Real-world study on HBsAg loss of combination therapy in HBeAg-negative chronic hepatitis B patients.

Combination therapy with pegylated interferon (PEG-IFN) and nucleos(t)ide analogues (NAs) can enhance hepatitis B surface antigen (HBsAg) clearance. However, the specific treatment strategy and the patients who would benefit the most are unclear. Therefore, we assessed the HBsAg loss rate of add-on PEG-IFN and explored the factors associated with HBsAg loss in chronic hepatitis B (CHB) patients. This was a real-world cohort study of adults with CHB. Hepatitis B e antigen (HBeAg)-negative NAs-treated patients with baseline HBsAg ≤1500 IU/ml and HBV DNA < the lower limit of detection, or 100 IU/ml, received 48 weeks of add-on PEG-IFN. The primary outcome of the study was the rate of HBsAg loss at 48 weeks of combination treatment. Using multivariable logistic regression analysis, we determined factors associated with HBsAg loss. HBsAg loss in 2579 patients (mean age: 41.2 years; 80.9% male) was 36.7% (947 patients) at 48 weeks. HBsAg loss was highest in patients from south-central and southwestern China (40.0%). Factors independently associated with HBsAg loss included: increasing age (odds ratio = 0.961); being male (0.543); baseline HBsAg level (0.216); HBsAg decrease at 12 weeks (between 0.5 and 1.0 log10 IU/ml [2.405] and >1.0 log10 IU/ml [7.370]); alanine aminotransferase (ALT) increase at 12 weeks (1.365); haemoglobin (HGB) decrease at 12 weeks (1.558). There was no difference in the primary outcomes associated with the combination regimen. In conclusion, HBsAg loss by combination therapy was higher in patients from southern China than those from the north. An increased chance of HBsAg loss was associated with baseline characteristics and dynamic changes in clinical indicators.

PEGylated NALC-functionalized gold nanoparticles for colorimetric discrimination of chiral tyrosine.

In this work, acid and matrix-tolerant multifunctionalized gold nanoparticles (AuNPs) with an integrated chiral selector towards tyrosine (Tyr) and polyethylenglycol (PEG) chains were developed for visual chiral discrimination of Tyr in biological samples under acid conditions. In brief, AuNPs multifunctionalized with N-acetyl-l-cysteine (NALC) and PEG (PEG/NALC-AuNPs) were prepared via a simple strategy. In the presence of l-Tyr, the color of PEG/NALC-AuNP solution changed from red to gray, while no obvious color change was observed with the introduction of d-Tyr, which indicated that the introduction of PEG onto the surface of AuNPs has no effect on the chiral recognition between l-Tyr and NALC. A computer-aided molecular model was used to clarify the chiral recognition mechanism between NALC and Tyr enantiomers and to further guide the optimization of sensitivity. The resultant PEG/NALC-AuNP sensor presented a significantly improved stability under acid and alkali conditions compared with conventional NALC-AuNPs, resulting in a wider dynamic range (500 nM-100 µM) and a 50 times reduced detection limit by simply adjusting the pH of the sensor system under acid conditions (pH 2-2.5). More importantly, the PEG/NALC-AuNPs can realize the visual chiral discrimination of Tyr enantiomers in biological samples due to their significantly improved long-term stability and reduced interaction towards non-target species.

[Efficacy of combination antiviral therapy following childbirth in pregnant HBV carriers receiving telbivudine for prevention of mother-to-child transmission].

OBJECTIVE: To observe the clinical efficacy of combination therapy with peg-IFNalpha and adefovir (CPIA) in women who were hepatfis B virus (HBV) carriers and had just given birth and received telbivudine (LdT) during pregnancy for prevention of mother-to-child transmission. METHODS: One-hundred-and-fifty third trimester-pregnant women who were HBV carriers with highly-viremic were treated with LdT until time of birth. After delivery, those women with alanine aminotransferase (ALT) level exceeding two times the upper limit of normal and HBV DNA level that had decreased more than 31 gIU/mL or hepatitis B e antigen (HBeAg) titer that had decreased more than 50% were switched to CPIA for 96 weeks. RESULTS: Following delivery, 45 of the women were switched to the CPIA treatment, of which 91.1% (41/45) achieved virological response, 55.6% (25/45) achieved HBeAg clearance or seroconversion, and 26.7% (12/45) achieved hepatitis B surface antigen (HBsAg) clearance or seroconversion.The immediate post-delivery (and pre-CPIA) levels of HBeAg and HBV DNA were negatively associated with HBeAg clearance. Ninety-eight of the total study participants stopped the LdT treatment and there were no cases of significant deterioration of liver function. CONCLUSION: Pregnant women who are HBV carriers and receive LdT for protection against mother-to-child transmission, and who show significant ALT elevation and decreased HBeAg titer and/or reduced HBV DNA after delivery, may be good candidates for the CPIA therapy following delivery.

Bone marrow suppression or active proliferation? An analysis of neutropenia after pegylated interferon treatment of patients with chronic hepatitis C.

BACKGROUND: Neutropenia is a common adverse effect of the treatment of chronic hepatitis C with pegylated interferon and ribavirin. However, the mechanism involved is unknown. The present study aimed to investigate the cause of treatment-induced neutropenia by determining cytokine levels in plasma and in bone marrow smears. METHODS: Fifteen patients with chronic hepatitis C were enrolled in this study. Plasma cytokine levels were determined using the Luminex assay before and during treatment. We simultaneously determined the levels of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and 7 other cytokines, and performed bone marrow cytology when blood cell counts indicated neutropenia. RESULTS: Only 1 bone marrow smear indicated a low cell proliferation level, whereas active proliferation was observed in the remaining 14 patients. The levels of G-CSF, GM-CSF, interleukin (IL)-2, IL-4, IL-6, and interferon (IFN)-γ decreased significantly in patients with neutropenia (p < 0.05). In contrast, the levels of IL-8, IL-10, and tumor necrosis factor (TNF)-α showed no significant change (p = 0.713, 0.930, 0.833, respectively) before or after treatment. CONCLUSIONS: The bone marrow of most patients with IFN-induced neutropenia showed active cell proliferation. Elevated G-CSF and GM-CSF but not bone marrow suppression was observed along with neutropenia after pegylated interferon treatment, suggesting a causative role of G-CSF and GM-CSF in neutropenia.

[Efficacy and safety of peginterferon alfa-2a (40 kd) plus adefovir for 96 weeks in HBeAg-negative chronic hepatitis B patients].

OBJECTIVE: To investigate the efficacy and safety of an extended course (96-week) of combination treatment with peginterferon alfa-2a (Peg-IFNa-2a; 40 kd] plus adefovir (ADV) for treating chronic hepatitis B (CHB) in Chinese patients with negativity for hepatitis B e antigen (HBeAg). METHODS: A total of 25 consecutive patients with HBeAg-negative CHB were administered Peg-IFNa-2a (135-180 mug/week) plus ADV (10 mg/day) for 96 weeks. All patients were followed-up for 24 weeks after treatment completion. Levels of hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HbsAg) were measured by fluorescence quantitative polymerase chain reaction (FQ-PCR) and chemiluminescent microparticle immunoassay, respectively, at 12-week intervals throughout the treatment course and at the end-of-follow-up (week 120). Patients underwent serological analysis at 3-6 month intervals during treatment and follow-up to evaluate occurrence of adverse events; serological parameters included blood count, markers of liver, kidney and thyroid function, and levels of autoantibodies and creatine kinase. RESULTS: For all patients, the 96-week course of Peg-IFNa-2a plus ADV reduced the level of HBV DNA below the detection threshold (less than 500 copies/ml by FQ-PCR). The overall rate of HBsAg seroconversion was 12% (3/25) at week 48, 28% (7/25) at week 96, and 32% (8/25) at week 120. The occurrences of adverse events were similar at week 48 and week 96. CONCLUSION: The extended-course Peg-IFNa-2a plus ADV combination therapy achieved a 100% virological response and better rates of HBsAg seroconversion than 48 weeks of therapy, without a decrease in safety.

[Changes in lymphocyte surface expression of CD8 and CD38 molecules in peripheral blood of inactive HBsAg carriers following pegylated interferon a-2a therapy].

OBJECTIVE: To investigate the effects of pegylated interferon a-2a (Peg-INFa-2a) treatment on expression of CD8 and CD38 surface molecules on lymphocytes from peripheral blood of inactive hepatitis B surface antigen (HBsAg) carriers. METHODS: Forty-four patients with hepatitis B virus (HBV) chronic infection (CHB) received a 48-week course of Peg-INFa-2a treatment, with 30 administered 135 mug/week and 14 administered 180 mug/week. Every 12 weeks of treatment, the subjects were assessed for HBsAg titer, presence of anti-hepatitis B e (HBe) antibody, serum alanine amino transaminase (ALT) levels, and lymphocyte surface expression of CD8 and CD38 molecules. Patients were classified as responders and non-responders according to standard parameters. Dynamic differences between the two groups over time were assessed by multivariate repeated measures ANOVA with Greenhouse-Geisser correction and differences at single time points were assessed by univariate ANOVA. Linear regression analysis was performed to evaluate the relationship of two variables. RESULTS: The responders showed a significantly higher increase in ALT at week 12 (60.75+/-24.95 U/L vs. non-responders: 37.03+/-18.45 U/L; t = 2.905, P less than 0.01) and significantly higher proportion of CD8+CD38+ cells at week 24 (71.20+/-11.70% vs. non-responders: 56.79+/-7.72%; F = 23.941, P less than 0.01). The decline in level of HBsAg at week 24 was positively correlated with the increase in ALT level at week 12 (r = 0.386, P less than 0.01) and with expression levels of CD8 and CD38 molecules on lymphocytes at week 24 (r = 0.397, P less than 0.01). CONCLUSION: Lower baseline levels of HBsAg correlated to better Peg-INFa-2a-related HBsAg clearance. Increased expression of CD8 and CD38 on lymphocytes is suggestive of intensive cellular immunity in CHB patients and may be related to HBV-induced hepatocyte damage and may promote the HBsAg clearance.

[Analysis of thyroid dysfunction and influencing factors in chronic hepatitis C patients treated with peg-IFNa-2a and ribavirin].

OBJECTIVE: To analyze the frequency of thyroid dysfunction and determine its influencing factors in chronic hepatitis C (CHC) patients treated with pegylated-interferon alpha (peg-IFNa)-2a and ribavirin (RBV) combination therapy. METHODS: A total of 194 CHC patients were treated with peg-IFNa-2a and RBV for 48 weeks. Development of thyroid dysfunction was recorded. Clinical and biological factors from pre-treatment (baseline) to post-treatment were statistically analyzed to determine correlation with thyroid dysfunction in this patient population. RESULTS: Fifty-two (26.80%) of 194 peg-IFNa-2a/RBV-treated patients developed thyroid dysfunction. Dysfunction severity ranged from hyperthyroidism (n = 1, 0.52%) and hypothyroidism (n = 10, 5.15%) to subclinical hyperthyroidism (n = 4, 2.06%) and subclinical hypothyroidism (n = 37, 19.07%). The dysfunction rate was significantly higher after peg-IFNa-2a/RBV treatment (26.80% vs. 12.37% at baseline, x2 = 12.829, P less than 0.05, odds ratio (OR) = 0.386, 95% confidence interval (CI): 0.226-0.657), in females (33.00% vs. 20.21% in males, P less than 0.05, 95% CI: 1.016-3.040), and in thyroid auto-antibody positive patients (64.29% vs. 23.89% in negative patients, P less than 0.05, 95% CI: 1.681-36.183). Early virological response did not have any significant effect on dysfunction rate (23.00% vs. 30.85% no early virological response, x2 = 1.522, P more than 0.05) nor did end of treatment response (27.19% vs. 26.25% no response at end of treatment, x2 = 0.021, P more than 0.05). Patients who developed thyroid dysfunction had higher interleukin (IL)-6 at baseline (i.e. before peg-IFNa-2a/RBV treatment) (27.08+/-14.90 vs. 11.65+/-5.46 in patients who maintained normal thyroid function, t = 3.127, P less than 0.05, 95% CI: 5.28-25.58). IL-6 levels were not significantly different between the two groups at 24 weeks (6.30+/-2.47 vs. 6.81+/-2.80, t = 0.352, P more than 0.05). IL-6 levels before and after 48 weeks of treatment in normal thyroid function patients were 27.08+/-14.90 and 6.30+/-2.47, t = 3.632, P less than 0.05, and in thyroid dysfunction patients were 11.65+/-5.46 and 6.81+/-2.80, t = 1.997, P more than 0.05. CONCLUSION: Peg-IFNa-2a/RBV combination therapy may cause thyroid dysfunction, especially hypothyroidism, in CHC patients. Female sex and thyroid auto-antibody positivity may put CHC patients at higher risk of developing thyroid dysfunction during peg-IFNa-2a/RBV therapy. Elevated IL-6 may be a predictive marker of peg-IFNa-2a/RBV-induced thyroid dysfunction.

Sensitive colorimetric detection of melamine in processed raw milk using asymmetrically PEGylated gold nanoparticles.

In this study, the asymmetrically modified gold nanoparticles (AuNPs) with relatively large size are proposed for highly sensitive detection of melamine in raw milk. At first, we found that the sensitivity of colorimetric detection of melamine based on the conventional citrate-stabilized AuNPs could be significantly increased (limit of detection by visual observation: from 1 µmol L-1 to 1 nmol L-1) via enlarging the size of AuNPs (from 13 to 42 nm). However, the large-sized AuNPs are unstable in the solution, and the accuracy of relevant aggregation-based colorimetric detection method is dramatically decreased due to the rapid evanishment of the color of solution caused by the precipitation of large-scaled AuNPs aggregates after introducing melamine. In view of this limitation, the stabilizing agent polyethylene glycol (PEG) is introduced onto the selected area at the surface of AuNPs to stabilize the large-sized AuNPs sensor and further adjust the aggregation behavior in an oriented and controllable manner. As a result, the addition of melamine into asymmetrically PEGylated AuNPs with large size could still induce a color change from purple to blue, but the color change could be maintained in aqueous solution for a long time. This improvement is mainly caused by forming stable and oriented oligomers of AuNPs taking advantage of the asymmetrical modification of AuNPs with PEG chain in this system. Such a way of aggregation leads to remarkably enhanced long-term stability and an at least 2 orders of magnitude wider dynamic detection range (1.05 nmol L-1 to 1 mmol L-1) compared with conventional AuNPs sensors. Finally, such a novel asymmetrically modified AuNPs sensor is successfully applied to detect melamine in the raw milk with the satisfactory spiked recovery from 99.6% to 103.7% and RSD of about 3.0%. This work provides a sensitive and reliable method to detect melamine in pretreated milk, indicating a new avenue to make innovation on colorimetric sensors for real sample detection.

[Factors associated with HBeAg seroconversion in chronic hepatitis B patients treated with interferon alfa-2a].

OBJECTIVE: The aim of this paper was to investigate the factors associated with viral response and HBeAg seroconversion and the relationship between them at different stages of interferon treatment in HBeAg-positive chronic hepatitis B patients. METHODS: PEG-IFN alfa-2a was injected subcutaneously in doses of 180 microg once a week for 48 weeks to HBeAg-positive chronic hepatitis B patients, and the patients were followed for another 24 weeks after the treatment. The serum HBV DNA load was measured by real-time quantitative PCR assay. Microparticle enzyme immunoassay analysis (MEIA) was then carried out by an automatic enzyme immunoassay analysis instrument to measure HBeAg and anti-HBe. Virological response and HBeAg seroconversion rates, and the factors associated with them were analyzed. RESULTS: The differences in ALT baselines between viral responding and non-responding groups were significant at treatment time and at the end of the follow-up period. These differences were also significant in patients with HBeAg seroconversion at 12 weeks and at the end of the follow-up period compared with the non-conversion group. No significant difference of HBV DNA baseline was observed between the HBeAg seroconversion and non-conversion group. At 12, 24 and 48 weeks, in patients with viral response during the treatment, their HBeAg seroconversion rates were 43.8%, 21.4% and 18.9% respectively; their respective HBeAg seroconversion rates remaining at 72 weeks were 42.9%, 33.3% and 27.6%. HBeAg seroconversion was related to HBV DNA negativity at 48 weeks treatment in the multivariate analysis (OR=2.15, 95.0% CI=1.744-2.664, P less than 0.01). CONCLUSIONS: Viral response and early and sustained HBeAg seroconversion were associated with pretreatment ALT levels. HBeAg seroconversion was related to viral response during IFN treatment, but not to the baseline HBV DNA load.

Extended treatment with peginterferon α-2a in combination with lamivudine or adefovir for 96 weeks yields high rates of HBeAg and HBsAg seroconversion.

OBJECTIVE: The study aimed to investigate the efficacy and safety of peginterferon α-2a (PEG IFNα-2a) in combination with lamivudine or adefovir in the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). METHODS: In total, 47 patients with HBeAg-positive CHB received either PEG IFNα-2a (135 µg once weekly) plus lamivudine (100 mg daily) or adefovir (10 mg daily). All patients completed 96 weeks of therapy and were followed up for a further 24 weeks. RESULTS: Baseline characteristics and treatment efficacy of the two groups were similar. All patients achieved hepatitis B virus (HBV) DNA <500 copies/mL at 96 weeks, and none had a virological rebound after stopping the therapy. The rate of HBeAg seroconversion was 46.8% at 48 weeks, increased to 74.5% at 96 weeks, and kept at 72.3% at 120 weeks. Hepatitis B surface antigen (HBsAg) seroconversion rate was 6.4% at 48 weeks, increased to 21.3% at 96 weeks, and kept at 27.7% at 120 weeks. CONCLUSIONS: Extended treatment with PEG IFNα-2a with lamivudine or adefovir for 96 weeks is a promising strategy to achieve high rates of sustainable HBeAg and HBsAg seroconversion and HBV DNA suppression in patients with HBeAg-positive CHB.

[Efficacy, influencing factors and safety of PEG-INF alpha-2a (PEG-INF-2a) in the treatment of chronic hepatitis C: analysis of 89 patients].

BACKGROUND: To investigate the efficacy, influencing factors and safety of PEG-INF alpha-2a (PEG-INF-2a) in the treatment of hepatitis C. METHODS: Totally 89 patients with hepatitis C were included in this study and 46 patients were treated with PEG-INF-2a (180 microg or 135 microg/week) and RBV 900 mg/d, 43 patients were treated with IFNalpha-2a (5 MIU/qod) and RBV 900 mg/d. The time of treatment was 48 weeks, and all the patients were visited 24 weeks after treatment. There were no significant differences between the two groups in pretreatment HCV-RNA, HCV genotype and other clinical data. The main parameters to evaluate the efficacy were virological and biochemical responses. The side effects were intensively observed. RESULTS: Sustained virological response (SVR) rate in PEG-IFNalpha-2a group was significantly higher than that in IFNalpha-2a group (56.5% and 19.5% respectively, P<0.001). As the patients were divided according to HCV genotype 1 and high virus load, the SVR rate of PEG-INF alpha-2a group was higher than IFNalpha-2a group (P<0.001). However, there was no significant difference between two groups in the patients with non-genotype 1 and low viral load (P=0.664, 0.116). Similar side-effects were observed in PEG-IFNalpha-2a group and IFNalpha-2a group, but the rate of weight decline and the degree of leukocyte decrease were more significant in PEG-INF alpha-2a group than in IFNalpha-2a group (P=0.001). CONCLUSION: The efficacy of PEG-INF alpha-2a in the treatment of chronic hepatitis C is superior to that of conventional IFNalpha-2a, PEG-INF alpha-2a had good tolerance and safety profiles.