RESUMEN
This study aims to understand the impact of early antiretroviral therapy (ART) on HIV-specific T-cell responses measured after treatment interruption may inform strategies to deliver ART-free immune-mediated viral suppression. HIV-specific T-cell immunity was analysed using gamma interferon enzyme-linked immunospot assays in two studies. SPARTAC included individuals with primary HIV infection randomised to 48 weeks of ART (n = 24) or no immediate therapy (n = 37). The PITCH (n = 7) cohort started antiretroviral therapy in primary infection for at least one year, followed by TI. In SPARTAC, participants treated in PHI for 48 weeks followed by TI for 12 weeks, and those who remained untreated for 60 weeks made similar HIV Gag-directed responses (both magnitude and breadth) at week 60. However, the treated group made a greater proportion of novel HIV Gag-directed responses by Week 60, suggestive of a greater reserve to produce new potentially protective responses. In the more intensively followed PITCH study, 6/7 participants showed dominant Gag and/or Pol-specific responses post-TI compared with pre-TI. Although early ART in PHI was not associated with major differences in HIV-specific immunity following TI compared with untreated participants, the potential to make more new Gag-directed responses warrants further investigation as this may inform strategies to achieve ART-free control.
RESUMEN
BACKGROUND: People with human immunodeficiency virus (HIV) on antiretroviral therapy (ART) with good CD4 T-cell counts make effective immune responses following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are few data on longer term responses and the impact of a booster dose. METHODS: Adults with HIV were enrolled into a single arm open label study. Two doses of ChAdOx1 nCoV-19 were followed 12 months later by a third heterologous vaccine dose. Participants had undetectable viraemia on ART and CD4 counts >350 cells/µL. Immune responses to the ancestral strain and variants of concern were measured by anti-spike immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA), MesoScale Discovery (MSD) anti-spike platform, ACE-2 inhibition, activation induced marker (AIM) assay, and T-cell proliferation. FINDINGS: In total, 54 participants received 2 doses of ChAdOx1 nCoV-19. 43 received a third dose (42 with BNT162b2; 1 with mRNA-1273) 1 year after the first dose. After the third dose, total anti-SARS-CoV-2 spike IgG titers (MSD), ACE-2 inhibition, and IgG ELISA results were significantly higher compared to Day 182 titers (P < .0001 for all 3). SARS-CoV-2 specific CD4+ T-cell responses measured by AIM against SARS-CoV-2 S1 and S2 peptide pools were significantly increased after a third vaccine compared to 6 months after a first dose, with significant increases in proliferative CD4+ and CD8+ T-cell responses to SARS-CoV-2 S1 and S2 after boosting. Responses to Alpha, Beta, Gamma, and Delta variants were boosted, although to a lesser extent for Omicron. CONCLUSIONS: In PWH receiving a third vaccine dose, there were significant increases in B- and T-cell immunity, including to known variants of concern (VOCs).
Asunto(s)
COVID-19 , Infecciones por VIH , Adulto , Humanos , VIH , ChAdOx1 nCoV-19 , Vacuna BNT162 , SARS-CoV-2 , COVID-19/prevención & control , Activación de Linfocitos , Vacunación , Infecciones por VIH/tratamiento farmacológico , Inmunoglobulina G , Anticuerpos AntiviralesRESUMEN
Duration of protection from SARS-CoV-2 infection in people living with HIV (PWH) following vaccination is unclear. In a substudy of the phase II/III the COV002 trial (NCT04400838), 54 HIV+ male participants on antiretroviral therapy (undetectable viral loads, CD4+ T cells > 350 cells/µL) received 2 doses of ChAdOx1 nCoV-19 (AZD1222) 4-6 weeks apart and were followed for 6 months. Responses to vaccination were determined by serology (IgG ELISA and Meso Scale Discovery [MSD]), neutralization, ACE-2 inhibition, IFN-γ ELISpot, activation-induced marker (AIM) assay and T cell proliferation. We show that, 6 months after vaccination, the majority of measurable immune responses were greater than prevaccination baseline but with evidence of a decline in both humoral and cell-mediated immunity. There was, however, no significant difference compared with a cohort of HIV-uninfected individuals vaccinated with the same regimen. Responses to the variants of concern were detectable, although they were lower than WT. Preexisting cross-reactive T cell responses to SARS-CoV-2 spike were associated with greater postvaccine immunity and correlated with prior exposure to beta coronaviruses. These data support the ongoing policy to vaccinate PWH against SARS-CoV-2, and they underpin the need for long-term monitoring of responses after vaccination.
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COVID-19 , Infecciones por VIH , COVID-19/prevención & control , ChAdOx1 nCoV-19 , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , SARS-CoV-2 , VacunaciónRESUMEN
BACKGROUND: Data on vaccine immunogenicity against SARS-CoV-2 are needed for the 40 million people globally living with HIV who might have less functional immunity and more associated comorbidities than the general population. We aimed to explore safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in people with HIV. METHODS: In this single-arm open-label vaccination substudy within the protocol of the larger phase 2/3 trial COV002, adults aged 18-55 years with HIV were enrolled at two HIV clinics in London, UK. Eligible participants were required to be on antiretroviral therapy (ART), with undetectable plasma HIV viral loads (<50 copies per mL), and CD4 counts of more than 350 cells per µL. A prime-boost regimen of ChAdOx1 nCoV-19, with two doses was given 4-6 weeks apart. The primary outcomes for this substudy were safety and reactogenicity of the vaccine, as determined by serious adverse events and solicited local and systemic reactions. Humoral responses were measured by anti-spike IgG ELISA and antibody-mediated live virus neutralisation. Cell-mediated immune responses were measured by ex-vivo IFN-γ enzyme-linked immunospot assay (ELISpot) and T-cell proliferation. All outcomes were compared with an HIV-uninfected group from the main COV002 study within the same age group and dosing strategy and are reported until day 56 after prime vaccination. Outcomes were analysed in all participants who received both doses and with available samples. The COV002 study is registered with ClinicalTrials.gov, NCT04400838, and is ongoing. FINDINGS: Between Nov 5 and Nov 24, 2020, 54 participants with HIV (all male, median age 42·5 years [IQR 37·2-49·8]) were enrolled and received two doses of ChAdOx1 nCoV-19. Median CD4 count at enrolment was 694·0 cells per µL (IQR 573·5-859·5). No serious adverse events occurred. Local and systemic reactions occurring during the first 7 days after prime vaccination included pain at the injection site (26 [49%] of 53 participants with available data), fatigue (25 [47%]), headache (25 [47%]), malaise (18 [34%]), chills (12 [23%]), muscle ache (19 [36%]), joint pain (five [9%]), and nausea (four [8%]), the frequencies of which were similar to the HIV-negative participants. Anti-spike IgG responses by ELISA peaked at day 42 (median 1440 ELISA units [EUs; IQR 704-2728]; n=50) and were sustained until day 56 (median 941 EUs [531-1445]; n=49). We found no correlation between the magnitude of the anti-spike IgG response at day 56 and CD4 cell count (p=0·93) or age (p=0·48). ELISpot and T-cell proliferative responses peaked at day 14 and 28 after prime dose and were sustained to day 56. Compared with participants without HIV, we found no difference in magnitude or persistence of SARS-CoV-2 spike-specific humoral or cellular responses (p>0·05 for all analyses). INTERPRETATION: In this study of people with HIV, ChAdOx1 nCoV-19 was safe and immunogenic, supporting vaccination for those well controlled on ART. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.
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Anticuerpos Antivirales/sangre , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , Infecciones por VIH/inmunología , SARS-CoV-2/inmunología , Adulto , Recuento de Linfocito CD4 , Vacunas contra la COVID-19/efectos adversos , ChAdOx1 nCoV-19 , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , VacunaciónRESUMEN
OBJECTIVE: To evaluate the performance of new lateral flow immunoassays (LFIAs) suitable for use in a national coronavirus disease 2019 (covid-19) seroprevalence programme (real time assessment of community transmission 2-React 2). DESIGN: Diagnostic accuracy study. SETTING: Laboratory analyses were performed in the United Kingdom at Imperial College, London and university facilities in London. Research clinics for finger prick sampling were run in two affiliated NHS trusts. PARTICIPANTS: Sensitivity analyses were performed on sera stored from 320 previous participants in the React 2 programme with confirmed previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Specificity analyses were performed on 1000 prepandemic serum samples. 100 new participants with confirmed previous SARS-CoV-2 infection attended study clinics for finger prick testing. INTERVENTIONS: Laboratory sensitivity and specificity analyses were performed for seven LFIAs on a minimum of 200 serum samples from participants with confirmed SARS-CoV-2 infection and 500 prepandemic serum samples, respectively. Three LFIAs were found to have a laboratory sensitivity superior to the finger prick sensitivity of the LFIA currently used in React 2 seroprevalence studies (84%). These LFIAs were then further evaluated through finger prick testing on participants with confirmed previous SARS-CoV-2 infection: two LFIAs (Surescreen, Panbio) were evaluated in clinics in June-July 2020 and the third LFIA (AbC-19) in September 2020. A spike protein enzyme linked immunoassay and hybrid double antigen binding assay were used as laboratory reference standards. MAIN OUTCOME MEASURES: The accuracy of LFIAs in detecting immunoglobulin G (IgG) antibodies to SARS-CoV-2 compared with two reference standards. RESULTS: The sensitivity and specificity of seven new LFIAs that were analysed using sera varied from 69% to 100%, and from 98.6% to 100%, respectively (compared with the two reference standards). Sensitivity on finger prick testing was 77% (95% confidence interval 61.4% to 88.2%) for Panbio, 86% (72.7% to 94.8%) for Surescreen, and 69% (53.8% to 81.3%) for AbC-19 compared with the reference standards. Sensitivity for sera from matched clinical samples performed on AbC-19 was significantly higher with serum than finger prick at 92% (80.0% to 97.7%, P=0.01). Antibody titres varied considerably among cohorts. The numbers of positive samples identified by finger prick in the lowest antibody titre quarter varied among LFIAs. CONCLUSIONS: One new LFIA was identified with clinical performance suitable for potential inclusion in seroprevalence studies. However, none of the LFIAs tested had clearly superior performance to the LFIA currently used in React 2 seroprevalence surveys, and none showed sufficient sensitivity and specificity to be considered for routine clinical use.
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Prueba Serológica para COVID-19 , COVID-19/diagnóstico , Inmunoensayo , SARS-CoV-2/aislamiento & purificación , Adulto , Anticuerpos Antivirales/sangre , COVID-19/sangre , COVID-19/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , SARS-CoV-2/inmunología , Sensibilidad y Especificidad , Estudios Seroepidemiológicos , Reino UnidoRESUMEN
There are no published studies of fertility measurements in people living with perinatally acquired HIV (PaHIV). We performed fertility investigations in 25 adults with PaHIV. Seven (78%) men had sperm morphology normal forms (%) below the fifth centile for the general population with four (44%) having no normal forms. Mean (SD) serum anti-Müllerian hormone level was 19.4 (9.5) pmol/l; lower than expected for this age group. A larger study is needed to verify our findings.
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Infecciones por VIH , Seropositividad para VIH , VIH-1 , Adulto , Estudios Transversales , Femenino , Fertilidad , Infecciones por VIH/complicaciones , Humanos , Masculino , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Accurate antibody tests are essential to monitor the SARS-CoV-2 pandemic. Lateral flow immunoassays (LFIAs) can deliver testing at scale. However, reported performance varies, and sensitivity analyses have generally been conducted on serum from hospitalised patients. For use in community testing, evaluation of finger-prick self-tests, in non-hospitalised individuals, is required. METHODS: Sensitivity analysis was conducted on 276 non-hospitalised participants. All had tested positive for SARS-CoV-2 by reverse transcription PCR and were ≥21 days from symptom onset. In phase I, we evaluated five LFIAs in clinic (with finger prick) and laboratory (with blood and sera) in comparison to (1) PCR-confirmed infection and (2) presence of SARS-CoV-2 antibodies on two 'in-house' ELISAs. Specificity analysis was performed on 500 prepandemic sera. In phase II, six additional LFIAs were assessed with serum. FINDINGS: 95% (95% CI 92.2% to 97.3%) of the infected cohort had detectable antibodies on at least one ELISA. LFIA sensitivity was variable, but significantly inferior to ELISA in 8 out of 11 assessed. Of LFIAs assessed in both clinic and laboratory, finger-prick self-test sensitivity varied from 21% to 92% versus PCR-confirmed cases and from 22% to 96% versus composite ELISA positives. Concordance between finger-prick and serum testing was at best moderate (kappa 0.56) and, at worst, slight (kappa 0.13). All LFIAs had high specificity (97.2%-99.8%). INTERPRETATION: LFIA sensitivity and sample concordance is variable, highlighting the importance of evaluations in setting of intended use. This rigorous approach to LFIA evaluation identified a test with high specificity (98.6% (95%CI 97.1% to 99.4%)), moderate sensitivity (84.4% with finger prick (95% CI 70.5% to 93.5%)) and moderate concordance, suitable for seroprevalence surveys.
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Anticuerpos Antivirales/análisis , COVID-19/diagnóstico , Inmunoensayo/métodos , Pandemias , SARS-CoV-2/inmunología , Adulto , COVID-19/epidemiología , COVID-19/virología , ADN Viral/análisis , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , SARS-CoV-2/genética , Estudios SeroepidemiológicosAsunto(s)
Fármacos Anti-VIH/farmacocinética , Antagonistas de los Receptores CCR5/administración & dosificación , Disfunción Cognitiva/tratamiento farmacológico , Infecciones por VIH/complicaciones , Imidazoles/farmacocinética , Fármacos Anti-VIH/líquido cefalorraquídeo , Fármacos Anti-VIH/uso terapéutico , Cognición/efectos de los fármacos , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/etiología , Infecciones por VIH/líquido cefalorraquídeo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Imidazoles/líquido cefalorraquídeo , Imidazoles/uso terapéutico , ARN Viral/líquido cefalorraquídeo , SulfóxidosRESUMEN
The CBTRUS Statistical Report: Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 20072011 comprehensively describes the current population-based incidence of primary malignant and non-malignant brain and CNS tumors in children ages 014 years, collected and reported by central cancer registries covering approximately 99.8% of the United States population (for 2011 only, data were available for 50 out of 51 registries). Overall, brain and CNS tumors are the most common solid tumor, the most common cancer, and the most common cause of cancer death in infants and children 014 years. This report aims to serve as a useful resource for researchers, clinicians, patients, and families.
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Neoplasias Encefálicas/epidemiología , Neoplasias del Sistema Nervioso Central/epidemiología , Glioma/epidemiología , Neoplasias de Células Germinales y Embrionarias/epidemiología , Sistema de Registros , Humanos , Análisis de Supervivencia , Estados Unidos/epidemiologíaRESUMEN
AIM: Indications for post-natal steroids among preterm infants are evolving. The objective of this study was to compare steroid use in 2 cohorts 5 years apart and to document the short- and long-term outcomes of our most recent cohort. METHODS: Retrospective chart review of infants born under 28 weeks of gestational age for two cohorts (January 2002-August 2003 and July 2008-March 2010). RESULTS: Two hundred and fourteen infants were included. More infants received steroids in the later cohort (20% vs 35%, p = 0.021) but survival rates did not improve. There was a shift towards hydrocortisone use (<7% vs 76%) and pulmonary indications (36% vs 61% of courses; p = 0.021). Patients died later (8 days vs 30 days; p = 0.02), with a strong correlation between time of death and total dose of steroids (r = 0.91; p = 0.01). Neurodevelopmental outcomes for patients who received steroids for pulmonary indications were inferior to those for the rest of the cohort (severe adverse outcome 26% vs 4.8%, p = 0.03). CONCLUSION: The improvement in short-term respiratory status of ill preterm patients was offset by a disturbing increase in age at death and no improvement in survival rates.