A randomised trial of anti-GM-CSF otilimab in severe COVID-19 pneumonia (OSCAR)

Background: Granulocyte–macrophage colony-stimulating factor (GM-CSF) and dysregulated myeloid cell responses are implicated in the pathophysiology and severity of COVID-19. Methods: In this randomised, sequential, multicentre, placebo-controlled, double-blind study, adults aged 18–79 years (Part 1) or ≥70 years (Part 2) with severe COVID-19, respiratory failure and systemic inflammation (elevated C-reactive protein/ferritin) received a single intravenous infusion of otilimab 90 mg (human anti-GM-CSF monoclonal antibody) plus standard care (NCT04376684). The primary outcome was the proportion of patients alive and free of respiratory failure at Day 28. Results: In Part 1 (n=806 randomised 1:1 otilimab:placebo), 71% of otilimab-treated patients were alive and free of respiratory failure at Day 28 versus 67% who received placebo; the model-adjusted difference of 5.3% was not statistically significant (95% CI −0.8–11.4%, p=0.09). A nominally significant model-adjusted difference of 19.1% (95% CI 5.2–33.1%, p=0.009) was observed in the predefined 70–79 years subgroup, but this was not confirmed in Part 2 (n=350 randomised) where the model-adjusted difference was 0.9% (95% CI −9.3–11.2%, p=0.86). Compared with placebo, otilimab resulted in lower serum concentrations of key inflammatory markers, including the putative pharmacodynamic biomarker CC chemokine ligand 17, indicative of GM-CSF pathway blockade. Adverse events were comparable between groups and consistent with severe COVID-19. Conclusions: There was no significant difference in the proportion of patients alive and free of respiratory failure at Day 28. However, despite the lack of clinical benefit, a reduction in inflammatory markers was observed with otilimab, in addition to an acceptable safety profile

Two cases of neural tube defects with dolutegravir use at conception in south Brazil

Dolutegravir (DTG) is amongst the most prescribed antiretrovirals worldwide and is recommended as first line regimen in most HIV treatment guidelines. Its use, although infrequently, had been associated to an increased chance of neural tube defects (NTD) in Botswana, Africa. Herein we describe two cases of NTD in women who conceived while taking DTG as part of their antiretroviral treatment in the city of Porto Alegre, Brazil

HIV-associated lipodystrophy: a review from a Brazilian perspective

The prognosis of human immunodeficiency virus (HIV)-infected individuals has dramatically improved worldwide since the introduction of highly antiretroviral therapy. Nevertheless, along with the decrease in mortality, several body modifications not initially related to HIV infection have been reported. Disorders in lipid and glucose metabolism, accompanied by body shape abnormalities and alterations in fat distribution, began to be described. A syndrome, named “HIV-associated lipodystrophy syndrome”, was coined to classify these clinical spectrum aspects. This syndrome involves not only metabolic alterations but also fat redistribution, with lipoatrophy due to subcutaneous fat loss (predominantly in the face and lower limbs) and lipohypertrophy related to central fat gain. These changes in body shape are very important to be recognized, as they are associated with worse morbidity and mortality. Self-esteem difficulties related to body alterations might lead to treatment failures due to medication adherence problems. Moreover, these alterations have been associated with an increased risk of cardiovascular events. Therefore, it is extremely important to identify this syndrome early in order to provide an even better quality of life for this population, as the clinical approach is not easy. Treatment change, medications to treat dyslipidemia, and surgical intervention are instruments to be used to try to correct these abnormalities. The aim of this study is to review clinical presentation, diagnosis, and management of body shape and metabolic complications of HIV infection from a Brazilian perspective, a medium income country with a large number of patients on antiretroviral therapy

Prevalence and Risk Factors Associated to Chronic Kidney Disease in HIV-Infected Patients on HAART and Undetectable Viral Load in Brazil

BACKGROUND: To determine the prevalence and associated factors with chronic kidney disease (CKD) in a cohort of HIV-positive individuals with undetectable viral load on HAART. METHODS: From March, 2009 to September 2009, 213 individuals between 18-70 years, period on HAART ≥12 months, viral load < 50 copies/mm(3), and CD4 ≥ 200 cells/mm(3), were consecutively enrolled at the outpatient clinic of Hospital de Clínicas, Porto Alegre, Brazil. Exclusion criteria were obesity, malnourishment, amputee, paraplegic, previous history of renal disease, pregnancy and hepatic insufficiency. Renal function was determined by estimated glomerular filtration rate (eGFR) assessed by the modification of diet in renal disease. CKD was defined as an eGFR less or equal than 60 ml/min/1.73 m(2), for a period of at least 3 months. Poisson regression was used to determine factors associated with CKD. RESULTS: CKD was diagnosed in 8.4% of the population, and after adjustment, the risk factors were hypertension (RR = 3.88, 95%CI, 1.84-8.16), time on HAART (RR = 1.15, 95%CI,1.03-1.27) and tenofovir exposure (RR = 2.25, 95%CI, 1.04-4.95). Higher weight (RR = 0.88 95%CI, 0.82-0.96) was associated to normal function. CONCLUSIONS: CKD was a common finding in this cohort of patients and was related to hypertension, time on HAART and tenofovir exposure. We suggest a more frequent monitoring of renal function, especially for those with risk factors to early identify renal impairment

Hepatic steatosis among people living with HIV in Southern Brazil : prevalence and risk factors

Chronic liver disease is an important cause of morbidity and mortality among people living with human immunodefciency virus (HIV) and is frequently related to non-alcoholic fatty liver disease (NAFLD). The objective is to estimate the prevalence and risk factors of hepatic steatosis among consecutive patients with stable HIV infection on antiretroviral therapy (ART). Also, the use of transient elastography (TE) as a mean to identify a subgroup at risk for non-alcoholic steatohepatitis (NASH) and/or liver fbrosis. HIV infected patients were enrolled between August2016 and February2017. Inclusion criteria: ≥18 years with undetectable HIV viral load. Exclusion criteria: pregnancy; alcohol intake ≥20g/day and co-infection B or C viruses. Patients underwent ultrasound (US) to diagnose liver steatosis. Signifcant fbrosis (≥F2) was estimated if at least one of the following were present: APRI>1.0, FIB4>3 and/ or liver stifness ≥7.1kPa. Subjects with TE≥7.1kPa were proposed a liver biopsy and NAFLD Scoring System (NAS)≥3 was considered as diagnosis of NASH. A total of 98 patients were included. Liver steatosis was diagnosed in 31 patients (31.6%) and was independently associated with male gender, BMI, ALT and total bilirubin levels. The prevalence of signifcant fbrosis assessed by TE, APRI and FIB4 was 26.9%, 6.4% and 3.2%, respectively. Seven patients had a TE result ≥7.1kPa. NASH was found in 5 (83.3%). Among HIV infected patients undergoing ART, almost one third have NAFLD. Neither TE, APRI or FIB4 were able to act as surrogates for signifcant liver fbrosis. Nevertheless, TE≥7.1kPa was able to accurately select a subgroup of patients at risk for NASH

The Evolving Genotypic Profile of HIV-1 Mutations Related to Antiretroviral Treatment in the North Region of Brazil

HIV related mutations can be associated with decreased susceptibility to antiretrovirals and treatment failures. There is scarce information about HIV mutations in persons failing HIV treatment in North of Brazil. Our aim was to evaluate evolution of HIV subtypes and mutations patterns related to antiretroviral therapy in this region. We investigated HIV resistance profile in adults failing antiretroviral regimen in Northern Brazil from January, 2004, through December, 2013. Genotype data was evaluated through Stanford University algorithm. There were 377 genotypes from different individuals to evaluate. Resistance mutations were similar to worldwide reports and related to antiretroviral exposure. Most prevalent mutations in the reverse transcriptase gene were M184V (80.1%) and K130N (40.6%). Thymidine associated mutations were more frequent in multiexperienced patients. Most common protease mutations were M46I, V82A, I54V, L90M, I84V, M46L, and L76V. Subtype B was the most prevalent (90.7%). There were differences between subtypes B and non-B mutations. We documented for the first time subtypes and patterns of HIV associated mutations in Northern Brazil. A1 subtype was identified for the first time in this area. Depending on drug regimen and how experienced the patient is, an empirical switch of a failing antiretroviral treatment could be a reasonable option

Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 lineages circulating in Brazil

Several COVID-19 vaccines have shown good efficacy in clinical trials, but there remains uncertainty about the efficacy of vaccines against different variants. Here, we investigate the efficacy of ChAdOx1 nCoV-19 (AZD1222) against symptomatic COVID-19 in a post-hoc exploratory analysis of a Phase 3 randomised trial in Brazil (trial registration ISRCTN89951424). Nose and throat swabs were tested by PCR in symptomatic participants. Sequencing and genotyping of swabs were performed to determine the lineages of SARS-CoV-2 circulating during the study. Protection against any symptomatic COVID-19 caused by the Zeta (P.2) variant was assessed in 153 cases with vaccine efficacy (VE) of 69% (95% CI 55, 78). 49 cases of B.1.1.28 occurred and VE was 73% (46, 86). The Gamma (P.1) variant arose later in the trial and fewer cases (N = 18) were available for analysis. VE was 64% (−2, 87). ChAdOx1 nCoV-19 provided 95% protection (95% CI 61%, 99%) against hospitalisation due to COVID-19. In summary, we report that ChAdOx1 nCoV-19 protects against emerging variants in Brazil despite the presence of the spike protein mutation E484K