Normal Alanine Aminotransferase Research Articles

Safety, pharmacodynamics, and antiviral activity of selgantolimod in viremic patients with chronic hepatitis B virus infection

Novel finite therapies for chronic hepatitis B (CHB) are needed, since lifelong treatment is usually required with current available oral antivirals. This phase II study (NCT03615066) evaluated the safety, pharmacodynamics, and antiviral activity of selgantolimod (a Toll-like receptor 8 agonist [TLR8]) with tenofovir alafenamide (TAF). Viremic patients with CHB not receiving treatment were stratified by HBeAg status and randomized 2:2:1 to TAF 25mg/day with selgantolimod 3mg orally once weekly (QW), selgantolimod 1.5mg QW, or placebo. Combination therapy continued until week (W)24, followed by TAF monotherapy until W48; patients then discontinued TAF and were followed until W96 (treatment-free follow-up [TFFU] period). The primary efficacy endpoint was the proportion with ≥1 log10 IU/ml HBsAg decline at W24. Sixty-seven patients received study drug; 27 were followed during TFFU. Nausea, headache, vomiting, fatigue, and dizziness were the most common adverse events. Most adverse events were grade 1. Alanine aminotransferase flares were not observed up to W48. Four patients experienced alanine aminotransferase and hepatitis flares during TFFU; all had HBV DNA increases. Selgantolimod increased serum cytokines and chemokines and redistributed several circulating immune cell subsets. No patients achieved the primary efficacy endpoint. Mean HBsAg changes were-0.12,-0.16, and-0.12 log10 IU/ml in the selgantolimod 3mg, selgantolimod 1.5mg, and placebo groups, respectively, at W48; HBV DNA declined in all groups by ≥2 log10 IU/ml as early as W2, with all groups rebounding to baseline during TFFU. No HBsAg or HBeAg loss or seroconversion was observed throughout TFFU. Selgantolimod up to 3mg was safe and well tolerated. Pharmacodynamics and antiviral activity in viremic patients support continued study of selgantolimod in combination CHB therapies. Novel therapeutics for chronic HBV infection are needed to achieve a functional cure. In this study, we confirmed the safety and tolerability of selgantolimod (formerly GS-9688, a TLR8) when administered with tenofovir alafenamide over 24 weeks in viremic patients with chronic HBV infection. Overall, declines in HBsAg levels with selgantolimod treatment were modest; subgroup analysis indicated that patients with alanine aminotransferase levels greater than the upper limit of normal had significantly greater declines compared to those with normal alanine aminotransferase levels (-0.20 vs. -0.03 log10 IU/ml; p <0.001). These findings suggest a potential differential response to selgantolimod based on patients' baseline HBV-specific immune response, which should be considered in future investigations characterizing the underlying mechanisms of selgantolimod treatment and in HBV cure studies using similar immunomodulatory pathways. NCT03615066 be found at https://www.gileadclinicaltrials.com/transparency-policy/.

Liver inflammation activity in patients with autoimmune hepatitis with normal alanine aminotransferase and immunoglobulin G levels

Background and aimsNormal serum transaminases and immunoglobulin G (IgG) levels are surrogate markers for hepatic histologic disease activity in autoimmune hepatitis (AIH). This study aimed to evaluate liver inflammation in patients with AIH with normal serum alanine aminotransferase (ALT) and IgG levels. MethodsTwo hundred and five AIH patients who underwent liver biopsy in four medical centers were included. Logistic regression analysis was used to identify risk factors associated with advanced inflammation. ResultsOne hundred and thirty-one (63.9 %) AIH patients had advanced liver inflammation, and 108 (52.7 %) patients had advanced liver fibrosis. 60.0 % of patients with normal ALT and 51.7 % of patients with normal ALT and IgG had advanced inflammation. However, 76.7 % and 35.0 % of patients with or without advanced fibrosis with normal ALT had advanced inflammation, while the corresponding proportions of advanced inflammation were 78.6 % and 26.7 % in patients with normal ALT and IgG, respectively. Moreover, 81.0 % and 44.8 % of patients with and without cirrhosis with normal ALT had advanced inflammation, while the corresponding proportions were 83.3 % and 29.4 % in patients with normal ALT and IgG, respectively. Red cell distribution width (OR = 1.325, 95%CI 1.045–1.681, P = 0.020) and PT (OR = 1.514, 95%CI 1.138–2.014, P = 0.004) were independent factors associated with advanced inflammation. ConclusionsHigh proportion of advanced inflammation was found in AIH patients with normal ALT and IgG levels despite without advanced fibrosis. Although using non-invasive methods may contribute to rule out liver fibrosis in AIH patients with normal ALT and IgG levels, liver biopsy is encouraged to assess liver inflammation.

Tenofovir amibufenamide vs tenofovir alafenamide for treating chronic hepatitis B: A real-world study.

The efficacy and safety profile of tenofovir amibufenamide (TMF) in chronic hepatitis B (CHB) patients is not well-established. To compare the efficacy and safety of TMF and tenofovir alafenamide (TAF) over a 48-wk period in patients with CHB. A total of 215 subjects meeting the inclusion criteria were enrolled and divided into two groups: TMF group (n = 106) and the TAF group (n = 109). The study included a comparison of virological response (VR): Undetectable hepatitis B virus DNA levels, alanine transaminase (ALT) normalization rates, renal function parameters, and blood lipid profiles. At 24 and 48 wk, VR rates for the TMF group were 53.57% and 78.57%, respectively, compared with 48.31% and 78.65% for the TAF group (P > 0.05). The VR rates were also similar in both groups among patients with low-level viremia, both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative subgroups. The TMF cohort showed ALT normalization and renal safety profiles similar to the TAF group. There was a notable increase in total cholesterol levels in the TAF group (P = 0.045), which was not observed in the TMF group (P > 0.05). In patients with liver cirrhosis, both groups exhibited comparable VR and ALT normalization rates and renal safety profiles. However, the fibrosis 4 score at 48 wk showed a significant reduction in the TAF group as compared to the TMF group within the liver cirrhosis subgroup. Our study found TMF is as effective as TAF in treating CHB and has a comparable safety profile. However, TAF may be associated with worsening lipid profiles.

Modelling HDV kinetics under the entry inhibitor bulevirtide suggests the existence of two HDV-infected cell populations

Bulevirtide (BLV) was approved for the treatment of compensated chronic hepatitis D virus (HDV) infection in Europe in 2020. However, research into the effects of the entry inhibitor BLV on HDV-host dynamics is in its infancy. Eighteen patients with HDV under nucleos(t)ide analogue treatment for hepatitis B, with compensated cirrhosis and clinically significant portal hypertension, received BLV 2mg/day. HDV RNA, alanine aminotransferase (ALT), and hepatitis B surface antigen (HBsAg) were measured at baseline, weeks 4, 8 and every 8 weeks thereafter. A mathematical model was developed to account for HDV, HBsAg and ALT dynamics during BLV treatment. Median baseline HDV RNA, HBsAg, and ALT were 4.9 log IU/ml [IQR: 4.4-5.8], 3.7 log IU/ml [IQR: 3.4-3.9] and 106 U/L [IQR: 81-142], respectively. During therapy, patients fit into four main HDV kinetic patterns: monophasic (n= 2), biphasic (n= 10), flat-partial response (n= 4), and non-responder (n= 2). ALT normalization was achieved in 14 (78%) patients at a median of 8 weeks (range: 4-16). HBsAg remained at pre-treatment levels. Assuming that BLV completely (∼100%) blocks HDV entry, modeling indicated that two HDV-infected cell populations exist: fast HDV clearing (median t1/2= 13 days) and slow HDV clearing (median t1/2= 44 days), where the slow HDV-clearing population consisted of ∼1% of total HDV-infected cells, which could explain why most patients exhibited a non-monophasic pattern of HDV decline. Moreover, modeling explained ALT normalization without a change in HBsAg based on a non-cytolytic loss of HDV from infected cells, resulting in HDV-free HBsAg-producing cells that release ALT upon death at a substantially lower rate compared to HDV-infected cells. The entry inhibitor BLV provides a unique opportunity to understand HDV, HBsAg, ALT, and host dynamics. Mathematical modeling of hepatitis D virus (HDV) treatment with the entry inhibitor bulevirtide (BLV) provides a novel window into the dynamics of HDV RNA and alanine aminotransferase. Kinetic data from patients treated with BLV monotherapy can be explained by hepatocyte populations with different basal HDV clearance rates and non-cytolytic clearance of infected cells. While further studies are needed to test and refine the kinetic characterization described here, this study provides a new perspective on viral dynamics, which could inform evolving treatment strategies for HDV.

Incidence and predictors of elevated postpartum alanine aminotransferase in chronic hepatitis B mothers: a prospective study protocol

BackgroundThe majority of HBeAg-positive mothers with chronic hepatitis B have high levels of viremia and inactive disease with normal alanine aminotransferase (ALT) during pregnancy. In addition, postpartum disease activation and ALT flare have been reported in the range of 15 − 35%. However, the current International Association Guidelines have not provided clear recommendations and a risk-stratified monitoring schedule. Furthermore, data are lacking on the definition of normal ALT in the postpartum period in mothers with chronic hepatitis B. The clinical features and ALT flare patterns in HBeAg-positive mothers versus HBeAg-negative mothers are not fully explored. Thus, we design a cohort study to investigate the aforementioned area and generate data to assist healthcare providers in better managing mothers with hepatitis B. We aim to assess the frequency of postpartum ALT flares and predictors for such events.MethodThis study is a single-center and prospective cohort study (n = 360) that consists of two groups of patients including HBsAg-positive mothers (n = 120) and healthy mothers without HBV infection (n = 240). In HBeAg-positive mothers, antiviral therapy during late pregnancy is permitted to prevent Mother-to-child transmission (MTCT) but discontinued at delivery if there is no further indication for the treatment. Mothers are enrolled at the gestational weeks of 12–24. After delivery, both mothers and their infants will be followed up until postpartum week 24. Clinical and laboratory data are collected every 4 weeks during the study except there are no follow-up visits at the postpartum weeks 16 and 20. The primary objective is the proportion of patients with postpartum ALT flares. The secondary objectives are independent risk factors during pregnancy for predicting postpartum ALT flares and the normal range of postpartum ALT levels in healthy mothers.DiscussionThe current study focuses on the incidence of postpartum ALT flares in mothers with chronic hepatitis B including subgroup analysis based on HBeAg status. The data will have several clinical implications, such as providing evidence for an appropriate monitoring schedule in CHB mothers after delivery. Further analyses on predictors of such events may assist clinicians in identifying mothers who might develop severe postpartum ALT flares. The data generated from healthy mothers have the potential to identify the patterns of ALT changes during pregnancy and postpartum, so we can gain a better understanding of the normal range of ALT in this subpopulation.Trial Registration Number at the Chinese Clinical Trial RegistryChiCTR2200061130.

Blood manganese and non-alcoholic fatty liver disease in a high manganese exposure area in China

Background and aimsManganese (Mn) deficiency and intoxication may affect nonalcoholic fatty liver disease (NAFLD) risk differently. We aimed to explore the association between blood Mn and NAFLD in an area with high Mn exposure in drinking water.MethodsWe conducted a case–control study among 1407 patients with NAFLD and 1774 sex- and age-matched healthy controls in a physical examination population in Zhoushan hospital, Zhejiang province in China. We used the restricted cubic splines method to investigate the dose–response relationship. Logistic regression models were applied to determine the risk of NAFLD, and severity of NAFLD.ResultsThe blood Mn concentration was higher in the NAFLD group than in the control group in women (16.1 ± 6.2 μg/L vs. 14.7 ± 6.4 μg/L, P = 0.022) and men (14.5 ± 6.3 μg/L vs. 13.6 ± 6.8 μg/L, P < 0.001). We found an inverted L shape relationship between blood Mn and NAFLD in both women and men. Compared to the lowest quartile, the adjusted odds ratio (OR) and 95% confidence interval (CI) of NAFLD for the highest quartile group was 1.646(1.222,2.217), 1.494(1.082,2.061), and 3.146(1.285,7.701) for the total population, men, and women. The positive relationship was only observed in those with fibrosis-4 score < 1.30 and normal alanine transaminase. Stratified analysis showed an interaction between smoking (P = 0.073), alcohol drinking (P = 0.013), and Mn, with a more prominent effect on the NAFLD in the never-smokers (OR = 2.153, 95% CI 1.408–3.290) and drinkers (OR = 2.596, 95% CI 1.608–4.191).ConclusionHigher blood Mn is associated with an elevated NAFLD risk in the high Mn exposure areas, especially in nonsmokers and drinkers. Further studies are needed to verify this result in the areas with high Mn exposure.

Association of Liver Function Test with Severity of Dengue Fever in Suburbs of Islamabad.

This study aimed to identify the key parameters to assist the early diagnosis of Dengue Infection to prevent severe outcomes. A cross-sectional study was conducted from June 2022 to December 2022 at a tertiary care hospital. 149 patients who presented with dengue symptoms for less than 5 days were enrolled in the study. Hepatic functioning was assessed by monitoring Serum Alanine Transaminase (ALT) (normal = 7-56 IU/L), and serum Aspartate Transaminase (AST) (normal = 10-40 IU/L) levels. Abdominal ultrasound and chest X-Ray were performed, and findings were recorded. Statistical analysis was done using SPSS Version 24. 81 patients (54.36%) were found to have Classical DF, while 46 patients (45.64%) were diagnosed with DHF or DSS. Dengue fever is more common in males than in females, and it disproportionately affects those under the age of 30. Only 81 (54.63%) of the total 149 individuals developed DF, but of those, 79 (74.4%) had normal ALT levels and 2 (4.26%) had elevated ALT levels. Among the 68 patients with DHF (45.64%), 41 (87.23%) had elevated ALT, while only 23 (22.55%) had normal ALT and all 4 (8.51%) with DSS did as well. The p-value for the correlation between platelet count and elevated ALT levels is 0.007, which is statistically significant. Management of dengue disease requires close monitoring of hepatic enzyme levels, particularly ALT and AST, along with the platelet count. It will aid in reducing the severity of the dengue virus. In addition, there should be particular outdoor exposure guidelines, particularly during dengue season evenings, i.e., monsoon.

Clinical Outcomes in Patients with High-Dose Methotrexate Toxicity Treated with Vs. without Glucarpidase

Background. High-dose methotrexate (HDMTX) is a cornerstone of treatment for lymphoma and leukemia involving the central nervous system, but can cause significant toxicity, which manifests predominantly as acute kidney injury (AKI) as well as bone marrow suppression and hepatotoxicity. Glucarpidase is a recombinant bacterial enzyme that cleaves 99% of circulating MTX to inactive metabolites within 15 minutes of its administration. It is approved for use in the setting of supratherapeutic MTX levels to mitigate renal and extrarenal toxicity. Despite its potent biochemical effects, no study has rigorously examined whether glucarpidase improves clinical outcomes in patients with HDMTX toxicity compared to controls not treated with glucarpidase. This key evidence gap has led to wide variation in the use of glucarpidase across institutions. Methods. We examined the clinical outcomes of patients with HDMTX-associated AKI (HDMTX-AKI) treated with and without glucarpidase across a large multicenter cohort of 684 adults from 26 major cancer centers across the US from 2000 to 2022. HDMTX-AKI was defined as a ≥1.5-fold increase in serum creatinine (SCr) within 4 days following treatment with HDMTX. We collected data on demographics, comorbidities, medications, laboratory values, and outcomes. The primary outcome was renal recovery, defined as a return of SCr to &amp;lt;1.5-fold baseline and absence of renal replacement therapy-dependence at hospital discharge. Prespecified subgroup analyses included those treated with glucarpidase in the first 60 hours following MTX initiation, and those with AKI stage 3 (increase in SCr ≥3-fold baseline) in the first 4 days following treatment with HDMTX. Secondary outcomes included absence of neutropenia, transaminitis, and mucositis on day 7. We used multivariable logistic regression to adjust for potential confounders. Models were adjusted for age, sex, race, baseline eGFR, body mass index, hypertension, diabetes mellitus, coronary artery disease, congestive heart failure, chronic liver disease, baseline WBC count, serum albumin, and LDH, MTX dose and infusion duration, urine pH, volume of IV fluids administered, leucovorin dose, and maximum fold-change in SCr, oliguria, and receipt of concomitant nephrotoxins in the first 4 days following MTX initiation. Results. Among the 684 patients with HDMTX-AKI, 207 (30.3%) were treated with glucarpidase and 477 (69.7%) were not. All patients treated with glucarpidase received it within the first 96 hours following initiation of HDMTX. The median time from HDMTX initiation to glucarpidase receipt was 54 hours (IQR, 44-66), with 65% of the patients receiving it within 60 hours, and 85% within 72 hours. Patients treated vs. not treated with glucarpidase were similar with respect to age, sex, race, MTX dose and infusion duration, and most baseline labs, including SCr, but had high higher plasma MTX levels at 24 and 36 hours and more severe AKI ( Table). Glucarpidase receipt was associated with a 2.43-fold higher adjusted odds of renal recovery (95% CI, 1.38-4.27) compared to no glucarpidase receipt ( Figure). The magnitude of association was considerably higher when the analysis was restricted to those treated with glucarpidase in the first 60 hours (odds ratio 4.94 [95% CI, 2.42-10.06] and to those with AKI stage 3 (odds ratio 7.08 [95% CI, 2.27-22.10]) ( Figure). Glucarpidase receipt was also associated with a higher likelihood of recovery from neutropenia and normalization of alanine aminotransferase (ALT) by day 7 ( Figure). There was no significant association between glucarpidase receipt and mucositis on day 7 ( Figure). Conclusions. In the largest study to date of HDMTX-AKI and the only one, to our knowledge, to include control patients, we found that patients who received glucarpidase had considerably higher odds of renal recovery, as well as recovery from neutropenia and normalization of liver enzymes, compared to those who did not receive glucarpidase. The magnitude of association with renal recovery was particularly evident in those treated with glucarpidase in the first 60 hours and in those with AKI stage 3. Though this is an observational study with the potential for residual confounding, our data support use of glucarpidase in patients with HDMTX-AKI, particularly in the first 60 hours following initiation of MTX.

Significant histological changes are not rare in indeterminate‐phase chronic hepatitis B patients with hepatitis B e antigen‐negative and normal alanine aminotransferase levels

AbstractBackground &amp; ObjectivesThe degree of liver injury in indeterminate chronic hepatitis B (CHB) infection patients with Hepatitis B e antigen(HBeAg)‐negative and persistently normal alanine aminotransferase (PNALT) levels is yet unclear. Therefore, we aimed to assess liver histological changes in such patients by liver biopsy and explore possible predictors.MethodsOverall, 711 HBeAg‐negative CHB patients with PNALT levels who underwent liver biopsy from January 2017 to June 2022 were included in this retrospective study. The relationships between histological changes and predictors were assessed by smooth curve fitting and multivariate logistic regression analysis models. Data were also analyzed using American Association for the Study of Liver Disease (AASLD) modified alanine aminotransferase (ALT) criteria.ResultsThe proportion of significant histological changes in the indeterminate phase was higher than that in the inactive phase (53.97% vs. 41.33%). The adjusted odds ratios (aORs) of significant necroinflammation and histological changes for the indeterminate phase were 2.05 and 1.43, respectively, when compared with the inactive phase by multivariate logistic regression analyses. Significant histological changes in the‐phase were positively associated with age, ALT, Aspartate aminotransferase (AST), Hepatitis B surface antigen (HBsAg), and Hepatitis B virus (HBV) DNA levels but negatively correlated with platelet (PLT) levels. HBV DNA ≥5 log10 U/L and PLT &lt;200 × 109/L were independent predictive factors for assessing histological changes in indeterminate‐phase patients. Similar analysis findings were obtained using the two sets of modified ALT criteria.ConclusionsSignificant histological changes are not rare in indeterminate‐phase CHB patients and are higher than in the inactive phase, regardless of the ALT criteria. Histological investigation is strongly suggested for intermediate stage patients with HBV DNA &gt;5 log10 U/L or PLT &lt;200 × 109/L and antiviral therapy should be considered for such patients.

Air pollution impede ALT normalization in chronic hepatitis B patients treated with nucleotide/nucleoside analogues.

Biochemical response is an important prognostic indicator in chronic hepatitis B (CHB) patients receiving nucleotide/nucleoside analogues (NAs). However, the effects of air pollution in alanine aminotransferase (ALT) normalization remain elusive. This longitudinal study recruited 80 hepatitis B e antigen-negative CHB patients who received NAs. ALT levels were measured during the first year of anti-hepatitis B virus therapy. Normal ALT levels were defined as <19 U/L for females and <30 U/L for males, and the risk factors associated with ALT abnormalities were analyzed. The daily estimations of air pollutants (particulate matter ≤2.5 µm in diameter (PM2.5), nitrogen dioxide, ozone (O3), and benzene) were aggregated into the mean estimation for the previous month based on the date of recruitment (baseline) and 1 year later. Sixteen patients (20.0%) had a baseline ALT > 40 U/L; overall, 41 (51.6%) had an abnormal ALT (≥19 U/L for females and ≥ 30 U/L for males). After 1 year of NA therapy, 75 patients (93.8%) had undetectable hepatitis B virus DNA levels. Mean post-treatment ALT levels were significantly lower than mean pretreatment levels (21.3 vs 30.0 U/L, respectively; P < .001). The proportion of patients with a normal ALT was also significantly higher after versus before treatment (71.2% vs 51.2%, respectively; P = .001). The strongest factors associated with ALT abnormality after 1 year of NA treatment were body mass index (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.05-1.54; P = .01) and ozone level (OR, 1.11; 95% CI, 1.02-1.22; P = .02). Among hepatitis B e antigen-negative CHB patients with relatively low viral loads, 1 year of NA treatment improved ALT levels after the adjustment for confounding factors and increased the proportion of patients with normal ALT levels. Air pollution affects the efficacy of ALT normalization.

Increased spine bone density in patients with chronic hepatitis B switched to tenofovir alafenamide: A prospective, multinational study.

Data on patients switched to tenofovir alafenamide (TAF) from nucleos(t)ide analogues (NUCs) other than tenofovir disoproxil fumarate are limited. To assess the treatment and renal/bone safety outcomes following the switch to TAF. We prospectively enrolled adult patients with chronic hepatitis B (CHB) who switched from any NUC to TAF at 14 centres in Japan, Korea, Taiwan and the U.S. Study outcomes were viral suppression (VR; HBV DNA < 20 IU/mL), biochemical response (BR; alanine aminotransferase normalisation), and changes in estimated glomerular filtration rate (eGFR) and T-scores (L-spine) by bone absorptiometry by 24 months after switch to TAF. We enrolled 270 eligible patients. Mean age was 58.1; 58.2% were male; 12.2% had cirrhosis and 73.3% previously received entecavir monotherapy. VR rate increased significantly from 95.2% to 98.8% by 24 months after the switch to TAF (p = 0.014). Between the switch and 24 months later, the mean spine T-score improved significantly from -1.43 ± 1.36 to -1.17 ± 1.38 (p < 0.0001), while there was no significant change in mean eGFR (88.4 ± 16.9-89.5 ± 16.3 mL/min/1.73 m2 , p = 0.13). On multivariable analysis adjusted for age, sex, baseline spine T-score and prior TDF or adefovir dipivoxil use, male sex was significantly associated with lower risk of worsening spine T-score (odds ratio: 0.29, p = 0.020), while age was significantly associated with a higher risk of worsening chronic kidney disease stage (OR: 1.07, p = 0.019). At 24 months after the switch to TAF, VR rates and spine bone density improved significantly while renal function remained stable.

Comparative effectiveness of seven interventions for chronic hepatitis D: a systematic review and network meta-analysis of randomized controlled trials

ObjectiveTo compare the effectiveness of seven major interventions [Bulevirtide (BLV), Interferon (IFN), Nucleoside analogs (NAs), BLV + IFN, BLV + NAs, IFN + NAs, and Placebo] to treat chronic hepatitis D.MethodsWe followed PRISMA-NMA guidelines, searched databases (Cochrane Library, PubMed, EMBASE, and Web Of Science) for eligible randomized controlled trials (RCTs), and applied STATA17.0 software to execute the meta-analysis.ResultsWe included 14 randomized controlled trials (814 patients) comparing seven different interventions. The results of the network meta-analysis showed that: ① Sustained virological response (after 24 weeks of follow-up): Four intervention groups (BLV + IFN, IFN alone, IFN + NAs, and NAs alone) were effective (relative risk (RR) = 13.30, 95% confidence interval (Cl) [1.68,105.32], RR = 12.13, 95% Cl [1.46,101.04], RR = 5.05, 95% Cl [1.68,15.19], RR = 5.03, 95% Cl [1.66,15.20]), with no statistically significant differences between the four groups. The top three in probability rankings were: BLV + NAs, BLV + IFN, and BLV alone (surface under the cumulative ranking curve (SUCRA) = 86.8%, 80.3%, and 48.4%; ② Sustained biochemical response (after 24 weeks of follow-up): BLV + IFN and IFN were superior to BLV (RR = 14.71, 95% Cl [1.14,189.07], RR = 16.67, 95% Cl [1.39,199.52]). The top three were BLV alone, BLV + NAs, and BLV + IFN (SUCRA = 86.9%,81.2%, and 64.3%). ③ Histological response: NAs were superior to BLV (RR = 2.08, 95% Cl [1.10,3.93]), whereas the difference between other treatment regimens was not statistically significant, and the top three in the probability ranking were BLV alone, BLV + NAs, and BLV + IFN (SUCRA = 75.6%, 75.6%, and 61.8%).ConclusionsIFN, IFN + BLV, and IFN + NAs were effective in clearing HDV RNA and normalizing alanine aminotransferase levels; however, IFN and IFN + NAs had a high rate of viral relapse at 24 weeks post-treatment follow-up. There was no additional benefit of adding NAs to IFN therapy for chronic hepatitis D; however, the combination of IFN + BLV significantly improved short-term HDV RNA clearance, which showed strong synergistic effects. The seven regimens included in the study did not contribute significantly to liver histological improvement. Therefore, the IFN + BLV combination has the most potential as a treatment option to improve the long-term prognosis or even cure chronic hepatitis D.Trial registrationThis systematic evaluation and meta-analysis was registered with PROSPERO under the registration number: CRD42022314544.)

ANTIVIRAL RESPONSE OF DRUGS USED AGAINST HBV PATIENTS OF KHYBER PAKHTUNKHWA, PAKISTAN

Hepatitis B virus is an ample cause of end-stage liver diseases and hepatocellular carcinoma. Effective treatment in high-risk countries such as Pakistan can help delay or prevent these consequences.The existing study aims to evaluate the response rates of antiviral drugs tenofovir and entecavir (6-48 months) based on different clinical parameters. Sera collected from HBV patients (43) subjected to DNA extraction, followed by real-time PCR detection. Furthermore, ICT was performed to detect HBs-Ag and ELISA for HBe-Ag. Response rate after 6 months of tenofovir treatments showed 100% normal creatinine and ultrasound and ALT (50%) and while in the case of entecavir, each ALT and ultrasound normalization (66.7%), showed creatinine (100%). The fatty liver was reported 50% and 33.3% after tenofovir and entecavir treatment, respectively. The response after 12 months of treatment with tenofovir showed normalization of ALT and ultrasound (84.6%), bilirubin and creatinine normalization (92.3%), and fatty liver (15.4%). Whereas bilirubin and creatinine levels showed (100%) normal, ALT and ultrasound normalization (80%) with 20% of patients having congenital left lobe of the liver after entecavir. Patients profiles after 24 months of tenofovir treatment showed normal ALT and ultrasound (85.7%), bilirubin (100%), and renal impairment observed in patients (14.3%). The 24 months entecavir treatment showed significant improvement in various clinical parameters normalization with 100% such as ALT, bilirubin, and creatinine in all patients. The efficacy of entecavir showed a significant response as compared to Tenofovir. Furthermore, nucleoside/nucleotide analogues enhanced its efficacy with longer treatment duration.

Effectiveness and Safety of Tenofovir Alafenamide in Treatment-Naïve and Treatment-Experienced Patients with Chronic Hepatitis B: Results of a Real-World Study from China

Background: Tenofovir alafenamide (TAF) has been effective against naïve patients with chronic hepatitis B (CHB) in phase 3 clinical trials. However, its real-world data are still limited. Objectives: This study aimed to investigate the effectiveness and safety of TAF in real-life situations in treatment-naïve (TN) and treatment-experienced (TE) CHB patients in China. Methods: This retrospective study enrolled TAF-treated patients between January 2019 and October 2020 at the outpatient clinic of West China Hospital. The primary endpoint was the rates of virologic response (VR), and the secondary endpoints were the proportion of normal alanine aminotransferase (ALT) and quantitative hepatitis B surface antigen (qHBsAg) levels. Safety endpoints comprised serum lipid profiles, changes in estimated glomerular filtration rate (eGFR), and serum creatinine (Scr). Results: A total of 161 TAF-treated patients were enrolled, including 49 TN patients and 112 TE patients. In the TN group, the VR rate at week 96 was 91.7% (22/24), and the proportion of normal ALT at week 96 was 95.8% (23/24). In the TE group, the VR rate at week 96 was 97.2% (69/71), and the proportion of normal ALT at week 96 was 90.1% (64/71). Serum qHBsAg levels decreased from 2930 to 1292 IU/mL in the TN group and 1158 to 533IU/mL in the TE group during 96 weeks of treatment (P = 0.05). For patients in the TN and TE groups, when compared to baseline measurements, serum creatinine increased (+7.91 vs. +6.62 mL/min/1.73 m2, P = 0.52) while eGFR decreased (-11.46 vs. -10.90 µmol/L, P = 0.82) at week 96. Simultaneously, triglycerides (TG) (+ 0.39 vs. + 0.31 mmol/L, P = 0.32), total cholesterol (TC) (+0.65 vs. +0.52 mmol/L, P = 0.02), and low-density lipoprotein cholesterol (LDL-C) (+0.25 vs. +0.25 mmol/L, P = 0.60) increased over time. Conclusions: TAF was highly effective in TN and TE CHB patients. However, there are potential risks in eGFR decrease and a continuous increase in lipidemia with the prolongation of medication time.

Gray zone of hepatitis B virus infection.

A substantial proportion of patients with chronic hepatitis B (CHB) do not fall into any of the defined phases and are considered to be in the "gray zone" or "indeterminate phase." Most of the current clinical practice guidelines have no recommendations for antiviral treatment for them. However, the gray zone CHB patients with significant hepatitis B virus levels (>2000 IU/mL) and persistently normal alanine aminotransferase (ALT) levels have a significantly high risk of hepatic inflammation, fibrosis, and hepatocellular carcinoma. The molecular, clinical, and economic data that we have reviewed collectively in this article provide support for simplification of treatment initiation strategies that incorporate broader treatment of adult patients with CHB in the gray zone (hepatitis B virus [HBV] DNA ≥2000 IU/mL), regardless of ALT levels.

The Effect of Molecular Adsorbent Recirculating System in Patients With Liver Failure: A Case Series of 44 Patients

Liver failure is associated with a high mortality rate, with many patients requiring transplant for definitive treatment. The Molecular Adsorbent Recirculating System (MARS) is a nonbiologic system that provides extracorporeal support.Literature on MARS therapy is mixed: outcomes support MARS therapy for patients with isolated acute liver failure, but data on patients with chronic disease is varied. Several case studies report success using MARS as a bridging treatment for patients awaiting transplant. The purpose of this case series is to present the outcomes of 44 patients who underwent MARS therapy forliver failure, 19 of whom used MARS therapy as a bridging therapy to transplant. This study retrospectively identified 44 patients who underwent MARS therapy for liver failure at Mayo Clinic, Jacksonville, between January 2014 and April 2021. Variables of interest included changes in laboratory markers of hepatic functioning, number and length of MARS therapy sessions, transplantation status, and mortality. Following MARS therapy, there were improvements in mean serum bilirubin, ammonia, urea, creatinine, International Normalized Ratio, alanine aminotransferase, and aspartate aminotransferase levels. Twenty-seven patients (61.36%) survived the hospital stay; 17 (38.63%) died in the hospital. The majority of surviving patients (n = 19; 73.07%) receivedliver transplant. Six did not require transplant (22.22%). All but 1 patient who received MARS as a bridging treatment to transplant survived the follow-up period (n = 18; 94.74%). Outcomes of these 44 cases suggest that MARS improves liver failure-associated laboratory parameters and may be effective therapy as a bridge to liver transplant.

Serum ribonucleotide reductase M2 is a potential biomarker for diagnosing and monitoring liver fibrosis in chronic hepatitis B patients.

It is known that ribonucleotide reductase M2 (RRM2) could be induced by hepatitis B virus (HBV) via DNA damage response. However, whether RRM2 is a potential biomarker for diagnosing and monitoring liver fibrosis in chronic hepatitis B (CHB) patients is still unclear. In this study, CHB patients from GSE84044 (a transcriptome data from GEO data set) were downloaded and RRM2 was selected as a hub gene. Interestingly, a positive correlation was found between serum RRM2 and liver fibrosis stage. The similar results were found in CHB patients with normal alanine aminotransferase (ALT). Notably, RRM2 could effectively differentiate preliminary fibrosis from advanced fibrosis in CHB patients with/without normal ALT. In addition, RRM2 had a better performance in diagnosing liver fibrosis than two commonly used noninvasive methods (aspartate aminotransferase-to-platelet ratio index and fibrosis index based on the four factors), two classic fibrotic biomarkers (hyaluronic acid and type IV collagen) as well as Mac-2 binding protein glycosylation isomer, a known serum fibrosis marker. Moreover, CHB patients with high RRM2, who were associated with advanced fibrosis, had higher expressions of immune checkpoints. Overall, serum RRM2 may be a promising biomarker for diagnosing and monitoring liver fibrosis in CHB patients.

Patients with low ALT levels are at increased risk for severe COVID-19.

Frailty is a known risk factor for many diseases, including COVID-19. However, many frail patients are undiagnosed as the diagnosis can be cumbersome. Alanine transaminase (ALT) is found not only in the liver but also in the muscle tissue, and multiple studies show that frail sarcopenic patients have lower ALT. Frail patients are at increased risk for severe COVID-19. We evaluated the association between pre-infection low ALT and the risk for severe COVID-19. We collected data regarding all subjects tested for SARS-CoV-2 between 1 March 2020 and 31 December 2021 from a national state-mandatory HMO in Israel, serving more than 1.3 million patients. Clinical and laboratory data were collected, including ALT from the year prior to infection. Severe COVID-19 was defined either as death, ICU admission, or ≥10 hospitalization days. Patients with low ALT (ALT ≤ 10 IU/l) were compared with patients with normal ALT (11-40 IU/l). Patients younger than 18 years with a diagnosis of liver disease and with ALT > 40 IU/l were excluded. During the study period, 58,961 patients tested positive for SARS-CoV-2. The patients in the low ALT group were younger (40.53 vs. 42.73, p < 0.001), less likely to be males (12.3 vs. 38.7%, p < 0.001), and had lower BMI (25.97 vs. 27.15, p < 0.001). The patients in the low ALT group had higher mortality (2.36 vs. 0.57%, p < 0.001), more ICU hospitalizations (0.49 vs. 0.41%, p = 0.47), and more prolonged hospitalizations [2.63% (95% CI 2-3.2%) vs. 0.98% (95% CI 0.86-1.1%) p < 0.001]. In multivariate logistic regression analyses, low ALT was associated with an increased risk of severe COVID-19, with increased mortality (OR 1.88, 95% CI 1.37-2.56) and prolonged hospitalization (OR 1.78, 95% CI 1.33-2.35). Low ALT level prior to infection is a significant risk factor for morbidity and mortality from COVID-19 infection. Further studies are warranted to address treatment options for this population.

Genetic variants and effect modifiers of QT interval prolongation in patients with sickle cell disease

BackgroundSickle cell disease (SCD) is a common inherited blood disorder among African Americans (AA), with premature mortality which has been associated with prolongation of the heart rate-corrected QT interval (QTc), a known risk factor for sudden cardiac death. Although numerous genetic variants have been identified as contributors to QT interval prolongation in the general population, their impact on SCD patients remains unclear. This study used an unweighted polygenic risk score (PRS) to validate the previously identified associations between SNPs and QTc interval in SCD patients, and to explore possible interactions with other factors that prolong QTc interval in AA individuals with SCD. MethodsIn SCD patients, candidate genetic variants associated with the QTc interval were genotyped. To identify any risk SNPs that may be correlated with QTc interval prolongation, linear regression was employed, and an unweighted PRS was subsequently constructed. The effect of PRS on the QTc interval was evaluated using linear regression, while stratification analysis was used to assess the influence of serum alanine transaminase (ALT), a biomarker for liver disease, on the PRS effect. We also evaluated the PRS with the two subcomponents of QTc, the QRS and JTc intervals. ResultsOut of 26 candidate SNPs, five risk SNPs were identified for QTc duration under the recessive model. For every unit increase in PRS, the QTc interval prolonged by 4.0 ms (95% CI: [2.0, 6.1]; p-value: <0.001) in the additive model and 9.4 ms in the recessive model (95% CI: [4.6, 14.1]; p-value: <0.001). Serum ALT showed a modification effect on PRS-QTc prolongation under the recessive model. In the normal ALT group, each PRS unit increased QTc interval by 11.7 ms (95% CI: [6.3, 17.1]; p-value: 2.60E-5), whereas this effect was not observed in the elevated ALT group (0.9 ms; 95% CI: [-7.0, 8.8]; p-value: 0.823). ConclusionSeveral candidate genetic variants are associated with QTc interval prolongation in SCD patients, and serum ALT acts as a modifying factor. The association of a CPS1 gene variant in both QTc and JTc duration adds to NOS1AP as evidence of involvement of the urea cycle and nitric oxide metabolism in cardiac repolarization in SCD. Larger replication studies are needed to confirm these findings and elucidate the underlying mechanisms.

Lowering the threshold of alanine aminotransferase for enhanced identification of significant hepatic injury in chronic hepatitis B patients.

The clinical and histological features of chronic hepatitis B (CHB) patients who fall into the "grey zone (GZ)" and do not fit into conventional natural phases are unclear. To explore the impact of varying the threshold of alanine aminotransferase (ALT) levels in identifying significant liver injury among GZ patients. This retrospective analysis involved a cohort of 1617 adult patients diagnosed with CHB who underwent liver biopsy. The clinical phases of CHB patients were determined based on the European Association for the Study of the Liver 2017 Clinical Practice Guidelines. GZ CHB patients were classified into four groups: GZ-A (HBeAg positive, normal ALT levels, and HBV DNA ≤ 107 IU/mL), GZ-B (HBeAg positive, elevated ALT levels, and HBV DNA < 104 or > 107 IU/mL), GZ-C (HBeAg negative, normal ALT levels, and HBV DNA ≥ 2000 IU/mL), and GZ-D (HBeAg negative, elevated ALT levels, and HBV DNA ≤ 2000 IU/mL). Significant hepatic injury (SHI) was defined as the presence of notable liver inflammation (≥ G2) and/or significant fibrosis (≥ S2). The results showed that 50.22% of patients were classified as GZ, and 63.7% of GZ patients developed SHI. The study also found that lowering the ALT treatment thresholds to the American Association for the Study of Liver Diseases 2018 treatment criteria (35 U/L for men and 25 U/L for women) can more accurately identify patients with significant liver damage in the GZ phases. In total, the proportion of patients with ALT ≤ 40 U/L who required antiviral therapy was 64.86% [(221 + 294)/794]. When we lowered the ALT treatment threshold to the new criteria (30 U/L for men and 19 U/L for women), the same outcome was revealed, and the proportion of patients with ALT ≤ 40 U/L who required antiviral therapy was 75.44% [(401 + 198)/794]. Additionally, the proportion of SHI was 49.1% in patients under 30 years old and increased to 55.3% in patients over 30 years old (P = 0.136). These findings suggest the importance of redefining the natural phases of CHB and using new ALT treatment thresholds for better diagnosis and management of CHB patients in the GZ phases.