Search

Background: Comorbidity of Myasthenia gravis (MG) and Graves' disease (GD) in treated HIV‐infected individuals has rarely been described and little study has been done on the link between HIV‐related immune reconstitution and autoimmune diseases occurring post antiretroviral therapy. Case Presentation: Here we report on a 33‐year‐old Chinese man with HIV infection who had been virologically suppressed since 2018. The patient was diagnosed with GD and was treated in 2020. Early in 2022, he developed fluctuating weakness and fatigue involving the bilateral extraocular muscles and limbs. With a positive neostigmine test, he was considered to have MG, but showed a poor response to oral medication. After multiple failed medication attempts, a thymectomy was finally performed to resolve his symptoms. The consecutive onset of immunological events may have partially resulted from immune reconstitution after viral control. Conclusions: This is a rare case of HIV‐related immune reconstitution‐associated autoimmune disease (IRAD) with comorbidity of MG and GD which was reported initially. Cooperation with multidisciplinary teams is essential to avoid misdiagnosis and to promote the overall health of HIV‐infected patients. [ABSTRACT FROM AUTHOR]

Objectives In recent years, integrase strand transfer inhibitor (INSTI)-containing regimens have been increasingly adopted in treatment for HIV/AIDS and promoted as non-occupational post-exposure prophylaxis in China. This study aims to describe the prevalence of resistance to integrase and drug resistance mutations (DRMs) among ART-naive patients in Shenzhen, China. Methods Serum samples and demographic information were collected from newly reported ART-naive patients in Shenzhen in 2020. The study sequenced the coding sequence of the HIV-1 integrase gene and determined the DRMs.​ Results In this study, 1682 newly reported cases were included and 1071 of them were successfully sequenced finally. The prevalence of primary drug resistance was 1.77%, with 19 samples showing varying degrees of resistance to INSTIs. The study detected six major DRMs in 16 individuals and eight accessory DRMs in 24 individuals. The prevalence of transmitted drug resistance (TDR) mutations was 1.21%, with five transmitted mutations detected in 13 individuals. The prevalence of drug resistance to raltegravir and elvitegravir was statistically higher than to bictegravir, cabotegravir and dolutegravir. Conclusions The prevalence of INSTI resistance in Shenzhen in 2020 was relatively high. ​Continued surveillance for resistance to INSTIs is recommended and treatment regimens should be adopted based on the pattern of resistance to INSTIs. ​Dolutegravir or bictegravir is first recommended when considering INSTIs as treatment regimens. [ABSTRACT FROM AUTHOR]

Since its discovery in the 1990s, the DNA vaccine has been of great interest because of its ability to elicit both humoral and cellular immune responses while showing relative advantages regarding producibility, stability and storage. However, when applied to human subjects, inadequate immunogenicity remains as the greatest challenge for the practical use of DNA vaccines. In this study, we generated a DNA vaccine Δ42PD1-P24 encoding a fusion protein comprised of the HIV-1 Gag p24 antigen and the extracellular domain of murine Δ42PD1, a novel endogenous Toll-like receptor 4 (TLR4) agonist. Using a mouse model, we found that Δ42PD1-P24 DNA vaccine elicited a higher antibody response and an increased number of IFN-γ-producing CD4 and CD8 T cells. Moreover, mice with Δ42PD1-P24 DNA vaccination were protected from a subcutaneous challenge with murine mesothelioma cells expressing the HIV-1 p24 antigen. Importantly, the Δ42PD1-mediated enhancement of immune responses was not observed in TLR4 knockout mice. Collectively, these data demonstrate that the immunogenicity and efficacy of DNA vaccines could be improved by the fusion of the extracellular domain of Δ42PD1 to target the immunogen to dendritic cells. [ABSTRACT FROM AUTHOR]

• Albuvirtide (ABT) is a novel long-acting HIV fusion inhibitor. • ABT combined with LPV/r was non-inferior to LPV/r based three-drug regimen. • ABT combined with LPV/r showed a good safety profile. • ABT combined with LPV/r showed a trend of improvement in renal function. • ABT might be an interesting alternative option for HIV treatment and prevention. [ABSTRACT FROM AUTHOR]

Objective: Individuals with HIV are at increased risk for osteoporosis. A healthy diet with adequate Ca is recommended to promote bone health. However, lengthy nutritional assessments pose barriers to routine screenings in clinical practice. This study aimed to examine the validity and reproducibility of a six-item dietary Ca screening tool among Chinese individuals with HIV.Design: We conducted a two time-point study in an outpatient setting. Volunteers self-administered the six-item tool upon enrolment and again at 1-month follow-up. At baseline, participants also completed a validated FFQ and surveys regarding demographic and clinical risk factors.Setting: Beijing, China; Shenzhen, Guangdong, China.Participants: Upon enrolment, 127 individuals with HIV participated in the study, of whom 83 completed the follow-up screening.Results: Mean age of participants was 35·2 (sd 9·3) years, average BMI was 22·8 (sd 3·8) kg/m2 and 89 % were men. Among the participants, 54·7 % reported Ca intake less than 800 mg/d. The six-item tool demonstrated fair-to-moderate relative validity with a correlation of 0·39 and 75·7 % of subjects classified in same/adjacent quartiles as the reference, and moderate-to-good reproducibility with a correlation of 0·60 and 83·1 % of subjects classified in same/adjacent quartiles. Finally, receiver operating characteristic analyses yielded a sensitivity of 87·0 % and a specificity of 39·4 % with optimised cut-off level.Conclusions: The six-item tool presented adequate validity and reproducibility to identify individuals with low Ca intake among the target population, providing a convenient instrument for categorising Ca intake in clinical practice, prompting referrals for further assessment, and raising awareness of dietary Ca in bone disease prevention. [ABSTRACT FROM AUTHOR]

Background: It is not completely clear whether a very high pre-therapy viral load (≥ 500 000 copies/ml) can impair the virological response. The aim of this study was to examine the influence of very high baseline HIV-RNA levels on long-term virological responses under one type of regimen. Methods: A retrospective study was performed based on data from two multicenter cohorts in China from January to November 2009, and from May 2013 to December 2015. Untreated HIV infected adults between 18 and 65 years old were recruited before receiving non-nucleoside reverse transcriptase inhibitor-based regimen. All patients had baseline HIV-RNA levels over 500 copies/ml, good adherence, and were followed for at least 24 weeks. Virological suppression was defined as the first HIV-RNA < 50 copies/ml. Virological failure was defined as any of incomplete viral suppression (HIV-RNA ≥ 200 copies/ml without virological suppression within 24 weeks of treatment) and viral rebound (confirmed HIV-RNA level ≥ 50 copies/ml after virological suppression). Chi-square test, Kaplan–Meier analysis, Cox proportional hazards model and Logistic regression were used to compare virological response between each pretreated viral load stratum. Results: A total of 758 treatment-naïve HIV patients in China were enlisted. Median follow-up time (IQR) was 144 (108–276) weeks. By week 48, rates of virological suppression in three groups (< 100 000, 100 000–500 000 and ≥ 500 000 copies/ml) were 94.1, 85.0, and 63.8%, respectively (P < 0.001). Very high baseline HIV viremia over 500 000 copies/ml were found to be associated with delayed virological suppression (≥ 500 000 vs < 100 000, adjusted relative hazard = 0.455, 95% CI: 0.32–0.65; P < 0.001) as well as incomplete viral suppression (≥ 500 000 vs < 100 000, adjusted odds ratio [aOR] = 6.084, 95% CI: 2.761–13.407; P < 0.001) and viral rebound (≥ 50 000 vs < 100 000, aOR = 3.671, 95% CI: 1.009–13.355, P = 0.048). Conclusions: Very high levels of pre-treatment HIV-RNA were related with delayed efficacy of NNRTI-based ART and increased risk of treatment failure. More potent initial regimens should be considered for those with this clinical character. [ABSTRACT FROM AUTHOR]

The authors sought to examine the prevalence of echocardiographic abnormalities in antiretroviral therapy (ART)–naive Chinese people living with HIV at baseline and 48 weeks after initiation of ART.Background. Persons living with human immunodeficiency virus (HIV) are at increased risk of developing cardiovascular disease. Few studies have focused on echocardiographic abnormalities in this population.Methods. China AIDS Clinical Trial 0810 is a prospective, multicenter cohort study of persons living with HIV (PLWH). We performed an echocardiography substudy of 325 PLWH. We examined the prevalence of left ventricular systolic dysfunction (LVSD), diastolic dysfunction (DD), pulmonary arterial hypertension (PAH), and increased left ventricular mass (ILVM) in antiretroviral therapy (ART)–naive PLWH at baseline and week 48 after initiation of ART.Results. Compared with age- and sex-matched healthy controls, PLWH had a higher prevalence of DD (16.5% vs 7.2%, P < .027) and a marginally significant higher prevalence of LVSD (7.3% vs 2.1%, P = .056). The increase in the prevalence of DD from baseline to week 48 in PLWH was marginally significant (P = .056). No significant difference was observed in the prevalence of LVSD, PAH, or ILVM at baseline and week 48 in PLWH. In logistic regression analysis of all participants, age was significantly associated with LVSD; HIV infection, age, and hypertension were associated with DD whereas HIV infection and hypertension were associated with ILVM at baseline. Logistic regression analysis of PLWH showed that only age was significantly associated with LVSD and DD.Conclusions. The prevalence of echocardiographic abnormalities was significantly higher in ART-naive PLWH than in controls. HIV infection was significantly associated with cardiac abnormalities. No significant change in echocardiographic abnormalities was observed after 48 weeks of ART. Longer-term prospective studies are warranted. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus–positive children enrolled in China's national pediatric antiretroviral therapy program experience a mortality rate of 2.3 per 100 child-years, survival rate of 94%, and improved treatment outcomes including elevated CD4 percentage, hemoglobin, and weight-for-age and height-for-age z scores after 3 years of follow-up.Background. The aim of this study was to describe 3-year mortality rates, associated risk factors, and long-term clinical outcomes of children enrolled in China's national free pediatric antiretroviral therapy (ART) program.Methods. Records were abstracted from the national human immunodeficiency virus (HIV)/AIDS case reporting and national pediatric ART databases for all HIV-positive children ≤15 years old who initiated ART prior to December 2010. Mortality risk factors over 3 years of follow-up were examined using Cox proportional hazards regression models. Life tables were used to determine survival rate over time. Longitudinal plots of CD4+ T-cell percentage (CD4%), hemoglobin level, weight-for-age z (WAZ) score, and height-for-age z (HAZ) score were created using generalized estimating equation models.Results. Among the 1818 children included in our cohort, 93 deaths were recorded in 4022 child-years (CY) of observed time for an overall mortality rate of 2.31 per 100 CY (95% confidence interval [CI], 1.75–2.78). The strongest factor associated with mortality was baseline WAZ score <−2 (adjusted hazard ratio [HR] = 9.1; 95% CI, 2.5–33.2), followed by World Health Organization stage III or IV disease (adjusted HR = 2.4; 95% CI, 1.1–5.2), and hemoglobin <90 g/L (adjusted HR = 2.2; 95% CI, 1.2–3.9). CD4%, hemoglobin level, WAZ score, and HAZ score increased over time.Conclusions. Our finding that 94% of children engaged in this program are still alive and of improved health after 3 years of treatment demonstrates that China's national pediatric ART program is effective. This program needs to be expanded to better meet treatment demands, and efforts to identify HIV-positive children earlier must be prioritized. [ABSTRACT FROM PUBLISHER]

Background: Cardiometabolic and cerebrovascular disease are strong independent contributors to cognitive impairment in people living with HIV. Data suggest that cardiovascular risk may play a greater role in cognitive health in women than in men with HIV. Methods: We performed a cross-sectional study of 104 participants with virologically suppressed HIV from 2 clinics in urban China. Participants underwent neuropsychological testing from which we calculated T scores globally and in 5 cognitive domains. We assessed cerebral vasoreactivity of the middle cerebral arteries in response to breath holding. We constructed linear regression models to determine associations between cerebrovascular and cognitive function overall and stratified by sex. Results: Women were younger than men (48 versus 51 years, P = 0.053), had fewer years of education (9 years versus 12 years, P = 0.004), and fewer cardiometabolic risk factors (0 versus 1 factor, P = 0.008). In a model with all participants, cerebrovascular function was significantly associated with global cognition (2.74 higher T score per 1-point higher cerebral vasoreactivity [SE 1.30], P = 0.037). Cerebrovascular function remained significantly associated with global cognition among women (4.15 higher T score [SE 1.78], P = 0.028) but not men (1.70 higher T score [SE 1.74], P = 0.33). The relationships between cerebrovascular function and specific cognitive domains followed a similar pattern, with significant associations present among women but not men. Conclusions: Women with well-controlled HIV may be more vulnerable to the effect of cerebrovascular injury on cognitive health than men. Studies evaluating strategies to protect against cognitive impairment in people living with HIV should include adequate representation of women and stratification of analyses by sex. [ABSTRACT FROM AUTHOR]

In 2003, the Chinese Government initiated a free antiretroviral therapy (ART) program focusing on adult AIDS patients. Pediatric antiretroviral (ARV) formulations were yet unavailable. It was not until July 2005, with the initiation of a two-stage program implemented by the Chinese Ministry of Health, that pediatric formulations became accessible in China. Initially, the pediatric ART program was piloted in six provinces with the highest incidences of pediatric HIV/AIDS. The pilot stage allowed the Chinese Center for Disease Control and Prevention (CCDC) to finalize entry criteria, treatment regimen, and patient monitoring and follow-up procedures. The second stage commenced at the end of 2006 when the program was scaled-up nationally. In order to guarantee treatment of pediatric patients, extensive training in the selection of appropriate ARV drug regimen and dosage was provided to doctors, often through on-site collaboration with domestic and international experts. The CCDC simultaneously established a pediatric ARV management system and a pediatric ART information system. CD4 count and other laboratory tests are being routinely performed on these pediatric patients. By the end of June 2009, 1529 pediatric patients had received ARV under the national program. However, challenges remain. Firstly, many children infected with HIV/AIDS live in rural areas where the treatment quality is hindered by the limited number of medical facilities and skilled medical workers. Secondly, much of the pediatric ARV drug supply depends on donation. An effort needs to be made by the Chinese Government to establish China's own drug procurement and supply system. [ABSTRACT FROM AUTHOR]

Factors that influence viral response when antiretroviral therapy (ART) is initiated in neonates are not well characterized. We assessed if there is consistency in predictive factors when operationalizing viral response using different methods. Data were collected from a clinical study in South Africa that started ART in neonates within 14 days of birth (2013–2018). Among 61 infants followed for ≥48 weeks after ART initiation, viral response through 72 weeks was defined by three methods: (1) clinical endpoints (virologic success, rebound, and failure); (2) time to viral suppression, i.e., any viral load (VL: copies/mL) <400, <50, or target not detected (TND) using time-to-event methods; and (3) latent class growth analysis (LCGA) to empirically estimate discrete groups with shared patterns of VL trajectories over time. We investigated the following factors: age at ART initiation, sex, birthweight, preterm birth, mode of delivery, breastfeeding, pre-treatment VL and CD4, maternal ART during pregnancy, and maternal VL and CD4 count. ART was initiated 0–48 h of birth among 57.4% of the infants, 48 h–7 days in 29.5% and 8–14 days in 13.1%. By Method 1, infants were categorized into 'success' (54.1%), 'rebound' (21.3%), and 'failure' (24.6%) for viral response. For Method 2, median time to achieving a VL <400, <50, or TND was 58, 123, and 331 days, respectively. For Method 3, infants were categorized into three trajectories: 'rapid decline' (29.5%), 'slow decline' (47.5%), and 'persistently high' (23.0%). All methods found that higher pre-treatment VL, particularly >100,000, was associated with less favorable viral outcomes. No exposure to maternal ART was associated with a better viral response, while a higher maternal VL was associated with less favorable viral response and higher maternal CD4 was associated with better viral response across all three methods. The LCGA method found that infants who initiated ART 8–14 days had less favorable viral response than those who initiated ART earlier. The other two methods trended in a similar direction. Across three methods to operationalize viral response in the context of early infant treatment, findings of factors associated with viral response were largely consistent, including infant pre-treatment VL, maternal VL, and maternal CD4 count. [ABSTRACT FROM AUTHOR]

We recently identified a novel alternatively spliced isoform of human programmed cell death 1 (PD-1), named Δ42PD1, which contains a 42-base-pair in-frame deletion compared with the full-length PD-1. Δ42PD1 is likely constitutively expressed on human monocytes and down-regulated in patients infected with human immunodeficiency virus type 1 (HIV-1). The mechanism underlying the regulation of Δ42PD-1 expression in monocytes remains unknown. By flow cytometry, we investigated the effect of Interferon-gamma (INF-γ) on the expression of Δ42PD1 in primary human monocytes as well as monocytic cell lines THP-1 and U937 cells. In addition, signaling pathway inhibitors and Δ42PD1-specific blocking antibody were used to explore the pathway involved in INF-γ-induced Δ42PD1 upregulation, and to elucidate the relationship between Δ42PD1 and TNF-α or IL-6 production by INF-γ primed monocytes in response to pre-fixed E. coli. Furthermore, we assessed T-cell proliferation, activation and cytokine production as enriched CD4+ T cells were co-cultured with THP-1 or U937 cells, with or without Δ42PD1-blocking antibody. Treatment of human peripheral blood mononuclear cells (PBMCs) with IFN-γ resulted in an approximately 4-fold increase in the expression of Δ42PD1 on monocytes. Similarly, IFN-γ upregulates Δ42PD1 expression on human monocytic cell lines THP-1 and U937, in a time- and dose-dependent manner. IFN-γ-induced Δ42PD1 upregulation was abolished by JAK inhibitors Ruxolitinib and Tasocitinib, PI3K inhibitor LY294002, and AKT inhibitor MK-2206, respectively, but not by STAT1 inhibitor and MAPK signaling pathway inhibitors. JAK, PI3K-AKT, and MAPK signaling inhibitors abolished effectively the production of TNF-α and IL-6 in INF-γ-primed monocytes in response to pre-fixed E. coli. In contrast, Δ42PD1-specific blocking antibody did not affect the IFN-γ-induced priming effect. Furthermore, the MFI ratio of Δ42PD1 to full-length PD-1 (PD-1 Δ/F ratio) was significantly and positively correlated with TNF-α (P = 0.0289, r = 0.6038) produced by circulating CD14+ monocytes in response to pre-fixed E. coli. Notably, Δ42PD1 blockage significantly inhibited CD4+ T-cells proliferation and cytokine production in the co-culture conditions. We demonstrated that IFN-γ increases Δ42PD1 expression on human monocytes via activating the PI3K/AKT signaling pathway downstream of JAKs, and that the PD-1 Δ/F ratio is a potential biomarker to predict the functional state of monocytes. Notably, we revealed the Δ42PD1 play a role in T-cell regulation, providing a novel potential approach to manipulate adaptive immune response. [ABSTRACT FROM AUTHOR]

Abstract: A series of 4-aminopyrimidines (1) was identified as novel HIV inhibitors of unknown molecular target. Structural modifications were carried out to establish its SAR and identify the linking site for target identification. A number of analogs were found to possess single digit inhibitory activity for HIV replication. Several analogs with various potential linkers, including a biotinated analog, also exhibited excellent potency, and could serve as tools for the identification of novel anti-HIV targets. [Copyright &y& Elsevier]

Abstract: The synthesis and preliminary structure–activity relationship of a series of pyrrolidinones are described. These pyrrolidinones have been characterized as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) which are highly potent against wild-type and drug-resistant human immunodeficiency viruses (HIV-1). [Copyright &y& Elsevier]

Abstract: A series of heterocycle-containing oxindoles was synthesized and their HIV antiviral activities were assessed. Some of these analogs exhibited potent inhibitory activities against both wild-type virus and a number of drug-resistant mutant viruses. In addition, oxindole 9z also showed promising pharmacokinetics. [Copyright &y& Elsevier]

Abstract: A novel oxindole was discovered as an HIV non-nucleoside reverse transcriptase inhibitor via HTS using a cell-based assay. Systematic structural modifications were carried out to establish its SAR. These modifications led to the identification of oxindoles with low nanomolar potency for inhibiting HIV replication. These novel and potent oxindoles could serve as advanced leads for further optimizations. [Copyright &y& Elsevier]