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Background and ObjectivesEvidence regarding the safety and efficacy of messenger RNA (mRNA) vaccines in patients with myasthenia gravis (MG) after immunosuppressive therapies is scarce. Our aim is to determine whether the mRNA-1273 vaccine is safe and able to induce humoral and cellular responses in patients with MG.MethodsWe performed an observational, longitudinal, prospective study including 100 patients with MG of a referral center for MG in our country, conducted from April 2021 to November 2021 during the vaccination campaign. The mRNA-1273 vaccine was scheduled for all participants. Blood samples were collected before vaccination and 3 months after a second dose. Clinical changes in MG were measured using the MG activities of daily life score at baseline and 1 week after the first and second doses. A surveillance of all symptoms of coronavirus disease 2019 (COVID-19) was conducted throughout the study. Humoral and cellular immune responses after vaccination were assessed using a spike-antibody ELISA and interferon gamma release assay in plasma. The primary outcomes were clinically significant changes in MG symptoms after vaccination, adverse events (AEs), and seroconversion and T-cell immune response rates.ResultsNinety-nine patients completed the full vaccination schedule, and 98 had 2 blood samples taken. A statistically significant worsening of symptoms was identified after the first and second doses of the mRNA-1273 vaccine, but this was not clinically relevant. Mild AEs occurred in 14 patients after the first dose and in 21 patients after the second dose. Eighty-seven patients developed a humoral response and 72 patients showed a T-cell response after vaccination. A combined therapy with prednisone and other immunosuppressive drugs correlated with a lower seroconversion ratio (OR = 5.97, 95% CI 1.46–24.09, p = 0.015) and a lower T-cell response ratio (OR = 2.83, 95% CI 1.13–7.13, p = 0.024).DiscussionOur findings indicate that the mRNA vaccination against COVID-19 is safe in patients with MG and show no negative impact on the disease course. Patients achieved high humoral and cellular immune response levels.Classification of EvidenceThis study provides Class IV evidence that patients with MG receiving the mRNA-1273 vaccine did not show clinical worsening after vaccination and that most of the patients achieved high cellular or immune response levels.

Blocking IL-6 pathways with sarilumab, a fully human anti-IL-6R antagonist may potentially curb the inflammatory storm of SARS-CoV2. In the present emergency scenario, we used "off-label"" sarilumab in 5 elderly patients in life-threatening condition not candidates to further active measures. We suggest that sarilumab can modulate severe COVID-19-associated Cytokine Release Syndrome."

Altres ajuts: GLD13/00168 Altres ajuts: GLD14/293 Altres ajuts: PERIS/SLT002-16-00101 Poor immunological recovery in treated HIV-infected patients is associated with greater morbidity and mortality. To date, predictive biomarkers of this incomplete immune reconstitution have not been established. We aimed to identify a baseline metabolomic signature associated with a poor immunological recovery after antiretroviral therapy (ART) to envisage the underlying mechanistic pathways that influence the treatment response. This was a multicentre, prospective cohort study in ART-naive and a pre-ART low nadir (

Supplemental Digital Content is available in the text, Objective: To compare the efficacy, safety, and impact on lipid fractions of switching from a ritonavir-boosted protease inhibitor (PI/r) to a dolutegravir (DTG) regimen. Methods: HIV type 1-infected adults more than 50 years or with a Framingham score more than 10% were eligible if plasma HIV RNA less than 50 copies per ml for at least 24 weeks while on a PI/r regimen. Patients were randomized to switch to DTG or to remain on PI/r. Primary endpoints were: proportion maintaining HIV RNA less than 50 copies per ml and percentage change from baseline of total cholesterol at week 48. Results: In total, 415 patients (32 sites in six European countries) were randomized: 205 to DTG and 210 to continue PI/r. About 89% were men, 87% more than 50 years, 74% had a Framingham score more than 10%, with a median CD4+ cell count of 617 cells per μl and suppressed viremia for a median of 5 years. At week 48, in the intent-to-treat analysis, treatment success rate was 93.1% in DTG group and 95.2% in PI/r group (difference −2.1%, 95% confidence interval −6.6 to 2.4, noninferiority demonstrated). There were four virological failures with DTG and one with PI/r with no emergent resistance mutations. There was no significant difference in severe adverse events or grade 3 or 4 adverse events or treatment modifying adverse events. Total cholesterol and other lipid fractions (except high-density lipoprotein cholesterol) improved significantly (P < 0.001) in the DTG group regardless of PI/r at baseline. Conclusion: Switching to a DTG regimen in virologically suppressed HIV type 1 patients with high cardiovascular disease risk was noninferior, and significantly improved lipid profiles.

Background: Conflicting reports on the effects of efavirenz (EFV) and lopinavir/ritonavir (LPV/r) on subcutaneous adipose tissue (SAT) have been described. Objective: The aim was to assess the 48-week molecular and clinical effects of LPV/r and EFV, combined with tenofovir/emtricitabine (TDF/FTC), on SAT of HIV-infected, antiretroviral-naive patients. Methods: Forty-four adults were started on LPV/r or EFV combined with TDF/FTC. Fasting metabolic tests, HIV RNA, CD4 cell count, and fat measured by dual x-ray absorptiometry scans were obtained at study entry and week 48. Mitochondrial DNA (mtDNA) and transcripts for mtDNA-encoded proteins and genes involved in inflammation, adipocyte differentiation, and metabolism were assessed in paired SAT biopsies. Results: Whole-body fat and limb fat mass increased in the LPV/r and EFV groups. MtDNA and cytochrome oxidase subunit II did not change, and cytochrome b increased significantly in EFV-treated patients. Tumor necrosis factor alpha and monocyte chemotactic protein-1 gene expression did not change in the LPV/r group, but these significantly increased in the EFV group. Interleukin 18 decreased in the LPV/r group, whereas it increased in the EFV group. Conclusions: Starting TDF/FTC plus EFV was associated with an increased expression of genes encoding for inflammatory cytokines in SAT in naive patients. Therapy with TDF/FTC plus LPV/r or EFV was associated with an increase in subcutaneous fat mass.

Introduction Peak bone mass (PBM) is the amount of bone present at the end of skeletal maturation. It is an important determinant of osteoporotic fracture risk. Data on the PBM in the HIV-infected population are lacking. Design and methods We performed a multicenter (6 centers in Spain), case-control study to assess PBM using dual-energy x-ray absorptiometry. We studied HIV-infected patients aged 20-30 years and compared them with age- and gender-matched non-HIV-infected controls. We also assessed the predictive factors for a low PBM. Results We included 307 subjects: 232 HIV-infected patients and 75 non-HIV-infected controls. Bone mineral density was similar in both groups although differences were seen in the total femur T-score (-0.15SD versus +0.50SD, respectively, P = 0.018). The percentage of osteopenia and osteoporosis was higher in the HIV-infected patients (56.5% and 10.7%, respectively) than in the controls (50.7% and 4%, respectively; P = 0.019). Osteoporosis was more frequent in HIV-infected men than in control men and HIV-infected women (12.2% versus 5.5% and 4.8%, P = 0.033). Protease inhibitors and nadir CD4 T-cells were negatively associated with PBM, whereas fat and lean mass were positively associated with PBM. Conclusions Bone mineral density was similar between HIV-infected patients aged 20-30 years than in age- and gender-matched controls. However, lower femoral T-scores and higher rate of osteopenia and osteoporosis were seen in HIV-infected men. Therapy with protease inhibitors, nadir CD4 counts, and fat and lean mass were predictive factors of PBM. Given that these patients will be living with HIV infection for many years, every effort should be made to modify risk factors.

Background: Detection of episomal HIV cDNA has been associated with greater levels of CD8 and CD4 T-cell activation in HIV-1-infected highly active antiretroviral therapy HAART)-suppressed individuals. However, HAART intensification exclusively reduced CD8 T-cell activation. Methods: We evaluated activation markers 12 weeks after raltegravir withdrawal in a previously described 48-week raltegravir intensification study. The subjects n = 34) were subgrouped into 2-LTR+ n = 12) or 2-LTR- n = 22) subgroups according to delectability of 2-LTR episomes during the intensification period. Results: The initial differences in CD8 T-cell activation between subgroups were lost after intensification. Linear mixed models revealed significant reductions in CD8 T-cell activation in both 2-LTR- and 2-LTR+ subgroups, suggesting that raltegravir impacts subjects irrespective of 2-LTR detection. Remarkably, a partial rebound in CD8 activation markers after raltegravir discontinuation was observed in the 2-LTR+ subgroup. This restored the differences between subgroups observed at study entry, particularly in terms of CD38 expression within CD8 memory T-cells. Conversely, CD4 T-cell activation remained unchanged in both subgroups during the study period, although an early and transient CD45RA(-) CD4 T-cell redistribution from tissues was apparent. Conclusions: CD8 T-cell activation undergoes reversible changes during raltegravir intensification and discontinuation in patients showing detectable 2-LTR circles. The general decrease in CD8 T-cell activation and a transient CD45RA(-) CD4 T-cell redistribution in intensified individuals may reflect residual viral replication during apparently suppressive HAART.

Background: To determine the role of fibroblast growth factor (FGF)-19 and FGF21 and the endocrine FGFs receptor system in the metabolic alterations that manifest in HIV-1-infected patients undergoing highly active antiretroviral treatment (HAART). Methods: Serum FGF19 and FGF21 levels were determined in 4 groups of individuals as follows: (1) HIV-1-infected HAART patients with lipodystrophy (n = 38); or (2) without lipodystrophy (n = 34); (3) untreated (naive) HIV-1-infected patients (n = 34); and (4) healthy controls (n = 31). Serum FGF19 levels were correlated with anthropometric, metabolic, HIV-1 infection-related, and HAART-related parameters and with FGF21 levels. The gene expression of FGF receptor 1 and the coreceptor beta-Klotho was analyzed in adipose tissue from 10 individuals from each group. Results: Serum FGF19 levels were significantly reduced in all groups of HIV-1-infected patients, whereas FGF21 levels were increased. FGF19 levels were negatively correlated with insulin resistance and insulin levels and positively correlated with high-density lipoprotein cholesterol. FGF19 was inversely correlated with cumulative exposure to nucleoside reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitor drugs. The expression of FGF receptor 1 and coreceptor beta-Klotho was reduced in adipose tissue from all groups of HIV-infected patients. Conclusions: FGF19 levels are reduced in HIV-1-infected patients, in contrast with FGF21 levels. Impaired expression of the corresponding receptor and coreceptor, which mediate the actions of endocrine FGFs in adipose tissue, suggests a resistance to the metabolic effects of FGF19 and FGF21 in HIV-1-infected patients. Considering the beneficial effects of endocrine FGFs on metabolism, the observed reduction in FGF19 levels and decreased sensitivity to endocrine FGFs in adipose tissue may contribute to metabolic alterations in HIV-1-infected patients.

Background: HIV-1 can induce disturbances in adipose tissue in infected subjects through the effects of some of its proteins or inflammation. It is not known whether this also takes place in HIV-1-infected long-term nonprogressors (LTNPs). Our objectives were to determine whether adipocyte differentiation/lipid, inflammatory, and mitochondrial parameters are perturbed in abdominal wall subcutaneous adipose tissue of untreated HIV-1-infected patients LTNPs. Methods: Cross-sectional study involving 10 LTNPs, 10 typical progressors (TPs), and 10 uninfected controls (UCs). The parameters assessed were peroxisome proliferator-activated receptor-gamma (PPAR gamma), lipoprotein lipase, and fatty acid-binding protein 4 mRNA (adipogenic/lipid); tumor necrosis factor-alpha, interleukin 18 (IL-18), beta 2-MCG, monocyte chemoattractant protein 1, CD1A, and C3 mRNA (inflammation); and cytochrome c oxidase subunit II (COII), COIV, CYCA, nuclear respiratory factor 1, PPAR gamma coactivator 1 alpha mRNA, and mtDNA content (mitochondrial). Results: Regarding adipogenic/lipid parameters, LTNPs had PPAR gamma, lipoprotein lipase, and fatty acid-binding protein 4 mRNA significantly decreased compared with UCs (P

The substitution by generic equivalents of some of the drugs included in fixed-dose antiretroviral coformulations (FDACs) poses the potential risk of disrupting these combinations and administering the components separately in order to incorporate the new generic drug, which offers a more competitive sales price. This may represent a step backwards in the advances achieved in simplicity and adherence to therapy, posing an increased risk of selective noncompliance of some of the separately administered drug substances. Available antiretroviral drugs must be administered for life in the affected individuals - both children and adults. The FDACs represent a significant advance in the simplification of antiretroviral therapy, facilitating adherence to complex and chronic treatments, and contributing to a quantifiable improvement in patient quality of life. These drug coformulations reduce the risk of treatment error, are associated with a lower risk of hospitalization, and can lessen the possibility of covert monotherapy in situations of selective noncompliance. Thus, FDACs can reduce the risk of selection of HIV-1 resistances, which not only adversely affect the treatment options of the individual patient but also constitute a public health problem, and further increase the cost and complexity of therapy. With the exception of those cases requiring dose adjustments, the preferential use of FDACs should be recommended for the treatment of HIV-1 infection in those situations when the agents included in the coformulation are drugs of choice. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Objective: HIV-1-infected patients with lipodystrophy show insulin resistance, dyslipidemia and other signs of metabolic syndrome. Fibroblast growth factor-21 (FGF21) is a novel metabolic regulator that has been suggested to exert beneficial effects on metabolic homeostasis and insulin sensitivity. Our goal was to determine the relationship between FGF21 levels and metabolic alterations in these patients. Research design and methods: Serum FGF21 levels were analyzed in 179 individuals belonging to four groups: HIV-1-infected, antiretroviral-treated patients that have developed lipodystrophy (n = 59); HIV-1-infected, antiretroviral-treated patients without lipodystrophy (n = 45); untreated (naive) HIV-1-infected patients (n = 41); and healthy control individuals (n 34). Serum FGF21 levels were correlated with parameters indicative of altered fat distribution, metabolic and cardiovascular risk, and in relation to HIV-1 infection and antiretroviral treatment regimens. Results: Serum FGF21 levels were increased in all HIV-1-infected patients, but the increases were most marked in those with lipodystrophy. FGF21 levels showed a strong positive correlation with indicators of lipodystrophy (trunk/apendicular fat ratio, waist-to-hip ratio), insulin resistance (fasting glucose, HOMA-R), dyslipidemia (low-density lipoprotein cholesterol), and liver injury (g-glutamyltransferase). Conclusions: FGF21 levels are increased in HIV-1-infected patients, especially in those with lipodystrophy, and this increase is closely associated with insulin resistance, metabolic syndrome and makers of liver damage. Further research will be required to determine whether the increase in FGF21 levels is caused by a compensatory response or resistance to FGF21, and to establish the potential of FGF21 as a biomarker of altered metabolism in HIV-1-infected, antiretroviral-treated patients. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Background: The strategy of switching nevirapine (NVP) twice daily to once daily was evaluated. Methods: Forty-eight-week randomized, open, multicenter trial. Stable HIV-infected patients on NVP twice daily for > 12-18 weeks with alanine aminotransferase (ALT)