Oral Simnotrelvir for Adult Patients with Mild-to-Moderate Covid-19.

BACKGROUND: Simnotrelvir is an oral 3-chymotrypsin-like protease inhibitor that has been found to have in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential efficacy in a phase 1B trial. METHODS: In this phase 2-3, double-blind, randomized, placebo-controlled trial, we assigned patients who had mild-to-moderate coronavirus disease 2019 (Covid-19) and onset of symptoms within the past 3 days in a 1:1 ratio to receive 750 mg of simnotrelvir plus 100 mg of ritonavir or placebo twice daily for 5 days. The primary efficacy end point was the time to sustained resolution of symptoms, defined as the absence of 11 Covid-19-related symptoms for 2 consecutive days. Safety and changes in viral load were also assessed. RESULTS: A total of 1208 patients were enrolled at 35 sites in China; 603 were assigned to receive simnotrelvir and 605 to receive placebo. Among patients in the modified intention-to-treat population who received the first dose of trial drug or placebo within 72 hours after symptom onset, the time to sustained resolution of Covid-19 symptoms was significantly shorter in the simnotrelvir group than in the placebo group (180.1 hours [95% confidence interval {CI}, 162.1 to 201.6] vs. 216.0 hours [95% CI, 203.4 to 228.1]; median difference, -35.8 hours [95% CI, -60.1 to -12.4]; P = 0.006 by Peto-Prentice test). On day 5, the decrease in viral load from baseline was greater in the simnotrelvir group than in the placebo group (mean difference [±SE], -1.51±0.14 log10 copies per milliliter; 95% CI, -1.79 to -1.24). The incidence of adverse events during treatment was higher in the simnotrelvir group than in the placebo group (29.0% vs. 21.6%). Most adverse events were mild or moderate. CONCLUSIONS: Early administration of simnotrelvir plus ritonavir shortened the time to the resolution of symptoms among adult patients with Covid-19, without evident safety concerns. (Funded by Jiangsu Simcere Pharmaceutical; ClinicalTrials.gov number, NCT05506176.).

Viral and host factors related to the clinical outcome of COVID-19.

In December 2019, coronavirus disease 2019 (COVID-19), which is caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in Wuhan (Hubei province, China)1; it soon spread across the world. In this ongoing pandemic, public health concerns and the urgent need for effective therapeutic measures require a deep understanding of the epidemiology, transmissibility and pathogenesis of COVID-19. Here we analysed clinical, molecular and immunological data from 326 patients with confirmed SARS-CoV-2 infection in Shanghai. The genomic sequences of SARS-CoV-2, assembled from 112 high-quality samples together with sequences in the Global Initiative on Sharing All Influenza Data (GISAID) dataset, showed a stable evolution and suggested that there were two major lineages with differential exposure history during the early phase of the outbreak in Wuhan. Nevertheless, they exhibited similar virulence and clinical outcomes. Lymphocytopenia, especially reduced CD4+ and CD8+ T cell counts upon hospital admission, was predictive of disease progression. High levels of interleukin (IL)-6 and IL-8 during treatment were observed in patients with severe or critical disease and correlated with decreased lymphocyte count. The determinants of disease severity seemed to stem mostly from host factors such as age and lymphocytopenia (and its associated cytokine storm), whereas viral genetic variation did not significantly affect outcomes.

The profile of HIV-1 drug resistance in Shanghai, China: a retrospective study from 2017 to 2021.

BACKGROUND: HIV-1 drug resistance is a huge challenge in the era of ART. OBJECTIVES: To investigate the prevalence and characteristics of acquired HIV-1 drug resistance (ADR) in Shanghai, China. METHODS: An epidemiological study was performed among people living with human immunodeficiency virus (PLWH) receiving ART in Shanghai from January 2017 to December 2021. A total of 8669 PLWH were tested for drug resistance by genotypic resistance testing. Drug resistance mutations (DRMs) were identified using the Stanford University HIV Drug Resistance Database program. RESULTS: Ten HIV-1 subtypes/circulating recombinant forms (CRFs) were identified, mainly including CRF01_AE (46.8%), CRF07_BC (35.7%), B (6.4%), CRF55_01B (2.8%) and CRF08_BC (2.4%). The prevalence of ADR was 48% (389/811). Three NRTI-associated mutations (M184V/I/L, S68G/N/R and K65R/N) and four NNRTI-associated mutations (V179D/E/T/L, K103N/R/S/T, V106M/I/A and G190A/S/T/C/D/E/Q) were the most common DRMs. These DRMs caused high-level resistance to lamivudine, emtricitabine, efavirenz and nevirapine. The DRM profiles appeared to be significantly different among different subtypes. CONCLUSIONS: We revealed HIV-1 subtype characteristics and the DRM profile in Shanghai, which provide crucial guidance for clinical treatment and management of PLWH.

Mpox patients' experience from infection to treatment and implications for prevention and control: A multicenter qualitative study in China.

Monkeypox (mpox), a viral zoonotic disease, is spreading worldwide. However, evidence that informs prevention and control strategies in the Asia Pacific Region is very limited. Our study aims to investigate the experiences of mpox patients from infection to treatment to provide scientific basis for the prevention and control. A multicenter qualitative design was used. A total of 15 mpox patients were recruited between July 6 and July 25, 2023, from six cities in China. Semistructured interviews were conducted by telephone and analyzed using the thematic analysis. The interview was divided into two sections: patients' experiences (prediagnosis experience, treatment-seeking experience, and quarantine experience) and advice. Prediagnosis experience was summarized into three themes: symptoms, possible routes of infection, and knowledge of mpox. Treatment-seeking experience was summarized into three themes: time of visit to hospital, diagnostic difficulties, and attitude toward diagnosis. Quarantine experience was summarized into three themes: body and mind reactions, reluctance to self-disclose infection status, and factors facilitating recovery. Themes identified from patients' advice were as follows: (1) Increase in testing channels and methods, (2) Development and introduction of vaccines, (3) Adjustment of quarantine program, (4) Improvement of treatment measures, and (5) Improvement of publicity and education. To effectively curb the mpox epidemic, structured measures are urgently needed to address the mpox-related stigma and discrimination. Targeted health education should be provided to MSM, focusing on the prevention, detection, and treatment services. Hospitals should enhance the training of clinicians in key departments including infectious disease and dermatology, to improve diagnostic capability and sensitivity. Furthermore, given the absence of specific antiviral medications, supervised home quarantine may be a good option.

iTRAQ-based proteomic study on monocyte cell model discovered an association of LAMP2 downregulation with HIV-1 latency.

BACKGROUND: Patients with immunodeficiency virus-1 (HIV-1) infection are challenging to be cured completely due to the existence of HIV-1 latency reservoirs. However, the knowledge of the mechanisms and biomarkers associated with HIV-1 latency is limited. Therefore, identifying proteins related to HIV-1 latency could provide new insights into the underlying mechanisms of HIV-1 latency, and ultimately contribute to the eradication of HIV reservoirs. METHODS: An Isobaric Tags for Relative and Absolute Quantification (iTRAQ)-labeled subcellular proteomic study was performed on an HIV-1 latently infected cell model (U1, a HIV-1-integrated U937 cell line) and its control (U937). Differentially expressed proteins (DEPs) were analyzed using STRING-DB. Selected DEPs were further evaluated by western blotting and multiple reaction monitoring technology in both cell model and patient-derived cluster of differentiation 4 (CD4)+ T cells. Finally, we investigated the relationship between a specific DEP lysosome-associated membrane glycoprotein 2 (LAMP2) and HIV-1 reactivation by panobinostat or lysosome regulation by a lysosomotropic agent hydroxychloroquine in U1 and U937 cells. RESULTS: In total, 110 DEPs were identified in U1 cells comparing to U937 control cells. Bioinformatics analysis suggested associations of the altered proteins with the immune response and endosomal/lysosomal pathway. LAMP2, leukocyte surface antigen CD47, CD55, and ITGA6 were downregulated in HIV-1 latent cells. Downregulated LAMP2 was further confirmed in resting CD4+ T cells from patients with latent HIV-1 infection. Furthermore, both HIV-1 reactivation by panobinostat and stimulation with hydroxychloroquine upregulated LAMP2 expression. CONCLUSIONS: Our results indicated the involvement of the endosomal/lysosomal pathway in HIV-1 latency in macrophage cell model. The down-modulation of LAMP2 was associated with HIV latency, and the restoration of LAMP2 expression accompanied the transition of viral latency to active infection. This study provides new insights into the mechanism of HIV-1 latency and potential strategies for eradicating HIV-1 reservoirs by targeting LAMP2 expression.

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.

Role of thymosin α1 in restoring immune response in immunological nonresponders living with HIV.

BACKGROUND: Immunological nonresponders (INRs) living with HIV are at increased risk of co-infection and multiple tumors, with no effective strategy currently available to restore their T-cell immune response. This study aimed to explore the safety and efficacy of thymosin α1 in reconstituting the immune response in INRs. METHODS: INRs with CD4 + T cell counts between 100 and 350 cells/µL were enrolled and received two-staged 1.6 mg thymosin α1 subcutaneous injections for 24 weeks (daily in the first 2 weeks and biweekly in the subsequent 22 weeks) while continuing antiretroviral therapy. T cell counts and subsets, the expression of PD-1 and TIM-3 on T cells, and signal joint T cell receptor excision circles (sjTREC) at week 24 were evaluated as endpoints. RESULTS: Twenty three INRs were screened for eligibility, and 20 received treatment. The majority were male (19/20), with a median age of 48.1 years (interquartile range: 40.5-57.0) and had received antiretroviral therapy for 5.0 (3.0, 7.3) years. Multiple comparisons indicated that CD4 + T cell count and sjTREC increased after initiation of treatment, although no significant differences were observed at week 24 compared to baseline. Greatly, levels of CD4 + T cell proportion (17.2% vs. 29.1%, P < 0.001), naïve CD4 + and CD8 + T cell proportion (17.2% vs. 41.1%, P < 0.001; 13.8% vs. 26.6%, P = 0.008) significantly increased. Meanwhile, the proportion of CD4 + central memory T cells of HIV latent hosts (42.7% vs. 10.3%, P < 0.001) significantly decreased. Moreover, the expression of PD-1 on CD4 + T cells (14.1% vs. 6.5%, P < 0.001) and CD8 + T cells (8.5% vs. 4.1%, P < 0.001) decreased, but the expression of TIM-3 on T cellsremained unaltered at week 24. No severe adverse events were reported and HIV viral loads kept stable throughout the study. CONCLUSIONS: Thymosin α1 enhance CD4 + T cell count and thymic output albeit as a trend rather than an endpoint. Importantly, it improves immunosenescence and decreases immune exhaustion, warranting further investigation. TRIAL REGISTRATION: This single-arm prospective study was registered with ClinicalTrials.gov (NCT04963712) on July 15, 2021.

Pterostilbene protects against H2 O2 -induced oxidative stress by regulating GAS6/Axl signaling in HL-1 cells.

Pterostilbene (PTE, trans-3,5-dimethoxy-4'-hydroxystilbene), a natural plant polyphenol, possesses numerous pharmacological effects, including antioxidant, antidiabetic, antiatherosclerotic, and neuroprotective aspects. This study aims to investigate whether PTE plays a protective role against oxidative stress injury by GAS6/Axl signaling pathway in cardiomyocytes. Hydrogen peroxide (H2 O2 )-induced oxidative stress HL-1 cells were used as models. The mechanism by which PTE protected oxidative stress is investigated by combining cell viability, cell ROS levels, apoptosis assay, molecular docking, quantitative real-time PCR, and western blot analysis. GAS6 shRNA was performed to investigate the involvement of GAS6/Axl pathways in PTE's protective role. The results showed that PTE treatment improved the cell morphology and viability, and inhibited the apoptosis rate and ROS levels in H2 O2 -injured HL-1 cells. Particularly, PTE treatment upregulated the levels of GAS6, Axl, and markers related to oxidative stress, apoptosis, and mitochondrial function related. Molecular docking showed that PTE and GAS6 have good binding ability. Taken together, PTE plays a protective role against oxidative stress injury through inhibiting oxidative stress and apoptosis and improving mitochondrial function. Particularly, GAS6/Axl axis is the surprisingly prominent in the PTE-mediated pleiotropic effects.

Construction and efficacy testing of DNA vaccines containing HLA-A*02:01-restricted SARS-CoV-2 T-cell epitopes predicted by immunoinformatics.

Vaccines play essential roles in the fight against the COVID-19 pandemic. The development and assessment of COVID-19 vaccines have generally focused on the induction and boosting of neutralizing antibodies targeting the SARS-CoV-2 spike (S) protein. Due to rapid and continuous variation in the S protein, such vaccines need to be regularly updated to match newly emerged dominant variants. T-cell vaccines that target MHC I- or II-restricted epitopes in both structural and non-structural viral proteins have the potential to induce broadly cross-protective and long-lasting responses. In this work, the entire proteome encoded by SARS-CoV-2 (Wuhan-hu-1) is subjected to immunoinformatics-based prediction of HLA-A*02:01-restricted epitopes. The immunogenicity of the predicted epitopes is evaluated using peripheral blood mononuclear cells from convalescent Wuhan-hu-1-infected patients. Furthermore, predicted epitopes that are conserved across major SARS-CoV-2 lineages and variants are used to construct DNA vaccines expressing multi-epitope polypeptides. Most importantly, two DNA vaccine constructs induce epitope-specific CD8 + T-cell responses in a mouse model of HLA-A*02:01 restriction and protect immunized mice from challenge with Wuhan-hu-1 virus after hACE2 transduction. These data provide candidate T-cell epitopes useful for the development of T-cell vaccines against SARS-CoV-2 and demonstrate a strategy for quick T-cell vaccine candidate development applicable to other emerging pathogens.

A Central Auditory Test reveals differences between drug treatment regimens in adults living with HIV.

OBJECTIVE: This exploratory study examined whether central auditory tests show differences between people living with HIV (PLWH) treated with two predominant antiretroviral drug therapy (ART) regimens. DESIGN: Cross-sectional. STUDY SAMPLE: 253 PLWH (mean age 39.8 years) from the Shanghai Public Health Clinical Centre, China. METHODS: The Hearing in Noise Test speech reception threshold (SRT) assessed central auditory function and the Montreal Cognitive Assessment (MoCA) assessed cognition. The relationship between ART regimen and SRT was evaluated with multivariable linear regression incorporating age, HIV duration, and peripheral hearing ability. Multivariable logistic regression was used to ascertain if SRT and ART regimen predicted MoCA impairment. RESULTS: The two predominant ART regimens differed by one drug (zidovudine or tenofovir). Participants taking the zidovudine-containing regimen had poorer SRT performance (p=.012) independent of age and hearing thresholds. MoCA scores did not differ between drug regimens, but a negative relationship was found between SRT and MoCA impairment (p=.048). CONCLUSIONS: ART regimens differed in their association with central auditory test performance likely reflecting neurocognitive changes in PLWH taking the zidovudine-containing regimen. Central auditory test performance also marginally predicted cognitive impairment, supporting further assessment of central auditory tests to detect neurocognitive deficits in PLWH.

Epidemiological characteristics, clinical manifestations, and mental health status of human mpox cases: A multicenter cross-sectional study in China.

Human mpox is occurring worldwide, however, evidence from the Asian Pacific Region is limited. In this multicenter cross-sectional study, information of confirmed mpox cases diagnosed between June 1 and July 31, 2023 in China. Information included demographic and epidemiological characteristics, and clinical manifestations, laboratory results, and mental health status of mpox cases. A total of 115 confirmed mpox cases were enrolled. All cases were men. A total of 102 (90.3%) identified as homosexual. The median age was 31.0 years (interquartile range 27.0-36.5). A total of 65 (56.5%) were HIV-positive, of whom 92.3% were receiving antiretroviral therapy (ART). A total of 19/39 (40.4%) had a CD4 cell count <500 cells/µL. Systemic features such as fever (73.0%), lymphadenopathies (49.6%), and myalgia (28.7%) were commonly observed. Skin lesions were present in all participants: 49.6% in the genital area and 27.0% in the perianal area. Vesicular rash (78.3%) and papular rash (44.3%) were the most common lesion morphologies. People living with HIV were more likely to have anxiety than those living without HIV. The majority of mpox cases had primary genital lesions and sexual activities before diagnosis, which supports the likelihood of sexual contact transmission. Guidelines on hospitalization and isolation protocols for mpox patients necessitate further confirmation.

Effects of Lianhuaqingwen Capsules in adults with mild-to-moderate coronavirus disease 2019: an international, multicenter, double-blind, randomized controlled trial.

BACKGROUND: In a randomized trial, Lianhuaqingwen (LHQW) capsule was effective for accelerating symptom recovery among patients with coronavirus disease 2019 (COVID-19). However, the lack of blinding and limited sample sizes decreased the level of clinical evidence. OBJECTIVES: To evaluate the efficacy and safety of LHQW capsule in adults with mild-to-moderate COVID-19. METHODS: We conducted a double-blind randomized controlled trial in adults with mild-to-moderate COVID-19 (17 sites from China, Thailand, Philippine and Vietnam). Patients received standard-of-care alone or plus LHQW capsules (4 capsules, thrice daily) for 14 days. The primary endpoint was the median time to sustained clinical improvement or resolution of nine major symptoms. RESULTS: The full-analysis set consisted of 410 patients in LHQW capsules and 405 in placebo group. LHQW significantly shortened the primary endpoint in the full-analysis set (4.0 vs. 6.7 days, hazards ratio: 1.63, 95% confidence interval: 1.39-1.90). LHQW capsules shortened the median time to sustained clinical improvement or resolution of stuffy or runny nose (2.8 vs. 3.7 days), sore throat (2.0 vs. 2.6 days), cough (3.2 vs. 4.9 days), feeling hot or feverish (1.0 vs. 1.3 days), low energy or tiredness (1.3 vs. 1.9 days), and myalgia (1.5 vs. 2.0 days). The duration to sustained clinical improvement or resolution of shortness of breath, headache, and chills or shivering did not differ significantly between the two groups. Safety was comparable between the two groups. No serious adverse events were reported. INTERPRETATION: LHQW capsules promote recovery of mild-to-moderate COVID-19 via accelerating symptom resolution and were well tolerated. Trial registration ChiCTR2200056727 .

Clinical characteristics and prognostic factors of 60 patients with acquired immune deficiency syndrome combined with Cryptococcus neoformans.

OBJECTIVE: Cryptococcal meningitis (CM) threatens people's health and is the main cause of opportunistic fungus-related death in acquired immune deficiency syndrome (AIDS) patients. Herein, we investigate the clinical characteristics and prognostic factors of AIDS patients with Cryptococcus neoformans in Wenzhou, Zhejiang Province, China. METHODS: Our study enrolled AIDS patients diagnosed with Cryptococcus neoformans infection who were hospitalised in our hospital. They were divided into Group A (32 patients with CM) and Group B (28 patients without CM) according to their diagnosis. The differences between the two groups of patients' clinical symptoms, imaging examinations and laboratory examinations were observed. Statistical methods were used to analyse the difference in prognosis between the two groups. RESULTS: Headache and fever were the most common clinical characteristics for patients with CM, while respiratory symptoms and fever were the most common clinical characteristics for patients without CM. The positive rate of cryptococcal capsular antigen, India ink staining and culture in the cerebrospinal fluid examination was higher in the CM patients than in the non-CM patients. The overall morbidity and mortality rate after systemic antifungal therapy was higher in the CM patients than in the non-CM patients. A higher incidence of headache, impaired consciousness, nuchal rigidity, first intracranial pressure > 200 mmH2O and mortality was observed in the CM patients than in the non-CM patients. Multifactorial logistic regression analysis showed that headache risk factors affecting the patient's prognosis at 12 weeks. CONCLUSION: Patients with AIDS diagnosed with Cryptococcus neoformans infection have insidious clinical symptoms in the early stage, and their manifestation is often non-specific, resulting in poor prognosis and high mortality among CM patients compared to patients without CM. Therefore, early identification and timely antifungal therapy before the disease progresses to meningitis are of great value in improving the survival rate of patients.

Multi-dimensional mismatch and barriers for promoting PrEP among men who have sex with men in China: a cross sectional survey from the Demand-side.

BACKGROUND: Men who have sex with men (MSM) is a key population for preventing HIV in China, yet pre-exposure prophylaxis (PrEP) is not widely accepted in this population. The objective of this manuscript was to assessed the barriers in the acknowledgement and uptake focusing the demand side. METHODS: An online questionnaire survey was conducted from December 2018 to January 2019. All participants were required to scan two-dimensional code which was the online crowdsourcing survey platform to complete the electronic questionnaire anonymously. RESULTS: Among 1915 MSM from thirty-four cities of China, 512 (26.7%) versus 1617 (84.4%) had an objective or subjective need of PrEP, respectively. One hundred and six (5.5%) reported affordability and only 23 (1.2%) had ever taken it. Age, living alone and occupation were associated with the objective needs. Age, income, sexual behavior were associated with actual usage. The participants who they had objective need to use PrEP are the population which we should focus on. CONCLUSION: A wide disconnect exists among the objective need, willingness, affordability and uptake of PrEP. Cost was the most prevalent barrier, accounting for 78.22% of individuals who needed and wished for PrEP but finally failed to receive it. The findings might facilitate optimizing future allocation of resources to better promote PrEP in Chinese MSM.

Health disparities affecting persons living with HIV and using substances in China.

Health disparities affecting persons living with HIV (PLWH) as well as those affecting individuals who use substances have been documented in China. However, health status and outcomes within the intersectional population of those who both live with HIV and use substances is not well understood. One hundred and sixty-nine PLWH receiving care in China completed surveys assessing HIV-clinical factors, substance use, and HIV-related physical health symptoms. We tested associations between substance use and health symptoms using multivariate logistic and ordinal regressions. Using one substance over the past week was associated with greater maximal severity of physical symptoms (p < .01); using two or more substances in the past week was associated with both increased total physical symptom severity (p < .05) and a dosage response in increased maximal severity (p < .01). Findings highlight the need for providers to address substance use for comprehensive care of PLWH to improve overall wellbeing.

Safety, Tolerability, Pharmacokinetics, and Acceptability of Oral and Long-Acting Cabotegravir in HIV-Negative Chinese Men.

Long-acting (LA) cabotegravir demonstrated superior efficacy versus daily oral standard-of-care for HIV-1 preexposure prophylaxis. This phase 1 study assessed safety, tolerability, pharmacokinetics, and acceptability of cabotegravir in 47 HIV-negative adult Chinese men at low risk of acquiring HIV-1. Participants received once-daily oral cabotegravir 30 mg for 4 weeks and, after a 1-week washout, five 600-mg (3-mL) intramuscular cabotegravir LA injections at weeks 5, 9, 17, 25, and 33. Pharmacokinetic plasma samples were intensively collected on day 27 (n = 17) and sparsely collected before each injection until 56 weeks after final injection (n = 47). Cabotegravir LA injections were acceptable and well tolerated. Common adverse events included injection site pain, injection site swelling, and upper respiratory tract infection. No drug-related serious adverse events or deaths occurred. Mean cabotegravir concentration remained above 1.33 µg/mL (8× in vitro protein-adjusted concentration for 90% of the maximum inhibition of viral growth [PA-IC90]) before each injection and above 0.166 µg/mL (PA-IC90) for >32 weeks after final injection. Trough concentrations remained above PA-IC90 in nearly all participants and showed minimal accumulation. Noncompartmental pharmacokinetic analysis was performed. Geometric mean of terminal half-life was 1.89 and 47 days after oral and LA dosing, respectively. Cabotegravir concentrations were estimated to remain quantifiable for 48.7 weeks after final injection. Steady-state area under the concentration-time curve (AUC), peak concentration, trough concentration, terminal half-life, time to peak concentration, and apparent clearance after cabotegravir oral and LA dosing were similar to those estimated in non-Asian men in historical studies. These results support further clinical development of cabotegravir LA in China. (This study has been registered at ClinicalTrials.gov under registration no. NCT03422172.).

PEBP1 suppresses HIV transcription and induces latency by inactivating MAPK/NF-κB signaling.

The latent HIV-1 reservoir is a major barrier to viral eradication. However, our understanding of how HIV-1 establishes latency is incomplete. Here, by performing a genome-wide CRISPR-Cas9 knockout library screen, we identify phosphatidylethanolamine-binding protein 1 (PEBP1), also known as Raf kinase inhibitor protein (RKIP), as a novel gene inducing HIV latency. Depletion of PEBP1 leads to the reactivation of HIV-1 in multiple models of latency. Mechanistically, PEBP1 de-phosphorylates Raf1/ERK/IκB and IKK/IκB signaling pathways to sequestrate NF-κB in the cytoplasm, which transcriptionally inactivates HIV-1 to induce latency. Importantly, the induction of PEBP1 expression by the green tea compound epigallocatechin-3-gallate (EGCG) prevents latency reversal by inhibiting nuclear translocation of NF-κB, thereby suppressing HIV-1 transcription in primary CD4+ T cells isolated from patients receiving antiretroviral therapy (ART). These results suggest a critical role for PEBP1 in the regulation of upstream NF-κB signaling pathways governing HIV transcription. Targeting of this pathway could be an option to control HIV reservoirs in patients in the future.

Efficacy and safety of miconazole muco-adhesive tablet versus itraconazole in oropharyngeal candidiasis: A randomized, multi-centered, double-blind, phase 3 trial.

Oropharyngeal candidiasis (OPC) is an opportunistic infection treated with anti-fungal agents. Herein, we evaluate the efficacy and safety of miconazole buccal tablets (MBT) and itraconazole capsules in the localized treatment of patients with OPC. In this multi-centered, double-blinded, phase III trial (CTR20130414), both males and non-pregnant females (≥18 years) with OPC were randomized (1:1) to MBT plus placebo (experimental group) or itraconazole capsules plus placebo (control group). The primary endpoint was clinical cure at the end-of-treatment period [visit 4 (V4)] while secondary endpoints were clinical remission rates, partial remission rates, mycological cure, clinical relapse, and adverse events (AEs). All endpoints were statistically analyzed in both the full analysis set (FAS) and per-protocol (PP) set. A total of 431 (experimental: 216; control: 215) subjects were included. At V4, in the FAS set, the clinical cure was achieved in 68% and 59% patients in experimental and control groups, respectively with a treatment difference of 9% [95% confidence interval (CI): -1,19; P < .001] demonstrating non-inferiority of MBT over itraconazole. At V4, mycological cure rates were 68.2% and 42.0% in the experimental group and control groups (P < .001), respectively in FAS. The relapse rates were 5.4% and 6.6%, respectively, in the experimental and control groups. A total of 210 patients experienced AEs during treatment with 47.7% in the experimental group and 49.8% in the control group with no deaths. This study demonstrated that once-daily treatment with MBT was non-inferior to itraconazole with higher mycological cure rates and was tolerable with mild AE in patients with OPC.

Miconazole is an antifungal drug against certain types of fungus or yeast infections. In this study, we showed that treatment with once-daily miconazole buccal tablets was as effective as systemic itraconazole capsules in Chinese patients infected by oropharyngeal candidiasis with minimum side effects.

Longitudinal trajectory of the association between quality of life and depression among people living with HIV in China: a mixed effects model.

ABSTRACTAlthough depression has been associated with low QOL, limited research has quantified the change of depression to improvement of QOL among naïve PLHIV using ART in Shanghai, China. This study examined the association between depression symptoms and QOL among Chinese PLWH in a six-month longitudinal study. Data were collected from 111 people living with HIV at baseline, 3rd month and 6th month after initiating ART, using the WHOQOL-HIV BREF and the Center for Epidemiologic Studies Depression Scale (CES-D), and analyzed using a mixed effects model. QOL is improved after initiating ART, while the symptoms of depression did not decrease significantly. The depression symptoms were strong and negatively associated with QOL and all domains of QOL, and the strength of this association decreased over time in the six months follow-up. ART had different impacts on depression symptoms and QOL. Besides, depression symptoms were strong and negatively associated with QOL among PLHIV over time. Mental health practitioners and nurses should consider the ART and time factors when designed interventions to improve QOL by targeting depression symptoms. Interventions designed to improve QOL and depression symptoms should be developed targeting both ART and self-management among PLHIV.

The Resting State Central Auditory Network: a Potential Marker of HIV-Related Central Nervous System Alterations.

OBJECTIVE: HIV positive (HIV+) individuals with otherwise normal hearing ability show central auditory processing deficits as evidenced by worse performance in speech-in-noise perception compared with HIV negative (HIV-) controls. HIV infection and treatment are also associated with lower neurocognitive screening test scores, suggesting underlying central nervous system damage. To determine how central auditory processing deficits in HIV+ individuals relate to brain alterations in the cortex involved with auditory processing, we compared auditory network (AN) functional connectivity between HIV+ adults with or without speech-in-noise perception difficulties and age-matched HIV- controls using resting-state fMRI. DESIGN: Based on the speech recognition threshold of the hearing-in-noise test, twenty-seven HIV+ individuals were divided into a group with speech-in-noise perception abnormalities (HIV+SPabnl, 38.2 ± 6.8 years; 11 males and 2 females) and one without (HIV+SPnl 34.4 ± 8.8 years; 14 males). An HIV- group with normal speech-in-noise perception (HIV-, 31.3 ± 5.2 years; 9 males and 3 females) was also enrolled. All of these younger and middle-aged adults had normal peripheral hearing determined by audiometry. Participants were studied using resting-state fMRI. Independent component analysis was applied to identify the AN. Group differences in the AN were identified using statistical parametric mapping. RESULTS: Both HIV+ groups had increased functional connectivity (FC) in parts of the AN including the superior temporal gyrus, middle temporal gyrus, supramarginal gyrus, and Rolandic operculum compared to the HIV- group. Compared with the HIV+SPnl group, the HIV+SPabnl group showed greater FC in parts of the AN including the middle frontal and inferior frontal gyri. CONCLUSIONS: The classical auditory areas in the temporal lobe are affected by HIV regardless of speech perception ability. Increased temporal FC in HIV+ individuals might reflect functional compensation to achieve normal primary auditory perception. Furthermore, increased frontal FC in the HIV+SPabnl group compared with the HIV+SPnl group suggest that speech-in-noise perception difficulties in HIV-infected adults also affect areas involved in higher-level cognition, providing imaging evidence consistent with the hypothesis that HIV-related neurocognitive deficits can include central auditory processing deficits.