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BACKGROUND: Defining patterns of symptoms in long COVID is necessary to advance therapies for this heterogeneous condition. Here we aimed to describe clusters of symptoms in individuals with long COVID and explore the impact of the emergence of variants of concern (VOCs) and vaccination on these clusters. METHODS: In a prospective, multi centre cohort study, individuals with symptoms persisting > 4 weeks from acute COVID-19 were divided into two groups based on timing of acute infection; pre-Alpha VOC, denoted wild type (WT) group and post-Alpha VOC (incorporating alpha and delta dominant periods) denoted VOC group. We used multiple correspondence analysis (MCA) and hierarchical clustering in the WT and VOC groups to identify symptom clusters. We then used logistic regression to explore factors associated with individual symptoms. RESULTS: A total of 417 individuals were included in the analysis, 268 in WT and 149 in VOC groups respectively. In both groups MCA identified three similar clusters; a musculoskeletal (MSK) cluster characterised by joint pain and myalgia, a cardiorespiratory cluster and a less symptomatic cluster. Differences in characteristic symptoms were only seen in the cardiorespiratory cluster where a decrease in the frequency of palpitations (10% vs 34% p = 0.008) and an increase in cough (63% vs 17% p < 0.001) in the VOC compared to WT groups was observed. Analysis of the frequency of individual symptoms showed significantly lower frequency of both chest pain (25% vs 39% p = 0.004) and palpitations (12% vs 32% p < 0.001) in the VOC group compared to the WT group. In adjusted analysis being in the VOC group was significantly associated with a lower odds of both chest pain and palpitations, but vaccination was not associated with these symptoms. CONCLUSION: This study suggests changes in long COVID phenotype in individuals infected later in the pandemic, with less palpitations and chest pain reported. Adjusted analyses suggest that these effects are mediated through introduction of variants rather than an effect from vaccination.
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COVID-19 , Síndrome Post Agudo de COVID-19 , Humanos , COVID-19/prevención & control , Estudios de Cohortes , Estudios Prospectivos , Vacunación , Dolor en el Pecho , FenotipoRESUMEN
BACKGROUND: Inflammation drives vascular dysfunction in HIV, but in low-income settings causes of inflammation are multiple, and include infectious and environmental factors. We hypothesized that patients with advanced immunosuppression could be stratified into inflammatory phenotypes that predicted changes in vascular dysfunction on ART. METHODS: We recruited Malawian adults with CD4 <100 cells/µL 2 weeks after starting ART in the REALITY trial (NCT01825031). Carotid femoral pulse-wave velocity (cfPWV) measured arterial stiffness 2, 12, 24, and 42 weeks post-ART initiation. Plasma inflammation markers were measured by electrochemiluminescence at weeks 2 and 42. Hierarchical clustering on principal components identified inflammatory clusters. RESULTS: 211 participants with HIV grouped into 3 inflammatory clusters representing 51 (24%; cluster-1), 153 (73%; cluster-2), and 7 (3%; cluster-3) individuals. Cluster-1 showed markedly higher CD4 and CD8 T-cell expression of HLADR and PD-1 versus cluster-2 and cluster-3 (all P < .0001). Although small, cluster-3 had significantly higher levels of cytokines reflecting inflammation (IL-6, IFN-γ, IP-10, IL-1RA, IL-10), chemotaxis (IL-8), systemic and vascular inflammation (CRP, ICAM-1, VCAM-1), and SAA (all P < .001). In mixed-effects models, cfPWV changes over time were similar for cluster-2 versus cluster-1 (relative fold-change, 0.99; 95% CI, .86-1.14; P = .91), but greater in cluster-3 versus cluster-1 (relative fold-change, 1.45; 95% CI, 1.01-2.09; P = .045). CONCLUSIONS: Two inflammatory clusters were identified: one defined by high T-cell PD-1 expression and another by a hyperinflamed profile and increases in cfPWV on ART. Further clinical characterization of inflammatory phenotypes could help target vascular dysfunction interventions to those at highest risk. CLINICAL TRIALS NETWORK: NCT01825031.
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Infecciones por VIH , Rigidez Vascular , Adulto , Biomarcadores , Linfocitos T CD8-positivos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , FenotipoRESUMEN
BACKGROUND: The objectives of this study were to investigate the relationships between polymorphisms at the interferon lambda (IFNL) locus and CD4+:CD8+ ratio normalisation in people living with HIV (PLWH) on effective antiretroviral therapy (ART); and to examine whether these polymorphisms influence the composition of T lymphocyte compartments in long-term treated HIV-1 infection. METHODS: A cross-sectional study in PLWH enrolled into the Mater Immunology study. We performed IFNL genotyping on stored samples and evaluated the association of IFNL single-nucleotide polymorphisms (rs368234815 and rs12979860) with CD4+:CD8+ ratio normalization (> 1) and expanded CD4+ and CD8+ T-cell subsets; CD45RO+CD62L+ (central-memory), CD45RO+ CD62L-(effector-memory) and CD45RO-CD62L+ (naïve), using logistic and linear regression models, respectively. RESULTS: 190 ambulatory PLWH recruited to the main study, 143 were included in the analysis (38 had no stored DNA and 9 no T-lymphocyte subpopulation). Of 143 included, the median age (IQR) was 45(39-48) years, 64% were male and 66% were of Caucasian ethnicity. Heterosexual-contact (36%), injecting drug-use (33%) and men who have sex with men (24%) were the most presented HIV-transmission risk groups. The majority of subjects (90.2%) were on ART with 79% of the cohort having an undetectable HIV-RNA (< 40 copies/ml) and the time since ART initiation was 7.5 (3.7-10.4) year. rs368234815 and rs12979860 displayed similar allelic frequencies, with minor alleles ΔG and T representing 39% and 42%, respectively, of circulating alleles. rs368234815 ΔG/ΔG minor homozygotes were significantly associated with increased odds for attaining a normalised CD4+:CD8+ ratio compared to rs368234815 T/T major homozygotes in PLWH virologically suppressed on effective ART (OR = 3.11; 95% CI [1.01:9.56]). rs368234815 ΔG/ΔG homozygosity was also significantly associated with lower levels of CD4+ effector memory T-cells (regression coefficient: - 7.1%, p = 0.04) and CD8+ naïve T-cell subsets were significantly higher in HIV-1 mono-infected PLWH with rs368234815 ΔG/ΔG (regression coefficient: + 7.2%, p = 0.04). CONCLUSIONS: In virally-suppressed, long-term ART-treated PLWH, rs368234815 ΔG/ΔG homozygotes were more likely to have attained normalisation of their CD4+:CD8+ ratio, displayed lower CD4+ effector memory and higher naive CD8+ T-cells. Further studies are needed to replicate our findings in other, larger and more diverse cohorts and to determine the impact of IFNL genetic-variation on CD4+:CD8+ ratio normalisation and clinical outcomes in PLWH.
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Fármacos Anti-VIH/uso terapéutico , Relación CD4-CD8 , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Interferones/genética , Adulto , Alelos , Estudios de Cohortes , Estudios Transversales , Femenino , Genotipo , Infecciones por VIH/inmunología , VIH-1 , Homosexualidad Masculina , Humanos , Memoria Inmunológica , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Respuesta Virológica Sostenida , Carga Viral/efectos de los fármacosRESUMEN
OBJECTIVES: Hepatitis C is one of the main causes of chronic liver diseases worldwide. One of the major barriers to effecting EU- and WHO-mandated HCV elimination by 2030 is underdiagnosis. Community-based screening strategies have been identified as important components of HCV models of care. HepCheck Europe is a large-scale intensified screening initiative aimed at enhancing identification of HCV infection among vulnerable populations and linkage to care. METHODS: Research teams across four European countries were engaged in the study and rolled out screening to high-risk populations in community addiction, homeless and prison services. Screening was offered to 2822 individuals and included a self-administered questionnaire, HCV antibody and RNA testing, liver fibrosis assessment and referral to specialist services. RESULTS: There was a 74% (n=2079) uptake of screening. The majority (85.8%, n=1783) were male. In total 44.6% (n=927) of the sample reported ever injecting drugs, 38.4% (n=799) reported ever being homeless and 27.9% (n=581) were prisoners. In total 397 (19%) active HCV infections were identified and 136 (7% of total sample and 34% of identified active infections) were new cases. Of those identified with active HCV infection, 80% were linked to care, which included liver fibrosis assessment and referral to specialist services. CONCLUSIONS: HepCheck's screening and linkage to care is a clear strategy for reaching high-risk populations, including those at highest risk of transmission who are not accessing any type of care in the community. Elimination of HCV in the EU will only be achieved by such innovative, patient-centred approaches.
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Atención a la Salud/métodos , Hepatitis C/diagnóstico , Hepatitis C/tratamiento farmacológico , Tamizaje Masivo/métodos , Adulto , Consumidores de Drogas/estadística & datos numéricos , Europa (Continente)/epidemiología , Estudios de Factibilidad , Femenino , Hepatitis C/epidemiología , Anticuerpos contra la Hepatitis C/sangre , Personas con Mala Vivienda/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Prisioneros/estadística & datos numéricos , Estudios Prospectivos , Marginación SocialRESUMEN
OBJECTIVES: To examine HCV prevalence and management among people who inject drugs (PWID) attending primary care and community-based health services at four European sites using baseline data from a multicentre feasibility study of a complex intervention (HepLink). METHODS: Primary care and community-based health services in Dublin, London, Bucharest and Seville were recruited from the professional networks of the HepLink consortium. Patients were eligible to participate if aged ≥18 years, on opioid substitution treatment or at risk of HCV (i.e. injecting drug use, homeless or incarcerated), and attended the service. Data on patient demographics and prior HCV management were collected on participants at baseline. RESULTS: Twenty-nine primary care and community-based health services and 530 patients were recruited. Baseline data were collected on all participants. Participants' mean age ranged from 35 (Bucharest) to 51 years (London), with 71%-89% male. Prior lifetime HCV antibody testing ranged from 65% (Bucharest) to 95% (Dublin) and HCV antibody positivity among those who had been tested ranged from 78% (Dublin) to 95% (Bucharest). Prior lifetime HCV RNA testing among HCV antibody-positive participants ranged from 17% (Bucharest) to 84% (London). Among HCV antibody- or RNA-positive participants, prior lifetime attendance at a hepatology/infectious disease service ranged from 6% (London) to 50% (Dublin) and prior lifetime HCV treatment initiation from 3% (London) to 33% (Seville). CONCLUSIONS: Baseline assessment of the HCV cascade of care among PWID attending primary care and community-based health services at four European sites identified key aspects of the care cascade at each site that need to be improved.
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Servicios de Salud Comunitaria/métodos , Hepatitis C/tratamiento farmacológico , Hepatitis C/epidemiología , Atención Primaria de Salud/métodos , Adulto , Consumidores de Drogas/estadística & datos numéricos , Europa (Continente)/epidemiología , Estudios de Factibilidad , Femenino , Hepatitis C/diagnóstico , Anticuerpos contra la Hepatitis C/sangre , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangreRESUMEN
BACKGROUND: Hepatitis C virus (HCV) is one of the main causes of chronic liver disease worldwide. Prevalence of HCV in homeless populations ranges from 3.9 to 36.2%. The HepCheck study sought to investigate and establish the characterisation of HCV burden among individuals who attended an intensified screening programme for HCV in homeless services in Dublin, Ireland. METHODS: The HepCheck study was conducted as part of a larger European wide initiative called HepCare Europe. The study consisted of three phases; 1) all subjects completed a short survey and were offered a rapid oral HCV test; 2) a convenience sample of HCV positive participants from phase 1 were selected to complete a survey on health and social risk factors and 3) subjects were tracked along the referral pathway to identify whether they were referred to a specialist clinic, attended the specialist clinic, were assessed for cirrhosis by transient elastography (Fibroscan) and were treated for HCV. RESULTS: Five hundred ninety-seven individuals were offered HCV screening, 73% were male and 63% reported having had a previous HCV screening. We screened 538 (90%) of those offered screening, with 37% testing positive. Among those who tested positive, 112 (56%) were 'new positives' and 44% were 'known positives'. Undiagnosed HCV was prevalent in 19% of the study sample. Active past 30-day drug use was common, along with attendance for drug treatment. Unstable accommodation was the most common barrier to attending specialist appointments and accessing treatment. Depression and anxiety, dental problems and respiratory conditions were common reported health problems. Forty-six subjects were referred to specialised services and two subjects completed HCV treatment. CONCLUSIONS: This study demonstrates that the current hospital-based model of care is inadequate in addressing the specific needs of a homeless population and emphasises the need for a community-based treatment approach. Findings are intended to inform HepCare Europe in their development of a community-based model of care in order to engage with homeless individuals with multiple co-morbidities including substance abuse, who are affected by or infected with HCV.
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Atención a la Salud/métodos , Hepatitis C/diagnóstico , Personas con Mala Vivienda , Adulto , Europa (Continente) , Femenino , Hepacivirus/inmunología , Hepatitis C/epidemiología , Anticuerpos contra la Hepatitis C/sangre , Antígenos de la Hepatitis C/sangre , Humanos , Irlanda/epidemiología , Masculino , Tamizaje Masivo , Prevalencia , Encuestas y CuestionariosRESUMEN
Despite a fivefold increased risk of thromboembolism in patients with cancer, the mechanism of arterial thromboembolism is poorly understood. To address this, we investigated platelet function in cancer patients and healthy controls using an assay that mimics the arterial vasculature. Blood samples from cancer patients (n = 36) and healthy controls (n = 22) were perfused through custom-made parallel-plate flow chambers coated with von Willebrand factor (VWF) under arterial shear (1,500 s-1). Multiparameter measurements of platelet interactions with the immobilized VWF surface were recorded by digital-image microscopy and analyzed using custom-designed platelet-tracking software. Six measured parameters that characterize in detail the surface motion and surface binding of several hundred platelets per blood sample differed significantly in those with cancer from the healthy donors. In particular, it was found that patients with cancer had decreased numbers of platelets interacting, translocating and adhering to VWF. There were also reductions in the speed and distances that platelets traveled on VWF in comparison to healthy controls. Platelet function differed between those with early-stage cancer compared to those with later stage cancer. Patients with advanced cancer had an increased number of platelets stably adhering to VWF and greater platelet surface coverage after a given time of interaction. To the best of our knowledge, our results demonstrate for the first time that dynamic platelet function is markedly different in patients with cancer compared to healthy donors.
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Neoplasias/sangre , Pruebas de Función Plaquetaria/métodos , Factor de von Willebrand/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Donantes de TejidosRESUMEN
BACKGROUND: Omega-3 long chain-polyunsaturated fatty acids (LC-PUFAs)-docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and eicosapentaenoic acid (EPA)- and omega-6 LC-PUFA arachidonic acid (ARA), are essential for optimum physical and mental development in children. Prior to this study, the blood omega-3 LC-PUFA levels were unknown in Zimbabwean children, particularly in those aged 7-9 years, despite the documented benefits of LC-PUFAs. Documentation of the LC-PUFA levels in this age group would help determine whether interventions, such as fortification, are necessary. This study aimed to determine dried whole blood spot omega-3 and omega-6 LC-PUFA levels and LC-PUFA reference intervals among a selected group of Zimbabwean children aged 7-9 years old. METHODS: We conducted a cross sectional study from September 2011 to August 2012 on a cohort of peri-urban, Zimbabwean children aged 7-9 years. The children were born to mothers enrolled at late pregnancy into an HIV prevention program between 2002 and 2004. Dried whole blood spots were sampled on butylated hydroxytoluene antioxidant impregnated filter papers and dried. LC-PUFAs were quantified using gas liquid chromatography. Differences in LC-PUFAs between groups were compared using the Kruskal Wallis test and reference intervals determined using non-parametric statistical methods. RESULTS: LC-PUFAs levels were determined in 297 Zimbabwean children of whom 170 (57.2 %) were girls. The study determined that LC-PUFAs (wt/wt) ranges were EPA 0.06-0.55 %, DPA 0.38-1.98 %, DHA 1.13-3.52 %, ARA 5.58-14.64 % and ARA: EPA ratio 15.47-1633.33. Sixteen participants had omega-3 LC-PUFAs levels below the determined reference intervals, while 18 had higher omega-6 LC-PUFAs. The study did not show gender differences in omega-3 and omega-6 LC-PUFAs levels (all p > 0.05). EPA was significantly higher in the 8 year age group compared to those aged 7 and 9 years (median; 0.20 vs 0.17 vs 0.18, respectively, p = 0.049). ARA: EPA ratio was significantly higher in the 7 year age group compared to those aged 8 and 9 years (median; 64.38 vs 56.43 vs 55.87 respectively, p = 0.014). CONCLUSIONS: In this cohort of children, lower EPA levels and higher ARA: EPA ratios were observed compared to those reported in apparently healthy children elsewhere. The high ARA: EPA ratios might increase the vulnerability of these children to inflammatory pathologies. Identification and incorporation into diet of locally produced foodstuffs rich in omega-3 LC-PUFAs is recommended as well as advocating for dietary supplementation with omega-3 fish oils and algae based oils.
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BACKGROUND: Reference intervals are used as an aid in the interpretation of laboratory results. Most developing countries do not have reference intervals specific to adolescents. This study was aimed at establishing hematological and biochemical reference intervals for adolescents aged ≥ 12 years to < 18 years. METHODS: A community based, cross sectional study was conducted using the multistage sampling technique. Participants were enrolled from the UZ-UCSF research study catchment areas of Harare, Chitungwiza, and Mutoko. Samples were transported for analysis at the UZ-UCSF Central Laboratory under recommended conditions. The data analysis presented in this paper is for 302 adolescents aged ≥ 12 to < 18. Non-parametric statistical methods were used to estimate the 95% reference limits for the hematological and biochemical parameters, with the lower limit defined as the 2.5 percentile and the upper limit defined as the 97.5 percentile of the distribution. RESULTS: A total of 302 adolescents were included. Results show significant differences between males and females in hematological parameters except platelets, eosinophils, basophils, and red cell distribution width. The biochemical parameters which showed significant differences between males and females were phosphate, ALP, ALT, AST, GGT, and lipase. CONCLUSIONS: Hematological indices and liver function tests differ significantly by gender and this should be considered when defining normal intervals.
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Adolescente , Recuento de Células Sanguíneas , Análisis Químico de la Sangre , Valores de Referencia , Estudios Transversales , Femenino , Humanos , Masculino , ZimbabweRESUMEN
BACKGROUND: Increasing numbers of HIV-infected patients in sub-Saharan Africa are exposed to antiretroviral therapy (ART), but there are few data on lipid changes on first-line ART, and even fewer on second-line. METHODS: DART was a randomized trial comparing monitoring strategies in Ugandan/Zimbabwean adults initiating first-line ART and switching to second-line at clinical/immunological failure. We evaluated fasting lipid profiles at second-line initiation and ≥48 weeks subsequently in stored samples from Zimbabwean patients switching before 18 September 2006. RESULTS: Of 91 patients switched to second-line ART, 65(73%) had fasting samples at switch and ≥48 weeks, 14(15%) died or were lost <48 weeks, 10(11%) interrupted ART for >14 days and 2(2%) had no samples available. 56/65(86%) received ZDV/d4T + 3TC + TDF first-line, 6(9%) ZDV/d4T + 3TC + NVP and 3(5%) ZDV + 3TC with TDF and NVP. Initial second-line regimens were LPV/r + NNRTI in 27(41%), LPV/r + NNRTI + ddI in 33(50%) and LPV/r + TDF + ddI/3TC/ZDV in 6(9%). At second-line initiation median (IQR) TC, LDL-C, HDL-C and TG (mmol/L) were 3.3(2.8-4.0), 1.7(1.3-2.2), 0.7(0.6-0.9) and 1.1(0.8-1.9) respectively. Levels were significantly increased 48 weeks later, by mean (SE) +2.0(0.1), +1.1(0.1), +0.5(0.05) and +0.4(0.2) respectively (p < 0.001; TG p = 0.01). 3% at switch vs 25% 48 weeks later had TC >5.2 mmol/L; 3% vs 25% LDL-C >3.4 mmol/L and 91% vs 41% HDL-C <1.1 mmol/L (p < 0.001). Similar proportions had TG >1.8 mmol/L (0 vs 3%) and TC/HDL-C ≥5 (40% vs 33%) (p > 0.15). CONCLUSION: Modest lipid elevations were observed in African patients on predominantly LPV/r + NNRTI-based second-line regimens. Routine lipid monitoring during second-line ART regimens may not be warranted in this setting but individual cardiovascular risk assessment should guide practice.
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Systemic inflammation and innate immune activation are associated with COVID-19 disease severity. Knowledge gaps remain in the relationships between microbiome, inflammation and COVID-19 disease severity. To better characterise these associations, we performed 16SrDNA analysis of stool samples in COVID-19 subjects to explore diversity and taxanomic composition. We correlated these to host inflammatory profiles, derived from soluble plasma biomarkers measured by bead-based fluorescence and electrochemiluminescence immunoassays. Associations of microbial diversity and inflammatory biomarkers on maximal COVID-19 severity (mild, moderate v severe/critical) was explored using logistic regression and weighted gene correlation network analysis (WGCNA). Of 79 subjects, 58% were male and 88% were Caucasian with 36% experiencing mild disease, 22% moderate disease and 40% critical/severe COVID-19. Hierarchical clustering and principal component analysis (PCo) revealed distinct inflammatory clusters that were found to correlate with 4 modules of microbiome profiles. Modules 3 and 4 were associated with both older age and severe/critical disease outcomes. These modules were enriched in pathogenic and inflammatory bacteria that mapped to a pro-inflammatory biomarker cluster. In contrast, module 1 exhibited enrichment of anti-inflammatory bacteria, was associated with younger age and mild/moderate disease outcomes and mapped to a less-inflamed biomarker cluster. This study provides further insights into links between host microbiome, inflammatory responses to SARS-CoV-2 infection and clinical COVID-19 disease severity, suggesting a role for the microbiome in shaping distinct host inflammatory responses to infection.
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COVID-19 , Microbiota , Humanos , Masculino , Femenino , SARS-CoV-2 , Inflamación , Gravedad del Paciente , BiomarcadoresRESUMEN
SARS-CoV-2 neutralising antibodies provide protection against COVID-19. Evidence from early vaccine trials suggested binding antibody thresholds could serve as surrogate markers of neutralising capacity, but whether these thresholds predict sufficient neutralising capacity against variants of concern (VOCs), and whether this is impacted by vaccine or infection history remains unclear. Here we analyse individuals recovered from, vaccinated or with hybrid immunity against SARS-CoV-2. An NT50 ≥ 100 IU confers protection in vaccine trials, however, as VOC induce a reduction in NT50, we use NT50 ≥ 1000 IU as a cut off for WT NT50 that would retain neutralisation against VOC. In unvaccinated convalescent participants, a receptor binding domain (RBD) IgG of 456 BAU/mL predicts an NT50 against WT of 1000 IU with an accuracy of 80% (95%CI 73-86%). This threshold maintains accuracy in determining loss of protective immunity against VOC in two vaccinated cohorts. It predicts an NT50 < 100 IU against Beta with an accuracy of 80% (95%CI 67-89%) in 2 vaccine dose recipients. In booster vaccine recipients with a history of COVID-19 (hybrid immunity), accuracy is 87% (95%CI 77-94%) in determining an NT50 of <100 IU against BA.5. This analysis provides a discrete threshold that could be used in future clinical studies.
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COVID-19 , Vacunas , Humanos , SARS-CoV-2 , COVID-19/prevención & control , Anticuerpos Antivirales , Inmunoglobulina G , Anticuerpos NeutralizantesRESUMEN
BACKGROUND: Hepatitis C virus (HCV) infection is common among people who inject drugs, yet well-described barriers mean that only a minority have accessed HCV treatment. Recent developments in HCV diagnosis and treatment facilitate innovative approaches to HCV care that improve access to, and uptake of, care by people who inject drugs. OBJECTIVE: This study aims to examine feasibility, acceptability, likely clinical effectiveness, and cost-effectiveness of an integrated model of HCV care for patients receiving opioid substitution treatment in general practice. METHODS: A pre- and postintervention design with an embedded economic analysis was used to establish the feasibility, acceptability, and clinical and cost-effectiveness of a complex intervention to optimize HCV identification and linkage to HCV treatment among patients prescribed methadone in primary care. The "complex intervention" comprised general practitioner (GP)/practice staff education, nurse-led clinical support, and enhanced community-based HCV assessment of patients. General practices in North Dublin were recruited from the professional networks of the research team and from GPs who attended educational sessions. RESULTS: A total of 135 patients from 14 practices participated. Follow-up data were collected 6 months after intervention from 131 (97.0%) patients. With regard to likely clinical effectiveness, among patients with HCV antibody positivity, there was a significant increase in the proportions of patients who had a liver FibroScan (17/101, 16.8% vs 52/100, 52.0%; P<.001), had attended hepatology/infectious diseases services (51/101, 50.5% vs 61/100 61.0%; P=.002), and initiated treatment (20/101, 19.8% vs 30/100, 30.0%; P=.004). The mean incremental cost-effectiveness ratio of the intervention was 13,255 (US $13,965.14) per quality-adjusted life-year gained at current full drug list price (39,729 [US $41,857.48] per course), which would be cost saving if these costs are reduced by 88%. CONCLUSIONS: The complex intervention involving clinical support, access to assessment, and practitioner education has the potential to enhance patient care, improving access to assessment and treatment in a cost-effective manner.
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BACKGROUND: Data on low bone mineral density (BMD) in people living with HIV (PLWH) are mainly derived from younger adults; little is known about how antiretroviral therapy (ART) and alterations in the renal-bone axis relate to BMD in older PLWH. METHODS: Cross-sectional study of men > 50 years and post-menopausal women with HIV. Antiretroviral therapy exposure was stratified into four groups based on use of tenofovir disoproxil fumarate (TDF) and protease inhibitors (PI): non-TDF/non-PI, non-TDF/PI, TDF/non-PI, and TDF/PI. Bone mineral density was measured by dual X-ray absorptiometry (DXA). Bone turnover/regulatory markers and renal tubular function were analysed in stored plasma and urine samples. The association of ART exposure and bone/renal biomarkers on BMD was explored using logistic regression models. RESULTS: 247 individuals (median [IQR] age 57 [53, 65] years; 47% female; 13% of Black ethnicity; CD4 count 643 [473, 811] cells/mm3; and 98% with HIV RNA < 200 copies/mL) were included. Bone turnover and renal tubular function differed significantly by ART exposure. In analyses adjusted for demographic and traditional renal/bone risk factors, exposure to TDF and PI was associated with a fourfold greater risk of low BMD at the femoral neck and exposure to TDF and/or PI with a threefold greater risk of low BMD at the lumbar spine. The relationship between ART and low BMD was not altered by further adjustment for bone turnover or renal tubular function markers. CONCLUSIONS: The associations between low BMD and ART exposure (TDF vs. non-TDF and boosted vs. unboosted third agents) were minimally affected by adjustments for bone and kidney biomarkers.
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Fármacos Anti-VIH , Infecciones por VIH , Adulto , Anciano , Fármacos Anti-VIH/efectos adversos , Antirretrovirales/efectos adversos , Biomarcadores , Densidad Ósea , Estudios Transversales , Femenino , Infecciones por VIH/complicaciones , Humanos , Riñón , Masculino , Persona de Mediana Edad , Tenofovir/efectos adversosRESUMEN
Background: We aimed to describe the clinical presentation of individuals presenting with prolonged recovery from coronavirus disease 2019 (COVID-19), known as long COVID. Methods: This was an analysis within a multicenter, prospective cohort study of individuals with a confirmed diagnosis of COVID-19 and persistent symptoms >4 weeks from onset of acute symptoms. We performed a multiple correspondence analysis (MCA) on the most common self-reported symptoms and hierarchical clustering on the results of the MCA to identify symptom clusters. Results: Two hundred thirty-three individuals were included in the analysis; the median age of the cohort was 43 (interquartile range [IQR], 36-54) years, 74% were women, and 77.3% reported a mild initial illness. MCA and hierarchical clustering revealed 3 clusters. Cluster 1 had predominantly pain symptoms with a higher proportion of joint pain, myalgia, and headache; cluster 2 had a preponderance of cardiovascular symptoms with prominent chest pain, shortness of breath, and palpitations; and cluster 3 had significantly fewer symptoms than the other clusters (2 [IQR, 2-3] symptoms per individual in cluster 3 vs 6 [IQR, 5-7] and 4 [IQR, 3-5] in clusters 1 and 2, respectively; Pâ <â .001). Clusters 1 and 2 had greater functional impairment, demonstrated by significantly longer work absence, higher dyspnea scores, and lower scores in SF-36 domains of general health, physical functioning, and role limitation due to physical functioning and social functioning. Conclusions: Clusters of symptoms are evident in long COVID patients that are associated with functional impairments and may point to distinct underlying pathophysiologic mechanisms of disease.
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BACKGROUND: Although reports suggest that most individuals with coronavirus disease 2019 (COVID-19) develop detectable antibodies postinfection, the kinetics, durability, and relative differences between immunoglobulin M (IgM) and immunoglobulin G (IgG) responses beyond the first few weeks after symptom onset remain poorly understood. METHODS: Within a large, well-phenotyped, diverse, prospective cohort of subjects with and without severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR)-confirmed infection and historical controls derived from cohorts with high prevalence of viral coinfections and samples taken during prior flu seasons, we measured SARS-CoV-2 serological responses (both IgG and IgM) using commercially available assays. We calculated sensitivity, specificity, and relationship with disease severity and mapped the kinetics of antibody responses over time using generalized additive models. RESULTS: We analyzed 1001 samples from 752 subjects, 327 with confirmed SARS-CoV-2 (29.7% with severe disease) spanning a period of 90 days from symptom onset. Sensitivity was lower (44.1%-47.1%) early (<10 days) after symptom onset but increased to >80% after 10 days. IgM positivity increased earlier than IgG-targeted assays, but positivity peaked between days 32 and 38 post-onset of symptoms and declined thereafter, a dynamic that was confirmed when antibody levels were analyzed, with a more rapid decline observed with IgM. Early (<10 days) IgM but not IgG levels were significantly higher in those who subsequently developed severe disease (signal/cutoff 4.20 [0.75-17.93] vs 1.07 [0.21-5.46]; Pâ =â .048). CONCLUSIONS: This study suggests that postinfectious antibody responses in those with confirmed COVID-19 begin to decline relatively early postinfection and suggests a potential role for higher IgM levels early in infection in the prediction of subsequent disease severity.
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BACKGROUND: Non-communicable diseases (NCDs) are increased amongst people living with HIV (PLWH) and are driven by persistent immune activation. The role of socioeconomic status (SES) in immune activation amongst PLWH is unknown, especially in low-income sub-Saharan Africa (SSA), where such impacts may be particularly severe. METHODS: We recruited Malawian adults with CD4<100 cells/ul two weeks after starting ART in the REALITY trial (NCT01825031), as well as volunteers without HIV infection. Clinical assessment, socioeconomic evaluation, blood draw for immune activation markers and carotid femoral pulse wave velocity (cfPWV) were carried out at 2- and 42-weeks post-ART initiation. Socioeconomic risk factors for immune activation and arterial stiffness were assessed using linear regression models. RESULTS: Of 279 PLWH, the median (IQR) age was 36 (31-43) years and 122 (44%) were female. Activated CD8 T-cells increased from 70% amongst those with no education to 88% amongst those with a tertiary education (p = 0.002); and from 71% amongst those earning less than 10 USD/month to 87% amongst those earning between 100-150 USD/month (p = 0.0001). Arterial stiffness was also associated with higher SES (car ownership p = 0.003, television ownership p = 0.012 and electricity access p = 0.029). Conversely, intermediate monocytes were higher amongst those with no education compared to a tertiary education (12.6% versus 7.3%; p = 0.01) and trended towards being higher amongst those earning less than 10 USD/month compared to 100-150 USD/month (10.5% versus 8.0%; p = 0.08). Water kiosk use showed a protective association against T cell activation (p = 0.007), as well as endothelial damage (MIP1ß, sICAM1 and sVCAM1 p = 0.047, 0.026 and 0.031 respectively). CONCLUSIONS: Socioeconomic risk factors for persistent inflammation amongst PLWH in SSA differ depending on the type of inflammatory pathway. Understanding these pathways and their socioeconomic drivers will help identify those at risk and target interventions for NCDs. Future studies assessing drivers of inflammation in HIV should include an SES assessment.
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Infecciones por VIH/epidemiología , Infecciones por VIH/patología , Inflamación/epidemiología , Inflamación/patología , Clase Social , Adulto , Biomarcadores/metabolismo , Velocidad de la Onda del Pulso Carotídeo-Femoral , Escolaridad , Composición Familiar , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/fisiopatología , Humanos , Renta , Inflamación/inmunología , Inflamación/fisiopatología , Malaui/epidemiología , Masculino , AguaRESUMEN
BACKGROUND: Whilst reporting improved renal and bone safety profiles, studies have noted changes in lipid profiles among people living with HIV (PLWH) receiving antiretroviral therapy (ART) switching away from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF). We aimed to characterize changes in lipids observed after switching to TAF-containing ART in a real-world setting. METHODS: A prospective study on PLWH enrolled in the UCD-ID Cohort study who switched to TAF-containing ART. Routine laboratory data [including lipids (total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides], ART history and use of lipid-lowering therapy (LLT) were analysed preswitch and postswitch to TAF. Dyslipidaemia was classified according to the National Cholesterol Education Program-Adult Panel III (NCEP-ATP III). Change in lipid parameters and change in the proportion of individuals with dyslipidaemia postswitch was assessed using the paired t-test and the Stuart--Maxwell test, respectively. RESULTS: Of 775 PLWH enrolled in the cohort, 238 switched to TAF containing ART, of whom 194 had both preswitch and postswitch lipids measured a median (IQR) 24 (14-41) weeks postswitch to TAF. TC, LDL, HDL, triglycerides and TCâ:âHDL ratio significantly increased postswitch [mean change (SE) mmol/l; +0.37 (0.06), Pâ<â0.001; +0.25 (0.06), Pâ<â0.001; +0.05 (0.02), Pâ=â0.003, +0.13 (0.07), Pâ=â0.02, and +0.16 (0.08), Pâ=â0.013) respectively]. There were significant increases in the proportions of PLWH with more severe dyslipidaemia postswitch across TC and LDL (both Pâ<â0.001). CONCLUSION: These data suggest clinically relevant, worsening lipid profiles postswitch to TAF, with a larger proportion of PLWH exceeding recommended lipid thresholds postswitch. How these changes will impact on cardiovascular risk or need for LLT remains to be determined.
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Adenina/análogos & derivados , Fármacos Anti-VIH/uso terapéutico , LDL-Colesterol/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/sangre , Tenofovir/uso terapéutico , Adenina/efectos adversos , Adenina/uso terapéutico , Adulto , Alanina , Fármacos Anti-VIH/efectos adversos , Colesterol/sangre , LDL-Colesterol/sangre , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tenofovir/administración & dosificación , Resultado del TratamientoRESUMEN
OBJECTIVES: Altered platelet function has been proposed as an underlying mechanism to explain increased risk of myocardial infarction in people living with HIV associated with use of the nucleoside reverse transcriptase inhibitor abacavir (ABC). We aimed to examine changes in platelet biomarkers in people living with HIV switching from ABC. METHODS: In a prospective, 48-week substudy of virally suppressed HIV-1-positive subjects randomized to remain on ABC/lamivudine (ABC/3TC) or switch to tenofovir disoproxil fumarate/emtricitabine, we measured soluble glycoprotein VI (sGPVI), soluble P-selectin, soluble CD40 ligand and von Willebrand factor in plasma collected over time and assessed differences using mixed effect models. RESULTS: Of 312 randomized participants, 310 were included in the analysis. Mean (SD) age 46.4 (9.3) years, 262 (85%) men and 201 (65%) white. At baseline, there was no significant between-group difference in sGPVI [tenofovir disoproxil fumarate/emtricitabine 3.75 (0.25) versus ABC/3TC 3.61 (0.22)âng/ml, Pâ=â0.69]. Greater increases in sGPVI from baseline to week 48 occurred in those switched from ABC/3TC (effect size +0.57âng/ml; 95% confidence interval, 0.2-0.94; Pâ=â0.003). There was no significant baseline difference or change overtime in soluble P-selectin, soluble CD40 ligand or von Willebrand factor between groups. CONCLUSION: The significant increases in sGPVI that occur with a switch from ABC/3TC are suggestive of changes in platelet function centred on platelet/collagen interactions and potentially represent an underlying mechanism to explain increased risk of myocardial infarction with ABC.
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Fármacos Anti-VIH/administración & dosificación , Colágeno/metabolismo , Didesoxinucleósidos/administración & dosificación , Sustitución de Medicamentos , Infecciones por VIH/tratamiento farmacológico , Glicoproteínas de Membrana Plaquetaria/análisis , Tenofovir/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Plaquetas/fisiología , Antígenos CD40/sangre , Femenino , Infecciones por VIH/patología , Humanos , Masculino , Persona de Mediana Edad , Selectina-P/sangre , Estudios Prospectivos , Resultado del Tratamiento , Adulto Joven , Factor de von Willebrand/análisisRESUMEN
OBJECTIVES: Creatinine is the biomarker of choice for use in estimates of kidney function in oncology patients. However as non-renal factors such as muscle mass can influence creatinine concentrations, we evaluated cystatin C as an alternative biomarker and its incorporation in GFR estimating formulae in an oncology setting. Measured GFR is infrequently undertaken in adult clinical practice with the consequent reliance on calculated GFR for patient assessment. DESIGN AND METHODS: Cystatin C and creatinine concentrations were evaluated from 134 oncology patients prior to commencing chemotherapeutic cycles. Estimates of creatinine clearance (Cockroft-Gault) and GFR (using Hoek, Jonsson, MDRD and CKD-EPI) were evaluated. Cystatin C-based GFR estimates (using CKD-EPI CysC and CKD-EPI SCr/CysC) were compared with the creatinine-based GFR estimates (CG, MDRD and CKD-EPI SCr) within the GFR ranges of 60-89, 45-59 and ≤44 mL/min/1.73 m2. RESULTS: Cystatin C concentrations were significantly higher in oncology patients both prior to commencing chemotherapy (F: P<0.01 and M: P<0.0001) and during cycles of treatment (F: P<0.0001 and M: P<0.01) when compared with a reference population. Cystatin C concentrations also increased significantly during chemotherapy (P<0.0001) in a subset of female patients evaluated. Poor agreement (average 42%) was demonstrated between CKD-EPI CysC and creatinine-based GFR estimates within the investigated GFR ranges, with improved agreement (average 55%) when using the combined CKD-EPI SCr/CysC formula. CONCLUSIONS: This study demonstrated a malignancy and treatment-mediated effect on cystatin C measures, which may confound its clinical utility in estimating GFR in oncology patients.