Proteomic snapshot of saliva samples predicts new pathways implicated in SARS-CoV-2 pathogenesis.

BACKGROUND: Information on the microbiome's human pathways and active members that can affect SARS-CoV-2 susceptibility and pathogenesis in the salivary proteome is very scarce. Here, we studied a unique collection of samples harvested from April to June 2020 from unvaccinated patients. METHODS: We compared 10 infected and hospitalized patients with severe (n = 5) and moderate (n = 5) coronavirus disease (COVID-19) with 10 uninfected individuals, including non-COVID-19 but susceptible individuals (n = 5) and non-COVID-19 and nonsusceptible healthcare workers with repeated high-risk exposures (n = 5). RESULTS: By performing high-throughput proteomic profiling in saliva samples, we detected 226 unique differentially expressed (DE) human proteins between groups (q-value ≤ 0.05) out of 3376 unambiguously identified proteins (false discovery rate ≤ 1%). Major differences were observed between the non-COVID-19 and nonsusceptible groups. Bioinformatics analysis of DE proteins revealed human proteomic signatures related to inflammatory responses, central cellular processes, and antiviral activity associated with the saliva of SARS-CoV-2-infected patients (p-value ≤ 0.0004). Discriminatory biomarker signatures from human saliva include cystatins, protective molecules present in the oral cavity, calprotectins, involved in cell cycle progression, and histones, related to nucleosome functions. The expression levels of two human proteins related to protein transport in the cytoplasm, DYNC1 (p-value, 0.0021) and MAPRE1 (p-value, 0.047), correlated with angiotensin-converting enzyme 2 (ACE2) plasma activity. Finally, the proteomes of microorganisms present in the saliva samples showed 4 main microbial functional features related to ribosome functioning that were overrepresented in the infected group. CONCLUSION: Our study explores potential candidates involved in pathways implicated in SARS-CoV-2 susceptibility, although further studies in larger cohorts will be necessary.

Expanding HIV clinical monitoring: the role of CD4, CD8, and CD4/CD8 ratio in predicting non-AIDS events.

BACKGROUND: While a low CD4/CD8 ratio during HIV treatment correlates with immunosenescence, its value in identifying patients at an increased risk for clinical events remains unclear. METHODS: We analyzed data from the CoRIS cohort to determine whether CD4 count, CD8 count, and CD4/CD8 ratio at year two of antiretroviral therapy (ART) could predict the risk of serious non-AIDS events (SNAEs) during the next five years. These included major adverse cardiovascular events, non-AIDS-defining malignancies, and non-accidental deaths. We used pooled logistic regression with inverse probability weighting to estimate the survival curves and cumulative risk of clinical events. FINDINGS: The study included 4625 participants, 83% male, of whom 200 (4.3%) experienced an SNAE during the follow-up period. A CD4/CD8 ratio <0.3 predicted an increased risk of SNAEs during the next five years (OR 1.63, 95% CI 1.03-2.58). The effect was stronger at a CD4/CD8 ratio cut-off of <0.2 (OR 3.09, 95% CI 1.57-6.07). Additionally, low CD4 count at cut-offs of <500 cells/µL predicted an increased risk of clinical events. Among participants with a CD4 count ≥500 cells/µL, a CD8 count ≥1500 cells/µL or a CD4/CD8 ratio <0.4 predicted increased SNAE risk. INTERPRETATION: Our results support the use of the CD4/CD8 ratio and CD8 count as predictors of clinical progression. Patients with CD4/CD8 ratio <0.3 or CD8 count ≥1500/µL, regardless of their CD4 count, may benefit from closer monitoring and targeted preventive interventions. FUNDING: This work was supported by CIBER (CB 2021), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea-NextGenerationEU; by the Spanish AIDS Research Network (RIS) RD16/0025/0001 project as part of the Plan Nacional R + D + I, and cofinanced by Instituto de Salud Carlos III (ISCIII)- Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER), ISCIII projects PI18/00154, PI21/00141, and ERDF, "A way to make Europe", ICI20/00058.

Incidence of Anal Cancer and Related Risk Factors in HIV-Infected Patients Enrolled in the National Prospective Spanish Cohort CoRIS.

BACKGROUND: People living with HIV have an increased risk of anal cancer. OBJECTIVE: To estimate anal cancer incidence and related risk factors in a national cohort of HIV-infected patients. DESIGN: Prospective multicenter cohort study. SETTINGS: Multicenter study including patients from the Spanish HIV Research Network. PATIENTS: We collected data from 16,274 HIV-infected treatment-naive adults recruited from January 2004 to November 2020. MAIN OUTCOMES MEASURES: The primary outcome measures of this study were the incidence and prevalence of anal carcinoma. The secondary outcome measures included the associations between baseline and time-dependent covariables and the primary end point. RESULTS: Twenty-six cases of anal cancer were diagnosed, 22 of which were incident cases resulting in a cumulative incidence of 22.29 of 100,000 person-years, which was stable during the study period. At the end of the study, 20 of the 43 centers had screening programs for high-grade anal dysplasia. Patients with anal cancer were males (26/26; 100% vs 13,833/16,248; 85.1%), were mostly men who have sex with men (23/26; 88.5% vs 10,017/16,248; 61.6%), had a median age of 43 years (interquartile range, 35-51), were more frequently previously diagnosed with an AIDS-defining illness (9/26; 34.6% vs 2429/16,248; 15%), and had lower nadir CD4 cell counts (115 vs 303 µL). About a third (34.6%, 9/26) were younger than 35 years. In multivariable analysis, men who have sex with men and patients with previous AIDS-defining illness had an 8.3-fold (95% CI, 1.9-36.3) and 2.7-fold (95% CI, 1.1-6.6) increased HR for developing anal cancer, respectively. Patients with higher CD4 cell counts during the follow-up showed a 28% lower risk per each additional 100 CD4 cell/µL (95% CI, 41%-22%). LIMITATIONS: Lack of information on some potential risk factors, screening, and treatment of high-grade anal dysplasia were not uniformly initiated across centers during the study period. CONCLUSIONS: Although the overall incidence in our study was low, there was a significant number of patients younger than 35 years with anal cancer. In addition to age, other factors, such as men who have sex with men and patients with severe immunosuppression (current or past), should be prioritized for anal cancer screening. INCIDENCIA DEL CNCER DE ANO Y LOS FACTORES DE RIESGO RELACIONADOS CON PACIENTES INFECTADOS POR VIH INCLUIDOS EN LA COHORTE PROSPECTIVA NACIONAL ESPAOLA CORIS: ANTECEDENTES:Las personas portadoras del virus de la inmunodeficiencia humana tienen un mayor riesgo de cáncer anal.OBJETIVO:Nosotros queremos estimar la incidencia de cáncer anal y los factores de riesgo relacionados en una cohorte nacional española de pacientes infectados por VIH.DISEÑO:Estudio de cohortes de tipo multicéntrico y prospectivo.ÁMBITO:Se incluyeron pacientes de la Red Española de Investigación en VIH.PACIENTES:Recolectamos los datos de 16,274 adultos infectados por el VIH que nunca habían recibido tratamiento, reclutados desde enero de 2004 hasta noviembre de 2020.MEDIDAS DE RESULTADO PRINCIPALES:Las medidas de resultado primarias de este estudio fueron la incidencia y la prevalencia del carcinoma anal. Las medidas de resultado secundarias incluyeron las asociaciones entre las covariables basales y dependientes del tiempo y el criterio principal de valoración.RESULTADOS:Se diagnosticaron 26 casos de cáncer anal, de los cuales 22 fueron casos incidentales resultando con una incidencia acumulada de 22,29/100.000 personas-año que se mantuvo estable durante el período de estudio.Al final de nuestro estudio, 20 de los 43 centros referentes tenían programas de detección de displasia anal de alto grado. Los pacientes con cáncer anal eran hombres (26/26; 100% vs 13 833/16 248; 85,1%), en su mayoría hombres que mantenían sexo con otros hombres (23/26; 88,5% vs 10 017/16 248; 61,6%), la mediana de edad fue de 43 años (IQR: 3 -51), 34,6% (9/26) < 35 años, previa y frecuentemente diagnosticados con una enfermedad definitoria de SIDA (9/26; 34,6% vs 2429/16248; 15%) y que tenían un punto opuesto mucho más bajo en el recuentos de células CD4 (115 µL frente a 303 µL).En el análisis multivariable, los hombres que tenían relaciones sexuales con otros hombres y los pacientes con enfermedades definitorias de sida anteriores, tenían un aumento de 8,3 veces (IC del 95%: 1,9 a 36,3) y de 2,7 veces (IC del 95%: 1,1 a 6,6) en el cociente de riesgos instantáneos para desarrollar cáncer anal, respectivamente. Los pacientes con recuentos de células CD4 más altos durante el seguimiento mostraron un riesgo 28 % menor por cada 100 células CD4/µl adicionales (95% IC: 41%- 22%).LIMITACIONES:La falta de información sobre algunos factores potenciales de riesgo, la detección y el tratamiento de la displasia anal de alto grado no se iniciaron uniformemente en todos los centros durante el período de estudio.CONCLUSIONES:Si bien la incidencia general en nuestro estudio fue baja, hubo un número significativo de pacientes de <35 años con cáncer anal. Además de la edad, otros factores como los hombres que tienen sexo con hombres y los pacientes con inmunosupresión severa (actual o pasada) deben priorizarse para la detección del cáncer anal. ( Traducción-Dr. Xavier Delgadillo ).

CD4/CD8 Ratio During Human Immunodeficiency Virus Treatment: Time for Routine Monitoring?

In the last decade, studies in persons with HIV (PWH) on antiretroviral therapy (ART) have shed light on the significance of persistently high CD8 counts and low CD4/CD8 ratios. A low CD4/CD8 ratio reflects increased immune activation and is associated with an increased risk of severe non-AIDS events. As a result, many clinicians now believe that the CD4/CD8 ratio can help in HIV monitoring, and many researchers now report it as an efficacy marker in interventional studies. However, the topic is more complex. Recent studies have not yielded unanimous conclusions on the ability of the CD4/CD8 ratio to predict adverse outcomes, and only some clinical guidelines recommend monitoring it. Knowledge gaps remain on the best cutoff points, associated clinical events, effects of treatments, and how the CD4/CD8 ratio could improve decision making in the clinic. Here, we critically review the literature, identify knowledge gaps, and discuss the role of the CD4/CD8 ratio as a marker for HIV monitoring.

The Negative Impact of COVID-19 in HCV, HIV, and HPV Surveillance Programs During the Different Pandemic Waves.

Background: The coronavirus disease 2019 (COVID-19) pandemic has been a worldwide stress test for health systems. 2 years have elapsed since the description of the first cases of pneumonia of unknown origin. This study quantifies the impact of COVID-19 in the screening program of chronic viral infections such as human papillomavirus (HPV), human immunodeficiency virus (HIV), and hepatitis C virus (HCV) along the six different pandemic waves in our population. Each wave had particular epidemiological, biological, or clinical patterns. Methods: We analyzed the number of samples for screening of these viruses from March 2020 to February 2022, the new infections detected in the pandemic period compared to the previous year, the time elapsed between diagnosis and linking to treatment and follow-up of patients, and the percentage of late HIV diagnosis. Moreover, we used the origin of the samples as a marker for quantifying the restoration of activity in primary care. Results: During the first pandemic year, the number of samples received was reduced by 26.7, 22.6, and 22.5% for molecular detection of HPV or serological HCV and HIV status respectively. The highest decrease was observed during the first wave with 70, 40, and 26.7% for HPV, HCV, and HIV. As expected, new diagnoses also decreased by 35.4, 58.2, and 40.5% for HPV, HCV, and HIV respectively during the first year of the pandemic. In the second year of the pandemic, the number of samples remained below pre-pandemic period levels for HCV (-3.6%) and HIV (-9.3%) but was slightly higher for HPV (8.0%). The new diagnoses in the second year of the pandemic were -16.1, -46.8, and -18.6% for HPV, HCV, and HIV respectively. Conclusions: Undoubtedly, an important number of new HPV, HCV, and HIV infections were lost during the COVID-19 pandemic, and surveillance programs were disrupted as a consequence of collapse of the health system. It is a priority to reinforce these surveillance programs as soon as possible in order to detect undiagnosed cases before the associated morbidity-mortality increases. New pandemic waves could increase the risk of reversing the achievements made over the last few decades.

An Easy-to-Implement Risk Score for Targeted Hepatitis C Virus Testing in the General Population.

Despite the effectiveness of available treatments, hepatitis C virus (HCV) remains a major public health problem, mainly due to the high percentage of undiagnosed individuals. We aim to create an easy-to-implement risk score to facilitate targeted HCV testing in the general population. This is a substudy derived from a prospective study in primary care in Madrid (Spain). Participants completed a 21-question risk assessment questionnaire, followed by HCV testing for those with at least one positive response and those >50 years of age, even if they did not answer positively. We used the population >50 years of age to fit a logistic regression model to create a score predicting the risk of a positive test result. We then performed a sensitivity analysis by applying the score obtained to the population <50 years of age, to assess its diagnostic accuracy. Data collected from 2,302 participants were included in the analysis. The prevalence of HCV infection was 1.3%. Five items were selected, showing a C-statistic of 0.896, i.e., male sex, Eastern European origin, use of intravenous drugs, self-perceived risk of acquired HCV infection, and past hepatitis or unexplained liver disease. The sensitivity was 98%, and the negative likelihood ratio was 0.05 for participants with scores of 0 (49.8% in our sample), ruling out HCV infection with high probability. We obtained similar estimates in the population <50 years of age. This tool achieved high diagnostic accuracy to target HCV testing. This could help optimize resources when universal screening is not feasible. IMPORTANCE Despite the highly effective treatments currently available, HCV remains one of the major public health problems related to an infectious agent, mainly because a high percentage of individuals remain undiagnosed. Universal screening has been proposed as a way to end this epidemic; however, it is not feasible in all settings due to different implementation barriers. With this work, we aim to collaborate in improving the diagnosis of HCV infection by creating a simple 5-item score that rules out HCV infection with a very high probability. Almost one-half of the participants in our sample did not present any affirmative answers to these questions, and their probability of being infected was close to 0%. This tool could be a useful strategy and could be considered a cost-effective alternative to optimize resources when universal screening is not feasible.

Implementation of a lung cancer screening initiative in HIV-infected subjects.

In this pilot program of low-dose computed tomography (LDCT) for the screening of lung cancer (LC) in a targeted population of people with HIV (PWH), its prevalence was 3.6%; the number needed to screen in order to detect one case of lung cancer was 28, clearly outweighing the risks associated with lung cancer screening. While data from additional cohorts with longitudinal measurements are needed, PWH are a target population for lung cancer screening with LDCT.

Exploiting the Microbiota for the Diagnosis of Anal Precancerous Lesions in Men Who Have Sex With Men.

BACKGROUND: While the microbiota has been associated with human papillomavirus malignant transformation, it is unclear whether anal bacteria could improve the low specificity of anal cytology for the screening of high-grade intraepithelial squamous neoplasia (HSIL). METHODS: We recruited men who have sex with men undergoing anal cytology and high-resolution anoscopy. We assessed the microbiota composition from fecal samples and cytobrush anal samples using 16S ribosomal DNA sequencing in participants with or without biopsy-proven HSIL (bHSIL). We selected bacterial biomarkers based on their linear discriminant analysis. We assessed their predictive performance using logistic regression and bootstrap resampling. RESULTS: We included 128 individuals, 47 (36.7%) with bHSIL and 99 (77.3%) with human immunodeficiency virus. We detected 40 potential predictors of bHSIL. Ruminococcaceae NK4A214 group, Alloprevotella genus, Prevotella melanonigenica, and Ruminococcaceae UCG-014 were the most predictive of bHSIL. From 35 false-positive cytologic results, the combination of these 4 biomarkers with the anal cytology reclassified to true-negative 33 individuals (94%) and showed good diagnostic performance (area under the receiver operating characteristic curve, 0.805; 95% confidence interval, .728-.882). CONCLUSIONS: We found anal-associated bacteria indicative of a higher risk of precancerous anal lesions, which combination was highly specific. The microbiota could be developed as a complementary diagnostic tool to overcome the limitations of the current screening strategy for anal cancer.

Hepatitis C and HIV combined screening in primary care: A cluster randomized trial.

Hepatitis C virus (HCV) and HIV are major causes of worldwide disease. We aimed to evaluate the effect of a combined screening programme, which included a risk-assessment questionnaire and rapid tests for point-of-care diagnosis, on screening and new diagnosis rates. This prospective, cluster randomized study was carried out in primary care. The intervention arm included a 4-hour educational programme, the use of a risk-assessment questionnaire and rapid tests. In the control centres, only the educational intervention was provided. The main variables compared were the screening coverage and the number and rate of new HCV and HIV diagnoses. Of a total of 7991 participants, 4670 (58.5%) and 2894 (36.2%) presented a risk questionnaire for HIV or HCV, respectively. The younger participants, men and those from Latin America and Eastern Europe, showed the greatest risk of presenting with a positive questionnaire. The overall screening coverage was higher within the intervention arm (OR 17.7; 95% CI 16.2-19.5; P < .001). Only two HIV-positives were identified compared to one in control centres. The rate of HCV diagnoses was higher among intervention centres, with 37 versus seven positive tests (OR 5.2; 95% CI 2.3-11.6; P < .001). Of them, 10 were new diagnoses and 27 had been previously diagnosed, although not linked to care. In conclusion, a simple operational programme can lead to an increase in HCV and HIV screening rates, compared to an exclusively educational programme. The selection of at-risk patients with a self-questionnaire and the use of rapid tests significantly increased the diagnostic rate of HCV infection.

HIV, Cancer, and the Microbiota: Common Pathways Influencing Different Diseases.

HIV infection exerts profound and perhaps irreversible damage to the gut mucosal-associated lymphoid tissues, resulting in long-lasting changes in the signals required for the coordination of commensal colonization and in perturbations at the compositional and functional level of the gut microbiota. These abnormalities in gut microbial communities appear to affect clinical outcomes, including T-cell recovery, vaccine responses, HIV transmission, cardiovascular disease, and cancer pathogenesis. For example, the microbial signature associated with HIV infection has been shown to induce tryptophan catabolism, affect the butyrate synthesis pathway, impair anti-tumoral immunity and affect oxidative stress, which have also been linked to the pathogenesis of cancer. Furthermore, some of the taxa that are depleted in subjects with HIV have proved to modulate the anti-tumor efficacy of various chemotherapies and immunotherapeutic agents. The aim of this work is to provide a broad overview of recent advances in our knowledge of how HIV might affect the microbiota, with a focus on the pathways shared with cancer pathogenesis.

Outcome of an HIV education program for primary care providers: Screening and late diagnosis rates.

BACKGROUND: Late HIV diagnosis remains one of the challenges in combating the epidemic. Primary care providers play an important role in screening for HIV infection. Our study aims to evaluate the relationship between knowledge and barriers to HIV testing and screening outcomes. The impact of an education program for primary care providers, towards improving HIV testing and late diagnosis rates, is also assessed. METHODS: A self-administered questionnaire that was developed within the framework of the European project OptTEST was used to examine HIV knowledge and barriers to HIV testing scores before and after being involved in an HIV education program. A quasi-experimental design with pre- and post-intervention measures was performed to investigate its impact. We performed multivariable logistic regression analysis to assess the relationship between variables for the HIV testing offer. RESULTS: A total of 20 primary care centers and 454 primary care staff were included. Baseline OptTEST results showed that more knowledgeable staff offered an HIV test more frequently (OR 1.07; CI 95% 1.01-1.13; p = 0.027) and had lower barrier scores (OR 0.89; CI 95% 0.77-0.95; p = 0.005). Nurses had lower scores in knowledge-related items (OR 0.28; CI 95% 0.17-0.46; p<0.001), but higher scores in barrier-related items than physicians (OR 3.28; CI 95% 2.01-5.46; p<0.001). Specific centers with more knowledgeable staff members had a significant association with a greater level of new HIV diagnosis rates (OR 1.61; CI 95% 1.04-2.49; p = 0.032). After the intervention, we found that 12 out of 14 individual questions showed improved scores. In the 6 months after the training program, we similarly found a higher HIV testing rate (OR 1.19; CI 1.02-1.42; p = 0.036). CONCLUSIONS: This study highlights the association between knowledge and barriers to HIV testing, including HIV testing rates. It shows that it is possible to modify knowledge and reduce perceived barriers through educational programs, subsequently improving HIV screening outcomes.

HIV infection epidemiology: a change of scenery.

Combination antiretroviral therapy has completely changed the landscape of HIV infection through the control of viral replication of the virus, the restoration of the immune system damage, and the reduction of the complications associated with immunodeficiency. As a consequence, the average age of people living with HIV has been increasing progressively, with a high proportion of diagnosed, as well as newly diagnosed, HIV-infected patients being older than 50 years throughout the world. With the longer life expectancy, characteristics commonly observed in aging are occurring in people with long-term HIV infection, including multiple chronic diseases, changes in cognitive and physical abilities, and the use of multiple medications. HIV-related specific factors, as well as a higher prevalence of environmental, classical factors, increase the risk of comorbidities in the aging HIV-infected population. A close collaboration between different specialists (HIV specialists, geriatricians, primary care physicians, and other specialists) is required to manage the clinical problems that older HIV-infected patients may present.