Coordinated Fc-effector and neutralization functions in HIV-infected children define a window of opportunity for HIV vaccination

OBJECTIVES: Antibody function has been extensively studied in HIV-infected adults but is relatively understudied in children. Emerging data suggests enhanced development of broadly neutralizing antibodies (bNAbs) in children but Fc effector functions in this group are less well defined. Here, we profiled overall antibody function in HIV-infected children. DESIGN: Plasma samples from a cross-sectional study of 50 antiretroviral therapy-naive children (aged 1-11 years) vertically infected with HIV-1 clade A were screened for HIV-specific binding antibody levels and neutralizing and Fc-mediated functions. METHODS: Neutralization breadth was determined against a globally representative panel of 12 viruses. HIV-specific antibody levels were determined using a multiplex assay. Fc-mediated antibody functions measured were antibody-dependent: cellular phagocytosis (ADCP); neutrophil phagocytosis (ADNP); complement deposition (ADCD) and natural killer function (ADNK). RESULTS: All children had HIV gp120-specific antibodies, largely of the IgG1 subtype. Fifty-four percent of the children exhibited more than 50% neutralization breadth, with older children showing significantly broader neutralization activity. Apart from ADCC, observed only in 16% children, other Fc-mediated functions were common (>58% children). Neutralization breadth correlated with Fc-mediated functions suggesting shared determinants of enhanced antibody function exist. CONCLUSIONS: These results are consistent with previous observations that children may develop high levels of neutralization breadth. Furthermore, the striking association between neutralization breadth and Fc effector function suggests that HIV vaccination in children could yield multifunctional antibodies. Paediatric populations may therefore provide an ideal window of opportunity for HIV vaccination strategies

Larval habitats of Anopheles gambiae s.s. (Diptera: Culicidae) influences vector competence to Plasmodium falciparum parasites

<p>Abstract</p> <p>Background</p> <p>The origin of highly competent malaria vectors has been linked to productive larval habitats in the field, but there isn't solid quantitative or qualitative data to support it. To test this, the effect of larval habitat soil substrates on larval development time, pupation rates and vector competence of <it>Anopheles gambiae </it>to <it>Plasmodium falciparum </it>were examined.</p> <p>Methods</p> <p>Soils were collected from active larval habitats with sandy and clay substrates from field sites and their total organic matter estimated. <it>An. gambiae </it>larvae were reared on these soil substrates and the larval development time and pupation rates monitored. The emerging adult mosquitoes were then artificially fed blood with infectious <it>P. falciparum </it>gametocytes from human volunteers and their midguts examined for oocyst infection after seven days. The wing sizes of the mosquitoes were also measured. The effect of autoclaving the soil substrates was also evaluated.</p> <p>Results</p> <p>The total organic matter was significantly different between clay and sandy soils after autoclaving (P = 0.022). A generalized liner model (GLM) analysis identified habitat type (clay soil, sandy soil, or lake water) and autoclaving (that reduces presence of microbes) as significant factors affecting larval development time and oocyst infection intensities in adults. Autoclaving the soils resulted in the production of significantly smaller sized mosquitoes (P = 0.008). Autoclaving clay soils resulted in a significant reduction in <it>Plasmodium falciparum </it>oocyst intensities (P = 0.041) in clay soils (unautoclaved clay soils (4.28 ± 0.18 oocysts/midgut; autoclaved clay soils = 1.17 ± 0.55 oocysts/midgut) although no difference (P = 0.480) in infection rates was observed between clay soils (10.4%), sandy soils (5.3%) or lake water (7.9%).</p> <p>Conclusion</p> <p>This study suggests an important nutritional role for organic matter and microbial fauna on mosquito fitness and vector competence. It shows that the quality of natural aquatic habitats of mosquito larvae may influence malaria parasite transmission potential by <it>An. gambiae</it>. This information can be important in targeting larval habitats for malaria control.</p

Lessons Learned Developing a Diagnostic Tool for HIV-Associated Dementia Feasible to Implement in Resource-Limited Settings: Pilot Testing in Kenya

Objective: To conduct a preliminary evaluation of the utility and reliability of a diagnostic tool for HIV-associated dementia (HAD) for use by primary health care workers (HCW) which would be feasible to implement in resource-limited settings. Background: In resource-limited settings, HAD is an indication for anti-retroviral therapy regardless of CD4 T-cell count. Anti-retroviral therapy, the treatment for HAD, is now increasingly available in resource-limited settings. Nonetheless, HAD remains under-diagnosed likely because of limited clinical expertise and availability of diagnostic tests. Thus, a simple diagnostic tool which is practical to implement in resource-limited settings is an urgent need. Methods: A convenience sample of 30 HIV-infected outpatients was enrolled in Western Kenya. We assessed the sensitivity and specificity of a diagnostic tool for HAD as administered by a primary HCW. This was compared to an expert clinical assessment which included examination by a physician, neuropsychological testing, and in selected cases, brain imaging. Agreement between HCW and an expert examiner on certain tool components was measured using Kappa statistic. Results: The sample was 57 % male, mean age was 38.6 years, mean CD4 T-cell count was 323 cells/mL, and 54 % had less than a secondary school education. Six (20%) of the subjects were diagnosed with HAD by expert clinical assessment. The diagnostic tool was 63 % sensitive and 67 % specific for HAD. Agreement between HCW and expert examiners was poor for many individual items of the diagnostic tool (K =.03–.65). This diagnostic tool had moderate sensitivity and specificity fo

Cerebrospinal fluid markers to distinguish bacterial meningitis from cerebral malaria in children

Background. Few hospitals in high malaria endemic countries in Africa have the diagnostic capacity for clinically distinguishing acute bacterial meningitis (ABM) from cerebral malaria (CM). As a result, empirical use of antibiotics is necessary. A biochemical marker of ABM would facilitate precise clinical diagnosis and management of these infections and enable rational use of antibiotics. Methods. We used label-free protein quantification by mass spectrometry to identify cerebrospinal fluid (CSF) markers that distinguish ABM (n=37) from CM (n=22) in Kenyan children. Fold change (FC) and false discovery rates (FDR) were used to identify differentially expressed proteins. Subsequently, potential biomarkers were assessed for their ability to discriminate between ABM and CM using receiver operating characteristic (ROC) curves. Results. The host CSF proteome response to ABM (Haemophilus influenza and Streptococcus pneumoniae) is significantly different to CM. Fifty two proteins were differentially expressed (FDR&lt;0.01, Log FC≥2), of which 83% (43/52) were upregulated in ABM compared to CM. Myeloperoxidase and lactotransferrin were present in 37 (100%) and 36 (97%) of ABM cases, respectively, but absent in CM (n=22). Area under the ROC curve (AUC), sensitivity, and specificity were assessed for myeloperoxidase (1, 1, and 1; 95% CI, 1-1) and lactotransferrin (0.98, 0.97, and 1; 95% CI, 0.96-1). Conclusion. Myeloperoxidase and lactotransferrin have a high potential to distinguish ABM from CM and thereby improve clinical management. Their validation requires a larger cohort of samples that includes other bacterial aetiologies of ABM

Lower rates of ART initiation and decreased retention among ART-naïve patients who consume alcohol enrolling in HIV care and treatment programs in Kenya and Uganda

Objectives Almost 13 million people are estimated to be on antiretroviral therapy in Eastern and Southern Africa, and their disease course and program effectiveness could be significantly affected by the concurrent use of alcohol. Screening for alcohol use may be important to assess the prevalence of alcohol consumption and its impact on patient and programmatic outcomes. Methods As part of this observational study, data on patient characteristics and alcohol consumption were collected on a cohort of 765 adult patients enrolling in HIV care in East Africa. Alcohol consumption was assessed with the AUDIT questionnaire at enrollment. Subjects were classified as consuming any alcohol (AUDIT score &gt;0), hazardous drinkers (AUDIT score ≥8) and hyper drinkers (AUDIT score ≥16). The effects of alcohol consumption on retention in care, death and delays in antiretroviral therapy (ART) initiation were assessed through competing risk (Fine &amp; Gray) models. Results Of all study participants, 41.6% consumed alcohol, 26.7% were classified as hazardous drinkers, and 16.0% as hyper drinkers. Depending on alcohol consumption classification, men were 3–4 times more likely to consume alcohol compared to women. Hazardous drinkers (median age 32.8 years) and hyper drinkers (32.7 years) were slightly older compared to non-hazardous drinkers (30.7 years) and non-hyper drinkers (30.8 years), (p-values = 0.014 and 0.053 respectively). Median CD4 at enrollment was 330 cells/μl and 16% were classified World Health Organization (WHO) stage 3 or 4. There was no association between alcohol consumption and CD4 count or WHO stage at enrollment. Alcohol consumption was associated with significantly lower probability of ART initiation (adjusted sub-distribution hazard ratio aSHR = 0.77 between alcohol consumers versus non-consumers; p-value = 0.008), and higher patient non-retention in care (aSHR = 1.77, p-value = 0.023). Discussion Alcohol consumption is associated with significant delays in ART initiation and reduced retention in care for patients enrolling in HIV care and treatment programs in East Africa. Consequently, interventions that target alcohol consumption may have a significant impact on the HIV care cascade. © 2020 Patsis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Outcomes of second‐line antiretroviral therapy among children living with HIV: a global cohort analysis

INTRODUCTION: Limited data describe outcomes on second‐line antiretroviral therapy (ART) among children globally. Our objective was to contribute data on outcomes among children living with HIV after initiation of second‐line ART in the context of routine care within a large global cohort collaboration. METHODS: Patient‐level data from 1993 through 2015 from 11 paediatric HIV cohorts were pooled. Characteristics at switch and through two years of follow‐up were summarized for children who switched to second‐line ART after starting a standard first‐line regimen in North America, Latin America, Europe, Asia, Southern Africa (South Africa & Botswana) and the rest of sub‐Saharan Africa (SSA). Cumulative incidences of mortality and loss to follow‐up (LTFU) were estimated using a competing risks framework. RESULTS: Of the 85,389 children on first‐line ART, 3,555 (4%) switched to second‐line after a median of 2.8 years on ART (IQR: 1.6, 4.7); 69% were from Southern Africa or SSA and 86% of second‐line regimens were protease inhibitor‐based. At switch, median age was 8.4 years and 50% had a prior AIDS diagnosis. Median follow‐up after switch to second‐line ranged from 1.8 years in SSA to 5.3 years in North America. Median CD4 counts at switch to second‐line ranged from 235 cells/mm^{3} in SSA to 828 cells/mm^{3} in North America. Improvements in CD4 counts were observed over two years of follow‐up, particularly in regions with lower CD4 counts at second‐line switch. Improvements in weight‐for‐age z‐scores were not observed during follow‐up. Cumulative incidence of LTFU at two years was <5% in all regions except SSA (7.1%) and Southern Africa (7.4%). Risk of mortality was <3% at two years of follow‐up in all regions, except Latin America (4.9%) and SSA (5.5%). CONCLUSIONS: Children switched to second‐line ART experience CD4 count increases as well as low to moderate rates of LTFU and mortality within two years after switch. Severe immune deficiency at time of switch in some settings suggests need for improved recognition and management of treatment failure in children