Accuracy and Efficiency of Machine Learning-Assisted Risk-of-Bias Assessments in "Real-World" Systematic Reviews : A Noninferiority Randomized Controlled Trial.

BACKGROUND: Automation is a proposed solution for the increasing difficulty of maintaining up-to-date, high-quality health evidence. Evidence assessing the effectiveness of semiautomated data synthesis, such as risk-of-bias (RoB) assessments, is lacking. OBJECTIVE: To determine whether RobotReviewer-assisted RoB assessments are noninferior in accuracy and efficiency to assessments conducted with human effort only. DESIGN: Two-group, parallel, noninferiority, randomized trial. (Monash Research Office Project 11256). SETTING: Health-focused systematic reviews using Covidence. PARTICIPANTS: Systematic reviewers, who had not previously used RobotReviewer, completing Cochrane RoB assessments between February 2018 and May 2020. INTERVENTION: In the intervention group, reviewers received an RoB form prepopulated by RobotReviewer; in the comparison group, reviewers received a blank form. Studies were assigned in a 1:1 ratio via simple randomization to receive RobotReviewer assistance for either Reviewer 1 or Reviewer 2. Participants were blinded to study allocation before starting work on each RoB form. MEASUREMENTS: Co-primary outcomes were the accuracy of individual reviewer RoB assessments and the person-time required to complete individual assessments. Domain-level RoB accuracy was a secondary outcome. RESULTS: Of the 15 recruited review teams, 7 completed the trial (145 included studies). Integration of RobotReviewer resulted in noninferior overall RoB assessment accuracy (risk difference, -0.014 [95% CI, -0.093 to 0.065]; intervention group: 88.8% accurate assessments; control group: 90.2% accurate assessments). Data were inconclusive for the person-time outcome (RobotReviewer saved 1.40 minutes [CI, -5.20 to 2.41 minutes]). LIMITATION: Variability in user behavior and a limited number of assessable reviews led to an imprecise estimate of the time outcome. CONCLUSION: In health-related systematic reviews, RoB assessments conducted with RobotReviewer assistance are noninferior in accuracy to those conducted without RobotReviewer assistance. PRIMARY FUNDING SOURCE: University College London and Monash University.

Perspectives of patients, family members, health professionals and the public on the impact of COVID-19 on mental health.

BACKGROUND: The coronavirus (COVID-19) pandemic has seen a global surge in anxiety, depression, post-traumatic stress disorder (PTSD), and stress. AIMS: This study aimed to describe the perspectives of patients with COVID-19, their family, health professionals, and the general public on the impact of COVID-19 on mental health. METHODS: A secondary thematic analysis was conducted using data from the COVID-19 COS project. We extracted data on the perceived causes and impact of COVID-19 on mental health from an international survey and seven online consensus workshops. RESULTS: We identified four themes (with subthemes in parenthesis): anxiety amidst uncertainty (always on high alert, ebb and flow of recovery); anguish of a threatened future (intense frustration of a changed normality, facing loss of livelihood, trauma of ventilation, a troubling prognosis, confronting death); bearing responsibility for transmission (fear of spreading COVID-19 in public; overwhelming guilt of infecting a loved one); and suffering in isolation (severe solitude of quarantine, sick and alone, separation exacerbating grief). CONCLUSION: We found that the unpredictability of COVID-19, the fear of long-term health consequences, burden of guilt, and suffering in isolation profoundly impacted mental health. Clinical and public health interventions are needed to manage the psychological consequences arising from this pandemic.

Core Outcome Measures for Trials in People With Coronavirus Disease 2019: Respiratory Failure, Multiorgan Failure, Shortness of Breath, and Recovery.

OBJECTIVES: Respiratory failure, multiple organ failure, shortness of breath, recovery, and mortality have been identified as critically important core outcomes by more than 9300 patients, health professionals, and the public from 111 countries in the global coronavirus disease 2019 core outcome set initiative. The aim of this project was to establish the core outcome measures for these domains for trials in coronavirus disease 2019. DESIGN: Three online consensus workshops were convened to establish outcome measures for the four core domains of respiratory failure, multiple organ failure, shortness of breath, and recovery. SETTING: International. PATIENTS: About 130 participants (patients, public, and health professionals) from 17 countries attended the three workshops. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Respiratory failure, assessed by the need for respiratory support based on the World Health Organization Clinical Progression Scale, was considered pragmatic, objective, and with broad applicability to various clinical scenarios. The Sequential Organ Failure Assessment was recommended for multiple organ failure, because it was routinely used in trials and clinical care, well validated, and feasible. The Modified Medical Research Council measure for shortness of breath, with minor adaptations (recall period of 24 hr to capture daily fluctuations and inclusion of activities to ensure relevance and to capture the extreme severity of shortness of breath in people with coronavirus disease 2019), was regarded as fit for purpose for this indication. The recovery measure was developed de novo and defined as the absence of symptoms, resumption of usual daily activities, and return to the previous state of health prior to the illness, using a 5-point Likert scale, and was endorsed. CONCLUSIONS: The coronavirus disease 2019 core outcome set recommended core outcome measures have content validity and are considered the most feasible and acceptable among existing measures. Implementation of the core outcome measures in trials in coronavirus disease 2019 will ensure consistency and relevance of the evidence to inform decision-making and care of patients with coronavirus disease 2019.

International Survey to Establish Prioritized Outcomes for Trials in People With Coronavirus Disease 2019.

OBJECTIVES: There are over 4,000 trials conducted in people with coronavirus disease 2019. However, the variability of outcomes and the omission of patient-centered outcomes may diminish the impact of these trials on decision-making. The aim of this study was to generate a consensus-based, prioritized list of outcomes for coronavirus disease 2019 trials. DESIGN: In an online survey conducted in English, Chinese, Italian, Portuguese, and Spanish languages, adults with coronavirus disease 2019, their family members, health professionals, and the general public rated the importance of outcomes using a 9-point Likert scale (7-9, critical importance) and completed a Best-Worst Scale to estimate relative importance. Participant comments were analyzed thematically. SETTING: International. SUBJECTS: Adults 18 years old and over with confirmed or suspected coronavirus disease 2019, their family members, members of the general public, and health professionals (including clinicians, policy makers, regulators, funders, and researchers). INTERVENTIONS: None. MEASUREMENTS: None. MAIN RESULTS: In total, 9,289 participants from 111 countries (776 people with coronavirus disease 2019 or family members, 4,882 health professionals, and 3,631 members of the public) completed the survey. The four outcomes of highest priority for all three groups were: mortality, respiratory failure, pneumonia, and organ failure. Lung function, lung scarring, sepsis, shortness of breath, and oxygen level in the blood were common to the top 10 outcomes across all three groups (mean > 7.5, median ≥ 8, and > 70% of respondents rated the outcome as critically important). Patients/family members rated fatigue, anxiety, chest pain, muscle pain, gastrointestinal problems, and cardiovascular disease higher than health professionals. Four themes underpinned prioritization: fear of life-threatening, debilitating, and permanent consequences; addressing knowledge gaps; enabling preparedness and planning; and tolerable or infrequent outcomes. CONCLUSIONS: Life-threatening respiratory and other organ outcomes were consistently highly prioritized by all stakeholder groups. Patients/family members gave higher priority to many patient-reported outcomes compared with health professionals.

Core Outcomes Set for Trials in People With Coronavirus Disease 2019.

OBJECTIVES: The outcomes reported in trials in coronavirus disease 2019 are extremely heterogeneous and of uncertain patient relevance, limiting their applicability for clinical decision-making. The aim of this workshop was to establish a core outcomes set for trials in people with suspected or confirmed coronavirus disease 2019. DESIGN: Four international online multistakeholder consensus workshops were convened to discuss proposed core outcomes for trials in people with suspected or confirmed coronavirus disease 2019, informed by a survey involving 9,289 respondents from 111 countries. The transcripts were analyzed thematically. The workshop recommendations were used to finalize the core outcomes set. SETTING: International. SUBJECTS: Adults 18 years old and over with confirmed or suspected coronavirus disease 2019, their family members, members of the general public and health professionals (including clinicians, policy makers, regulators, funders, researchers). INTERVENTIONS: None. MEASUREMENTS: None. MAIN RESULTS: Six themes were identified. "Responding to the critical and acute health crisis" reflected the immediate focus on saving lives and preventing life-threatening complications that underpinned the high prioritization of mortality, respiratory failure, and multiple organ failure. "Capturing different settings of care" highlighted the need to minimize the burden on hospitals and to acknowledge outcomes in community settings. "Encompassing the full trajectory and severity of disease" was addressing longer term impacts and the full spectrum of illness (e.g. shortness of breath and recovery). "Distinguishing overlap, correlation and collinearity" meant recognizing that symptoms such as shortness of breath had distinct value and minimizing overlap (e.g. lung function and pneumonia were on the continuum toward respiratory failure). "Recognizing adverse events" refers to the potential harms of new and evolving interventions. "Being cognizant of family and psychosocial wellbeing" reflected the pervasive impacts of coronavirus disease 2019. CONCLUSIONS: Mortality, respiratory failure, multiple organ failure, shortness of breath, and recovery are critically important outcomes to be consistently reported in coronavirus disease 2019 trials.

Performance of a Novel Low-Cost, Instrument-Free Plasma Separation Device for HIV Viral Load Quantification and Determination of Treatment Failure in People Living with HIV in Malaysia: a Diagnostic Accuracy Study.

HIV viral load (VL) testing is the recommended method for monitoring the response of people living with HIV and receiving antiretroviral therapy (ART). The availability of standard plasma VL testing in low- and middle-income countries (LMICs), and access to this testing, are limited by the need to use fresh plasma. Good specimen collection methods for HIV VL testing that are applicable to resource-constrained settings are needed. We assessed the diagnostic performance of the filtered dried plasma spot (FDPS), created using the newly developed, instrument-free VLPlasma device, in identifying treatment failure at a VL threshold of 1,000 copies/ml in fresh plasma. Performance was compared with that of the conventional dried blood spot (DBS). Venous blood samples from 201 people living with HIV and attending an infectious disease clinic in Malaysia were collected, and HIV VL was quantified using fresh plasma (the reference standard), FDPS, and DBS specimens. VL testing was done using the Roche Cobas AmpliPrep/Cobas TaqMan v2.0 assay. At a threshold of 1,000 copies/ml, the diagnostic performance of the FDPS was superior (sensitivity, 100% [95% confidence interval {CI}, 89.1 to 100%]; specificity, 100% [95% CI, 97.8 to 100%]) to that of the DBS (sensitivity, 100% [95% CI, 89.4 to 100%]; specificity, 36.8% [95% CI, 29.4 to 44.7%]) (P < 0.001). A stronger correlation was observed between the FDPS VL and the plasma VL (r = 0.94; P < 0.001) than between the DBS VL and the plasma VL (r = 0.85; P < 0.001). The mean difference in VL measures between the FDPS and plasma (plasma VL minus FDPS VL) was 0.127 log10 copies/ml (standard deviation [SD], 0.32), in contrast to -0.95 log10 copies/ml (SD, 0.84) between the DBS and plasma. HIV VL measurement using the FDPS outperformed that with the DBS in identifying treatment failure at a threshold of 1,000 copies/ml and compared well with the quantification of VL in plasma. The FDPS can be an attractive alternative to fresh plasma for improving access to HIV VL monitoring among people living with HIV on ART in LMICs.

Recruiting people with HIV to an online self-management support randomised controlled trial: barriers and facilitators.

Background Recruitment of people to randomised trials of online interventions presents particular challenges and opportunities. The aim of this study was to evaluate factors associated with the recruitment of people with HIV (PWHIV) and their doctors to the HealthMap trial, a cluster randomised trial of an online self-management program. METHODS: Recruitment involved a three-step process. Study sites were recruited, followed by doctors caring for PWHIV at study sites and finally PWHIV. Data were collected from study sites, doctors and patient participants. Factors associated with site enrolment and patient participant recruitment were investigated using regression models. RESULTS: Thirteen study sites, 63 doctor participants and 728 patient participants were recruited to the study. Doctors having a prior relationship with the study investigators (odds ratio (OR) 13.3; 95% confidence interval (CI) 3.0, 58.7; P = 0.001) was positively associated with becoming a HealthMap site. Most patient participants successfully recruited to HealthMap (80%) had heard about the study from their HIV doctor. Patient enrolment was associated with the number of people with HIV receiving care at the site (ß coefficient 0.10; 95% CI 0.04, 0.16; P = 0.004), but not with employing a clinic or research nurse to help recruit patients (ß coefficient 55.9; 95% CI -2.55, 114.25; P = 0.06). CONCLUSION: Despite substantial investment in online promotion, a previous relationship with doctors was important for doctor recruitment, and doctors themselves were the most important source of patient recruitment to the HealthMap trial. Clinic-based recruitment strategies remain a critical component of trial recruitment, despite expanding opportunities to engage with online communities.

The systematic development of a complex intervention: HealthMap, an online self-management support program for people with HIV.

BACKGROUND: Despite persistent calls for HIV care to adopt a chronic care approach, few HIV treatment services have been able to establish service arrangements that prioritise self-management. To prevent cardiovascular and other chronic disease outcomes, the HealthMap program aims to enhance routine HIV care with opportunities for self-management support. This paper outlines the systematic process that was used to design and develop the HealthMap program, prior to its evaluation in a cluster-randomised trial. METHODS: Program development, planning and evaluation was informed by the PRECEDE-PROCOEDE Model and an Intervention Mapping approach and involved four steps: (1) a multifaceted needs assessment; (2) the identification of intervention priorities; (3) exploration and identification of the antecedents and reinforcing factors required to initiate and sustain desired change of risk behaviours; and finally (4) the development of intervention goals, strategies and methods and integrating them into a comprehensive description of the intervention components. RESULTS: The logic model incorporated the program's guiding principles, program elements, hypothesised causal processes, and intended program outcomes. Grounding the development of HealthMap on a clear conceptual base, informed by the research literature and stakeholder's perspectives, has ensured that the HealthMap program is targeted, relevant, provides transparency, and enables effective program evaluation. CONCLUSIONS: The use of a systematic process for intervention development facilitated the development of an intervention that is patient centred, accessible, and focuses on the key determinants of health-related outcomes for people with HIV in Australia. The techniques used here may offer a useful methodology for those involved in the development and implementation of complex interventions.

Modeling the Effects of Vorinostat In Vivo Reveals both Transient and Delayed HIV Transcriptional Activation and Minimal Killing of Latently Infected Cells.

Recent efforts to cure human immunodeficiency virus type-1 (HIV-1) infection have focused on developing latency reversing agents as a first step to eradicate the latent reservoir. The histone deacetylase inhibitor, vorinostat, has been shown to activate HIV RNA transcription in CD4+ T-cells and alter host cell gene transcription in HIV-infected individuals on antiretroviral therapy. In order to understand how latently infected cells respond dynamically to vorinostat treatment and determine the impact of vorinostat on reservoir size in vivo, we have constructed viral dynamic models of latency that incorporate vorinostat treatment. We fitted these models to data collected from a recent clinical trial in which vorinostat was administered daily for 14 days to HIV-infected individuals on suppressive ART. The results show that HIV transcription is increased transiently during the first few hours or days of treatment and that there is a delay before a sustained increase of HIV transcription, whose duration varies among study participants and may depend on the long term impact of vorinostat on host gene expression. Parameter estimation suggests that in latently infected cells, HIV transcription induced by vorinostat occurs at lower levels than in productively infected cells. Furthermore, the estimated loss rate of transcriptionally induced cells remains close to baseline in most study participants, suggesting vorinostat treatment does not induce latently infected cell killing and thus reduce the latent reservoir in vivo.

Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy.

UNLABELLED: Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells. TRIAL REGISTRATION: ClinicalTrials.gov NCT01365065.

The Positive Outlook Study: A Randomised Controlled Trial Evaluating Online Self-Management for HIV Positive Gay Men.

The aim of this paper was to evaluate the effectiveness of an online self-management program in improving health outcomes and well-being for gay men living with HIV in Australia. The online Positive Outlook Program was based on self-efficacy theory and used a self-management approach to enhance HIV-positive gay men's skills, confidence and abilities to manage the psychosocial issues associated with HIV in daily life. The 7-week program was delivered in closed groups and comprised information modules, action-planning activities, moderated discussion boards, and weekly peer-facilitated 'live chats'. A randomised controlled trial was conducted to establish the effectiveness of the Positive Outlook program compared to a 'usual care' control. Participants were HIV-positive gay men 18 years or older living in Australia. Primary outcomes were evaluated at three time-points (baseline, post-intervention and 12-week's post-intervention follow-up) and included HIV-related quality of life (PROQOL-HIV), outcomes of health education (HeiQ) and HIV specific self-efficacy (Positive Outlook Self-Efficacy Scale). A total of 132 gay men with HIV in Australia were randomly allocated to the intervention (n = 68) or usual care control (n = 64) groups. Maximum likelihood marginal-linear modelling indicated significant improvement in the intervention group on the PROQOL-HIV subscales of body change (p = 0.036), social relationships (p = 0.035) and emotional distress (p = 0.031); the HeiQ subscales of health-directed activity (p = 0.048); constructive attitudes and approaches (p = 0.015); skill and technique acquisition (p = 0.046) and health service navigation (p = 0.008); and the Positive Outlook Self-Efficacy Scale on the subscales of relationships (p = 0.019); social participation (p = 0.006); and emotions (p = 0.041). Online delivery of self-management programs is feasible and has the potential to improve quality of life, self-management skills and domain specific self-efficacy for gay men with HIV.

HealthMap: a cluster randomised trial of interactive health plans and self-management support to prevent coronary heart disease in people with HIV.

BACKGROUND: The leading causes of morbidity and mortality for people in high-income countries living with HIV are now non-AIDS malignancies, cardiovascular disease and other non-communicable diseases associated with ageing. This protocol describes the trial of HealthMap, a model of care for people with HIV (PWHIV) that includes use of an interactive shared health record and self-management support. The aims of the HealthMap trial are to evaluate engagement of PWHIV and healthcare providers with the model, and its effectiveness for reducing coronary heart disease risk, enhancing self-management, and improving mental health and quality of life of PWHIV. METHODS/DESIGN: The study is a two-arm cluster randomised trial involving HIV clinical sites in several states in Australia. Doctors will be randomised to the HealthMap model (immediate arm) or to proceed with usual care (deferred arm). People with HIV whose doctors are randomised to the immediate arm receive 1) new opportunities to discuss their health status and goals with their HIV doctor using a HealthMap shared health record; 2) access to their own health record from home; 3) access to health coaching delivered by telephone and online; and 4) access to a peer moderated online group chat programme. Data will be collected from participating PWHIV (n = 710) at baseline, 6 months, and 12 months and from participating doctors (n = 60) at baseline and 12 months. The control arm will be offered the HealthMap intervention at the end of the trial. The primary study outcomes, measured at 12 months, are 1) 10-year risk of non-fatal acute myocardial infarction or coronary heart disease death as estimated by a Framingham Heart Study risk equation; and 2) Positive and Active Engagement in Life Scale from the Health Education Impact Questionnaire (heiQ). DISCUSSION: The study will determine the viability and utility of a novel technology-supported model of care for maintaining the health and wellbeing of people with HIV. If shown to be effective, the HealthMap model may provide a generalisable, scalable and sustainable system for supporting the care needs of people with HIV, addressing issues of equity of access. TRIAL REGISTRATION: Universal Trial Number (UTN) U111111506489; ClinicalTrial.gov Id NCT02178930 submitted 29 June 2014.

Chronic Disease Self-Management by People With HIV.

As HIV has transitioned into a chronic disease, reappraisal of clinical management has occurred with chronic disease self-management (CDSM) as one possibility. However, despite extensive work on CDSM across a range of diseases, little attention has focused on psychosocial contexts of the lives of people for whom programs are intended. This article reports semi-structured interviews used to explore health practices and motivations of 33 people with HIV (PWHIV) in Australia. Within participants' accounts, different forms of subjectivity and agency emerged with implications for how they understood and valued health-related behaviors. Four themes arose: health support and disclosure, social support and stigma, employment/structure, and health decisions beyond HIV. The experience of stigma and its intersection with CDSM remains relatively un-chartered. This study found stigma shapes agency and engagement with health. Decisions concerning health behaviors are often driven by perceived social and emotional benefit embedded in concerns of disclosure and stigma.

Living systematic reviews: an emerging opportunity to narrow the evidence-practice gap.

The current difficulties in keeping systematic reviews up to date leads to considerable inaccuracy, hampering the translation of knowledge into action. Incremental advances in conventional review updating are unlikely to lead to substantial improvements in review currency. A new approach is needed. We propose living systematic review as a contribution to evidence synthesis that combines currency with rigour to enhance the accuracy and utility of health evidence. Living systematic reviews are high quality, up-to-date online summaries of health research, updated as new research becomes available, and enabled by improved production efficiency and adherence to the norms of scholarly communication. Together with innovations in primary research reporting and the creation and use of evidence in health systems, living systematic review contributes to an emerging evidence ecosystem.

Associations between surface markers on blood monocytes and carotid atherosclerosis in HIV-positive individuals.

Chronic HIV infection is associated with increased risk of cardiovascular disease (CVD), including in patients with virological suppression. Persistent innate immune activation may contribute to the development of CVD via activation of monocytes in these patients. We investigated whether changes in monocyte phenotype predict subclinical atherosclerosis in virologically suppressed HIV-positive individuals with low cardiovascular risk. We enroled 51 virologically suppressed HIV-positive individuals not receiving protease inhibitors or statins and 49 age-matched uninfected controls in this study. Carotid artery intima-media thickness (cIMT) was used as a surrogate marker for CVD, and traditional risk factors, including Framingham risk scores, were recorded. Markers of monocyte activation (CD14, CD16, CCR2, CX3CR1, CD38, HLA-DR and CD11b) were measured in whole-blood samples by flow cytometry. Associations were assessed using univariate and multivariate median regressions. Median cIMT was similar between HIV-positive and HIV-negative participants (P=0.3), although HIV-positive patients had significantly higher Framingham risk score (P=0.009) and systemic inflammation. Expression of two monocyte markers, CD11b and CX3CR1, independently predicted carotid artery thickness in HIV-positive individuals after controlling for Framingham risk score (P=0.025 and 0.015, respectively). These markers were not predictive of carotid artery thickening in controls. Our study indicates that monocyte surface markers may serve as novel predictors of CVD in HIV-positive individuals and is consistent with an important role for monocyte activation in the progression of HIV-related cardiovascular pathology.

Targets for intervention to improve virological outcomes for patients receiving free antiretroviral therapy in Tamil Nadu, India.

Operational research to identify factors predicting poor clinical outcomes is critical to maximize patient care and prolong first-line regimens for those receiving free antiretroviral therapy (ART) in India. We sought to identify social or clinical factors amenable to intervention that predict virological outcomes after 12 months of ART. We examined a retrospective cohort of consecutive adults initiating free nonnucleoside reverse transcriptase inhibitor-based regimens. Individuals remaining in care 12 months post-ART initiation were tested for HIV viral load and surveyed to identify barriers and facilitators to adherence, and to determine clinic travel times and associated costs. Uni- and multivariate logistic regression identified factors predicting HIV viral load >200 copies/mL after 12 months of ART. Of 230 adults initiating ART, 10% of patients died, 8% transferred out, 5% were lost to follow-up, and 174/230 (76%) completed 12 months of ART, the questionnaire, and viral load testing. HIV viral load was <200 copies/mL in 140/174 (80%) patients. In multivariate models, being busy with work or caring for others (OR 2.9, p < 0.01), having clinic transport times ≥ 3 hours (OR 3.0, p = 0.02), and alcohol use (OR 4.8, p = 0.03) predicted viral load >200 copies/mL after 12 months of ART. Clinical outcomes following ART are related to programmatic factors such as prolonged travel time and individual factors such as being busy with family or using alcohol. Simple interventions that alter these factors should be evaluated to improve clinical outcomes for populations receiving free ART in similar settings.

Cryptococcosis-IRIS is associated with lower cryptococcus-specific IFN-γ responses before antiretroviral therapy but not higher T-cell responses during therapy.

BACKGROUND: Cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS) may be driven by aberrant T-cell responses against cryptococci. We investigated this in human immunodeficiency virus (HIV)-infected patients with treated cryptococcal meningitis (CM) commencing combination antiretroviral therapy (cART). METHODS: Mitogen- and cryptococcal mannoprotein (CMP)-activated (CD25+CD134+) CD4+ T cells and -induced production of interferon-gamma (IFN-γ), IL-10, and CXCL10 were assessed in whole blood cultures in a prospective study of 106 HIV-CM coinfected patients. RESULTS: Patients with paradoxical C-IRIS (n = 27), compared with patients with no neurological deterioration (no ND; n = 63), had lower CMP-induced IFN-γ production in 24-hour cultures pre-cART and 4 weeks post-cART (P = .0437 and .0257, respectively) and lower CMP-activated CD4+ T-cell counts pre-cART (P = .0178). Patients surviving to 24 weeks had higher proportions of mitogen-activated CD4+ T cells and higher CMP-induced CXCL10 and IL-10 production in 24-hour cultures pre-cART than patients not surviving (P = .0053, .0436 and .0319, respectively). C-IRIS was not associated with higher CMP-specific T-cell responses before or during cART. CONCLUSION: Greater preservation of T-cell function and higher CMP-induced IL-10 and CXCL10 production before cART are associated with improved survival while on cART. Lower CMP-induced IFN-γ production pre-cART, but not higher CMP-specific T-cell responses after cART, were risk factors for C-IRIS.

Chemokine levels and chemokine receptor expression in the blood and the cerebrospinal fluid of HIV-infected patients with cryptococcal meningitis and cryptococcosis-associated immune reconstitution inflammatory syndrome.

BACKGROUND: Human immunodeficiency virus-infected patients with treated cryptococcal meningitis who start combination antiretroviral therapy (cART) are at risk of further neurological deterioration, in part caused by paradoxical cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS). We hypothesized that C-IRIS is associated with alterations of chemokine receptor expression on T cells and chemokine concentrations in cerebrospinal fluid (CSF) that enhance recruitment of T-helper 1 cells and/or myeloid cells to the central nervous system. METHODS: In a prospective study of 128 human immunodeficiency virus-infected patients with cryptococcal meningitis who received antifungal therapy followed by cART, we examined the proportions of CD4(+) and CD8(+) T cells expressing CCR5 and/or CXCR3, in CSF and whole blood and the concentrations of CXCL10, CCL2, and CCL3 in stored CSF and plasma. RESULTS: The proportion of CD4(+) and CD8(+) T cells expressing CXCR3(+)CCR5(+) and the concentrations of CXCL10, CCL2 and CCL3 were increased in CSF compared with blood at cART initiation (P < .0001). Patients with C-IRIS (n = 26), compared with those with no neurological deterioration (n = 63), had higher CSF ratios of CCL2/CXCL10 and CCL3/CXCL10 and higher proportions of CXCR3(+)CCR5(+)CD8(+)T cells in CSF compared with blood at cART initiation (P = .03, .0053, and .02, respectively). CONCLUSION: CD8(+) T-cell and myeloid cell trafficking to the central nervous system may predispose patients to C-IRIS.