Case report: lactic acidosis and rhabdomyolysis during telbivudine and tenofovir treatment for chronic hepatitis B.

BACKGROUND: Current treatment options for chronic hepatitis B (CHB) are pegylated interferon alpha and nucleoside analogues (NAs). NAs have relatively fewer side effects than interferon alpha, and generally well tolerated. Previously 12.9% of patients on telbivudine treatment were reported to develop severe elevation of serum creatine phosphokinase (CPK) levels, but related clinical disease, like lactic acidosis (LA) and rhabdomyolysis (RM) were rare. The pathophysiology may be mitochondrial toxicity, for the NAs inhibit not only hepatitis B virus (HBV) polymerase, but also the host mitochondrial DNA polymerase γ. As mitochondria are the main sites of oxidative phosphorylation, there will be an increase of pyruvate reduction to lactic acid and insufficient adenosine triphosphate. The accumulation of lactic acid causes LA, while lack of energy leads to cell dysfunction and mitochondria-associated disease, including RM. All five NAs, except tenofovir, have been reported causing LA and RM. Here we report the first case of CHB patients developing fatal LA and RM during telbivudine and tenofovir treatment. CASE PRESENTATION: The patient is a 51-year-old man who was hospitalized in November 2015. He had taken telbivudine regularly because of CHB. Later, tenofovir was added to antiviral treatment because of HBV resistance. Then he had myalgia, chest tightness and anorexia. The blood lactate was 12.7 mmol/L. The arterial blood gas analysis showed pH 7.25, base excess 21.1 mmol/L. CPK was 991 U/L, myoglobin was 1745 ng/ml and creatine was 83 µmol/L. Abdomen magnetic resonance revealed cirrhosis. Muscle biopsy revealed myogenic lesion with abnormality of mitochondria and fat metabolism. The patient was diagnosed with Hepatitis B envelope Antigen positive CHB, cirrhosis, LA and RM characterized by myalgia and elevated myoglobin. He was given tenofovir alone as antiviral treatment instead. After hemodialysis and 4 weeks` treatment of corticosteroids, his symptoms recovered, and blood lactate gradually returned to a normal range. CONCLUSIONS: This case shows that tenofovir may trigger muscle damage and fatal RM in combination with telbivudine treatment in CHB patients. Thus, patients receiving tenofovir and telbivudine should be closely monitored for muscular abnormalities, blood lactate level and other mitochondrial toxicity associated side effects.

A novel noninvasive index for the prediction of moderate to severe fibrosis in chronic hepatitis B patients.

BACKGROUNDS: The evaluation of liver fibrosis stages is essential for the clinical management of chronic hepatitis B (CHB). AIMS: To develop and validate a novel noninvasive index for moderate to severe fibrosis (≥S2) in CHB patients. METHODS: A total of 401 CHB patients who underwent liver biopsy were divided into the training (n = 300) and validation (n = 101) cohort. Histological severity was scored using a modified Scheuer system. Clinical and laboratory assessments were collected. RESULTS: In the training cohort, PACG, a novel index combining the quantitative hepatitis B core antibody (qAnti-HBc), platelet count (PLT), and albumin globulin ratio (A/G), presented better diagnostic performance (AUROC = 0.814) than that of APRI (0.735, p = 0.007) and FIB-4 (0.749, p = 0.014). In the validation cohort, the AUROC of the PACG, APRI, FIB-4 and Fibroscan were 0.834, 0.806, 0.791 and 0.810, respectively. More importantly, a higher and lower cutoff of PACG for predicting ≥S2 fibrosis or not had a >90% sensitivity and specificity, with a diagnostic accuracy of 85.9%. CONCLUSION: PACG is a promising noninvasive alternative to liver biopsy in CHB patients for the evaluation of moderate to severe fibrosis.

Role of quantitative hepatitis B core antibody levels in predicting significant liver inflammation in chronic hepatitis B patients with normal or near-normal alanine aminotransferase levels.

AIM: Chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) levels are not free from significant hepatic lesions. Recently, there has been an improved understanding of the clinical significance of quantitative hepatitis B core antibody levels (qAnti-HBc) during CHB management. In this cross-sectional study, we evaluated the utility of qAnti-HBc in identifying significant liver inflammation in CHB patients. METHODS: A total of 469 patients (training set, n = 363; validation set, n = 106) who underwent liver biopsy (LB) were included. The qAnti-HBc levels were quantified and the relationship between histology and serum markers was systematically analyzed. RESULTS: In the training set, qAnti-HBc levels were found to have significant diagnostic value for moderate to severe liver inflammation (≥G2) in all patients (area under the receiver operating characteristic curve [AUROC] = 0.768; 95% confidence interval [CI], 0.721-0.810; P < 0.001) and in patients with normal or near-normal ALT levels (AUROC = 0.767; 95% CI, 0.697-0.828; P < 0.001). Our novel index (AC index) for the identification of ≥G2 inflammation, which combined the qAnti-HBc and ALT levels, significantly improved diagnostic performance (AUROC = 0.813; 95% CI, 0.768-0.852) compared to the use of ALT alone (AUROC = 0.779; 95% CI, 0.732-0.821) in all patients. In the validation set, the AC index showed an improved AUROC of 0.890 (95% CI, 0.814-0.942) and 0.867 (95% CI, 0.749-0.943) in all patients and patients with normal ALT levels, respectively. CONCLUSIONS: The qAnti-HBc level predicts significant liver inflammation well, even in patients with normal or near-normal ALT levels. Compared with the conventional ALT level, the AC index is a more reliable non-invasive biomarker for significant liver inflammation in CHB patients.

Serum M2BPGi level is a novel predictive biomarker for the responses to pegylated interferon-α treatment in HBeAg-positive chronic hepatitis B patients.

Serum Mac-2-binding protein glycosylation isomer (M2BPGi) level was found to be a useful prognostic marker for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients treated with nucleoside/nucleotide analogs (NUCs) therapy, and the aim of our study is to evaluate the clinical implementation of M2BPGi level in the prediction of antiviral responses to pegylated-interferon-α (PEG-IFN-α) treatment in HBeAg-positive CHB patients. Ninety-six CHB patients who received PEG-IFN-α treatment for at least 48 weeks were recruited. The serum M2BPGi, alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), HBeAg, and HBV DNA levels at baseline, weeks 4, 12, and 24 after PEG-IFN-α treatment were determined and their associations with antiviral responses were evaluated and the virological response (VR) rate and serological response (SR) rate after 48 weeks of treatment were 65.6% and 35.4%, respectively. Baseline serum M2BPGi level was significantly different between VR and non-VR (P = 0.002) or SR and non-SR groups (P = 0.012). Multivariate analyses suggested that baseline serum M2BPGi level was independently associated with VR and SR of PEG-IFN-α treatment at week 48. The area under the ROC curve (AUC) of baseline M2BPGi was 0.682 in predicting VR, which was superior to HBsAg (AUC = 0.566) or HBV DNA (AUC = 0.567). The AUC of baseline M2BPGi in predicting SR was 0.655, which was also higher than that of HBsAg (AUC = 0.548) or HBV DNA (AUC = 0.583). These results suggested that baseline serum M2BPGi level was a novel predictor of VR and SR for PEG-IFN-α treatment in HBeAg-positive CHB patients.

Analysis of immunological mechanisms exerted by HBsAg-HBIG therapeutic vaccine combined with Adefovir in chronic hepatitis B patients.

An HBsAg-HBIG therapeutic vaccine (Yeast-derived Immune Complexes, YIC) for chronic hepatitis B (CHB) patients has undergone a series of clinical trials. The HBeAg sero-conversion rate of YIC varied from 21.9% to 14% depending on the immunization protocols from 6 to 12 injections. To analyze the immunological mechanisms exerted by 6 injections of YIC, 44 CHB patients were separately immunized with YIC, alum as adjuvant control or normal saline as blank control, with add on of antiviral drug Adefovir in all groups. Kinetic increase in Th1 and Th2 cells CD4+ T cell sub-populations with association in decrease in Treg cells and increase of Tc1 and Tc17 cells in CD8+ T cells were observed in YIC immunized group. No such changes were found in the other groups. By multifunctional analysis of cytokine profiles, significant increase of IL-2 levels was observed, both in CD4+ and CD8+ T cells in the YIC immunized group, accompanied by increase in IFN-gamma and decrease of inhibitory factors (IL-10, TGF-ß and Foxp3) in CD4+ T cells. In the alum immunized group, slight increase of IL-10, TGF-ß and Foxp3 in CD4+ T cells was found after the second injection, but decreased after more injections, suggesting that alum induced early inflammatory responses to a certain extent. Similar patterns of responses of IL-17A and TNF-α in CD8+T cells were shown between YIC and the saline group. Results indicate that add on of Adefovir, did not affect host specific immune responses.

Low Serum Hepatitis B Surface Antigen Level Predicts Compensated Cirrhosis Caused by Chronic Hepatitis B in HBeAg Positive Patients in East China.

BACKGROUNDS: Serum hepatitis B surface antigen (HBsAg) levels are associated with fibrosis in patients with chronic hepatitis B (CHB) infection. OBJECTIVES: The aim of our study was to evaluate serum HBsAg level as a biomarker for compensated cirrhosis in hepatitis B e antigen (HBeAg) positive CHB patients. PATIENTS AND METHODS: Two-hundred and one HBeAg-positive Chinese CHB patients with or without cirrhosis were enrolled in this retrospective study. Cirrhosis was diagnosed based on liver biopsy. Furthermore, patients with decompensated cirrhosis were excluded. A statistical analysis was performed regarding the association between serum HBsAg level and compensated cirrhosis. RESULTS: Patients with compensated cirrhosis had a significantly lower mean serum HBsAg level compared to those without cirrhosis (3.27 Log10 IU/mL VS 4.17 Log10 IU/mL, P < 0.001). Furthermore, examining the correlation with compensated cirrhosis revealed that lower level of serum HBsAg was a significant factor in multivariate analysis. The area under the receiver operating characteristics curve of serum HBsAg was 0.856 for compensated cirrhosis. A positive predictive value of 66.2% and negative predictive value of 90.7% were obtained with a cut-off value of < 3.60 Log10 IU/mL (4000 IU/mL) of serum HBsAg. Moreover, the rate of compensated cirrhosis increased to 75.0% after combining with APRI > 2. CONCLUSIONS: In HBeAg positive CHB patients, low serum HBsAg level is a useful predictor of compensated cirrhosis.

Precore/basal core promoter mutants quantification throughout phases of hepatitis B virus infection by Simpleprobe.

AIM: To investigate precore/basal core promoter (PC/BCP) mutants throughout hepatitis B virus (HBV) infection and to determine their relationship to hepatitis B early antigen (HBeAg) titers. METHODS: We enrolled 191 patients in various stages of HBV infection at the Huashan Hospital and the Taizhou Municipal Hospital from 2010 to 2012. None of the patients received antiviral therapy. HBV DNA from serum, was quantified by real-time PCR. The HBV genotype was determined by direct sequencing of the S gene. We used the Simpleprobe ultrasensitive quantitative method to detect PC/BCP mutants in each patient. We compared the strain number, percentage, and the changes in PC/BCP mutants in different phases, and analyzed the relationship between PC/BCP mutants and HBeAg by multiple linear regression and logistic regression. RESULTS: Patients with HBV infection (n = 191) were assigned to groups by phase: Immune tolerance (IT) = 55, Immune clearance (IC) = 67, Low-replicative (LR) = 49, and HBeAg-negative hepatitis (ENH) = 20. Of the patients (male, 112; female, 79) enrolled, 122 were HBeAg-positive and 69 were HBeAg-negative. The median age was 33 years (range: 18-78 years). PC and BCP mutation detection rates were 84.82% (162/191) and 96.86% (185/191), respectively. In five HBeAg-negative cases, we detected double mutation G1896A/G1899A. The logarithm value of PC mutant quantities (log10 PC) significantly differed in IT, IC, and LR phases, as well as in the ENH phase (F = 49.350, P < 0.001). The logarithm value of BCP mutant quantities (log10 BCP) also differed during the four phases (F = 25.530, P < 0.001). Log10 PC and log10 BCP values were high in the IT and IC phases, decreased in the LR phase, and increased in the ENH phase, although the absolute value at this point remained lower than that in the IT and IC phases. PC mutant quantity per total viral load (PC%) and BCP mutant quantity per total viral load (BCP%) differed between phases (F = 20.040, P < 0.001; F = 10.830, P < 0.001), with PC% and BCP% gradually increasing in successive phases. HBeAg titers negatively correlated with PC% (Spearman's rho = -0.354, P < 0.001) and BCP% (Spearman's rho = -0.395, P < 0.001). The negative correlation between PC% and HBeAg status was significant (B = -5.281, P = 0.001), but there was no such correlation between BCP% and HBeAg status (B = -0.523, P = 0.552). CONCLUSION: PC/BCP mutants become predominant in a dynamic and continuous process. Log10 PC, log10 BCP, PC% and BCP% might be combined to evaluate disease progression. PC% determines HBeAg status.