Anti-PD-L1 antibody ASC22 in combination with a histone deacetylase inhibitor chidamide as a "shock and kill" strategy for ART-free virological control: a phase II single-arm study.

The combination of ASC22, an anti-PD-L1 antibody potentially enhancing HIV-specific immunity and chidamide, a HIV latency reversal agent, may serve as a strategy for antiretroviral therapy-free virological control for HIV. People living with HIV, having achieved virological suppression, were enrolled to receive ASC22 and chidamide treatment in addition to their antiretroviral therapy. Participants were monitored over 24 weeks to measure changes in viral dynamics and the function of HIV-specific CD8+ T cells (NCT05129189). 15 participants completed the study. At week 8, CA HIV RNA levels showed a significant increase from baseline, and the values returned to baseline after discontinuing ASC22 and chidamide. The total HIV DNA was only transiently increased at week 4 (P = 0.014). In contrast, integrated HIV DNA did not significantly differ from baseline. Increases in the proportions of effector memory CD4+ and CD8+ T cells (TEM) were observed from baseline to week 24 (P = 0.034 and P = 0.002, respectively). The combination treatment did not succeed in enhancing the function of HIV Gag/Pol- specific CD8+ T cells. Nevertheless, at week 8, a negative correlation was identified between the proportions of HIV Gag-specific TEM cells and alterations in integrated DNA in the T cell function improved group (P = 0.042 and P = 0.034, respectively). Nine adverse events were solicited, all of which were graded 1 and resolved spontaneously. The combined treatment of ASC22 and chidamide was demonstrated to be well-tolerated and effective in activating latent HIV reservoirs. Further investigations are warranted in the context of analytic treatment interruption.

Prevalence and associated factors of low bone mineral density in people living with HIV: a cross-sectional study.

This study examined low bone mineral density (BMD) prevalence and associated factors among Chinese people living with HIV (PLWH), uncovering a persistent high BMD risk in older individuals, even after adjusting for age and body mass index (BMI). Notably, lopinavir/ritonavir (LPV/r) therapy was linked to reduced BMD, highlighting the imperative need for regular BMD monitoring and interventions in older PLWH. PURPOSE: HIV infection and antiretroviral therapy (ART) have been shown to contribute to lower BMD, resulting in an increased susceptibility to osteopenia and osteoporosis. However, there is limited knowledge about the prevalence of reduced BMD and its associated factors among Chinese PLWH. In this cross-sectional study, we aimed to investigate the prevalence and factors associated with low BMD among PLWH in China. METHODS: We retrospectively enrolled PLWH and non-HIV volunteers who underwent dual-energy X-ray absorptiometry (DXA) scans to measure bone density. Demographic information, laboratory test results, ART regimens, and treatment duration were collected. Univariate and multiple regression analyses were performed to identify factors influencing abnormal bone mass in PLWH. RESULTS: A total of 829 individuals were included in this study, comprising the HIV group (n = 706) and the non-HIV group (n = 123). The prevalence of low BMD among all PLWH was found to be 13.88% (98 out of 706). However, among PLWH aged 50 years and above, the prevalence increased to 65.32% (81 out of 124). In contrast, control subjects in the same age group had a prevalence of 38.21% (47 out of 123). After adjusting for age and BMI, older PLWH still demonstrated a higher prevalence of low BMD compared to the non-HIV group (68.24% vs 34.94%, P < 0.001). Multivariate analysis revealed that older age was strongly associated with a higher risk of low BMD among PLWH, with an odds ratio (OR) of 6.28 for every 10-year increase in age in the ART-naïve population (95% confidence intervals [CIs], 3.12-12.65; P < 0.001) and OR of 4.83 in the ART-experienced population (3.20-7.29, P < 0.001). Within the ART-experienced group, current LPV/r treatment was associated with an increased risk of low BMD (OR = 3.55, 1.24-10.14, P < 0.05), along with lower BMI (OR = 0.84, 0.75-0.95, P < 0.05), and elevated alkaline phosphatase (OR = 1.02, 1.01-1.03, P < 0.01). CONCLUSION: The prevalence of low BMD is higher among PLWH aged 50 years and above compared to non-HIV individuals. The use of LPV/r for ART is associated with reduced BMD. These findings emphasize the importance of regular monitoring of BMD in older PLWH and the need for appropriate interventions to mitigate the risks of osteopenia and osteoporosis in this population.

Comprehensive risk factor predictions for 3-year survival among HIV-associated and disseminated cryptococcosis involving lungs and central nervous system.

BACKGROUND: The global mortality rate resulting from HIV-associated cryptococcal disease is remarkably elevated, particularly in severe cases with dissemination to the lungs and central nervous system (CNS). Regrettably, there is a dearth of predictive analysis regarding long-term survival, and few studies have conducted longitudinal follow-up assessments for comparing anti-HIV and antifungal treatments. METHODS: A cohort of 83 patients with HIV-related disseminated cryptococcosis involving the lung and CNS was studied for 3 years to examine survival. Comparative analysis of clinical and immunological parameters was performed between deceased and surviving individuals. Subsequently, multivariate Cox regression models were utilized to validate mortality predictions at 12, 24, and 36 months. RESULTS: Observed plasma cytokine levels before treatment were significantly lower for IL-1RA (p < 0.001) and MCP-1 (p < 0.05) when in the survivor group. Incorporating plasma levels of IL-1RA, IL-6, and high-risk CURB-65 score demonstrated the highest area under curve (AUC) value (0.96) for predicting 1-year mortality. For 1-, 2- and 3-year predictions, the single-factor model with IL-1RA demonstrated superior performance compared to all multiple-variate models (AUC = 0.95/0.78/0.78). CONCLUSIONS: IL-1RA is a biomarker for predicting 3-year survival. Further investigations to explore the pathogenetic role of IL-1RA in HIV-associated disseminated cryptococcosis and as a potential therapeutic target are warranted.

Efficacy evaluation of pulmonary hypertension therapy in patients with portal pulmonary hypertension: A systematic review and meta-analysis.

Objective: To determine the therapeutic effect of pulmonary arterial hypertension (PAH) agents for portal pulmonary hypertension (POPH). Design: Systematic review and meta-analysis. Background: POPH is a serious complication of end-stage liver disease with a low survival rate. Liver transplantation (LT) is an effective treatment. Due to the presence of POPH, some patients cannot undergo LT. After PAH treatment, patients with POPH can obtain good hemodynamics and cardiac function for LT, but there are no standard guidelines. Methods: Two independent researchers searched PubMed, EMBASE, Cochrane Library, and Web of Science for studies published from inception to 27 September 2022, focusing on the changes in hemodynamics and cardiac function in all patients with POPH to understand the effect of PAH treatment on the entire population of POPH patients. Among these, we specifically analyzed the changes in hemodynamics and cardiac function in moderate and severe POPH patients. After collecting the relevant data, a meta-analysis was carried out using the R program meta-package. Results: A total of 2,775 literatures were retrieved, and 24 literatures were included. The results showed that in all POPH patients (n = 1,046), the following indicators were significantly improved with PAH agents: mPAP: (MD = -9.11 mmHg, p < 0.0001); PVR: (MD = -239.33 dyn·s·cm-5, p < 0.0001); CO: (MD = 1.71 L/min, p < 0.0001); cardiac index: (MD = 0.87 L/(min·m2), p < 0.0001); 6MWD: (MD = 43.41 m, p < 0.0001). In patients with moderate to severe POPH (n = 235), the following indicators improved significantly with PAH agents: mPAP (MD = -9.63 mmHg, p < 0.0001); PVR (MD = -259.78 dyn·s·cm-5, p < 0.0001); CO (MD = 1.76 L/min, p < 0.0001); Cardiac index: (MD = 1.01 L/(min·m2), p = 0.0027); 6MWD: (MD = 61.30 m, p < 0.0001). Conclusion: The application of PAH agents can improve cardiopulmonary hemodynamics and cardiac function in patients with POPH, especially in patients with moderate to severe POPH, and the above changes are more positive. Systematic Review Registration: https://inplasy.com, identifier INPLASY202250034.

Correlation between serum cytokines and clinicopathological features in patients with drug-induced liver injury.

Objectives: Changes in serum levels of cytokines have been proposed as possible biological markers of tissue damage, including drug-induced liver injury (DILI). Here, we aimed to screen cytokine markers that have guiding significance for the degree of inflammation of DILI. Patients and methods: 54 patients with DILI were retrospectively analyzed as the experimental group, and 14 healthy subjects were randomly selected as the control group. A total of 20 cytokines were detected by using a cytokine protein antibody chip, and differentially expressed proteins were screened. Results: There were significant differences in serum cytokines between DILI patients and healthy controls. Compared with the control group, the DILI group expressed 11 differential proteins. IL-8, TNF RII, TNFα, TNF RI, MIP-1ß, MIP-1α, and IL-1ß were differentially expressed in DILI patients with different degrees of inflammation from G1 to G4. MIG, IL-12p40, and IL-10 were differentially expressed in the higher degree of inflammation groups (G2, G3, and G4 groups). Tissue inhibitor of metalloproteinases-1 (TIMP-1) was differentially expressed in the group with the highest inflammation degree (G4 group). Chemokine C-C motif ligand 1 (I-309) was only differentially expressed in the lowest inflammation group (G1 group). Conclusion: The changes and differential expression of specific cytokine levels were helpful for evaluating different degrees of inflammation of DILI.

Significance of initiating antiretroviral therapy in the early stage of HIV infection.

A growing number of guidelines now recommend that human immunodeficiency virus (HIV) infected patients should be given early antiretroviral therapy (ART), especially in acute HIV infection. ART during early infection can limit viral reservoirs and improve immune cell function. From a societal prospect, early-infected individuals who achieve a state of viral suppression through ART can reduce the chance of HIV transmission and reduce the acquired immunodeficiency syndrome (AIDS)-related disease burden. However, there are many problems in the early diagnosis and treatment of HIV infection, including personal and social factors, which hinder the implementation and development of early treatment. It is recommended that initiating ART in the early stage of HIV infection, combined with other treatment strategies, so as to achieve functional cure.

Long-term case-fatality rate of nontuberculous mycobacterial disease in people living with HIV.

BACKGROUND: Few data are available regarding the long-term case-fatality rate (CFR) among people living with HIV (PLWH) with nontuberculous mycobacteria (NTM) disease. The aim of this study is to analyze the long-term CFR in patients with NTM disease and to identify risk factors for their death. METHODS: A retrospective cohort study of 379 cases of microbiologically confirmed NTM disease in PLWH was conducted from January 1, 2012, to December 31, 2020, in Shanghai, China. We used Kaplan-Meier survival analysis and the log-rank test to compare the long-term CFR in patients with disseminated NTM (DNTM) and localized NTM disease. Univariate Cox proportional hazards regression analysis and a stepwise Cox proportional hazards regression model were used to estimate the predictors of long-term CFR. RESULTS: The cohort was followed up for a median of 26 months. The total CFR was 15.7% by one year and increased to 22.6% at 5 years after the diagnosis of NTM disease. The 5-year CFR of PLWH with DNTM was significantly higher than that of PLWH with localized NTM (26.7% vs 19.6% for DNTM and localized NTM disease, respectively). Older age [hazard ratio (HR) = 1.04, 95% confidence interval (CI): 1.02-1.06, P < 0.001], comorbidity (HR = 2.05, 95% CI: 1.21-3.49, P < 0.01), DNTM (HR = 2.08, 95% CI: 1.17-3.68, P < 0.05), and HIV viral load (HR = 1.32, 95% CI: 1.12-1.55, P < 0.001) were all independent risk factors for long-term CFR. In the subgroup analysis, time to culture positivity was negatively correlated with CFR in patients with DNTM (HR = 0.90, 95% CI: 0.82-0.98, P < 0.05). CONCLUSIONS: NTM was associated with a high long-term CFR in PLWH. Further approaches to prevent NTM disease in PLWH are urgently needed.

Utility of urine lipoarabinomannan (LAM) in diagnosing mycobacteria infection among hospitalized HIV-positive patients.

OBJECTIVES: Cross-reactivity with nontuberculous mycobacteria (NTM) species might limit the use of urine lipoarabinomannan (LAM) test to diagnose tuberculosis (TB) in people living with HIV (PLWH). This study aimed to investigate the utility of the LAM test among hospitalized HIV-positive patients. METHODS: This prospective study enrolled HIV-positive inpatients with any TB symptom or seriously ill patients with advanced immunodeficiency. Urine samples were tested using the Alere Determine LAM Ag, and participants were categorized as confirmed TB, confirmed NTM infection, unclassified mycobacteria infection, and no mycobacteria infection based on microbiologic reference standards. RESULTS: A total of 382 participants were included. The prevalence of confirmed TB and NTM infection was 5.24% (20 of 382) and 4.45% (17 of 382), respectively. The sensitivity and specificity of the urine LAM for TB diagnosis were 65.00% (95% confidence interval [CI] 40.78-84.61) and 89.36% (95% CI 85.68-92.36), respectively. The LAM test for NTM yielded a sensitivity of 58.82% (95% CI 32.92-81.56) and specificity of 88.61% (95% CI 84.87-91.70). Notably, the negative predictive values of the urine LAM for TB and NTM were 97.85% (95% CI 95.63-99.13) and 97.85% (95% CI 95.63-99.13), respectively. CONCLUSIONS: Cross-reactivity with NTM cause high false-positive LAM for TB diagnosis in PLWH. The correct identification of mycobacteria species is crucial for deciding treatment strategies.

Update: Drug treatment options for coronavirus disease 2019 (COVID-19).

Coronavirus disease 19 (COVID-19) continues to rage as a global pandemic. A number of potential therapeutic agents have been explored over the past year or two. However, numerous drugs that were expected to prove highly effective, such as lopinavir/ritonavir and remdesivir, have been found to have little benefit in large clinical trials. Interleukin-6 receptor antagonists, glucocorticoids, Janus kinase inhibitors, and some antivirals have been found to provide significant benefits in terms of reducing viral load, reducing the time of nucleic acid conversion, or improving survival. For example, bamlanivimab and etesevimab, which are newly designed monoclonal antibodies against the surface spike protein S1 subunit receptor-binding domain (RBD) of SARS-CoV-2, have a significant effect on reducing the viral load and the hospitalization rate of patients with mild COVID-19. Several vaccines against SARS-CoV-2 have been widely administered worldwide and have provided good protection. Nevertheless, the increasingly hardy variants of the virus have raised the requirements for vaccine design. Perhaps RBD-based vaccines are a viable way to defend against variants, but this still needs to be verified in a large sample. Therefore, this paper provides an update on the treatment options for COVID-19 based on three previously proposed dimensions of drug screening: standard assays of existing broad-spectrum antivirals, screening of chemical libraries, and redevelopment of new, specific drugs.

Prevalence and Associated Factors of Portopulmonary Hypertension in Patients with Portal Hypertension: A Case-Control Study.

BACKGROUND AND AIMS: There are few studies on the prevalence and clinical characteristics of portopulmonary hypertension (POPH) in patients with portal hypertension. In addition, invasive right heart catheterization further limits the clinical diagnosis of POPH patients. METHODS: From January 2018 to December 2019, 1004 patients with portal hypertension were treated in the Department of Hepatology, the First Hospital of Jilin University. Based on the inclusion and exclusion criteria, 188 patients with portal hypertension were finally included. We collected complete clinical data, laboratory examinations, and imaging examinations. Patients were divided into a POPH group and a non-POPH group based on echocardiographic results. We calculated the prevalence of POPH in patients with portal hypertension. The differences in clinical characteristics of the two groups of patients were compared. RESULTS: The prevalence of POPH in patients with portal hypertension was 2.8%. Among the 188 patients with portal hypertension with fingertip oxygen saturation < 95% at rest, 28 patients had POPH (12 males and 16 females), with an average age of 63 ± 8, and 160 patients did not have POPH (110 males, 50 women), with an average age of 59 ± 11. The proportion of women in the POPH group (P < 0.01) and patients without liver cancer (P = 0.044) was high. Compared to patients without POPH, patients with POPH had lower hemoglobin (related to the severity of anemia, P < 0.01), higher creatinine (P < 0.05), and lower partial pressure of oxygen and carbon dioxide (P < 0.05). Patients with POPH had a higher incidence of atrial enlargement, ventricular enlargement, mitral valve regurgitation, tricuspid regurgitation, pulmonary artery widening, pericardial effusion, and aortic regurgitation than those without POPH. The risk of POPH did not increase with the aggravation of the Child-Pugh classification. CONCLUSION: The prevalence of POPH in patients with portal hypertension is 2.8%. The proportion of women and nonliver cancer in POPH patients was higher than that in non-POPH patients. In addition, the POPH group had higher creatinine and lower hemoglobin, and echocardiography showed that POPH patients had more cardiac structural changes. In patients with portal hypertension, the risk in patients with POPH has nothing to do with the Child-Pugh classification and MELD score.

Herb-induced autoimmune-like hepatitis associated with Xiang-tian-guo (Swietenia macrophylla seeds): A case report and literature review.

RATIONALE: Drug-induced liver injury (DILI) has a relatively low incidence, whereas the incidence of herb-induced liver injury (HILI) is still under investigation. As a special type of DILI, the diagnosis of drug-induced autoimmune-like hepatitis presents a persistent challenge, because this condition has partial characteristics of both DILI and autoimmune hepatitis (AIH), such as a certain history of medication use and histology that similar is to AIH. Thus, the differential diagnosis between DILI and AIH can be confusing. PATIENT CONCERNS: A 67-year-old woman taking xiang-tian-guo for 6 months was admitted to our hospital with a complaint of experiencing jaundice for 2 weeks. DIAGNOSIS: A liver biopsy exhibited interface inflammation, foam cells, and "rosette" -like hepatocytes. She was diagnosed with herb-induced liver injury (hepatocellular and acute), a RUCAM score of 7 (probable), a severity for grade 4 liver injury, and accompanied autoimmune-like changes. INTERVENTIONS: The patient was instructed to cease the administration of suspicious drugs. The patient also received liver protection and albumin transfusion. OUTCOMES: After 25 days of hospitalization, the patients aminotransferase levels returned to normal. No recurrence was observed after the administration of the treatments and a close follow-up. LESSONS: We must to be vigilant about the safety of xiang-tian-guo as a herbal medicine. When faced with the difficulty of distinguishing between AIH and DILI, long-term follow-up observations for recurrence can aid clinicians in making a judgment.

Role of echocardiography in screening for portopulmonary hypertension in liver transplant candidates: a meta-analysis.

OBJECTIVES: To demonstrate the screening value of echocardiography for portopulmonary hypertension (POPH) in liver transplant candidates. DESIGN: Systematic review and meta-analysis. BACKGROUND: POPH is a complication of end-stage liver disease that adversely affects the outcome of orthotopic liver transplant. There are no specific symptoms in the early stage of POPH. POPH reduce the survival rate of patients with end-stage liver disease specially if they are not diagnosed. Therefore, early detection may improve prognosis. The objective of this study is to explore the screening value of echocardiography on liver transplant candidates for screening of POPH compared to right heart catheterization (RHC). METHOD: PubMed, EMBASE and the Cochrane Library were searched by two independent reviewers for potentially eligible studies published up to 30 June 2019 to retrieve data based on per-patient analysis. STATA, Meta-DiSc, and RevMan were applied to perform this meta-analysis. RESULTS: Our search yielded 1576 studies, of which 11 satisfied the inclusion criteria. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and area under the summary receiver operating characteristic (SROC) curve (AUC) of echocardiography for POPH were 0.85 (95% CI [0.65-0.94]), 0.83 (95% CI [0.73-0.90]), 4.99 (95% CI [3.03-8.21]), 0.19 (95% CI [0.07-0.46]), and 0.91 (95% CI [0.88-0.93]), respectively. Deeks' funnel plot did not indicate the existence of publication bias (P = 0.66). CONCLUSIONS: Echocardiography, a noninvasive modality, provides superior screening for POPH, but the diagnosis of POPH still requires RHC. PROSPERO registration number CRD42019144589.