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Background We evaluated the patterns of peripheral Toll-like receptor (TLR) signaling activity and the expression of TLRs and natural killer (NK) cell activation in a cohort of patients experiencing severe hepatitis flares after stopping nucleot(s)ide analogues (NAs) therapy. Methods Samples were collected longitudinally from patients with chronic hepatitis B who were enrolled in a prospective study of NA discontinuation. Patients experiencing hepatitis flares were compared with patients with normal alanine aminotransferase. Peripheral blood mononuclear cells (PBMCs) were stimulated with TLR ligands and cytokine secretion in the cell culture supernatant measured. Expression of TLR2/4, NKG2D, NKp46, and triggering receptor expressed on myeloid cells 1 (TREM-1) on monocytes, NK, and NK-T cells was measured. Results Seventeen patients with severe reactivation hepatitis flares were compared to 12 nonflare patients. Hepatitis flares were associated with increased activity of TLR2–8 and TLR9 signaling in PBMCs at the time of peak flare compared to baseline. Hepatitis flares were also associated with (1) upregulation of TLR2 and (2) TREM-1 receptor expression on NK. There were no differences at baseline between flare patients and nonflare patients. Conclusions Hepatitis flares off NA therapy have a significant innate inflammatory response with upregulation of TLR signaling on peripheral monocytes and TLR2 and TREM-1 expression on NK cells. This implicates the innate immune system in the immunopathogenesis of hepatitis B flares. [ABSTRACT FROM AUTHOR]

Summary: Background: Antenatal antiviral therapy (AVT) is effective in preventing mother‐to‐child transmission (MTCT) in chronic hepatitis B (CHB); tenofovir disoproxil fumarate (TDF) is the preferred agent. Tenofovir alafenamide (TAF) is a prodrug of tenofovir (TFV) similar to TDF, with improved bone and renal safety. There are no data on TAF breast milk pharmacokinetics and exposure to breastfeeding infants in CHB. Aim: To assess the pharmacokinetics of TAF/TFV in breastfeeding women with CHB on TAF monotherapy. Methods: Pregnant women with CHB requiring AVT commenced TAF 25 mg daily at third trimester or postpartum. Sample collection occurred while breastfeeding and taking TAF for minimum 4 weeks. Maternal blood, breast milk and infant urine samples were collected. Drug concentrations were measured by LCMS/MS analyses using validated methods. Non‐compartmental analyses were performed to quantify the pharmacokinetic parameters. Results: Eight women provided samples. In breast milk and plasma, median TAF half‐life was 0.81 and 0.94 h, respectively, and Cmax 1.69 and 120.5 ng/ml, respectively. Median maternal breast milk to plasma (M/P) ratio of TAF was 0.029; for and TFV it was 2.809. The relative infant dose of TAF was 0.005% of maternal dose, well below safety threshold of 5–10%. TFV was detectable in three out of seven infant urine samples with median steady‐state concentration of 5 ng/ml being 300–2500 times less than reported adult steady‐state urine concentrations in those taking TAF and TDF, respectively. Conclusions: In this first pharmacokinetic study of TAF monotherapy in breastfeeding women with CHB, concentrations of TAF and TFV were low in breast milk with negligible infant exposure, supporting the use of TAF to prevent MTCT. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Kayes et al papers. To view these articles, visit https://doi.org/10.1111/apt.17040 [ABSTRACT FROM AUTHOR]

A number of antiviral agents used against Human Immunodeficiency Virus (HIV) infection and hepatitis B virus (HBV) mono or co-infection have been associated with real nephrotoxicity (including tenofovir disoproxil fumarate (TDF), atazanavir, indinavir and lopinavir) or apparent changes in renal function (e.g. cobicistat, ritonavir, rilpivirine and dolutegravir). Patients with HIV are at higher risk of acute and chronic renal dysfunction, so baseline assessment and ongoing monitoring of renal function is an important part of routine management of patients with HIV. Given the paucity of evidence in this area, we sought to establish a consensus view on how routine monitoring could be performed in Australian patients on ART regimens, especially those involving TDF. A group of nephrologists and prescribers (an HIV physician and a hepatologist) were assembled by Gilead to discuss practical and reasonable renal management strategies for patients particularly those on TDF-based combination regimens (in the case of those with HIV-infection) or on TDF-monotherapy (in the case of HBV-mono infection). The group considered which investigations should be performed as part of routine practice, their frequency, and when specialist renal referral is warranted. The algorithm presented suggests testing for serum creatinine along with plasma phosphate and an assessment of urinary protein (rather than albumin) and glucose. Here we advocate baseline tests of renal function at initiation of therapy. If creatinine excretion inhibitors (e.g. cobicistat or rilpivirine) are used as part of the ART regimen, we suggest creatinine is rechecked at 4 weeks and this value used as the new baseline. Repeat testing is suggested at 3-monthly intervals for a year and then at least yearly thereafter if no abnormalities are detected. In patients with abnormal baseline results, renal function assessment should be performed at least 6 monthly. In HBV mono-infected patients advocate that a similar testing protocol may be logical. [ABSTRACT FROM AUTHOR]

Perinatal transmission of hepatitis B virus still occurs despite immunoprophylaxis in approximately 9% of children from highly viraemic mothers. Antiviral therapy in this setting has been suggested, however with limited evidence to direct agent choice. Methods We conducted a multi-centre, prospective, opt-in observational study of antiviral safety and efficacy in pregnant women with high viral load (>7logIU/ml); lamivudine was used from 2007 to 2010 and tenofovir disoproxil fumarate (TDF) from late 2010. Outcomes of treated and untreated cohorts were compared. Results 120 women with 130 pregnancies used TDF (58), lamivudine (52 including four who switched due to TDF intolerance) and no therapy (20). 96% were HBeAg positive, with baseline viral load mean 7.8logIU/ml (±0.72) and ALT median 25U/L (18.75-33). Duration of antiviral theraphy before birth was mean 58days (±19) TDF and 53 (±14) lamivudine. Viral load declined by 3.64logIU/ml (±0.9) TDF and 2.81logIU/ml (±1.33) lamivudine. Virologic failure (birth viral load >7IU/ml) occurred in 3% and 18% respectively. Congenital abnormality rate and neonatal growth centiles were similar across cohorts. Perinatal transmission reduced significantly to 2% and 0% in TDF and lamivudine cohorts, compared with 20% in untreated. Conclusions TDF in this setting is safe, effective and more potent than lamivudine. Antiviral therapy did not adversely impact obstetric or infant parameters. More TDF intolerance occurred than expected. Perinatal transmission was significantly reduced in antiviral therapy cohorts. [ABSTRACT FROM AUTHOR]