BACKGROUND & AIMS:Patients with chronic hepatitis B (CHB) with low hepatitis B surface antigen (HBsAg) levels and suppressed hepatitis B virus (HBV) DNA on nucleos(t)ide analogues (NAs) may achieve functional cure with peginterferon α (PegIFNα)-based therapy. This real-world multicenter study (Everest Project) in China aimed to evaluate the effectiveness and safety of PegIFNα-2b and determine the predictors of HBsAg loss. METHODS:Patients with NA-suppressed CHB who were hepatitis B e antigen (HBeAg)-negative, had HBsAg ≤1500 IU/mL, and undetectable HBV DNA, were administered PegIFNα-2b for 48 weeks, either as a switch-to or add-on therapy. The primary endpoint was HBsAg loss at week 48. RESULTS:Among 15,896 patients in the full analysis set (FAS) and 12,260 in the per-protocol set (PPS), HBsAg loss rate at week 48 was 26.4% and 33.8%, respectively, after propensity score weighting, with no significant difference between switch-to and add-on groups. Key predictors of HBsAg loss included lower baseline HBsAg and HBsAg decline >63.3% at week 12 and >95.3% at week 24. Among patients who underwent >24 weeks of post-treatment follow-up, HBsAg loss rates at week 24 were 28.7% and 35.6% in the FAS and PPS, respectively. Of those who received consolidation therapy, 85.9% maintained HBsAg loss at week 72. Adverse event-related discontinuation occurred in 5.6% and 4.4% of those in the FAS and PPS, respectively. CONCLUSIONS:PegIFNα-2b enhances HBsAg loss in patients with NA-suppressed, HBeAg-negative CHB with low HBsAg levels. Baseline and on-treatment predictors support the achievement of a functional cure. CLINICALTRIALS:gov, Number: NCT04035837.

The objective of this study was to investigate the efficacy and safety of oral tolvaptan for hyponatremia in patients with cirrhosis in China. In this post hoc subgroup analysis of a phase 2 clinical trial of oral tolvaptan for hyponatremia due to cirrhosis, heart failure, and syndrome of inappropriate antidiuretic hormone secretion in China, patients with hyponatremia due to cirrhosis received placebo or tolvaptan for 7 days (15 mg titrated to 30 or 60 mg/day). The primary endpoint was the average daily change in serum sodium level from baseline to days 4 and 7. We enrolled 131 patients (90 males, 41 females) with cirrhosis mainly due to CHB (70.2

Background and Aims: Tenofovir alafenamide (TAF) has demonstrated comparable efficacy to tenofovir disoproxil fumarate (TDF), with improved renal and bone safety, in Chinese participants with chronic hepatitis B enrolled in two Phase 3 trials. This study aimed to evaluate the long-term virologic efficacy, serological and biochemical responses, resistance, and renal and bone safety of TAF over eight years in this population. Methods: Participants completing the threeyear double-blind phase were eligible to receive open-label TAF 25 mg/day for up to an additional five years (totaling eight years). Analyses of viral suppression (HBV DNA < 29 IU/mL), alanine aminotransferase normalization, serological responses, resistance surveillance, and safety outcomes were conducted. Results: Among 334 enrolled participants, 212 of 227 participants randomized to TAF continued open-label TAF (TAF-TAF), and 99 of 107 participants on TDF switched to open-label TAF (TDF-TAF). At Year 8, 79.3% (180/227) and 78.5% (84/107) of participants in the TAF-TAF and TDF-TAF groups, respectively, achieved viral suppression (missing = failure); rates increased to 95.2% (180/189) and 95.5% (84/88) when excluding missing data. Alanine aminotransferase normalization rates remained high and comparable between groups. Serologic response rates continued to increase over time, with higher rates observed in the TAF-TAF group. Estimated glomerular filtration rate (by Cockcroft-Gault) and hip/spine bone mineral density remained stable in the TAF-TAF group through eight years; the small declines in these renal and bone parameters observed during doubleblind TDF treatment improved after switching to open-label TAF. No resistance to TAF was detected. Conclusions: Longterm TAF treatment demonstrated durable virologic efficacy, sustained biochemical and serological responses, and favorable renal and bone safety over eight years in Chinese participants with chronic hepatitis B.

Standardized anti-hepatitis B virus (HBV) guidelines for HBV/tuberculosis (TB) co-infected patients during antituberculosis therapy (ATT) are lacking, especially for hepatitis B e antigen (HBeAg)-negative patients with low baseline HBV DNA. It remains unclear whether liver injury during ATT is caused by ATT itself (antituberculosis drug-induced liver injury, AT-DILI) or by HBV reactivation. We aimed to characterize HBV reactivation liver injury in this understudied population and to distinguish it from AT-DILI. We conducted a retrospective multi-center study of 10 consecutive HBeAg-negative HBV/TB co-infected patients with suspected ATT-induced liver injury. HBV reactivation was defined as ≥ 2 log IU/mL HBV DNA increase or conversion from undetectable to detectable. Liver injury was defined as ALT > 3 × ULN with symptoms, or ALT > 5 × ULN, or total bilirubin > 2 × ULN. Key indicators were measured via standardized methods; analyses used SPSS 23.0 and GraphPad Prism 9.0. All 10 patients met the criteria for HBV reactivation, with HBV DNA increasing from 3.0 ± 0.6 to 7.4 ± 0.4 log IU/mL (P < 0.001), and 60

BACKGROUND:Hepatitis B virus (HBV) evades the innate immunity and leads to persistent chronic infection, but the molecular mechanism is still not well known. AIM:To investigate whether HBV-miR-3 is involved in HBV immune evasion. METHODS:HBV-miR-3 agomir and antagomir were employed to verify the effectiveness of HBV-miR-3 on cGAS-Sting-IFN pathway through the experiments on relative luciferase activity, cGAS protein expression, Sting phosphorylation and interferon (IFN) production. RESULTS:HBV-miR-3 down-regulates cGAS protein expression post-transcriptionally by inhibition of cGAS 3'-untranslated region (3'-UTR) activity, which results in lower Sting phosphorylation and IFN production. HBV-miR-3 antagomir rescued cGAS protein expression, Sting phosphorylation and IFN-β production. CONCLUSION:HBV-miR-3 plays an important role in HBV immunity evasion by targeting cGAS 3'-UTR and interfering with cGAS-Sting-IFN pathway.

AIMS:The transcription factor OCT4A, a well-established master pluripotency factor, exerts regulatory effects on cell fate determination that are closely associated with its protein levels. This study aims to uncover the downstream gene profile features relevant to tumorigenic potential mediated by OCT4A under varying protein abundance in somatic cancer cells (SCCs). MATERIALS AND METHODS:CRISPR-Cas9-mediated knockout and doxycycline-inducible OCT4A expression systems were established in cervical (HeLa) and hepatocellular (HepG2, Huh7) cancer cells. Single-cell sequencing, spatial transcriptomic and survival analysis data were used to elucidate the expression pattern of OCT4 in somatic cancer tissues and its prognostic relevance. The plate colony formation assay was performed to assess the tumorigenic capacity of SCCs, and Bulk RNA sequencing coupled with weighted gene co-expression network analysis (WGCNA) identified dose-relevant downstream pathways. Functional enrichment, survival modeling, and RT-qPCR validation were used to construct OCT4A-dose-dependent transcriptional regulatory networks. KEY FINDINGS:OCT4 transcript, is heterogeneously present and confined to a small subset of tumor cells within somatic cancer tissues, with a significantly higher proportion of OCT4-positive cells in tumor tissues compared to paired paraneoplastic tissues and is significantly correlated with poor prognosis in SCCs. Endogenous low-level OCT4A positively regulates tumorigenic capacity predominantly through targeting non-coding genes, whereas high-level OCT4A suppresses tumorigenic capacity primarily via protein-coding genes in SCCs. A prognostic model based on high-level OCT4A-regulated protein-coding genes was associated with favorable clinical outcomes, aligning with in vitro phenotypic results. SIGNIFICANCE:Our findings further confirm in SCCs that the functional pleiotropy of OCT4A is closely linked to its protein abundance, and further systematically elucidate the molecular signatures of OCT4A-regulated downstream gene networks associated with tumorigenic phenotypes at differential protein levels, providing novel insights for its translational exploitation in both oncological intervention and regenerative medicine strategies.

BACKGROUND C-X-C chemokine receptor type 5 (CXCR5)+CD8+ T cells represent a unique immune subset with dual roles, functioning as cytotoxic cells in persistent viral infections while promoting B cell responses. Despite their importance, the specific role of CXCR5+CD8+ T cells in chronic hepatitis B (CHB), particularly during interferon-alpha (IFN-α) treatment, is not fully understood. This study aims to elucidate the relationship between CXCR5+CD8+ T cells and sustained serologic response (SR) in patients undergoing 48 weeks of pegylated IFN-α (peg-IFN-α) treatment for CHB. AIM To elucidate the relationship between CXCR5+CD8+ T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-α treatment for CHB. METHODS This study enrolled 60 patients with hepatitis Be antigen (HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-α treatment. Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months, HBeAb-negative, hepatitis B virus DNA levels exceeding 2 × 104 copies/mL, and alanine aminotransferase (ALT) levels between 2 and 10 times the upper limit of normal. Blood samples were collected at baseline and at weeks 12, 24, 48, and a 24-week treatment-free follow-up (week 72) to measure serum interleukin (IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1 (PD-L1) expression on CD8+ T cells by flow cytometry, CXCR5 is a chemokine receptor that directs immune cells to specific tissues, while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity. RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5+CD8+ T cells compared to healthy controls (P < 0.01). Notably, CXCR5+CD8+ T cells were prominently expressed in patients who achieved sustained SR compared to non-SR (NSR). A significant correlation was observed between CXCR5 and PD-L1 expression (r = -0.189, P = 0.002). However, there was no significant correlation between serum IL-21 levels and CXCR5+CD8+ lymphocytes (r = -0.03, P = 0.625) or serum ALT levels (r = 0.026, P = 0.678). CONCLUSION The enhanced expression of CXCR5+CD8+ T cells in patients achieving HBeAg seroconversion during IFN-α treatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B. This study highlights the potential of CXCR5+CD8+ T cells as immune regulators in CHB, which may inform future therapeutic strategies to optimize antiviral treatments.

Background and Aims: After 3 -years (144 week) of double-blind treatment in Chinese chronic hepatitis B patients in two ongoing phase 3 studies, tenofovir alafenamide (TAF) showed similar efficacy to tenofovir disoproxil fumarate (TDF), with improved renal and bone safety. In this study, we aimed to report the 5 -year results from 2 years into the open -label TAF treatment phase. Methods: All participants completing the 144 -week double-blind treatment were eligible to receive open -label TAF 25 mg once daily up to week 384. Serial analysis of viral suppression (hepatitis B virus DNA <2 9 IU/mL), alanine aminotransferase normalization, serological responses, and safety outcomes at year 5 (week 240) was performed. Results: The openlabel phase included 93% (311/334) of the enrolled participants, which included 212 who switched from double-blind TAF to open -label TAF (TAF-TAF) and 99 who switched from double-blind TDF to open -label TAF (TDF-TAF). Baseline characteristics were comparable. Week 240 viral suppression rates were similar between groups [93.4% vs. 93.9%; difference: -1.5%, (95% CI: -6.4 to -3.5), p=0.857]. Alanine aminotransferase normalization and serological response rates were higher in the TAF-TAF group than in the TDF-TAF group. The frequencies of adverse events and laboratory abnormalities were low and similar between groups. Both groups had similar small numerical declines from baseline in estimated glomerular filtration rate at year 5 (week 240, -2.85 mL/min vs. -3.29 mL/min, p=0.910). The greater declines in renal and bone parameters in the TDF-TAF group through week 144 improved after switching to TAF. Conclusions: The 5 -year TAF treatment efficacy was high and similar to that of 3 -year TDF followed by 2 -year TAF in Chinese chronic hepatitis B patients. Favorable effects on bone and renal parameters were sustained with TAF treatment alone and were observed following the switch from TDF to TAF.

OBJECTIVES:Hepatic fibrosis is a common pathological basis for many chronic liver diseases and can progress to cirrhosis, a leading cause of mortality in liver diseases. Early identification and reversal of hepatic fibrosis are key in the treatment of chronic liver disease. This study aims to compare the expression levels of serum core fucosylated low molecular weight kininogen (LMWK-Fc) and alpha-galactosylated (α-Gal) antibodies in patients with hepatic fibrosis at different stages, and to evaluate their diagnostic efficacy for hepatic fibrosis. METHODS:A retrospective analysis was conducted on 275 patients with chronic liver disease who visited the Department of Infectious Diseases at the Second Xiangya Hospital of Central South University between June 2022 and March 2023. Among these, 115 patients underwent liver biopsy. Based on the extent of collagen deposition and its impact on liver structure and microcirculation, patients were staged from 0 to 4: S0 (no significant collagen deposition in liver tissues; liver structure and microcirculation are normal), S1 (mild collagen deposition in liver tissues, with partial disruption of lobule structure, but microcirculation remains largely normal), S2 (moderate collagen deposition in liver tissues, with partial disruption of lobule structure and microcirculation), S3 (extensive collagen deposition in liver tissues, with substantial disruption of lobule structure and microcirculation), and S4 (development of cirrhosis, with heavy collagen deposition, complete disruption of lobule structure, and severe impairment of microcirculation). Patients were grouped as no fibrosis (S0), fibrosis (S1-S2), and significant fibrosis (S3-S4). For the 160 patients without liver biopsy, they were categorized based on liver stiffness measurement (LSM) value: no fibrosis (F0: LSM<7.3 kPa), fibrosis (F1-F2: LSM 7.3-12.4 kPa), and significant fibrosis (F3-F4: LSM>12.4 kPa). Demographic data (age, gender) and laboratory indicators (alanine transaminase, aspartate transaminase, gamma-glutamyl transferase, alkaline phosphatase, alpha-fetoprotein, platelet count) were collected to calculate the fibrosis-4 index (FIB-4) and aspartate aminotransferase-to-platelet ratio index (APRI). Serum LMWK-Fc and α-Gal antibodies were measured and compared across the groups, and their correlation with fibrosis severity was analyzed. The receiver operating characteristic (ROC) curve was used to assess the predictive value of serum LMWK-Fc and α-Gal antibody levels for hepatic fibrosis. RESULTS:Among the 160 patients without complete liver biopsy, serum α-Gal antibody and LMWK-Fc levels increased progressively from the no fibrosis group to the significant fibrosis group, with statistically significant differences (P<0.05). Among the 115 patients with liver biopsy, serum LMWK-Fc levels were significantly higher in the fibrosis group and the significant fibrosis groups compared with the no fibrosis group, and α-Gal antibody levels were significantly higher in the significant fibrosis group compared with the no fibrosis group and the fibrosis group (P<0.001, P=0.032, respectively). Univariate and multivariate linear regression analyses showed that hepatic fibrosis was correlated with gender and LMWK-Fc levels (both P<0.05), but not with age, α-Gal antibody levels, FIB-4, or APRI (all P>0.05). CONCLUSIONS:The expression levels of serum LMWK-Fc and α-Gal antibodies vary across different stages of hepatic fibrosis, suggesting a potential association with fibrosis progression. LMWK-Fc levels have a certain predictive value for the diagnosis of hepatic fibrosis.

HBV-miR-3 is encoded by HBV and takes part in pathogenesis of HBV-related liver disease. Whether HBV-miR-3 has a relationship with HBV replication and is predictive of PegIFN-α treatment response is still unknown. HBV-miR-3 quantification is based on qRT-PCR. The relationship of HBV-miR-3 and HBV replication, and predictive value of HBV-miR-3 were evaluated in a cohort of 650 HBeAg positive patients from a multi-center, randomized phase III clinical trial for the study of PegIFN-a2b. HBV-miR-3 is significantly positively related to HBVDNA, HBVpgRNA, HBeAg and HBsAg at baseline and at all the different time points during PegIFN-α treatment. Both univariate regression analyses and multivariate logistic regression analyses showed HBV-miR-3 is a predictor of HBeAg seroconversion in the patients treated with PegIFN-α at weeks of 0, 12, and 24. 70.0% of patients with HBV-miR-3 < 3log at week 12 achieved HBeAg seroconversion, otherwise, with HBV-miR-3 > 6log at week 12 no patient obtained HBeAg seroconversion. Conbination of HBV-miR-3 and HBeAg is more strongly predictive of HBeAg seroconversion (83.64%) at week 12. HBV-miR-3 is new biomarker for HBV replication and positively correlated to HBV replication. HBV-miR-3 is also an early predictor of HBeAg seroconversion in the patients treated with PegIFN-α.

Background: This study aimed to identify the factors that influence voriconazole (VCZ) plasma concentrations and optimize the doses of VCZ in patients with end-stage liver disease (ESLD). Methods: Patients with ESLD who received a VCZ maintenance dose of 100 mg twice daily (group A, n = 57) or the VCZ maintenance dose of 50 mg twice daily (group B, n = 37), orally or intravenously, were enrolled in this study. Trough plasma concentrations (C min ) of VCZ between 1 and 5 mg/L were considered within the therapeutic target range. Results: The VCZ C min was determined in 94 patients with ESLD. The VCZ C min of patients in group A was remarkably higher than those in group B (4.85 ± 2.53 mg/L vs 2.75 ± 1.40 mg/L; P < 0.001). Compared with group A, fewer patients in group B had VCZ C min outside the therapeutic target (23/57 vs. 6/37, P = 0.021). Univariate and multivariate analyses suggested that both body weight and Model for End-Stage Liver Disease scores were closely associated with the VCZ C min in group B. Conclusions: These data indicate that dose optimization based on body weight and Model for End-Stage Liver Disease scores is required to strike an efficacy–safety balance during VCZ treatment in patients with ESLD.

Background and Aims:Tenofovir amibufenamide (TMF) is a novel phosphoramidated prodrug of tenofovir with noninferior efficacy and better bone and renal safety to tenofovir disoproxil fumarate (TDF) in 48 weeks of treatment. Here, we update 96-week comparison results. Methods:Patients with chronic hepatitis B were assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks. The virological suppression was defined as HBV DNA levels <20 IU/mL at week 96. Safety was evaluated thoroughly with focusing on bone, renal, and metabolic parameters. Results:Virological suppression rates at week 96 were similar between TMF and TDF group in both HBeAg-positive and HBeAg-negative populations. Noninferior efficacy was maintained in the pooled population, while it was first achieved in patients with HBV DNA ≥7 or 8 log10 IU/mL at baseline. Non-indexed estimated glomerular filtration rate for renal safety assessment was adopted, while a smaller decline of which was seen in the TMF group than in the TDF group (p=0.01). For bone mineral density, patients receiving TMF displayed significantly lower reduction levels in the densities of spine, hip, and femur neck at week 96 than those receiving TDF. In addition, the lipid parameters were stable after week 48 in all groups while weight change still showed the opposite trend. Conclusions:TMF maintained similar efficacy at week 96 compared with TDF with continued superior bone and renal safety profiles (NCT03903796).

Background and Aim HBV DNA can be reduced using antiviral drugs in patients with chronic hepatitis B (CHB); however, the rate of HBeAg seroconversion remains low. A clinical trial was conducted to assess the efficacy and safety of a de novo designed liposome-based nanoparticle lipopeptide vaccine, epsilon PA-44, for CHB. Approach and Results A two-stage phase 2 trial, which included a 76-week, randomized, double-blind, placebo-controlled trial (stage 1) and a 68-week open-label extension (stage 2), was conducted in 15 centers across China (Clinicaltrials.gov No. NCT00869778). In stage 1, 360 human leukocyte antigen A2 (HLA-A2)-positive and HBeAg-positive patients were randomly and equally distributed to receive six subcutaneous injections of 600 mu g or 900 mu g epsilon PA-44 or placebo at week 0, 4, 8, 12, 20, and 28. In stage 2, 183 patients received extended 900 mu g epsilon PA-44, and 26 patients were observed for relapse without further treatment. The primary endpoint was the percentage of patients with HBeAg seroconversion at week 76. At week 76, patients receiving 900 mu g epsilon PA-44 achieved significantly higher HBeAg seroconversion rate (38.8%) versus placebo (20.2%) (95% CI, 6.9-29.6%; p = 0.002). With a combined endpoint of HBeAg seroconversion, alanine aminotransferase normalization and HBV DNA < 2,000 IU/mL, both 900 mu g (18.1%) and 600 mu g (14.3%), resulted in significantly higher rate versus placebo (5.0%) (p = 0.002 and p = 0.02, respectively) at week 76. In stage 2, none (0 of 20) of 900 mu g epsilon PA-44-treated patients experienced serologic relapse. The safety profile of epsilon PA-44 was comparable to that of placebo. Conclusions Among HLA-A2-positive patients with progressive CHB, a finite duration of 900 mu g epsilon PA-44 monotherapy resulted in significantly higher HBeAg seroconversion rate than placebo and sustained off-treatment effect. A phase 3 trial is ongoing (ChiCTR2100043708).

This prospective observational study aimed to clinically describe voriconazole administrations and trough concentrations in patients with Child–Pugh class C and to investigate the variability of trough concentration. A total of 144 voriconazole trough concentrations from 43 Child–Pugh class C patients were analyzed. The majority of patients (62.8%) received adjustments. The repeated measured trough concentration was higher than the first and final ones generally (median, 4.33 vs. 2.99, 3.90 mg/L). Eight patients with ideal initial concentrations later got supratherapeutic with no adjusted daily dose, implying accumulation. There was a significant difference in concentrations among the six groups by daily dose (p = 0.006). The bivariate correlation analysis showed that sex, CYP2C19 genotyping, daily dose, prothrombin time activity, international normalized ratio, platelet, and Model for end-stage liver disease score were significant factors for concentration. Subsequently, the first four factors mentioned above entered into a stepwise multiple linear regression model (variance inflation factor <5), implying that CYP2C19 testing makes sense for precision medicine of Child–Pugh class C cirrhosis patients. The equation fits well and explains the 34.8% variety of concentrations (R2 = 0.348). In conclusion, it needs more cautious administration clinically due to no recommendation for Child–Pugh class C patients in the medication label. The adjustment of the administration regimen should be mainly based on the results of repeated therapeutic drug monitoring.

BACKGROUND AND AIMS:Tenofovir alafenamide (TAF) has similar efficacy to tenofovir disoproxil fumarate (TDF) but with improved renal and bone safety in chronic hepatitis B patients studied outside of China. We report 3-year results from two phase 3 studies with TAF in China (Clinicaltrials.gov: NCT02836249 and NCT02836236).METHODS:Chinese hepatitis B e antigen (HBeAg)-positive and -negative chronic hepatitis B patients with viremia and elevated alanine aminotransferase were randomized 2:1 to TAF or TDF treatment groups and treated in a double-blind fashion for 144 weeks (3 years). Efficacy responses were assessed by individual study while safety was assessed by a pooled analysis.RESULTS:Of the 334 patients (180 HBeAg-positive and 154 HBeAg-negative) randomized and treated, baseline characteristics were similar between groups. The overall mean age was 38 years and 73% were male. The mean HBV DNA was 6.4 log10 IU/mL. The median alanine aminotransferase was 88 U/L, and 37% had a history of antiviral use. At week 144, the proportion with HBV DNA <29 IU/mL was similar among the two groups, with TAF at 83% vs. TDF at 79%, and TAF at 93% vs. TDF at 92% for the HBeAg-positive and -negative patients, respectively. In each study, higher proportions of TAF than TDF patients showed normalized alanine aminotransferase (via the American Association for the Study of Liver Diseases and the China criteria) and showed loss of HBsAg; meanwhile, the HBeAg seroconversion rates were similar. Treatment was well-tolerated among the TAF patients, who showed a smaller median decline in creatinine clearance (-0.4 vs. -3.2 mL/min; p=0.014) and less percentage change in bone mineral density vs. TDF at hip (-0.95% vs. -1.93%) and spine (+0.35% vs. -1.40%).CONCLUSIONS:In chronic hepatitis B patients from China, TAF treatment provided efficacy similar to TDF but with better renal and bone safety at 3 years.

Aims Voriconazole is a broad‐spectrum antifungal agent for the treatment of invasive fungal infections. There is limited information about the pharmacokinetics and appropriate dosage of voriconazole in patients with liver dysfunction. This study aimed to explore the relationship between voriconazole trough concentration (C trough ) and toxicity, identify the factors significantly associated with voriconazole pharmacokinetic parameters and propose an optimised voriconazole dosing regimen for patients with liver dysfunction. Methods The study prospectively enrolled 51 patients with 272 voriconazole concentrations. Receiver operating characteristic curves were used to explore the relationship between voriconazole C trough and toxicity. The pharmacokinetic data was analysed with nonlinear mixed‐effects method. Dosing simulations stratified by total bilirubin (TBIL, TBIL‐1: TBIL < 51 μmol/L; TBIL‐2: 51 μmol/L ≤ TBIL < 171 μmol/L; TBIL‐3: TBIL ≥ 171 μmol/L) were performed. Results Receiver operating characteristic curve analysis revealed that voriconazole C trough of ≤ 5.1 mg/L were associated with significantly lower the incidence of adverse events. A 1‐compartment pharmacokinetic model with first‐order absorption and elimination was used to describe the data. Population pharmacokinetic parameters of clearance, volume of distribution and oral bioavailability were 0.88 L/h, 148.8 L and 88.4%, respectively. Voriconazole clearance was significantly associated with TBIL and platelet count. The volume of distribution increased with body weight. Patients with TBIL‐1 could be treated with a loading dose of 400 mg every 12 hours (q12h) for first day, followed by a maintenance dose of 100 mg q12h administered orally or intravenously. TBIL‐2 and TBIL‐3 patients could be treated with a loading dose of 200 mg q12h and maintenance doses of 50 mg q12h or 100 mg once daily and 50 mg once daily orally or intravenously, respectively. Conclusions Lower doses and longer dosing intervals should be considered for patients with liver dysfunction. TBIL‐based dosing regimens provide a practical strategy for achieving voriconazole therapeutic range and therefore maximizing treatment outcomes.

SummaryBackgroundTenofovir amibufenamide (TMF) can provide more efficient delivery than tenofovir disoproxil fumarate (TDF).AimTo compare the efficacy and safety of TMF and TDF for 48 weeks in patients with chronic hepatitis B (CHB).MethodsWe performed a randomised, double‐blind, non‐inferiority study at 49 sites in China. Patients with CHB were assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo. The primary efficacy endpoint was the proportion of patients with hepatitis B virus (HBV) DNA less than 20 IU/mL at week 48. We also assessed safety, particularly bone, renal and metabolic abnormalities.ResultsWe randomised 1002 eligible patients. The baseline characteristics were well balanced between groups. After a median 48 weeks of treatment, the non‐inferiority criterion was met in all analysis sets. In the HBeAg‐positive population, 50.2% of patients receiving TMF and 53.7% receiving TDF achieved HBV DNA less than 20 IU/mL. In the HBeAg‐negative population, 88.9% and 87.8%, respectively, achieved HBV DNA less than 20 IU/mL in the TMF and TDF groups. Patients receiving TMF had significantly less decrease in bone mineral density at both hip (P < 0.001) and spine (P < 0.001), and a smaller increase in serum creatinine at week 48 (P < 0.05). Other safety results were similar between groups.ConclusionTMF was non‐inferior to TDF in terms of anti‐HBV efficacy and showed better bone and renal safety. (NCT03903796).

We read with great interest the letter by Janapala et al., 2020Janapala R.N. Patel J. Belfaqeeh O. Alhashmi A. Pourmand A. Novaferon, treatment in COVID-19 patients.Int J Infect Dis. 2020; (Available online 25 November 2020 In Press)https://doi.org/10.1016/j.ijid.2020.11.180Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar about our study of Novaferon as a potential antiviral drug in a randomized trial conducted in February, 2020 (Zheng et al., 2020aZheng F. Zhou Y. Zhou Z. Ye F. Huang B. Huang Y. et al.SARS-CoV-2 clearance in COVID-19 patients with Novaferon treatment: a randomized, open-label, parallel-group trial.Int J Infect Dis. 2020; 99: 84-91https://doi.org/10.1016/j.ijid.2020.07.053Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). The main points raised by these authors are addressed below. Aerosolized interferon-α (IFNα) treatment of respiratory viral infections has been generally practiced and recommended for COVID-19 treatment in China. The recommended dose of IFNα is 5 × 106 IU twice daily by inhalation, which equals a daily dose of 100 μg IFNα (1 × 107 IU daily, relative activity 1 × 108 IU/mg). As a mutant of IFNα with enhanced antiviral potency, Novaferon by aerosolized administration was thus considered a potential treatment for COVID-19. In addition, up to 40 μg Novaferon by daily injection has been applied in cancer patients and was well tolerated in a phase I trial (available at the official website of Chinese National Medicinal Products Admiration). The inhaled dose of 20 μg Novaferon twice daily (40 μg daily) for treatment of COVID-19 was determined accordingly. Our trial in early February paralleled the lopinavir/ritonavir trial by Cao et al., 2020Cao B. Wang Y. Wen D. Liu W. Wang J. Fan G. et al.A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19.N Engl J Med. 2020; 382: 1787-1799https://doi.org/10.1056/NEJMoa2001282Crossref PubMed Scopus (3751) Google Scholar in late January. At that time, nobody was able to predict the effect of lopinavir/ritonavir on COVID-19. Lopinavir/ritonavir remained a recommended standard-of-care antiviral drug for COVID-19 in China from January until the results of the RECOVERY trial of lopinavir/ritonavir were released (RECOVERY Collaborative Group, 2020RECOVERY Collaborative Group Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial.Lancet. 2020; 396: 1345-1352https://doi.org/10.1016/S0140-6736(20)32013-4Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar). It was rational to propose lopinavir/ritonavir as the control in our trial. Because of lack of experience, early medical interventions for COVID-19 needed to be adjustable by physicians. It was inadequate to fix the Novaferon treatment course at 7 days. Although the small sample size prevented us from stratifying the participants with regard to the actual duration of Novaferon treatment, all enrolled participants were strictly randomized into the three observation arms. The rates of viral clearance on day 6 of treatment and the time to viral clearance basically excluded the systemic impact of the slightly different treatment courses on the individual participants, and minimized bias due to the 7–10 days of Novaferon treatment. We agree with Janapala et al. that as 95% of participants in our study had moderate COVID-19, caution should be taken in extending the results to patients with severe COVID-19. As the median time to viral clearance in the Novaferon group and the lopinavir/ritonavir group was 4 days compared with 7 days in the Novaferon plus lopinavir/ritonavir group, we stated that both Novaferon groups with or without the combination of lopinavir/ritonavir exhibited a similar extent of viral clearance enhancement in comparison with the lopinavir/ritonavir group. The dynamic changes of viral loads in COVID-19 were related to the time of symptom onset and the disease severity (Zheng et al., 2020bZheng S. Fan J. Yu F. Feng B. Lou B. Zou Q. et al.Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January–March 2020: retrospective cohort study.BMJ. 2020; 369: 1-8https://doi.org/10.1136/bmj.m1443Crossref Scopus (1035) Google Scholar). It would be valuable to stratify patients on the basis of the time from symptom onset to the time of treatment in larger COVID-19 studies. Currently, several toxicity grading scales are applied in clinical studies. The World Health Organization toxicity grading scale referred in our article is given in World Health Organization, 1979World Health Organization WHO Handbook for Reporting Results of Cancer Treatment. WHO offset Publication No. 48. World Health Organization, Geneva1979https://apps.who.int/iris/handle/10665/37200Google Scholar. This work was supported by the National Science and Technology Major Project (2017ZX10202201, 2017ZX10202203), the National Key Research and Development Program of China (No. 2016YFD0500301), the Natural Science Foundation of Hunan Province of China (2018JJ2452) and Specialized Science and Technology Project of Hunan Province of China (2020SK3013).