Nirmatrelvir-ritonavir therapy and COVID-19 vaccination improve clinical outcomes of SARS-CoV-2 Omicron variant infection.

To evaluate the effect of Nirmatrelvir-ritonavir therapy and coronavirus disease 2019 (COVID-19) vaccination on clinical outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron infection, we retrospectively analyzed the clinical data of 762 adult patients with confirmed Omicron BA2.2 variant infection, of them 488 patients received standard therapy and 274 patients received Nirmatrelvir-ritonavir therapy. Subjects were matched by propensity score matching using R language, the baseline factors were balanced by the nearest-neighbor matching method and were compared, together with the factors including progression to severe/critical disease, viral clearance time, length of hospital stay, and virological rebound of SARS-CoV-2 infection. Nirmatrelvir-ritonavir therapy significantly accelerated viral clearance at Days 14 and  28 during hospitalization, but it had no impact on disease progression, length of hospital stay, or infection rebound. In contrast, COVID-19 vaccination before admission was positively correlated with the viral clearance rate and negatively correlated with disease progression in a dose-dependent way. COVID-19 vaccination reduced the probability of infection rebound. Other factors such as the number of comorbidities, pneumonia on-admission, and high D2 levels were positively correlated with disease progression. Our study strongly recommended booster COVID-19 vaccination for the elderly population, particularly patients with comorbidities to prevent critical disease.

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.

Adipose-derived stem cells show hepatic differentiation potential and therapeutic effect in rats with acute liver failure.

Hepatocyte transplantation contributes to the repair of liver damage, but hepatocyte resources are limited, making it difficult for this to become a routine treatment. Previous studies have confirmed that mesenchymal stem cells (MSCs) can be induced to differentiate into hepatocyte-like cells (HLCs) by adding different cytokine combinations in vitro, and they then play some roles of hepatocytes. Our previous studies found that the differentiation ability of stem cells is closely related to the origin of the tissue. To identify the mesenchymal stem cells that are most suitable for hepatic differentiation and the treatment of liver failure, we use a three-phase induction process in which human adipose-derived stem cells (hADSCs) and umbilical cord mesenchymal stem cells (hUCMSCs) are induced to differentiate towards HLCs in vitro, and rats with acute liver failure (ALF) induced by D-gal are cured by MSCs and MSC-derived HLCs (MSCs-HLC), respectively. We find that hADSCs are stronger than hUCMSCs in hepatic differentiation ability, and they have a better curative effect when using hADSCs-HLC or jointly using hADSCs and hADSCs-HLC, which has positive significance for hepatocyte regeneration, recovery of liver function and reduction of systemic inflammatory reaction, finally improving the survival rate of rats with acute liver failure.

Clinical characteristics and risk factors for poor prognosis among HIV patients with Talaromyces marneffei bloodstream infection.

BACKGROUND: Talaromyces marneffei (TM) bloodstream infection is common in Acquired Immunodeficiency Syndrome (AIDS) patients with extreme immunodeficiency in Southeast Asia and South China, however, clinical case study on TM bloodstream infection is scarce. We retrospectively analyzed the clinical characteristics of TM bloodstream infection in hospitalized AIDS patients and determined the outcomes of hospitalization after diagnosis in our hospital over the past 5 years. METHODS: From January 2015 to July 2020, 87 cases of TM detected by blood culture in patients admitted to our center were collected. The admission complaints, blood cells, biochemistry, CD4 and CD8 cell counts and 1,3-ß-D-glucan (BDG), procalcitonin (PCT), CRP level on the day of blood culture test, and outcomes during hospitalization were analyzed. Logistic regression analysis was performed for the risk factors for poor prognosis (60 cases). Spearman correlation analysis was used to analyze the correlation between peripheral blood cells, albumin and the time required for TM turnaround in blood culture. The difference was statistically significant when the P value was < 0.05. RESULTS: A total of 87 patients were collected, with a median age of 34 years, a median hemoglobin of 94 g/L and CD4 count of 7/µl. The rate of TM bloodstream infection among all in-hospital patients increased from 0.99% in 2015 to 2.09% in 2020(half year). Patients with TM bloodstream infection with CD8 count < 200/µl had a 12.6-fold higher risk of poor prognosis than those with CD8 count > 200/µl (p = 0.04), and those with BDG < 100 pg/mL had a 34.9-fold higher risk of poor prognosis than those with BDG > 100 pg/mL (p = 0.01). CONCLUSIONS: TM bloodstream infection is becoming more common in advanced AIDS patients in endemic areas. For those patients with extremely low CD4 and CD8 cell counts below 200/µl is with an increased risk of poor prognosis.

Incidence and spectrum of infections among HIV/AIDS patients with lymphoma during chemotherapy.

Introduction Lymphoma is the most common cancer in HIV/AIDS patients. Chemotherapy regiments recommended for lymphomas in HIV-negative patients are also used for lymphomas in HIV/AIDS patients. Little is known about the infections among HIV/AIDS patients with lymphoma undergoing chemotherapy. Methods This retrospective study investigated the incidence, spectrum of and risk factors for infections during chemotherapy in 164 HIV/AIDS patients with lymphoma admitted to Shanghai Public Health Clinical Center from July 2013 to December 2020. Results The median age of the patients was 43 years old; 90.9% (149/164) were male. A total of 112 (68.3%) patients had a CD4 count < 200 cells/µL at lymphoma diagnosis. Diffuse large B-cell lymphoma (56%, 91/164) and Burkitt lymphoma (28%, 46/164) were the two most common subtypes of lymphoma. Among the 137 patients who underwent chemotherapy (total cycles = 749), 58.4% (80/137) of patients experienced a total of 153 episodes of infection, with an incidence rate of 20.4% (153/749). The most commonly seen infections were lung infection (29.2%, 40/137) and febrile neutropenia (27.0%, 37/137). Multivariate analysis showed that grade 4 neutropenia during chemotherapy (OR = 7.128, 95% CI 3.051-16.654, p < 0.001) and duration of antiretroviral treatment at lymphoma diagnosis <6 months (OR = 3.520, 95% CI 1.432-8.653, p = 0.006) were independent risk factors for infection during chemotherapy. Conclusions A large proportion of HIV/AIDS patients with lymphoma may be at risk of infection during chemotherapy. Effective measures should be taken for patients with high risk factors to prevent the occurrence of infection.

Untargeted GC/TOFMS unravel metabolic profiles in cerebrospinal fluid of Chinese people living with HIV.

BACKGROUND: Metabolic syndrome becomes a focus of clinical cares to people living with HIV (PLHIV) globally. This study aimed to explore the metabolic profiles in cerebrospinal fluid (CSF) of Chinese people living with HIV (PLHIV). METHODS: Cerebrospinal fluid samples from PLHIV and healthy controls were collected from our hospital. Then, the metabolic profiles of CSFs were analyzed PLHIV with healthy individual as the normal controls using the untargeted GC/TOFMS. Following this, kyoto encyclopedia of genes and genomes annotation and pathway analysis were performed to further explore the underlying mechanism of these metabolic alterations in cognitive impairment of PLHIV. RESULTS: Both PCA analysis and OPLS-DA had presented that most samples were localized in 95% CI and the gap between control and HIV could significantly separate from each other. Upon this quality control, a total of 82 known metabolites were identified in CSF between PLHIV and healthy controls. Clustering of these metabolites presented that these differentially expressed metabolites could markedly distinguish HIV from healthy controls. Further pathway analyses showed that TCA cycle (citric acid, fumaric acid, lactate, et al.), amino acid (arginine, proline, alanine, aspartate, glutamine, et al.), lipid (cholesterol, butyrate, et al.) metabolisms were significantly changed in CSF of PLHIV, which might affect the cognitive status of PLHIV via affecting neuron energy support, signaling transduction, and neuroinflammation. CONCLUSION: Metabolic profiles were significantly altered in CSF and might play key roles in the etiology of cognitive impairment of PHLIV. Further explore the exact mechanism for these metabolic changes might be useful for cognitive impairment management of PHLIV.

Mycobacterium tuberculosis co-infection is associated with increased surrogate marker of the HIV reservoir.

BACKGROUND: Tuberculosis (Tb) is the most frequent opportunistic infection among people living with HIV infection. The impact of Tb co-infection in the establishment and maintenance of the HIV reservoir is unclear. METHOD: We enrolled 13 HIV-infected patients with microbiologically confirmed Tb and 10 matched mono-HIV infected controls. Total HIV DNA in peripheral blood mononuclear cells (PBMCs), plasma interleukin-7 (IL-7) concentrations and the activities of indoleamine 2,3-dioxygenase (IDO) were measured for all the participants prior to therapy and after antiretroviral therapy (ART). RESULTS: After a duration of 16 (12, 22) months' ART, patients co-infected with Tb who were cured of Tb maintained higher levels of HIV DNA compared with mono-HIV infected patients [2.89 (2.65- 3.05) log10 copies/106 cells vs. 2.30 (2.11-2.84) log10 copies/106 cells, P = 0.008]. The levels of on-ART HIV DNA were positively correlated with the baseline viral load (r = 0.64, P = 0.02) in Tb co-infected group. However, neither plasma IL-7 concentration nor plasma IDO activity was correlated with the level of on-ART HIV DNA. CONCLUSIONS: Tb co-infection was associated with the increased surrogate marker of the HIV reservoir, while its mechanism warrants further examination.

Use of comedications and potential drug-drug interactions in people living with HIV in China.

BACKGROUND: Because people living with HIV (PLWH) are ageing, they will inevitably develop non-communicable diseases (NCDs) and the number of non-HIV medications will increase. Drug-drug interactions(DDIs) will become an ever-increasing issue. However, little is known about this important issue in Chinese PLWH. This study aimed to investigate the prevalence and risk factors of DDIs among PLWH in China. METHODS: Chinese PLWH aged ≥18 years were enrolled prospectively from October 2018 to April 2019 and after informed consent was obtained, they were ask to fill out a questionnaire about comorbidity and co-medications. Potential DDIs were identified using the University of Liverpool HIV Drug Interaction Checker. RESULTS: A total of 1804 questionnaires were included. Antiretroviral drugs (ARVs) that most frequently were prescribed were lamivudine (96.18%), efavirenz(64.64%) and tenofovir(60.62%). 16.96% of the participations reported current co-infection with HIV and14.69% reported NCDs. 263(14.57%) participations reported they had used co-medications in the past six months while 186(10.31%) reported they were taking co-medications. Age≥50 years (p < 0.001), living in developed areas(p < 0.001) and lower CD4 cell count(p = 0.045) were independently associated with the use of co-medications. Potential DDIs were identified in 54 (19.15%) persons using co-medications. Age≥50 [OR = 2.272(1.241-4.158)], PLWH with NCDs[OR = 2.889(1.509-5.532)] and usage of protease inhibitors[OR = 2.538(1.250-5.156)] were independently associated with the potential DDIs. CONCLUSION: The prevalence of the use of co-medications and potential DDIs among Chinese PLWH are low. Older age, NCDs and use of PIs were risk factors for the potential of developing DDIs. With the aging of PLWH, co-medications and DDIs in China warrants more attention.

Plasma Indoleamine 2,3-Dioxygenase Activity Is Associated With the Size of the Human Immunodeficiency Virus Reservoir in Patients Receiving Antiretroviral Therapy.

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme that metabolizes tryptophan to immunosuppressive kynurenines. We investigated whether IDO activity is associated with the size of HIV reservoir. METHODS: Total human immunodeficiency virus (HIV) DNA in peripheral blood mononuclear cells (PBMCs) from 127 HIV-infected patients receiving antiretroviral therapy (ART) was quantified. Tryptophan and kynurenine concentrations, as well as microbial translocation markers, were measured in plasma samples. T-cell activation and exhaustion in PBMCs were assessed by flow cytometry. RESULTS: Elevated IDO activity prior to ART correlated with on-ART HIV DNA (r = 0.35, P = .004), but was not associated with pre-ART HIV DNA. A median duration of 15 months of ART significantly decreased IDO activity; however, these levels were still higher than those observed in HIV-uninfected controls. Among treated participants, IDO activity positively correlated with their concurrent HIV DNA (r = 0.36, P < .0001). Multivariate model showed an independent association of pre-ART CD4/CD8 ratio (adjusted odds ratio [aOR], 0.75 per 0.1 increase [95% confidence interval {CI}, .62-.91]) and on-ART IDO activity (aOR, 1.09 per nM/µM increase [95% CI, 1.04-1.14]) with higher levels of HIV DNA on-ART. A lack of association of the microbial translocation markers was observed with the size of HIV reservoir. HIV DNA positively correlated with the proportions of activated CD4 T and CD8 T cells and exhausted CD4 T cells. CONCLUSIONS: We observed a positive correlation between IDO activity and total HIV DNA in blood, highlighting the important role of immunometabolic aberrations in HIV persistence.

Speech in Noise Perception as a Marker of Cognitive Impairment in HIV Infection.

OBJECTIVES: Human immunodeficiency virus positive (HIV+) individuals report hearing difficulties, but standard audiological tests show no, or small, changes in peripheral hearing ability. The hearing complaints may reflect central nervous system (CNS) auditory processing deficits, rather than middle or inner ear problems, and may result from CNS damage due to HIV infection or treatment. If central auditory task performance and cognitive deficits in HIV+ individuals are shown to be related, then central auditory tests might serve as a "window" into CNS function in these patients. DESIGN: We measured cognitive performance (Mandarin Montreal Cognitive Assessment [MoCA]) and speech in noise perception (Mandarin hearing-in-noise test [HINT]) in 166 normal-hearing HIV+ individuals (158 men, 8 women, average age 36 years) at the Shanghai Public Health Clinical Center in Shanghai, China. Data collection included audiometry, tympanometry, and the Amsterdam Inventory of Auditory Handicap (AIAH), which assesses the subjective ability to understand speech and localize sound. RESULTS: Subjects had no middle ear disease and met criteria for normal-hearing sensitivity (all thresholds 20 dB HL or less). A significant negative relationship between speech reception thresholds (SRT) and MoCA scores (r = 0.15, F = 28.2, p < 0.001) existed. Stepwise linear regression showed that when the factors of age, MoCA scores, hearing thresholds, and education level were considered, only age and MoCA scores contributed independently to the SRT results (overall model r = 0.30, F = 38.8, p < 0.001). Subjective hearing complaints from the AIAH supported the HINT results. AIAH and MoCA scores were also related (r = 0.05, F = 8.5, p = 0.004), with those with worse MoCA scores having more problems on the AIAH. When the cohort was divided into those with normal and abnormal performance on the MoCA, those with abnormal performance on the MoCA had significantly higher average SRTs (p < 0.001). CONCLUSIONS: Understanding speech in noise measured both objectively with the HINT and subjectively with the AIAH was inversely related to cognitive abilities despite a normal ability to hear soft sounds determined by audiometry. Although age was also an important independent factor affecting speech perception, the age relationship within the speech findings in this study may represent more than just age-related declines in speech in noise understanding. Although reliable data on disease duration are not available, the older members of this cohort likely had HIV longer and probably had more severe symptoms at presentation than the younger members because early detection and treatment of HIV in Shanghai has improved over time. Therefore, the age relationship may also include elements of disease duration and severity. Speech perception, especially in challenging listening conditions, involves cortical and subcortical centers and is a demanding neurological task. The problems interpreting speech in noise HIV+ individuals have may reflect HIV-related or HIV treatment-related, central nervous damage, suggesting that CNS complications in HIV+ individuals could potentially be diagnosed and monitored using central auditory tests.

Trends in and Risk Factors for Drug Resistance in Mycobacterium tuberculosis in HIV-Infected Patients.

Trends in and risk factors for drug resistance in Mycobacterium tuberculosis (M. tuberculosis) in human immunodeficiency virus (HIV)-infected patients with active tuberculosis were analyzed. The clinical data of M. tuberculosis and HIV-coinfected patients treated at the Shanghai Public Health Clinical Center between 2010 and 2022 were collected. The diagnosis of tuberculosis was confirmed by solid or liquid culture. The phenotypic drug susceptibility test was carried out via the proportional method, and the resistance to first-line and second-line drugs was analyzed. Logistic regression analysis was performed to identify associated risk factors for drug resistance in M. tuberculosis. Of the 304 patients with a M. tuberculosis-positive culture and first-line drug susceptibility test results, 114 (37.5%) were resistant to at least one first-line anti-tuberculosis drug. Of the 93 patients with first-line and second-line drug susceptibility test results, 40 (43%) were resistant to at least one anti-tuberculosis drug, and 20 (21.5%), 27 (29.0%), 19 (20.4%), 16 (17.2%), and 14 (15.1%) were resistant to rifampicin, streptomycin, ofloxacin, levofloxacin, and moxifloxacin, respectively; 17 patients (18.3%) had multidrug-resistant tuberculosis (MDR-TB). Between 2010 and 2021, the rate of resistance to streptomycin and rifampicin ranged from 14.3% to 40.0% and from 8.0% to 26.3%, respectively, showing an increasing trend year by year. From 2016 to 2021, the rate of resistance to quinolones fluctuated between 7.7% and 27.8%, exhibiting an overall upward trend. Logistic regression analysis showed that being aged <60 years old was a risk factor for streptomycin resistance, mono-drug resistance, and any-drug resistance (RR 4.139, p = 0.023; RR 7.734, p = 0.047; RR 3.733, p = 0.009). Retreatment tuberculosis was a risk factor for resistance to rifampicin, ofloxacin, of levofloxacin (RR 2.984, p = 0.047; RR 4.517, p = 0.038; RR 6.277, p = 0.014). The drug resistance rates of M. tuberculosis to rifampicin and to quinolones in HIV/AIDS patients were high and have been increasing year by year. Age and a history of previous anti-tuberculosis treatment were the main factors associated with the development of drug resistance in HIV/AIDS patients with tuberculosis.

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.

Analysis of the immunologic status of a newly diagnosed HIV positive population in China.

BACKGROUND: The immunologic status of a newly diagnosed HIV positive population in the era of antiretroviral therapy in China has not been extensively evaluated. We conducted a cross-sectional survey to evaluate the CD4 counts of newly diagnosed HIV-infected persons and determine the factors influencing these counts in China. METHODS: Two thousand eight hundred and sixty-six newly diagnosed HIV-infected patients from 10 provinces in China were selected during 2009 to 2010. Serum samples were collected to measure CD4 counts by flow cytometry. Demographics and medical histories were recorded. Multivariate logistic regression models were used to analyze factors associated with low CD4 count (<100 cells/mm3) at HIV diagnosis. RESULTS: Among the 2866 patients, 2159 (75.33%) were male. Mean age was 40 years (range: 18-86 years). The median CD4 count at HIV diagnosis was 83 cells/mm3, 72.02% of the patients had a CD4 count that was ≤200 cells/mm3, 53.98% had CD4 counts <100 cells/mm3. The difference in CD4 counts between males and females was not statistically significant (P=0.469). The median CD4 count differed significantly according to age (P=0.002), province (P<0.001), ethnicity (P<0.001) and HIV transmission route (P<0.001). In multivariate logistic analysis, factors associated with greater odds of low CD4 count at HIV diagnosis included male sex, younger age, HIV transmission route classified as unknown transmission risk, having been diagnosed in provinces Guangxi, Henan, Heilongjiang, Jiangxi, Shanghai and Yunnan. CONCLUSIONS: At the time of HIV diagnosis, a large proportion of HIV-infected patients in China had an initial CD4 count that was consistent with relatively advanced disease. Low CD4 count was associated with male gender, younger age, route of HIV transmission and geographical areas. HIV testing policy that promotes routine testing for HIV infection is needed to facilitate earlier HIV diagnosis.

Effects of rifampicin, CYP2B6 and ABCB1 polymorphisms on efavirenz plasma concentration in Chinese patients living with HIV and tuberculosis.

BACKGROUND: Tuberculosis (TB) is the leading opportunistic infection of people living with human immunodeficiency virus (HIV; PLWH). Cytochrome P450 (CYP) 2B6 and ATP-binding cassette sub-family B member 1 (ABCB1) are involved in the metabolism and transportation of efavirenz. The study was aimed to investigate the effects of rifampicin, CYP2B6 and ABCB1 polymorphisms on efavirenz exposure in Chinese PLWH co-infected with TB. METHOD: PLWH were screened according to inclusion and exclusion criteria and divided into HIV group and HIV/TB group. Efavirenz plasma concentration (C0) was determined, dose-adjusted concentration (C0/D) was calculated, and genotypes of CYP2B6 516G>T, 785A>G, and ABCB1 2677G>T, 3435C>T were analyzed. RESULTS: 252 PLWH were enrolled, including 75 co-infected with TB and concomitant with rifampicin. Efavirenz C0 and C0/D were both higher in HIV group (1.94 µg/mL, 0.2007 (µg/ml)/(mg/kg/d)) compared with HIV/TB group (1.52 µg/mL, 0.1557 (µg/ml)/(mg/kg/d)) (p = .001). Efavirenz C0/D was significantly higher in patients with variant genotypes of CYP2B6 516G>T and 785A>G (p<.001), and was significantly lower in HIV/TB group compared with HIV group among patients with CYP2B6 516 GG, TT, and 785 AA, AG genotypes (p < .05). CONCLUSION: Efavirenz exposure is reduced by co-administration with rifampicin, and related to genetic polymorphisms of CYP2B6.

Zanubrutinib, lenalidomide, and rituximab (ZR2 regimen) for HIV-associated diffuse large B-cell lymphoma: a real-world analysis from China.

Seven patients with HIV-associated diffuse large B-cell lymphoma (HIV-DLBCL) who did not derive benefit from traditional first-line or second-line chemotherapy were all eventually treated with zanubrutinib, rituximab, and lenalidomide (the ZR2 regimen). Three patients had a complete response, three had a partial response, and one showed stable disease. The complete response rate was 42.9%, the overall response rate was 85.7%. Three patients developed either neutropenia or thrombocytopenia, and one died of lung infection 3 months after diagnosis.

Thalidomide for Recurrence of Symptoms following HIV-Associated Cryptococcal Meningitis.

INTRODUCTION: Cryptococcal meningitis (CM) is a serious and fatal fungal infection that affects individuals infected with human immunodeficiency virus (HIV). Despite treatment, recurrence of symptoms is common and could lead to poor outcomes. Corticosteroids are not always useful in treating symptom recurrence following HIV/CM; thus, alternative therapy is needed. Thalidomide has been reported to be effective in treating symptom recurrence in several patients with HIV/CM. This retrospective study aimed to investigate the efficacy and safety of thalidomide in the treatment of symptom recurrence following HIV/CM. METHODS: Patients who were treated with thalidomide for symptom recurrence following HIV/CM were retrospectively included. Clinical outcomes and adverse events were recorded and analyzed. RESULTS: Sixteen patients admitted between July 2018 and September 2020 were included in the analysis. During a median follow-up period of 295 (166, 419) days, all patients achieved clinical improvement in a median of 7 (4, 20) days. Among them, nine (56%) achieved complete resolution of symptoms at a median of 187 (131, 253) days, including 40% (2/5) of immune reconstitution inflammatory syndrome (IRIS), 50% (3/6) of patients with elevated ICP only, and 80% (4/5) of patients with symptoms only. Seven (43%) patients experienced nine episodes of adverse events, but no severe adverse event attributable to thalidomide was observed. None of the patients withdrew from thalidomide due to adverse events. CONCLUSION: Thalidomide appears to be effective and safe in treating different types of symptom recurrence in HIV/CM. This study provides preliminary evidence supporting future randomized clinical trials to further investigate the efficacy and safety of thalidomide in treating symptom recurrence in this population.

Efficacy of Efavirenz-Based Regimen in Antiretroviral-Naïve Patients with HIV-1 V179D/E Mutations in Shanghai, China.

INTRODUCTION: This study aimed to evaluate the prevalence of HIV-1 mutation V179D/E and the effect of V179D/E on the virological response to first-line efavirenz-based regimens among antiretroviral treatment (ART)-naïve patients. METHODS: An ambispective cohort study was conducted. All ART-naïve patients who underwent baseline genotypic resistance testing between January 2019 and November 2021 were included in the analysis of the prevalence of the V179D/E mutation. Then, patients with identified V179D/E received the efavirenz-based regimen or the protease inhibitor (PI)/integrase strand transfer inhibitor (INSTI)-based regimen. The virological and immunological outcomes at week 48 were compared between the two groups. RESULTS: HIV-1 mutation V179D/E was identified in 252 out of 2568 ART-naïve patients, with a prevalence of 9.8% in Shanghai, China. A total of 206 participants were included in the efficacy analysis. Forty-six patients with altered ART regimens or incomplete follow-up data were excluded from the analysis. The baseline characteristics were comparable between the efavirenz group (n = 109) and the PI/INSTI group (n = 97). At week 48, a total of 96 participants (88.1%) in the efavirenz group and 92 participants (94.8%) in the PI/INSTI group had a viral load lower than 50 copies/mL (chi-square test, p = 0.086). In both groups, a lower proportion of participants achieved virological suppression among participants with a baseline viral load of at least 100,000 copies/mL compared with those with lower than 100,000 copies/mL (66.7% vs. 96.1% in the efavirenz group, p < 0.001; 87.1% vs. 98.4% in the PI/INSTI group, p = 0.039). The median increase from baseline in the CD4 count at week 48 was significantly greater in the PI/INSTI group (192 cells/µL) than in the efavirenz group (154 cells/µL) (p = 0.029). CONCLUSION: There is a high prevalence of V179D/E in ART-naïve patients with HIV-1 in Shanghai, China. The first-line efavirenz-based regimen may be not suitable for patients with HIV-1 mutation V179D/E, especially for those with a baseline viral load of at least 100,000 copies/mL. The study was registered at the Chinese Clinical Trial Registry (ChiCTR2000034787).

Survival and prognostic factors of progressive multifocal leukoencephalopathy in people living with HIV in modern ART era.

Background: The incidence of progressive multifocal leukoencephalopathy (PML) in people living with HIV (PLWH) is 2%-4%. Currently, there is no effective therapeutic strategy for the treatment of PML in PLWH, resulting in a mortality of up to 50%. This study aimed to identify risk factors of death and prognostic markers in people living with HIV with PML. Methods: A retrospective cohort study of AIDS-related PML individuals was conducted from January 1, 2015, to October 1, 2022, in Shanghai, China. PLWH who were diagnosed with PML for the first time were included. Kaplan-Meier curve and Cox regression were used to analyze the survival and its predictors. Levels of inflammatory markers and immune checkpoint inhibitors in blood and cerebrospinal fluid (CSF) were measured in the prestored samples using bead-based multiplex assay Indolamine 2,3-dioxygenase was determined using ELISA. Results: Twenty of 71 subjects had initiated antiretroviral therapy (ART) before PML onset and no patients discontinued ART during this period. In total, 34 patients (47.9%) had opportunistic infections (OIs), the median CD4+ T cell count was 73.0 (33.0-149.0) cells/µL. The estimated probability of survival at six months was 78% (95% confidential intervals [CIs]:0.63-0.85). OIs, low CD4+ T cell count were associated with lower estimated six-month survival (hazard ratio 8.01, 95% CIs: 1.80-35.00, P=0.006 and 5.01, 95% CIs:1.57-16.03, p=0.007). Indolamine 2,3-dioxygenase activity in CSF of non-survivors group were higher than survivors group (p<0.05). Conclusions: The survival rate of AIDS-related PML in the modern ART era was higher than the survival rate a decade ago. Low CD4+T cell count, OIs, were all associated with death of individuals with AIDS-related PML. The role of IDO in AIDS-related PML warrant further investigation.

Elevated indoleamine 2,3-dioxygenase activity is associated with endothelial dysfunction in people living with HIV and ROS production in human aortic endothelial cells in vitro.

The precise role of indoleamine 2,3-dioxygenase (IDO) in cardiovascular diseases (CVD) among people living with HIV (PLWH) is still under debate, despite recognized links. This study aimed to investigate the impact of elevated IDO activity on endothelial dysfunction in PLWH. A total of 38 PLWH, who had not previously received anti-retroviral therapy (ART), were enrolled in the study. These participants were monitored for 36 months following the initiation of ART. Measurements including plasma levels of IDO activity, markers of endothelial dysfunction, inflammatory factors, and lipids. In vitro, human aortic endothelial cells (HAEC) were exposed to interferon-γ, an IDO inhibitor, a kynurenine 3-hydroxylase (KMO) inhibitor, as well as different concentrations of kynurenine. Pre-ART, PLWH demonstrated notably elevated plasma concentrations of soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1(sVCAM-1), and IDO activity in comparison to healthy controls. Post-ART, both IDO activity and sICAM-1 levels experienced a significant decrease, with IDO activity reaching levels comparable to those observed in healthy controls. Furthermore, a positive correlation was observed between IDO activity and sICAM-1 (p = 0.0002), as well as sVCAM-1 (p < 0.0001) before ART. In vitro, the augmentation of kynurenine concentration in the medium and the induction of IDO expression in HAEC resulted in increased production of reactive oxygen species (ROS), with minimal impact on endothelial dysfunction. From these findings, it can be concluded that long-term ART has the potential to restore the heightened IDO activity observed in PLWH. The overexpression of IDO primarily influences the expression of ROS in HAEC.

Efficacy and safety of Paxlovid in severe adult patients with SARS-Cov-2 infection: a multicenter randomized controlled study.

Background: Nirmatrelvir plus ritonavir (Paxlovid) reduced the risk of hospitalization or death by 89% in high-risk, ambulatory adults with COVID-19. We aimed at studying the efficacy and safety of Paxlovid in hospitalized adult patients with SARS-Cov-2 (Omicron BA.2.2 variant) infection and severe comorbidities. Methods: We conducted an open-label, multicenter, randomized controlled trial in which hospitalized adult patients with severe comorbidities were eligible and assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 h for 5 days with standard treatment or only standard treatment. All-cause mortality on day 28, the duration of SARS-CoV-2 RNA clearance, and safety were evaluated. Findings: 264 patients (mean age, 70.35 years; 122 [46.21%] female) who met the criteria were enrolled at 5 sites in Shanghai from April 10 to May 19 in 2022. After randomization, a total of 132 patients were assigned to receive Paxlovid treatment plus standard treatment, and 132 patients were assigned to receive only standard treatment. The overall 28-day mortality was 4.92%, 8 patients died in the standard treatment group and 5 died in the Paxlovid plus standard treatment group. There was no significant difference in mortality from any cause at 28 days between the Paxlovid plus standard treatment group and the standard treatment group (absolute risk difference [ARD], 2.27; 95% CI -2.94 to 7.49, P = 0.39). There was no significant difference in the duration of SARS-CoV-2 RNA clearance among the two groups (mean days, 10 in Paxlovid plus standard treatment group and 10.50 in the standard treatment group; ARD, -0.62; 95% CI -2.29 to 1.05, P = 0.42). The incidence of adverse events that occurred during the treatment period was similar in the two groups (any adverse event, 10.61% with Paxlovid plus standard treatment vs. 7.58% with the standard, P = 0.39; serious adverse events, 4.55% vs. 3.788%, P = 0.76). Interpretation: Paxlovid showed no significant reduction in the risk of all-cause mortality on day 28 and the duration of SARS-CoV-2 RNA clearance in hospitalized adult COVID-19 patients with severe comorbidities. Funding: National Natural Science Foundation of China (grant number: 82172152, 81873944).