Determinants of HIV late presentation among men who have sex with men in Portugal (2014-2019): who's being left behind?

Introduction: HIV late presentation (LP) remains excessive in Europe. We aimed to analyze the factors associated with late presentation in the MSM population newly diagnosed with HIV in Portugal between 2014 and 2019. Methods: We included 391 newly HIV-1 diagnosed Men who have Sex with Men (MSM), from the BESTHOPE project, in 17 countrywide Portuguese hospitals. The data included clinical and socio-behavioral questionnaires and the viral genomic sequence obtained in the drug resistance test before starting antiretrovirals (ARVs). HIV-1 subtypes and epidemiological surveillance mutations were determined using different bioinformatics tools. Logistic regression was used to estimate the association between predictor variables and late presentation (LP). Results: The median age was 31 years, 51% had a current income between 501-1,000 euros, 28% were migrants. 21% had never been tested for HIV before diagnosis, with 42.3% of MSM presenting LP. 60% were infected with subtype B strains. In the multivariate regression, increased age at diagnosis, higher income, lower frequency of screening, STI ever diagnosed and higher viral load were associated with LP. Conclusion: Our study suggests that specific subgroups of the MSM population, such older MSM, with higher income and lower HIV testing frequency, are not being targeted by community and clinical screening services. Overall, targeted public health measures should be strengthened toward these subgroups, through strengthened primary care testing, expanded access to PrEP, information and promotion of HIV self-testing and more inclusive and accessible health services.

Altered IgG glycosylation at COVID-19 diagnosis predicts disease severity.

The nature of the immune responses associated with COVID-19 pathogenesis and disease severity, as well as the breadth of vaccine coverage and duration of immunity, is still unclear. Given the unpredictability for developing a severe/complicated disease, there is an urgent need in the field for predictive biomarkers of COVID-19. We have analyzed IgG Fc N-glycan traits of 82 SARS-CoV-2+ unvaccinated patients, at diagnosis, by nano-LC-ESI-MS. We determined the impact of IgG Fc glyco-variations in the induction of NK cells activation, further evaluating the association between IgG Fc N-glycans and disease severity/prognosis. We found that SARS-CoV-2+ individuals display, at diagnosis, variations in the glycans composition of circulating IgGs. Importantly, levels of galactose and sialic acid structures on IgGs are able to predict the development of a poor COVID-19 disease. Mechanistically, we demonstrated that a deficiency on galactose structures on IgG Fc in COVID-19 patients appears to induce NK cells activation associated with increased release of IFN-γ and TNF-α, which indicates the presence of pro-inflammatory immunoglobulins and higher immune activation, associated with a poor disease course. This study brings to light a novel blood biomarker based on IgG Fc glycome composition with capacity to stratify patients at diagnosis.

SARS-CoV-2 Infection Drives a Glycan Switch of Peripheral T Cells at Diagnosis.

COVID-19 is a highly selective disease in which SARS-CoV-2 infection can result in different clinical manifestations ranging from asymptomatic/mild to severe disease that requires hospitalization. In this study, we demonstrated that SARS-CoV-2 infection results in a glycosylation reprogramming of circulating lymphocytes at diagnosis. We identified a specific glycosignature of T cells, defined upon SARS-CoV-2 infection and apparently triggered by a serological factor. This specific glycan switch of T cells is detected at diagnosis being more pronounced in asymptomatic patients. We further demonstrated that asymptomatic patients display an increased expression of a viral-sensing receptor through the upregulation of DC-SIGN in monocytes. We showed that higher levels of DC-SIGN in monocytes at diagnosis correlates with better COVID-19 prognosis. This new evidence pave the way to the identification of a novel glycan-based response in T cells that may confer protection against SARS-CoV-2 infection in asymptomatic patients, highlighting a novel prognostic biomarker and potential therapeutic target.

Composition of the immunoglobulin G glycome associates with the severity of COVID-19.

A large variation in the severity of disease symptoms is one of the key open questions in coronavirus disease 2019 (COVID-19) pandemics. The fact that only a small subset of people infected with severe acute respiratory syndrome coronavirus 2 develops severe disease suggests that there have to be some predisposing factors, but biomarkers that reliably predict disease severity have not been found so far. Since overactivation of the immune system is implicated in a severe form of COVID-19 and the immunoglobulin G (IgG) glycosylation is known to be involved in the regulation of different immune processes, we evaluated the association of interindividual variation in IgG N-glycome composition with the severity of COVID-19. The analysis of 166 severe and 167 mild cases from hospitals in Spain, Italy and Portugal revealed statistically significant differences in the composition of the IgG N-glycome. The most notable difference was the decrease in bisecting N-acetylglucosamine in severe patients from all three cohorts. IgG galactosylation was also lower in severe cases in all cohorts, but the difference in galactosylation was not statistically significant after correction for multiple testing.

First report of concomitant cryptococcal meningitis and anti-NMDAR encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder, seen most often in young adults and children, triggered by tumors or infections. We report a case of cryptococcal meningitis in a patient with sarcoidosis, presenting prominent neuropsychiatric symptoms, electroencephalographic features of autoimmune encephalitis and positive anti-NMDAR antibodies in the cerebrospinal fluid, raising the hypothesis of an infectious immune-mediated mechanism triggering the production of anti-NMDAR antibodies. Since anti-NMDAR encephalitis is potentially fatal and has significant morbidity, further descriptions of its etiological associations are essential to early identification and prompt treatment.

Non-AIDS-related comorbidities in people living with HIV-1 aged 50 years and older: The AGING POSITIVE study.

OBJECTIVE: To characterize the profile of non-AIDS-related comorbidities (NARC) in the older HIV-1-infected population and to explore the factors associated with multiple NARC. METHODS: This was a multicentre, cross-sectional study including HIV-1-infected patients aged ≥50 years, who were virologically suppressed and had been on a stable antiretroviral therapy (ART) regimen for at least 6 months. A multiple regression model explored the association between demographic and clinical variables and the number of NARC. RESULTS: Overall, 401 patients were enrolled. The mean age of the patients was 59.3 years and 72.6% were male. The mean duration of HIV-1 infection was 12.0 years and the median exposure to ART was 10.0 years. The mean number of NARC was 2.1, and 34.7% of patients had three or more NARC. Hypercholesterolemia was the most frequent NARC (60.8%), followed by arterial hypertension (39.7%) and chronic depression/anxiety (23.9%). Arterial hypertension and diabetes mellitus were the most frequently treated NARC (95.6% and 92.6% of cases, respectively). The linear regression analysis showed a positive relationship between age and NARC (B=0.032, 95% confidence interval 0.015-0.049; p=0.0003) and between the duration of HIV-1 infection and NARC (B=0.039, 95% confidence interval 0.017-0.059; p=0.0005). CONCLUSIONS: A high prevalence of NARC was found, the most common being metabolic, cardiovascular, and psychological conditions. NARC rates were similar to those reported for the general population, suggesting a larger societal problem beyond HIV infection. A multidisciplinary approach is essential to reduce the burden of complex multi-morbid conditions in the HIV-1-infected population.

Cytomegalovirus acute infection with pulmonary involvement in an immunocompetent patient.

Introduction: Cytomegalovirus (CMV) infection in healthy adults is usually asymptomatic or causes a mild mononucleosis syndrome, while severe infections are rare in immunocompetent patients and poorly documented. When described, gastrointestinal tract and the central nervous systems are the most frequent sites of severe CMV infection. Lung disease can occur, but it's rare. Clinical case: A 29 years old man presenting with a 2-weeks history of fever, headache, malaise, dry non-productive cough and thoracic pleuritic pain, without improvement after one-week therapy with levofloxacin. Blood exams showed lymphocytosis of almost 50%, nine percent of atypical lymphocytes and elevated transaminases. Thoracic CT-scan showed bilateral infiltrate with internal air bronchogram. Blood serology showed positivity for CMV IgG and IgM, with low CMV IgG avidity. Serum and bronchoalveolar detection of CMV by polymerase chain reaction (PCR) technique was also positive. Cultures were all negative. The patient became increasingly hypoxemic and the liver transaminases worsening, the reason for which ganciclovir was started. He made a full recovery and was discharged seven days later with oral valganciclovir, completing a 3 weeks antiviral course at home. Discussion: CMV pneumonia is a rare condition, however it's one of the three most common cause of severe viral community acquired pneumonia (CAP), along with influenza and adenovirus. CMV pneumonia should be considered in patients with atypical lymphocytes and mildly elevated serum transaminases. Conclusion: In immunocompetent hosts, even with severe CMV-CAP, the prognosis is good. However, antiviral treatment should be considered in the rare occasion of severe CMV infection. Nevertheless, more studies are needed to clarify the clinical benefit of antiviral treatment.

Effectiveness of Psycho-Educational Intervention in HIV Patients' Treatment.

Adherence to Highly Active Antiretroviral Therapy (HAART) is the main prognostic factor associated with HIV disease progression and death. The aim was to evaluate the effectiveness of a psycho-educational program to promote adherence to HAART in HIV patients. A longitudinal study (n = 102) over 9 months in an Infectious Diseases Hospital was carried out. Adherence to HAART was measured with standardized scales and values of viral load. Two groups were defined: adherents and non-adherents. In the latter, a psycho-educational program was implemented and 6 months later measured adherence to HAART. Knowledge about the infection, CD4 T lymphocytes and HIV-ribonucleic acid values were measured before and after this program. The sample was predominantly male (70%), heterosexual (78%), with a mean age of 49 (SD = 12.7) years, and 48% of participants were not adhering to HAART. After the program, non-adherence decreased to 21.6%. Knowledge about the infection increased from 79 to 97%. A significant increase in CD4 T lymphocytes (mean 540-580) and a decrease in viral load (mean 5411-3052) were observed, the latter of statistical significance. This program seems to be feasible and efficient, improving adherence to HAART.

[Hepatitis C in drug addicts: access and treatment compliance]. / Hepatite C em toxicodependentes: acompanhamento e acesso à terapêutica.

Currently, hepatitis C is a serious public health problem. It is estimated that there are 180 million people with chronic infection by hepatitis C virus (HCV) worldwide and that the prevalence of this infection in the Portuguese population ranges between 1 and 1.5%. In Portugal, there are neither up-to-date guidelines for treatment, nor recommendations for the diagnosis and management of patients with HCV and, in particular, for the endovenous drug users. The present article gathers consensus information regarding clinical practice and suggests some guidelines to the management and treatment accessibility of drug addicted patients with chronic infection by HCV, in Portugal.

[Resistance in hepatitis B virus]. / Resistencias en el virus de la hepatitis B.

The development hepatitis B virus (HBV) polymerase inhibitors has revolutionised the treatment of chronic HBV infection. However, the emergence of resistance mutations can compromise their clinical efficacy and it is mandatory to know the mechanisms of these resistances, its clinical implications, strategies for prevention and how to deal with the rescue. Since HBV has a high degree of replication and a high error rate, during their life cycle it will produce a large number of punctual mutations in individuals with active replication. Due to the large size of the HBV genome, all the possible changes may occur daily and should be screened before starting any antiviral therapy. Therefore, in individuals infected with HBV there is a mixture of similar viruses that evolves over time (quasispecies), some of which are carriers of resistance mutations to antivirals, which explains why they can be selected quickly after exposure to drug. Of the five drugs approved in Europe for the treatment of hepatitis B, three of them (lamivudine, adefovir and entecavir) are likely to be affected directly by these mutations, as well as other active drugs, such as telbivudine, tenofovir and the emtricitabine. The characterization of the resistance mutations is helpful for the prevention and the optimization of antiviral therapies.

Resistencias en el virus de la hepatitis B / Resistance in hepatitis B virus

El desarrollo de fármacos inhibidores de la polimerasa del virus de la hepatitis B (VHB) ha revolucionado el tratamiento de la infección crónica por el VHB. Sin embargo, la aparición de resistencias puede comprometer su eficacia clínica y se han de conocer los mecanismos de estas resistencias, sus implicaciones clínicas, las estrategias para su prevención y cómo abordar el rescate. Dado que el VHB tiene un alto grado de replicación y una gran tasa de error, durante su ciclo vital se producen un gran número de mutaciones puntuales en individuos con replicación activa. Debido al gran tamaño del genoma del VHB, todos los posibles cambios puntuales se pueden producir diariamente y deben considerarse como preexistentes a cualquier medicación. Por tanto, en los individuos infectados por el VHB hay una mezcla de virus semejantes que evolucionan en el tiempo (cuasiespecies), algunos de los cuales son portadores de mutaciones de resistencia a los antivirales, lo que explica que puedan seleccionarse rápidamente tras la exposición al fármaco. De los cinco fármacos aprobados en Europa para el tratamiento de la hepatitis B, tres de ellos (lamivudina, adefovir y entecavir) son susceptibles de verse afectados directamente por dichas mutaciones, así como otros fármacos activos, como son la telbivudina, el tenofovir y la emtricitabina. La caracterización de dichas mutaciones de resistencia ayuda tanto a su prevención como a la optimización del tratamiento antiviral

The development hepatitis B virus (HBV) polymerase inhibitors has revolutionised the treatment of chronic HBV infection. However, the emergence of resistance mutations can compromise their clinical efficacy and it is mandatory to know the mechanisms of these resistances, its clinical implications, strategies for prevention and how to deal with the rescue. Since HBV has a high degree of replication and a high error rate, during their life cycle it will produce a large number of punctual mutations in individuals with active replication. Due to the large size of the HBV genome, all the possible changes may occur daily and should be screened before starting any antiviral therapy. Therefore, in individuals infected with HBV there is a mixture of similar viruses that evolves over time (quasispecies), some of which are carriers of resistance mutations to antivirals, which explains why they can be selected quickly after exposure to drug. Of the five drugs approved in Europe for the treatment of hepatitis B, three of them (lamivudine, adefovir and entecavir) are likely to be affected directly by these mutations, as well as other active drugs, such as telbivudine, tenofovir and the emtricitabine. The characterization of the resistance mutations is helpful for the prevention and the optimization of antiviral therapies

Resistencias en el virus de la hepatitis B / Resistance in hepatitis B virus

El desarrollo de fármacos inhibidores de la polimerasa del virus de la hepatitis B (VHB) ha revolucionado el tratamiento de la infección crónica por el VHB. Sin embargo, la aparición de resistencias puede comprometer su eficacia clínica y se han de conocer los mecanismos de estas resistencias, sus implicaciones clínicas, las estrategias para su prevención y cómo abordar el rescate. Dado que el VHB tiene un alto grado de replicación y una gran tasa de error, durante su ciclo vital se producen un gran número de mutaciones puntuales en individuos con replicación activa. Debido al gran tamaño del genoma del VHB, todos los posibles cambios puntuales se pueden producir diariamente y deben considerarse como preexistentes a cualquier medicación. Por tanto, en los individuos infectados por el VHB hay una mezcla de virus semejantes que evolucionan en el tiempo (cuasiespecies), algunos de los cuales son portadores de mutaciones de resistencia a los antivirales, lo que explica que puedan seleccionarse rápidamente tras la exposición al fármaco. De los cinco fármacos aprobados en Europa para el tratamiento de la hepatitis B, tres de ellos (lamivudina, adefovir y entecavir) son susceptibles de verse afectados directamente por dichas mutaciones, así como otros fármacos activos, como son la telbivudina, el tenofovir y la emtricitabina. La caracterización de dichas mutaciones de resistencia ayuda tanto a su prevención como a la optimización del tratamiento antiviral(AU)

The development hepatitis B virus (HBV) polymerase inhibitors has revolutionised the treatment of chronic HBV infection. However, the emergence of resistance mutations can compromise their clinical efficacy and it is mandatory to know the mechanisms of these resistances, its clinical implications, strategies for prevention and how to deal with the rescue. Since HBV has a high degree of replication and a high error rate, during their life cycle it will produce a large number of punctual mutations in individuals with active replication. Due to the large size of the HBV genome, all the possible changes may occur daily and should be screened before starting any antiviral therapy. Therefore, in individuals infected with HBV there is a mixture of similar viruses that evolves over time (quasispecies), some of which are carriers of resistance mutations to antivirals, which explains why they can be selected quickly after exposure to drug. Of the five drugs approved in Europe for the treatment of hepatitis B, three of them (lamivudine, adefovir and entecavir) are likely to be affected directly by these mutations, as well as other active drugs, such as telbivudine, tenofovir and the emtricitabine. The characterization of the resistance mutations is helpful for the prevention and the optimization of antiviral therapies(AU)