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BACKGROUND: The application time of dolutegravir (DTG) is relatively short, and the treatment experience is insufficient. Therefore, evidence is required to shed more light on the effectiveness and safety issues of DTG in China. OBJECTIVES: To assess the effectiveness and safety of a DTG vs. efavirenz (EFV) antiviral regimens (the current mainstream regimen). METHODS: This was a retrospective cohort study. Data of people with HIV (PWH), who started initial DTG-based or EFV-based antiretroviral therapy at the Chengdu Public Health Clinical Medical Center from January 2018 to October 2020, were collected. Effectiveness indicators such as CD4+ T-cell recovery and HIV viral suppression, and safety indicators, including blood routine, liver and kidney function, and occurrence of abnormal blood lipids after DTG vs. EFV-based antiviral regimen treatments, were analyzed. RESULTS: A total of 656 patients were eligible, of which 611 patients were included in the study. Most of the PWHs in our center were young men (86.25%). Nearly one-third of the participants were coinfected with syphilis. The median baseline HIV viral load was 4.70 log10 copies/mL. The median CD4+ T-cell count was 254 cells/mm3. More participants started on EFV-based regimens than DTG-based regimens (82.32% vs. 17.67%). The time to reach the target value (CD4 > 350 cells/mm3) in the DTG group was shorter than that in the EFV group (408 days vs. 522 days), and the percentage of reaching the CD4 target value of the DTG group was higher than that of the EFV group (41.04% vs. 33.76%) in 1 year. The effect of virologic suppression (<50 copies/mL) in the DTG group was superior to that in the EFV group. The use of DTG-containing treatment regimens was significantly related to a quicker virologic suppression (hazard ratio, 1.76; 95% confidence interval of 1.40-2.21, P < 0.0001). The safety data analysis of laboratory indicators showed that there was no significant difference in the incidence of adverse events between the 2 groups. CONCLUSIONS: A DTG-based regimen may be more conducive to the CD4 recovery than the EFV-based regimen. The virologic suppression of the DTG group may be superior to that of the EFV group. DTG-based regimens might be the preferred treatment option for people with HIV for initial HIV treatment.
Subject(s)
Anti-HIV Agents , HIV Infections , HIV Seropositivity , HIV-1 , Alkynes , Anti-HIV Agents/adverse effects , Benzoxazines/adverse effects , Cyclopropanes , HIV Infections/drug therapy , HIV Seropositivity/drug therapy , Heterocyclic Compounds, 3-Ring , Humans , Male , Oxazines , Piperazines , Pyridones , Retrospective StudiesABSTRACT
SARS-CoV-2 infection of the upper airway and the subsequent immune response are early, critical factors in COVID-19 pathogenesis. By studying infection of human biopsies in vitro and in a hamster model in vivo, we demonstrated a transition in tropism from olfactory to respiratory epithelium as the virus evolved. Analyzing each variants revealed that SARS-CoV-2 WA1 or Delta infects a proportion of olfactory neurons in addition to the primary target sustentacular cells. The Delta variant possesses broader cellular invasion capacity into the submucosa, while Omicron displays longer retention in the sinonasal epithelium. The olfactory neuronal infection by WA1 and the subsequent olfactory bulb transport via axon is more pronounced in younger hosts. In addition, the observed viral clearance delay and phagocytic dysfunction in aged olfactory mucosa is accompanied by a decline of phagocytosis related genes. Furthermore, robust basal stem cell activation contributes to neuroepithelial regeneration and restores ACE2 expression post-infection. Together, our study characterized the nasal tropism of SARS-CoV-2 strains, immune clearance, and regeneration post infection. The shifting characteristics of viral infection at the airway portal provides insight into the variability of COVID-19 clinical features and may suggest differing strategies for early local intervention.
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Control of SARS-CoV-2 (SCV-2) transmission is a major priority that requires understanding SCV-2 replication dynamics. We developed and validated novel droplet digital PCR (ddPCR) assays to quantify SCV-2 subgenomic RNAs (sgRNAs), which are only produced during active viral replication, and discriminate them from full-length genomic RNAs (gRNAs) in a multiplexed format. We applied this multiplex ddPCR assay to 144 cross-sectional nasopharyngeal samples. sgRNAs were quantifiable across a range of qPCR cycle threshold (Ct) values and correlated with Ct values. The ratio of sgRNA:gRNA was remarkably stable across a wide range of Ct values, whereas adjusted amounts of N sgRNA to a human housekeeping gene declined with higher Ct values. Interestingly, adjusted sgRNA and gRNA amounts were quantifiable in culture-negative samples, although levels were significantly lower than in culture-positive samples. Longitudinal daily testing of 6 persons for up to 14 days revealed that sgRNA is concordant with culture results during the first week of infection but may be discordant with culture later in infection. Further, sgRNA:gRNA is constant during infection despite changes in viral culture. These data indicate stable viral transcription during infection. More work is needed to understand why cultures are negative despite persistence of viral RNAs.
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ObjectivesCOVID-19 has brought unprecedented attention to the crucial role of diagnostics in pandemic control. We compared SARS-CoV-2 test performance by sample type and modality in close contacts of SARS-CoV-2 cases. MethodsClose contacts of SARS-CoV-2 positive individuals were enrolled after informed consent. Clinician-collected nasopharyngeal (NP) swabs in viral transport media (VTM) were tested with a nucleic acid test (NAT). NP VTM and self-collected passive drool were tested using the PerkinElmer real-time reverse transcription PCR (RT-PCR) assay. For the first 4 months of study, mid-turbinate swabs were tested using the BD Veritor rapid antigen test. NAT positive NP samples were tested for infectivity using a VeroE6TMPRSS2 cell culture model. ResultsBetween November 17, 2020, and October 1, 2021, 235 close contacts of SARS-CoV-2 cases were recruited, including 95 with symptoms (82% symptomatic for <5 days) and 140 asymptomatic individuals. NP swab reference tests were positive for 53 (22.6%) participants; 24/50 (48%) were culture positive. PerkinElmer testing of NP and saliva samples identified an additional 28 (11.9%) SARS-CoV-2 cases who tested negative by clinical NAT. Antigen tests performed for 99 close contacts showed 83% positive percent agreement (PPA) with reference NAT among early symptomatic persons, but 18% PPA in others; antigen tests in 8 of 11 (72.7%) culture-positive participants were positive. ConclusionsContacts of SARS-CoV-2 cases may be falsely negative early after contact, which more sensitive platforms may identify. Repeat or serial SARS-CoV-2 testing with both antigen and molecular assays may be warranted for individuals with high pretest probability for infection.
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The global effort to vaccinate people against SARS-CoV-2 in the midst of an ongoing pandemic has raised questions about the nature of vaccine breakthrough infections and the potential for vaccinated individuals to transmit the virus. These questions have become even more urgent as new variants of concern with enhanced transmissibility, such as Delta, continue to emerge. To shed light on how vaccine breakthrough infections compare with infections in immunologically naive individuals, we examined viral dynamics and infectious virus shedding through daily longitudinal sampling in a small cohort of adults infected with SARS-CoV-2 at varying stages of vaccination. The durations of both infectious virus shedding and symptoms were significantly reduced in vaccinated individuals compared with unvaccinated individuals. We also observed that breakthrough infections are associated with strong tissue compartmentalization and are only detectable in saliva in some cases. These data indicate that vaccination shortens the duration of time of high transmission potential, minimizes symptom duration, and may restrict tissue dissemination.
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Several vaccines have been introduced to combat the coronavirus infectious disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current SARS-CoV-2 vaccines include mRNA-containing lipid nanoparticles or adenoviral vectors that encode the SARS-CoV-2 Spike (S) protein of SARS-CoV-2, inactivated virus, or protein subunits. Despite growing success in worldwide vaccination efforts, additional capabilities may be needed in the future to address issues such as stability and storage requirements, need for vaccine boosters, desirability of different routes of administration, and emergence of SARS-CoV-2 variants such as the Delta variant. Here, we present a novel, well-characterized SARS-CoV-2 vaccine candidate based on extracellular vesicles (EVs) of Salmonella typhimurium that are decorated with the mammalian cell culture-derived Spike receptor-binding domain (RBD). RBD-conjugated outer membrane vesicles (RBD-OMVs) were used to immunize the golden Syrian hamster (Mesocricetus auratus) model of COVID-19. Intranasal immunization resulted in high titers of blood anti-RBD IgG as well as detectable mucosal responses. Neutralizing antibody activity against wild-type and Delta variants was evident in all vaccinated subjects. Upon challenge with live virus, hamsters immunized with RBD-OMV, but not animals immunized with unconjugated OMVs or a vehicle control, avoided body mass loss, had lower virus titers in bronchoalveolar lavage fluid, and experienced less severe lung pathology. Our results emphasize the value and versatility of OMV-based vaccine approaches.
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To catalyze SARS-CoV-2 research including development of novel interventive and preventive strategies, we characterized progression of disease in depth in a robust COVID-19 animal model. In this model, male and female golden Syrian hamsters were inoculated intranasally with SARS-CoV-2 USA-WA1/2020. Groups of inoculated and mock-inoculated uninfected control animals were euthanized at day 2, 4, 7, 14, and 28 days post-inoculation to track multiple clinical, pathology, virology, and immunology outcomes. SARS-CoV-2-inoculated animals consistently lost body weight during the first week of infection, had higher lung weights at terminal timepoints, and developed lung consolidation per histopathology and quantitative image analysis measurements. High levels of infectious virus and viral RNA were reliably present in the respiratory tract at days 2 and 4 post-inoculation, corresponding with widespread necrosis and inflammation. At day 7, when infectious virus was rare, interstitial and alveolar macrophage infiltrates and marked reparative epithelial responses (type II hyperplasia) dominated in the lung. These lesions resolved over time, with only residual epithelial repair evident by day 28 post-inoculation. The use of quantitative approaches to measure cellular and morphologic alterations in the lung provides valuable outcome measures for developing therapeutic and preventive interventions for COVID-19 using the hamster COVID-19 model.
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In the ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more severe outcomes are reported in males compared with females, including hospitalizations and deaths. Animal models can provide an opportunity to mechanistically interrogate causes of sex differences in the pathogenesis of SARS-CoV-2. Adult male and female golden Syrian hamsters (8-10 weeks of age) were inoculated intranasally with 105 TCID50 of SARS-CoV-2/USA-WA1/2020 and euthanized at several time points during the acute (i.e., virus actively replicating) and recovery (i.e., after the infectious virus has been cleared) phases of infection. There was no mortality, but infected male hamsters experienced greater morbidity, losing a greater percentage of body mass, developing more extensive pneumonia as noted on chest computed tomography, and recovering more slowly than females. Treatment of male hamsters with estradiol did not alter pulmonary damage. Virus titers in respiratory tissues, including nasal turbinates, trachea, and lungs, and pulmonary cytokine concentrations, including IFN{beta} and TNF, were comparable between the sexes. However, during the recovery phase of infection, females mounted two-fold greater IgM, IgG, and IgA responses against the receptor-binding domain of the spike protein (S-RBD) in both plasma and respiratory tissues. Female hamsters also had significantly greater IgG antibodies against whole inactivated SARS-CoV-2 and mutant S-RBDs, as well as virus neutralizing antibodies in plasma. The development of an animal model to study COVID-19 sex differences will allow for a greater mechanistic understanding of the SARS-CoV-2 associated sex differences seen in the human population. ImportanceMen experience more severe outcomes from COVID-19 than women. Golden Syrian hamsters were used to explore sex differences in the pathogenesis of a human clinical isolate of SARS-CoV-2. After inoculation, male hamsters experienced greater sickness, developed more severe lung pathology, and recovered more slowly than females. Sex differences in disease could not be reversed by estradiol treatment in males and were not explained by either virus replication kinetics or the concentrations of inflammatory cytokines in the lungs. During the recovery period, antiviral antibody responses in the respiratory tract and plasma, including to newly emerging SARS-CoV-2 variants, were greater in females than male hamsters. Greater lung pathology during the acute phase combined with reduced antiviral antibody responses during the recovery phase of infection in males than females illustrate the utility of golden Syrian hamsters as a model to explore sex differences in the pathogenesis of SARS-CoV-2 and vaccine-induced immunity and protection. One Sentence SummaryFollowing SARS-CoV-2 infection, male hamsters experience worse clinical disease and have lower antiviral antibody responses than females.
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Objective To study the drug resistance situation of Mycobacterium tuberculosis strains isolated from the patients with HIV/AIDS complicating tuberculosis (TB).Methods One hundred and ninety-six inpatients with AIDS complicating TB in our hospital from January 2012 to December 2015 were collected.The drug resistance situation of Mycobacterium tuberculosis strains cultured from sputum/tissue fluid/fiber liquid and pathological tissue submitted samples in the patients with AIDS complicating active TB was analyzed.The BACTEC MGIT960 systems was adopted to perform the bacterial identification.The drug sensitivity test was conducted by using 960 culture testing system.Results One hundred and ninety-six strains of Mycobacterium tuberculosis were cultured,the total drug resistance rate of Mycobacterium tuberculosis was 26.02％.These cases were divided into the ＞100/μL and ≤100/μL groups according to different CD4+ T cells count.The drug resistance situation of Mycobacterium tuberculosis to 4 kinds of first line anti-TB drugs were compared between these two groups.The comparison results found that the resistance rate of Mycobacterium tuberculosis strains to the first line anti-TB drugs had no statistical difference between the two groups (P＞0.05).The resistance rates of first line anti-TB drugs from high to low were isoniazid,rifampicin,streptomycin and ethambutol.The drug resistance rate of Mycobacterium tuberculosis strains to 5 types of drug resistant TB had no statistical difference(P＞0.05).Conclusion The drug resistance rate in the initial patients with HIV complicating TB is consistent with the average initial drugresistance level of TB patients in our country.The TB drug resistance rate in the patients with HIV complicating TB has no correlation with CD4+ T cells count.
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Objective To compare the difference of immune responses to hepatitis B virus (HBV) vaccine in human immunodeficiency virus (HIV)-1-infected patients with different CD4+ T-lymphocyte counts.Methods HIV-1-infected patients who visited clinic at the Public Health Clinical Center of Chengdu were enrolled and divided into two groups according to CD4+ T-lymphocytes counts.CD4+ T-lymphocytes ＜200/μL,which were and ≥200/μL.All patients were injected intramuscularly with 20 μg of HBV vaccine at month 0,1 and 6,respectively.Vaccination responses were measured at1 and 7 months after first dose.The serum anti-hepatitis B sarface antigen titers of ≥ 10 mIU/mL were considered positive.The serum anti-HBs positive rates was compared by Chi-square test and anti-HBs titers was compared by Mann-Whitney test.Results Ninety-five HIV-1-infected patients were finally enrolled into the analysis,with 55 patients in group of CD4+ T-lymphocytes ＜200/μL and 40 patients in group of CD4+ T-lymphocytes ≥200/μL.The serum anti-HBs positivity rates at 1 and 7 months after first dose in group of CD4+ T-lymphocytes ＜200/μL were 40.0％ (22/55) and 50.9％ (28/55),respectively,which were 47.5％ (19/40) and 75.0％ (30/40) in group of CD4+ Tlymphocytes ≥200/μL.There was no significant difference of serum anti-HBs positivity rates between two groups after 1 month (x2 =5.652,P=0.017).But a significant higher positivity rate was found in group of CD4+ T-lymphocytes ≥200/μL than in group ofCD4+ Tlymphocytes＜200/μL after 7 months (x2=0.531,P=0.466).The median titers of anti-HBs at 7 months were 10.44 mIU/mL in grouP of CD4+ T-lymphocytes ＜ 200/μL and 222.73 mIU/ml in group of CD4+ T-lymphocytes ≥200/μL.There was significant difference of anti-HBs titers between two groups (Z=-3.600,P＜0.01).No patients experienced side effects to HBV vaccine.Logistic regression model analysis indicated that only CD4+ Tlymphocytes was related to anti-HBs positivity after HBV vaccination.Conclusions HIV-1-infected patients with CD4+ T-lymphocytes ≥200/μL have higher serum anti-HBs positivity rates and higher anti HBs titers than patients with CD4+ T-lymphocytes ＜200/μL.However,patients with CD4+ T lymphocytes ＜200/μL also have relatively low immune response.Thus,HBV vaccination should be conducted in all these patients at high risk.
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Objective To study clinical characters and prognosis of AIDS patients with opportunistic infections in Sichuan prov-ince .Methods We performed an retrospective analysis of 1 465 AIDS patients with opportunistic infections who were admitted into the transmitted disease hospital of Chengdu in recent 10 years .Results The overall mortality during hospitalization was 15 .49% . The leading cause of death was respiratory failure due to pneumonia (n=150 ,74 .62% ) or meningitis(n=47 ,23 .86% ) .Descending rank order of common opportunistic infections were respiratory tract ,the mouth swallows ,central nervous system ,gastrointestinal tract skin ,blood system .Descending rank order of common sites of infections were respiratory tract ,oropharynx ,central nervous system ,gastrointestinal tract skin ,reproductive tract .The multiple infections are common :more than 50% of patients suffering from two or more infections(50 .77% ) .Complexity of infection sites :42 .18% dual infection sites and 17 .20% three or more infec-tion sites .Conclusion The opportunistic infections disease spectrum of AIDS in Sichuan area has its own characteristics :multiple infections and multiple infections sites are both common ,death risks are high ,conditions of patients are severe generally ,and respir-atory failure is the main cause of death .
