Inflammation and Immune Activation in HIV infection

Although widespread availability of antiretroviral therapy (ART) has markedly enhanced survival in HIV-1 infected individuals, its long-term use and cessation has been linked to an increase in non-AIDS morbidity and mortality. The pathogenesis of these complications is thought to reflect excessive immune activation and inflammation. The SMART trial showed that in chronic HIV-1 infection, inflammatory and coagulation biomarkers were predictive of all cause mortality, and that stopping ART lead to a rise in these biomarkers. The impact of interrupting ART started in primary HIV-1 infection (PHI) on these biomarkers is unknown. This thesis examines the effect of different stages of HIV-1 infection on markers of inflammation, coagulation and immune activation, and focuses on the effects of short-course ART in participants enrolled in the SPARTAC trial; a blinded RCT investigating the role of short-course ART versus no therapy in PHI. Baseline parameters associated with biomarkers of inflammation, coagulation, immune activation, endothelial activation and microbial translocation, and the effect of starting and stopping ART on IL-6 and D-dimer levels, were examined in SPARTAC participants. Viral dynamics on treatment discontinuation were compared in PHI (SPARTAC) to chronic infection (SMART). The majority of biomarkers were raised in HIV-1 infected individuals compared to healthy controls and highly correlated with HIV RNA levels. Viral and host factors, including age, HLA type and viral tropism, determined levels of T-cell activation. IL-6 and D-dimer fell significantly on commencing ART but rebounded to baseline levels within 4 weeks of stopping. Viral rebound after stopping ART initiated in PHI was lower than that observed in chronic infection. This work highlights factors associated with immune activation and inflammation in PHI, which could potentially be used to identify individuals at high risk of disease progression. Immune activation and inflammation are influenced by direct effects of the virus, ART and other variables. The clinical impact of these findings warrants further investigation

Measuring and modelling the crustal response to the 2011 eruption of Nabro volcano, Eritrea

Nabro volcano, situated to the east of the Afar Rift Zone, erupted on 12 June 2011. Eruptions at such off-rift volcanoes are infrequent, and consequently the plumbing systems are poorly understood. In this thesis I present post-eruption InSAR and seismic data to delineate the plumbing system of Nabro. I also investigate the temporal evolution of the system. I discuss my findings in reference to the tectonics of the Afar Rift Zone, off-rift volcanism and compare the findings to volcanoes world wide. I present 6 weeks of continuous seismic activity from an array of 7 seismic stations deployed following the eruption. For the analysis I locate and relocate hypocentres, determine focal mechanisms, calculate b-values and cross-correlate waveforms. I have relocated the hypocentres of 456 earthquakes and used the spatial pattern to interpret the local and regional crustal response to the eruption. The shallow earthquakes beneath Nabro's caldera delineate a NE-SW thrust fault which dips 45 degrees to the SE and extends across the caldera floor. This accommodates the stress change following the eruption, rather than movement on ring faults. The NE-SW fault plane is not associated with measurable surface deformation, indicating that it does not contribute much to the caldera deformation. A 10 km deep cluster highlights potential magma migration pathways directly beneath Nabro. On the flanks of the volcano, a linear pattern of earthquakes illuminate possible minor faults. There is also a cluster of earthquakes beneath Mallahle caldera at a depth of 6 km; the b-value for this cluster is 0.97 and is lower than that for clusters under Nabro (b=1.3). This implies that the earthquakes generated at Mallahle are not dominated by magmatic processes and occur in rock with a stronger rheology. Therefore, the seismicity I observed is likely due to changes in the stress field resulting from the subsidence at Nabro, and not caused by magma movement beneath Mallahle. TerraSAR-X and COSMO-SkyMed were both tasked to prioritise the acquisition of SAR data over the volcanic centre. During the following 15 months, Nabro was imaged 129 times by these satellites, with an acquisition every 5 days on average. I processed the 25 images acquired by TerraSAR-X between 1 July 2011 and 5 October 2012 on descending orbit 046, to create 34 interferograms. I complemented these with 19 images from ascending orbit 130 spanning 6 July 2011 to 10 October 2012 from ascending orbit 130, which I used to create 21 interferograms. I produced velocity ratemaps and time series using pi-RATE, showing subsidence of 25 cm/yr offset by 2 km to the SW of Nabro's caldera. COSMO-SkyMed satellite also imaged the volcano on a descending track between 26 June 2011 and 18 July 2012 within the Italian Space Agency project SAR4Volcanoes: a total of 64 images were acquired and used to produce 171 interferograms. I combined the InSAR data sets using a modelling approach to produce a detailed time series of the deflation of a Mogi source at 6.4 km depth. The time series shows that the volcano continued to subside for the entire period of observation, with the most rapid subsidence in the first 12 weeks, followed by subsidence at a slowly declining rate. I assessed the impact of atmosphere delays, using the outputs from ERA-Interim (ERA-I), a global atmospheric model computed by the European Centre for Medium-range Weather Forecasting (ECMWF), to correct each SAR acquisition. The atmospheric correction noticeably reduced the scatter in the time series, and removed the two atmospheric artefacts apparent in the COSMO-SkyMed time series. This result highlighted the importance of applying atmospheric corrections using independent sources of information. This contrasts with a standard approach of filtering in space and time which did not completely remove these atmospheric errors. Without the ERA-I correction the time series appeared to show pulses of recharge; with the correction continued subsidence is observed. I explore mechanisms that might explain the long-lived subsidence at Nabro volcano. In particular, I tested models of thermal contraction, degassing, fluid migration and viscoelasticity. Degassing is the most likely cause of deformation, although contraction due to cooling may also contribute. The long term post-eruption subsidence is unusual in comparison to other active volcanoes. I suggest that the low magma supply rate, combined with the high rate of passive degassing, induces an overall subsidence of the ground surface above Nabro

Soluble toll-like receptor 2 is a biomarker for sepsis in critically ill patients with multi-organ failure within 12 h of ICU admission

Soluble TLR2 levels are elevated in infective and inflammatory conditions, but its diagnostic value with sepsis-induced multi-organ failure has not been evaluated. 37 patients with a diagnosis of severe sepsis/septic shock (sepsis) and 27 patients with organ failure without infection (SIRS) were studied. Median (IQR) plasma sTLR2 levels were 2.7 ng/ml (1.4–6.1) in sepsis and 0.6 ng/ml (0.4–0.9) in SIRS p < 0.001. sTLR2 showed good diagnostic value for sepsis at cut-off of 1.0 ng/ml, AUC:0.959. We report the ability of sTLR2 levels to discriminate between sepsis and SIRS within 12 h of ICU admission in patients with multi-organ failure

Health-related quality of life in people living with HIV with cognitive symptoms: assessing relevant domains and associations

This study aimed to validate and assess a comprehensive set of illness-specific health-related quality of life (HRQL) domains in people living with HIV (PLWH) with cognitive symptoms. One hundred and three HIV patients with cognitive symptoms (n = 93 male, 90.3%) were identified from two UK HIV clinics and complete a series of validated scales measuring seven HRQL domains identified as important to HRQL by PLWH with cognitive impairment. These included: physical functioning, cognition, social connectedness, self-concept, HIV stigma, acceptance of and perceived control over cognitive health, and physical and mental health and wellbeing. Exploratory factor analysis confirmed that domain total scores loaded onto one main factor, representing HRQL. Scale cut-off scores revealed a significant proportion of patients scored outside the normal range on single domains (between 26.2% and 79.6%), and many patients on multiple domains (40.8% on 4 or more domains). We found evidence of poor HRQL across domains in the majority of PLWH with cognitive symptoms and identified domains driving these experiences. This provides targets for intervention development and clinical action to maintain or improve HRQL in PLWH with cognitive symptoms or impairment

“A fog that impacts everything”: a qualitative study of health-related quality of life in people living with HIV who have cognitive impairment

Background Cognitive impairment (CI) in people living with HIV (PLWH) is an important health concern in the context of an ageing HIV population. Impacting 14–28% of PLWH, CI is associated with lower health-related quality of life (HRQoL), however, evaluation of the illness-specific factors comprising HRQoL in PLWH with CI have not been assessed. Objective We sought to contribute evidence toward an understanding of HRQoL and identify domains of HRQoL in PLWH with CI. Methods Qualitative interviews with 25 PLWH with objective CI related to HIV disease were conducted with participants attending HIV clinics in the UK. Clinically significant CI was defined based on The European AIDS Clinical Society guidelines, requiring: (i) subjective reporting of cognitive symptoms; (ii) symptoms to be related to HIV (e.g. potentially confounding non-HIV related conditions have been excluded or are being optimally managed) and; (iii) formal neuropsychological assessment confirming CI. Median age was 56 years (range 35–80); 18 participants were men (72%); 11 (44%) were white British and 8 (32%) were Black African; 14 (56%) were men that have sex with men and 10 (40%) were heterosexual; median number of years living with HIV was 17 (range 1–34); and all participants were on combination antiretroviral therapy. Analyses employed techniques from grounded theory, underpinned by an inductive, collaborative team-based approach. Results Findings revealed seven interrelated domains comprising HRQoL experiences were identified: Physical function, Cognition, Social connectedness, Physical and mental health, Stigma, Self-concept, and Control and acceptance, and each was defined by specific descriptive components. Conclusion This study provides valuable insights on the factors that drive HRQoL in PLWH with CI and contribute to a body of evidence which provides targets for the development of targeted interventions to maintain or improve quality of life

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570