BACKGROUND: Hepatitis B surface antigen (HBsAg) clearance is vital for a functional cure of hepatitis B virus (HBV) infection. However, the incidence and predictors of HBsAg seroclearance in patients co-infected with HBV and human immunodeficiency virus (HIV) remain largely unknown in Guangdong, China. METHODS: Between 2009 and 2019, patients co-infected with HBV/HIV undergoing antiretroviral therapy (ART) in Guangzhou Eighth People's Hospital affiliated to Guangzhou Medical University were retrospectively reviewed with the endpoint on December 31, 2020. The incidence and risk factors for HBsAg seroclearance were evaluated using Kaplan-Meier and multivariate Cox regression analyses. RESULTS: A total of 1550 HBV/HIV co-infected patients were included in the study, with the median age of 42 years and 86.0% (1333/1550) males. Further, 98.3% (1524/1550) received ART containing tenofovir disoproxil fumarate (TDF) plus lamivudine (3TC). HBV DNA was examined in 1283 cases at the last follow-up. Over the median 4.7 years of follow-up, 8.1% (126/1550) patients achieved HBsAg seroclearance, among whom 50.8% (64/126) obtained hepatitis B surface antibody, 28.1% (137/488) acquired hepatitis B e antigen seroconversion, and 95.9% (1231/1283) undetectable HBV DNA. Compared with patients who maintained HBsAg positive, cases achieving HBsAg seroclearance showed no differences in age, gender, CD4 + T cell count, alanine aminotransferase (ALT) level, or fibrosis status; however, they presented lower HBV DNA levels, lower HBsAg levels, and higher rates of HBV genotype B at the baseline. Multivariate analysis showed that baseline HBsAg <1500 cutoff index (COI) (adjusted hazard ratio [aHR], 2.74, 95% confidence interval [95% CI]: 1.48-5.09), ALT elevation >2 × upper limit of normal during the first six months after receiving ART (aHR, 2.96, 95% CI: 1.53-5.77), and HBV genotype B (aHR, 3.73, 95% CI: 1.46-9.59) were independent predictors for HBsAg seroclearance (all P <0.01). CONCLUSIONS Long-term TDF-containing ART has high anti-HBV efficacy including relatively high overall HBsAg seroclearance in HBV/HIV co-infected patients. Lower baseline HBsAg levels, HBV genotype B, and elevated ALT levels during the first six months of ART are potential predictors of HBsAg seroclearance.
Male ; Humans ; Adult ; Hepatitis B Surface Antigens ; Hepatitis B virus/genetics* ; HIV Infections/drug therapy* ; HIV ; DNA, Viral ; Incidence ; Coinfection/drug therapy* ; Retrospective Studies ; Tenofovir/therapeutic use* ; Lamivudine/therapeutic use* ; Hepatitis B, Chronic/drug therapy*

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reapproved for heart failure (HF) therapy in patients with and without diabetes. However, the initial glucose-lowering indication of SGLT2i has impeded their uses in cardiovascular clinical practice. A challenge of SGLT2i then becomes how to separate their anti-HF activity from glucose-lowering side-effect. To address this issue, we conducted structural repurposing of EMPA, a representative SGLT2 inhibitor, to strengthen anti-HF activity and reduce the SGLT2-inhibitory activity according to structural basis of inhibition of SGLT2. Compared to EMPA, the optimal derivative JX01, which was produced by methylation of C2-OH of the glucose ring, exhibited weaker SGLT2-inhibitory activity (IC₅₀ > 100 nmol/L), and lower glycosuria and glucose-lowering side-effect, better NHE1-inhibitory activity and cardioprotective effect in HF mice. Furthermore, JX01 showed good safety profiles in respect of single-dose/repeat-dose toxicity and hERG activity, and good pharmacokinetic properties in both mouse and rat species. Collectively, the present study provided a paradigm of drug repurposing to discover novel anti-HF drugs, and indirectly demonstrated that SGLT2-independent molecular mechanisms play an important role in cardioprotective effects of SGLT2 inhibitors.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular mortality in patients with diabetes mellitus but the protective mechanism remains elusive. Here we demonstrated that the SGLT2 inhibitor, Empagliflozin (EMPA), suppresses cardiomyocytes autosis (autophagic cell death) to confer cardioprotective effects. Using myocardial infarction (MI) mouse models with and without diabetes mellitus, EMPA treatment significantly reduced infarct size, and myocardial fibrosis, thereby leading to improved cardiac function and survival. In the context of ischemia and nutritional glucose deprivation where autosis is already highly stimulated, EMPA directly inhibits the activity of the Na⁺/H⁺ exchanger 1 (NHE1) in the cardiomyocytes to regulate excessive autophagy. Knockdown of NHE1 significantly rescued glucose deprivation-induced autosis. In contrast, overexpression of NHE1 aggravated the cardiomyocytes death in response to starvation, which was effectively rescued by EMPA treatment. Furthermore, in vitro and in vivo analysis of NHE1 and Beclin 1 knockout mice validated that EMPA's cardioprotective effects are at least in part through downregulation of autophagic flux. These findings provide new insights for drug development, specifically targeting NHE1 and autosis for ventricular remodeling and heart failure after MI in both diabetic and non-diabetic patients.
Animals ; Diabetes Mellitus ; Diabetes Mellitus, Type 2/drug therapy* ; Glucose ; Humans ; Mice ; Myocardial Infarction/metabolism* ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use* ; Ventricular Remodeling

Background::Chronic liver disease has emerged as a leading cause of non-acquired immune deficiency syndrome (AIDS)-related mortality in hepatitis C virus (HCV)/human immunodeficiency virus (HIV)-coinfected patients. The relationship between CD4 cell count and HIV-related opportunistic infections and tumors has been well characterized; however, it is unclear whether CD4 cell count is associated with HCV-related hepatic events.Methods::This observational cohort study enrolled HCV/HIV-coinfected patients from the National Free Antiretroviral Treatment Program of China from 2004 to 2019 in Guangzhou. The primary outcome was a composite of hepatic events, including cirrhosis complications, hepatocellular carcinoma (HCC), and liver-related mortality. Kaplan-Meier survival and multivariate logistic regression analyses were performed.Results::Among the 793 patients, 43 developed hepatic events during a median follow-up of 6.7 years, including 35 cirrhosis complications, 13 HCC cases, and 14 cases of liver-related mortality. The 5-year and 10-year cumulative incidences of hepatic events were 4.2% and 9.3%, respectively. Patients who developed hepatic events had a less satisfactory increase in CD4 cell count, lower peak CD4 (354.5 cells/μL vs. 560.0 cells/μL, P < 0.001), and lower percentage of peak CD4 > 500 cells/μL (30.2% vs. 60.7%, P < 0.001) after the initiation of antiretroviral therapy (ART) than those who did not. The cumulative incidences of hepatic events were higher in patients with lower peak CD4 levels with adjusted odds ratios of 3.96 (95% confidence interval [CI]: 1.51-10.40), 2.25 (95% CI: 0.87-5.86), and 0.98 (95% CI: 0.35-2.74) for patients with peak CD4 at <200 cells/μL, 200-350 cells/μL, and 351 to 500 cells/μL, respectively, relative to those with peak CD4 > 500 cells/μL. Peak CD4 was negatively associated with the risk of hepatic events in a dose-response manner ( P-value for trend = 0.004). Conclusion::Persistently low CD4 cell counts after ART are independently associated with a high risk of hepatic events in HCV/HIV-coinfected patients, highlighting the important role of immune reconstitution in improving liver outcomes.

Objective: To investigate the utilization of inpatient health care among the elderlies in Shandong province, and to analyze the factors affecting the inpatient services utilization, so as to provide reference for the elderlies to utilize the inpatient services reasonably. Methods: The survey was conducted in Shandong province in August 2017. Multi-stage stratified cluster random sampling method was used to select 7 070 residents aged 60 and above in 6 counties and districts of Shandong province as the objects of the survey. The survey included the basic family and personal information of the elderlies as well as the utilization of hospitalization services. Chi-square test and rank sum test were used for univariate analysis, and logistic regression was applied for influencing factors. Results: The annual hospitalization rate of the elderlies in Shandong province was 18.1%, and 9.6% of those in need of hospitalization failed to enjoy the service. The annual hospitalization rate of the elderlies aged 80 years and over was 19.9%, and 5.5% of the patients in need had not been hospitalized. Among the inpatient institutions, the proportion of township health centers/community health service centers, county-level(district) medical institutions, prefecture-level medical institutions and provincial-level medical institutions was 29.2%, 29.1%, 37.7% and 1.4%, respectively.Factors influencing the utilization of hospitalization services for the elderlies included age, self-assessment of health, physical examination, chronic diseases, type of medical insurance and income level. Conclusions More attention should be paid to the hospitalization services for the elderlies aged 80 years and over. Effective measures should be taken to guide the elderlies to fully use primary medical resources. The prevention and control of chronic diseases should be strengthened to promote the rational use of inpatient health services among the elderlies. In addition, more attention should be paid to low-income elderlies to meet their hospitalization needs.

Objective: To understand the referral status and the willingness for downward referral among rural elderlies with hospital stay experiences in the past year in Shandong province, and to explore its influencing factors on the willingness for downward referral. Methods: Three prefecture-level cities in Shandong province were sampled by multi-stage stratified random sampling in August 2017. Questionnaire survey was conducted among 910 rural elderlies(over 60 years old)who had been hospitalized in the past year. The study included the basic information, the hospitalization experience, and perception of essential medicines system, ego-resiliency, the referral status and willingness for downward referral. Rank sum test, Chi-square test and t test were used for univariate analysis, and logistic regression was applied for influencing factors. Results: Among 910 rural elderlies who had been hospitalized in the past year, 53(5.8%) were referred to other medical institutions in their recent hospitalization, and 597(65.6%)were willing to be referred downward. The main reason for their reluctance for downward referral was that the medical competency of primary medical institutions was low; and the main reason for willingness for downward referral was being close to home. The results showed that marital status, impression for the national essential medicines system and ego-resiliency were the influencing factors of their willingness to downward referral among rural elderlies who had been hospitalized in the past year(P<0.05). Conclusions The referral rate and willingness for downward referral among the rural elderlies in Shandong province are relatively low. We should further enhance the service capacity of primary medical institutions, strengthen the publicity and implementation of the national essential medicines system, pay attention to help with the elderlies′ negative emotions caused by diseases, and improve their ego-resiliency.

Objective: To investigate the optimal duration of pegylated-alpha interferon (Peg-INFα) combined with ribavirin (RBV) in treating chronic hepatitis C infection in human immunodeficiency virus (HIV)-infected patients. Methods: A multicenter prospective study was conducted. The study subjects were divided into two groups; HIV/HCV co-infections (Group A, n = 158) and control with HCV-monoinfections (Group B, n = 60). All recruited patients received standard Peg-INFα plus RBV therapy. Group A was divided into 3 subgroups according to CD4⁺ cell counts: A1 subgroup, 79 cases, CD4⁺ counts > 350 cells /μl, who received anti-HCV before combination antiretroviral therapy(cART); A2 subgroup, 45 cases, CD4⁺ counts between 200 and 350 cells/μl, who did not start anti-HCV until they could tolerate cART well; A3 subgroup, 34 cases, CD4⁺ counts < 200 cells /μl, cART was administered first, and anti-HCV therapy was started when CD4⁺ counts > 200 cells/μl. The anti-HCV efficacy of two groups and 3 subgroups were compared. Statistical analysis for normal distribution and homogeneity of variance data was calculated by t-test and the counting data was analyzed by χ ² test. The Mann-Whitney U test was used for non-normal data. A one-way analysis of variance (ANOVA) was used for the comparison of multiple groups, followed by SNK method. Multiple independent samples were used for non-parametric tests. Results: There was no significant difference in age and baseline HCV RNA levels between groups and subgroups (P > 0.05). By an intent-to-treat (ITT) analysis, in Group A, the ratio of complete early virological response (cEVR) rate was 75.3% (119/158), the ratio of end of treatment virological response (eTVR) rate was 68.4% (108/158), and the ratio of sustained virological response (SVR) rate was 48.7% (77/158); in Group B, the ratio of cEVR rate was 93.3% (56/60), the ratio of eTVR rate was 90.0% (54/60), and the ratio of SVR rate was 71.7% (43/60); The therapeutic index of Group A were lower than those of Group B (P≤0.05). By per-protocol (PP) analysis, the ratio of cEVR rate in Group A [75.2% (88/112)] was still lower than that in Group B [93.3% (56/60)], but no significant differences were found in the ratio of eTVR rate and SVR rate between 2 groups (P > 0.05). Comparing the efficacy of subgroups (A1, A2 and A3) by ITT analysis, the ratios of cEVR rate were respectively 78.5% (62/79), 75.6% (34/45) and 67.6% (23/34); the ratios of eTVR rate were respectively 68.4%(54/79), 80.0%(36/45)and 52.9%(18/34); and the ratios of SVR rate were respectively 41.8%(33/79), 64.4%(29/45)and 44.1%(15/34). The ratio of eTVR in subgroup A2 was obviously higher than that in subgroup A3 and the ratio of SVR in subgroup A2 was statistically higher than that of subgroup A1(P≤0.05). However, by PP analysis, no significant differences of the therapeutic indexes were found among the respective subgroups (P > 0.05). Conclusion HIV-HCV co-infected patients would have better anti-HCV efficacy with Peg-INFα-2a plus RBV than HCV- monoinfected patients. The best time for initiating anti-HCV therapy in HIV-HCV co-infected patients is when CD4⁺ counts 200 cells/ μl.

Objective To explore the risk factors for the prognosis of acquired immunodeficiency syndrome (AIDS)-related lymphoma (ARL).Methods A total of 32 patients with ARL were enrolled in this study from Guangzhou Eighth People's Hospital during August 2011 and July 2014,who were followed up for 2 to 48 months (median 9 months).The risk factors for the prognosis of ARL were analyzed by Logistic regression analysis.Results A total of 32 patients were included,among whom 27 were males and the rest were females,with a mean age of (42.8± 13.5) years (ranging from 4 to 70 years).Regarding the clinical staging at the initial diagnosis,6 cases (18.8 ％) were classified as stage Ⅰ,4 cases (12.5％) stage Ⅱ,5 cases (15.6％) stage Ⅲ,and 17 cases (53.1％) stage Ⅳ.As for international prognostic index (IPI) score,4 cases (12.5％) were in the low risk group (IPI 0-1),5 cases (15.6％) in the low-middle group (IPI 2),8 cases (25.0％) in the middle-high risk group (IPI 3),and 15 cases (46.9 ％) in the high risk group (IPI 4-5).According to the pathological diagnosis,26 cases (81.2％) were B cell non-Hodgkin lymphoma (NHL),4 cases (12.5％) were T cell NHL,and 2 cases (6.2％) were Hodgkin lymphoma (HL) nodular sclerosis.In total,23 cases (71.9％) had received highly active antiretroviral therapy (HAART) before the first hospital visit or within one month after the diagnosis of lymphoma.Sixteen (50.0％) cases received standard chemotherapy regimen formulated by the oncology specialists.A total of 17 patients died,with the mortality rate of 53.1％.By univariate analysis,the prognostic factors included age (OR=0.915,P=0.012),high lactate dehydrogenase (OR=1.006,P=0.021) value at baseline,receiving HAART (OR =12.444,P=0.011),and standard chemotherapy regimen (OR=13.000,P=0.001).By multivariate Logistic regression,receiving standard chemotherapy regimen (OR=0.035,P=0.022) was the only prognostic factor of ARL.Conclusions The mortality of ARL is high and the most common pathological type was NHL.The prognosis could be improved by standard chemotherapy regimen on the basis of HAART.

Very low density lipoprotein receptor (VLDLR) is thought to participate in the patho-genesis of atherosclerosis induced by VLDL and β-VLDL. The present study was undertaken to elu-cidate the effects of VLDL and β-VLDL on VLDLR expression and its signaling pathway. RAW264.7 cells were incubated with VLDL and β-VLDL. The expression of VLDLR mRNA was detected by RT-PCR. The transcriptional activity of VLDLR gene was detected in recombinant plasmid pGL4.2VR-luciferase transfected RAW264.7. Western blot assay was used to detect the changes of phosphorylated ERK1/2 protein. Inhibitors or activators were used to observe the signal pathway in-volving VLDLR expression regulation. The results showed that VLDL and β-VLDL stimulated ERKI/2 activity in a PKC-dependent manner. VLDL or β-VLDL-induced VLDLR expression on macrophages was extremely abolished by inhibitors ERKI/2 or PKC. Our findings revealed that VLDL or β-VLDL-induced VLDLR expression via PKC/ERK cascades and the effect was linked to the transcriptional activation of VLDLR gene promoter.

Abstract: Large-scale clinical trial is an important measure of clinical evaluation on drugs. This paper introduces the concept and features of large-scale clinical trial, the possibility and necessity of large-scale clinical trial of traditional Chinese medicine, as well as its administration and quality control, with Myocardial Infarction Secondary Prevention Study in Traditional Chinese Medicine (MISPS-TCM), a National Program Subject, as an example.