Matrix metallopeptidase plasma levels among HIV-infected children and adolescents with and without HIV-associated chronic lung disease

Background and objectives: Among HIV-infected children and adolescents who are receiving antiretroviral therapy, chronic lung disease (CLD) is a major cause of morbidity and mortality. Matrix metallopeptidases (MMPs) are involved in a wide range of physiological processes including the breakdown and turn-over of extracellular matrix. The majority of clinical studies investigating the role of MMPs in lung pathology have been conducted among adults and none have been focused on children with HIV infection and CLD. The objectives of this study were to measure and compare the plasma levels of MMPs among HIV-infected children with and without CLD and investigate the associations between plasma MMPs levels and clinical and laboratory parameters among study participants. Methods: Data was collected as part of the BREATHE trial, a double-blind, randomized controlled trial in Harare (Zimbabwe) and Blantyre (Malawi). In total 296 children and adolescents were included in the study. Anamnestic data, spirometry and blood samples were obtained from study participants. Statistical differences between groups were calculated using the Mann-Whitney U test and chi-square test. Associations between MMPs and other study parameters were analyzed using regression and were adjusted for age, sex, being underweight, ART regimen and prior treatment for TB. Results: MMP-1, -7, -8, -10 and -12 were significantly higher among participants with CLD compared to participants without CLD. MMP-10 was significantly higher among those treated for TB (3.09 [IQR 2.88-3.24] vs. 2.94 [IQR 2.81-3.11], P=0.006). Logistical regression showed a significant association between presence of CLD and elevated plasma levels of MMP-1 (OR=3.169 (95% CI 1.257 – 7.988), P=0.014), MMP-7 (OR= 4.981 (95% CI 1.626 – 15.262), P=0.005) and MMP-10 (8.487 (95% CI 2.102 – 34.265), P=0.003). Conclusions: In this population of HIV-infected sub-Saharan African children and adolescents, a significant association between CLD status and elevated plasma levels of MMP-1, -7 and -10 was found. These results suggest that those with CLD may have upregulated expression or dysfunctional regulation of MMPs which may lead to sustained lung impairment

Cytomegalovirus-SpecificImmunoglobulin G is associated with chronic lung disease in children and adolescents from sub-Saharan Africa with perinatal HIV infection

This is a pre-copyedited, author-produced version of an article accepted for publication in Clinical Infectious Diseases following peer review. The version of record Bowen, Sovershaeva E, Charlton, Schive C, Odland j, McHugh G, Bandason T, Mayin, Ferrand RA, Yindom L, Rowland-Jones. Cytomegalovirus-SpecificImmunoglobulin G is associated with chronic lung disease in children and adolescents from sub-Saharan Africa with perinatal HIV infection. Clinical Infectious Diseases. 2020 is available online at: https://doi.org/10.1093/cid/ciaa1757.In a cross-sectional study of 296 children and adolescents from Zimbabwe living with perinatal human immunodeficiency virus, individuals with the top tertile of cytomegalovirus-specific immunoglobulin G titer had an increased odds of chronic lung disease (odds ratio, 3.33; 95% confidence interval, 1.37–8.85; P = .010)

Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial

International audienceAbstract Background Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI − 0.1% [− 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (− 3.2% [− 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. Conclusion This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu ( 2022-500385-99-00 )