Pretreatment drug resistance in people living with HIV: A large retrospective cohort study in Chongqing, China.

OBJECTIVES: The emergence of pretreatment drug resistance (PDR) caused by increased usage of antiretroviral therapy (ART) represents a significant challenge to HIV management. In this study, we evaluated the prevalence of PDR in people living with HIV (PLWH) in Chongqing, China. METHODS: We retrospectively collected the data of 1110 ART-naïve PLWH in Chongqing from January 1, 2018 to June 30, 2021. HIV-1 genotypes and drug resistance were analyzed using the HIV-1 pol sequence. Risk factors associated with PDR were evaluated via the logistic regression model. RESULTS: Nine genotypes were detected among 1110 participants, with CRF07_BC (55.68%) being the dominant genotype, followed by CRF01_AE (21.44%), CRF08_BC (14.14%), and other genotypes (8.74%). Of all the participants, 24.14% exhibited drug resistance mutations (DRMs). The predominant DRMs for non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTIs) were V179D/E/A/DIN (13.60%) and M184V/I (1.44%), respectively, whereas only two major DRMs (M46L and I54L) were identified for protease inhibitors (PIs). The total prevalence of PDR was 10.54%, with 2.43%, 7.66%, and 1.71% participants exhibiting PDR to NRTIs, NNRTIs, and PIs, respectively. Furthermore, female PLWH, delays in ART initiation, and the CRF08_BC genotype were associated with a higher risk of PDR. CONCLUSIONS: Our study provides the first large cohort data on the prevalence of PDR in Chongqing, China. HIV-1 genotypes are diverse and complex, with a moderate level of PDR, which does not reach the threshold for the initiation of a public health response. Nevertheless, continuous surveillance of PDR is both useful and advisable.

Central nervous system aspergillosis misdiagnosed as Toxoplasma gondii encephalitis in a patient with AIDS: a case report.

BACKGROUND: Patients with acquired immunodeficiency syndrome (AIDS) tend to suffer from several central nervous system (CNS) infections due to hypoimmunity. However, CNS aspergillosis (CNSAG) is extremely rare and difficult to diagnose. Thus, it is easily misdiagnosed. CASE PRESENTATION: We reported a 47-year-old male AIDS patient with ghosting vision and anhidrosis on the left head and face. He was accordingly diagnosed with Toxoplasma gondii encephalitis (TE) at other hospitals, for which he received regular anti-Toxoplasma gondii and anti-human immunodeficiency virus (anti-HIV) treatment. Then, the patient was transferred to our hospital due to a lack of any improvement with the prescribed treatment. The patient's neurological examination revealed no abnormalities at admission, only a slight change in the cerebrospinal fluid. His cranial magnetic resonance imaging (MRI) revealed multiple abnormal signals in the brain parenchyma, and his blood was positive for Toxoplasma gondii IgG antibody. The initial diagnosis at our hospital was also TE. Considering the poor efficacy of anti-TE treatment, cerebrospinal fluid metagenomics next-generation sequencing (mNGS) was performed, but no pathogenic bacteria were detected. However, Aspergillus fumigatus was detected in the cerebrospinal fluid via targeted next-generation sequencing (tNGS) and bronchoalveolar alveolar lavage fluid via mNGS. The diagnosis was accordingly revised to CNSAG combined with his other clinical manifestations. After administering voriconazole antifungal therapy, the patient's symptoms were relieved, with improved absorption of the intracranial lesions. CONCLUSIONS: The present case experience indicates the need for clinicians to strengthen their understanding of CNSAG. Moreover, for patients with diagnostic difficulties, early mNGS and tNGS (using biological samples with only a few pathogens) are helpful for early diagnosis and treatment, potentially allowing patients to achieve favorable outcomes.

Initiating antiretroviral therapy within 2 weeks of anti-Pneumocystis treatment does not increase mortality or AIDS-defining events in patients with HIV-associated moderate to severe Pneumocystis pneumonia: results of a prospective observational multicenter study.

BACKGROUND: The mortality rate remains high among patients with coinfection with Pneumocystis pneumonia (PCP) and HIV. The timing for initiation of antiretroviral therapy (ART) after a diagnosis of moderate to severe PCP remains controversial, however. We therefore designed the present study to determine the optimal timing for ART initiation in AIDS-associated PCP (AIDS/PCP) patients. METHODS: This was a multicenter, observational, prospective clinical trial. Eligible participants were recruited from 14 hospitals in mainland China, and assigned to an Early ART arm (initiation of ART ≤ 14 days after PCP diagnosis) and a Deferred ART arm (initiation of ART > 14 days after PCP diagnosis). The primary outcomes were death and the incidence of AIDS-defining events at week 48. The secondary outcomes were the changes in CD4+ T-cell counts from baseline values at weeks 12, 24, and 48, the virological suppression rate at week 24 and week 48, the rate of development of PCP-associated immune reconstitution inflammatory syndrome (PCP/IRIS), and the rate of adverse events over 48 weeks. RESULTS: The present study was performed using the data of 363 participants, with 169 participants in the Early ART arm, and 194 participants in the Deferred ART arm. Immunological and virological outcomes were found to be similar in both treatment arms. At week 48, there were no significant differences for the incidence of mortality (20 vs. 26, p = 0.860), and AIDS-defining events (17 vs. 26, p = 0.412). Over 48 weeks, the rates of PCP/IRIS (2 vs. 3, p = 1.000), adverse events (70 vs. 72, p = 0.465), and grade 3 or 4 adverse events (28 vs. 34, p = 0.919) did not reach statistical significance. A significant difference observed between two study arms was that 11 participants (55.0%) in the Early ART arm compared to 23 participants (88.5%) in the Deferred ART arm (p = 0.026) succumbed before ART had ever been started. CONCLUSIONS: Early ART initiation results in no increase in mortality, AIDS-defining events, IRIS, adverse events, and immunological or virological outcomes. These results support the early initiation of ART in patients with moderate to severe AIDS/PCP. Clinical trial registration The present trial was registered at Chinese Clinical Trial Registry (ChiCTR1900021195). Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362 .

Establishment of a novel scoring model for mortality risk prediction in HIV-infected patients with cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CM) remains a leading cause of death in HIV-infected patients, despite advances in CM diagnostic and therapeutic strategies. This study was performed with the aim to develop and validate a novel scoring model to predict mortality risk in HIV-infected patients with CM (HIV/CM). METHODS: Data on HIV/CM inpatients were obtained from a Multicenter Cohort study in China. Independent risk factors associated with mortality were identified based on data from 2013 to 2017, and a novel scoring model for mortality risk prediction was established. The bootstrapping statistical method was used for internal validation. External validation was performed using data from 2018 to 2020. RESULTS: We found that six predictors, including age, stiff neck, impaired consciousness, intracranial pressure, CD4+ T-cell count, and urea levels, were associated with poor prognosis in HIV/CM patients. The novel scoring model could effectively identify HIV/CM patients at high risk of death on admission (area under curve 0.876; p<0.001). When the cut-off value of 5.5 points or more was applied, the sensitivity and specificity was 74.1 and 83.8%, respectively. Our scoring model showed a good discriminatory ability, with an area under the curve of 0.879 for internal validation via bootstrapping, and an area under the curve of 0.886 for external validation. CONCLUSIONS: Our developed scoring model of six variables is simple, convenient, and accurate for screening high-risk patients with HIV/CM, which may be a useful tool for physicians to assess prognosis in HIV/CM inpatients.

A Peptide-Based Magnetic Chemiluminescence Enzyme Immunoassay for Serological Diagnosis of Coronavirus Disease 2019.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel ß-coronavirus, causes severe pneumonia and has spread throughout the globe rapidly. The disease associated with SARS-CoV-2 infection is named coronavirus disease 2019 (COVID-19). To date, real-time reverse-transcription polymerase chain reaction (RT-PCR) is the only test able to confirm this infection. However, the accuracy of RT-PCR depends on several factors; variations in these factors might significantly lower the sensitivity of detection. METHODS: In this study, we developed a peptide-based luminescent immunoassay that detected immunoglobulin (Ig)G and IgM. The assay cutoff value was determined by evaluating the sera from healthy and infected patients for pathogens other than SARS-CoV-2. RESULTS: To evaluate assay performance, we detected IgG and IgM in the sera from confirmed patients. The positive rate of IgG and IgM was 71.4% and 57.2%, respectively. CONCLUSIONS: Therefore, combining our immunoassay with real-time RT-PCR might enhance the diagnostic accuracy of COVID-19.

Development of a risk scoring system for prognostication in HIV-related toxoplasma encephalitis.

BACKGROUND: This study aims to evaluate specific risk factors influencing prognosis of HIV-infected patients with toxoplasma encephalitis (TE) in order to develop a prognostic risk scoring system for them. METHODS: This is a six-center retrospective study of hospitalized HIV/TE patients. Data including six-week mortality after diagnosis, baseline characteristics, clinical features, laboratory tests and radiological characteristics of eligible patients were assimilated for risk model establishing. RESULTS: In this study, the six-week mortality among 94 retrospective cases was 11.7% (11/94). Seven specific risk factors, viz. time from symptom onset to presentation, fever, dizziness, CD4+ T-cell counts, memory deficits, patchy brain lesions, and disorders of consciousness were calculated to be statistically associated with mortality. A criterion value of '9' was selected as the optimal cut-off value of the established model. The AUC of the ROC curve of this scoring model was 0.976 (p < 0.001). The sensitivity and specificity of the risk scoring model was 100.0 and 86.9%, respectively, which were 81.8 and 94.1% of this scoring model in the verification cohort, respectively. CONCLUSIONS: The developed scoring system was established with simple risk factors, which also allows expeditious implementation of accurate prognostication, and appropriate therapeutic interventions in HIV-infected patients with TE.

Evaluation of Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis in Southwest China.

The purpose of this study was to determine the diagnostic efficacy of Xpert MTB/RIF assay for rapid diagnosis of Tuberculosis (TB) and detection of rifampicin (RIF) resistance in patients suspected of having EPTB, assessing it against traditional culture and drug susceptibility test (DST) by proportional method, and the ability to predict multidrug resistance TB by Xpert MTB/RIF assay. In this study, the Xpert MTB/RIF assay was applied to 1,614 extrapulmonary specimens. Compared with TB culture and Composite Reference Standard (CRS), the Xpert MTB/RIF assay had a high sensitivity and specificity for detection of EPTB. Depending on the culture method or CRS as the standard, sensitivity of the Xpert MTB/RIF assay for detection of MTB in pleural effusion, cerebrospinal fluid, thoracic drainage fluid and throat swabs specimens were lower than that of other specimens. According to the experimental results, we have reason to believe that Xpert MTB/RIF assay is a rapid and simple technique with high sensitivity and specificity for diagnosing EPTB and detecting drug resistance in variety of specimens. Xpert MTB/RIF assay combined with DST maybe identify more cases of multi-drug resistant tuberculosis (MDR-TB).

The Imbalance Between Intestinal Th17 and Treg Cells Is Associated with an Incomplete Immune Reconstitution During Long-Term Antiretroviral Therapy in Patients with HIV.

Studies assessing the gut mucosal immune balance in HIV-infected patients using intestinal samples are scarce. In this study, we used intestinal mucosal specimens from the ileocecal region of seven immunological nonresponders (INRs), nine immunological responders (IRs), and six HIV-negative controls. We investigated T helper 17 (Th17) and T regulatory (Treg) cell counts and their ratio, zonula occludens-1 (ZO-1), intestinal fatty acid-binding protein (I-FABP), tumor necrosis factor-α, CD4+ T cell counts, HIV DNA, and cell-associated HIV RNA. The results showed that INRs had lower Th17 and higher Treg cell counts than IR, resulting in a significant difference in the Th17/Treg ratio between IRs and INRs. In addition, INRs had lower ZO-1 and higher I-FABP levels than IRs. The Th17/Treg ratio was positively associated with ZO-1 and negatively associated with I-FABP levels. There was a positive correlation between Th17/Treg ratio and CD4+ T cell counts and a negative correlation between the Th17/Treg ratio and HIV DNA in the intestine. Our study suggests that the imbalance of Th17/Treg in the intestine is a characteristic of incomplete immune reconstitution to antiretroviral therapy and is associated with intestinal damage.

Severe intestinal barrier damage in HIV-infected immunological non-responders.

The intestinal epithelial barrier plays an important role during human immunodeficiency virus (HIV) disease progression. However, the extent to which the intestinal epithelial barrier is damaged in immunological non-responders (INRs) and immunological responders (IRs) is largely unknown. In this study, we investigated and compared the levels of intestinal gland damage and related molecules, including the tight junction protein claudin-1, apoptosis marker caspase-3, HIV DNA, CD4+ T cell count, and inflammation marker tumor necrosis factor-α (TNF-α) among the IRs (n = 10), INRs (n = 8), and healthy controls (HCs, n = 7). Intestinal damage was not completely restored in both INRs and IRs and was more serious in INRs than that in IRs. Moreover, intestinal damage was positively correlated with HIV DNA levels and negatively correlated with CD4+ T cell counts. These results provide insight into understanding the characteristics of intestinal epithelial barrier damage between IRs and INRs.

Immunological tolerance of human hepatocyte xenograft induced by adenovirus vector-mediated CTLA4Ig gene transfer.

BACKGROUND: Systemic administration of CTLA4Ig has been applied in inducing immunological tolerance of hepatocyte implants, but has potential for systemic immune inhibition. This study was designed to induce hepatocyte immunological tolerance by locally expressing CTLA4Ig in an attempt to improve the effectiveness of cell transplantation. METHODS: A normal human liver cell line (L02) was transfected with adenovirus vector containing the CTLA4Ig gene (Ad-CTLA4Ig-EGFP) in vitro, and the expression of CTLA4Ig by transfected cells was assessed by fluorescent imaging and immunocytochemical staining. Transfected cells then were injected into the spleen of Sprague-Dawley rats, the survival of cells was determined by immunohistochemistry, and the immune status was examined through CD4+ and CD69+ T cell-counts and ELISA detection of IL-2 in peripheral blood. RESULTS: L02 cells expressed CTLA4Ig in the cytoplasm for >4 weeks. Surviving L02 cells were observed in the experimental group at 3 and 4 weeks post-transplantation, while none was detected in the control group. Furthermore, the percentages of CD4+ and CD4+CD69+ T cells in the CTLA4-transfected group were 24.5% and 45.1%, markedly lower than those in the control group at 4 weeks post-transplantation (P<0.01). Furthermore, the IL-2 level was also lower in the CTLA4-transfected group than in the control group. CONCLUSION: Adenovirus-mediated CTLA4Ig gene transfer into human hepatocytes has the potential to become an effective method of inducing immunological tolerance in hepatocyte transplantation.

Therapeutic lumbar puncture and lumbar drainage: which is more effective for the management of intracranial hypertension in HIV patients with cryptococcal meningitis? Results of a prospective non-randomized interventional study in China.

OBJECTIVE: This study aimed to evaluate the effectiveness of therapeutic lumbar drainage (LD) compared to therapeutic lumbar puncture (LP) for the management of intracranial hypertension (ICH) among HIV-positive patients with cryptococcal meningitis (CM). METHODS: The study was a multicenter prospective non-randomized interventional clinical trial. One hundred and sixteen HIV-associated CM patients were identified who presented with ICH (≥250 mmH2O). The LP group comprised 76 cases, while the LD group consisted of 40 cases. We compared mortality, intracranial pressure (ICP) normalization rate, and clinical symptom remission at 10 weeks, between the two groups. RESULTS: The cumulative mortality at week 10 was 22.4% in the LP group and 20% in the LD group (p = .927), without any significant difference in mortality between the two groups. Improvement after treatment at 2-weeks, ICP normalization, and headache reversal event occurrence in the two groups showed no significant difference (p > .05). The incidence of CSF Cryptococcus clearance at two weeks in the LD group was significantly higher than in the LP group (p < .05). The frequency of invasive lumbar therapeutic procedures in the LP group during the first week was higher than that of the LD group (p < .05). Localized infection at the puncture site occurred more frequently in the LD group than in the LP group (p < .05). CONCLUSION: For HIV-positive CM patients with an elevated ICP, LD and LP are comparably effective and safe options to normalize ICP. LP increases the frequency of invasive lumbar therapeutic procedures but does not incur more risk of infection events at the puncture site, while LD may accelerate CSF Cryptococcus clearance but may induce more frequent localized infection. TRIAL REGISTRATION: This study was registered as one of 12 trials under a general project at the Chinese Clinical Trial Registry (ChiCTR1900021195).

Selective elimination of host cells harboring replication-competent human immunodeficiency virus reservoirs: a promising therapeutic strategy for HIV cure.

ABSTRACT: Many seminal advances have been made in human immunodeficiency virus (HIV)/AIDS research over the past four decades. Treatment strategies, such as gene therapy and immunotherapy, are yielding promising results to effectively control HIV infection. Despite this, a cure for HIV/AIDS is not envisioned in the near future. A recently published academic study has raised awareness regarding a promising alternative therapeutic option for HIV/AIDS, referred to as "selective elimination of host cells capable of producing HIV" (SECH). Similar to the "shock and kill strategy," the SECH approach requires the simultaneous administration of drugs targeting key mechanisms in specific cells to efficiently eliminate HIV replication-competent cellular reservoirs. Herein, we comprehensively review the specific mechanisms targeted by the SECH strategy. Briefly, the suggested cocktail of drugs should contain (i) latency reversal agents to promote the latency reversal process in replication-competent reservoir cells, (ii) pro-apoptotic and anti-autophagy drugs to induce death of infected cells through various pathways, and finally (iii) drugs that eliminate new cycles of infection by prevention of HIV attachment to host cells, and by HIV integrase inhibitor drugs. Finally, we discuss three major challenges that are likely to restrict the application of the SECH strategy in HIV/AIDS patients.

Effectiveness of adjunctive corticosteroid therapy in patients with severe COVID-19: A retrospective cohort study.

BACKGROUND: The effectiveness of adjunctive corticosteroid use in patients with coronavirus disease 2019 (COVID-19) remains inconclusive. AIM: To investigate the effectiveness of adjunctive corticosteroid therapy in patients with severe COVID-19. METHODS: We conducted a retrospective analysis of the difference in several outcomes between patients with severe COVID-19 who received corticosteroid therapy (the corticosteroid group) and patients with severe COVID-19 who did not receive corticosteroid therapy (the non-corticosteroid group). RESULTS: Seventy-five patients were included in this study. Of these, 47 patients were in the corticosteroid group and 28 patients were in the non-corticosteroid group. There were no differences between the two groups in the total length of hospital stay, the length of intensive care unit stay, high-flow oxygen days, non-invasive ventilator days, invasive ventilation days, and mortality rate. Total lesion volume ratio, consolidation volume ratio and ground-glass opacity volume ratio in the corticosteroid group decreased significantly on day 14, while those in the non-corticosteroid group did not show a significant decrease. CONCLUSION: Our results show that adjunctive corticosteroid use did not significantly improve clinical outcomes in severe COVID-19 patients, but might promote the absorption of pulmonary lesions. Larger multicenter randomized controlled studies may be needed to confirm this.

Long Non-coding RNA LINC00847 Induced by E2F1 Accelerates Non-small Cell Lung Cancer Progression Through Targeting miR-147a/IFITM1 Axis.

Background: Long non-coding RNAs (lncRNAs) can remarkably regulate human malignancies in terms of the development and the progression. Previously, lncRNA LINC00847 (LINC00847) has been reported to present dysregulation in several tumors. However, the expression and function of LINC00847 in non-small cell lung cancer (NSCLC) have not been investigated. Methods: RT-qPCR was performed to determine the expressions of LINC00847 in collected tissue samples and cell lines. The clinical significance of LINC00847 was statistically analyzed. CCK-8 test, cell scratch test and trans-well test were used to evaluate the proliferation, invasion and migration abilities of NSCLC cells, respectively. The xenograft tumor model was constructed to confirm the effects of LINC00847 knockdown on NSCLC in vivo. Further, luciferase reporter assays and Western blot were performed to explore molecular mechanisms underlying the functions of LINC00847. Results: Increased expressions of LINC00847 were observed in NSCLC samples as well as cell lines. Additionally, E2F1 could be capable of directly binding to the LINC00847 promoter region, followed by promoting its expression. Clinically, LINC00847 high-expression could lead to poor prognosis of NSCLC patients. Functionally, LINC00847 knockdown noticeably repressed NSCLC cell growth and metastasis. Mechanically, miR-147a/IFITM1 axis was a downstream target of LINC00847, and silencing of miR-147a could rescue the anti-cancer effects of LINC00847 knockdown on NSCLC cell behaviors. Conclusion: Overall, up regulation of LINC00847 induced by E2F1 promoted the progression of NSCLC by modulating miR-147a/IFITM1 axis, representing a novel regulatory mechanism for NSCLC progression.

Timing of antiretroviral therapy for HIV-infected patients with cytomegalovirus retinitis: study protocol of a multi-center prospective randomized controlled trial.

BACKGROUND: Cytomegalovirus retinitis (CMVR) is an important opportunistic infection (OI) occurring mainly in patients with acquired immunodeficiency syndrome (AIDS) and has the potential to cause severe visual impairment and blindness among AIDS patients. Subsequent to the adoption and implementation of widespread antiretroviral therapy (ART), the prognosis of AIDS-associated CMVR has been substantially improved. Nevertheless, the equivocal clinical evidence as regards the optimal timing for ART initiation in patients with an established CMVR diagnosis is required. We therefore designed the present study in order to investigate the optimal timing for ART initiation in AIDS/CMVR patients. METHODS: This will be a prospective, randomized controlled trial to be performed at 17 hospitals in mainland China. A total of 300 participants with CMVR will be randomly assigned to an early ART initiation group (ART initiation within 2 weeks after anti-CMV therapy), or a deferred ART initiation group (initiation of ART more than 2 weeks after anti-CMV therapy) at a 1:1 ratio. All participants will receive 48 weeks of follow-up after anti-CMV therapy initiation. Our primary outcome will be the incidence of visual loss (to a visual acuity worse than 20/40 or 20/200) in the two groups during the 48-week follow-up period. Secondary outcomes will include changes in HIV virological suppression and serum CD4+ T-cell counts, the incidence of mortality, retinitis progression (movement of the peripheral border of a CMV lesion ≥ ½ disc diameter, or occurrence of a new CMV lesion), retinal detachment, immune recovery uveitis (IRU), and other OIs and adverse events between the two study groups during the 48 weeks of follow-up. DISCUSSION: The study aims to investigate the optimal timing for ART initiation in AIDS/CMVR patients. We hope to be able to extract robust clinical evidence for use in optimal AIDS/CMVR management should our trial be successful. TRIAL REGISTRATION: This research was registered as one of the twelve clinical trials under the name of a general project "A study for precision diagnosing and treatment strategies in difficult-to-treat AIDS cases and HIV-infected patients with highly fatal or highly disabling opportunistic infections", ChiCTR1900021195. Registered on 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362 .

The Effect of Early vs. Deferred Antiretroviral Therapy Initiation in HIV-Infected Patients With Cryptococcal Meningitis: A Multicenter Prospective Randomized Controlled Analysis in China.

Background: The optimal timing for initiation of antiretroviral therapy (ART) in HIV-positive patients with cryptococcal meningitis (CM) has not, as yet, been compellingly elucidated, as research data concerning mortality risk and the occurrence of immune reconstitution inflammatory syndrome (IRIS) in this population remains inconsistent and controversial. Method: The present multicenter randomized clinical trial was conducted in China in patients who presented with confirmed HIV/CM, and who were ART-naïve. Subjects were randomized and stratified into either an early-ART group (ART initiated 2-5 weeks after initiation of antifungal therapy), or a deferred-ART group (ART initiated 5 weeks after initiation of antifungal therapy). Intention-to-treat, and per-protocol analyses of data for these groups were conducted for this study. Result: The probability of survival was found to not be statistically different between patients who started ART between 2-5 weeks of CM therapy initiation (14/47, 29.8%) vs. those initiating ART until 5 weeks after CM therapy initiation (10/55, 18.2%) (p = 0.144). However, initiating ART within 4 weeks after the diagnosis and antifungal treatment of CM resulted in a higher mortality compared with deferring ART initiation until 6 weeks (p = 0.042). The incidence of IRIS did not differ significantly between the early-ART group and the deferred-ART group (6.4 and 7.3%, respectively; p = 0.872). The percentage of patients with severe (grade 3 or 4) adverse events was high in both treatment arms (55.3% in the early-ART group and 41.8% in the deferred-ART group; p=0.183), and there were significantly more grade 4 adverse events in the early-ART group (20 vs. 13; p = 0.042). Conclusion: Although ART initiation from 2 to 5 weeks after initiation of antifungal therapy was not significantly associated with high cumulative mortality or IRIS event rates in HIV/CM patients compared with ART initiation 5 weeks after initiation of antifungal therapy, we found that initiating ART within 4 weeks after CM antifungal treatment resulted in a higher mortality compared with deferring ART initiation until 6 weeks. In addition, we observed that there were significantly more grade 4 adverse events in the early-ART group. Our results support the deferred initiation of ART in HIV-associated CM. Clinical Trials Registration: www.ClinicalTrials.gov, identifier: ChiCTR1900021195.

Preference for daily versus on-demand pre-exposure prophylaxis for HIV and correlates among men who have sex with men: the China Real-world Oral PrEP Demonstration study.

INTRODUCTION: This study explores the preference for daily versus on-demand pre-exposure prophylaxis (PrEP) among men who have sex with men (MSM) in developing countries when both regimens are available. METHODS: From 11 December 2018 to 19 October 2019, we recruited MSM for an open-label real-world PrEP demonstration study in four major cities in China. Subjects selected their preferred PrEP (oral tenofovir/emtricitabine) regimen (daily vs. on-demand) at recruitment and underwent on-site screening before initiation of PrEP. We used logistic regression to assess preference for daily PrEP and correlates. RESULTS: Of 1933 recruited MSM, the median age was 29 years, 7.6% was currently married to or living with a female; the median number of male sexual partners was four and 6.1% had used post-exposure prophylaxis (PEP) in the previous six months. HIV infection risk was subjectively determined as very high (>75%) in 7.0% of subjects, high (50% to 75%) in 13.3%, moderate (25% to 49%) in 31.5% and low or none (0% to 24%) in 48.1%. On average, participants preferred on-demand PrEP over daily PrEP (1104 (57.1%) versus 829 (42.9%)) at recruitment. In multivariable analysis, currently being married to or living with a female was associated with 14.6 percentage points lower preference for daily PrEP (marginal effect = -0.146 [95% CI: -0.230, -0.062], p = 0.001); whereas the number of male sexual partners (marginal effect = 0.003 [95% CI: 0.000, 0.005], p = 0.034) and a subjective assessment of being very high risk of HIV infection (vs. low and no risk, marginal effect size = 0.105 [95% CI: 0.012, 0.198], p = 0.027) were associated with increased preference for daily versus on-demand PrEP. Among the 1933 potential participants, 721 (37.3%) did not attend the subsequent on-site screening. Lower-income, lower education level, lower subjective expected risk of HIV infection risk and younger age positively correlated with the absence of on-site screening. CONCLUSIONS: MSM in China prefer both daily and on-demand PrEP when both regimens are provided free. Social structural factors and subjective risk of HIV infection have significant impacts on PrEP preference and use. The upcoming national PrEP guideline should consider incorporating both regimens and the correlates to help implement PrEP in China.

A study for precision diagnosing and treatment strategies in difficult-to-treat AIDS cases and HIV-infected patients with highly fatal or highly disabling opportunistic infections: Study protocol for the optimal early intervention for cryptococcal antigenemia in HIV-infected patients.

BACKGROUND: Asymptomatic cryptococcal antigenemia is a state of cryptococcal infection commonly seen in immunocompromised HIV-infected persons. Without early intervention, a proportion of HIV-infected persons with cryptococcal antigenemia may go on to develop cryptococcosis, especially cryptococcal meningitis, which is associated with high mortality. The benefits of antifungal intervention and optimal therapeutic intervention regimens for HIV-infected persons with cryptococcal antigenemia remain controversial. We therefore designed the present study in order to investigate the necessity of, and the optimal regimens for antifungal intervention in the clinical management of cryptococcal antigenemia in HIV-infected populations. METHODS/DESIGN: This study will be an open-labeled, multi-center, prospective, randomized controlled trial, and 450 eligible participants will be randomized into a control arm and 2 intervention arms at a 1:1:1 ratio, with 150 subjects in each arm. Participants in the control arm will not receive antifungal treatment during the study period. Participants in intervention arm 1 will receive oral fluconazole 800 mg/day for 2 weeks, followed by 400 mg/day for 8 weeks and 200 mg/day for 42 weeks, and participants in intervention arm 2 will receive oral fluconazole 400 mg/day for 52 weeks. The primary outcome is the incidence of CM among the 3 groups during the study period. The secondary outcomes include the differences in all-cause mortality, proportion of patients reverting to blood CrAg negativity, change of CrAg titers, and adverse events among the 3 groups during the follow-up period. DISCUSSION: We envisage that the results of this study will reveal the necessity of, and the optimal therapeutic regimens for, antifungal intervention in clinical management of HIV-infected patients with cryptococcal antigenemia. TRIAL REGISTRATION: The study was registered as one of the 12 clinical trials under a general project at the Chinese Clinical Trial Registry on February 1, 2019, and the registration number of the general project is ChiCTR1900021195.

A study for precision diagnosing and treatment strategies in difficult-to-treat AIDS cases and HIV-infected patients with highly fatal or highly disabling opportunistic infections.

BACKGROUND: An increased frequency of toxoplasma encephalitis, caused by Toxoplasma gondii, has been reported in AIDS patients, especially in those with CD4+ T cell counts <100 cells/µL. Several guidelines recommend the combination of pyrimethamine, sulfadiazine, and leucovorin as the preferred regimen for AIDS-associated toxoplasma encephalitis. However, it is not commonly used in China due to limited access to pyrimethamine and sulfadiazine. The synergistic sulfonamides tablet formulation is a combination of trimethoprim (TMP), sulfadiazine and sulfamethoxazole (SMX), and is readily available in China. Considering its constituent components, we hypothesize that this drug may be used as a substitute for sulfadiazine and TMP-SMX. We have therefore designed the present trial, and propose to investigate the efficacy and safety of synergistic sulfonamides combined with clindamycin for the treatment of toxoplasma encephalitis. METHODS/DESIGN: This study will be an open-labeled, multi-center, prospective, randomized, and controlled trial. A total of 200 patients will be randomized into TMP-SMX plus azithromycin group, and synergistic sulfonamides plus clindamycin group at a ratio of 1:1. All participants will be invited to participate in a 48-week follow-up schedule once enrolled. The primary outcomes will be clinical response rate and all-cause mortality at 12 weeks. The secondary outcomes will be clinical response rate and all-cause mortality at 48 weeks, and adverse events at each visit during the follow-up period. DISCUSSION: We hope that the results of this study will be able to provide reliable evidence for the efficacy and safety of synergistic sulfonamides for its use in AIDS patients with toxoplasma encephalitis. TRIAL REGISTRATION: This study was registered as one of 12 clinical trials under the name of a general project at chictr.gov on February 1, 2019, and the registration number of the general project is ChiCTR1900021195. This study is still recruiting now, and the first patient was screened on March 22, 2019.

Asymptomatic cryptococcal antigenemia in HIV-infected patients: a review of recent studies.

The prevalence of asymptomatic cryptococcal antigenemia (ACA) in human immunodeficiency virus (HIV) infected individuals has been observed to be elevated. The prevalence of ACA ranges from 1.3% to 13%, with different rates of prevalence in various regions of the world. We reviewed studies conducted internationally, and also referred to two established expert consensus guideline documents published in China, and we have concluded that Chinese HIV-infected patients should undergo cryptococcal antigen screening when CD4 T-cell counts fall below 200 cells/µL and that the recommended treatment regimen for these patients follow current World Health Organization guidelines, although it is likely that this recommendation may change in the future. Early screening and optimized preemptive treatment for ACA is likely to help decrease the incidence of cryptococcosis, and is lifesaving. Further studies are warranted to explore issues related to the optimal management of ACA.