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Background: The residual life of a patient with human immunodeficiency virus (HIV) is of major interest to patients and their physicians. While existing analyses of HIV patient survival focus mostly on data collected at baseline, residual life analysis allows for dynamic analysis based on additional data collected over a period of time. As survival times typically exhibit a right-skewed distribution, the median provides a more useful summary of the underlying distribution than the mean. In this paper, we propose an efficient inference procedure that fits a semiparametric quantile regression model assessing the effect of longitudinal biomarkers on the residual life of HIV patients until the development of dyslipidemia, a disease becoming more prevalent among those with HIV. Methods: For estimation of model parameters, we propose an induced smoothing method that smooths nonsmooth estimating functions based on check functions. For variance estimation, we propose an efficient resampling-based estimator. The proposed estimators are theoretically justified. Simulation studies are used to evaluate their finite sample performances, including their prediction accuracy. We analyze the Korea HIV/AIDS cohort study data to examine the effects of CD4 (cluster of differentiation 4) cell count on the residual life of HIV patients to the onset of dyslipidemia. Results: The proposed estimator is shown to be consistent and normally distributed asymptotically. Under various simulation settings, our estimates are approximately unbiased. Their variances estimates are close to the empirical variances and their computational efficiency is superior to that of the nonsmooth counterparts. Two measures of prediction performance indicate that our method adequately reflects the dynamic character of longitudinal biomarkers and residual life. The analysis of the Korea HIV/AIDS cohort study data shows that CD4 cell count is positively associated with residual life to the onset of dyslipidemia but the effect is not statistically significant. Conclusions: Our method enables direct prediction of residual lifetimes with a dynamic feature that accommodates data accumulated at different times. Our estimator significantly improves computational efficiency in variance estimation compared to the existing nonsmooth estimator. Analysis of the HIV/AIDS cohort study data reveals dynamic effects of CD4 cell count on the residual life to the onset of dyslipidemia. [ABSTRACT FROM AUTHOR]

Background: The number of elderly people living with HIV (EPLHIV) has increased significantly as a result of antiretroviral treatment (ART) and this has brought about a variety of psychosocial challenges that have an impact on their quality of life (QoL). Various psychosocial interventions have been tried or implemented in Sub-Saharan Africa (SSA) to improve QoL of EPLHIV. However, there is paucity of data on the types and effectiveness of these interventions. This systematic review, therefore, aims to explore available psychosocial interventions in SSA and their effectiveness in improving the QoL of EPLHIV. Methods: We will search PubMed, PsycINFO, LILACS, Cochrane Library, Google Scholar, HINARI, Africa Journals Online, Scopus and Web of Science to retrieve publications on psychosocial interventions implemented to improve QoL of EPLHIV from inception of the identified databases to 31st December 2023 without language restrictions. Also, supplementary sources such as conference proceedings, preprint repositories, databases of dissertations, as well as WHO and governmental databases can be explored for additional studies. For unpublished studies, trial registries and experts would be contacted, and reference lists of retrieved papers will be manually searched. Retrieved studies will be deduplicated using Mendeley and exported to Rayyan. At least two reviewers will independently select studies, extract data and assess the quality of the included studies using validated tools. Dichotomous outcomes data will be assessed and reported as odds ratio (OR) or risk ratio (RR) and for continuous outcomes, mean difference (MD) will be used; all reported with their 95% confidence interval (CI). Heterogeneity will be explored graphically by inspecting the overlapping of CIs and assessed quantitatively using the I2 statistic. Expected outcomes: This systematic review will be the first to rigorously identify psychosocial intervention on QoL of EPLHIV in SSA and assess their effectiveness with the aim to provide regional and country- specific data that will inform the selection and implementation of appropriate and socially acceptable policies across countries in SSA. Key findings of the review are expected to contribute critical evidence on availability, types and effectiveness of psychosocial interventions for improving quality of life of vulnerable elderly persons in SSA living with HIV. Furthermore, the review will explore any variation and possible correlates of psychosocial interventions by age, sex, CD4 count (if available), setting and geographic location within SSA that will provide healthcare professionals with reliable evidence, with the ultimate goal of inspiring countries in SSA to adopt innovative interventions to improve HIV care. Trial registration: Systematic review registration: The systematic review protocol has been registered in the International Prospective Register for Systematic Reviews (PROSPERO), with registration ID CRD42021278218. [ABSTRACT FROM AUTHOR]

Simple Summary: The extracellular matrix surrounding or infiltrating tumor tissues, tumor cells, endothelial cells, immune cells, fibroblasts, macrophages, as well as soluble molecules like cytokines and growth factors secreted by these cells, constitute the complex biological structure known as the tumor microenvironment (TME). The cellular and non-cellular components of TME have a role in the development of tumors and the immune response, which offers novel insights for targeted therapies. Depleting existing cells, stopping them from being attracted to tumor locations, and reprogramming them into antitumor subtypes are the three primary categories of therapeutic approaches. TME exhibits complicated connections between Hodgkin/Reed–Sternberg cells and microenvironment and plays a crucial role in classical Hodgkin lymphoma (CHL) as well. Numerous studies have demonstrated that an extensive understanding of the CHL microenvironment, including the identification of all cellular components and variables implicated in the pathogenesis, is essential for improving prognostic stratification and developing innovative targeted treatments. Although classical Hodgkin lymphoma (CHL) is typically curable, 15–25% of individuals eventually experience a relapse and pass away from their disease. In CHL, the cellular microenvironment is constituted by few percent of H/RS (Hodgkin/Reed–Sternberg) tumor cells surrounded from a heterogeneous infiltration of inflammatory cells. The interplay of H/RS cells with other immune cells in the microenvironment may provide novel strategies for targeted immunotherapies. In this paper we analyzed the microenvironment content in CHL patients with responsive disease (RESP) and patients with relapsed/refractory disease to treatment (REL). Our results indicate the increase of CD68+ and CD163+ macrophages, the increase of PDL-1+ cells and of CD34+ microvessels in REL patients respective to RESP patients. In contrast we also found the decrease of CD3+ and of CD8+ lymphocytes in REL patients respective to RESP patients. Finally, in REL patients our results show the positive correlation between CD68+ macrophages and PDL-1+ cells as well as a negative correlation between CD163+ and CD3+. [ABSTRACT FROM AUTHOR]

Background: The association structure linking the longitudinal and survival sub-models is of fundamental importance in the joint modeling framework and the choice of this structure should be made based on the clinical background of the study. However, this information may not always be accessible and rationale for selecting this association structure has received relatively little attention in the literature. To this end, we aim to explore four alternative functional forms of the association structure between the CD4 count and the risk of death and provide rationale for selecting the optimal association structure for our data. We also aim to compare the results obtained from the joint model to those obtained from the time-varying Cox model.Methods: We used data from the Centre for the AIDS Programme of Research in South Africa (CAPRISA) AIDS Treatment programme, the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPiT) study, an open-label, three armed randomised, controlled trial between June 2005 and July 2010 (N=642). In our analysis, we combined the early and late integrated arms and compared results to the sequential arm. We utilized the Deviance Information Criterion (DIC) to select the final model with the best structure, with smaller values indicating better model adjustments to the data.Results: Patient characteristics were similar across the study arms. Combined integrated therapy arms had a reduction of 55% in mortality (HR:0.45, 95% CI:0.28-0.72) compared to the sequential therapy arm. The joint model with a cumulative effects functional form was chosen as the best association structure. In particular, our joint model found that the area under the longitudinal profile of CD4 count was strongly associated with a 21% reduction in mortality (HR:0.79, 95% CI:0.72-0.86). Where as results from the time-varying Cox model showed a 19% reduction in mortality (HR:0.81, 95% CI:0.77-0.84).Conclusions: In this paper we have shown that the "current value" association structure is not always the best structure that expresses the correct relationship between the outcomes in all settings, which is why it is crucial to explore alternative clinically meaningful association structures that links the longitudinal and survival processes. [ABSTRACT FROM AUTHOR]

Aspergillus spp. are ubiquitous and cause severe infections in immunocompromised patients. Less is known about its incidence and prognosis in patients with HIV/AIDS. We reviewed the mortality of invasive aspergillosis in HIV/AIDS patients. Pubmed, Embase and Medline databases were used to search for articles. Studies were excluded if they contained other aspergillosis risk factors, no original or patient survival data or were not in English. From 747 articles published, 54 studies and case reports were identified following reading, published between 1985 and 2021, with 54% papers prior to 2000 reporting 853 patients from 16 countries, none from Africa. 707 (83%) patients died with an average time from diagnosis to death of 77.5 days. Postmortem diagnosis was seen in 21% of deaths recorded. A national series from France of 242 cases of invasive aspergillosis diagnosed in life recorded a 3 month mortality of 68% pre-ART, falling to 31% after introduction of ART and voriconazole. CD4 count was recorded in 39 studies and ranged from 2 to >1000 cells/mm3; only 8 patients (1.8%) had a CD4 > 100 cells/mm3. Aspergillosis occurs in patients with HIV/AIDS and associated with high mortality but its slow progression should allow diagnosis and treatment with improved outcome. [ABSTRACT FROM AUTHOR]

This paper presents an innovative Bayesian method for assessing the status and progression of HIV infection using biomarkers such as the CD4 count and viral load variables. A distribution of viral loads in subjects starting antiretroviral treatment and followed over time may show a mixture of two subgroups: one subgroup representing "non-progressor" subjects and another subgroup of "progressor" subjects. In modeling these groups, we use a mass point and a right-skewed continuous distribution in which trajectories of repeated observations of viral load exhibit multiphasic features along with a gradual transition period. The commonly used method for describing these phasic patterns is a bent-cable model with a quadratic function for modeling the gradual transition phase. A quadratic function may be too restrictive for adequately modeling the transition period. Thus, we we extend the bent-cable model within the context of a two-component Tobit growth model by relaxing the assumption of a quadratic function for a gradual transition period and accounting for measurement errors in CD4 count. The proposed methods are demonstrated using real data from an AIDS clinical study. [ABSTRACT FROM AUTHOR]

Objectives: HIV virological failure remains a major threat to programme success in sub‐Saharan Africa. While HIV drug resistance (HIVDR) and inadequate adherence are the main drivers of virological failure, the individual, clinical and health system characteristics that lead to poor outcomes are not well understood. The objective of this paper is to identify those characteristics among people failing first‐line antiretroviral therapy (ART). Methods: We enrolled a cohort of adults in HIV care experiencing virological failure on first‐line ART at five sites and used standard statistical methods to characterize them with a focus on three domains: individual/demographic, clinical, and health system, and compared each by country of enrolment. Results: Of 840 participants, 51% were women, the median duration on ART was 3.2 years [interquartile range (IQR) 1.1, 6.4 years] and the median CD4 cell count prior to failure was 281 cells/µL (IQR 121, 457 cells/µL). More than half of participants [53%; 95% confidence interval (CI) 49–56%] stated that they had > 90% adherence and 75% (95% CI 72–77%) took their ART on time all or most of the time. Conversely, the vast majority (90%; 95% CI 86–92%) with a completed genotypic drug resistance test had any HIV drug resistance. This population had high health system use, reporting a median of 3 (IQR 2.6) health care visits and a median of 1 (IQR 1.1) hospitalization in the preceding 6 months. Conclusions: Patients failing first‐line ART in sub‐Saharan Africa generally report high rates of adherence to ART, have extremely high rates of HIV drug resistance and utilize significant health care resources. Health systems interventions to promptly detect and manage treatment failure will be a prerequisite to establishing control of the HIV epidemic. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the heterogeneity of change of posttraumatic growth (PTG) among people living with HIV (PLWH) in a 1-year prospective study. The goal was also to identify sociodemographic and clinical covariates and differences in baseline coping strategies. Particularly, time since diagnosis and positive reframing coping were of special interest. The sample consisted of 115 people with medically confirmed diagnosis of HIV infection. The participants filled out paper-and-pencil questionnaires three times with an interval of 6 months, including also sociodemographic and clinical data. Four trajectories of PTG were identified: curvilinear, low stable, high stable, and rapid change. Participants' gender, education level, CD4 count and time since HIV diagnosis occurred to be significant covariates of class membership. Positive reframing and self-distraction differentiated only between the high stable and the rapid change trajectory, with lower values in the latter. The study results call for attention to the complexity of PTG patterns in a face of struggling with HIV infection. Specifically, interventions in clinical practice should take into account the fact that there is no single pattern of PTG that fits all PLWH and that these differences may be related to the sociodemographic and clinical characteristics as well as to coping strategies representing meaning-making mechanism. [ABSTRACT FROM AUTHOR]

Marginal structural models (MSMs) with inverse probability weighted estimators (IPWEs) are widely used to estimate causal effects of treatment sequences on longitudinal outcomes in the presence of time‐varying confounding and dependent censoring. However, IPWEs for MSMs can be inefficient and unstable if weights are estimated by maximum likelihood. To improve the performance of IPWEs, covariate balancing weight (CBW) methods have been proposed and recently extended to MSMs. However, existing CBW methods for MSMs are inflexible for practical use because they often do not handle dependent censoring, nonbinary treatments, and longitudinal outcomes (instead of eventual outcomes at a study end). In this paper, we propose a joint calibration approach to CBW estimation for MSMs that can accommodate (1) both time‐varying confounding and dependent censoring, (2) binary and nonbinary treatments, (3) eventual outcomes and longitudinal outcomes. We develop novel calibration restrictions by jointly eliminating covariate associations with both treatment assignment and censoring processes after weighting the observed data sample (i.e., to optimize covariate balance in finite samples). Two different methods are proposed to implement the calibration. Simulations show that IPWEs with calibrated weights perform better than IPWEs with weights from maximum likelihood and the "Covariate Balancing Propensity Score" method. We apply our method to a natural history study of HIV for estimating the effects of highly active antiretroviral therapy on CD4 cell counts over time. [ABSTRACT FROM AUTHOR]

Accurate health estimation of massive battery packs and efficient optimization of data storage have become major technical challenges with the development of big data platforms. In this paper, multi-level energy indicators are defined to reflect the overall health state of the battery pack, and battery pack health assessment is achieved through energy estimation. A visual feature learning method is proposed to extract features from partial cell charging voltage profiles image and the relationship between features and energy indicators is constructed by the hybrid convolutional neural network. The effectiveness of the proposed method is verified on the dataset generated by the battery pack model considering cell inconsistency, and the mean absolute percentage error of each energy indicator estimation is less than 1%. Additionally, validations are carried out on simulated data with sampling noise and two cases of experimental data to verify the stability of the method. The proposed visual feature learning method provides a new idea for the data storage and health monitoring of massive battery packs on the big data platform. • Multi-level energy indicators are proposed to reflect the battery pack health. • Battery pack dataset generated based on orthogonal combination of inconsistency parameters. • Extract visual features from partial cell charging voltage profiles image. • Good anti-interference ability against sampling noise. [ABSTRACT FROM AUTHOR]

The use of surrogate markers to examine the effectiveness of a treatment has the potential to decrease study length and identify effective treatments more quickly. Most available methods to investigate the usefulness of a surrogate marker involve restrictive parametric assumptions and tend to focus on settings where the surrogate is measured at a single point in time. However, in many clinical settings, the potential surrogate marker is often measured repeatedly over time, and thus, the surrogate marker information is a trajectory of measurements. In addition, it is often difficult in practice to correctly specify the relationship between a treatment, primary outcome, and surrogate marker trajectory. In this paper, we propose a model‐free definition for the proportion of the treatment effect on the primary outcome that is explained by the treatment effect on the longitudinal surrogate markers. We propose three novel flexible methods to estimate this proportion, develop the asymptotic properties of our estimators, and investigate the robustness of the estimators under multiple settings via a simulation study. We apply our proposed procedures to an AIDS clinical trial dataset to examine a trajectory of CD4 counts as a potential surrogate. [ABSTRACT FROM AUTHOR]

In this paper, we provide a unified framework for two-sample t-test with partially paired data. We show that many existing two-sample t-tests with partially paired data can be viewed as special members in our unified framework. Some shortcomings of these t-tests are discussed. We also propose the asymptotically optimal weighted linear combination of the test statistics comparing all four paired and unpaired data sets. Simulation studies are used to illustrate the performance of our proposed asymptotically optimal weighted combinations of test statistics and compare with some existing methods. It is found that our proposed test statistic is generally more powerful. Three real data sets about CD4 count, DNA extraction concentrations, and the quality of sleep are also analyzed by using our newly introduced test statistic. [ABSTRACT FROM AUTHOR]

Background: Antiretroviral therapy has prolonged the lives of those with human immunodeficiency virus (HIV), but the effects of chronic infection on their health-related quality of life (HRQoL) remain a concern. Numerous instruments have been developed to measure HRQoL, yet evidence of their cross-cultural equivalence and continued applicability is limited. We adapted the WHOQOL-HIV BREF to French and assessed its psychometric properties in a sample of community-dwelling adults living with HIV who were mostly virally suppressed.Methods: We conducted a cross-sectional study within the ANRS CO3 Aquitaine cohort from July 2018 to May 2019. Five hundred eighty-six participants were consecutively enrolled at their HIV-consultations and completed either a web-based (n = 406) or paper self-administered assessment (n = 180). The means and standard deviations for items and domains were computed and the presence of floor and ceiling effects assessed. We evaluated internal consistency by calculating Cronbach's alpha coefficients per domain. We assessed construct validity by performing a Confirmatory Factor Analysis (CFA). Concurrent, convergent and discriminant validity were assessed with Pearson's correlations and known-group validity was assessed according to CD4 cell count, viral load, Centers for Disease Control and Prevention clinical categories for HIV, and hospitalization of more than 48 h within 2 years of the most recent consultation using one-way analysis of variance and independent t-tests.Results: Five hundred eighty-six PLWH were included in this analysis. Their median age was 55; 73% were male; 85% were of French descent; 99% were on ART and 93% were virally suppressed. We found floor effects for one and ceiling effects for 11 items. Four of the six domains showed good internal consistency (α range: 0.63-0.79). CFA showed that the WHOQOL-HIV BREF's six-domain structure produced an acceptable fit (SRMR = 0.059; CFI = 0.834; RMSEA = 0.07; 90% CI: 0.06-0.08). It showed good concurrent, convergent and discriminant validity. There was some evidence of known-group validity. The personal beliefs domain had the highest score (15.04 ± 3.35) and the psychological health domain had the lowest (13.70 ± 2.78).Conclusions: The French WHOQOL-HIV BREF has acceptable measurement properties. Its broad conceptualisation of HRQoL, going beyond physical and mental health, may be of particular value in our older, treatment-experienced and virally suppressed population.Trial Registration: ClinicalTrials.gov NCT03296202 (Archived by WebCite at http://www.webcitation.org/6zgOBArps ). [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is a new human infectious disease. The etiology for this outbreak is a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus far, related research on COVID-19 is still in preliminary stage. This paper summarized the latest outcomes of corresponding study from Chinese centers and clarified the hematopoietic abnormality caused by SARS-CoV-2 and potential mechanism. Lymphopenia was common in the early stage after the onset of COVID-19. A significant decrease was observed in peripheral CD4+ and CD8+ T lymphocytes. As the illness progressed, neutrophilia emerged in several cases, and patients with severe critical pulmonary conditions showed higher neutrophils than common type. Thrombocytopenia was resulting from the consumption and/or the reduced production of platelets in damaged lungs. Anemia was not observed notably, but the decrease in hemoglobin was frequent. The activation of monocyte-macrophage system aggravates the immune damage of lung and other tissues, which leads to the increase of D-dimer, prothrombin time, and platelet consumption. [ABSTRACT FROM AUTHOR]

Introduction: Combination antiretroviral therapy has become the standard care of human immunodeficiency virus (HIV)-infected patients and has further led to a dramatically decreased progression probability to acquired immune deficiency syndrome (AIDS) for patients under such a therapy. However, responses of the patients to this therapy have recorded heterogeneous complexity and high dynamism. In this paper, we simultaneously model long-term viral suppression, viral rebound, and state-specific duration of HIV-infected patients. Methods: Full-parametric and semi-parametric Markov multistate models were applied to assess the effects of covariates namely TB co-infection, educational status, marital status, age, quality of life (QoL) scores, white and red blood cell parameters, and liver enzyme abnormality on long-term viral suppression, viral rebound and state-specific duration for HIV-infected individuals before and after treatment. Furthermore, two models, one including and another excluding the effect of the frailty, were presented and compared in this study. Results: Results from the diagnostic plots, Akaike information criterion (AIC) and likelihood ratio test showed that the Weibull multistate frailty model fitted significantly better than the exponential and semi-parametric multistate models. Viral rebound was found to be significantly associated with many sex partners, higher eosinophils count, younger age, lower educational level, higher monocyte counts, having abnormal neutrophils count, and higher liver enzyme abnormality. Furthermore, viral suppression was also found to be significantly associated with higher QoL scores, and having a stable sex partner. The analysis result also showed that patients with a stable sex partner, higher educational levels, higher QoL scores, lower eosinophils count, lower monocyte counts, and higher RBC indices were more likely to spend more time in undetectable viral load state. Conclusions: To achieve and maintain the UNAIDS 90% suppression targets, additional interventions are required to optimize antiretroviral therapy outcomes, specifically targeting those with poor clinical characteristics, lower education, younger age, and those with many sex partners. From a methodological perspective, the parametric multistate approach with frailty is a flexible approach for modeling time-varying variables, allowing for dealing with heterogeneity between the sequence of transitions, as well as allowing for a reasonable degree of flexibility with a few additional parameters, which then aids in gaining a better insight into how factors change over time. [ABSTRACT FROM AUTHOR]

Aims: To describe stroke syndromes and transcranial Doppler (TCD) findings in children with human immunodeficiency virus (HIV) and examine the associations between TCD and clinical and laboratory data.Method: We enrolled 42 children (24 males, 18 females) with HIV (median age=7y 6mo; 2y 7mo-15y 6mo), with and without stroke who underwent a TCD examination of the anterior and posterior circulations to derive time-averaged maximum mean velocity (TAMMV) measurements for comparison with previous studies. Clinical and laboratory variables were extracted from the medical records.Results: Of the 42 children with HIV, five had right-sided hemiparesis, three had chronic lung disease, two occurred post-varicella infection, one after herpetic oral ulceration, and one had a poorly functioning left ventricle. Neuroimaging showed middle cerebral artery (MCA) TAMMV greater than 200cm/s, moyamoya-like arteriopathy, left basal ganglia infarction with ipsilateral stenosis, hygroma consistent with venous thrombosis, and a hyperdense left MCA. Eight neurologically asymptomatic children had atypical TCD. The CD4 cell count was non-significantly lower in 6 out of 30 children with atypical TCD (median=21.5; interquartile range=16.1-26.5) compared with the remainder (median=29; interquartile range=21.3-35.0; p=0.09).Interpretation: A variety of stroke syndromes occur in children with HIV. TCD suggests atypical intracranial vessels and/or haemodynamics in some children with HIV infection, consistent with vasculopathy, possibly related directly to immunodeficiency and/or infection.What This Paper Adds: A range of stroke syndromes are found in children with human immunodeficiency virus (HIV). Transcranial Doppler (TCD) velocities in HIV are commonly outside the range for typically developing children. TCD and neuroimaging data in children with HIV suggest intracranial vasculopathy as one mechanism for stroke. CD4 cell count is non-significantly lower in children with HIV and atypical TCD. [ABSTRACT FROM AUTHOR]

Objectives: Despite recent pharmacological progress, memory impairment is still frequently reported in people living with HIV. We aimed to conduct a systematic literature review investigating the presence of impairment of (sub)components of memory function in patients prescribed highly active antiretroviral therapy (ART). Methods: We adopted a cognitive neuropsychological model of memory function as the theoretical framework, distinguishing between a short‐term working memory component and a long‐term component of memory, along with their specific (sub)components. We systematically searched for the presence of impairment of each (sub)component in the selected papers. Careful consideration was given to study design and methods and control of covariates. Results: Only the central executive component of working memory has been consistently reported to be impaired in HIV infection. The other two (sub)components, namely the phonological loop and the visuospatial sketchpad, were unimpaired. Discordant results have been obtained as to verbal and visual episodic memory, as some authors reported an association with HIV infection, whereas others did not. There is little evidence for semantic memory deficit in HIV infection, while there are suggestions that the neural substrate of implicit memory may be damaged by the effects of HIV infection and inflammation. Most studies in this area have been conducted in small samples and with poor control for covariates. Thus, conclusions regarding the association of memory dysfunction with HIV infection are hampered by methodological issues such as selection bias and unmeasured confounding. Conclusions: The task remains for future research to ascertain the impact of HIV infection on memory function. [ABSTRACT FROM AUTHOR]

In this paper, we assess the effect of tuberculosis pericarditis treatment (prednisolone) on CD4 count changes over time and draw inferences in the presence of missing data. We accounted for the missing data and performed sensitivity analyses to assess robustness of inferences, from a model that assumes that the data are missing at random, to models that assume that the data are not missing at random. Our sensitivity approaches are within the shared-parameter model framework. We implemented the approach by Creemers and colleagues to the CD4 count data and performed simulation studies to evaluate the performance of this approach. We also assessed the influence of potentially influential subjects, on parameter estimates, via the global influence approach. Our results revealed that inferences from missing at random analysis model are robust to not missing at random models and influential subjects did not overturn the study conclusions about prednisolone effect and missing data mechanism. Prednisolone was found to have no significant effect on CD4 count changes over time and also did not interact with anti-retroviral therapy. The simulation studies produced unbiased estimates of prednisolone effect with lower mean square errors and coverage probabilities approximately equal the nominal coverage probability. [ABSTRACT FROM AUTHOR]

Background: CD4 cell counts is widely used as a biomarker for treatment progression when studying the efficacy of drugs to treat HIV-infected patients. In the past, it had been also used in determining eligibility to initiate antiretroviral therapy. The main aim of this was to model the evolution of CD4 counts over time and use this model for an early prediction of subject-specific time to cross a pre-specified CD4 threshold. Methods: Hospital based retrospective cohort study of HIV-infected patients was conducted from January 2009 to December 2014 at University of Gondar hospital, Northwest Ethiopia. Fractional polynomial random effect model is used to model the evolution of CD4 counts over time in response to treatment and to estimate the individual probability to be above a pre-selected CD4 threshold. Human subject research approval for this study was received from University of Gondar Research Ethics Committee and the medical director of the hospital. Results: A total of 1347 patients were included in the analysis presented in this paper. The cohort contributed a total of 236.58 per 100 person-years of follow-up. Later the data were divided into two periods: the first is the estimation period in which the parameters of the model are estimated and the second is the prediction period. Based on the parameters from the estimation period, model based prediction for the time to cross a threshold was estimated. The correlations between observed and predicted values of CD4 levels in the estimation period were 0.977 and 0.982 for Neverapine and Efavirenz containing regimens, respectively; while the correlation between the observed and predicted CD4 counts in the prediction period are 0.742 and 0.805 for NVP and EFV, respectively. Conclusions: The model enables us to estimate a subject-specific expected time to cross a CD4 threshold and to estimate a subject-specific probability to have CD4 count above a pre-specified threshold at each time point. By predicting long-term outcomes of CD4 count of the patients one can advise patient about the potential ART benefits that accrue in the long-term. [ABSTRACT FROM AUTHOR]

The National Health Service in the United Kingdom categorises research and research-like activities in five ways, such as 'service evaluation', 'clinical audit', 'surveillance', 'usual practice' and 'research'. Only activities classified as 'research' require review by the Research Ethics Committees. It is argued, in this position paper, that the current governance of research and research-like activities does not provide sufficient ethical oversight for projects classified as 'service evaluation'. The distinction between the categories of 'research' and 'service evaluation' can be a grey area. A considerable percentage of studies are considered as non-research and therefore not eligible to be reviewed by the Research Ethics Committee, which scrutinises research proposals rigorously to ensure they conform to established ethical standards, protecting research participants from harm, preserving their rights and providing reassurance to the public. This article explores the ethical discomfort potentially inherent in the activity currently labelled as 'service evaluation'. [ABSTRACT FROM AUTHOR]

In this paper, we investigate the effect of tuberculosis pericarditis (TBP) treatment on CD4 count changes over time and draw inferences in the presence of missing data. We accounted for missing data and conducted sensitivity analyses to assess whether inferences under missing at random (MAR) assumption are sensitive to not missing at random (NMAR) assumptions using the selection model (SeM) framework. We conducted sensitivity analysis using the local influence approach and stress-testing analysis. Our analyses showed that the inferences from the MAR are robust to the NMAR assumption and influential subjects do not overturn the study conclusions about treatment effects and the dropout mechanism. Therefore, the missing CD4 count measurements are likely to be MAR. The results also revealed that TBP treatment does not interact with HIV/AIDS treatment and that TBP treatment has no significant effect on CD4 count changes over time. Although the methods considered were applied to data in the IMPI trial setting, the methods can also be applied to clinical trials with similar settings. [ABSTRACT FROM AUTHOR]

When modeling longitudinal data, the true values of time-varying covariates may be unknown because of detection-limit censoring or measurement error. A common approach in the literature is to empirically model the covariate process based on observed data and then predict the censored values or mismeasured values based on this empirical model. Such an empirical model can be misleading, especially for censored values since the (unobserved) censored values may behave very differently than observed values due to the underlying data-generation mechanisms or disease status. In this paper, we propose a mechanistic nonlinear covariate model based on the underlying data-generation mechanisms to address censored values and mismeasured values. Such a mechanistic model is based on solid scientific or biological arguments, so the predicted censored or mismeasured values are more reasonable. We use a Monte Carlo EM algorithm for likelihood inference and apply the methods to an AIDS dataset, where viral load is censored by a lower detection limit. Simulation results confirm that the proposed models and methods offer substantial advantages over existing empirical covariate models for censored and mismeasured covariates. [ABSTRACT FROM AUTHOR]

Background: Malawi introduced an ambitious public health program known as "Option B+" which provides all HIV-infected pregnant and breastfeeding women with lifelong combination antiretroviral therapy, regardless of WHO clinical stage or CD4 cell count. The PMTCT Uptake and REtention (PURE) study aimed at evaluating the effect of peer-support on care-seeking and retention in care. Methods/design: PURE Malawi was a three-arm cluster randomized controlled trial that compared facility-based and community-based models of peer support to standard of care under Option B+ strategy. Each arm was expected to enroll a minimum of 360 women with a total minimum sample size of 1080 participants. 21 sites (clusters) were selected for inclusion in the study. This paper describes the site selection, recruitment, enrollment process and baseline characteristics of study sites and women enrolled in the trial. Results: Study implementation was managed by 3 partner organizations; each responsible for 7 study sites. The trial was conducted in the South East, South West, and Central West zones of Malawi, the zones where the implementing partners operate. Study sites included 2 district hospitals, 2 mission hospitals, 2 rural hospitals, 13 health centers and 1 private clinic. Enrollment occurred from November 2013 to November 2014, over a median period of 31 weeks (range 17-51) by site. A total of 1269 HIV-infected pregnant (1094) and breastfeeding (175) women, who were eligible to initiate ART under Option B+, were enrolled. Each site reached or surpassed the minimum sample size. Comparing the number of women enrolled versus antenatal cohort reports, sites recruited a median of 90% (IQR 75-100) of eligible reported women. In the majority of sites the ratio of pregnant and lactating women enrolled in the study was similar to the ratio of reported pregnant and lactating women starting ART in the same sites. The median age of all women was 27 (IQR 22-31) years. All women have ≥20 months of possible follow-up time; 96% ≥ 2 years (24-32 months). Conclusion: The PURE Malawi study showed that 3 implementing partner organizations could successfully recruit a complex cohort of pregnant and lactating women across 3 geographical zones in Malawi within a reasonable timeline. Trial registration: This study is registered at clinicaltrials.gov - ID Number NCT02005835. Registered 4 December, 2013. [ABSTRACT FROM AUTHOR]

Background: Routine laboratory monitoring is part of the basic care package offered to people living with the Human Immunodeficiency Virus (PLHIV). This paper aims to identify the proportion of PLHIVs with clinical and immunological failure who are virologically suppressed and risk being misclassified as treatment failures.Methods: A retrospective analysis of patient viral load data collected between January 2013 and June 2014 was conducted. Of the patients classified as experiencing either clinical or immunological failure, we evaluated the proportion of true (virological) failure, and estimated the sensitivity and specificity of the immunological and clinical criteria in diagnosing true treatment failure.Results: Of the 27,418 PLHIVs aged 2-80 years on ART in the study period, 6.8% (n = 1859) were suspected of treatment failure and their viral loads analysed. 40% (n = 737) demonstrated viral suppression (VL < 1000 copies/ml). The median viral load (VL) was 3317 copies/ml (IQR 0-47,547). Among the 799 (2.9%) PLHIVs on ART classified as having clinical failure, 41.1% (n = 328) of them had confirmed viral suppression. Of the 463 (1.7%) classified as having immunological failure, 36.9% (n = 171) had confirmed viral suppression. The sensitivity of the clinical criteria in diagnosing true failure was 61% (CI 58%-65%) while that of the immunological criteria 38% (CI 35%-42%). The specificity of the clinical criteria was 34% (CI 30%-39%) while that of the immunological criteria 66% (61%-70%). Age below 20 years was associated with a high viral load (p < .001). Sex and ART regimen were not associated with the viral load.Conclusion: Clinical and immunological criteria alone are not sufficient to identify true treatment failure. There is need for accurate treatment failure diagnosis through viral load testing to avoid incorrect early or delayed switching of patients to second-line regimens. This study recommends increased viral load testing in line with the Kenya's ART guidelines. [ABSTRACT FROM AUTHOR]

HIV and AIDS has serious repercussions on psychological, social and physical well-being, and the assessment of Quality of Life (QoL) of people living with HIV and AIDS is essential to gauge how these challenges are met. The WHOQoL-HIV Bref forms part of a suite of instruments developed by the World Health Organisation. The purpose of this paper is to describe the quality of life of a sample of HIV-infected students at a South African university, as well as explain the internal consistency between questions within each of the QoL domains. A descriptive, cross-sectional study design using a quantitative approach was applied. A non-probability, purposive sampling approach was utilized and students enrolled in the antiretroviral therapy or wellness programme were invited to voluntarily participate in this study. The WHOQOL-HIV Bref was self-administered after explanation of the questions by a registered, trained health care professional. A total of 63 students returned completed questionnaires that were included in the analysis. Acceptable to good reliability scores were established for the following domains: Level of Independence; Social Relations; Environment and Spiritual or Personal Beliefs. Assessing QoL in the sample, the lowest score was for “Spirituality” and the highest “Social Relations”. The “Physical” and “Psychological” domain scores for females were significantly lower than the score for males. There was no significant difference between any of the domain scores among participants with CD4 cell counts above or below 350 cells/mm3. In general the performance of this sample is encouraging and it is recommended that the measure be utilized for QoL screening, and further research. The WHOQOL-HIV Bref for students does not contain an academic wellness component which should be added considering the significant effects of HIV on neuropsychological functioning. Also further investigation into the reasons for poor scores obtained in physical and psychological well-being in females should be encouraged. [ABSTRACT FROM PUBLISHER]

Joint models for longitudinal and time-to-event data are particularly relevant to many clinical studies where longitudinal biomarkers could be highly associated with a time-to-event outcome. A cutting-edge research direction in this area is dynamic predictions of patient prognosis (e.g., survival probabilities) given all available biomarker information, recently boosted by the stratified/personalized medicine initiative. As these dynamic predictions are individualized, flexible models are desirable in order to appropriately characterize each individual longitudinal trajectory. In this paper, we propose a new joint model using individual-level penalized splines (P-splines) to flexibly characterize the coevolution of the longitudinal and time-to-event processes. An important feature of our approach is that dynamic predictions of the survival probabilities are straightforward as the posterior distribution of the random P-spline coefficients given the observed data is a multivariate skew-normal distribution. The proposed methods are illustrated with data from the HIV Epidemiology Research Study. Our simulation results demonstrate that our model has better dynamic prediction performance than other existing approaches. © 2017 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Advancements in antiretroviral therapy have drastically increased the life expectancy for those infected with HIV. Today, a new subgroup of older patients with long-term controlled HIV exists, and its populace is continuously mounting. Therefore, it is essential to understand the enduring effects of chronic suppressed HIV infection in order to further improve HIV management in these patients. This paper will examine the role of HIV in chronic inflammation and immune dysfunction, the dynamic interaction that exists between comorbidity and HIV, and the potential consequences of long-term antiretroviral therapy in an effort to provide the best management options for the virally suppressed HIV patient. [ABSTRACT FROM AUTHOR]

Purposes: The aim of this study was to determine the effects of nutritional status at the start of highly active anti-retroviral therapy on treatment outcomes among HIV/AIDS patients taking HAART at Jimma University Specialized Hospital. Methods: We performed a retrospective cohort study involving 340 adults who started highly active anti-retroviral therapy. The patients have been clinically followed for 2 years. Data were extracted from paper based medical charts by trained data collectors from January 30 to February 28, 2014 using data collection format. We entered data into Epi data version 3.1 and then exported to SPSS for windows version 21. Predictors of CD4 change were identified using multivariable linear regression model. Time to an event (death) was estimated by Kaplan--Meier and predictors of mortality were identified by Cox proportional hazard model. Results: Out of 340 patients, 42 patients died during the follow-up. Twenty-five (59.5 %) deaths were from malnourished group. Age, baseline CD4, sex, baseline HAART and marital status were significant predictors of immunologic recovery at different time points. Malnutrition was associated with lower CD4 recovery and greater hazard of death. Conclusions: Malnutrition tends to decrease CD4 recovery and predisposes patient to early death. [ABSTRACT FROM AUTHOR]

In order to achieve optimal benefits of antiretroviral therapy (ART), caregivers of children receiving ART are required to attend routine clinic visits monthly and administer medication to the child as prescribed. Yet, the level of adherence to these behaviours varies considerably in many settings. As a way to achieve optimal adherence in rural KwaZulu-Natal, caregivers are required to attend routine counselling sessions at HIV treatment clinics that are centred on imparting information, motivation, and behavioural skills related to medication administration. According to the information-motivation-behavioural skills model, information related to adherence, motivation, and behavioural skills are necessary and fundamental determinants of adherence to ART. The purpose of the study was to observe and document the content of adherence counselling sessions that caregivers attending rural clinics in KwaZulu Natal receive. We observed 25 adherence counselling sessions, which lasted on average 8.1 minutes. Counselling typically consisted of counsellors recording patient attendance, reporting CD4 count and viral load results to caregivers, emphasising dose times, and asking caregivers to name their medications and dosage amounts. Patients were seldom asked to demonstrate how they measure the medication. They were also not probed for problems regarding treatment, even when an unsuppressed VL was reported to a caregiver. This paper calls attention to the sub-optimal level of counselling provided to patients on ART and the urgent need to standardise and improve the training, support, and debriefing provided to counsellors. [ABSTRACT FROM PUBLISHER]

For persons living with HIV/AIDS, the relationship between stress and clinical outcomes has received little attention in current research, yet represents an important area for future research and intervention. Chronic illness has been theorized to place additional demands on a person that may exceed their ability to cope with daily life, leading to long-term stress, which then increases the risk for negative health outcomes in persons already at risk. This paper reviews the existing global literature to answer two main questions: (1) how is stress conceptualized in research with persons living with HIV/AIDS? and (2) what are the current findings linking stress to clinical outcomes? Twenty-three articles are included in the final review. Findings reveal that researchers conceptualize stress in multiple ways for persons living with HIV/AIDS, including depressive symptomology, post-traumatic stress, life events, emotions linked to stress, and biological markers (such as cortisol levels and autonomic nervous system activity). Further, findings related to the link between stress and clinical outcomes are mixed; however, stress was shown to be related to lower CD4 cell counts, higher viral load, and disease progression. Several studies also showed a link between stress and poorer treatment adherence. Implications and directions for future research are discussed, including further thought into how we conceptualize stress for persons living with HIV, future research that is necessary to elucidate current mixed findings on the link between stress and clinical outcomes, and preliminary suggestions for intervention to prevent and alleviate stress in this population. [ABSTRACT FROM PUBLISHER]

Background: Skin and soft tissue infections (SSTIs) are common in the era of community-associated methicillin resistant Staphylococcus aureus among HIV-infected patients. Recurrent infections are frequent. Risk factors for recurrence after an initial SSTI have not been well-studied.Methods: Retrospective cohort study, single center, 2005-2009. Paper and electronic medical records were reviewed by one of several physicians. Subjects with initial SSTI were followed until the time of SSTI recurrence. Standard descriptive statistics were calculated to describe the characteristics of subjects who did and did not develop a recurrent SSTI. Kaplan-Meier methods were used to estimate the risk of recurrent SSTI. A Cox regression model was developed to identify predictors of SSTI recurrence.Results: 133 SSTIs occurred in 87 individuals. 85 subjects were followed after their initial SSTI, of whom 30 (35.3 %) had a recurrent SSTI in 118.3 person-years of follow-up, for an incidence of second SSTI of 253.6 SSTIs/1000 person-years (95 % CI 166.8-385.7). The 1-year Kaplan-Meier estimated risk of a second SSTI was 29.2 % (95 % CI 20.3-41.0 %), while the 3-year risk was 47.0 % (95 % CI 34.4-61.6 %). Risk factors for recurrent SSTI in a multivariable Cox regression model were non-hepatitis liver disease (HR 3.44; 95 % CI 1.02-11.5; p = 0.05), the presence of an intravenous catheter (HR 6.50; 95 % CI 1.47-28.7; p = 0.01), and a history of intravenous drug use (IVDU) (HR 2.80; 95 % CI 1.02-7.65; p = 0.05); African-American race was associated with decreased risk of recurrent SSTI (HR 0.12; 95 % CI 0.04-0.41; p < 0.01). Some evidence was present for HIV viral load ≥ 1000 copies/mL as an independent risk factor for recurrent SSTI (HR 2.21; 95 % CI 0.99-4.94; p = 0.05). Hemodialysis, currently taking HAART, CD4+ count, trimethoprim-sulfamethoxazole or azithromycin use, initial SSTI type, diabetes mellitus, incision and drainage of the original SSTI, or self-report of being a man who has sex with men were not associated with recurrence.Conclusion: Of HIV-infected patients with an SSTI, nearly 1/3 had a recurrent SSTI within 1 year. Risk factors for recurrent SSTI were non-hepatitis liver disease, intravenous catheter presence, a history of IVDU, and non-African-American race. Low CD4+ count was not a significant risk factor for recurrence. [ABSTRACT FROM AUTHOR]

An important marker for identifying the progression of human immunodeficiency virus (HIV) infection in an individual is the CD4 cell count. Antiretroviral therapy (ART) is a treatment for HIV/AIDS (AIDS, acquired immune-deficiency syndrome) which prolongs and improves the lives of patients by improving the CD4 cell count and strengthen the immune system. This strengthening of the immune system in terms of CD4 count, not only depends on various biological factors, but also other behavioral factors. Previous studies have shown the effect of CD4 count on the mortality, but nobody has attempted to study the factors which are likely to influence the improvement in CD4 count of patients diagnosed of AIDS and undergoing ART. In this paper, we use Poisson regression model (GPR) for exploring the effect of various socio-demographic covariates such as age, gender, geographical location, and drug usage on the improvement in the CD4 count of AIDS patients. However, if the CD4 count data suffers from under or overdispersion, we use GPR model and compare it with negative binomial distribution. Finally, the model is applied for the analysis of data on patients undergoing the ART in the Ram Manohar Lohia Hospital, Delhi, India. The data exhibited overdispersion and hence, GPR model provided the best fit. [ABSTRACT FROM PUBLISHER]

Background: South Africa (SA) has expanded efforts to reduce mother-to-child transmission of HIV (MTCT) to less than 2% at six weeks after birth and to less than 5% at 18 months postpartum by 2016. Despite improved antiretroviral regimens and coverage between 2001 and 2016, there is little data on infant HIV drug resistance. This paper tracks the prevalence of HIV drug resistance patterns amongst HIV infected infants from three nationally representative studies that assessed the effectiveness of national programs to prevent MTCT (PMTCT). The first study was conducted in 2010 (under the dual therapy PMTCT policy), the second from 2011 to 12 (PMTCT Option A policy) and the third from 2012 to 13 (PMTCT Option A policy). From 2010 to 2013, infant non-nucleoside reverse transcriptase inhibitor (NNRTI) exposure increased from single dose to daily throughout breastfeeding; maternal nucleoside reverse transcriptase inhibitor (NRTI) and NNRTI exposure increased with initiation of NNRTI-and NRTI- containing triple antiretroviral therapy (ART) earlier in gestation and at higher CD4 cell counts.Methods: Three nationally representative surveys were conducted in 2010, 2011-12 and 2012-13. During the surveys, mothers with known, unknown, or no exposure to antiretrovirals for PMTCT and their infants were included, and MTCT was measured. For this paper, infant dried blood spots (iDBS) from HIV PCR positive infants aged 4-8 weeks, with consent for additional iDBS testing, were analysed for HIV drug resistance at the National Institute of Communicable Diseases (NICD), SA, using an in-house assay validated by the Centers for Disease Control and Prevention (CDC). Total viral nucleic acid was extracted from 2 spots and amplified by nested PCR to generate a ~ 1 kb amplicon that was sequenced using Sanger sequencing technologies. Sequence assembly and editing was performed using RECall v3.Results: Overall, HIV-1 drug resistance was detected in 51% (95% Confidence interval (CI) [45-58%]) of HIV PCR positive infants, 37% (95% CI [28-47%]) in 2010, 64% (95% CI [53-74%]) in 2011 and 63% (95% CI [47-77%]) in 2012 (p < 0.0001), particularly to the NNRTI drug class. Pooled analyses across all three surveys demonstrated that infants whose mothers received ART showed the highest prevalence of resistance (74%); 26% (21/82) of HIV PCR positive infants with no or undocumented antiretroviral drug (ARV) exposure harboured NNRTI resistance.Conclusions: These data demonstrate increasing NNRTI resistance amongst newly-diagnosed infants in a high HIV prevalence setting where maternal ART coverage increased across the years, starting earlier in gestation and at higher CD4 cell counts. This is worrying as lifelong maternal ART coverage for HIV positive pregnant and lactating women is increasing. Also of concern is that resistant virus was detected in HIV positive infants whose mothers were not exposed to ARVs, raising questions about circulating resistant virus. Numbers in this group were too small to assess trends over the three years. [ABSTRACT FROM AUTHOR]

The incidence of human immunodeficiency virus (HIV) is the rate at which new HIV infections occur in populations. The development of accurate, practical, and cost-effective approaches to estimation of HIV incidence is a priority among researchers in HIV surveillance because of limitations with existing methods. In this paper, we develop methods for estimating HIV incidence rates using multiple biomarkers in biological samples collected from a cross-sectional survey. An advantage of the method is that it does not require longitudinal follow-up of individuals. We use assays for BED, avidity, viral load, and CD4 cell count data from clade B samples collected in several US epidemiologic cohorts between 1987 and 2010. Considering issues of accuracy, cost, and implementation, we identify optimal multiassay algorithms for estimating incidence. We find that the multiple-biomarker approach to cross-sectional HIV incidence estimation corrects the significant deficiencies of currently available approaches and is a potentially powerful and practical tool for HIV surveillance. [ABSTRACT FROM AUTHOR]

Objectives The aim of the paper was to describe the association of religion with HIV outcomes in newly diagnosed Africans living in London. Methods A survey of newly diagnosed HIV-positive Africans attending 15 HIV treatment centres across London was carried out between April 2004 and February 2006. Confidential self-completed questionnaires were used, linked to clinical records. Bivariate analyses were conducted to ascertain whether religious beliefs were associated with late diagnosis, antiretroviral therapy, and immunological and virological outcome 6 months post diagnosis. Results A total of 246 Black Africans were eligible and included in the analysis: 62.6% were women, and the median age was 34 years. The median CD4 count at diagnosis was 194 cells/ μL (range 0-1334 cells/ μL) and 75.6% presented late, as defined as a CD4 count < 350 cells/ μL. Most participants were religious: non- Roman Catholic Christians (55.7%), Roman Catholics (35.2%) and Muslims (6.1%). Only 1.2% stated that they did not have a religion. Participants who attended religious services at least monthly were more likely to believe that 'faith alone can cure HIV' than those who attended less frequently (37.7% vs. 15.0%; P = 0.002). A small proportion (5.2%) believed that taking antiretroviral therapy implied a lack of faith in God. Bivariate analysis found no relationship between religiousness (as measured using frequency of attendance at religious services and religious attitudes or beliefs) and late diagnosis, changes in CD4 count/viral load 6 months post diagnosis, or initiation of antiretroviral therapy. Conclusions Strong religious beliefs about faith and healing are unlikely to act as a barrier to accessing HIV testing or antiretroviral treatment for Black Africans living in London. [ABSTRACT FROM AUTHOR]

Background: COVID-19 pathophysiology and the predictive factors involved are not fully understood, but lymphocytes dysregulation appears to play a role. This paper aims to evaluate lymphocyte subsets in the pathophysiology of COVID-19 and as predictive factors for severe disease. Patient and methods: A prospective cohort study of patients with SARS-CoV-2 bilateral pneumonia recruited at hospital admission. Demographics, medical history, and data regarding SARS-CoV-2 infection were recorded. Patients systematically underwent complete laboratory tests, including parameters related to COVID-19 as well as lymphocyte subsets study at the time of admission. Severe disease criteria were established at admission, and patients were classified on remote follow-up according to disease evolution. Linear regression models were used to assess associations with disease evolution, and Receiver Operating Characteristic (ROC) and the corresponding Area Under the Curve (AUC) were used to evaluate predictive values. Results: Patients with critical COVID-19 showed a decrease in CD3+CD4+ T cells count compared to non-critical (278 (485 IQR) vs. 545 (322 IQR)), a decrease in median CD4+/CD8+ ratio (1.7, (1.7 IQR) vs. 3.1 (2.4 IQR)), and a decrease in median CD4+MFI (21,820 (4491 IQR) vs. 26,259 (3256 IQR)), which persisted after adjustment. CD3+CD8+ T cells count had a high correlation with time to hospital discharge (PC = −0.700 (−0.931, −0.066)). ROC curves for predictive value showed lymphocyte subsets achieving the best performances, specifically CD3+CD4+ T cells (AUC = 0.756), CD4+/CD8+ ratio (AUC = 0.767), and CD4+MFI (AUC = 0.848). Conclusions: A predictive value and treatment considerations for lymphocyte subsets are suggested, especially for CD3CD4+ T cells. Lymphocyte subsets determination at hospital admission is recommended. [ABSTRACT FROM AUTHOR]

Background: Dropout is a common problem in longitudinal clinical trials and cohort studies, and is of particular concern when dropout occurs for reasons that may be related to the outcome of interest. This paper reviews common parametric models to account for dropout and introduces a Bayesian semi-parametric varying coefficient model for exponential family longitudinal data with non-ignorable dropout.Methods: To demonstrate these methods, we present results from a simulation study and estimate the impact of drug use on longitudinal CD4 + T cell count and viral load suppression in the Women's Interagency HIV Study. Sensitivity analyses are performed to consider the impact of model assumptions on inference. We compare results between our semi-parametric method and parametric models to account for dropout, including the conditional linear model and a parametric frailty model. We also compare results to analyses that fail to account for dropout.Results: In simulation studies, we show that semi-parametric methods reduce bias and mean squared error when parametric model assumptions are violated. In analyses of the Women's Interagency HIV Study data, we find important differences in estimates of changes in CD4 + T cell count over time in untreated subjects that report drug use between different models used to account for dropout. We find steeper declines over time using our semi-parametric model, which makes fewer assumptions, compared to parametric models. Failing to account for dropout or to meet parametric assumptions of models to account for dropout could lead to underestimation of the impact of hard drug use on CD4 + cell count decline in untreated subjects. In analyses of subjects that initiated highly active anti-retroviral treatment, we find that the estimated probability of viral load suppression is lower in models that account for dropout.Conclusions: Non-ignorable dropout is an important consideration when analyzing data from longitudinal clinical trials and cohort studies. While methods that account for non-ignorable dropout must make some unavoidable assumptions that cannot be verified from the observed data, many methods make additional parametric assumptions. If these assumptions are not met, inferences can be biased, making more flexible methods with minimal assumptions important. [ABSTRACT FROM AUTHOR]