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 .

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 .

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.

No Statistically Apparent Difference in Antiviral Effectiveness Observed Among Ribavirin Plus Interferon-Alpha, Lopinavir/Ritonavir Plus Interferon-Alpha, and Ribavirin Plus Lopinavir/Ritonavir Plus Interferon-Alpha in Patients With Mild to Moderate Coronavirus Disease 2019: Results of a Randomized, Open-Labeled Prospective Study.

BACKGROUND: Currently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally, causing an unprecedented pandemic. However, there is no specific antiviral therapy for coronavirus disease 2019 (COVID-19). We conducted a clinical trial to compare the effectiveness of three antiviral treatment regimens in patients with mild to moderate COVID-19. METHODS: This was a single-center, randomized, open-labeled, prospective clinical trial. Eligible patients with mild to moderate COVID-19 were randomized into three groups: ribavirin (RBV) plus interferon-α (IFN-α), lopinavir/ritonavir (LPV/r) plus IFN-α, and RBV plus LPV/r plus IFN-α at a 1:1:1 ratio. Each patient was invited to participate in a 28-d follow-up after initiation of an antiviral regimen. The outcomes include the difference in median interval to SARS-CoV-2 nucleic acid negativity, the proportion of patients with SARS-CoV-2 nucleic acid negativity at day 14, the mortality at day 28, the proportion of patients re-classified as severe cases, and adverse events during the study period. RESULTS: In total, we enrolled 101 patients in this study. Baseline clinical and laboratory characteristics of patients were comparable among the three groups. In the analysis of intention-to-treat data, the median interval from baseline to SARS-CoV-2 nucleic acid negativity was 12 d in the LPV/r+IFN-α-treated group, as compared with 13 and 15 d in the RBV+IFN-α-treated group and in the RBV+LPV/r+ IFN-α-treated group, respectively (p=0.23). The proportion of patients with SARS-CoV-2 nucleic acid negativity in the LPV/r+IFN-α-treated group (61.1%) was higher than the RBV+ IFN-α-treated group (51.5%) and the RBV+LPV/r+IFN-α-treated group (46.9%) at day 14; however, the difference between these groups was calculated to be statistically insignificant. The RBV+LPV/r+IFN-α-treated group developed a significantly higher incidence of gastrointestinal adverse events than the LPV/r+ IFN-α-treated group and the RBV+ IFN-α-treated group. CONCLUSIONS: Our results indicate that there are no significant differences among the three regimens in terms of antiviral effectiveness in patients with mild to moderate COVID-19. Furthermore, the combination of RBV and LPV/r is associated with a significant increase in gastrointestinal adverse events, suggesting that RBV and LPV/r should not be co-administered to COVID-19 patients simultaneously. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, ID: ChiCTR2000029387. Registered on January 28, 2019.

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 antiretroviral therapy timing in AIDS patients with toxoplasma encephalitis.

BACKGROUND: Toxoplasma encephalitis (TE) is one of the main opportunistic infections in acquired immunodeficiency syndrome (AIDS) patients, and represents a social burden due to its high prevalence and morbidity. Concomitant antiretroviral therapy (ART), together with effective anti- toxoplasma combination therapy, is an effective strategy to treat AIDS-associated TE (AIDS/TE) patients. However, the timing for the initiation of ART after diagnosis of TE remains controversial. We therefore designed the present study to determine the optimal timing for ART initiation in AIDS/TE patients. METHODS/DESIGN: This trial is a 17-center, randomized, prospective clinical study with 2 parallel arms. A total of 200 participants will be randomized at a 1:1 ratio into the 2 arms: the early ART initiation (≤14 days after TE diagnosis) arm and the deferred ART (>14 days after TE diagnosis) arm. The primary outcome will be the difference of mortality between the 2 arms at 48 weeks. The secondary outcomes will be the differences between the 2 arms in the changes of CD4+ counts from baseline to week 48, the rate of virologic suppression (HIV ribonucleic acid <50 copies/mL) from baseline to week 48, the incidence of TE-associated immune reconstitution inflammatory syndrome during the study period, and the incidence of adverse effects during the study period. DISCUSSION: This present trial aims to evaluate the optimal timing for ART initiation in AIDS/TE patients, and will provide strong evidence for AIDS/TE treatment should it be successful. TRIAL REGISTRATION: This trial was registered as one of the 12 trials under the name of a general project at the chictr.gov (http://www.chictr.org.cn/showproj.aspx?proj=35362) 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.