Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial

Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756

Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence:the randomized phase 2a TITAN trial

Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756 .</p

Respiratory dysfunction three months after severe COVID-19 is associated with gut microbiota alterations

Background: Although coronavirus disease 2019 (COVID-19) is primarily a respiratory infection, mounting evidence suggests that the gastrointestinal (GI) tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and are related to long-term respiratory dysfunction remains unknown. Methods: Plasma was collected during hospital admission and after three months from the NOR-Solidarity trial (n = 181) and analysed for markers of gut barrier dysfunction and inflammation. At the three-month follow-up, pulmonary function was assessed by measuring the diffusing capacity of the lungs for carbon monoxide (DLCO ). Rectal swabs for gut microbiota analyses were collected (n = 97) and analysed by sequencing the 16S rRNA gene. Results: Gut microbiota diversity was reduced in COVID-19 patients with respiratory dysfunction, defined as DLCO below the lower limit of normal three months after hospitalisation. These patients also had an altered global gut microbiota composition, with reduced relative abundance of 20 bacterial taxa and increased abundance of five taxa, including Veillonella, potentially linked to fibrosis. During hospitalisation, increased plasma levels of lipopolysaccharide-binding protein (LBP) were strongly associated with respiratory failure, defined as pO2 /fiO2 -(P/F ratio)Respiratory dysfunction three months after severe COVID-19 is associated with gut microbiota alterationsacceptedVersio

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Chronic immune activation and inflammation in HIV-infected immunological non-responders: A study of innate and adaptive immunity and effect of probiotic intervention

Despite modern antiretroviral therapy (ART) and persistent viral suppression, approximately 12-30% of people living with HIV (PLWH) do not normalize their CD4+ T cell count, denoted immunological non-responders (INR). INR have increased risk of developing AIDS defining illnesses, non-AIDS related morbidities and higher mortality, probably in part caused by increased chronic immune activation and inflammation. Alterations in the gut microbiota and destruction of the gut mucosal barrier with subsequent leakage of microbial products into the systemic circulation could be one of the sources of chronic inflammation. This thesis aimed to characterize differences in chronic immune activation and inflammation between a cohort of INR and a cohort of ART-treated PLWH with adequate CD4 recovery, to search for biomarkers for incomplete CD4 gain on ART and to evaluate the effects of probiotic intervention in virally suppressed PLWH with a subnormal CD4 count. The patients were recruited from Oslo University Hospital with contribution from Karolinska University Hospital. Blood and fecal samples were collected. The INR cohort displayed a more activated innate and adaptive immune system compared with PLWH on ART with normalized CD4 counts. In particular, plasma interferon-inducible protein 10 (IP-10) was increased in the INR cohort and associated with reduced future CD4 recovery. In a randomized controlled pilot study, eight weeks of intervention with a multistrain probiotic was well tolerated, induced shifts in the gut microbiota consistent with the probiotic strains administered, and seemed to reduce markers of coagulation and inflammation. These findings contribute to the understanding of the immunological mechanisms causing an inadequate CD4 recovery in INR. The usefulness IP-10 as a potential biomarker for incomplete CD4 gain in clinical practice, as well as the potential beneficial effect of probiotic intervention have to be further elaborated in larger prospective studies

A one-year observational study of all hospitalized and fatal acute poisonings in Oslo: Epidemiology, intention and follow-up

Background Up to date information on poisoning trends is important. This study reports the epidemiology of all hospitalized acute poisonings in Oslo, including mortality, follow-up referrals, and whether the introduction of over-the-counter sales of paracetamol outside pharmacies had an impact on the frequency of poisonings. Methods All acute poisonings of adults (≥16 years) treated at the five hospitals in Oslo from April 2008 to April 2009 were included consecutively in an observational cross-sectional multicentre study. A standardized form was completed by the treating physician, which covered the study aims. All deaths by poisoning in and outside hospitals were registered at the Institute of Forensic Medicine. Results There were 1065 hospital admissions of 912 individuals; 460 (50%) were male, and the median age was 36 years. The annual incidence was 2.0 per 1000. The most frequent toxic agents were ethanol (18%), benzodiazepines (15%), paracetamol (11%), and opioids (11%). Physicians classified 46% as possible or definite suicide attempts, 37% as accidental overdoses with substances of abuse (AOSA), and 16% as other accidents. Twenty-four per cent were discharged without any follow-up and the no follow-up odds were highest for AOSA. There were 117 deaths (eight in hospital), of which 75% were males, and the median age was 41 years. Thus, the annual mortality rate was 25 per 100 000 and the in-hospital mortality was 0.8%. Opioids were the most frequent cause of death. Conclusions The incidence of hospitalized acute poisonings in Oslo was similar to that in 2003 and there was an equal sex distribution. Compared with a study performed in Oslo in 2003, there has been an increase in poisonings with a suicidal intention. The in-hospital mortality was low and nine out of ten deaths occurred outside hospitals. Opioids were the leading cause of death, so preventive measures should be encouraged among substance abusers. The number of poisonings caused by paracetamol remained unchanged after the introduction of over-the-counter sales outside pharmacies and there were no deaths, so over-the-counter sales may be considered safe

A one-year observational study of all hospitalized acute poisonings in Oslo: complications, treatment and sequelae

Abstract Objectives Changes in poisoning trends may affect both complications and outcomes in patients with acute poisoning. This study reports the treatments given and the frequency of complications, also related to treatment, mortality and sequelae related to various toxic agents. Methods All acute poisonings in adults (≥16 years) admitted to the five hospitals in Oslo were included consecutively during one year (2008 to 2009) in an observational cross-sectional multicenter study. A standardized form was completed by the treating physician, which covered the study aims. Results There were 1065 admissions in 912 patients. The median length of hospital stay was one day, and 49% were observed in an intensive care unit (ICU). Active treatment was given to 83%, and consisted of supportive therapy (70%), antidote(s) (38%), activated charcoal (16%) and gastric lavage (9%). The most commonly used antidotes were flumazenil (19%), naloxone (17%) and N-acetylcysteine (11%). The rate of treatment-related complications was 2.4% (21/884). Neither flumazenil, naloxone, nor the combination, was associated with convulsions or other complications. Among those receiving N-acetylcysteine, 5% (6/120) developed allergic reactions, one of which mandated discontinuation of treatment. Nineteen percent presented in a coma. Complications developed in 30%, compared with 18% in a 2003 study, mainly respiratory depression (12%), prolonged QTc interval (6%) and hypotension (5%). Eight patients died (0.8%) and five (0.5%) survived with permanent sequelae, mainly anoxic brain damage. Discussion Few patients stayed more than two days. The use of the ICU was liberal, considering that only one out of five presented in a coma. Antidotes were frequently given diagnostically. Although N-acetylcysteine induced allergic reactions, most were mild and treatment discontinuation was only necessary once. The frequency of complications had almost doubled in five years, although the poisoning pattern was largely unchanged. However, few patients developed permanent sequelae.</p

Activated dendritic cells and monocytes in HIV immunological nonresponders: HIV-induced interferon-inducible protein-10 correlates with low future CD4+ recovery

Objective: To explore monocyte and dendritic cell immune responses, and their association with future CD4+ gain in treated HIV patients with suboptimal CD4+ recovery. Design: A cross-sectional study of HIV-infected, virally suppressed individuals on antiretroviral therapy for at least 24 months; 41 immunological nonresponders (INRs) (CD4+ cell count 600 cells/μl). Ten HIV-infected antiretroviral therapy-naive and 10 HIV-negative healthy persons served as controls. CD4+ cell counts were registered after median 2.4 and 4.7 years. Methods: Monocyte, dendritic-cell and T-cell activation and regulatory T cells (Tregs) were analyzed by flow cytometry. In INR and immunological responder subgroups matched on age and nadir CD4+ cell count, upregulation of interferon-inducible protein-10 (IP-10) and indoleamine 2,3-dioxygenase in monocytes and dendritic cells and cytokines in cell supernatants were measured in vitro in peripheral blood mononuclear cells stimulated with aldrithiol-2-inactivated HIV-1. Results: The INR group displayed higher spontaneous activation of both monocytes (HLA-DR+) and myeloid and plasmacytoid dendritic cells (HLA-DR+, CD83+ and CD86+) compared with immunological responders, and this was associated with increased T-cell activation (CD38+HLA-DR+), an effector memory T-cell phenotype and activated Tregs. The IP-10 response in monocytes after in-vitro HIV stimulation was negatively associated with prospective CD4+ gain. IP-10, indoleamine 2,3-dioxygenase and cytokines levels were comparable between the groups, but inversely correlated with activated Tregs in INRs. Conclusion: HIV-infected individuals with suboptimal immune recovery demonstrated more activated monocytes and in particular dendritic cells, compared with patients with acceptable CD4+ gain. A high level of HIV-specific IP-10 expression in monocytes may be predictive of future CD4+ recovery

Activated dendritic cells and monocytes in HIV immunological nonresponders: HIV-induced interferon-inducible protein-10 correlates with low future CD4+ recovery

Objective: To explore monocyte and dendritic cell immune responses, and their association with future CD4+ gain in treated HIV patients with suboptimal CD4+ recovery. Design: A cross-sectional study of HIV-infected, virally suppressed individuals on antiretroviral therapy for at least 24 months; 41 immunological nonresponders (INRs) (CD4+ cell count + cell count >600 cells/μl). Ten HIV-infected antiretroviral therapy-naive and 10 HIV-negative healthy persons served as controls. CD4+ cell counts were registered after median 2.4 and 4.7 years. Methods: Monocyte, dendritic-cell and T-cell activation and regulatory T cells (Tregs) were analyzed by flow cytometry. In INR and immunological responder subgroups matched on age and nadir CD4+ cell count, upregulation of interferon-inducible protein-10 (IP-10) and indoleamine 2,3-dioxygenase in monocytes and dendritic cells and cytokines in cell supernatants were measured in vitro in peripheral blood mononuclear cells stimulated with aldrithiol-2-inactivated HIV-1. Results: The INR group displayed higher spontaneous activation of both monocytes (HLA-DR+) and myeloid and plasmacytoid dendritic cells (HLA-DR+, CD83+ and CD86+) compared with immunological responders, and this was associated with increased T-cell activation (CD38+HLA-DR+), an effector memory T-cell phenotype and activated Tregs. The IP-10 response in monocytes after in-vitro HIV stimulation was negatively associated with prospective CD4+ gain. IP-10, indoleamine 2,3-dioxygenase and cytokines levels were comparable between the groups, but inversely correlated with activated Tregs in INRs. Conclusion: HIV-infected individuals with suboptimal immune recovery demonstrated more activated monocytes and in particular dendritic cells, compared with patients with acceptable CD4+ gain. A high level of HIV-specific IP-10 expression in monocytes may be predictive of future CD4+ recovery

A one-year observational study of all hospitalized and fatal acute poisonings in Oslo: Epidemiology, intention and follow-up

Abstract Background Up to date information on poisoning trends is important. This study reports the epidemiology of all hospitalized acute poisonings in Oslo, including mortality, follow-up referrals, and whether the introduction of over-the-counter sales of paracetamol outside pharmacies had an impact on the frequency of poisonings. Methods All acute poisonings of adults (≥16 years) treated at the five hospitals in Oslo from April 2008 to April 2009 were included consecutively in an observational cross-sectional multicentre study. A standardized form was completed by the treating physician, which covered the study aims. All deaths by poisoning in and outside hospitals were registered at the Institute of Forensic Medicine. Results There were 1065 hospital admissions of 912 individuals; 460 (50%) were male, and the median age was 36 years. The annual incidence was 2.0 per 1000. The most frequent toxic agents were ethanol (18%), benzodiazepines (15%), paracetamol (11%), and opioids (11%). Physicians classified 46% as possible or definite suicide attempts, 37% as accidental overdoses with substances of abuse (AOSA), and 16% as other accidents. Twenty-four per cent were discharged without any follow-up and the no follow-up odds were highest for AOSA. There were 117 deaths (eight in hospital), of which 75% were males, and the median age was 41 years. Thus, the annual mortality rate was 25 per 100 000 and the in-hospital mortality was 0.8%. Opioids were the most frequent cause of death. Conclusions The incidence of hospitalized acute poisonings in Oslo was similar to that in 2003 and there was an equal sex distribution. Compared with a study performed in Oslo in 2003, there has been an increase in poisonings with a suicidal intention. The in-hospital mortality was low and nine out of ten deaths occurred outside hospitals. Opioids were the leading cause of death, so preventive measures should be encouraged among substance abusers. The number of poisonings caused by paracetamol remained unchanged after the introduction of over-the-counter sales outside pharmacies and there were no deaths, so over-the-counter sales may be considered safe.</p