levels did not significantly change after 24 weeks (Wilcoxon paired P=0.220). CONCLUSION: Serum TMAO levels in PLWH were associated with multimorbidity, higher cardiovascular risk and subclinical atherosclerosis and were not affected by 6 months of high-dose probiotic supplementation.

Cerebrospinal fluid abacavir concentrations in HIV-positive patients following once-daily administration.

Abacavir is a widely used nucleotide reverse transcriptase inhibitor, for which cerebrospinal fluid (CSF) exposure has been previously assessed in twice-daily recipients. We studied abacavir CSF concentrations in 61 and nine HIV-positive patients taking abacavir once daily and twice daily, respectively. Patients on once-daily abacavir had higher plasma and CSF concentrations (96 vs. 22 ng ml-1 , P = 0.038 and 123 vs. 49 ng ml-1 , P = 0.038) but similar CSF-to-plasma ratios (0.8 vs. 0.5, P = 0.500). CSF abacavir concentrations were adequate in patients receiving once-daily treatment.

Role of CYP24A1, VDR and GC gene polymorphisms on deferasirox pharmacokinetics and clinical outcomes.

ß-Thalassemia patients develop deficiency in vitamin D absorption and liver hydroxylation, resulting in extremely low calcitriol levels. We explored the role of single-nucleotide polymorphisms (SNPs) involved in vitamin D metabolism, transport and activity on deferasirox pharmacokinetics and outcomes (effectiveness trough levels (Ctrough) and the area under the curve (AUC) cutoffs of 20 µg ml-1 and 360 µg ml-1 h-1, respectively; nonresponse AUC limit of 250 µg ml-1 h-1). Ninety-nine ß-thalassemic patients were enrolled. Drug plasma Ctrough and AUC were measured by the high-performance liquid chromatography system coupled with an ultraviolet determination method. Allelic discrimination for VDR, CYP24A1, CYP27B1 and GC gene SNPs was performed by real-time PCR. CYP24A1 22776 TT significantly influenced Cmin and negatively predicted it in regression analysis. CYP24A1 3999 CC was associated with Ctrough and Cmin and was a negative predictor of Tmax, whereas CYP24A1 8620 GG seemed to have a role in Ctrough, AUC, t1/2 and Cmin, and was an AUC negative predictor factor. Considering treatment outcome, Cdx2 and GC 1296 were retained in regression analysis as AUC efficacy cutoff negative predictors.

Usefulness of PET in recognizing and managing vasculitides.

PURPOSE OF REVIEW: The aim of this article was to review the recent contributions to the scoring methods of PET in vasculitis as well as to its role in the diagnostic work-up. RECENT FINDINGS: Both visual and semiquantitative scoring methods can be used to interpret PET scans. PET has been shown to be both sensitive and specific in the diagnosis of large-vessel vasculitis. In addition, it also has a role in predicting vascular complications. SUMMARY: There is a need to better standardize the scoring methods used to interpret PET scans. In clinical practice, PET is useful to diagnose untreated individuals with suspected large-vessel vasculitis and contributes to identify patients at risk for vascular complications.

Efficacy of sofosbuvir and ledipasvir in an HCV+ gastro-resected patient.

WHAT IS KNOWN AND OBJECTIVE: The second-generation direct-acting antivirals represented the first major turning point for the eradication of HCV infection in almost all settings of patients. However, no data were available on use in gastro-resected patients. CASE DESCRIPTION: We report on a gastrectomized patient with chronic hepatitis C infection. She was treated with sofosbuvir and ledipasvir (SOF/LDV) for 12 weeks, with measurement of blood levels of the drugs. She obtained sustained virological response at week 12 and 24 without dose adjustment. WHAT IS NEW AND CONCLUSION: This case report can provide information useful for clinical practice in this set of patients and can open new perspectives in evaluating actual SOF/LDV bioavailability.

Treatment with direct-acting antiviral agents of hepatitis C virus infection in injecting drug users: A prospective study.

In this prospective study, we evaluated the effectiveness and tolerability of novel therapies against hepatitis C virus (HCV) in a cohort of PWID enrolled at our centre from April 2015 to July 2016. In this analysis, a total of 174 patients were included: eleven (6.3%) were treated with pegylated interferon (PEG-IFN) and ribavirin (RBV) containing regimens, 163 (93.7%) with IFN-free treatments. RBV has been used in 70 patients (40.2%); 59 (33.9%) patients were in opioid substitution therapy (OST) with methadone or buprenorphine. Overall, sustained virological response (SVR) has been observed in 162 subject (93.1%), breakthrough (BT) in three (1.7%), relapse in one (0.6%) and dropout in eight (4.6%). Treatment was interrupted for clinical conditions in seven patients: six (3.4%) had hepatic decompensation and one died for hepatocellular carcinoma (HCC). In multivariate analysis, predictive factors of treatment failure were as follows: albumin level below 3 g/dL (OR=7.190; 95% IC=1.236-41.837; P<.001), MELD score >10 (OR=5.886; 95% IC=1.411-35.994; P<.001) and years of HCV infection >20 (OR=1.286; 95% IC=0.556-9.455; P=.016). In conclusion, treatment with DAAs was effective and well tolerated in PWID; cirrhotic subjects with MELD > 10 and albumin low level showed a higher risk of developing serious adverse events and treatment failure.

Relationship between the early boceprevir-S isomer plasma concentrations and the onset of breakthrough during HCV genotype 1 triple therapy.

In a prospective cohort of 18 patients treated with boceprevir, we examined the role of boceprevir plasma concentration at the onset of breakthrough during the treatment. Nine patients experienced breakthrough during therapy. The resistance patterns were as follows: S122S/R, I132V, T54A/I132V, V156S/I170A, V36M/T54S/R155K, V36M/R155K and T54/R155K. Boceprevir-S isomer (SCH 534128) median concentration in patients with breakthrough was 48.3 ng/mL (interquartile range 43-58 ng/mL); in others, it was significantly (p 0.019) higher: 151 ng/mL. Low boceprevir plasma concentration can lead to virologic resistance; therapeutic drug monitoring should be used to prevent the onset of viral breakthrough during triple-regimen therapy with boceprevir.

Role of CYP27B1+2838 promoter polymorphism in the treatment of chronic hepatitis B HBeAg negative with PEG-interferon.

In HBV-infected patients, the vitamin D deficiency has been related to chronic liver diseases, progression of hepatic fibrosis and poor response to the treatment. The CYP27B1 gene, which encodes the 1-α-hidroxylase and involved in the 1,25-dihydroxyvitamin D synthesis, was recently associated to type-1 diabetes, autoimmune disorders and treatment response in HCV. Then, we aimed to investigate the role of CYP27B1 polymorphisms in HBV treatment with PEG-IFN. We retrospectively enrolled 190 patients with chronic hepatitis B HBeAg negative treated for 48 weeks with PEG-IFN α-2a. We examined the role of rs4646536 CYP27B1 SNP (CYP27B1+2838) according to virological and serological response. Our results showed that the TT genotype of CYP27B1+2838 was significantly prevalent in patients with end-of-therapy virological response (37.6%) vs CT/CC (9.4%) (P < 0.001). Virological relapse was prevalent in patients with CT/CC genotype (12.6%) vs TT genotype (2.1%) (P < 0.001). TT genotype was also related to HBsAg loss (P = 0.004) and anti-HBs appearance (P = 0.002). In the multivariate analysis, the TT genotype resulted to be a good positive predictor of sustained virological response (OR = 5.632, IC = 1.938-16.368, P = 0.001) and serological response (OR = 6.161, IC = 1.856-20.457, P = 0.003). The CYP27B1+2838 polymorphism may be useful as pretreatment factor to selection of patients with higher probability of response to therapy.

Significant early higher ribavirin plasma concentrations in patients receiving a triple therapy with pegylated interferon, ribavirin and telaprevir.

The new standard of care for treatment for infection with genotype 1a/b of HCV now is the combination of telaprevir (TLV) with ribavirin (RBV) and pegylated interferon (Peg-IFN). Although this new therapy gives a higher response rate than the Peg-IFNα plus RBV treatment, a greatly higher rate of anaemia onset has been reported in all clinical trials. Because haemolysis is a typical concentration-dependent side effect of RBV, modulated by ITPA gene polymorphisms, we aimed to compare the early RBV plasma exposure of nine patients after 2 weeks of treatment with triple therapy with RBV concentrations of 187 patients treated with RBV and Peg-IFNα over the same time scale; this comparison was performed also stratifying patients according to ITPA polymorphism genotype and anaemia onset after 1 month of treatment. All TLV-treated patients had unfavourable ITPA genetic profile and developed anaemia. Moreover, both the rate of anaemia onset and the haemoglobin loss at 1 month were significantly higher in patients treated with TLV. This observation has been confirmed also in patients with the same ITPA genetic profile in double therapy. Strikingly, also early RBV plasma concentrations were significantly higher in patients treated with TLV. These unbiased results confirm the observations recently reported and suggest that the high rate of anaemia onset could be mainly due to the increased RBV exposure, probably caused by a 'boosting effect' by TLV. These data highlight the great importance of early therapeutic drug monitoring of RBV in the management of anaemia in the triple therapy.