ABSTRACT
BACKGROUND: The efficacy of different nucleos(t)ide analogs in the treatment of chronic hepatitis B virus (CHB) with severe acute exacerbation (SAE) remained unclear. Thus, this study aimed to compare the short-term efficacy of tenofovir disoproxil fumarate (TDF) and entecavir (ETV) in patients having CHB with SAE. METHODS: We analyzed consecutive patients with treatment-naive CHB receiving TDF (nâ =â 36) or ETV (nâ =â 65) for SAE. The primary endpoint was overall mortality or receipt of liver transplantation (LT) by 24 weeks. The secondary endpoints are the comparison of ETV vs. TDF influences on renal function and virological and biochemical responses at 4, 12, 24, and 48 weeks. RESULTS: The baseline characteristics were comparable between the two groups. By 24 weeks, 8 (22%) patients in the TDF group and 10 (15%) patients in the ETV group had either died (nâ =â 15) or received LT (nâ =â 3) ( P â =â 0.367). Cox-regression multivariate analysis revealed age ( P â =â 0.003), baseline international normalized ratio of prothrombin time ( Pâ =â 0.024), and early presence of hepatic encephalopathy ( P â =â 0.003) as independent factors associated with mortality or LT. The two groups of patients achieved comparable biochemical and virological responses at 48 weeks. No significant difference was found in the estimated glomerular filtration rate (eGFR) between the TDF and the ETV groups. However, a significant reduction in the eGFR at 48 weeks, as compared with the baseline, was found in each group. CONCLUSION: TDF and ETV achieved similar short-term clinical outcomes and treatment responses in CHB patients with SAE.
Subject(s)
Antiviral Agents , Guanine , Hepatitis B, Chronic , Tenofovir , Humans , Guanine/analogs & derivatives , Guanine/therapeutic use , Guanine/adverse effects , Female , Male , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/complications , Hepatitis B, Chronic/mortality , Tenofovir/therapeutic use , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Middle Aged , Adult , Treatment Outcome , Liver Transplantation , Retrospective Studies , Disease Progression , Severity of Illness Index , Glomerular Filtration Rate/drug effects , DNA, Viral/blood , Viral Load , Time Factors , Hepatitis B virus/drug effects , Hepatitis B virus/genetics , Proportional Hazards ModelsABSTRACT
Different antiviral treatments for chronic hepatitis B (CHB) have been known to have different metabolic effects. This study aimed to reveal whether tenofovir alafenamide (TAF)-induced dyslipidemia and its associated outcomes are significant. This study utilized 15-year historical cohort including patients with CHB in Korea and consisted of two parts: the single-antiviral and switch-antiviral cohorts. In the single-antiviral cohort, patients were divided into four groups (entecavir [ETV]-only, tenofovir disoproxil fumarate [TDF]-only, TAF-only, and non-antiviral). Propensity score matching (PSM) and linear regression model were sequentially applied to compare metabolic profiles and estimated atherosclerotic cardiovascular disease (ASCVD) risks longitudinally. In the switch-antiviral cohort, pairwise analyses were conducted in patients who switched NAs to TAF or from TAF. In the single-antiviral cohort, body weight and statin use showed significant differences between groups before PSM, but well-balanced after PSM. Changes in total cholesterol were significantly different between groups (-2.57 mg/dL/year in the TDF-only group and +2.88 mg/dL/year in the TAF-only group; p = 0.002 and p = 0.02, respectively). In the TDF-only group, HDL cholesterol decreased as well (-0.55 mg/dL/year; p < 0.001). The TAF-only group had the greatest increase in ASCVD risk, followed by the TDF-only group and the non-antiviral group. In the switch-antiviral cohort, patients who switched from TDF to TAF had a higher total cholesterol after switching (+9.4 mg/dL/year) than before switching (-1.0 mg/dL/year; p = 0.047). Sensitivity analysis on data with an observation period set to a maximum of 3 years for NA treatment showed consistent results on total cholesterol (-2.96 mg/dL/year in the TDF-only group and +3.09 mg/dL/year in the TAF-only group; p = 0.001 and p = 0.005, respectively). Another sensitivity analysis conducted on statin-treated patients revealed no significant change in cholesterol and ASCVD risk. TAF was associated with increased total cholesterol, whereas TDF was associated with decreased total and HDL cholesterol. Both TAF and TDF were associated with increased ASCVD risks, and statin use might mitigate these risks.
Subject(s)
Antiviral Agents , Cardiovascular Diseases , Hepatitis B, Chronic , Tenofovir , Humans , Male , Hepatitis B, Chronic/drug therapy , Female , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Tenofovir/therapeutic use , Tenofovir/adverse effects , Tenofovir/analogs & derivatives , Middle Aged , Adult , Republic of Korea/epidemiology , Dyslipidemias/chemically induced , Dyslipidemias/epidemiology , Cohort Studies , Guanine/analogs & derivatives , Guanine/therapeutic use , Guanine/adverse effects , AlanineABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Antiviral therapy can alleviate liver fibrosis in chronic hepatitis B, but it has a limited effect on advanced liver fibrosis/cirrhosis. Traditional Chinese medicine (TCM), particularly FuZheng HuaYu (FZHY) tablet, appears to have an antifibrotic effect, but its improving resolution of hepatitis b virus (HBV) -associated advanced fibrosis and experienced anti-viral treatment has not been investigated. AIM OF THE STUDY: To observe the safety and efficacy of adjunctive FZHY on the HBV-associated cirrhosis patients who received 2 years of entecavir but still with advanced fibrosis. METHODS: An open-label, multicentre, single arm trial. 251 patients were included and treated with TCM consisted of FZHY tablets 1.6 g and granules, three times a day in addition to entecavir 0.5 mg daily for an additional 48 weeks. Primary outcome was regression of fibrosis (the proportion of patients with a 1-point decrease in the Ishak liver fibrosis score from baseline to week 48). RESULTS: Fibrosis regression occurred in 94 of 184 patients with paired liver biopsy (51.09%, 95% CI: 43.9ï½58.0). In 132 compensated cirrhosis patients (Ishak score ≥5), 56.06% (74/132, 95% CI: 47.5ï½64.2) showed fibrosis regression and reached the goal of 54% (15% more than entecavir mono-therapy). 10 patients occurred adverse reaction, most of them were mild, and all recovered or achieved remission. CONCLUSIONS: The combination therapy of FZHY, TCM granules and ETV could regress the liver fibrosis in the patients with HBV cirrhosis, who experienced 2 years of ETV treatment, and it is safe and well tolerated.
Subject(s)
Guanine , Hepatitis B, Chronic , Antiviral Agents/adverse effects , Drugs, Chinese Herbal , Guanine/adverse effects , Guanine/analogs & derivatives , Hepatitis B virus , Hepatitis B, Chronic/drug therapy , Humans , Liver Cirrhosis/drug therapy , Liver Cirrhosis/pathology , Tablets , Treatment OutcomeSubject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Guanine/adverse effects , Guanine/analogs & derivatives , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Tenofovir/adverse effects , Tenofovir/therapeutic useABSTRACT
BACKGROUND AND AIMS: Entecavir (ETV) and tenofovir alafenamide (TAF) are the preferred agents in patients with predisposing factors for nephrotoxicity, but no studies to date have directly compared the renal safety of the two antiviral agents. Hence, we compared the risk of kidney function decline among patients with treatment-naïve chronic hepatitis B (CHB) treated with ETV or TAF. METHODS: This study included 1988 patients with treatment-naïve CHB who were treated with ETV (n = 1839) or TAF (n = 149) between 2007 and 2020 for ETV and between 2017 and 2020 for TAF. The primary outcome was chronic kidney disease (CKD) progression, defined as an increase in CKD stage by at least one stage for at least three consecutive months. RESULTS: A 1:1 propensity score match yielded 149 patients in each treatment group. The mean estimated glomerular filtration rate (eGFR) was 100.6 ml/min/1.73 m2 vs. 101.3 ml/min/1.73 m2 in the ETV and TAF groups respectively. A total of 61 patients developed a progression in CKD stage ≥ 1, of which 47 and 14 patients were from the ETV- and TAF-treated groups respectively (19.9 vs. 5.1 per 1000 person-years; p < .001). The risk of progression in CKD stage ≥1 was significantly higher in patients treated with ETV, even when adjusted for potential confounders (adjusted hazard ratio 4.05; 95% CI 2.14-7.68; p < .001). CONCLUSIONS: ETV was associated with a higher risk of kidney function decline than TAF in patients with treatment-naïve CHB. Therefore, further prospective randomized studies are needed.
Subject(s)
Alanine , Guanine , Hepatitis B, Chronic , Kidney Diseases , Tenofovir , Alanine/adverse effects , Antiviral Agents/adverse effects , Guanine/adverse effects , Guanine/analogs & derivatives , Hepatitis B, Chronic/drug therapy , Humans , Kidney Diseases/epidemiology , Risk Assessment , Tenofovir/adverse effects , Tenofovir/analogs & derivatives , Treatment OutcomeABSTRACT
Soluble immune checkpoint molecules are emerging novel mediators of immune regulation. However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-naïve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3 years). Of the 16 proteins, soluble inducible T-cell co-stimulator (≥ 164.71 pg/mL; p = 0.014), soluble programmed cell death-1 (sPD-1) (≤ 447.27 pg/mL; p = 0.031), soluble CD40 (≤ 493.68 pg/mL; p = 0.032), and soluble herpes virus entry mediator (≤ 2470.83 pg/mL; p = 0.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level ≤ 447.27 pg/mL (p = 0.014; hazard ratio [HR], 4.537) and α-fetoprotein level ≥ 6.4 ng/mL (p = 0.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment.
Subject(s)
Antiviral Agents/therapeutic use , Carcinoma, Hepatocellular/prevention & control , Guanine/analogs & derivatives , Hepatitis B, Chronic/drug therapy , Liver Neoplasms/prevention & control , Nucleosides/therapeutic use , Programmed Cell Death 1 Receptor/blood , Adult , Aged , Biomarkers/blood , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/virology , Female , Fluoroimmunoassay , Guanine/adverse effects , Guanine/therapeutic use , Hepatitis B, Chronic/blood , Hepatitis B, Chronic/diagnosis , Hepatitis B, Chronic/virology , Humans , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/virology , Male , Middle Aged , Predictive Value of Tests , Time Factors , Treatment Outcome , Young AdultABSTRACT
PURPOSE: TRC102, a small-molecule base-excision repair inhibitor, potentiates the cytotoxicity of pemetrexed and reverses resistance by binding to chemotherapy-induced abasic sites in DNA. We conducted a phase I clinical trial combining pemetrexed and TRC102 with cisplatin-radiation in stage III nonsquamous non-small cell lung cancer (NS-NSCLC). PATIENTS AND METHODS: Fifteen patients were enrolled from 2015 to 2019. The primary objective was to determine the dose-limiting toxicity and maximum tolerated dose of TRC102 in combination with pemetrexed, cisplatin, and radiotherapy. Secondary objectives were to assess toxicity, tumor response, and progression-free survival at 6 months. Based on our preclinical experiments, pemetrexed-TRC102 was given on day 1, and cisplatin/radiotherapy was initiated on day 3. This schedule was duplicated in the second cycle. After completion, two additional cycles of pemetrexed-cisplatin were given. Toxicities were assessed using NCI CTACAE versions 4/5. RESULTS: The median age was 69 years (45-79) with the median follow-up of 25.7 months (range, 7.9-47.4). No dose-limiting toxicities and no grade 5 toxicity were seen. Hematologic and gastrointestinal toxicities were the most common side effects. No clinical radiation pneumonitis was seen. Of 15 evaluable patients, three had complete response (20%), and 12 had partial response (80%). The 6-month progression-free survival was 80%, and the 2-year overall survival was 83%. CONCLUSIONS: Pemetrexed-TRC102 combined with cisplatin/radiotherapy in NS-NSCLC is safe and well tolerated. The recommended phase II dose is 200 mg TRC102 along with cisplatin-pemetrexed. No additional safety signal was seen beyond the expected CRT risks. A phase II trial, integrating post-CRT immunotherapy with this aggressive DNA-damaging regimen, is warranted.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/radiotherapy , Cisplatin , DNA Repair , Glutamates/adverse effects , Guanine/adverse effects , Humans , Lung Neoplasms/drug therapy , Pemetrexed/adverse effects , Platinum/therapeutic useABSTRACT
Of the antiviral agents currently available to patients with chronic hepatitis B (CHB), entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are 2 of 3 first-line agents.1-3 Given the well-known renal and bone toxicity associated with TDF,4 major international hepatitis B virus treatment guidelines recommend ETV over TDF in patients with predisposing factors to kidney function decline.1-3 However, as evidenced by recent studies, nephrotoxicity of antiviral agents is still an issue under debate.5-7 Therefore, we investigated the differences in the risk of kidney function decline in patients with treatment-naive CHB who were treated with ETV or TDF.
Subject(s)
Hepatitis B, Chronic , Antiviral Agents/adverse effects , Guanine/adverse effects , Guanine/analogs & derivatives , Hepatitis B virus , Hepatitis B, Chronic/drug therapy , Humans , Kidney , Retrospective Studies , Tenofovir/adverse effects , Treatment OutcomeABSTRACT
Entecavir (ETV) is widely used in the treatment of hepatitis B, but there are only a few reports about entecavir-associated thrombocytopenia, and it is considered as an immediate response and inappropriate to continue the treatment with other nucleoside analogues. Now, we report the third case, and this case was delayed response and we switched to treatment with tenofovir (TDF). There was a 66-year-old female who was infected with hepatitis B virus (HBV). Her platelet count decreased from 111*109/L to 3*109/L and was prone to gum bleeding and skin ecchymosis after she received ETV treatment for 88 days. As a treatment option, ETV was replaced by TDF immediately, frequent platelets transfusions and thrombopoietin were applied for several days, daily prednisone of 50 mg was concomitantly taken, and then platelet count improved after 10 days. She was diagnosed with entecavir-associated thrombocytopenia after analysis of the temporal relationship and exclusion of other causes of thrombocytopenia by blood and bone marrow examinations. Our case suggested that the platelet count should be monitored regularly in patients during ETV treatment, and it may be a feasible option to choose TDF to maintain antiviral treatment when entecavir-associated thrombocytopenia occurs.
Subject(s)
Drug Monitoring/methods , Guanine/analogs & derivatives , Hepatitis B/drug therapy , Platelet Count/methods , Platelet Transfusion/methods , Prednisone/administration & dosage , Thrombocytopenia , Aged , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Drug Substitution/methods , Female , Glucocorticoids/administration & dosage , Guanine/administration & dosage , Guanine/adverse effects , Humans , Tenofovir/administration & dosage , Thrombocytopenia/blood , Thrombocytopenia/chemically induced , Thrombocytopenia/physiopathology , Thrombocytopenia/therapy , Treatment OutcomeABSTRACT
BACKGROUND: It is controversial whether entecavir or tenofovir differs in reducing hepatocellular carcinoma (HCC) risk. We aimed to compare the efficacy of entecavir and tenofovir in reducing HCC risk in chronic hepatitis B (CHB) patients. METHODS: This retrospective study included 607 nucleos(t)ide naive CHB patients who had received entecavir or tenofovir. Patients who developed HCC during the first 12 months of therapy were excluded. Cumulative HCC incidences at years 2, 3, 4, 5 and 10 were compared between entecavir and tenofovir groups. Factors associated with HCC were determined by univariate and multivariate analyses. RESULTS: Nineteen (3.1%) patients developed HCC, 12 (4.8%) in entecavir group and 7 (1.9%) in tenofovir group (P = .045). In the entire cohort, cumulative HCC incidences at years 2, 3, 4, 5 and 10 were 1.8%, 2.9%, 4.4%, 5.2% and 9.9% in entecavir group, and 0.6%, 2.4%, 2.4%, 2.4% and 3.7% in tenofovir group, respectively (log-rank P = .130). In multivariate analysis, age ≥50 years, cirrhosis, decompensated cirrhosis, high GGT and low platelet levels were associated with HCC in the entire cohort. In advanced fibrosis/cirrhosis cohort, cumulative HCC incidences at years 2, 3, 4, 5 and 10 were 4.6%, 7.1%, 8.6%, 12.1% and 15.5% in entecavir group, and 1.8%, 5.6%, 5.6%, 5.6% and 8.5% in tenofovir group, respectively (log-rank P = .267). In multivariate analysis, age ≥50 years, decompensated cirrhosis, high GGT and low platelet levels were associated with HCC in the advanced fibrosis/cirrhosis cohort. CONCLUSION: Entecavir and tenofovir are similarly effective in reducing HCC risk in CHB patients.
Subject(s)
Antiviral Agents/therapeutic use , Carcinoma, Hepatocellular/prevention & control , Guanine/analogs & derivatives , Hepatitis B, Chronic/drug therapy , Liver Neoplasms/prevention & control , Tenofovir/therapeutic use , Aged , Aged, 80 and over , Antiviral Agents/adverse effects , Carcinoma, Hepatocellular/etiology , Female , Guanine/adverse effects , Guanine/therapeutic use , Hepatitis B, Chronic/complications , Humans , Liver Cirrhosis/drug therapy , Liver Neoplasms/etiology , Male , Middle Aged , Retrospective Studies , Risk Factors , Tenofovir/adverse effects , Turkey/epidemiologyABSTRACT
INTRODUCTION: Aspirin may reduce the risk of chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) in patients receiving antiviral treatment. We aimed to investigate the impact of aspirin on reducing HCC risk in patients treated with first-line oral nucleos(t)ide analogs (NAs; entecavir and/or tenofovir disoproxil fumarate). METHODS: We conducted a territorywide, retrospective cohort study in NA-treated CHB patients between 2000 and 2018 from the electronic healthcare data repository in Hong Kong. Subjects were classified into aspirin users for at least 90 days during NA treatment (aspirin group) or no aspirin or any other antiplatelet use during follow-up period (no aspirin group). Incidence rates of HCC and gastrointestinal bleeding (GIB) in 2 groups with propensity score matching with 1:3 ratio. RESULTS: Of 35,111 NA-treated CHB patients of mean age of 53.0 years and 61.6% men, sixty-nine (4.0%) and 1,488 (4.5%) developed HCC at a median (interquartile range) of 2.7 (1.4-4.8) years and 3.2 (1.8-6.0) years in the aspirin group and no aspirin group, respectively. A duration-dependent association between aspirin and the risk of HCC was observed (subhazard ratio [sHR] 3 months-2 years: 0.65; 95% confidence interval [CI] 0.47-0.92; sHR 2-5 years: 0.63; 95% CI 0.43-0.94; sHR from ≥5 years: 0.41; 95% CI 0.18-0.91). Patients who took aspirin for ≤2 years had significantly higher risk of GIB (sHR: 1.73, 95% CI 1.07-2.79) than those not receiving aspirin. The risk of GIB started declining with the longer use of aspirin and becoming insignificant for ≥5 years' use (sHR: 0.79, 95% CI 0.19-3.21). DISCUSSION: Long-term aspirin use is associated with a lower risk of HCC in a duration-dependent manner in NA-treated CHB patients without a significant increase in the risk of gastrointestinal adverse effects.
Subject(s)
Antiviral Agents/administration & dosage , Aspirin/administration & dosage , Carcinoma, Hepatocellular/epidemiology , Gastrointestinal Hemorrhage/epidemiology , Hepatitis B, Chronic/drug therapy , Liver Neoplasms/epidemiology , Adult , Aged , Alanine/administration & dosage , Alanine/adverse effects , Antiviral Agents/adverse effects , Aspirin/adverse effects , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/prevention & control , Carcinoma, Hepatocellular/virology , Drug Therapy, Combination/adverse effects , Drug Therapy, Combination/methods , Female , Follow-Up Studies , Gastrointestinal Hemorrhage/chemically induced , Guanine/administration & dosage , Guanine/adverse effects , Guanine/analogs & derivatives , Hepatitis B, Chronic/pathology , Hong Kong/epidemiology , Humans , Incidence , Liver Neoplasms/pathology , Liver Neoplasms/prevention & control , Liver Neoplasms/virology , Male , Middle Aged , Retrospective Studies , Tenofovir/administration & dosage , Tenofovir/adverse effects , Tenofovir/analogs & derivativesABSTRACT
It remains controversial whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) is associated with different clinical outcomes for chronic hepatitis B (CHB). This study aimed to compare the long-term risk of ETV versus TDF on hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) in CHB patients from a large multi-institutional database in Taiwan. From 2011 to 2018, a total of 21,222 CHB patients receiving ETV or TDF were screened for eligibility. Patients with coinfection, preexisting cancer and less than 6 months of follow-up were excluded. Finally, 7248 patients (5348 and 1900 in the ETV and TDF groups, respectively) were linked to the National Cancer Registry database for the development of HCC or ICC. Propensity score matching (PSM) (2:1) analysis was used to adjust for baseline differences. The HCC incidence between two groups was not different in the entire population (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.66-1.02, p = 0.078) and in the PSM population (HR 0.83; 95% CI 0.65-1.06, p = 0.129). Among decompensated cirrhotic patients, a lower risk of HCC was observed in TDF group than in ETV group (HR 0.54; 95% CI 0.30-0.98, p = 0.043, PSM model). There were no differences between ETV and TDF groups in the ICC incidence (HR 1.84; 95% CI 0.54-6.29, p = 0.330 in the entire population and HR 1.04; 95% CI 0.31-3.52, p = 0.954 in the PSM population, respectively). In conclusion, treatment with ETV and TDF showed a comparable long-term risk of HCC and ICC in CHB patients.
Subject(s)
Carcinoma, Hepatocellular , Guanine/analogs & derivatives , Hepatitis B virus , Hepatitis B, Chronic , Liver Neoplasms , Tenofovir/administration & dosage , Adult , Aged , Carcinoma, Hepatocellular/epidemiology , Carcinoma, Hepatocellular/etiology , Female , Follow-Up Studies , Guanine/administration & dosage , Guanine/adverse effects , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/epidemiology , Humans , Incidence , Liver Neoplasms/epidemiology , Liver Neoplasms/etiology , Male , Middle Aged , Risk Factors , Time FactorsABSTRACT
Sulfur mustard (SM), a chemical warfare agent, is a strong alkylating compound that readily reacts with numerous biomolecules. The goal of the present work was to define and validate new biomarkers of exposure to SM that could be easily accessible in urine or plasma. Because investigations using SM are prohibited by the Organisation for the Prohibition of Chemical Weapons, we worked with 2-chloroethyl ethyl sulfide (CEES), a monofunctional analog of SM. We developed an ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) approach to the conjugate of CEES to glutathione and two of its metabolites: the cysteine and the N-acetylcysteine conjugates. The N7-guanine adduct of CEES (N7Gua-CEES) was also targeted. After synthesizing the specific biomarkers, a solid-phase extraction protocol and a UHPLC-MS/MS method with isotopic dilution were optimized. We were able to quantify N7Gua-CEES in the DNA of HaCaT keratinocytes and of explants of human skin exposed to CEES. N7Gua-CEES was also detected in the culture medium of these two models, together with the glutathione and the cysteine conjugates. In contrast, the N-acetylcysteine conjugate was not detected. The method was then applied to plasma from mice cutaneously exposed to CEES. All four markers could be detected. Our present results thus validate both the analytical technique and the biological relevance of new, easily quantifiable biomarkers of exposure to CEES. Because CEES behaves very similar to SM, the results are promising for application to this toxic of interest.
Subject(s)
Chemical Warfare Agents/adverse effects , Glutathione/analogs & derivatives , Guanine/analogs & derivatives , Mustard Gas/analogs & derivatives , Animals , Cell Line , Chemical Warfare Agents/analysis , Chromatography, High Pressure Liquid/methods , Environmental Exposure/adverse effects , Glutathione/adverse effects , Guanine/adverse effects , Humans , Keratinocytes/drug effects , Mice , Mustard Gas/adverse effects , Mustard Gas/analysis , Skin/drug effects , Tandem Mass Spectrometry/methods , Toxicity Tests/methodsABSTRACT
O6-carboxymethylguanine (O6-CMG) is a mutagenic DNA adduct that forms at increased levels when people eat meat. It has been studied as a potential initiating event in colorectal carcinogenesis. It can arise from alkylation of guanine in DNA by electrophilic degradation products of N-nitroso compounds. There is significant data regarding biochemical and cellular process, including DNA repair and translesion DNA synthesis that control O6-CMG accumulation, persistence, and mutagenicity. Mutation spectra arising from the adduct closely resemble common mutations in colorectal cancer; however, gaps remain in understanding the biochemical processes that regulate how and where the damage persists in the genome. Addressing such questions relies on advances in chemistry such as synthesis approaches and bioanalytical methods. Results of research in this area help advance our understanding of the toxicological relevance of O6-CMG-modified DNA. Further attention should focus on understanding how a combination of genetic and environmental factors control its biological persistence and how this information can be used as a basis of biomoniotoring and prevention efforts to help mitigate colon cancer risk.
Subject(s)
Colorectal Neoplasms/metabolism , DNA Adducts/metabolism , DNA, Neoplasm/metabolism , Guanine/analogs & derivatives , Colorectal Neoplasms/pathology , DNA Adducts/adverse effects , Guanine/adverse effects , Guanine/metabolism , Humans , Red Meat/adverse effectsABSTRACT
Background/Aims: Clinical equivalence of generic antiviral agents for chronic hepatitis B (CHB) has not been demonstrated, particularly in cases with previous antiviral resistance. Entecavir 1 mg is prescribed frequently as a mono- or combination therapy in antiviral-resistant CHB patients. This study evaluated the efficacy and safety of switching to generic entecavir 1 mg (Baracle®) in CHB patients taking brand-name entecavir 1 mg (Baraclude®) alone or in combination with other nucleotide analogs after the development of antiviral resistance. Methods: This study was a single-arm prospective study. The primary endpoint was undetectable HBV DNA (<20 IU/mL) at 12 months after switching treatment. The biochemical and serologic responses, virologic breakthrough, and antiviral resistance rates were also evaluated. Results: Forty CHB patients with undetectable HBV DNA through the brand-name entecavir 1 mg treatment as a mono- or combination therapy after developing antiviral resistance to nucleos(t)ide analogs were enrolled in this study. No significant difference in the HBV DNA non-detection rate was observed between the baseline and 12 months after switching therapy (p=0.324). Furthermore, non-inferiority of the generic entecavir 1 mg to the brand-name entecavir 1 mg with 10% margin in maintaining undetectable HBV DNA was demonstrated (95% CI -2.80 to 8.20%). Similarly, no difference in the biochemical response rate was observed after switching therapy. Serum hepatitis B e antigen loss was observed in 12.5%. No virologic breakthrough was reported. Conclusions: Generic entecavir 1 mg is a reasonable alternative to the brand-name entecavir 1 mg in antiviral-resistant CHB patients with viral suppression.
Subject(s)
Antiviral Agents , DNA, Viral , Drug Resistance, Viral , Guanine/analogs & derivatives , Hepatitis B virus , Hepatitis B, Chronic , Adult , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , DNA, Viral/blood , Drug Substitution , Drugs, Generic/adverse effects , Drugs, Generic/pharmacokinetics , Drugs, Generic/therapeutic use , Female , Guanine/adverse effects , Guanine/pharmacokinetics , Guanine/therapeutic use , Hepatitis B virus/drug effects , Hepatitis B virus/genetics , Hepatitis B virus/isolation & purification , Hepatitis B, Chronic/blood , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/virology , Humans , Male , Middle Aged , Prospective Studies , Therapeutic Equivalency , Treatment OutcomeABSTRACT
BACKGROUND: It is unclear whether tenofovir disoproxil fumarate and entecavir differ in their association with risk of hepatocellular carcinoma in patients with chronic hepatitis B, and previous meta-analyses have shown conflicting conclusions with substantial heterogeneity. We aimed to analyse the updated data and elucidate the source of heterogeneity. METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane library for relevant studies with time-to-event data for incident hepatocellular carcinoma occurring in patients with chronic hepatitis B who received tenofovir disoproxil fumarate or entecavir monotherapy with follow-up of at least 1 year. Studies published between Jan 1, 2006, and April 17, 2020, and abstracts from international conferences in 2018 and 2019 were included. We pooled covariate adjusted hazard ratios (HRs) for hepatocellular carcinoma using a random-effects model, assessed heterogeneity among included studies using the I2 statistic and Cochran's Q test, and identified the source of heterogeneity using prespecified subgroup analyses. This study is registered with PROSPERO, ID CRD42020176513. FINDINGS: 31 studies involving 119â053 patients were analysed. The 5-year cumulative incidence of hepatocellular carcinoma was 5·97% (95% CI 5·81-6·13, 28 studies) for entecavir and 3·06% (2·86-3·26, 13 studies) for tenofovir disoproxil fumarate in studies with unmatched populations (p<0·0001). For all eight studies matched by propensity score, the 5-year cumulative incidence was 3·44% (95% CI 3·08-3·80) for entecavir and 3·39% (2·94-3·83) for tenofovir disoproxil fumarate (p=0·87). Analysis of 14 comparative studies with covariate adjustment found that tenofovir disoproxil fumarate and entecavir had similar risk of hepatocellular carcinoma (primary outcome); adjusted HR 0·88, 95% CI 0·73-1·07; p=0·20), although heterogeneity was significant (I2=56·4%, p=0·0038). In a subgroup analysis for hospital-based clinical cohorts, there was no difference in hepatocellular carcinoma incidence between the two regimens (adjusted HR 1·03, 95% CI 0·88-1·21; I2=0%). However, tenofovir disoproxil fumarate was associated with a lower risk of hepatocellular carcinoma compared with entecavir in administrative database research (adjusted HR 0·67, 0·59-0·76; I2=0%). INTERPRETATION: Our study found no significant difference between tenofovir disoproxil fumarate and entecavir in their association with incident hepatocellular carcinoma. We suggest that treatment should be guided by patient tolerability and affordability rather than whether one drug is more effective than the other. FUNDING: Supported in part by E-DA Hospital (EDAHP 106008; EDAHP 103046).
Subject(s)
Antiviral Agents/administration & dosage , Carcinoma, Hepatocellular/epidemiology , Guanine/analogs & derivatives , Hepatitis B, Chronic/drug therapy , Liver Neoplasms/epidemiology , Tenofovir/administration & dosage , Antiviral Agents/adverse effects , Guanine/administration & dosage , Guanine/adverse effects , Humans , Incidence , Tenofovir/adverse effectsABSTRACT
BACKGROUND: Hepatitis B infection is a significant worldwide health issue, predispose to the development of liver cirrhosis and hepatocellular carcinoma. Entecavir is a potent oral antiviral agent of high genetic barrier for the treatment of chronic hepatitis B infection. Cutaneous adverse reaction associated with entecavir has rarely been reported in literature. As our knowledge, this case was the first case reported on entecavir induced lichenoid drug eruption. CASE PRESENTATION: 55 year old gentlemen presented with generalised pruritic erythematous rash on trunk and extremities. Six weeks prior to his consultation, antiviral agent entecavir was commenced for his chronic hepatitis B infection. Skin biopsy revealed acanthosis and focal lymphocytes with moderate perivascular lymphocyte infiltration. Skin condition recovered completely after caesation of offending drug and short course of oral corticosteroids. CONCLUSION: This case highlight the awareness of clinicians on the spectrum of cutaneous drug reaction related to entecavir therapy.
Subject(s)
Exanthema , Hepatitis B, Chronic , Liver Neoplasms , Antiviral Agents/adverse effects , Exanthema/chemically induced , Guanine/adverse effects , Guanine/analogs & derivatives , Hepatitis B virus , Hepatitis B, Chronic/drug therapy , Humans , Liver Neoplasms/drug therapy , Middle Aged , Treatment OutcomeABSTRACT
Conflicting results have been reported regarding which of entecavir (ETV) or tenofovir disoproxil fumarate (TDF) is associated with better outcomes. Chronic hepatitis B patients who started ETV or TDF between 2010 and 2015 were analysed. The primary outcomes were hepatocellular carcinoma and death and transplantation. The impact of the treatment on the primary outcomes was analysed using Cox proportional hazards models in the entire and propensity score-matched cohorts. A total of 404 patients (180 and 224 in the ETV and TDF groups, respectively) were analysed. The median duration of follow-up was significantly longer in the ETV group (64.0 vs. 49.1 months; P < 0.001). Virological response (79.4% vs. 68.4%; P = 0.018) and sustained virological suppression (59.7% vs. 45.2%; P = 0.005) were significantly higher in the TDF group. TDF was associated with lower hepatocellular carcinoma [hazard ratio (HR) 0.31, 95% confidence interval (95% CI), 0.12â0.79; P = 0.014]; however, statistical significance was not reached after adjusting sustained virological suppression using propensity score matching (HR 0.36, 95% CI 0.12â1.14; P = 0.08). Death and transplantation was comparable. In conclusion, the impact of TDF on the lower hepatocellular carcinoma was blunted after adjusting sustained virological suppression. Further comparison in a larger number of patients who show sustained virological suppression over a longer period of time is needed.
Subject(s)
Antiviral Agents/adverse effects , Carcinoma, Hepatocellular/mortality , Guanine/analogs & derivatives , Hepatitis B virus/drug effects , Hepatitis B, Chronic/drug therapy , Liver Transplantation/mortality , Tenofovir/adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Hepatocellular/chemically induced , Carcinoma, Hepatocellular/epidemiology , Carcinoma, Hepatocellular/virology , DNA, Viral , Female , Follow-Up Studies , Guanine/adverse effects , Hepatitis B, Chronic/virology , Humans , Liver Neoplasms/chemically induced , Liver Neoplasms/epidemiology , Liver Neoplasms/mortality , Liver Neoplasms/virology , Liver Transplantation/statistics & numerical data , Male , Middle Aged , Retrospective Studies , Survival Rate , Treatment Outcome , Viral Load , Young AdultABSTRACT
AIMS: Tenofovir (TDF) is an antiviral drug with potential risk of kidney injury. The study is aimed at comparing the incidence of acute kidney injury (AKI) between TDF and entecavir (ETV) treatment in hepatitis B virus- (HBV-) related acute on chronic liver failure (ACLF). METHODS: Treatment-naive patients with HBV-related ACLF were included. Propensity score matching was used to balance the baseline characteristics between ETV and TDF groups. The risk of AKI and the efficacy of TDF and ETV were compared. RESULTS: A total of 95 cases with HBV-related ACLF were included in this study, with 74.74% of male and a mean age of 47.01 ± 14.71 years. The antiviral therapy was initiated within 2 days after admission, with 39 cases on the TDF group and 56 on the ETV group. Patients in the TDF group had higher AST, hemoglobin, and serum sodium levels and lower MELD-Na score. After propensity matching, 39 cases of TDF and 39 of ETV were included in the final analysis. No difference was found in the changes of creatinine and cystatin C from baseline to 4 weeks after treatment between ETV and TDF groups. AKI was developed in 1 (2.56%) patient in the ETV group and 2 (5.13%) in the TDF group within one month (P = 0.556). Survival analysis revealed no significant difference in the 6-month mortality between the two groups (P = 0.813). Cox analysis showed that the type of antiviral drug or the development of AKI was not an independent risk factor for the outcomes. CONCLUSIONS: Compared to ETV, TDF did not increase the risk of AKI nor the mortality in patients with HBV-related ACLF in the short time.
Subject(s)
Acute Kidney Injury/chemically induced , Acute-On-Chronic Liver Failure/complications , Acute-On-Chronic Liver Failure/drug therapy , Antiviral Agents/adverse effects , Guanine/analogs & derivatives , Hepatitis B/complications , Hepatitis B/drug therapy , Tenofovir/adverse effects , Acute Kidney Injury/complications , Acute Kidney Injury/epidemiology , Acute-On-Chronic Liver Failure/epidemiology , Adult , Female , Guanine/adverse effects , Hepatitis B/epidemiology , Humans , Male , Middle Aged , Retrospective Studies , Risk Factors , Treatment OutcomeABSTRACT
BACKGROUND: Limited data exist regarding tenofovir disoproxil fumarate (TDF) safety and effectiveness in chronic hepatitis B virus-infected (CHB) patients with renal impairment (RI). AIMS: To compare real-world data on renal safety and effectiveness of TDF vs entecavir (ETV) in CHB patients with moderate-to-severe RI. METHODS: Retrospective, non-interventional, cohort study analysing medical records for TDF/ETV-treated CHB patients (54 European centres). Included patients experienced moderate-to-severe RI (creatinine clearance 20-60 mL/min [Cockcroft-Gault]) either before TDF/ETV initiation ('before' subgroup [baseline = treatment initiation]) or after TDF/ETV initiation ('after' subgroup [baseline = first RI occurrence]). The primary objective was TDF safety, particularly renal-related adverse events of special interest (AESI). TDF and ETV safety and effectiveness were compared and multivariate analyses were performed using inverse probability treatment weighting. RESULTS: 'Before' subgroup included 107 TDF- and 91 ETV-treated patients; 'after' subgroup included 212 TDF- and 77 ETV-treated patients. Mean baseline creatinine clearance was higher for TDF- vs ETV-treated patients (both subgroups). Median follow-up was 3.1 years (both treatments). AESI were more frequent with TDF vs ETV ('before': 18.7% vs 8.8%; 'after': 9.9% vs 3.9%); however, differences were not significant by multivariate analysis. Only TDF-treated patients experienced renal tubular dysfunction (6.5% 'before'; 1.9% 'after') as well as renal adverse events leading to treatment discontinuation (8.4% 'before'; 7.1% 'after'). Effectiveness was similar between treatments. CONCLUSIONS: Overall safety was similar for TDF vs ETV (both subgroups). Given that renal tubular dysfunction occurred with TDF and not with ETV, renal safety concerns may be greater with TDF in CHB patients with RI.