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Background: In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]).We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.Methods and Findings: Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case-control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0-4.1; p = 0.05), 8.3 (95% CI, 3.3-20.8; p < 0.0001), and 12.4 (95% CI, 4.2-37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case-control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1-3.1; p = 0.02) to 1.5 (95% CI, 0.8-2.8) and 1.4 (95% CI, 0.8-2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively.Conclusions: IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation. [ABSTRACT FROM AUTHOR]

Background: Detailed longitudinal studies of HIV-positive individuals in West Africa are lacking. Here the HIV prevalence, incidence, all-cause mortality, and the proportion of individuals receiving treatment with cART in two cohorts of participants in Ebola-related studies are described., Setting: Individuals of all ages were enrolled and followed at four sites in the area of Monrovia, Liberia., Methods: Two cohorts identified in response to the Ebola epidemic are described to provide insights into the current state of the HIV epidemic. HIV testing was performed at baseline for participants in both cohorts and during follow-up in one cohort., Results: Prevalence and incidence of HIV (prevalence of 3.1% for women and 1.4% for men and incidence of 3.3 per 1,000) were higher in these cohorts compared to 2018 national estimates (prevalence of 1.3% and incidence of 0.39 per 1,000). Most participants testing positive did not know their status prior to testing. Of those who knew they were HIV positive, 7.9% reported being on antiretroviral treatment. The death rate among those with HIV was 12.3% compared to 1.9% in HIV-negative individuals (adjusted odds ratio of 6.87). While higher levels of d-dimer were associated with increased mortality, this was not specific to those with HIV, however lower hemoglobin levels were associated with increased mortality among those with HIV., Conclusion: These findings point to a need to perform further research studies aimed at fulfilling these knowledge gaps and address current shortcomings in the provision of care for those living with HIV in Liberia., Competing Interests: The authors have declared that no competing interests exist.

Background: The epidemiology of acute febrile illness, a common cause of hospitalization in Indonesia, has not been systematically studied., Methodology/principal Findings: This prospective observational study enrolled febrile patients (temperature ≥38°C) aged ≥1 year from July 2013 until June 2016 at eight government referral teaching hospitals in seven provincial capitals in Indonesia. Patients were managed according to the hospital standard-of-care (SOC), and blood samples were drawn for molecular and serological assays. Clinical data, laboratory results, and specimens for additional tests were collected at enrollment, days 14-28, and at three months. Regular follow-up visits were then scheduled for every three months either until symptoms resolved or until one year. In total, this study included 1,486 adult and pediatric patients presenting with multi-organ (768, 51.7%), gastrointestinal (497, 33.0%), respiratory (114, 7.7%), constitutional (62, 4.2%), skin and soft-tissue (24, 1.6%), central nervous system (17, 1.1%), or genitourinary (4, 0.3%) manifestations. Microbiological diagnoses were found in 1,003/1,486 (67.5%) participants, of which 351/1,003 (35.0%) were not diagnosed during hospitalization using SOC diagnostic tests. Missed diagnoses included all cases caused by Rickettsia spp., chikungunya, influenza, and Seoul virus. The most common etiologic agents identified were dengue virus (467, 46.6%), Salmonella spp. (103, 10.3%), and Rickettsia spp. (103, 10.3%). The overall mortality was 89 (5.9%)., Conclusions/significance: Febrile illness in Indonesia has various microbiologic etiologies and substantial overall mortality. Diagnostic limitations and lack of epidemiologic data resulted in potentially treatable, and at times fatal, diseases being missed., Competing Interests: The authors have declared that no competing interests exist.

Rapidly increasing number of therapeutic antibodies are being repurposed to imaging probes for noninvasive diagnosis, as well as monitoring during treatment or disease recurrence. Though antibody-based imaging involves tracer doses (~3 log lower than therapeutic doses), and immune responses are severely reduced in patients with impaired immunity, formation of anti-tracer antibodies (ATA) has been observed hampering further diagnostic monitoring. Here, we explored the potential to develop humoral responses to intravenously administered tracer dose of a monoclonal antibody F(ab΄)2 fragment, and associated with host related immune measures in 49 rhesus macaques categorized into healthy (uninfected controls), SIV-progressors, SIV non-progressors, or total body irradiated (TBI). Antibody fragment administered in tracer amount (~100μg) induced immune responses with significantly lower odds in SIV-progressors or TBI macaques (P<0.005) as compared to healthy animals. Peripheral blood (PB) CD4+ cell counts, but not CD20+ cell levels, were associated with significantly higher risk of developing a humoral response (P<0.001). Doubling the PB CD4+ counts is associated with an odds ratio of developing an immune response of 1.73. Among SIV-infected animals, CD4+ cell count was a stronger predictor of immune response than plasma SIV-RNA levels. Both SIV-progressors and TBI macaques showed higher odds of responses with increasing CD4+ counts, however when compared to healthy or SIV non-progressors with similar CD4+ count, they were still functionally incompetent in generating a response (P<0.01). Moreover, presence of ATA in systemic circulation altered the in vivo biodistribution by increasing hepatic uptake and decreasing plasma radiotracer clearance, with minimal to no binding detected in targeted tissues.

Objective: IL-15 has been postulated to play an important role in HIV-1 infection, yet there are conflicting reports regarding its expression levels in these patients. We sought to measure the level of IL-15 in a large, well characterised cohort of HIV-1 infected patients and correlate this with well known markers of inflammation, including CRP, D-dimer, sCD163 and sCD14., Design and Methods: IL-15 levels were measured in 501 people (460 patients with HIV-1 infection and 41 uninfected controls). The HIV-1 infected patients were divided into 4 groups based on viral load: <50 copies/ml, 51-10,000 copies/ml, 10,001-100,000 copies/ml and >100,000 copies/ml. The Mann Whitney test (non-parametric) was used to identify significant relationships between different patient groups., Results: IL-15 levels were significantly higher in patients with viral loads >100,000 copies/ml (3.02 ± 1.53 pg/ml) compared to both uninfected controls (1.69 ± 0.37 pg/ml, p<0.001) or patients with a viral load <50 copies/ml (1.59 ± 0.40 pg/ml (p<0.001). There was a significant correlation between HIV-1 viremia and IL-15 levels (Spearman r = 0.54, p<0.001) and between CD4+ T cell counts and IL-15 levels (Spearman r = -0.56, p<0.001)., Conclusions: IL-15 levels are significantly elevated in HIV-1 infected patients with viral loads >100,000 copies/ml compared to uninfected controls, with a significant direct correlation noted between IL-15 and HIV-1 viremia and an inverse correlation between IL-15 levels and CD4+ T cell counts. These data support a potential role for IL-15 in the pathogenesis of HIV-associated immune activation., Competing Interests: The authors have declared that no competing interests exist.

Background: Data from prospectively planned cohort studies on risk of major clinical outcomes and prognostic factors for patients with influenza A(H1N1)pdm09 virus are limited. In 2009, in order to assess outcomes and evaluate risk factors for progression of illness, two cohort studies were initiated: FLU 002 in outpatients and FLU 003 in hospitalized patients., Methods and Findings: Between October 2009 and December 2012, adults with influenza-like illness (ILI) were enrolled; outpatients were followed for 14 days and inpatients for 60 days. Disease progression was defined as hospitalization and/or death for outpatients, and hospitalization for >28 days, transfer to intensive care unit (ICU) if enrolled from general ward, and/or death for inpatients. Infection was confirmed by RT-PCR. 590 FLU 002 and 392 FLU 003 patients with influenza A (H1N1)pdm09 were enrolled from 81 sites in 17 countries at 2 days (IQR 1-3) and 6 days (IQR 4-10) following ILI onset, respectively. Disease progression was experienced by 29 (1 death) outpatients (5.1%; 95% CI: 3.4-7.2%) and 80 inpatients [death (32), hospitalization >28 days (43) or ICU transfer (20)] (21.6%; 95% CI: 17.5-26.2%). Disease progression (death) for hospitalized patients was 53.1% (26.6%) and 12.8% (3.8%), respectively, for those enrolled in the ICU and general ward. In pooled analyses for both studies, predictors of disease progression were age, longer duration of symptoms at enrollment and immunosuppression. Patients hospitalized during the pandemic period had a poorer prognosis than in subsequent seasons., Conclusions: Patients with influenza A(H1N1)pdm09, particularly when requiring hospital admission, are at high risk for disease progression, especially if they are older, immunodeficient, or admitted late in infection. These data reinforce the need for international trials of novel treatment strategies for influenza infection and serve as a reminder of the need to monitor the severity of seasonal and pandemic influenza epidemics globally., Trial Registration: ClinicalTrials.gov Identifiers: FLU 002--NCT01056354, FLU 003--NCT01056185.

Objective: IL-27 is an immunomodulatory cytokine with potent anti-HIV properties in PBMCs, CD4+ T cells, macrophages and immature dendritic cells. Previous smaller studies have suggested that HIV-1 infection may alter IL-27 and influence HIV-1 pathogenesis. The aim of this study was to examine the relationship between plasma IL-27 levels in a well-characterised cohort of HIV-1 infected patients., Methods: Patients were stratified into four groups based on HIV-1 viral load and matched according to age, gender and those receiving antiretroviral treatment. IL-27 levels and C-reactive protein (CRP) were measured using electrochemiluminescence assays. D-dimer and CD4+ T cell counts were measured using an Enzyme Linked Fluorescence Assay and FACS, respectively. sCD14 and sCD163 were measured using ELISA. HIV-1 viral load was measured by bDNA or qRT-PCR assays., Results: Plasma IL-27 levels were measured in 505 patients (462 HIV+, 43 controls). The mean level (±SEM) of IL-27 in controls was 2990.7±682.1 pg/ml, in the <50 copies/ml group it was 2008.0±274.8 pg/ml, in the 51-10,000 copies group it was 1468.7±172.3 pg/ml, in the 10,001-100,000 copies/ml group it was 1237.9±127.3 pg/ml and in the >100,000 copies/ml group it was 1590.1±223.7 pg/ml. No statistically significant difference in IL-27 levels between groups were seen. There were no correlations noted between IL-27 and HIV-1 viral load or CD4+ T cell counts. There was a small correlation noted between D-dimer and IL-27 (Spearman r = 0.09, p = 0.03) and sCD163 and IL-27 (Spearman r = 0.12, p = 0.005). No correlation was observed between IL-27 and CRP or sCD14 levels., Conclusions: This is the largest study examining the levels of plasma IL-27 in HIV-1 infection. While IL-27 levels are not significantly altered in HIV-1 infection compared to uninfected controls there may be a small association between IL-27 and D-dimer levels and IL-27 and sCD163 levels.

HIV infection and the associated chronic immune activation alter T cell homeostasis leading to CD4 T cell depletion and CD8 T cell expansion. The mechanisms behind these outcomes are not totally defined and only partially explained by the direct cytopathic effect of the virus. In this manuscript, we addressed the impact of lymphopenia and chronic exposure to IFN-α on T cell homeostasis. In a lymphopenic murine model, this interaction led to decreased CD4 counts and CD8 T cell expansion in association with an increase in the Signal Transducer and Activator of Transcription 1 (STAT1) levels resulting in enhanced CD4 T cell responsiveness to IFN-α. Thus, in the setting of HIV infection, chronic stimulation of this pathway could be detrimental for CD4 T cell homeostasis.

Background: Prospective studies establishing the temporal relationship between the degree of inflammation and human influenza disease progression are scarce. To assess predictors of disease progression among patients with influenza A(H1N1)pdm09 infection, 25 inflammatory biomarkers measured at enrollment were analyzed in two international observational cohort studies., Methods: Among patients with RT-PCR-confirmed influenza A(H1N1)pdm09 virus infection, odds ratios (ORs) estimated by logistic regression were used to summarize the associations of biomarkers measured at enrollment with worsened disease outcome or death after 14 days of follow-up for those seeking outpatient care (FLU 002) or after 60 days for those hospitalized with influenza complications (FLU 003). Biomarkers that were significantly associated with progression in both studies (p<0.05) or only in one (p<0.002 after Bonferroni correction) were identified., Results: In FLU 002 28/528 (5.3%) outpatients had influenza A(H1N1)pdm09 virus infection that progressed to a study endpoint of complications, hospitalization or death, whereas in FLU 003 28/170 (16.5%) inpatients enrolled from the general ward and 21/39 (53.8%) inpatients enrolled directly from the ICU experienced disease progression. Higher levels of 12 of the 25 markers were significantly associated with subsequent disease progression. Of these, 7 markers (IL-6, CD163, IL-10, LBP, IL-2, MCP-1, and IP-10), all with ORs for the 3(rd) versus 1(st) tertile of 2.5 or greater, were significant (p<0.05) in both outpatients and inpatients. In contrast, five markers (sICAM-1, IL-8, TNF-α, D-dimer, and sVCAM-1), all with ORs for the 3(rd) versus 1(st) tertile greater than 3.2, were significantly (p≤.002) associated with disease progression among hospitalized patients only., Conclusions: In patients presenting with varying severities of influenza A(H1N1)pdm09 virus infection, a baseline elevation in several biomarkers associated with inflammation, coagulation, or immune function strongly predicted a higher risk of disease progression. It is conceivable that interventions designed to abrogate these baseline elevations might affect disease outcome.

Background: The SMART study was a trial of intermittent use of antiretroviral therapy (ART) (drug conservation [DC]) versus continuous use of ART (viral suppression [VS]) as a strategy to reduce toxicities, including cardiovascular disease (CVD) risk. We studied the predictive value of high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and D-dimer with CVD morbidity and mortality in HIV-infected patients who were enrolled in SMART beyond other measured CVD risk factors., Methods: A blood sample was available in 5098 participants who were enrolled in the SMART study for the measurement of IL-6, hsCRP and D-dimer. Hazard ratios (HR) with 95% CI for CVD events were estimated for each quartile (Q) for each biomarker vs the 1(st) quartile and for 1 SD higher levels. For both treatment groups combined, unadjusted and adjusted HRs were determined using Cox regression models., Results: There were 252 participants who had a CVD event over a median follow-up of 29 months. Adjusted HRs (95% CI) for CVD for Q4 vs Q1 were 4.65 (2.61, 8.29), 2.10 (1.40, 3.16), and 2.14 (1.38, 3.33) for IL-6, hsCRP and D-dimer, respectively. Associations were similar for the DC and VS treatment groups (interaction p-values were >0.30). The addition of the three biomarkers to a model that included baseline covariates significantly improved model fit (p<0.001). Area under the curve (AUC) estimates improved with inclusion of the three biomarkers in a model that included baseline covariates corresponding to other CVD risk factors and HIV factors (0.741 to 0.771; p<0.001 for difference)., Conclusions: In HIV-infected individuals, IL-6, hsCRP and D-dimer are associated with an increased risk of CVD independent of other CVD risk factors. Further research is needed to determine whether these biomarkers can be used to improve CVD risk prediction among HIV positive individuals.

Background: Levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer predict mortality in HIV patients on antiretroviral therapy (ART) with relatively preserved CD4+ T cell counts. We hypothesized that elevated pre-ART levels of these markers among patients with advanced HIV would be associated with an increased risk of death following the initiation of ART., Methods: Pre-ART plasma from patients with advanced HIV in South Africa was used to measure hsCRP, IL-6 and D-dimer. Using a nested case-control study design, the biomarkers were measured for 187 deaths and two controls matched on age, sex, clinical site, follow-up time and CD4+ cell counts. Odds ratios were estimated using conditional logistic regression. In addition, for a random sample of 100 patients, biomarkers were measured at baseline and 6 months following randomization to determine whether ART altered their levels., Results: Median baseline biomarkers levels for cases and controls, respectively, were 11.25 vs. 3.6 mg/L for hsCRP, 1.41 vs. 0.98 mg/L for D-dimer, and 9.02 vs. 4.20 pg/mL for IL-6 (all p<0.0001). Adjusted odds ratios for the highest versus lowest quartile of baseline biomarker levels were 3.5 (95% CI: 1.9-6.7) for hsCRP, 2.6 (95%CI 1.4-4.9) for D-dimer, and 3.8 (95% CI: 1.8-7.8) for IL-6. These associations were stronger for deaths that occurred more proximal to the biomarker measurements. Levels of D-dimer and IL-6, but not hsCRP, were significantly lower at month 6 after commencing ART compared to baseline (p<0.0001)., Conclusions: Among patients with advanced HIV disease, elevated pre-ART levels of hsCRP, IL-6 and D-dimer are strongly associated with early mortality after commencing ART. Elevated levels of inflammatory and coagulation biomarkers may identify patients who may benefit from aggressive clinical monitoring after commencing ART. Further investigation of strategies to reduce biomarkers of inflammation and coagulation in patients with advanced HIV disease is warranted., Trial Registration: Parent study: ClinicalTrials.gov NCT00342355.

Objective: The objective of the trial was to evaluate in a pilot setting the safety and efficacy of interleukin-2 (IL-2) therapy when used without concomitant antiretroviral therapy as a treatment for HIV infection., Design and Setting: This was a multicentre randomised three-arm trial conducted between September 1998 and March 2001 at three clinical centres in the United Kingdom., Participants: Participants were 36 antiretroviral treatment naïve HIV-1-infected patients with baseline CD4 T lymphocyte counts of at least 350 cells/mm(3)., Interventions: Participants were randomly assigned to receive IL-2 at 15 million international units (MIU) per day (12 participants) or 9 MIU/day (12 participants) or no treatment (12 participants). IL-2 was administered by twice-daily subcutaneous injections for five consecutive days every 8 wk., Outcome Measures: Primary outcome was the change from baseline CD4 T lymphocyte count at 24 wk. Safety and plasma HIV RNA levels were also monitored every 4 wk through 24 wk. The two IL-2 dose groups were combined for the primary analysis., Results: Area under curve (AUC) for change in the mean CD4 T lymphocyte count through 24 wk was 129 cells/mm(3) for those assigned IL-2 (both dose groups combined) and 13 cells/mm(3) for control participants (95% CI for difference, 51.3-181.2 cells/mm(3); p = 0.0009). Compared to the control group, significant increases in CD4 cell count were observed for both IL-2 dose groups: 104.2/mm(3) (p = 0.008) and 128.4 cells/mm(3) (p = 0.002) for the 4.5 and 7.5 MIU dose groups, respectively. There were no significant differences between the IL-2 (0.13 log(10) copies/ml) and control (0.09 log(10) copies/ml) groups for AUC of change in plasma HIV RNA over the 24-wk period of follow-up (95% CI for difference, -0.17 to 0.26; p = 0.70). Grade 4 and dose-limiting side effects were in keeping with those previously reported for IL-2 therapy., Conclusions: In participants with HIV infection and baseline CD4 T lymphocyte counts of at least 350 cells/mm(3), intermittent subcutaneous IL-2 without concomitant antiretroviral therapy was well tolerated and produced significant increases in CD4 T lymphocyte counts and did not adversely affect plasma HIV RNA levels.