Serine proteases are involved in many normal metabolic processes but also contribute to diseases of several organ systems, including viral and gastrointestinal diseases and oncology. Upamostat is an ...orally bioavailable prodrug of WX-UK1, which is most active against trypsins and closely related enzymes.
Research over the past two decades suggests several diseases in the three areas noted above which upamostat may be active. Upamostat has been studied clinically against several cancers and for outpatient treatment of COVID-19. Preclinical and clinical pharmacokinetic and metabolism studies demonstrate good bioavailability, sustained tissue levels, and high concentrations of the active moiety, WX-UK1, in stool, potentially important for treatment of gastrointestinal diseases. Clinical studies suggest activity against SARS-CoV-2; results against pancreatic cancer are also encouraging, though studies in both indications are not definitive. The drug was very well tolerated for periods of 2 weeks to several months.
Upamostat is an orally bioavailable serine protease inhibitor with an excellent safety profile and favorable pharmacokinetic properties. It has demonstrated preliminary evidence of efficacy against COVID-19, and nonclinical data suggest potential applicability against other viral illnesses, gastrointestinal diseases, and cancer.
Low bone mineral density (BMD) is prevalent in human immunodeficiency virus (HIV)-infected subjects. Initiation of antiretroviral therapy is associated with a 2%–6% decrease in BMD over the first 2 ...years, a decrease that is similar in magnitude to that sustained during the first 2 years of menopause. Recent studies have also described increased fracture rates in the HIV-infected population. The causes of low BMD in individuals with HIV infection appear to be multifactorial and likely represent a complex interaction between HIV infection, traditional osteoporosis risk factors, and antiretroviral-related factors. In this review, we make the point that HIV infection should be considered as a risk factor for bone disease. We recommend screening patients with fragility fractures, all HIV-infected post-menopausal women, and all HIV-infected men ⩾50 years of age. We also discuss the importance of considering secondary causes of osteoporosis. Finally, we discuss treatment of the more severe cases of bone disease, while outlining the caveats and gaps in our knowledge.
Objectives
The aim of the study was to explore the relationships between lymphocyte and monocyte activation, inflammation, and subclinical vascular disease among HIV‐1‐infected patients on ...antiretroviral therapy (ART).
Methods
Baseline mean common carotid artery (CCA) intima‐media thickness (IMT) and carotid plaque (IMT > 1.5cm) were evaluated in the first 60 subjects enrolled in the Stopping Atherosclerosis and Treating Unhealthy Bone with Rosuvastatin in HIV (SATURN‐HIV) trial. All subjects were adults on stable ART with evidence of heightened T‐cell activation (CD8+CD38+HLA‐DR+ ≥ 19%) or increased inflammation (high‐sensitivity C‐reactive protein ≥ 2mg/L). All had fasting low‐density lipoprotein (LDL) cholesterol ≤ 130mg/dL.
Results
Seventy‐eight per cent of patients were men and 65% were African‐American. Median (interquartile range) age and CD4 count were 47 (43, 52) years and 648 (511, 857) cells/μL, respectively. All had HIV‐1 RNA < 400 HIV‐1 RNA copies/mL. Mean CCA‐IMT was correlated with log‐transformed CD8+CD38+HLA‐DR+ percentage (r = 0.326; P = 0.043), and concentrations of interleukin‐6 (r = 0.283; P = 0.028), soluble vascular cell adhesion molecule (sVCAM; r = 0.434; P = 0.004), tumour necrosis factor‐α receptor‐I (TNFR‐I; r = 0.591; P < 0.0001) and fibrinogen (r = 0.257; P = 0.047). After adjustment for traditional cardiovascular disease (CVD) risk factors, the association with TNFR‐I (P = 0.007) and fibrinogen (P = 0.033) remained significant. Subjects with plaque (n = 22; 37%) were older mean (standard deviation) 51 (7.7) vs. 43 (9.4) years, respectively; P = 0.002, and had a higher CD8+CD38+HLA‐DR+ percentage median (interquartile range) 31% (24, 41%) vs. 23% (20, 29%), respectively; P = 0.046 and a higher sVCAM concentration mean (standard deviation) 737 (159) vs. 592 (160) ng/mL, respectively; P = 0.008 compared with those without plaque. Pro‐inflammatory monocyte subsets and serum markers of monocyte activation (soluble CD163 and soluble CD14) were not associated with CCA‐IMT or plaque.
Conclusions
Participants in SATURN‐HIV have a high level of inflammation and immune activation that is associated with subclinical vascular disease despite low serum LDL cholesterol.
Background. Stavudine is widely used in developing countries. Lipoatrophy and mitochondrial toxicity have been linked to stavudine use, but it is unclear whether switching to a lower dose can reduce ...these toxicities while maintaining human immunodeficiency virus (HIV) suppression. Methods. HIV-infected subjects receiving standard-dose stavudine with undetectable HIV type 1 RNA for ⩾6 months were randomized (ratio, 3:2) to receive one-half of the stavudine dose (switch arm) or to maintain the dose (continuation arm) while continuing to receive all other prescribed antiretrovirals. The following measurements were obtained at baseline and week 48: fasting lactate, pyruvate, and lipid levels; results of whole-body dual-energy x-ray absorptiometry; and mitochondrial DNA (mtDNA) measurements in fat and peripheral blood mononuclear cells. Change from baseline to week 48 was compared within and between groups. Results. Twenty-four patients (79% of whom were men and 79% of whom were African American; median age, 45 years) were enrolled in the study, 15 were enrolled in the switch arm, and 9 were enrolled in the continuation arm. The median duration of stavudine treatment was 55 months (range, 21–126 months). The median CD4 cell count was 558 cells/mm3 (range, 207–1698 cells/mm3). At baseline, the study arms had similar demographic characteristics and laboratory indices, except for body mass index, total lean body mass, and triglyceride levels (all of which were higher in the switch arm). Three patients (2 in the switch arm) discontinued the study because of study-unrelated reasons. CD4 cell counts remained unchanged. At 48 weeks, 6 patients (4 27% in the switch arm and 2 22% in the continuation arm) had detectable HIV RNA levels (median, 972 copies/mL; range, 60–49,400 copies/mL). All patients with detectable HIV RNA levels reported significant lapses in treatment adherence; none exhibited mutations in HIV genotype. After the treatment switch, significant changes from study entry to week 48 were noted only for lactate level (median change, −0.27 mmol/L; range, −1.2 to 0.25 mmol/L; P=.02) and fat mtDNA (median change, 40 copies/cell; range, −49 to 261 copies/cell; P=.02). In the continuation arm, a significant loss of bone mineral density was seen at week 48 (median change, −1.7%; range, −6.3% to 0.8%; P=.02). The only significant between-group difference was the change in bone mineral density from baseline (P=.003). Conclusions. Reducing stavudine dose by one-half increased fat mtDNA and decreased lactate levels, suggesting improvement in mitochondrial indices while preserving HIV suppression in subjects who maintained adherence. A significant loss of bone mineral density was seen in patients receiving standard-dose stavudine but not in those receiving low-dose stavudine. These results suggest that switching to low-dose stavudine may improve mitochondrial indices while maintaining virological suppression.
Objectives
Soluble CD14 (sCD14) is a monocyte activation marker associated with increased mortality in HIV infection. We assessed 48‐week changes in sCD14 and other inflammatory biomarkers in ...virologically suppressed, HIV‐infected women switching to raltegravir (RAL) from a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI).
Methods
HIV‐infected women with central adiposity and HIV‐1 RNA < 50 HIV‐1 RNA copies/mL continued their thymidine‐sparing nucleoside reverse transcriptase inhibitor (NRTI) backbone and were randomized to switch to open‐label RAL at week 0 (immediate) or 24 (delayed). In an exploratory analysis, inflammatory biomarkers were measured on stored fasting plasma.
Results
Of the 37 evaluable subjects, 78% were non‐White; the median age was 43 years, the median body mass index (BMI) was 32 kg/m2 and the median CD4 count was 558 cells/μL. At baseline, biomarker values were similar between groups. After 24 weeks, median sCD14 significantly declined in subjects switching to RAL −21% (P < 0.001) vs. PI/NNRTI −5% (P = 0.49); between‐group P < 0.01. After 48 weeks, immediate‐switch subjects maintained this decline and delayed‐switch subjects experienced a similar decline following the switch to RAL (−10%; within‐group P < 0.01). Immediate‐switch subjects also experienced an initial increase in tumour necrosis factor (TNF)‐α that was neither maintained after 48 weeks nor seen in delayed‐switch subjects. After adjustment for multiple testing, only declines in sCD14 remained significant.
Conclusions
In this randomized trial of women with central adiposity, a switch to RAL from a PI or NNRTI was associated with a statistically significant decline in sCD14. Further studies are needed to determine whether integrase inhibitors have improved monocyte activation profiles compared with PIs and/or NNRTIs, and whether measured differences between antiretroviral agents translate to demonstrable clinical benefit.
Objectives
The risk of cardiometabolic complications in children with perinatally acquired HIV infection (PHIVs) and in perinatally HIV‐exposed but uninfected children (HEUs) and its relationship to ...systemic inflammation and markers of gut integrity are not well established. In this current study, we assed insulin resitance in PHIV compared to HEUs and HIV unexposed uninfected children and explored potential association with intestinal damage biomarkers.
Methods
This was a cross‐sectional study in PHIVs, HEUs and HIV‐unexposed, uninfected children (HUUs) aged 2–10 years enrolled in Uganda. PHIVs were on stable antiretroviral therapy (ART) with HIV viral load < 400 HIV‐1 RNA copies/mL. Insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMA‐IR). We measured markers of systemic inflammation, monocyte activation and gut integrity. Kruskal–Wallis tests were used to compare markers by HIV status; Pearson correlation and multiple linear regressions were used to assess associations of the HOMA‐IR index with biomarkers of intestinal damage and translocation.
Results
Overall, 172 participants were enrolled in the study (57 PHIVs, 59 HEUs and 56 HUUs). The median age was 7.8 interquartile range (IQR) 6.39, 8.84 years, 55% were female and the median body mass index (BMI) was 15 (IQR 14.3, 15.8) kg/m2. Among PHIVs, the median CD4% was 37%, and 93% had viral load ≤ 20 copies/mL. PHIVs had higher waist:hip ratio, high‐density lipoprotein (HDL) cholesterol, triglycerides and HOMA‐IR index than the other groups (P ≤ 0.02). Factors correlated with insulin resistance included higher BMI and HDL cholesterol and lower soluble tumour necrosis factor receptor I (sTNFRI) (P ≤ 0.02). There was no correlation between any of the other inflammatory or gut biomarkers and HOMA‐IR index (P ≥ 0.05). After adjusting for age and sTNFRI, BMI remained independently associated with the HOMA‐IR index (β = 0.16; P < 0.01).
Conclusions
Despite viral suppression, Ugandan PHIVs have disturbances in glucose metabolism. Higher BMI, and not immune activation or alteration of gut integrity, was associated with insulin resistance in this population.
Background. Human immunodeficiency virus (HIV)-infected individuals are at increased risk of cardiovascular disease (CVD) due in part to inflammation. Statins decrease inflammation in the general ...population, but their effect during HIV infection is largely unknown. Methods. This is an ongoing randomized, double-blinded, placebo-controlled trial to evaluate the effect of statin therapy on inflammatory markers during HIV infection. Subjects received rosuvastatin 10 mg daily or placebo for 24 weeks. Subjects were receiving stable (>12 weeks) antiretroviral therapy and had a low-density lipoprotein (LDL) cholesterol level of ≤130 mg/dL and evidence of heightened immune activation or inflammation. This was a prespecified interim analysis. Results. A total of 147 subjects were enrolled (78% were male, 70% were black, and the median age was 47 years). By 24 weeks, LDL cholesterol levels had decreased in the statin group, compared with an increase in the placebo group (-28% vs + 3.8%; P < .01). A 10% reduction in the lipoprotein-associated phospholipase A₂ (Lp-PLA₂) level was seen in the statin group, compared with a 2% reduction in the placebo group (P < .01). In multivariable regression, receipt of statin treatment and having a nadir CD4⁺ T-cell count of ≤100 cell/µL were the only statistically significant predictors of a decrease in Lp-PLA₂ level. Markers of systemic inflammation did not change significantly between groups. Conclusions. Twenty-four weeks of rosuvastatin therapy significantly decreased the level of Lp-PLA₂, a vascularspecific, inflammatory enzyme that predicts cardiovascular events in the general population. Statins may hold promise as a means of attenuating CVD risk in HIV-infected individuals by decreasing Lp-PLA₂ levels.
Background.Human immunodeficiency virus (HIV)-infected patients are at increased risk of cardiovascular disease, which may be related to chronic inflammation and endothelial dysfunction despite ...virological control with antiretroviral therapy. The relationship between carotid intima-media thickness (IMT), a surrogate marker for cardiovascular disease, proinflammatory cytokines, and endothelial activation markers has not been fully explored in HIV-infected patients who are receiving antiretroviral therapy. Methods.We conducted a prospective, cross-sectional, observational study of treated HIV-infected patients and healthy control subjects to evaluate the relationship between carotid IMT, proinflammatory cytokines, endothelial activation biomarkers, and metabolic parameters in treated HIV-infected patients, compared with healthy control subjects. Results.We enrolled 73 HIV-infected patients and 21 control subjects. Common carotid artery and internal carotid artery IMT measurements, as well as tumor necrosis factor-α, high-sensitivity C-reactive protein, interleukin-6, myeloperoxidase, and soluble vascular cell adhesion molecule-1 levels were higher in the HIV-infected group. High-sensitivity C-reactive protein was the only biomarker that was positively correlated with carotid IMT in both groups. In the HIV-infected group, soluble vascular cell adhesion molecule-1 was positively correlated with all inflammatory cytokine levels. In multiple regression analysis, soluble vascular cell adhesion molecule-1, myeloperoxidase, and tumor necrosis factor-α levels were all associated with internal carotid artery IMT in the HIV-infected group, whereas age was associated with both common carotid artery and internal carotid artery IMT. Conclusions.Enhanced endothelial activation, inflammation, and increased carotid IMT occur in HIV-infected patients despite antiretroviral therapy. Inflammatory markers are associated with endothelial activation, and both are associated with internal carotid artery IMT, supporting a potential role of inflammation in endothelial activation and cardiovascular disease in HIV infection.
Objectives
Both renal disease and systemic inflammation predict non‐AIDS‐defining events and overall mortality in HIV‐infected patients. Here, we sought to determine the relationships between renal ...disease and circulating inflammation markers.
Methods
We performed a secondary analysis of AIDS Clinical Trials Group Study A5224s to determine if markers of renal disease urine protein:creatinine ratio (uPCR), urine albumin:creatinine ratio (uACR), and estimated glomerular filtration rate (eGFR), using Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) creatinine and cystatin C‐creatinine were associated with markers of systemic inflammation high‐sensitivity C‐reactive protein, interleukin‐6, tumour necrosis factor (TNF)‐α, soluble TNF‐α receptor I (sTNFRI), sTNFRII, and soluble vascular cellular and intercellular adhesion molecules. We correlated these renal and inflammatory markers prior to antiretroviral initiation and after 96 weeks of therapy.
Results
We found that eGFR (estimated using CKD‐EPI cystatin C‐creatinine), uPCR, and uACR were significantly correlated with most assessed markers of systemic inflammation prior to antiretroviral initiation. uPCR and eGFR (using CKD‐EPI cystatin C‐creatinine), but not uACR, remained significantly correlated with most of the assessed inflammatory markers after 96 weeks of antiretroviral therapy (ART). Most of these correlations, although statistically significant, were < 0.50. eGFR using CKD‐EPI creatinine was much less frequently associated with inflammation markers and only significantly correlated with sTNFR1 at week 0 and with sTNFRI and II at week 96.
Conclusions
Renal disease and function were associated with systemic inflammation in HIV infection, both before and after ART. Systemic inflammation may partially explain the relationships between proteinuria, albuminuria, and reduced renal function and future adverse outcomes.
Background. Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have anti-inflammatory effects that are independent of their lipid-lowering properties. Despite ...suppressive antiretroviral therapy (ART), elevated levels of immune activation and inflammation often persist. Methods. The Stopping Atherosclerosis and Treating Unhealthy Bone With Rosuvastatin in HIV (SATURN-HIV) trial is a randomized, double-blind, placebo-controlled study, designed to investigate the effects of rosuvastatin (10 mg/daily) on markers of cardiovascular disease risk in ART-treated human immunodeficiency virus (HIV)–infected subjects. A preplanned analysis was to assess changes in markers of immune activation at week 24. Subjects with low-density lipoprotein cholesterol <130 mg/dL and heightened immune activation (%CD8 + CD38 + HLA-DR + ≥19%, or plasma high-sensitivity C-reactive protein ≥2 mg/L) were randomized to receive rosuvastatin or placebo. We measured plasma (soluble CD14 and CD163) and cellular markers of monocyte activation (proportions of monocyte subsets and tissue factor expression) and T-cell activation (expression of CD38, HLA-DR, and PD1). Results. After 24 weeks of rosuvastatin, we found significant decreases in plasma levels of soluble CD14 (-13.4% vs 1.2%, P = .002) and in proportions of tissue factor–positive patrolling (CD14 Dim CD16 + ) monocytes (-38.8% vs -11.9%, P = .04) in rosuvastatin-treated vs placebo-treated subjects. These findings were independent of the lipid-lowering effect and the use of protease inhibitors. Rosuvastatin did not lead to any changes in levels of T-cell activation. Conclusions. Rosuvastatin treatment effectively lowered markers of monocyte activation in HIV-infected subjects on antiretroviral therapy. Clinical Trials Registration. NCT01218802.
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