Risk Of Clinical Disease Progression Research Articles

New insights on the mechanisms of myocardial injury in hypertensive patients with COVID-19

Abstract Introduction Cardiac comorbidities, particularly hypertension, are highly prevalent in patients hospitalized with COVID-19 and are related directly to the risk of clinical disease progression. Cardiac injury is the most frequently reported cardiac abnormality in these patients. Diverse forms and mechanisms of myocardial injury, including acute myocardial ischemia due to plaque rupture, oxygen supply/demand imbalance, non-ischemic injuries such as myocarditis, direct virus-mediated injury, and immune system dysregulation, have been described in patients with COVID-19. Purpose The mechanism of the association among hypertension, COVID-19 and cardiac injury and the reasons for worse clinical progression in these patients have not been elucidated clearly. Considering that myocardial injury due to direct SARS-CoV-2 infection is rare and that the immune system is often dysregulated in patients with COVID-19, and also that cytokine storm and lymphopenia are important immune markers of progression to severe disease, the present study aimed to investigate the immune profile of hypertensive patients with COVID-19 and myocardial injury to obtain a better understanding of the immune dysregulation and to provide new insights on the mechanism of myocardial injury in hypertensive patients with this disease. Methods All patients were selected prospectively from a multicenter registry of adults hospitalized with confirmed COVID-19. Cases had hypertension and myocardial injury, defined by troponin levels above the 99th percentile upper reference limit, and controls were hypertensive patients with no myocardial injury. Biomarkers and immune cell subsets were quantified and compared between the two groups. A multiple logistic regression model was used to analyze the associations of clinical and immune variables with myocardial injury. Results The sample comprised 193 patients divided into two groups: 47 cases and 146 controls. Relative to controls, cases had lower total lymphocyte count, percentage of T lymphocytes, CD8+CD38+ mean fluorescence intensity (MFI), and percentage of CD8+ human leukocyte antigen DR isotope (HLA-DR)+ CD38–cells and higher percentage of natural killer lymphocytes, natural killer group 2A (NKG2A)+ MFI, percentage of CD8+CD38+cells, CD8+HLA-DR+MFI, CD8+NKG2A+MFI, and percentage of CD8+HLA-DR–CD38+cells. On multivariate regression, the CD8+HLA-DR+MFI, CD8+CD38+MFI, and total lymphocyte count were associated significantly with myocardial injury. Conclusion Our findings suggest that lymphopenia, CD8+CD38+MFI, and CD8+HLA-DR+MFI are immune biomarkers of myocardial injury in hypertensive patients with COVID-19. The immune signature described here may aid in understanding the mechanisms underlying myocardial injury in these patients. The study data might open a new window for improvement in the treatment of hypertensive patients with COVID-19 and myocardial injury.

Prognostic models for predicting clinical disease progression, worsening and activity in people with multiple sclerosis.

Prognostic models for predicting clinical disease progression, worsening and activity in people with multiple sclerosis.

The impact of viraemia on inflammatory biomarkers and CD4+ cell subpopulations in HIV-infected children in sub-Saharan Africa.

To determine the impact of virological control on inflammation and cluster of differentiation 4 depletion among HIV-infected children initiating antiretroviral therapy (ART) in sub-Saharan Africa. Longitudinal cohort study. In a sub-study of the ARROW trial (ISRCTN24791884), we measured longitudinal HIV viral loads, inflammatory biomarkers (C-reactive protein, tumour necrosis factor alpha, interleukin 6 (IL-6), soluble CD14) and (Uganda only) whole blood immunophenotype by flow cytometry in 311 Zimbabwean and Ugandan children followed for median 3.5 years on first-line ART. We classified each viral load measurement as consistent suppression, blip/post-blip, persistent low-level viral load or rebound. We used multi-level models to estimate rates of increase or decrease in laboratory markers, and Poisson regression to estimate the incidence of clinical events. Overall, 42% children experienced viral blips, but these had no significant impact on immune reconstitution or inflammation. Persistent detectable viraemia occurred in one-third of children and prevented further immune reconstitution, but had little impact on inflammatory biomarkers. Virological rebound to ≥5000 copies/ml was associated with arrested immune reconstitution, rising IL-6 and increased risk of clinical disease progression. As viral load testing becomes more available in sub-Saharan Africa, repeat testing algorithms will be required to identify those with virological rebound, who need switching to prevent disease progression, whilst preventing unnecessary second-line regimen initiation in the majority of children with detectable viraemia who remain at low risk of disease progression.

Clinical outcomes following DAA therapy in patients with HCV-related cirrhosis depend on disease severity

HCV-infected patients with cirrhosis achieve high sustained virological response (SVR) rates with direct-acting antivirals (DAAs) even after hepatic decompensation. We aimed to assess the clinical outcome following DAAs among patients with compensated and decompensated cirrhosis in relation to SVR and changes in model for end-stage liver disease (MELD) score. Consecutive DAA-treated chronic HCV-infected patients with cirrhosis from 4 hepatology clinics were included. The primary endpoint in survival analyses was clinical disease progression, defined as liver failure, hepatocellular carcinoma, liver transplantation or death. In total, 868 patients were included with a median age of 59 (IQR 54-65) years; 719 (83%) with Child-Pugh A cirrhosis and 149 (17%) with Child-Pugh B/C cirrhosis. SVR was attained by 647 (90%) Child-Pugh A patients and 120 (81%) Child-Pugh B/C patients. During a median follow-up of 28 (IQR 20-36) months, 102 (14%) Child-Pugh A patients and 96 (64%) Child-Pugh B/C patients experienced clinical disease progression. SVR was independently associated with an improved event-free survival in patients with Child-Pugh A cirrhosis (adjusted hazard ratio [HR] 0.47; 95% CI 0.27-0.82, p= 0.007), but not in patients with Child-Pugh B/C cirrhosis (adjusted HR 1.23; 95% CI 0.67-2.26; p= 0.51). Twelve weeks post-DAAs, 28 (19%) patients with Child-Pugh B/C cirrhosis had ≥2-point MELD decline, but their 2-year event-free survival did not differ from those with a stable MELD (47.9%; 95% CI 28.7-67.1 vs. 48.9%; 95% CI 38.1-59.7, respectively, p= 0.99). Among patients with chronic HCV infection, DAA-induced SVR was associated with a reduced risk of clinical disease progression in patients with Child-Pugh A cirrhosis but not in patients with Child-Pugh B/C cirrhosis. In Child-Pugh B/C cirrhosis, a ≥2-point MELD decline did not translate into improved clinical outcome. Chronic HCV infection can be cured with antiviral therapy. In this study, we evaluated the long-term effects of antiviral therapy on liver-related complications in patients with cirrhosis. Our results suggest that patients with compensated cirrhosis who were cured of their HCV infection have a lower rate of complications. In contrast, the rate of complications was not related to virological cure among those with decompensated cirrhosis. While these patients seem to remain in need of liver transplantation, antiviral therapy may lower their priority on the liver transplantation waiting list.

Superior Memory Reduces 8-year Risk of Mild Cognitive Impairment and Dementia But Not Amyloid β-Associated Cognitive Decline in Older Adults.

To prospectively examine 8-year risk of clinical disease progression to mild cognitive impairment (MCI)/dementia in older adults ≥60 with superior episodic memory (SuperAgers) compared to those cognitively normal for their age (CNFA). Additionally, to determine the extent to which SuperAgers were resilient to the negative effects of elevated amyloid-beta (Aβ+) on cognition. Participants were classified as SuperAgers based on episodic memory performance consistent with younger adults aged 30-44 and no impairment on non-memory tests (n = 179), and were matched with CNFA on age, sex, education, and follow-up time (n = 179). Subdistribution hazard models examined risk of clinical progression to MCI/dementia. Linear mixed models assessed the effect of Aβ on cognition over time. Prevalence of Aβ+ and APOE ε4 was equivalent between SuperAgers and CNFA. SuperAgers had 69%-73% reduced risk of clinical progression to MCI/dementia compared to CNFA (HR: 0.27-0.31, 95% CI: 0.11-0.73, p < .001). Aβ+ was associated with cognitive decline in verbal memory and executive function, regardless of SuperAger/CNFA classification. In the absence of Aβ+, equivalent age-related changes in cognition were observed between SuperAgers and CNFA. SuperAgers displayed resilience against clinical progression to MCI/dementia compared to CNFA despite equivalent risk for Alzheimer's disease (AD); however, SuperAgers had no greater protection from Aβ+ than CNFA. The deleterious effects of Aβ on cognition persist regardless of baseline cognitive ability. Thus, superior cognitive performance does not reflect resistance against the neuropathological processes associated with AD, and the observed resilience for SuperAgers may instead reflect neuropsychological criteria for cognitive impairment.

Large disparities in HIV treatment cascades between eight European and high-income countries - analysis of break points.

IntroductionPatients on antiretroviral treatment with undetectable HIV RNA levels have a significantly lower risk of clinical disease progression and onward HIV transmission. This study aimed to estimate and compare the percentage of all HIV-positive people who are diagnosed, are linked to care, are taking antiretroviral treatment and have undetectable HIV RNA, in eight European and high-income countries: the United States, the United Kingdom, France, the Netherlands, Denmark, Australia, British Columbia (Canada) and Georgia.Materials and MethodsFor each country, the number of people in five key stages of the HIV treatment cascade was collected: 1. HIV infected, 2. Known to be HIV positive, 3. Linked to care, 4. Taking antiretroviral treatment, and 5. Having undetectable HIV RNA. Estimates were extracted from national reports [1–3], the UNAIDS database, conference proceedings [4] and peer-reviewed articles [5–7]. The quality of the estimates and reporting methods were assessed individually for each country, with selection criteria such as availability of nationwide database and routinely collected data. Treatment cascades were constructed using estimates from 2010 to 2012.ResultsAs shown in Table 1, the percentage of all infected people with undetectable HIV RNA ranged from 20% in Georgia to 59% in Denmark. Of the high-income countries, the United States has the lowest percentage of individuals with undetectable viral load (25% to median 52%), associated with the highest HIV incidence rate (15.30 per 100,000 to median 6.07 per 100,000). The pattern of the cascades differed between countries: in the United States, there is a fall from 66% to 33% (−33%) between linkage to care and start of antiretroviral treatment. However, in Georgia, the greatest loss in continuum was zat diagnosis, with 48% of undiagnosed HIV-positive individuals.ConclusionsThere are great disparities among European and high-income countries in the percentage of HIV-positive individual with undetectable HIV RNA. Furthermore, the treatment cascades show different key break points, underlying inequalities in HIV care between countries.

The Cost of Managing HIV Infection in Highly Treatment-Experienced, HIV-Infected Adults in France

Highly active antiretroviral therapy (HAART) has greatly enhanced HIV management, lowering the risk of clinical disease progression and death by substantially improving HIV-induced immune deficiency. Lower CD4 cell counts have consistently been associated with higher direct costs of HIV patient care. The aim of this study was to analyze HIV costs of care in France at different levels of HIV-induced immune deficiency (as measured by the CD4 cell count) using recent data from treatment-experienced patients. This analysis used data from the French Hospital Database in HIV, containing data on approximately 50% of the French HIV population. Patients were included in the analysis if they had visited a participating centre from 2003 to 2005, had CD4 cell counts determined at least twice during the study period, and had been prescribed at least two nucleoside reverse transcriptase inhibitors, one non-nucleoside reverse transcriptase inhibitor and two protease inhibitors since their first consultation. Resources consumed were counted and aggregated according to the CD4 cell count level. Standard costs were applied. Periods with the lowest CD4 cell counts were associated with increased prescription rates of antiviral agents (other than anti-HIV agents), antiparasitic drugs and antimycobacterial agents. Antiretroviral treatments accounted for 80% of all medications prescribed during the study period. Hospitalization rates decreased with increasing CD4 cell counts, with 0.72 hospitalizations per patient-year for those with CD4 cell counts of 50 cells/mm³ or less compared with 0.05 per patient-year for patients with CD4 cell counts greater than 500 cells/mm³. There was a clear trend towards lower mean healthcare costs per patient-year with decreasing immune deficiency; from €34,286 to €12,361. Our study showed an association between the degree of HIV-induced immune deficiency (measured by CD4 cell count) and the costs of managing HIV infection among highly pre-treated, HIV-infected individuals in France in the HAART era.

Interruption of combination antiretroviral therapy and risk of clinical disease progression to AIDS or death

The aim of the study was to compare incidence rates (IRs) of AIDS/death in patients with and without treatment interruption (TI) of combination antiretroviral therapy (cART) for periods of 3 months or more for different categories of CD4 cell count and viral load, and to determine risk factors for clinical progression to AIDS/death. Patients starting cART with a CD4 cell count and a viral load available within 6 months of starting cART were included in the study. The IR and risk factors of TI were determined. We assessed the incidence rate ratios (IRRs) for TI and AIDS/death events using Poisson regression models. Of 3811 patients included in the study, 26% were ART-naïve prior to cART. The median date of starting cART was July 1997, the median CD4 cell count was 226 cells/microL and the median viral load was 4.36 log(10) HIV-1 RNA copies/mL. We observed 1243 interruptions and 403 AIDS-events/deaths. The IR of AIDS/death was higher in patients with lower CD4 cell counts or higher viral loads, regardless of TI. After adjusting for baseline factors, the IR of AIDS/death was significantly higher in the TI group than in the non-TI group [IRR 2.63; 95% confidence interval (CI) 2.01-3.44; P<0.0001]; this could be explained by current CD4 cell counts and viral loads, as the CD4 cell count- and viral load-adjusted IRR was 1.14 (95% CI 0.86-1.51; P=0.37). Within the TI group, patients with a current CD4 cell count of <200 cells/microL had a 3-fold higher risk of AIDS/death than those with a CD4 cell count of 200-350 cells/microL, whereas patients with a current CD4 cell count of >350 cells/microL had a 4-fold lower risk of disease progression. TI is common in clinical practice. The risk of AIDS/death increased more than 2-fold for patients stopping all cART regimen drugs for 3 months or more. Among patients experiencing a TI, those with low CD4 cell counts, high viral loads or prior AIDS had an increased risk of AIDS/death. Hence, TI should be discouraged and closely monitored if it occurs.

Treatment interruption in advanced failing patients

To discuss the rationale and results of clinical trials examining treatment interruption in HIV-positive patients with advanced disease who are experiencing therapy failure. In the past it was thought that treatment interruptions in patients experiencing therapy failure might bring about an improved virologic response to treatment via drug re-sensitization. All of the major international clinical trials, with the exception of the Giga-HAART trial, however, have found no benefit of treatment interruption in this group of patients. Moreover, most of the trials have shown an increased risk for disease progression or death. It has also been shown that even patients with no or few treatment options, staying on a failing regimen may have some clinical benefit relative to treatment interruption. Treatment interruption in advanced failing patients may be a dangerous course of action due to the increased risk of clinical disease progression and decline in CD4 cell count. Staying on therapy, even a failing therapy, may have some benefit, at least until new drugs become available.

Structured treatment interruptions (STI) in chronic unsuppressed HIV infection in adults

Structured treatment interruptions (STI) in chronic unsuppressed HIV infection in adults

Serum Neopterin, an Immune Activation Marker, Independently Predicts Disease Progression in Advanced HIV-1 Infection

CD4+ T lymphocyte (CD4) counts and plasma human immunodeficiency virus (HIV) type 1 RNA concentrations predict clinical outcome in HIV-1 infection. Our objective was to assess the independent prognostic value for disease progression of soluble markers of immune system activation. This retrospective marker-validation study utilized previously obtained clinical and laboratory data, including CD4+ cell counts, and made use of stored frozen serum samples to assay for levels of beta2-microglobulin, neopterin, endogenous interferon, triglycerides, interleukin-6, soluble tumor necrosis factor- alpha receptor II, and HIV-1 RNA, and to determine HIV genotypic reverse-transcriptase inhibitor resistance. The 152 patients who participated in this study represented a subsample of participants in AIDS Clinical Trials Group (ACTG) 116B/117, a randomized trial that demonstrated the clinical benefit of didanosine over zidovudine monotherapy in persons with advanced HIV-1 infection. Marker data were analyzed in relation to protocol-defined clinical disease progression, using Cox proportional hazards models. The median duration of follow-up was 344 days. Elevated baseline values for neopterin (P=.0009), endogenous interferon (P=.00039) and interleukin-6 (P=.0007) were each associated with greater subsequent risk of clinical disease progression. In a head-to-head comparison that was adjusted for CD4+ cell count (P=.0165) and HIV-1 RNA level (P=.1220), we found that elevated values for neopterin (P=.0002) and, to a lesser extent, endogenous interferon (P=.0053) were the strongest predictors of increased risk of clinical disease progression 6 months later. Soluble markers of immune activation add prognostic information to CD4 counts and viral load for risk of disease progression in advanced HIV-1 infection. The robust performance of neopterin, an inexpensive and reliably measured serum marker, supports its potential suitability for patient monitoring, particularly in resource-limited settings.

Starting highly active antiretroviral therapy: why, when and response to HAART.

Highly active antiretroviral therapy (HAART) has dramatically improved the prognosis of patients with HIV, although it remains unclear as to the best time to start treatment to reduce the risk of clinical progression. The initial virological response to HAART, by reducing viral load to below the limit of detection, is essential for reducing the risk of drug resistance, which in the longer term may lead to a deterioration in immune function and an increased risk of clinical disease progression. There has been a switch to more conservative therapy recently, given concerns about toxicities and the difficulties of adhering to a complicated regimen long term.

Uniform risk of clinical progression despite differences in utilization of highly active antiretroviral therapy: Swiss HIV Cohort Study.

To compare the initiation of highly active antiretroviral therapy (HAART) in HIV-infected patients according to sex, route of HIV acquisition and education, and to assess the impact of differences in utilization on the probability of progression to AIDS. Swiss HIV Cohort Study, a national prospective multi-centre study. A total of 3342 patients, including 1007 (30%) women. HIV was acquired through injection drug use in 1155 (35%) cases and through sex between men in 1172 (35%). Twenty-eight per cent (957) of participants had attained only the minimum level of schooling. At baseline, the median CD4 cell count was 269x10(6)/l cells, median HIV-1 RNA was 4.3 log10 copies/ml and 2917 (87%) were free of AIDS. Kaplan-Meier life tables and Cox proportional hazards regression. During 7007 person-years of follow-up 2285 (69%) patients started HAART and 318 (10%) developed a new AIDS event. In multivariable analysis controlling for CD4 cell count, viral load and disease stage at baseline, the probability of starting HAART was lower in injection drug users compared with men who have sex with men, hazard ratio 0.63 (95% confidence intervals 0.56-0.70) and in patients with minimum schooling compared with those with vocational training, hazard ratio 0.82 (0.75-0.91). The risk of progression to AIDS was similar among men and women, patients with a history of injecting drug use, and patients with lower educational attainment in both univariable and multivariable analysis. HIV-infected injecting drug users and those with lower levels of educational attainment start HAART later than other patient groups. The deferred initiation of therapy in these patients does not, however, appear to translate into an increased risk of clinical disease progression. This observation has important implications for treatment policy and the design of future clinical trials.