Zhaoping Zhang

Stringent cessation criterion results in better durability of lamivudine treatment: a prospective clinical study in hepatitis B e antigen‐positive chronic hepatitis B patients

Summary.  The cessation criteria for lamivudine treatment vary in published articles and their results are contradictory, especially factors predicting relapse. To clarify these contradictions, this long‐term follow‐up study of 125 Chinese hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B patients was designed with stringent cessation criterion. All patients received lamivudine and achieved HBeAg seroconversion (group A, n = 82) or loss (group B, n = 43) with undetectable hepatitis B virus (HBV) DNA by PCR assay during the treatment. Lamivudine was withdrawn ≥6 months after HBeAg seroconversion/loss occurred. The median treatment durations were 24 (12–54) months and 36 (18–89) months in group A and group B, respectively. Patients were followed up for median 24 (2–84) months. The cumulative relapse (defined as serum HBV DNA ≥104 copies/mL) rates in the two groups at months 12, 24, 36 and 48 were 23.4%vs 35.0%, 25.0%vs 37.7%, 25.0%vs 41.1% and 29.4%vs 41.1%, respectively (log‐rank test, P = 0.119). For patients whose total treatment duration ≥18 months in group A, the cumulative relapse rates at months 12, 24, 36 and 48 were 18.3%, 20.1%, 20.1% and 25.1%, which was significantly lower than those with a shorter duration (log‐rank test, P = 0.002). The mean age and median total duration were statistically different between relapsers and nonrelapsers in group A (33.9 ± 13.6 vs 23.1 ± 11.0 years, P < 0.001 and 24 vs 26 months, P = 0.003). Cox regression revealed that age was the only predictive factor for relapse (RR, 1.069; 95% CI, 1.032–1.106, P < 0.001). Patients aged <30 years relapsed less frequently in 5 years (12.3%vs 53.5%, P = 0.001). In conclusion, for patients who maintained HBeAg seroconversion for ≥6 months and total duration for ≥18 months, lamivudine withdrawal is a reasonable option. Prolonged treatment may be required for patients aged greater than 30 years to reduce relapse.

Gamma-glutamyl-transpeptidase to platelet ratio is not superior to APRI,FIB-4 and RPR for diagnosing liver fibrosis in CHB patients in China

The gamma-glutamyl transpeptidase to platelet ratio (GPR) is a novel index to estimate liver fibrosis in chronic hepatitis B (CHB). Few studies compared diagnostic accuracy of GPR with other non-invasive fibrosis tests based on blood parameters. We analyzed diagnostic values of GPR for detecting liver fibrosis and compared diagnostic performances of GPR with APRI (aspartate aminotransferase-to-platelet ratio index), FIB-4 (fibrosis index based on the four factors), NLR (neutrophil-to-lymphocyte ratio), AAR (aspartate aminotransferase/alanine aminotransferase ratio) and RPR (red cell distribution width-to-platelet ratio) in HBeAg positive CHB and HBeAg negative CHB. We found AUROCs of GPR in predicting significant liver fibrosis, advanced liver fibrosis and liver cirrhosis were 0.732 (95% CI 0.663 to 0.801), 0.788 (95% CI 0.729 to 0.847) and 0.753 (95% CI 0.692 to 0.814), respectively. Further comparisons showed the diagnostic performance of GPR was not significantly different with APRI, FIB-4 and RPR in identifying significant fibrosis, advanced fibrosis and cirrhosis, but it was significantly superior to AAR and NLR in both HBeAg positive CHB and HBeAg negative CHB. In conclusion, GPR does not show advantages than APRI, FIB-4 and RPR in identifying significant liver fibrosis, advanced liver fibrosis and liver cirrhosis in both HBeAg positive CHB and HBeAg negative CHB in China.

A scoring model for predicting prognosis of patients with severe fever with thrombocytopenia syndrome

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging epidemic infectious disease caused by the SFTS bunyavirus (SFTSV) with an estimated high case-fatality rate of 12.7% to 32.6%. Currently, the disease has been reported in mainland China, Japan, Korea, and the United States. At present, there is no specific antiviral therapy for SFTSV infection. Considering the higher mortality rate and rapid clinical progress of SFTS, supporting the appropriate treatment in time to SFTS patients is critical. Therefore, it is very important for clinicians to predict these SFTS cases who are more likely to have a poor prognosis or even more likely to decease. In the present study, we established a simple and feasible model for assessing the severity and predicting the prognosis of SFTS patients with high sensitivity and specificity. This model may aid the physicians to immediately initiate prompt treatment to block the rapid development of the illness and reduce the fatality of SFTS patients.

A novel predictive model using routinely clinical parameters to predict liver fibrosis in patients with chronic hepatitis B

Objectives Noninvasive models have been established for the assessment of liver fibrosis in patients with chronic hepatitis B(CHB). However, the predictive performance of these established models remains inconclusive. We aimed to develop a novel predictive model for liver fibrosis in CHB based on routinely clinical parameters. Results Platelets(PLT), the standard deviation of red blood cell distribution width(RDW-SD), alkaline phosphatase(ALP) and globulin were independent predictors of significant fibrosis by multivariable analysis. Based on these parameters, a new predictive model namely APRG(ALP/PLT/RDW-SD/globulin) was proposed. The areas under the receiver-operating characteristic curves(AUROCs) of APRG index in predicting significant fibrosis(≥F2), advanced fibrosis(≥F3) and liver cirrhosis(≥F4) were 0.757(95%CI 0.699 to 0.816), 0.763(95%CI 0.711 to 0.816) and 0.781(95%CI 0.728 to 0.835), respectively. The AUROCs of the APRG were significantly higher than that of aspartate transaminase(AST) to PLT ratio index(APRI), RDW to PLT ratio(RPR) and AST to alanine aminotransferase ratio(AAR) to predict significant fibrosis, advanced fibrosis and cirrhosis. The AUROCs of the APRG were also significantly higher than fibrosis-4 score (FIB-4) (0.723, 95%CI 0.663 to 0.783) for cirrhosis(P=0.034) and better than gamma-glutamyl transpeptidase(GGT) to PLT ratio(GPR) (0.657, 95%CI 0.590 to 0.724) for significant fibrosis(P=0.001). Materials and Methods 308 CHB patients who underwent liver biopsy were enrolled. The diagnostic values of the APRG for liver fibrosis with other noninvasive models were compared. Conclusions The APRG has a better diagnostic value than conventionally predictive models to assess liver fibrosis in CHB patients. The application of APRG may reduce the need for liver biopsy in CHB patients in clinical practice.OBJECTIVES Noninvasive models have been established for the assessment of liver fibrosis in patients with chronic hepatitis B(CHB). However, the predictive performance of these established models remains inconclusive. We aimed to develop a novel predictive model for liver fibrosis in CHB based on routinely clinical parameters. RESULTS Platelets(PLT), the standard deviation of red blood cell distribution width(RDW-SD), alkaline phosphatase(ALP) and globulin were independent predictors of significant fibrosis by multivariable analysis. Based on these parameters, a new predictive model namely APRG(ALP/PLT/RDW-SD/globulin) was proposed. The areas under the receiver-operating characteristic curves(AUROCs) of APRG index in predicting significant fibrosis(≥F2), advanced fibrosis(≥F3) and liver cirrhosis(≥F4) were 0.757(95%CI 0.699 to 0.816), 0.763(95%CI 0.711 to 0.816) and 0.781(95%CI 0.728 to 0.835), respectively. The AUROCs of the APRG were significantly higher than that of aspartate transaminase(AST) to PLT ratio index(APRI), RDW to PLT ratio(RPR) and AST to alanine aminotransferase ratio(AAR) to predict significant fibrosis, advanced fibrosis and cirrhosis. The AUROCs of the APRG were also significantly higher than fibrosis-4 score (FIB-4) (0.723, 95%CI 0.663 to 0.783) for cirrhosis(P=0.034) and better than gamma-glutamyl transpeptidase(GGT) to PLT ratio(GPR) (0.657, 95%CI 0.590 to 0.724) for significant fibrosis(P=0.001). MATERIALS AND METHODS 308 CHB patients who underwent liver biopsy were enrolled. The diagnostic values of the APRG for liver fibrosis with other noninvasive models were compared. CONCLUSIONS The APRG has a better diagnostic value than conventionally predictive models to assess liver fibrosis in CHB patients. The application of APRG may reduce the need for liver biopsy in CHB patients in clinical practice.

Platelet Count and Prediction of Bleeding in Patients With Liver Cirrhosis

analysis uses odds ratios to assess efficacy and tolerability. Specifically, the odds of drug-treated patients experiencing diarrhea compared to placebo-treated patients in the same trials are calculated. This approach controls for minor differences in definitions of efficacy or diarrhea adverse events because placebo-treated patients from the same trial are used as controls. For example, consider the frequency of diarrhea adverse events in CIC patients in the separate Phase III randomized, doubleblind, placebo-controlled trials (RCTs) for plecanatide and linaclotide. (Note: in order to minimize debate, only FDA-approved documents are used here [1–3].) Five percent of plecanatide-treated CIC patients (3 mg/day) experienced diarrhea while 16% of linaclotide-treated CIC patients (145 μg/day) had diarrhea., [1, 2]. This suggests that plecanatide is less likely to cause diarrhea than linaclotide. However, placebo rates of diarrhea in these RCTs also need to be examined. For plecanatide, the rates of diarrhea vs placebo are 5% vs 1%, respectively. For linaclotide, the rates of diarrhea are 16% vs 5%, respectively. In this example, plecanatide-treated patients are 5× more likely to have diarrhea compared to placebo-treated patients, but it is only 3× with linaclotide vs placebo. Therefore, any direct statements or indirect inferences that diarrhea is less common with plecanatide are not supported by the evidence. Why are diarrhea adverse events lower for placebo-treated CIC patients in plecanatide RCTs compared to linaclotide RCTs? First, patients in linaclotide trials underwent safety assessments on four occasions (weeks 2, 4, 8, and 12) vs thrice in plecanatide trials (weeks 4, 8, and 12). Second, definitions of diarrhea adverse events seem different. This correspondence and FDA documents [2-4] further clarify this issue. Dr. Griffin states that when patients reported “diarrhea” in plecanatide trials, then this was recorded verbatim and counted as a diarrhea adverse event [4]. I apologize for this omission and appreciate the correction. Second, Dr. Griffin states that prior publications provided comprehensive definitions that I ignored. Actually, Dr. Griffin’s letter and the revised 2018 plecanatide prescribing information [3] provide a small, but important, expansion of definitions reported in RCTs. Specifically, it is not simply an increase in BMs that included an assessment of bothersomeness. “Reports of loose stools... were recorded as adverse reactions if they were also reported to be bothersome to the patient” [1]. This is important because reports of “loose stools”, “mushy stools”, “stools watery”, etc. were MedDRA (Medical Dictionary for Regulatory Activities) terms that were recorded as diarrhea adverse events in linaclotide RCTs, regardless of bothersomeness (www. accessdata.fda.gov/drugsatFDA_docs/ nda/2012/202811orig1s000medr.pdf). This difference may have increased reports of diarrhea adverse events in both linaclotide-treated patients and placebo-treated patients in linaclotide RCTs. Ultimately, this debate ignores our primary point, when using odds ratios to control for frequency of adverse events in placebo-treated patients, the odds of diarrhea with active drug vs placebo are similar for plecanatide and linaclotide. This conclusion is supported by our meta-regression. Dr. Griffin’s primary concern is that our methodology is flawed because a network meta-analysis is the only way to make comparisons between drugs in the absence of a head-to-head comparison. Although a detailed discussion of meta-regression is beyond the scope of this reply, meta-regression is frequently used without a network meta-analysis to compare outcomes with two different drugs [5]. Also, this manuscript underwent additional biostatistical review by editors with expertise in this field while we respectfully note that Dr. Griffin has no research experience with meta-analysis. Therefore, we believe that the results of our meta-regression, which did not demonstrate any differences in efficacy or tolerability between linaclotide vs plecanatide, are valid.

Emodin Alleviates Liver Fibrosis of Mice by Reducing Infiltration of Gr1hi Monocytes

Emodin, as a major active component of Rheum palmatum L. and Polygonum cuspidatum, has been reported to have antifibrotic effect. However, the mechanism of emodin on antifibrotic effect for liver fibrosis was still obscure. In the present study, we aimed to investigate whether emodin can alleviate carbon tetrachloride- (CCl4-) induced liver fibrosis through reducing infiltration of Gr1hi monocytes. Liver fibrosis was induced by intraperitoneal CCl4 injection in mice. Mice in the emodin group received emodin treatment by gavage. Pretreatment with emodin significantly protected mice from liver inflammation and fibrosis revealed by the decreased elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as reduced hepatic necrosis and fibrosis by analysis of hematoxylin-eosin (HE) staining, Masson staining, α-smooth muscle actin (α-SMA), and collagen-I immunohistochemistry staining. Further, compared to CCl4 group, mice in the emodin group showed significantly less intrahepatic infiltration of Gr1hi monocytes. Moreover, emodin significantly inhibited hepatic expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), granulin (GRN), monocyte chemoattractant protein 1 (MCP-1), and chemokine ligand 7 (CCL7), which was in line with the decreased numbers of intrahepatic Gr1hi monocytes. In conclusion, emodin can alleviate the degree of liver fibrosis by reducing infiltration of Gr1hi monocytes. These results suggest that emodin is a promising candidate to prevent and treat liver fibrosis.

A novel index using routine clinical parameters for predicting significant liver inflammation in chronic hepatitis B

Identifying the degree of liver inflammation is critical for therapeutic judgement of patients with chronic hepatitis B (CHB). However, we lack indexes which can accurately predict significant liver inflammation in patients with CHB. This study aimed to develop a simple predictive index for liver inflammation in CHB using routine clinical parameters. A total of 519 patients with CHB who underwent liver biopsy were enrolled and randomly divided into training (n = 346) and validation cohorts (n = 173). Based on routine clinical parameters, gamma‐glutamyl transpeptidase (GGT; P = 0.031) and platelets (PLT; P < 0.001) were identified as independent predictors of significant inflammation by multivariable analysis in the training cohort. Accordingly, the GGT to PLT ratio (GPR) was developed to amplify the opposing effects for predicting liver inflammation. In the training cohort, the AUCs of GPR in predicting significant inflammation were 0.791 (95% CI: 0.742‐0.839), 0.783 (95% CI: 0.717‐0.849) and 0.791 (95% CI: 0.716‐0.867) in the entire patients with CHB, HBeAg‐positive CHB patients and HBeAg‐negative CHB patients, respectively. The diagnostic performance of GPR for significant inflammation was significantly superior to that of alanine aminotransferase (ALT), aspartate transaminase (AST) and GGT in all patients with CHB and HBeAg‐positive CHB patients, but was comparable with ALT, AST and GGT in HBeAg‐negative CHB patients. In the validation cohort, the diagnostic performance of GPR in assessing significant liver inflammation was also superior to other indexes in all patients with CHB and HBeAg‐positive CHB patients, but was comparable with GGT in HBeAg‐negative CHB patients. Thus, GPR can be a novel and simple index for predicting significant liver inflammation in CHB, especially for HBeAg‐positive CHB.

Characterization of clinical features and outcome for human-to-human transmitted severe fever with thrombocytopenia syndrome

Abstract Background: Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening infectious disease identified in 2009. SFTS is mainly transmitted by contact with ticks or animals; however, sporadic reports suggested that SFTS could be transmitted among humans. Objectives: We aimed to comprehensively characterize clinical features and disease progression of SFTS acquired by human-to-human transmission. Study design: A retrospective study of 90 SFTS patients was performed in a tertiary hospital of Nanjing, China, from October 2010 to October 2016. Seven cases of secondary SFTS were identified based on their epidemic timeline. Their clinical presentations, dynamic laboratory results and clinical outcome were analyzed. Results: First, 20 out of 83 primary SFTS patients were deceased, leading to a case-fatality ratio of 24.1%, while all secondary patients survived, suggesting a superior clinical outcome for secondary infection. Moreover, clinical symptoms and laboratory tests in primary and secondary SFTS patients were analyzed, respectively. Secondary SFTS patients developed milder clinical manifestation in the absence of neurological disorder and multiple organ failure. Further, clinical laboratory tests revealed that secondary patients had less disturbed key laboratory parameters, compared to those in primary SFTS patients. During day 7–13 post illness onset, most of the clinical laboratory results of secondary patients went back to normal range. They also had significantly lower level of viral load than primary patients. Conclusions: Secondary SFTS acquired through human-to-human transmission leads to milder clinical representations and superior prognoses compared to primary SFTS, suggesting that the transmission route makes a difference in disease progression and clinical outcome of SFTS disease.

Curcumin reduces Ly6Chi monocyte infiltration to protect against liver fibrosis by inhibiting Kupffer cells activation to reduce chemokines secretion

Curcumin has been reported to have anti-fibrotic effect. However, the anti-fibrotic mechanism of curcumin for liver fibrosis remains obscure. In the presenting study, we aimed to investigate whether curcumin reduce chemokines secretion by inhibiting kupffer cells (KCs) activation to decrease Ly6Chi monocyte infiltration in the treatment of liver fibrosis. Liver fibrosis was induced by intraperitoneal carbon tetrachloride (CCl4)-injection in mice. Mice in curcumin group received curcumin treatment by gavage. Pretreatment with curcumin significantly protected mice from liver inflammation and fibrosis. Compared to CCl4 group, mice in the curcumin group showed significantly less intrahepatic infiltration of Ly6Chi monocytes, but no difference of other leucocyte subtypes. Moreover, curcumin significantly reduced Ly6Chi monocytes associated pro-inflammatory and pro-fibrogenic cytokines, which was in line with the decreased numbers of intrahepatic Ly6Chi monocytes. Further study found that curcumin is able to decrease KCs activation and monocyte chemokines, which explains why curcumin can reduce Ly6Chi monocytes infiltration during liver fibrosis. In vitro, we discovered that curcumin prevents the polarization of macrophages toward M1 and reduces monocyte chemokines secretion, which is involved with ERK1/2 and p38 pathways. Taken together, for the first time, we verified that curcumin can reduce chemokines secretion by inhibiting KCs activation to decrease Ly6Chi monocyte infiltration in the treatment of liver fibrosis. These results suggested that curcumin may be considered a promising candidate in the prevention and treatment of liver fibrosis.

Can Transient Elastography Predict Fibrosis Regression in Patients with Chronic Hepatitis B During Long-Term Antiviral Therapy?

Can Transient Elastography Predict Fibrosis Regression in Patients with Chronic Hepatitis B During Long-Term Antiviral Therapy?