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Further insight into humoral viral immunity after hematopoietic cell transplantation (HCT) could have potential impact on donor selection or monitoring of patients. Currently, estimation of humoral immune recovery is inferred from lymphocyte counts or immunoglobulin levels and does not address vulnerability to specific viral infections. We interrogated the viral antibody repertoire before and after HCT using a novel serosurvey (VirScan) that detects immunoglobulin G responses to 206 viruses. We performed VirScan on cryopreserved serum from pre-HCT and 30, 100, and 365 days after myeloablative HCT from 37 donor-recipient pairs. We applied ecologic metrics (α- and ß-diversity) and evaluated predictors of metrics and changes over time. Donor age and donor/recipient cytomegalovirus (CMV) serostatus and receipt systemic glucocorticoids were most strongly associated with VirScan metrics at day 100. Other clinical characteristics, including pre-HCT treatment and conditioning, did not affect antiviral repertoire metrics. The recipient repertoire was most similar (pairwise ß-diversity) to that of donor at day 100, but more similar to pre-HCT self by day 365. Gain or loss of epitopes to common viruses over the year post-HCT differed by donor and recipient pre-HCT serostatus, with highest gains in naive donors to seropositive recipients for several human herpesviruses and adenoviruses. We used VirScan to highlight contributions of donor and recipient to antiviral humoral immunity and evaluate longitudinal changes. This work builds a foundation to test whether such systematic profiling could serve as a biomarker of immune reconstitution, predict clinical events after HCT, or help refine selection of optimal donors.
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Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Epitopos/imunologia , Transplante de Células-Tronco Hematopoéticas , Imunidade Humoral , Adulto , Anticorpos Antivirais/sangue , Formação de Anticorpos/genética , Citomegalovirus/imunologia , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Doadores de Tecidos , Transplantados , Transplante HomólogoRESUMO
PURPOSE OF REVIEW: The relationship between antiretroviral therapy (ART) and cancer treatment outcomes among people living with HIV (PLWH) in low- and middle-income countries (LMICs) is complex and poorly understood for many cancers. We aimed to summarize existing evidence from LMICs regarding the benefit of ART on cancer treatment-related outcomes. RECENT FINDINGS: We included twelve observational studies that reported associations between ART status and cancer treatment outcomes among HIV-positive patients in LMICs. Most confirmed ART was associated with improved cancer treatment outcomes. Heterogeneity in cancers under study, outcome measurement, categorization of ART status, and reporting of HIV-related immune function made formal comparison between studies untenable. Where evaluated, ART generally has a positive effect on cancer outcomes in people with HIV in LMICs. However, there remains a substantial gap in the literature regarding the impact of ART on treatment outcomes for most cancer types. Future research should focus on the optimal timing and integration of ART and cancer treatment for PLWH with strategies applicable to constrained-resource settings.
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Fármacos Anti-HIV , Infecções por HIV , Neoplasias , Fármacos Anti-HIV/uso terapêutico , Países em Desenvolvimento , Infecções por HIV/tratamento farmacológico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Pobreza , Resultado do TratamentoRESUMO
We investigated whether countries with higher coverage of childhood live vaccines [BCG or measles-containing-vaccine (MCV)] have reduced risk of coronavirus disease 2019 (COVID-19)-related mortality, while accounting for known systems differences between countries. In this ecological study of 140 countries using publicly available national-level data, higher vaccine coverage, representing estimated proportion of people vaccinated during the last 14 years, was associated with lower COVID-19 deaths. The associations attenuated for both vaccine variables, and MCV coverage became no longer significant once adjusted for published estimates of the Healthcare access and quality index (HAQI), a validated summary score of healthcare quality indicators. The magnitude of association between BCG coverage and COVID-19 death rate varied according to HAQI, and MCV coverage had little effect on the association between BCG and COVID-19 deaths. While there are associations between live vaccine coverage and COVID-19 outcomes, the vaccine coverage variables themselves were strongly correlated with COVID-19 testing rate, HAQI and life expectancy. This suggests that the population-level associations may be further confounded by differences in structural health systems and policies. Cluster randomised studies of booster vaccines would be ideal to evaluate the efficacy of trained immunity in preventing COVID-19 infections and mortality in vaccinated populations and on community transmission.
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COVID-19/imunologia , COVID-19/prevenção & controle , Imunidade Inata/imunologia , SARS-CoV-2/imunologia , Cobertura Vacinal/estatística & dados numéricos , Vacina BCG/administração & dosagem , Vacina BCG/imunologia , COVID-19/mortalidade , Atenção à Saúde/normas , Atenção à Saúde/estatística & dados numéricos , Humanos , Imunização Secundária/normas , Imunização Secundária/estatística & dados numéricos , Modelos Lineares , Vacina contra Sarampo/administração & dosagem , Vacina contra Sarampo/imunologia , Qualidade da Assistência à Saúde/normas , Qualidade da Assistência à Saúde/estatística & dados numéricosRESUMO
This review highlights current interventional clinical trials for HIV-associated malignancies (HIVAMs), with emphasis on 4 mechanistic areas: immunomodulatory therapies and gene therapies, including immune checkpoint inhibitors; cytotoxic therapies; novel tumor-targeted and virally targeted therapies in both AIDS-defining and non-AIDS-defining cancers (NADC); and other screening or topical/ablative interventions. A search on ClinicalTrials.gov located 35 trials, including 12 immunomodulatory or gene therapy trials, 6 cytotoxic therapy trials, 10 trials of therapies with tumor or viral molecular targets, and 7 trials evaluating screening interventions or topical or ablative therapies. Study drugs, mechanisms, and outcomes of interest, including future directions, are discussed. Targeted therapies and immunotherapies address not only the tumor but underlying viral oncogens, including possible benefits on HIV-specific immunologic control. The resulting science from the trials listed in this review will provide important translational breakthroughs for people living with HIV (PLWH) and cancer. We highlight disease-specific challenges that could be addressed in future studies, including testing the safety and efficacy of cutting-edge immunotherapy and targeted treatments used in the general cancer population, and improving gaps in knowledge and practice for cancer screening and its treatment, especially in low-resource regions. Additional important considerations include identification of novel therapies for virally mediated tumors that disproportionally present in PLWH, how to treat persons with HIVAM and advanced immunosuppression, and how to comanage both diseases in antiretroviral therapy-naïve persons and those receiving care in settings where supportive therapies for hematologic toxicities and infections are limited. Current and future clinical trials should address needs of both resource-replete and -limited regions, as well as cancers that are uncommon in or respond differently to HIV-negative populations (eg, Kaposi sarcoma or anal cancer), in addition to an increased focus on NADCs not traditionally linked with HIV, such as lung or gastrointestinal tumors.
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Infecções por HIV/complicações , HIV/patogenicidade , Imunoterapia/métodos , Neoplasias/terapia , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Ensaios Clínicos como Assunto , Terapia Genética/métodos , HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/terapia , Infecções por HIV/virologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Terapia de Alvo Molecular/métodos , Neoplasias/imunologia , Neoplasias/mortalidade , Neoplasias/virologia , Proteínas Oncogênicas Virais/antagonistas & inibidores , Proteínas Oncogênicas Virais/imunologia , Fatores de Risco , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Increased risk of adverse birth outcomes is well described in women with systemic lupus erythematosus (SLE), but risk of maternal or infant infection in the peripartum period has not been well studied. We conducted a population-based cohort study of infection risk in women with and without SLE and their infants. METHODS: Linked birth-hospital discharge data identified 1297 deliveries to women with SLE and a 4:1 comparison cohort of deliveries to women without SLE in Washington State, 1987-2013. Maternal and infant infections during the first 30 days after delivery were identified. Relative risks (RR) and 95% confidence intervals (CI) were estimated. RESULTS: Women with SLE were 1.7 times more likely (95% CI 1.4, 2.0) to have an infection during the birth hospitalisation and more likely to receive antibiotics during labour (RR 1.3, 95% CI 1.1, 1.5), though there was no increased risk of chorioamnionitis in women with SLE. Infants of women with SLE had an increased risk for an infection during the birth hospitalisation (RR 2.2, 95% CI 1.3, 3.5), although the size of the difference was smaller when adjusted for gestational age (RR 1.4, 95% CI 0.9, 2.1). Risks of neonatal infection, sepsis, receipt of antibiotics, and admission to neonatal intensive care were also increased, and were also attenuated after adjustment for gestational age. CONCLUSIONS: Women with SLE have an increased risk of peripartum infections and antibiotic exposure. Their neonates have a greater likelihood of infection, much of which is attributable to preterm birth.
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Doenças do Recém-Nascido/etiologia , Infecções/etiologia , Lúpus Eritematoso Sistêmico/complicações , Complicações Infecciosas na Gravidez/etiologia , Adulto , Antibacterianos/uso terapêutico , Estudos de Casos e Controles , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Doenças do Recém-Nascido/epidemiologia , Doenças do Recém-Nascido/microbiologia , Infecções/epidemiologia , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Lúpus Eritematoso Sistêmico/microbiologia , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Risco , Fatores de Risco , Sepse/epidemiologia , Sepse/etiologia , Adulto JovemRESUMO
BACKGROUND: Tenofovir is a potent anti-human immunodeficiency virus (HIV) agent that decreased risk of herpes simplex virus type 2 (HSV-2) acquisition in HIV pre-exposure prophylaxis trials. Whether tenofovir has utility in established HSV-2 disease is unclear. METHODS: We randomized immunocompetent women with symptomatic HSV-2 infection to oral tenofovir disoproxil fumarate (TDF)/placebo vaginal gel, oral placebo/tenofovir (TFV) vaginal gel, or double placebo (ratio 2:2:1) in a one-way cross-over trial. Women collected genital swabs twice daily for HSV PCR during 4-week lead-in and 5-week treatment phases. The primary intent-to-treat end point was within-person comparison of genital HSV shedding and lesion rates. RESULTS: 64 women completed the lead-in phase and were randomized. Neither TDF nor TFV gel decreased overall shedding or lesion rate in the primary analysis; TFV gel decreased quantity of HSV DNA by -0.50 (-0.86-0.13) log10 copies/mL. In the per-protocol analysis, TDF reduced shedding (relative risk [RR] = 0.74, P = .006) and lesion rates (RR = 0.75, P = .032); quantity of virus shed decreased by 0.41 log10 copies/mL. CONCLUSIONS: Oral TDF modestly decreased HSV shedding and lesion rate, and quantity of virus shed when used consistently. Vaginal TFV gel decreased quantity of virus shed by 60%. In contrast to effects on HSV-2 acquisition, tenofovir is unlikely to provide clinically meaningful reductions in the frequency of HSV shedding or genital lesions. CLINICAL TRIALS REGISTRATION: NCT01448616.
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Antivirais/uso terapêutico , Herpes Genital/tratamento farmacológico , Herpesvirus Humano 2/isolamento & purificação , Tenofovir/uso terapêutico , Eliminação de Partículas Virais , Administração Intravaginal , Administração Oral , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Herpes Genital/patologia , Humanos , Pessoa de Meia-Idade , Placebos/administração & dosagem , Resultado do TratamentoRESUMO
INTRODUCTION: Despite recommendations by the Centers for Disease Control (CDC) that all adults be offered non-targeted HIV screening in all care settings, screening in acute-care settings remains unacceptably low. We performed an observational study to evaluate an HIV screening pilot in an academic-community partnership health center urgent care clinic. METHODS: We collected visit data via encounter forms and demographic and laboratory data from electronic medical records. A post-pilot survey of perceptions of HIV screening was administered to providers and nurses. Multivariable analysis was used to identify factors associated with completion of testing. RESULTS: Visit provider and triage nurse were highly associated with both acceptance of screening and completion of testing, as were younger age, male gender, and race/ethnicity. 23.5% of patients completed tests, although 36.0% requested screening; time constraints as well as risk perceptions by both the provider and patient were cited as limiting completion of screening. Post-pilot surveys showed mixed support for ongoing HIV screening in this setting by providers and little support by nurses. CONCLUSIONS: Visit provider and triage nurse were strongly associated with acceptance of testing, which may reflect variable opinions of HIV screening in this setting by clinical staff. Among patients accepting screening, visit provider remained strongly associated with completion of testing. Despite longstanding recommendations for non-targeted HIV screening, further changes to improve the testing and results process, as well as provider education and buy-in, are needed to improve screening rates.
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To assess whether biomarkers of systemic inflammation are associated with HIV acquisition or with the timing of ART initiation ("immediate", at diagnosis, versus "deferred", at 24 weeks post-diagnosis) in men-who-have-sex-with-men (MSM) and transgender women, we conducted a retrospective study comparing inflammatory biomarkers in participants' specimens collected before infection and after ≥2 years of effective ART. We measured biomarkers in four longitudinally collected plasma, including two specimens collected from each participant before and two after HIV acquisition and confirmed ART-suppression. Biomarkers were quantified by enzyme-linked immuno-assay or Meso Scale Discovery. When evaluating systematic variation in these markers over time, we found that multiple biomarkers consistently varied across participants' two pre-infection or two post-ART-suppression specimens. Additionally, we compared changes in biomarkers after vs before HIV acquisition. Across 47 participants, the levels of C-reactive protein (CRP), monocyte chemo-attractant protein-1, tumor necrosis factor-α and interferon gamma-induced protein-10 significantly increased while leptin and lipopolysaccharide binding protein (LBP) significantly decreased following HIV infection. Randomization to deferred-ART initiation was associated with greater increases in CRP and no decrease in LBP. Acquisition of HIV appeared to induce systemic inflammation, with elevation of biomarkers previously associated with infections and cardiovascular disease. Initiation of ART during the early weeks of infection tempered the increase in pro-inflammatory biomarkers compared to delaying ART for ~24 weeks after HIV diagnosis. These findings provide insight into potential mediators by which immediate-ART initiation improves health outcomes, perhaps because immediate-ART limits the size of the HIV reservoir or limits immune dysregulation that in turn trigger systemic inflammation.
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Biomarcadores , Infecções por HIV , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/sangue , Masculino , Biomarcadores/sangue , Feminino , Adulto , Estudos Retrospectivos , Inflamação/sangue , Pessoa de Meia-Idade , Proteínas de Fase Aguda/metabolismo , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análise , Fármacos Anti-HIV/uso terapêutico , Pessoas Transgênero , Proteínas de Transporte , Glicoproteínas de MembranaRESUMO
Background: Data on tecovirimat effectiveness for human mpox are limited. We conducted a retrospective cross-sectional interview-based study to identify associations between tecovirimat treatment and the mpox clinical course. Methods: Using public health surveillance data from King County, Washington, we recruited and interviewed persons diagnosed with mpox during May-October 2022. We calculated descriptive statistics on demographics, vaccination status, comorbidities, and symptoms including 3 self-reported dates (symptom onset, first date of symptom improvement, and illness resolution). We used multivariable linear regression, stratified by illness severity, to evaluate the association of tecovirimat treatment with time to symptom improvement and time to illness resolution. We compared individuals who did not receive tecovirimat to participants who started tecovirimat early (≤5 days from symptom onset) and late (>5 days and ≤28 days from symptom onset) in their illness. Results: Of 465 individuals diagnosed with mpox, 115 (25%) participated in this study. Eighty participants (70%) received tecovirimat and 43 (37%) initiated tecovirimat early. Sixty-eight (59%) reported severe symptoms during their illness, including proctitis (n = 38 [33%]), rectal bleeding (n = 27 [24%]), or severe pain (n = 24 [21%]). In the multivariable analysis, early tecovirimat was associated with shorter time to symptom improvement (-5.5 days, P = .04) among participants with severe illness but not among those with nonsevere illness (0.9 day, P = .66). Early tecovirimat was not associated with faster illness resolution, regardless of severity. Conclusions: Our small study suggests that early tecovirimat initiation may hasten subjective symptomatic improvement in people with severe mpox. Larger randomized trials are needed to evaluate this finding.
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Fármacos Anti-HIV/uso terapêutico , Antineoplásicos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Neoplasias/tratamento farmacológico , Guias de Prática Clínica como Assunto , Medicina Baseada em Evidências/métodos , Medicina Baseada em Evidências/normas , HIV/efeitos dos fármacos , HIV/isolamento & purificação , Infecções por HIV/complicações , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Oncologia/métodos , Oncologia/normas , Neoplasias/imunologia , Neoplasias/virologia , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de TempoRESUMO
Statistical analysis to evaluate mechanistic pathways can be limited by non-causal associations as well as co-linearity of high-dimensional data. Here, we present a protocol evaluating statistical associations between multiple exposure variables (sociodemographic and behavioral), immune biomarkers, and HIV acquisition. We describe steps for study setup, combining Least Absolute Shrinkage and Selective Operator with the standard regression approach, and building nested models. This approach can determine to what extent associations between risks for exposure contributes to HIV acquisition with or without associated changes in immune activation. For complete details on the use and execution of this protocol, please refer to Bender Ignacio et al.1.
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Infecções por HIV , Humanos , Infecções por HIV/epidemiologiaRESUMO
Background: Prior randomized clinical trials have reported benefit of fluvoxamine ≥200â mg/d vs placebo for patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: This randomized, double-blind, placebo-controlled, fully remote multisite clinical trial evaluated whether fluvoxamine prevents clinical deterioration in higher-risk outpatients with acute coronavirus disease 2019 (COVID-19). Between December 2020 and May 2021, nonhospitalized US and Canadian participants with confirmed symptomatic infection received fluvoxamine (50â mg on day 1, 100â mg twice daily thereafter) or placebo for 15 days. The primary modified intent-to-treat (mITT) population included participants who started the intervention within 7 days of symptom onset with a baseline oxygen saturation ≥92%. The primary outcome was clinical deterioration within 15 days of randomization, defined as having both (1) shortness of breath (severity ≥4 on a 0-10 scale or requiring hospitalization) and (2) oxygen saturation <92% on room air or need for supplemental oxygen. Results: A total of 547 participants were randomized and met mITT criteria (n = 272 fluvoxamine, n = 275 placebo). The Data Safety Monitoring Board recommended stopping early for futility related to lower-than-predicted event rates and declining accrual concurrent with vaccine availability in the United States and Canada. Clinical deterioration occurred in 13 (4.8%) participants in the fluvoxamine group and 15 (5.5%) participants in the placebo group (absolute difference at day 15, 0.68%; 95% CI, -3.0% to 4.4%; log-rank P = .91). Conclusions: This trial did not find fluvoxamine efficacious in preventing clinical deterioration in unvaccinated outpatients with symptomatic COVID-19. It was stopped early and underpowered due to low primary outcome rates. Clinical Trials Registration: ClinicalTrials.gov Identifier: NCT04668950.
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Importance: Development of effective, scalable therapeutics for SARS-CoV-2 is a priority. Objective: To test the efficacy of combined tixagevimab and cilgavimab monoclonal antibodies for early COVID-19 treatment. Design, Setting, and Participants: Two phase 2 randomized blinded placebo-controlled clinical trials within the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-2/A5401 platform were performed at US ambulatory sites. Nonhospitalized adults 18 years or older within 10 days of positive SARS-CoV-2 test and symptom onset were eligible and were enrolled from February 1 to May 31, 2021. Interventions: Tixagevimab-cilgavimab, 300 mg (150 mg of each component) given intravenously (IV) or 600 mg (300 mg of each component) given intramuscularly (IM) in the lateral thigh, or pooled placebo. Main Outcomes and Measures: Coprimary outcomes were time to symptom improvement through 28 days; nasopharyngeal SARS-CoV-2 RNA below the lower limit of quantification (LLOQ) on days 3, 7, or 14; and treatment-emergent grade 3 or higher adverse events through 28 days. Results: A total of 229 participants were randomized for the IM study and 119 were randomized for the IV study. The primary modified intention-to-treat population included 223 participants who initiated IM tixagevimab-cilgavimab (n = 106) or placebo treatment (n = 117) (median age, 39 [IQR, 30-48] years; 113 [50.7%] were men) and 114 who initiated IV tixagevimab-cilgavimab (n = 58) or placebo treatment (n = 56) (median age, 44 [IQR, 35-54] years; 67 [58.8%] were women). Enrollment in the IV study was stopped early based on a decision to focus on IM product development. Participants were enrolled at a median of 6 (IQR, 4-7) days from COVID-19 symptom onset. Significant differences in time to symptom improvement were not observed for IM tixagevimab-cilgavimab vs placebo or IV tixagevimab-cilgavimab vs placebo. A greater proportion in the IM tixagevimab-cilgavimab arm (69 of 86 [80.2%]) than placebo (62 of 96 [64.6%]) had nasopharyngeal SARS-CoV-2 RNA below LLOQ at day 7 (adjusted risk ratio, 1.33 [95% CI, 1.12-1.57]) but not days 3 and 14; the joint test across time points favored treatment (P = .003). Differences in the proportion below LLOQ were not observed for IV tixagevimab-cilgavimab vs placebo at any of the specified time points. There were no safety signals with either administration route. Conclusions: In these 2 phase 2 randomized clinical trials, IM or IV tixagevimab-cilgavimab was safe but did not change time to symptom improvement. Antiviral activity was more evident in the larger IM trial. Trial Registration: ClinicalTrials.gov Identifier: NCT04518410.
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COVID-19 , Adulto , Feminino , Humanos , Masculino , Anticorpos Monoclonais , Tratamento Farmacológico da COVID-19 , RNA Viral , SARS-CoV-2RESUMO
Prior studies attempting to link biomarkers of immune activation with risk of acquiring HIV have relied on cross sectional samples, most without proximity to HIV acquisition. We created a nested case-control study within the Sabes study in Peru, and assessed a panel of plasma immune biomarkers at enrollment and longitudinally, including within a month of diagnosis of primary HIV or matched timepoint in controls. We used machine learning to select biomarkers and sociobehavioral covariates predictive of HIV acquisition. Most biomarkers were indistinguishable between cases and controls one month before HIV diagnosis. However, levels differed between cases and controls at study entry, months to years earlier. Dynamic changes in IL-2, IL-7, IL-10, IP-10 and IL-12, rather than absolute levels, jointly predicted HIV risk when added to traditional risk factors, and there was modest effect modification of biomarkers on association between sociobehavioral risk factors and HIV acquisition.
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AZD7442 (Evusheld) is a combination of two human anti-severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) monoclonal antibodies (mAbs), tixagevimab (AZD8895) and cilgavimab (AZD1061). Route of administration is an important consideration to improve treatment access. We assessed pharmacokinetics (PKs) of AZD7442 absorption following 600 mg administered intramuscularly (i.m.) in the thigh compared with 300 mg intravenously (i.v.) in ambulatory adults with symptomatic COVID-19. PK analysis included 84 of 110 participants randomized to receive i.m. AZD7442 and 16 of 61 randomized to receive i.v. AZD7442. Serum was collected prior to AZD7442 administration and at 24 hours and 3, 7, and 14 days later. PK parameters were calculated using noncompartmental methods. Following 600 mg i.m., the geometric mean maximum concentration (Cmax ) was 38.19 µg/mL (range: 17.30-60.80) and 37.33 µg/mL (range: 14.90-58.90) for tixagevimab and cilgavimab, respectively. Median observed time to maximum concentration (Tmax ) was 7.1 and 7.0 days for tixagevimab and cilgavimab, respectively. Serum concentrations after i.m. dosing were similar to the i.v. dose (27-29 µg/mL each component) at 3 days. The area under the concentration-time curve (AUC)0-7d geometric mean ratio was 0.9 for i.m. vs. i.v. Participants with higher weight or body mass index were more likely to have lower concentrations with either route. Women appeared to have higher interparticipant variability in concentrations compared with men. The concentrations of tixagevimab and cilgavimab after administration i.m. to the thigh were similar to those achieved with i.v. after 3 days from dosing. Exposure in the i.m. group was 90% of i.v. over 7 days. Administration to the thigh can be considered to provide consistent mAb exposure and improve access.
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Tratamento Farmacológico da COVID-19 , Humanos , Adulto , Masculino , Feminino , SARS-CoV-2 , Anticorpos MonoclonaisRESUMO
BACKGROUND: Although immune activation is associated with HIV acquisition, the nature of inflammatory profiles that increase HIV risk, which may include responses to M. tuberculosis (Mtb) infection, are not well characterized. METHODS: We conducted a nested case-control study using cryopreserved samples from persons who did and did not acquire HIV during the multinational Step clinical trial of the MRKAd5 HIV-1 vaccine. PBMCs from the last HIV-negative sample from incident HIV cases and controls were stimulated with Mtb-specific antigens (ESAT-6/CFP-10) and analyzed by flow cytometry with intracellular cytokine staining and scored with COMPASS. We measured inflammatory profiles with five Correlates of TB Risk (CoR) transcriptomic signatures. Our primary analysis examined the association of latent Mtb infection (LTBI; IFNγ+CD4+ T cell frequency) or RISK6 CoR signature with HIV acquisition. Conditional logistic regression analyses, adjusted for known predictors of HIV acquisition, were employed to assess whether TB-associated immune markers were associated with HIV acquisition. RESULTS: Among 465 participants, LTBI prevalence (21.5% controls vs 19.1% cases, p = 0.51) and the RISK6 signature were not higher in those who acquired HIV. In exploratory analyses, Mtb antigen-specific polyfunctional CD4+ T cell COMPASS scores (aOR 0.96, 95% CI 0.77, 1.20) were not higher in those who acquired HIV. Two CoR signatures, Sweeney3 (aOR 1.38 (1.07, 1.78) per SD change) and RESPONSE5 (0.78 (0.61, 0.98)), were associated with HIV acquisition. The transcriptomic pattern used to differentiate active vs latent TB (Sweeney3) was most strongly associated with acquiring HIV. CONCLUSIONS: LTBI, Mtb polyfunctional antigen-specific CD4+ T cell activation, and RISK6 were not identified as risks for HIV acquisition. In exploratory transcriptomic analyses, two CoR signatures were associated with HIV risk after adjustment for known behavioral and clinical risk factors. We identified host gene expression signatures associated with HIV acquisition, but the observed effects are likely not mediated through Mtb infection.
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Infecções por HIV , Tuberculose Latente , Mycobacterium tuberculosis , Tuberculose , Antígenos de Bactérias , Linfócitos T CD4-Positivos , Estudos de Casos e Controles , Infecções por HIV/complicações , Humanos , Tuberculose/complicaçõesRESUMO
INTRODUCTION: Early systemic and central nervous system viral replication and inflammation may affect brain integrity in people with HIV, leading to chronic cognitive symptoms not fully reversed by antiretroviral therapy (ART). This study examined associations between cognitive performance and markers of CNS injury associated with acute HIV infection and ART. METHODS: HIV-infected MSM and transgender women (average age: 27 years and education: 13 years) enrolled within 100 days from the estimated date of detectable infection (EDDI). A cognitive performance (NP) protocol was administered at enrollment (before ART initiation) and every 24 weeks until week 192. An overall index of cognitive performance (NPZ) was created using local normative data. Blood (n = 87) and cerebrospinal fluid (CSF; n = 29) biomarkers of inflammation and neuronal injury were examined before ART initiation. Regression analyses assessed relationships between time since EDDI, pre-ART biomarkers, and NPZ. RESULTS: Adjusting for multiple comparisons, shorter time since EDDI was associated with higher pre-ART VL and multiple biomarkers in plasma and CSF. NPZ scores were within the normative range at baseline (NPZ = 0.52) and at each follow-up visit, with a modest increase through week 192. Plasma or CSF biomarkers were not correlated with NP scores at baseline or after ART. CONCLUSIONS: Biomarkers of CNS inflammation, immune activation, and neuronal injury peak early and then decline during acute HIV infection, confirming and extending results of other studies. Neither plasma nor CSF biomarkers during acute infection corresponded to NP scores before or after sustained ART in this cohort with few psychosocial risk factors for cognitive impairment.
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Infecções por HIV , Adulto , Biomarcadores , Cognição , Estudos de Coortes , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Inflamação/complicaçõesRESUMO
Background: Identifying characteristics associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA shedding may be useful to understand viral compartmentalization, disease pathogenesis, and risks for viral transmission. Methods: Participants were enrolled August 2020 to February 2021 in ACTIV-2/A5401, a placebo-controlled platform trial evaluating investigational therapies for mild-to-moderate coronavirus disease 2019 (COVID-19), and underwent quantitative SARS-CoV-2 RNA testing on nasopharyngeal and anterior nasal swabs, oral wash/saliva, and plasma at entry (day 0, pretreatment) and days 3, 7, 14, and 28. Concordance of RNA levels (copies/mL) across compartments and predictors of nasopharyngeal RNA levels were assessed at entry (n = 537). Predictors of changes over time were evaluated among placebo recipients (n = 265) with censored linear regression models. Results: Nasopharyngeal and anterior nasal RNA levels at study entry were highly correlated (r = 0.84); higher levels of both were associated with greater detection of RNA in plasma and oral wash/saliva. Older age, White non-Hispanic race/ethnicity, lower body mass index (BMI), SARS-CoV-2 immunoglobulin G seronegativity, and shorter prior symptom duration were associated with higher nasopharyngeal RNA at entry. In adjusted models, body mass index and race/ethnicity associations were attenuated, but the association with age remained (for every 10 years older, mean nasopharyngeal RNA was 0.27â log10â copies/mL higher; P < .001). Examining longitudinal viral RNA levels among placebo recipients, women had faster declines in nasopharyngeal RNA than men (mean change, -2.0 vs -1.3â log10â copies/mL, entry to day 3; P < .001). Conclusions: SARS-CoV-2 RNA shedding was concordant across compartments. Age was strongly associated with viral shedding, and men had slower viral clearance than women, which could explain sex differences in acute COVID-19 outcomes.
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BACKGROUND: Understanding the spectrum of COVID-19 in people with HIV (PWH) is critical to provide clinical guidance and risk reduction strategies. SETTING: Centers for AIDS Research Network of Integrated Clinic System, a US multisite clinical cohort of PWH in care. METHODS: We identified COVID-19 cases and severity (hospitalization, intensive care, and death) in a large, diverse HIV cohort during March 1, 2020-December 31, 2020. We determined predictors and relative risks of hospitalization among PWH with COVID-19, adjusted for disease risk scores. RESULTS: Of 16,056 PWH in care, 649 were diagnosed with COVID-19 between March and December 2020. Case fatality was 2%; 106 (16.3%) were hospitalized, and 12 died. PWH with current CD4 count <350 cells/mm 3 [aRR 2.68; 95% confidence interval (CI): 1.93 to 3.71; P < 0.001] or lowest recorded CD4 count <200 cells/mm 3 (aRR 1.67; 95% CI: 1.18 to 2.36; P < 0.005) had greater risks of hospitalization. HIV viral load and antiretroviral therapy status were not associated with hospitalization, although most of the PWH were suppressed (86%). Black PWH were 51% more likely to be hospitalized with COVID-19 compared with other racial/ethnic groups (aRR 1.51; 95% CI: 1.04 to 2.19; P = 0.03). Chronic kidney disease, chronic obstructive pulmonary disease, diabetes, hypertension, obesity, and increased cardiovascular and hepatic fibrosis risk scores were associated with higher hospitalization risk. PWH who were older, not on antiretroviral therapy, and with current CD4 count <350 cells/mm 3 , diabetes, and chronic kidney disease were overrepresented among PWH who required intubation or died. CONCLUSIONS: PWH with CD4 count <350 cells/mm 3 , and a history of CD4 count <200 cells/mm 3 , have a clear excess risk of severe COVID-19, accounting for comorbidities associated with severe outcomes. PWH with these risk factors should be prioritized for COVID-19 vaccination and early treatment and monitored closely for worsening illness.
Assuntos
COVID-19 , Infecções por HIV , Insuficiência Renal Crônica , Contagem de Linfócito CD4 , COVID-19/complicações , COVID-19/epidemiologia , Vacinas contra COVID-19 , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Insuficiência Renal Crônica/complicações , Estados Unidos/epidemiologiaRESUMO
OBJECTIVES: To define the incidence of clinically detected coronavirus disease 2019 (COVID-19) in people with HIV (PWH) in the United States and evaluate how racial and ethnic disparities, comorbidities, and HIV-related factors contribute to risk of COVID-19. DESIGN: Observational study within the CFAR Network of Integrated Clinical Systems cohort in seven cities during 2020. METHODS: We calculated cumulative incidence rates of COVID-19 diagnosis among PWH in routine care by key characteristics including race/ethnicity, current and lowest CD4+ cell count, and geographic area. We evaluated risk factors for COVID-19 among PWH using relative risk regression models adjusted with disease risk scores. RESULTS: Among 16â056 PWH in care, of whom 44.5% were black, 12.5% were Hispanic, with a median age of 52âyears (IQR 40-59), 18% had a current CD4+ cell count less than 350âcells/µl, including 7% less than 200; 95.5% were on antiretroviral therapy (ART), and 85.6% were virologically suppressed. Overall in 2020, 649 PWH were diagnosed with COVID-19 for a rate of 4.94 cases per 100 person-years. The cumulative incidence of COVID-19 was 2.4-fold and 1.7-fold higher in Hispanic and black PWH respectively, than non-Hispanic white PWH. In adjusted analyses, factors associated with COVID-19 included female sex, Hispanic or black identity, lowest historical CD4+ cell count less than 350 cells/µl (proxy for CD4+ nadir), current low CD4+â:âCD8+ ratio, diabetes, and obesity. CONCLUSION: Our results suggest that the presence of structural racial inequities above and beyond medical comorbidities increased the risk of COVID-19 among PWH. PWH with immune exhaustion as evidenced by lowest historical CD4+ cell count or current low CD4+â:âCD8+ ratio had greater risk of COVID-19.