Potential for high dynamic range Sedia Limiting Antigen antibody assay to support viral load monitoring during antiretroviral therapy.

INTRODUCTION: Viral Load (VL) monitoring is a crucial component of patient care during antiretroviral therapy (ART) but is not routinely available in many resource-constrained settings, where millions of patients will require care for decades to come. We hypothesise a serologic 'recent infection' test (Sedia LAg assay) which has a high dynamic range for detecting antigen-driven antibody response can provide informative proxies for VL trajectories. METHODS: A retrospective study where we analysed data linked via specimens in a well-described repository for recent infection test benchmarking (CEPHIA collaboration). Patient panels were comprised of 1) observations straddling ART start; 2) observations from a period of stable viral suppression; 3) observations straddling rebound after a period of viral suppression. We analysed an individual's Sedia LAg ELISA normalised optical density (ODn) trends within these categories. Using groups 2) and 3) we evaluated the specificity and sensitivity of a proposed proxy for "the latest observation is at a time of VL rebound"; proxy was defined as follows: we estimated patient-specific mean-previous-ODn for all observations with at least two preceding virally suppressed observations. We considered various thresholds to define both "VL suppression" and "ODn uptick". RESULTS: In regression analysis by category: 1) ODn gradients are statistically significantly negative just after ART-start (p = 0.010); 2) During periods of stable viral suppression, ODn tended to decline, but not statistically significantly, for a range of clinically meaningful "VL suppression" thresholds; 3) comparing ODn values just before, versus at, "VL rebound", ODn changes were statistically significantly increasing at rebound (p = 0.001). In the analysis comparing groups 2) and 3), at a Z score threshold of 0.8, the proposed proxy for a first viral rebound had an observed specificity and sensitivity both close to 90%. CONCLUSION: The high dynamic range of serological tests previously investigated for defining 'recent infection' has potential, as demonstrated using the Sedia LAg ELISA, to provide meaningful information about the success of ART, during treatment initiation, at times of stable suppression, and to flag possible viral rebound. It should be investigated how this can be combined with patient management workflows and (clinical and) other data, to provide efficiencies in long-term monitoring viral control in resource-limited settings.

Aligning the principles and practice of research integrity and research fairness in global health: a mixed-methods study.

INTRODUCTION: In the past decade, global health research has seen a growing emphasis on research integrity and fairness. The concept of research integrity emerged in response to the reproducibility crisis in science during the late 2000s. Research fairness initiatives aim to enhance ownership and inclusivity in research involving partners with varying powers, decision-making roles and resource capacities, ultimately prioritising local health research needs. Despite extensive academic discussions, empirical data on these aspects, especially in the context of global health, remain limited. METHODS: To address this gap, we conducted a mixed-methods study focusing on research integrity and fairness. The study included an online frequency survey and in-depth key informant interviews with researchers from international research networks. The dual objectives were to quantify the frequency of practices related to research integrity and fairness and explore the determinants influencing these practices in global health. RESULTS: Out of 145 participants in the quantitative survey (8.4% response rate), findings indicate that global health researchers generally adhere to principles of research integrity and fairness, with variations in reported behaviours. The study identified structural, institutional and individual factors influencing these patterns, including donor landscape rigidity, institutional investments in relationship building, guidelines, mentoring and power differentials among researchers. CONCLUSION: This research highlights that, despite some variations, there is a substantial alignment between research integrity and fairness, with both sharing similar determinants and the overarching goal of enhancing research quality and societal benefits. The study emphasises the potential to explicitly recognise and leverage these synergies, aligning both agendas to further advance global health research.

The Biodistribution and Utility of 99mTc-Ethylenedicysteine-Deoxyglucose (99mTc-Glucosamine) in the Identification of Active Disease in Patients with Rheumatoid Arthritis-a Single Center Prospective Study.

Purpose: Our objectives were to investigate the utility of 99mTc-ethylenedicysteine-deoxyglucose (ECDG) in identifying active disease in the joints of patients with rheumatoid arthritis (RA), as well as to evaluate the biodistribution of this radiopharmaceutical. Methods: A prospective study was conducted at the Department of Nuclear Medicine of the University of the Free State/Universitas Academic Hospital in Bloemfontein, South Africa. Twenty-two participants from the rheumatology department diagnosed with RA according to the ACR/EULAR classification criteria were enrolled. Participants were injected with 20-25 mCi of 99mTc-ECDG. Flow, blood pool, whole body, delayed static, and SPECT/CT images were acquired. Known sites of disease were qualitatively assessed for intensity of uptake, and disease severity was graded (Grade 0-3). Results: Twenty-two participants were studied. The median (interquartile range) age was 59 (49-68) years, and the majority (n = 21; 95.5%) were females. There was abnormal increased uptake of 99mTc-ECDG noted in majority of the sites of known disease, including unknown sites. SPECT/CT imaging localized radiotracer uptake specifically to the synovial space. Similar biodistribution of radiotracer was noted in all patients, irrespective of disease severity or fasting status. Conclusion: 99mTc-ECDG can efficiently assess disease activity in the joints of patients with RA. It accumulates in sites of both clinical and subclinical disease and might be a very useful tool for the rheumatologist in the management of patients with RA.

Elicitation of domain knowledge for a machine learning model for paediatric critical illness in South Africa.

Objectives: Delays in identification, resuscitation and referral have been identified as a preventable cause of avoidable severity of illness and mortality in South African children. To address this problem, a machine learning model to predict a compound outcome of death prior to discharge from hospital and/or admission to the PICU was developed. A key aspect of developing machine learning models is the integration of human knowledge in their development. The objective of this study is to describe how this domain knowledge was elicited, including the use of a documented literature search and Delphi procedure. Design: A prospective mixed methodology development study was conducted that included qualitative aspects in the elicitation of domain knowledge, together with descriptive and analytical quantitative and machine learning methodologies. Setting: A single centre tertiary hospital providing acute paediatric services. Participants: Three paediatric intensivists, six specialist paediatricians and three specialist anaesthesiologists. Interventions: None. Measurements and main results: The literature search identified 154 full-text articles reporting risk factors for mortality in hospitalised children. These factors were most commonly features of specific organ dysfunction. 89 of these publications studied children in lower- and middle-income countries. The Delphi procedure included 12 expert participants and was conducted over 3 rounds. Respondents identified a need to achieve a compromise between model performance, comprehensiveness and veracity and practicality of use. Participants achieved consensus on a range of clinical features associated with severe illness in children. No special investigations were considered for inclusion in the model except point-of-care capillary blood glucose testing. The results were integrated by the researcher and a final list of features was compiled. Conclusion: The elicitation of domain knowledge is important in effective machine learning applications. The documentation of this process enhances rigour in such models and should be reported in publications. A documented literature search, Delphi procedure and the integration of the domain knowledge of the researchers contributed to problem specification and selection of features prior to feature engineering, pre-processing and model development.

Development of artificial neural network models for paediatric critical illness in South Africa.

Objectives: Failures in identification, resuscitation and appropriate referral have been identified as significant contributors to avoidable severity of illness and mortality in South African children. In this study, artificial neural network models were developed to predict a composite outcome of death before discharge from hospital or admission to the PICU. These models were compared to logistic regression and XGBoost models developed on the same data in cross-validation. Design: Prospective, analytical cohort study. Setting: A single centre tertiary hospital in South Africa providing acute paediatric services. Patients: Children, under the age of 13 years presenting to the Paediatric Referral Area for acute consultations. Outcomes: Predictive models for a composite outcome of death before discharge from hospital or admission to the PICU. Interventions: None. Measurements and main results: 765 patients were included in the data set with 116 instances (15.2%) of the study outcome. Models were developed on three sets of features. Two derived from sequential floating feature selection (one inclusive, one parsimonious) and one from the Akaike information criterion to yield 9 models. All developed models demonstrated good discrimination on cross-validation with mean ROC AUCs greater than 0.8 and mean PRC AUCs greater than 0.53. ANN1, developed on the inclusive feature-et demonstrated the best discrimination with a ROC AUC of 0.84 and a PRC AUC of 0.64 Model calibration was variable, with most models demonstrating weak calibration. Decision curve analysis demonstrated that all models were superior to baseline strategies, with ANN1 demonstrating the highest net benefit. Conclusions: All models demonstrated satisfactory performance, with the best performing model in cross-validation being an ANN model. Given the good performance of less complex models, however, these models should also be considered, given their advantage in ease of implementation in practice. An internal validation study is now being conducted to further assess performance with a view to external validation.

Quantitative interpretation of Sedia LAg Assay test results after HIV diagnosis.

BACKGROUND: Testing for 'recent HIV infection' is common in surveillance, where only population-level estimates (of incidence) are reported. Typically, 'recent infection' is a category, obtained by applying a threshold on an underlying continuous biomarker from some laboratory assay(s). Interpreting the biomarker values obtained for individual subjects, as estimates of the date of infection, has obvious potential applications in the context of studies of early infection, and has also for some years attracted significant interest as an extra component of post-test counselling and treatment initiation. The applicable analyses have typically run aground on the complexity of the full biomarker growth model, which is in principle a non-linear mixed-effects model of unknown structure, the fitting of which seems infeasible from realistically obtainable data. METHODS: It is known that to estimate Mean Duration of Recent Infection (MDRI) at a given value of the recent/non-recent -infection discrimination threshold, one may compress the full biomarker growth model into a relation capturing the probability of a recent test result as a function of time t since infection, given a value of assay threshold h which defines the recent/non-recent discrimination. We demonstrate that the derivative (gradient), with respect to h. of the probability of recent infection, seen as a function of both t and h, is identical to the formal likelihood relevant to Bayesian inference of the time since seroconversion, for a subject yielding an assay result h, at or close to the date of their first positive HIV test. This observation bypasses the need for fitting a complex detailed biomarker growth model. Using publicly available data from the CEPHIA collaboration, we calibrated this likelihood function for the Sedia Lag assay, and performed Bayesian inference on hypothetical infection data. RESULTS: We demonstrate the generation of posteriors for infection date, for patients with various delays between their last negative and first positive HIV test, and a range of LAg assay results (ODn) hypothetically obtained on the date of the first positive result. CONCLUSION: Depending on the last-negative / first-positive interval, there is a range of ODn values that yields posteriors significantly different from the uniform prior one would be left with based merely on interval censoring. Hence, a LAg ODn obtained on the date of, or soon after, diagnosis contains potentially significant information about infection dating. It seems worth analysing other assays with meaningful dynamic range, especially tests already routinely used in primary HIV diagnosis (for example chemiluminescent assays and reader/cartridge lateral flow tests which admit objective variable line intensity readings) which have a sufficient dynamic range that corresponds to a clinically meaningful range of times-since-infection that are worth distinguishing from each other.

The epidemiological profile of meningitis among adults in a South African district hospital.

Introduction: understanding the epidemiological profile of a disease in a particular region allows for proper planning of public health resources for prevention, early diagnosis and treatment. In this present study, we describe the epidemiological profile of viral, fungal, tuberculous and bacterial meningitis among adults at National District Hospital (NDH), Free State province, over three years period (January 2017 to December 2019). Methods: a retrospective, observational study of all adult meningitis cases, managed at the National District Hospital (NDH) Bloemfontein, Free State Province, South Africa between January 2017 and December 2019. Results: of the 236 case files reviewed, majority (93.2%; n=220) of the patients managed for meningitis were black, as well as males (55.5%; n = 131). Higher incidence was found between the ages 20 to 49 (81.7%). Of those who died, the majority (n = 14; 63.6%) were males, in the age group 40-49 (n = 7; 31.8%), had TB meningitis (n = 12; 54.5%), were HIV positive (n = 20; 90.9%), and had cell count <100 cells/mm3 (n = 10; 45.5%). Conclusion: our study suggests that combining information on patient demography, co-morbidities, clinical presentation, and examination findings can substantially contribute to raising clinical suspicion, leading to swift identification, diagnosis, and treatment of patients.

An Artificial Neural Network Model for Pediatric Mortality Prediction in Two Tertiary Pediatric Intensive Care Units in South Africa. A Development Study.

Objectives: The performance of mortality prediction models remain a challenge in lower- and middle-income countries. We developed an artificial neural network (ANN) model for the prediction of mortality in two tertiary pediatric intensive care units (PICUs) in South Africa using free to download and use software and commercially available computers. These models were compared to a logistic regression model and a recalibrated version of the Pediatric Index of Mortality 3. Design: This study used data from a retrospective cohort study to develop an artificial neural model and logistic regression model for mortality prediction. The outcome evaluated was death in PICU. Setting: Two tertiary PICUs in South Africa. Patients: 2,089 patients up to the age of 13 completed years were included in the study. Interventions: None. Measurements and Main Results: The AUROC was higher for the ANN (0.89) than for the logistic regression model (LR) (0.87) and the recalibrated PIM3 model (0.86). The precision recall curve however favors the ANN over logistic regression and recalibrated PIM3 (AUPRC = 0.6 vs. 0.53 and 0.58, respectively. The slope of the calibration curve was 1.12 for the ANN model (intercept 0.01), 1.09 for the logistic regression model (intercept 0.05) and 1.02 (intercept 0.01) for the recalibrated version of PIM3. The calibration curve was however closer to the diagonal for the ANN model. Conclusions: Artificial neural network models are a feasible method for mortality prediction in lower- and middle-income countries but significant challenges exist. There is a need to conduct research directed toward the acquisition of large, complex data sets, the integration of documented clinical care into clinical research and the promotion of the development of electronic health record systems in lower and middle income settings.

A systematic review and meta-analysis of the sensitivity of antibody tests for the laboratory confirmation of COVID-19.

Aim: The aim of this study was to investigate the utility of serological tests for the diagnosis of COVID-19 during the first week of symptom onset in patients confirmed with the real-time RT-PCR. Materials & methods: A systematic review and meta-analysis of 58 publications were performed using data obtained from Academic Search Ultimate, Africa-wide, Scopus, Web of Science and MEDLINE. Results: We found that the highest pooled sensitivities were obtained with ELISA IgM-IgG and chemiluminescence immunoassay IgM tests. Conclusion: Serological tests have low sensitivity within the first week of symptom onset and cannot replace nucleic acid amplification tests. However, serological assays can be used to support nucleic acid amplification tests.

Comorbidities in SARS-CoV-2 Patients: a Systematic Review and Meta-Analysis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread across the globe at unprecedented speed and is showing no signs of slowing down. The outbreak of coronavirus disease 2019 (COVID-19) has led to significant health burden in infected patients especially in those with underlying comorbidities. The aim of this study was to evaluate the correlation between comorbidities and their role in the exacerbation of disease in COVID-19 patients leading to fatal outcomes. A systematic review was conducted using data from MEDLINE, Scopus, Web of Science, and EMBASE databases published from 1 December 2019 to 15 September 2020. Fifty-three articles were included in the systematic review. Of those 53 articles, 8 articles were eligible for meta-analysis. Hypertension, obesity, and diabetes mellitus were identified to be the most prevalent comorbidities in COVID-19 patients. Our meta-analysis showed that cancer, chronic kidney diseases, diabetes mellitus, and hypertension were independently associated with mortality in COVID-19 patients. Chronic kidney disease was statistically the most prominent comorbidity leading to death. However, despite having high prevalence, obesity was not associated with mortality in COVID-19 patients.IMPORTANCE COVID-19 has plagued the world since it was first identified in December 2019. Previous systematic reviews and meta-analysis were limited by various factors such as the usage of non-peer reviewed data and were also limited by the lack of clinical data on a global scale. Comorbidities are frequently cited as risk factors for severe COVID-19 outcomes. However, the degree to which specific comorbidities impact the disease is debatable. Our study selection involves a global reach and covers all comorbidities that were reported to be involved in the exacerbation of COVID-19 leading to fatal outcomes, which allows us to identify the specific comorbidities that have higher risk in patients. The study highlights COVID-19 high-risk groups. However, further research should focus on the status of comorbidities and prognosis in COVID-19 patients.

Correction: Cumulative viral load as a predictor of CD4+ T-cell response to antiretroviral therapy using Bayesian statistical models.

[This corrects the article DOI: 10.1371/journal.pone.0224723.].

Cumulative viral load as a predictor of CD4+ T-cell response to antiretroviral therapy using Bayesian statistical models.

INTRODUCTION: There are Challenges in statistically modelling immune responses to longitudinal HIV viral load exposure as a function of covariates. We define Bayesian Markov Chain Monte Carlo mixed effects models to incorporate priors and examine the effect of different distributional assumptions. We prospectively fit these models to an as-yet-unpublished data from the Tshwane District Hospital HIV treatment clinic in South Africa, to determine if cumulative log viral load, an indicator of long-term viral exposure, is a valid predictor of immune response. METHODS: Models are defined, to express 'slope', i.e. mean annual increase in CD4 counts, and 'asymptote', i.e. the odds of having a CD4 count ≥500 cells/µL during antiretroviral treatment, as a function of covariates and random-effects. We compare the effect of using informative versus non-informative prior distributions on model parameters. Models with cubic splines or Skew-normal distributions are also compared using the conditional Deviance Information Criterion. RESULTS: The data of 750 patients are analyzed. Overall, models adjusting for cumulative log viral load provide a significantly better fit than those that do not. An increase in cumulative log viral load is associated with a decrease in CD4 count slope (19.6 cells/µL (95% credible interval: 28.26, 10.93)) and a reduction in the odds of achieving a CD4 counts ≥500 cells/µL (0.42 (95% CI: 0.236, 0.730)) during 5 years of therapy. Using informative priors improves the cumulative log viral load estimate, and a skew-normal distribution for the random-intercept and measurement error results is a better fit compared to using classical Gaussian distributions. DISCUSSION: We demonstrate in an unpublished South African cohort that cumulative log viral load is a strong and significant predictor of both CD4 count slope and asymptote. We argue that Bayesian methods should be used more frequently for such data, given their flexibility to incorporate prior information and non-Gaussian distributions.

Performance comparison of the Maxim and Sedia Limiting Antigen Avidity assays for HIV incidence surveillance.

BACKGROUND: Two manufacturers, Maxim Biomedical and Sedia Biosciences Corporation, supply CDC-approved versions of the HIV-1 Limiting Antigen Avidity EIA (LAg) for detecting 'recent' HIV infection in cross-sectional incidence estimation. This study assesses and compares the performance of the two assays for incidence surveillance. METHODS: We ran both assays on a panel of 2,500 well-characterized HIV-1-infected specimens. We analysed concordance of assay results, assessed reproducibility using repeat testing and estimated mean durations of recent infection (MDRIs) and false-recent rates (FRRs) for a range of normalized optical density (ODn) thresholds, alone and in combination with viral load thresholds. We defined three hypothetical surveillance scenarios, similar to the Kenyan and South African epidemics, and a concentrated epidemic. These scenarios allowed us to evaluate the precision of incidence estimates obtained by means of various recent infection testing algorithms (RITAs) based on each of the two assays. RESULTS: The Maxim assay produced lower ODn values than the Sedia assay on average, largely as a result of higher calibrator readings (mean OD of 0.749 vs. 0.643), with correlation of normalized readings lower (R2 = 0.908 vs. R2 = 0.938). Reproducibility on blinded control specimens was slightly better for Maxim. The MDRI of a Maxim-based algorithm at the 'standard' threshold (ODn ≤1.5 & VL >1,000) was 201 days (95% CI: 180,223) and for Sedia 171 (152,191). The difference Differences in MDRI were estimated at 32.7 (22.9,42.8) and 30.9 days (21.7,40.7) for the two algorithms, respectively. Commensurately, the Maxim algorithm had a higher FRR in treatment-naive subjects (1.7% vs. 1.1%). The two assays produced similar precision of incidence estimates in the three surveillance scenarios. CONCLUSIONS: Differences between the assays can be primarily attributed to the calibrators supplied by the manufacturers. Performance for surveillance was extremely similar, although different thresholds were optimal (i.e. produced the lowest variance of incidence estimates) and at any given ODn threshold, different estimates of MDRI and FRR were obtained. The two assays cannot be treated as interchangeable: assay and algorithm-specific performance characteristic estimates must be used for survey planning and incidence estimation.

Systematic review of statistically-derived models of immunological response in HIV-infected adults on antiretroviral therapy in Sub-Saharan Africa.

INTRODUCTION: In Sub-Saharan African (SSA) resource limited settings, Cluster of Differentiation 4 (CD4) counts continue to be used for clinical decision making in antiretroviral therapy (ART). Here, HIV-infected people often remain with CD4 counts <350 cells/µL even after 5 years of viral load suppression. Ongoing immunological monitoring is necessary. Due to varying statistical modeling methods comparing immune response to ART across different cohorts is difficult. We systematically review such models and detail the similarities, differences and problems. METHODS: 'Preferred Reporting Items for Systematic Review and Meta-Analyses' guidelines were used. Only studies of immune-response after ART initiation from SSA in adults were included. Data was extracted from each study and tabulated. Outcomes were categorized into 3 groups: 'slope', 'survival', and 'asymptote' models. Wordclouds were drawn wherein the frequency of variables occurring in the reviewed models is indicated by their size and color. RESULTS: 69 covariates were identified in the final models of 35 studies. Effect sizes of covariates were not directly quantitatively comparable in view of the combination of differing variables and scale transformation methods across models. Wordclouds enabled the identification of qualitative and semi-quantitative covariate sets for each outcome category. Comparison across categories identified sex, baseline age, baseline log viral load, baseline CD4, ART initiation regimen and ART duration as a minimal consensus set. CONCLUSION: Most models were different with respect to covariates included, variable transformations and scales, model assumptions, modelling strategies and reporting methods, even for the same outcomes. To enable comparison across cohorts, statistical models would benefit from the application of more uniform modelling techniques. Historic efforts have produced results that are anecdotal to individual cohorts only. This study was able to define 'prior' knowledge in the Bayesian sense. Such information has value for prospective modelling efforts.

Reevaluating Cumulative HIV-1 Viral Load as a Prognostic Predictor: Predicting Opportunistic Infection Incidence and Mortality in a Ugandan Cohort.

Recent studies have evaluated cumulative human immunodeficiency virus type 1 (HIV-1) viral load (cVL) for predicting disease outcomes, with discrepant results. We reviewed the disparate methodological approaches taken and evaluated the prognostic utility of cVL in a resource-limited setting. Using data on the Infectious Diseases Institute (Makerere University, Kampala, Uganda) cohort, who initiated antiretroviral therapy in 2004-2005 and were followed up for 9 years, we calculated patients' time-updated cVL by summing the area under their viral load curves on either a linear scale (cVL1) or a logarithmic scale (cVL2). Using Cox proportional hazards models, we evaluated both metrics as predictors of incident opportunistic infections and mortality. Among 489 patients analyzed, neither cVL measure was a statistically significant predictor of opportunistic infection risk. In contrast, cVL2 (but not cVL1) was a statistically significant predictor of mortality, with each log10 increase corresponding to a 1.63-fold (95% confidence interval: 1.02, 2.60) elevation in mortality risk when cVL2 was accumulated from baseline. However, whether cVL is predictive or not hinges on difficult choices surrounding the cVL metric and statistical model employed. Previous studies may have suffered from confounding bias due to their focus on cVL1, which strongly correlates with other variables. Further methodological development is needed to illuminate whether the inconsistent predictive utility of cVL arises from causal relationships or from statistical artifacts.

Characteristics of Sexually Transmitted Infections among High-Risk HIV-Positive Patients Attending an Urban Clinic in Uganda.

BACKGROUND: Sexually transmitted infections (STIs) significantly increase HIV transmission. Sexually transmitted infections may be asymptomatic and therefore remain undiagnosed in HIV-positive persons. Routine screening and treatment of STIs in HIV-positive high-risk populations in sub-Saharan Africa have not been described previously. METHODS: We reviewed data from an HIV-positive high-risk population at the Infectious Diseases Institute, Makerere University, a large urban HIV clinic, between July 2011 and April 2012. Our high-risk population cohort included female sex workers, long-distance drivers, barmaids, taxi drivers, commercial motorcycle "boda-boda" riders, soldiers, police officers, prison officers, security guards, prisoners, and fishermen. RESULTS: Of 355 participants enrolled in the high-risk population's program, 21.4% were diagnosed with an STI either clinically or microbiologically. The STIs diagnosed in this population were syphilis, hepatitis B, genital herpes, human papilloma virus infection (condylomata acuminata), nongonococcal urethritis (NGU), and gonorrhea. Rates of syphilis, hepatitis B, genital herpes, condylomata acuminata, NGU, and gonorrhea were 8.5%, 7.0%, 5.4%, 1.4%, 1.4%, and 0.3%, respectively. CONCLUSION: Clinical and microbiologically diagnosed STIs were diagnosed in nearly one-fourth of the HIV-positive high-risk population. HIV care programs should note our high rates of STIs among HIV-positive high-risk populations and consider routine screening and treatment algorithms for these populations in their own settings.

Outcomes in a Cohort of Patients Started on Antiretroviral Treatment and Followed up for a Decade in an Urban Clinic in Uganda.

BACKGROUND: Short-medium term studies from sub-Saharan Africa show that, despite high early mortality, substantial loss to program, and high rates toxicity, patients on antiretroviral treatment have achieved outcomes comparable to those in developed settings. However, these studies were unable to account for long term outcomes of patients as they stayed longer on treatment. OBJECTIVES: We aim to describe ten years outcomes of one of the first cohort of HIV positive patients started on antiretroviral treatment (ART) in Sub-Saharan Africa. METHODS: We report 10-years outcomes including mortality, retention, CD4-count response, virological outcomes, ART regimens change from a prospective cohort of 559 patients initiating ART and followed up for 10 years Uganda. RESULTS: Of 559 patients, 69.1% were female, median age (IQR) was 38 (33-44) years, median CD4-count (IQR) 98 (21-163) cell/µL; 74% were started on stavudine, lamivudine and nevirapine, 26% on zidovudine, lamivudine and efavirenz. After 10 years 361 (65%) patients were still in the study; 127 (22.7%) had died; 30 (5%) were lost to follow-up; 27 (5%) transferred; 18 (3%) withdrew consent. The probability of death was high in the first year (0.15, 95%, CI 0.12-0.18). The median CD4 count increased from 98 to 589 cell/µL (IQR: 450-739 cell/µL) with a median increase of 357 cells/µL (IQR: 128-600 cells/µL); 7.4% never attained initial viral suppression and of those who did 31.7% experienced viral failure. Three hundred and two patients had at least one drug substitution while on first line after a median of 40 months; 66 (11.9%) of the patients were switched to a second line PI-based regimen due to confirmed treatment failure. CONCLUSIONS: Despite the high rate of early mortality due to advanced disease at presentation the outcomes from this cohort are encouraging, particularly the remarkable and incremental immune-recovery and a satisfactory rate of virologic suppression.

Global health leadership training in resource-limited settings: a collaborative approach by academic institutions and local health care programs in Uganda.

INTRODUCTION: Due to a limited health workforce, many health care providers in Africa must take on health leadership roles with minimal formal training in leadership. Hence, the need to equip health care providers with practical skills required to lead high-impact health care programs. In Uganda, the Afya Bora Global Health Leadership Fellowship is implemented through the Makerere University College of Health Sciences (MakCHS) and her partner institutions. Lessons learned from the program, presented in this paper, may guide development of in-service training opportunities to enhance leadership skills of health workers in resource-limited settings. METHODS: The Afya Bora Consortium, a consortium of four African and four U.S. academic institutions, offers 1-year global health leadership-training opportunities for nurses and doctors. Applications are received and vetted internationally by members of the consortium institutions in Botswana, Kenya, Tanzania, Uganda, and the USA. Fellows have 3 months of didactic modules and 9 months of mentored field attachment with 80% time dedicated to fellowship activities. Fellows' projects and experiences, documented during weekly mentor-fellow meetings and monthly mentoring team meetings, were compiled and analyzed manually using pre-determined themes to assess the effect of the program on fellows' daily leadership opportunities. RESULTS: Between January 2011 and January 2015, 15 Ugandan fellows (nine doctors and six nurses) participated in the program. Each fellow received 8 weeks of didactic modules held at one of the African partner institutions and three online modules to enhance fellows' foundation in leadership, communication, monitoring and evaluation, health informatics, research methodology, grant writing, implementation science, and responsible conduct of research. In addition, fellows embarked on innovative projects that covered a wide spectrum of global health challenges including critical analysis of policy formulation and review processes, bottlenecks in implementation of national HIV early infant diagnosis and prevention of mother-to-child HIV-transmission programs, and use of routine laboratory data about antibiotic resistance to guide updates of essential drug lists. CONCLUSION: In-service leadership training was feasible, with ensured protected time for fellows to generate evidence-based solutions to challenges within their work environment. With structured mentorship, collaborative activities at academic institutions and local health care programs equipped health care providers with leadership skills.

Steady-state pharmacokinetics of rilpivirine under different meal conditions in HIV-1-infected Ugandan adults.

OBJECTIVES: To investigate the effect of food on the steady-state pharmacokinetics of rilpivirine when administered as a fixed-dose combination tablet containing tenofovir disoproxil fumarate, emtricitabine plus rilpivirine (TDF/FTC/RPV) in HIV-1-infected Ugandan patients. METHODS: This was an open-label, three-period, longitudinal pharmacokinetic study with patients serving as their own controls. Fifteen consenting and virologically suppressed HIV-1-infected adults were switched from an efavirenz-based regimen to TDF/FTC/RPV for 56 days. Enrolled patients underwent 24 h blood sampling with TDF/FTC/RPV dosing in the fasted state (day 42), with a low-fat meal (11 g of fat/353 kcal, day 49) and with a moderate-fat meal (19 g of fat/589 kcal, day 56; reference). A viral load assessment was performed on day 56. RESULTS: Rilpivirine AUC0-24 was significantly decreased by 16% (geometric mean ratio, 90% CI: 0.84, 0.73-0.96) during administration in the fasted state when compared with AUC0-24 during administration with a moderate-fat meal. Similarly, rilpivirine C24 was significantly decreased by 21% (0.79, 0.65-0.97) in the fasted state compared with a moderate-fat meal. Pharmacokinetic parameters were unchanged during administration with a low-fat meal, except for C24, which was significantly increased by 15% (1.15, 1.01-1.31) when compared with the moderate-fat meal. Rilpivirine Cmax was similar under the three meal conditions. Virological suppression was unchanged at the end of the study. CONCLUSIONS: A food effect was observed for steady-state pharmacokinetic parameters of rilpivirine (AUC0-24 and C24) when TDF/FTC/RPV was administered in the fasted state compared with the moderate-fat meal. The TDF/FTC/RPV formulation can be administered with either a low-fat or moderate-fat meal.

Integration of antenatal syphilis screening in an urban HIV clinic: a feasibility study.

BACKGROUND: Syphilis infection during pregnancy leads to avoidable morbidity and mortality and remains a significant problem in sub-Saharan Africa. Despite global initiatives to increase the proportion of pregnant women screened, implementation has been slow. We sought to investigate the feasibility of adding syphilis screening within an integrated antenatal HIV clinic. METHODS: Pregnant women attending the HIV antenatal clinic were sequentially enrolled and consenting participants answered a questionnaire on sexual behavior and previous pregnancies, provided sociodemographic data, and were tested using rapid plasmin reagin (RPR). If positive, participants were treated with benzathine penicillin. All were given a partner notification slip and were followed up after delivery to determine birth outcomes. RESULTS: 584 of 606 (95.7%) women approached and consented to test for syphilis. 570 women were enrolled (median age 29 (IQR 25-32) with a median (IQR) CD4 of 372 (257-569) cells/µL). Of the 5.1% (29/570) with a positive RPR, all were asymptomatic, were successfully contacted, and treated with benzathine penicillin without adverse reactions. Overall, 61 (12.1%) of the participants had an adverse birth outcome. In the bivariate analysis, only age was significantly different between those with and without a positive RPR (RR = 1.15, 95% CI 1.065-1.248; p < 0.001). Partners of only 10 (34.5%) participants returned for treatment. CONCLUSIONS: Structural interventions such as opt-out testing for syphilis within integrated HIV-antenatal care clinics are feasible and capitalize on the excellent care programs that have already been established for HIV care. Novel approaches are required for partner notification.